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15,726,945 | PENDING | THERMAL ENERGY STORAGE PALLET | A pallet for shipping goods, the pallet having a rigid member, a phase change material, and a temperature indicate. The rigid member includes a phase change material compartment. A phase change material is disposed in the phase change material compartment. The temperature indicator indicates a thermal state of the pallet | 1. A pallet for shipping goods, comprising: a rigid member comprising a phase change material compartment; a phase change material disposed in the phase change material compartment; and a temperature indicator that indicates a thermal state of the pallet, 2. The pallet of claim 1, wherein the rigid member further comprises: a first structured sheet; and a second structured sheet separated from the first structured sheet, wherein the phase change material compartment is disposed between the first structured sheet and the second structured sheet. 3. The pallet of claim 2, wherein the phase change material compartment comprises: a hollow portion; and at least one standoff disposed in the hollow portion, wherein the standoff directly connects the first structured sheet and the second structured sheet. 4. The pallet of claim 3, wherein the standoff maintains a separation distance between the first structured sheet and the second structured sheet. 5. The pallet of claim 3, wherein the first structured sheet and the second structured sheet are bonded, and wherein the bonding hermetically seals the hollow portion. 6. The pallet of claim 2, wherein the first structured sheet is a thermal insulator. 7. The pallet of claim 6, wherein the thermal insulator is a plastic, 8. The pallet of claim 2, wherein the second structured sheet is a thermal insulator. 9. The pallet of claim 8, wherein the thermal insulator is a plastic. 10. The pallet of claim 1, wherein the rigid member further comprises a receptacle for a fork of a forklift, 11. The pallet of claim 1, wherein the thermal state is a ratio of a first portion of the phase change material that is solid to a second portion of the phase change material that is not solid. 12. The pallet of claim 1, wherein the phase change material comprises: a first material having a liquid to solid phase transition temperature; and a second material that modifies a viscosity of the first material, 13. The pallet of claim 12, wherein a modified viscosity of the first material is greater than 100 centipoise. 14. The pallet of claim 12, wherein a modified viscosity of the first material is greater than 1000 centipoise. 15. The pallet of claim 12, wherein a modified viscosity of the first material is greater than 5000 centipoise. 16. The pallet of claim 12, wherein the liquid to solid phase transition temperature is at a regulation temperature of the goods. 17. The pallet of claim 12, wherein the liquid to solid phase transition temperature is at a shipping temperature. 18. A method of shipping goods, comprising: obtaining a to-be-shipped good and a shipping plan; selecting a thermal energy storage pallet based on the to-be-shipped good and the shipping plan; solidifying a phase change material disposed within the thermal energy storage pallet; shipping, using the thermal energy storage pallet, the to be-shipped good; and maintaining a temperature of the to-be-shipped good during the shipping using, at least in part, the phase change material of the thermal energy storage pallet. 19. The method of claim 18, wherein the shipping plan specifies a regulation temperature during the shipping and a duration of the shipping. 20. The method of claim 19, wherein selecting the thermal energy storage pallet comprises: determining a quantity of the phase change material based on, at least in part, the duration of the shipping; and matching the quantity of the phase change material to a phase change material holding capacity of the thermal energy storage pallet 21. The method of claim 18, wherein maintaining a temperature of the to-be-shipped good comprises: absorbing, by the phase change material, heat during the shipping; and changing a portion of the phase change material from a solid state to a liquid state in response to absorbing the heat. | BRIEF DESCRIPTION OF DRAWINGS Certain embodiments of the invention will be described with reference to the accompanying drawings. However, the accompanying drawings illustrate only certain aspects or implementations of the invention by way of example and are not meant to limit the scope of the claims. FIG. 1 shows an isometric diagram of a thermal energy storage pallet in accordance with one or more embodiments of the invention. FIG. 2 shows a cross section diagram of a thermal energy storage pallet in accordance with one or more embodiments of the invention. FIG. 3 shows an isometric diagram of a second thermal energy storage pallet in accordance with one or more embodiments of the invention. FIG. 4 shows an isometric diagram of a third thermal energy storage pallet in accordance with one or more embodiments of the invention. FIG. 5 shows a cross section diagram of a structured deck in accordance with one or more embodiments of the invention. FIG. 6 shows a flowchart of a method of shipping goods in accordance with one or more embodiments of the invention. FIG. 7 shows an isometric diagram of an insulated structure in accordance with one or more embodiments of the invention. DETAILED DESCRIPTION Specific embodiments will now be described with reference to the accompanying figures. In the following description, numerous details are set forth as examples of the invention. It will be understood by those skilled in the art that one or more embodiments of the present invention may be practiced without these specific details and that numerous variations or modifications may be possible without departing from the scope of the invention. Certain details known to those of ordinary skill in the art are omitted to avoid Obscuring the description. In general, embodiments of the invention relate to devices, systems, and/or methods for temperature control. When goods are shipped, the goods may be loaded onto a pallet. During shipping, the pallet and goods may be exposed to ambient conditions that cause the temperature of the goods to change due to heat exchange between the goods and the ambient conditions. Changing the temperature of the goods during shipping may degrade a quality of the goods. For example, the shelf life of fresh produce may be greatly degraded if the temperature of the produce is not maintained during shipping. A pallet in accordance with embodiments of the invention may store thermal energy and thereby regulate the temperature of the goods during shipping. The pallet may include a quantity of phase change material that has a liquid to solid phase transition temperature at or near a regulating temperature of the goods. If the goods and the pallet are exposed to ambient conditions that causes heat exchange, the quantity of phase change material may absorb heat or release heat and melt or solidify, respectively. Absorbing or releasing heat by the quantity of phase change material may maintain the goods at/near the regulation temperature by at least reducing the effects of the heat exchange. For example, the phase change material may reduce the fractional contribution of the heat exchange effect on the goods. FIG. 1 shows a thermal energy storage pallet (100) in accordance with one or more embodiments of the invention. The thermal energy storage pallet (100) may regulate the temperature of goods disposed on the pallet. In one or more embodiments, the thermal energy storage pallet (100) may regulate the temperature of the goods by at least reducing the effects of heat exchange with an ambient environment while the goods are shipped and/or stored. The thermal energy storage pallet (100) may thermally protect the goods by sharing a significant portion of the effect of heat exchange between the goods and an ambient environment. The thermal energy storage pallet (100) may include a quantity of phase change material that changes state in response to heat exchange between the goods and/or the pallet and the environment surrounding the pallet. Changing state may regulate the temperature of the goods disposed on the thermal energy storage pallet. The thermal energy storage may include a structured deck (110), forklift fork receivers (120), and a temperature indicator (130). Each of the components of the system are described below. The structured deck (110) may be a platform or other structure on which goods may be disposed. Goods may be placed and/or secured to the structured deck (110) during shipping. The structured deck (110) may be formed of rigid and/or semi-rigid materials to provide torsion and tensile strength sufficient to support the weight of goods disposed on the structured deck (110). The structured deck (110) may include phase change material disposed within the structured deck (110). The structure deck (110) may include voids, hollow portions, or other structures for storing of phase change material. For additional details regarding the structured deck (110) see FIG. 2. For additional examples of structured decks see FIGS. 4 and 5. The forklift fork receivers (120) may be recesses, voids, or other structures for receiving forks of a forklift or other device for transporting structures. In some embodiments of the invention, the thermal energy storage pallet (100) may include two forklift fork receivers (120), as seen in FIG. 1, that traverse a length of the thermal energy storage pallet (100). By including two forklift fork receivers (120) that traverse the length of the pallet, the thermal energy storage pallet may be picked up by a forklift from either side by inserting the forks at either end of the length of the pallet. The thermal energy storage pallet (100) may include any number of forklift fork receivers (120) without departing from the invention. For additional examples of forklift fork receivers, see FIG. 3. The temperature indicator (130) may be a physical device that indicates a thermal state of the thermal energy storage pallet (100). The thermal state of the thermal energy storage pallet (100) indicates a ratio of a portion a phase change material disposed within the pallet that is in a desired state, e.g., solid, to a second portion of the phase change material that is not in the desired state, e.g., liquid. In one or more embodiments of the invention, the temperature indicator (130) may be a passive device. For example, the temperature indicator (130) may be a thermal chromic device that changes color depending on the temperature. In another example, the temperature indicator (130) may be a thermometer that displays a temperature. In one or more embodiments of the invention, the temperature indicator (130) may be a physical computing device operably connected to a temperature sensor. The computing device may be, for example, an embedded system, a system on a chip, or a microcontroller. The computing device may be another type of device without departing from the invention. The computing device may include a processor operably connected to a non-transitory computer readable storage medium (CRM) for storing instructions. The instructions stored on the non-transitory CRM, when executed by the processor, may cause the computing device to periodically measure a thermal state of the thermal energy storage pallet (100) via the temperature sensor. The computing device may relay, display, or otherwise convey the thermal state of the thermal energy storage pallet (100) to a user. The computing device may also store, during shipping, the thermal state of the pallet during the shipping (e.g., a series of time stamped entries that specify thermal state). Once the shipping is complete, the computing device may relay, display, or otherwise convey the thermal state of the thermal energy storage pallet (100) to the user during the shipping. In one or more embodiments of the invention, the computing device may include a positioning system. The positioning system may be a physical device that reports a position of the thermal energy storage pallet (100) to the computing device. The positioning system may be, for example, a global positioning system receiver that determines a position based on one or more received electromagnetic signals. The computing device may store, during shipping, the position of the thermal energy storage during the shipping (e.g., a series of time stamped entries that specify a position, location, or other geographic information). Once the shipping is complete, the computing device may relay, display, or otherwise convey the position of the thermal energy storage pallet to a user during the shipping. In one or more embodiments of the invention, the computing device may include a cellular transceiver, a satellite transceiver, and/or another type of wireless communication system transceiver. The transceiver may he operable connected to a communications system and thereby enable the computing device to exchange data with other devices connected to the communication system. The communication system may also he connected with the internet and thereby enable the computing device to exchange data with any device connected to the internet. In one or more embodiments of the invention, the computing device may he connected to a user device via the communication system. The user device may be, for example, a cellular phone, a tablet computer, a desktop computer, a server, a high performance computing system, a cloud service, or any other type of device reachable via internet or a communication system. The computing device may convey the thermal state and/or the position of the thermal energy storage pallet to the user device by way of the communication system. Thus, the computing device may relay, display, or otherwise convey information to a user via the user device. While the temperature sensor is described as being operably connected to a computing device, embodiments of the invention are not limited to a temperature sensor operating as a slave device. In one or more embodiments of the invention, the temperature sensor may be autonomous device including a communication system transceiver. The temperature sensor may be programmed to periodically relay the thermal state of the thermal energy storage pallet to a user device via a communication system using the transceiver. In other words, in some embodiments of the invention the temperature sensor may relay measurement to a remote monitoring system accessible by a user. The access may he directly, e.g., directly to a system, or indirectly, e.g., through a web portal, thin client, network connection, or other indirect method. While not shown in FIG. 1, the thermal energy storage pallet (100) may include access ports for receiving phase change material. The access ports (100) may be apertures or other structures for access an internal volume of the pallet where phase change material may be stored. Thus, phase change material may be placed into the interior of the pallet via the access ports. The access ports may be reusable, e.g., able to be opened and closed, or one time use, e.g., once closed form a hermetic seal. FIG. 2 shows a cross section diagram of a thermal energy storage pallet (100) in accordance with embodiments of the invention. The cross section shown in FIG. 2 is taken along the X-Y plane shown in FIG. 1. As seen from FIG. 2, the structured deck (110) may include an upper sheet (210), a lower sheet (220), standoffs (230), and phase change material (240). Each of the components of the system is described below. The upper sheet (210) and lower sheet (220) may be rigid or semi-rigid members that impart torsional and tensile strength to the thermal energy storage pallet (100). In one or more embodiments of the invention, the upper sheet (210) and lower sheet (220) may be a plastic material. The plastic material may be, for example, Teflon, nylon, polystyrene, polypropylene, polyethylene, high density polyethylene, or acrylonitrile butadiene styrene. The sheets may be other plastics without departing from the invention. Each of the sheets may have a shape that forms the structured deck (110) and the forklift fork receivers (120). For example, sheets of plastic may be molded into shapes that includes a deck and recesses for receiving forks that enable the thermal energy storage pallet (100) to be picked up by a forklift, Each of the sheets may be separated from each other and thereby form a hollow portion or cavity between the sheets. While the sheets shown in FIG. 2 are illustrated as being at a fixed distance from each other, embodiments of the invention includes sheets that have a distance between each other that vary. For example, the distance between the sheets may become larger or smaller along the length of the sheet to form a hollow portion or cavity that varies across the length and width of the thermal energy storage pallet (100). Standoffs (230) and phase change material (240) may be disposed within the hollow portion or cavity to impart structural strength and thermal storage capacity, respectively. The standoffs (230) may be structural members. For example, the standoffs (230) may be posts, blocks, honeycomb, or any other type of structural members. Each of the standoffs may be disposed between the upper sheet (210) and the lower sheet (220). In some embodiments of the invention, the standoffs (230) may be attached to each of the sheets. In one or more embodiments of the invention, the standoffs (230) may be a plastic material. The plastic material may be, for example, Teflon, nylon, polystyrene, polypropylene, polyethylene, high density polyethylene, or acrylonitrile butadiene styrene. The standoffs (230) may be other plastics and/or other materials without departing from the invention. The standoffs (230) may add structural strength to the thermal energy storage pallet. For example, the standoffs (230) may maintain separation between the upper sheet (210) and lower sheet (220) when forces are applied to the thermal energy storage pallet (100). For example, goods disposed on thermal energy storage pallet may apply force to the thermal energy storage pallet (100). Placement of standoffs (230) between the upper sheet (210) and lower sheet (220) provide sufficient structural strength to the sheets so that the thermal energy storage pallet (100) does not deform or break in response to the forces applied by goods disposed on the pallet (100). The phase change material (240) may be a material having a configurable liquid phase to solid phase transition temperature. Transitioning from a solid to a liquid or a liquid to a solid may absorb or release heat, respectively. Releasing or absorbing heat may regulate a temperature of a good disposed near the phase change material, In one or more embodiments of the invention, the liquid phase to solid phase transition temperature may be configured based on a regulation temperature during shipping. For example, for goods that are to be regulated at a temperature of 32° Fahrenheit, the liquid phase to solid phase transition temperature may be set to 32° Fahrenheit. In one or more embodiments of the invention, the liquid phase to solid phase transition temperature may be configured based on a regulation temperature of a cooling system that is used to maintain the temperature of the goods during shipping. For example, for a cooling system that has a regulation temperature of 32° Fahrenheit, the liquid phase to solid phase transition temperature of the phase change material may be set to 28° Fahrenheit. In one or more embodiments of the invention, the phase change material may be configured to not leak out of the thermal energy storage pallet in the event of a penetration, or other mechanical modification of the thermal energy storage pallet. For example, phase change material may be disposed in an internal cavity or other structure of the thermal energy storage pallet. During use, a fork of a forklift may be pressed against the thermal energy storage pallet with sufficient pressure to penetrate the thermal energy storage pallet. Penetrating the thermal energy storage pallet may result in the formation of a passage way or other structure that may allow phase change material to leak out of the thermal energy storage pallet via the passage way if the phase change material is not configured to not leak out of the thermal energy storage pallet. In one or more embodiments of the invention, the phase change material may be a liquid having a viscosity that prevents the phase change material from leaking out of thermal energy storage pallet. In one or more embodiments of the invention, the liquid may have a viscosity of greater than 100 centipoise. In one or more embodiments of the invention, the liquid may have a viscosity of greater than 1000 centipoise. In one or more embodiments of the invention, the liquid may have a viscosity of greater than 5000 centipoise. In one or more embodiments of the invention, the phase change material may be a liquid including an aggregate. The aggregate may be solid particles or other structure dispersed in the liquid. The aggregate may, in the event of the formation of a passage way between an interior volume of the thermal energy storage pallet and an exterior environment, fill the passage way and thereby seal the passage way. The aggregate may be, for example, fibers, solid particles, or other materials. In other embodiments of the invention, the aggregate may be a material, dissolved in the liquid, that solidifies when the liquid is flowing through a passage way and thereby seals the passage way. In one or more embodiments of the invention, the phase change material may be an aggregate. The aggregate may include discrete particles. Each discrete particle may include a material that acts as a phase change material that is encapsulated in an enclosure. A size of the enclosure may be selected so that that particles are unable to pass through a passage way of a size that is smaller than the size of the enclosure. For example, the particles may be 5 mm spherical particles. The size of the particles would prevent the particles from traversing a passage having a diameter of 4 mm and thereby prevent the phase change material from leaking out of the thermal energy storage pallet. In still further embodiments of the invention, the phase change material may include a bladder, or other structure, that encapsulates a liquid that acts as the phase change material. The bladder may prevent the phase change material from leaking out of the thermal energy storage pallet. FIG. 3 shows a second thermal energy storage pallet (300) in accordance with one or more embodiments of the invention. The second thermal energy storage pallet (300) includes a structured deck (340) and a temperature indicator (330) similar to the structured deck (110) and temperature indicator (130), respectively, shown in FIG. 1. Unlike the thermal energy storage pallet (100), shown in FIG. 1, the second thermal energy storage pallet (300) includes a first set of forklift fork receivers (310) and a second set of forklift fork receivers (320). Each set of forklift receivers are configured to receive forks from a forklift and thereby enable the second thermal energy storage pallet (100) to be easily transported using a forklift. The first set of forklift fork receivers (310) are aligned to a first axis, e.g., the Z axis, and the second set of forklift fork receivers (320) are aligned to a second axis, e.g., the X axis. Thus, the second thermal energy storage pallet (300) may be picked up from all four sides using a forklift, e.g., a four-way pallet, FIG. 4 shows a third thermal energy storage pallet in accordance with one or more embodiments of the invention. The third thermal energy storage pallet (300) includes a pallet (410), a temperature indicator (420), and a structured deck (430) that may be affixed or reversibly affixed to the pallet (410). Each of the components are described below. The pallet (410) may be a physical structure for holding goods during shipping. The pallet (410) may be a wooden structure. The pallet (410) may have any shape or structure to hold the goods during shipping without departing from the invention. The temperature indicator (420) is similar to the temperature indicator described with respect to FIG. 1. The structured deck (430) is similar to the structured deck (110) shown in FIG. 1. Unlike the structure deck (110) shown in FIG. 1, the structured deck (430) is a planar structure or otherwise shaped to attach to the pallet (410). For additional details regarding the structured deck (430) see FIG. 5. FIG. 5 shows a cross section diagram of the structured deck (430) shown in FIG. 4. The cross section shown in FIG. 5 is taken along the X-Y plane shown in FIG. 4. As seen from FIG. 5, the structured deck (430) includes an upper sheet (510), a lower sheet (520), standoffs (530), and phase change material (540). Each of the aforementioned components is similar to the like named components shown in FIG. 1. However, the upper sheet (510) and lower sheet (520) are planar, or substantially planar to enable the structured deck (430) to attach to the standard wood or plastic pallet. In other embodiments of the invention, the structure deck (430) may be attached to other support structures without departing from the invention. For example, an additional support structure may be disposed between the structure deck (430) and the pallet. In another example, the structure deck (430) may be attached to a second structure that serves a similar purpose to that of a pallet. FIG. 6 shows a flowchart in accordance with one or more embodiments of the invention. The method depicted in FIG. 6 may be used to ship goods in accordance with one or more embodiments of the invention. One or more steps shown in FIG. 6 may be omitted, repeated, and/or performed in a different order among different embodiments. In Step 600, a to-be-shipped good and a shipping plan are obtained. The to-be-shipped good may be any type of good. For example, good to-be-shipped good may be wine, milk, produce, meat, dairy products, flowers, chocolate, and/or refrigerated goods. A quantity of the to-be-shipped good may also be obtained. The shipping plan may specify how the to-be-shipped goods will be shipped. For example, the shipping plan may specify segments of a shipping route, a duration of each shipping segment, and a type of conveyance used during each segment. The conveyance may be a type of container, a regulation temperature of the container, and/or an insulation rating of the container. The shipping plan may also specify other types of goods that are to be shipped in the shipment. In Step 610, a thermal energy storage (TES) pallet is selected based on, at least in part, the to-be-shipped good and the shipping plan. In one or more embodiments of the invention, the TES pallet is selected based on a regulation temperature of the to-be-shipped good. The regulation may be determined based on a type of the good. For example, each type of good may have an associated ideal shipping temperature that minimizes degradation of the good during shipping. The temperature of the good may be matched to a TES pallet that includes phase change material having a liquid to solid phase transition temperature at the same temperature as the regulation temperature of the good. In one or more embodiments of the invention, the TES pallet is selected based on a regulation temperature specified by a conveyance used during the shipping. For example, during shipping a first segment of the shipping plan may specify that a good will be shipped in a refrigerated container having a regulation temperature of 40° Fahrenheit. The regulation temperature of the conveyance may be matched to a TES pallet that includes phase change material having a liquid to solid phase transition temperature at the same temperature as the regulation temperature of the conveyance. In one or more embodiments of the invention, a thermal state of the selected TES pallet may be determined after the TES pallet is selected. The thermal state may be whether the phase change material disposed within the TES pallet is solidified. The thermal state may be determined by, for example, using a thermal state indicator of the TES pallet. If the thermal state of the TES pallet indicates that the phase change material is not solidified, the TES pallet may be chilled until the phase change material is solidified. In one or more embodiments of the invention, TES pallets may be stored in a chilled environment to cause the phase change material disposed within the TES pallet to solidify before selection of the TES pallet. In Step 620, the to-be-shipped goods are shipped using the selected TES pallet. The goods may be shipped by loading the goods onto or securing the goods to the TES pallet and then shipping them in accordance with the shipping plan. In Step 630, the temperature of the to-be-shipped good is maintained during the shipping using, at least in part, the thermal energy storage pallet. Prior to the shipping, the goods may be stored on the pallet in a chilled space that solidifies a phase change material of the pallet. In one or more embodiments of the invention, the TES pallet maintains the temperature of the to-be-shipped goods by shielding the goods from heat exchange with an ambient environment. FIG. 7 shows an example of an insulated structure (700) for shipping goods in accordance with embodiments of the invention. Goods (710) are loaded onto or secured to TES pallets (720). The TES pallets (720) and goods (710) are loaded into the insulated structure (700). To load the TES pallets (720) and goods (710), a floor (701) of the insulated structure (700) must be capable of supporting forklifts or other heavy equipment. Due to the structural requirements of the floor (701), the floor (701) is not thermally insulated unlike the other surfaces of the insulated structure (700). The insulated structure (700) is shipped according to the shipping plan. During shipping, the insulated structure (700) is exposed to an ambient environment having a different temperature than the internal volume of the insulated structure (700). The temperature differential causes heat exchange between the internal volume of the insulated structure (700) and the ambient environment. The five sides of the insulated structure (700) that are thermally insulated reduce the rate of heat exchange. Heat exchange through the floor (701) of the insulated structure (700) is not reduced due to the absence of thermal insulation. Placing the TES pallets (720) on the floor (701) shields the goods (710) from heat exchange through the floor (701). In response to heat exchange through the floor (701), the phase change material disposed within the TES pallets (720) may undergo a liquid to solid or a solid to liquid phase transition. By undergoing a phase transition, the phase change material may reduce the impact of heat exchange through the floor (701) has on a temperature of the goods (710), While not shown in FIG. 7, some conveyances may include an active temperature regulation device such as a chilled air generation unit, an air conditioner, etc. While the active temperature regulation device may reduce the impact of heat exchange through the floor (701), a portion of the goods that are placed either directly or indirectly on the floor (701) may still exchange heat with the environment surrounding the insulated structure and thereby be degraded by temperature change. Placement of the TES pallets (720) between the goods (710) and the floor (701) may prevent the aforementioned heat exchange and maintain the portion of the goods that would otherwise be degraded. One or more embodiments of the invention may provide one or more of the following advantages: i) a TES pallet in accordance with embodiments of the invention may improve the energy efficiency of a refrigeration system in which the TES pallet is disposed, ii) a TES pallet in accordance with embodiments of the invention may improve the energy efficiency of the on-board refrigeration unit, including diesel or other fuel consumption of on-board electrical generation, iii) a TES pallet in accordance with embodiments of the invention may improve the temperature stability inside a warehouse where the TES pallet is disposed, iv) a TES pallet in accordance with embodiments of the invention may improve food quality of refrigerated products by reducing the range of temperature fluctuations during storage, v) a TES pallet disposed in a conveyance in accordance with embodiments of the invention may improve the temperature stability inside the conveyance, vi) a TES pallet disposed in a conveyance in accordance with embodiments of the invention may improve the shelf life of fresh perishable items by providing greater temperature protection while in transit, vii) a TES pallet disposed in a conveyance in accordance with embodiments of the invention may absorb heat infiltration into the container reducing the thermal workload of the on-board refrigeration unit, viii) a TES pallet in accordance with embodiments of the invention may be stackable or nestable with other TES pallets to reduce storage space requirements, and ix) a TES pallet in accordance with embodiments of the invention may be reusable, cleanable, and reduce the cost of shipping by replacing a consumable portion of a shipping plan. While the invention has been described above with respect to a limited number of embodiments, those skilled in the art, having the benefit of this disclosure, will appreciate that other embodiments can he devised which do not depart from the scope of the invention as disclosed herein. Accordingly, the scope of the invention should be limited only by the attached claims. | <SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>Certain embodiments of the invention will be described with reference to the accompanying drawings. However, the accompanying drawings illustrate only certain aspects or implementations of the invention by way of example and are not meant to limit the scope of the claims. FIG. 1 shows an isometric diagram of a thermal energy storage pallet in accordance with one or more embodiments of the invention. FIG. 2 shows a cross section diagram of a thermal energy storage pallet in accordance with one or more embodiments of the invention. FIG. 3 shows an isometric diagram of a second thermal energy storage pallet in accordance with one or more embodiments of the invention. FIG. 4 shows an isometric diagram of a third thermal energy storage pallet in accordance with one or more embodiments of the invention. FIG. 5 shows a cross section diagram of a structured deck in accordance with one or more embodiments of the invention. FIG. 6 shows a flowchart of a method of shipping goods in accordance with one or more embodiments of the invention. FIG. 7 shows an isometric diagram of an insulated structure in accordance with one or more embodiments of the invention. detailed-description description="Detailed Description" end="lead"? | B65D1938 | 20171006 | 20180412 | 75879.0 | B65D1938 | 0 | CIRIC, LJILJANA V | Pallet with Thermal Energy Storage | SMALL | 0 | ACCEPTED | B65D | 2,017 |
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15,726,985 | PENDING | Stock Level Determination | In some embodiments, apparatuses and methods are provided herein useful to determine a stock level for products on a product display using a mirror to provide a view of the product display and/or products stocked thereon. The mirror can have a convex or segmented convex configuration to provide a wider field-of-view than a flat mirror. Further, the system described herein can include an electronic imager or machine readable code scanner that utilizes the mirror to capture an image of the product display and products stocked thereon or to scan machine readable codes on the product display or products. The image or scan can then be sent to a control circuit for analysis and stock level determination. The control circuit can also create workflow tasks to check the product display, restock, order more inventory, and the like. | 1. A stock level indication apparatus comprising: a merchandising unit including a back wall and a product support member mounted to the back wall, the product support member having a surface configured to receive products thereon extending between a front edge and a back edge thereof; a mirror mounted to the merchandising unit adjacent to a rear portion of the product support member and spaced therefrom so as to not interfere with products received thereon, the mirror oriented to provide a view of the surface of the product support member and products received thereon from a position adjacent to the front edge of the product support member; a scanning device disposed adjacent to the front edge of the product support member and configured to scan the product support member and/or the products received thereon using the mirror; a control circuit in communication with the scanning device and configured to analyze the scan of the product support member and/or the products to determine a stock level for the product support member. 2. The stock level indication apparatus of claim 1, wherein the mirror comprises a convex mirror. 3. The stock level indication apparatus of claim 1, wherein the mirror comprises a convexly segmented mirror. 4. The stock level indication apparatus of claim 1, wherein the product support member comprises a shelf, the merchandising unit includes a plurality of shelves; and the mirror is mounted to the back wall of the merchandising unit and spaced from a bottom surface of an above shelf of the plurality of shelves. 5. The stock level indication apparatus of claim 1, wherein the product support member comprises a shelf, the merchandising unit includes a plurality of shelves; and the mirror is mounted to a bottom surface of one of the plurality of shelves. 6. The stock level indication apparatus of claim 1, wherein the scanning device comprises a mobile electronic imager. 7. The stock level indication apparatus of claim 1, wherein the scanning device comprises a barcode reader. 8. The stock level indication apparatus of claim 1, wherein the scanning device is configured to scan the product support member and/or the products received thereon using the mirror from a plurality of heights. 9. The stock level indication apparatus of claim 1, wherein the scanning device is configured to scan the product support member and/or the products received thereon using the mirror from a plurality of different horizontal positions. 10. The stock level indication apparatus of claim 1, wherein the control circuit is configured to send a low stock signal in response to determining that the stock level indicates a number of products on the product support member is less than a predetermined number. 11. The stock level indication apparatus of claim 1, wherein the control circuit is configured to analyze the scan for empty space on the product support member to determine the stock level. 12. The stock level indication apparatus of claim 1, wherein the control circuit is configured to analyze the scan to count products received on the product support member to determine the stock level. 13. A method for providing an indication of stock level, the method comprising: scanning a surface of a product support member mounted to a back wall of a merchandising unit and/or products received on the surface of the product support member with a scanning device using a mirror mounted to the merchandising unit adjacent to a rear portion of the product support member and spaced therefrom so as to not interfere with products received thereon to create a scan, the mirror oriented to provide a view of the surface of the product support member and products received thereon from a position adjacent to the front edge of the product support member; analyzing the scan with a control circuit to determine a stock level for the product support member. 14. The method of claim 13, wherein the mirror comprises a convex mirror such that the scan shows a distorted view, and analyzing the scan comprises undistorting the scan. 15. The method of claim 13, wherein the mirror comprises a convexly segmented mirror. 16. The method of claim 13, wherein scanning the surface of the product support member comprises moving the scanning device along a vertical axis to obtain scans from a plurality of heights. 17. The method of claim 13, wherein scanning the surface of the product support member comprises moving the scanning device along a horizontal plane to obtain scans from a plurality of different positions. 18. The method of claim 13, wherein the scanning device comprises a mobile electronic imager, and scanning the surface of the product support member comprises capturing an image of the surface of the product support member. 19. The method of claim 13, wherein the scanning device comprises a barcode reader, and scanning the surface of the product support member comprises scanning barcodes of products received on the surface of the product support member. 20. The method of claim 13, wherein analyzing the scan with the control circuit comprises analyzing the scan for empty space on the product support member to determine the stock level. 21. The method of claim 13, wherein analyzing the scan with the control circuit comprises analyzing the scan to count products received on the product support member to determine the stock level. 22. The method of claim 13, further comprising sending a low stock signal with the control circuit in response to determining that the stock level indicates a number of products on the product support member is less than a predetermined number. | CROSS-REFERENCE TO RELATED APPLICATION This application claims the benefit of the following U.S. Provisional Application No. 62/412,342 filed Oct. 25, 2016, which is incorporated herein by reference in its entirety. TECHNICAL FIELD This invention relates generally to retail shelving and, more particularly, to stock level tracking of products for retail merchandising units. BACKGROUND Retail stores often utilize modular shelving units to display products for sale. It can be important to maintain an accurate count of inventory during operation of the store. Pursuant to this, associates have to count products on the shelves. It can be difficult for associates to accurately determine a count of products on the shelves and, as such, one method to ensure an accurate count to remove all of the products from the shelves. Accordingly, the associates must then restock the products on the shelves. Prior attempts at automating the tracking of stock levels indirectly have been difficult to implement due to prohibitive costs and technical limitations. BRIEF DESCRIPTION OF THE DRAWINGS Disclosed herein are embodiments of systems, apparatuses and methods pertaining to determining a stock level of products on a product display and creating workflow tasks in response to detecting a low stock level. This description includes drawings, wherein: FIG. 1 is a perspective view of an example merchandising unit in accordance with some embodiments. FIG. 2 is a diagrammatic side elevational view of a stock level detection system showing a convex mirror and a camera device in accordance with several embodiments. FIG. 3 is a diagrammatic side elevational view of a stock level detection system showing a segmented, stepped mirror and a scanner device in accordance with some embodiments. FIG. 4 is a flowchart in accordance with several embodiments. Elements in the figures are illustrated for simplicity and clarity and have not necessarily been drawn to scale. For example, the dimensions and/or relative positioning of some of the elements in the figures may be exaggerated relative to other elements to help to improve understanding of various embodiments of the present invention. Also, common but well-understood elements that are useful or necessary in a commercially feasible embodiment are often not depicted in order to facilitate a less obstructed view of these various embodiments of the present invention. Certain actions and/or steps may be described or depicted in a particular order of occurrence while those skilled in the art will understand that such specificity with respect to sequence is not actually required. The terms and expressions used herein have the ordinary technical meaning as is accorded to such terms and expressions by persons skilled in the technical field as set forth above except where different specific meanings have otherwise been set forth herein. DETAILED DESCRIPTION Generally speaking, pursuant to various embodiments, systems, apparatuses and methods are provided herein useful to determine a stock level for products on a product display, such as a shelf of a shelving unit or other merchandizing fixtures, such as shelf pegs, hook racks, and so forth. A mirror provides a view of the product display and/or products stocked thereon to thereby determine a stock level for the product or how many products on are the display. Advantageously, the mirror can have a convex configuration or a segmented convex configuration to provide a wider field-of-view than a flat mirror. Further, the system described herein can include an electronic imager or machine readable code scanner that utilizes the mirror to capture an image of the product display and products stocked thereon or to scan machine readable codes on the product display or products. The image or scan can then be sent to a control circuit for analysis and stock level determination. The control circuit can also create workflow tasks to check the product display, restock, order more inventory, and the like. So configured, the system described herein can monitor the stock level on one or more product displays and automatically provide a notification for low stock levels. An example merchandising unit 10 is shown in FIG. 1. Based on a particular use, multiple merchandizing units 10 can be aligned in a row to produce an aisle in a retail location. The merchandizing unit 10 includes a base portion 12 and a back wall 14 extending upwardly therefrom. The base portion 12 can include a base deck 16 and a kick plate 18, as commonly configured. The merchandising unit 10 can further include one or more product support members mounted thereto, such as shelves 24 or rows of pegs or hooks 25. In one form, as shown on a top portion 10a of the merchandizing unit 10, the merchandizing unit can be a shelving unit including a plurality of shelf notches 20 vertically disposed adjacent to lateral edges 22 of the back wall 14 to provide anchor points for the shelves 24 mounted thereto. Of course, the shelves 24 can be mounted to the back wall 14 in any suitable way, including using fasteners, snap-fit structure, friction fitting, or the like. Additionally, although the product support member is described herein with reference to a shelf on a shelving unit, any suitable form, location, and/or mounting location can be utilized. For example, the product support member can be a table, a shelf mounted to a wall, or the like. In another form, as shown on a bottom portion 10b of the merchandizing unit 10, the pegs or hooks 25 can be mounted to the back wall 14 thereof, such as in a plurality of rows. After the merchandizing unit 10 is assembled, associates can then stock products 26 on the shelves 24 or pegs 25. A stock level indication system 30 is shown in FIGS. 1-3. The system 30 includes a mirror 32 mounted to the merchandizing unit 10 above one of the shelves 24 and oriented to provide a view of the shelf 24 and any products 26 stocked thereon from a vantage point, such as generally horizontally in front of the merchandizing unit 10. In some embodiments, the mirror 32 can be configured to provide an expanded field-of-view. In a first approach as shown in FIG. 2, a surface 33 of the mirror 32 can have a convexly curved configuration. In a second approach as shown in FIG. 3, the mirror 32 can be composed of a plurality of segments 34 that are arranged in a stepped configured to approximate a curved surface. For example, as shown, adjacent segments 34 can be mounted offset from one another to produce a mirror 32 having a field-of-view similar to that of a convex mirror using the planar segments 34. In either instance, the mirror 32 can be geometrically optimized according to specific dimensions and configurations to provide a view of the shelf 32. In shelving unit embodiments, the mirror 32 is preferably mounted above a rear portion 36 of the shelf 24, and preferably extending to a rear edge 62 thereof, so that, from a position in front of the merchandising unit 10, a majority of an upper surface 38 of the shelf 24 can be viewed through the mirror 32 from one viewing position. Further, positioning the mirror 32 above the rear portion 36 of the shelf 24 provides a view thereof that may be blocked by facing products 26. In peg or hook embodiments, the mirror 32 is preferably mounted below the rear portion 36 of the peg 25, and preferably extending to the rear edge 62 thereof, to provide a view of the products 26 hanging from an outer surface 39 of the peg 25. Alternatively, the mirror 32 can be mounted above the pegs 25 and below the hanging products 26 from above pegs 25. In this alternative form, the orientations and references would be similar to the shelving unit embodiments. The mirror 32 can be mounted to the merchandizing unit 10 in a variety of suitable configurations to provide satisfactory views. For example, the mirror 32 can be mounted to the back wall 14 and/or a bottom surface 40 of the shelf 24 or other structure disposed above the shelf 24. In some embodiments, a front 42 of the shelf 24 or peg 25 can include a hanging tag, edge, or other display 44 that could obscure a view of the mirror 32. Accordingly, in some embodiments, the mirror 32 can be spaced from the shelf bottom surface 40 or can include a spacer member or portion 46 so that the mirror 32 is visible beneath the tag 44 from in front of the merchandizing unit 10. Advantageously, by one approach, the system 30 can include an electronic imager 48, such as a camera, to capture images of a reflection of the shelf 24 or peg 25 using the mirror 32 showing products 26 stocked thereon as well as any empty space. By another approach, the system 30 can include a scanner 50 configured to read machine-readable codes. So configured, the scanner 50 can be utilized to scan machine-readable codes using the mirror 32. In a first form, the scanner 50 can be configured to scan barcodes 52 or other machine-readable codes disposed on or in the packaging of the products 26. As such, the number of barcodes 52 scanned will provide an indication of stock level. In a second form, the shelf upper surface 38 can have symbologies or other machine readable codes 54 disposed thereon. As such, when products 26 are stocked on the shelf 24, the products 26 will block the symbologies 54 from view of the scanner 50. A number or size of scanned symbologies 54 can provide an indication of a stock level on the shelf 24. The electronic imager 48 and/or scanner 50 can be utilized to provide line-of-sight examination of the shelf 24 or peg 25 and the stock level thereof using the mirror 32. In some embodiments, the camera 48 and/or scanner 50 can be carried by an associate, such as using auto-stabilizing mechanisms. So configured, the associate can carry the camera 48 and/or scanner 50 horizontally past the merchandising units 10 and each of the shelves 24 or rows of pegs 25 thereof. The associate can further vertically move the camera 48 and/or scanner 50 along the merchandising unit 10 so that each shelf 24 or row or pegs 25 can be analyzed. In further embodiments, the camera 48 and/or scanner 50 can be mounted to a movable structure 56, such as a cart or the like, so that it can move down an aisle to photograph or scan shelves 24 or pegs 25 on a plurality of merchandizing units 10. By one approach, the camera 48 or scanner can have a set height so that the camera/scanner 48, 50 provides an indication of stock level from one perspective/height from in front of the merchandizing unit 10. Further, the cart 56 can be continuously moved horizontally past the merchandizing unit 10 or can be stopped in front thereof for the camera 48 and/or scanner 50 to operate. By another approach, the camera and/or scanner 50 can have an adjustable height so that it can be aligned with the mirrors 32 of multiple shelves 24 or pegs 25 on a merchandizing unit 10. For example, the camera 48 and/or scanner 50 can be mounted to a telescoping structure 58. If desired, to provide a dynamic view of the shelf 24, the camera/scanner 48, 50 can be configured to continuously or periodically operate as it is moved upwardly or downwardly to provide multiple perspectives of the shelf 24 or pegs 25 through the mirror 32 and thereby provide a more comprehensive view of the shelf 24 or pegs 25. For example, the camera/scanner 48, 50 can operate in response to determining that the mirror 32 or a machine readable code 52, 54 is in view, according to modular and stocking information for the shelving unit, and so forth. As such, the camera/scanner 48, 50 can have onboard circuitry to determine its location and height, such as by telemetry, gps, Wi-Fi triangulation, a range finder, capture location data, and so forth. By one approach, the cart 56 can be manually moved down an aisle by an associate. By another approach, the cart 56 can be a robot or drone configured to receive command signals and follow predetermined paths through a retail location. Moreover, the height of the camera 48 and/or scanner 50 can be manually adjusted, such as with the help of mirror height indicators, or can be automatically adjusted with a control circuit operating a motor or the like according to modular and product data for a retail location. Next, the image and/or scan can be sent to a control circuit 60 for analysis. The term control circuit refers broadly to any microcontroller, computer, or processor-based device with processor, memory, and programmable input/output peripherals, which is generally designed to govern the operation of other components and devices. It is further understood to include common accompanying accessory devices, including memory, transceivers for communication with other components and devices, etc. These architectural options are well known and understood in the art and require no further description here. The control circuit 60 may be configured (for example, by using corresponding programming stored in a memory as will be well understood by those skilled in the art) to carry out one or more of the steps, actions, and/or functions described herein. In embodiments utilizing the camera 48, the control circuit 60 can be configured with image analysis software as commonly understood to determine a stock level of products 26 on the shelf 24 or pegs 25. As set forth above, the analysis can be directed to determine an amount of empty shelf space and/or determining a number of visible products 26 stocked on the shelf 24 or pegs 25. Due to the enhanced field-of-view provided by the mirror 32, the image may be distorted. Accordingly, the control circuit 60 can utilize algorithms as commonly understood to deconstruct the distorted image and further algorithms to produce an accurate count of the products 26 and/or an accurate determination of empty shelf space from the deconstructed image. By one approach, the control circuit 60 can receive or retrieve modular information for the merchandising unit 10 and product information for the products 26 stocked on the shelf 24 or pegs 25 to aid in the determination. The modular and product information can include shelf/peg dimensions, product dimensions, a number of products in a fully stocked configuration, a number of products corresponding to a low stock configuration, and the like. If desired, the system 30 can include a light source 61 oriented to project light into the mirror to thereby provide an illuminated view of the shelf 24 or pegs 25 for the camera 48 or scanner 50. The light source 61 can be mounted or coupled to the camera 48 or scanner 50 or can be separate therefrom, such as mounted to the merchandising unit 10 or the cart 56. In a preferred form, the light source 61 can be oriented in a generally parallel direction to the camera 48 or scanner 50 orientation and the shelf upper surface 38 or pegs 25. The various characteristics of the exemplary systems 30 will now be described with reference to FIGS. 2 and 3. Although embodiments utilizing a shelf 24 are described and shown, peg or hook merchandising units 10 can include similar references, albeit from a flipped perspective. Reference “a” refers to the focal point for the mirror 32, which is behind the mirror 32 due to the curved configuration thereof. The focal point is the optimal point for a view of the shelf upper surface 38. Reference “b” refers to an angle of reflection for the most oblique perspective that allows for a rear 48 of shelf to be visible through the mirror 32 from a perspective parallel to a vector “r.” Reference “c” refers to a vertically shiftable angle of reflection where the upper surface 38 of the shelf 24 is visible through the mirror 32 via a perspective parallel to the vector “r.” Reference “d” refers to the normal line of the mirror 32 or the angle of reflection that is aligned with the focal point “a” of the mirror 32 that maximizes the view of the shelf 24. Reference “e” refers to an example angle of reflection that can be used to indicate a low stock level for the shelf 24. Accordingly, if the analysis of the control circuit 60 determines that there are no products 26 from a rear edge 62 of the shelf 24 up until this angle, the system 30 may initiate an action or report about the data collected. Reference “f” refers to an example angle of reflection that represents the most acute angle for a camera/scanner perspective to have a clear view of the shelf 24 and any products 26 stocked thereon. Stated another way, the example angle “f” can correspond to a maximum viewable surface of the shelf 24 and any products 26 stocked thereon. FIGS. 2 and 3 include grayed-out areas 27 corresponding to areas for products that are currently out of stock. Reference “g” refers to a vertical distance between a lowermost, rear point 64 of the mirror 32 and a point on the mirror corresponding to the angle “c.” This distance “g” may be used to calculate, in part, the sell through of products 26 on the shelf 24 and can be used in the algorithm. Reference “h” refers to a vertical distance the lowermost, rear point 64 of the mirror 32 and a point on the mirror 32 corresponding to the angle “e” representing the recognition of a low stock level that would initiate some action by the inventory system. Reference “i” refers to a vertical distance between the shelf upper surface 38 and an upper surface 38 of the shelf 24 above. This vertical height “i” is a variable usually dependent on the height of the products 26 stocked on the shelf 24 with any necessary headroom for handling of the products 26. Reference “j” refers to the height of the products 26. Reference “k” refers to the distance between the rear edge 62 of the shelf 24 and a point on the shelf 24 aligned with the normal line “a” of the mirror 32. This distance “k” may correspond or be proportionate to the maximum possible viewable portion of the shelf upper surface 38. The distance may also be associated with a low stock level and creation of a corresponding low stock signal. Reference “l” refers to a distance between the rear edge 62 of the shelf 24 and a point on the shelf 24 that represents a desired low stock product amount. This distance “l” can be equal to distance “k,” can correspond to product dimensions, a distance representative of the action needed, a distance proportionate to the maximum possible viewable surface of the shelf 24 or products 26, and so forth. Reference “m” refers to a distance that the downwardly hanging tag 44 extends and a corresponding height of the spacer member 46. Reference “n” refers to a vertical height of the mirror 32. The vertical height “n” may be constrained by the shelf available height “i,” the height of the product “j,” the overhang “m” of the tag 44, and any additional space needed for proper reflection angles. Reference “o” refers to a depth of the shelf 32, which can influence or determine the maximum viewable upper surface 38 that the mirror 32 can to reflect out into the camera 48 or scanner 50. Reference “p” refers to a horizontal height corresponding to a lower edge 66 of the tag 44 and reference “q” refers to a vertical space between the top of the products 26 and the lower edge 66 of the tag 44 for viewing by the camera 48 and scanner 50. Reference “r” refers to an optimum vector and angle for the camera 48 or scanner 50 to view a reflection of the shelf 32 and any products 26 stocked thereon. Viewing from perspectives above or below of the vector “r” also functions, but provides a smaller and/or more distorted view of the shelf 24. Reference “s” refers to a vector at a height and angle for providing external lighting to shine on the mirror 32 to illuminate the shelf 24 and products 26 stocked thereon for viewing by the camera 48 or scanner 50. Reference “t” refers to a depth of the mirror 32 that provides a normal angle to a desired maximum viewable surface of the shelf 24 and products 26. In some embodiments, a stock level indication apparatus is described herein that includes a merchandising unit including a back wall and a product support member mounted to the back wall. The product support member has a surface configured to receive products thereon extending between a front edge and a back edge thereof. The stock level indication apparatus further includes a mirror mounted to the merchandising unit adjacent to a rear portion of the product support member and spaced therefrom so as to not interfere with products received thereon. The mirror is oriented to provide a view of the surface of the product support member and products received thereon from a position adjacent to the front edge of the product support member. The stock level indication apparatus further includes a scanning device disposed adjacent to the front edge of the product support member and configured to scan the product support member and/or the products received thereon using the mirror and a control circuit in communication with the scanning device and configured to analyze the scan of the product support member and/or the products to determine a stock level for the product support member. By several approaches, the product support member can be a shelf, the merchandising unit can include a plurality of shelves; and the mirror can be mounted to the back wall of the merchandising unit and spaced from a bottom surface of an above shelf of the plurality of shelves. By other approaches, the mirror can be mounted to a bottom surface of one of the plurality of shelves. By some approaches, the mirror is a convex mirror. By further approaches, the mirror is a convexly segmented mirror. By several approaches, the scanning device is a mobile electronic imager. By further approaches, the scanning device is a barcode reader. By some approaches, the control circuit can be configured to send a low stock signal in response to determining that the stock level indicates a number of products on the product support member is less than a predetermined number. By several approaches, the control circuit can be configured to analyze the scan for empty space on the product support member to determine the stock level. By further approaches, the control circuit can be configured to analyze the scan to count products received on the product support member to determine the stock level. In several embodiments, a method for providing an indication of stock level is described herein that includes scanning a surface of a product support member mounted to a back wall of a merchandising unit and/or products received on the surface of the product support member with a scanning device using a mirror mounted to the merchandising unit adjacent to a rear portion of the product support member and spaced therefrom so as to not interfere with products received thereon to create a scan, the mirror oriented to provide a view of the surface of the product support member and products received thereon from a position adjacent to the front edge of the product support member; and analyzing the scan with a control circuit to determine a stock level for the product support member. By some approaches, the mirror comprises a convex mirror such that the scan shows a distorted view, and analyzing the scan comprises undistorting the scan. By several approaches, scanning the surface of the product support member comprises moving the scanning device along a vertical axis to obtain scans from a plurality of heights. By some approaches, scanning the surface of the product support member comprises moving the scanning device along a horizontal plane to obtain scans from a plurality of different positions. By some approaches, the scanning device can be a mobile electronic imager, and scanning the surface of the product support member comprises capturing an image of the surface of the product support member. By further approaches, the scanning device can be a barcode reader, and scanning the surface of the product support member comprises scanning barcodes of products received on the surface of the product support member. By several approaches, analyzing the scan with the control circuit comprises analyzing the scan for empty space on the product support member to determine the stock level. By some approaches, analyzing the scan with the control circuit comprises analyzing the scan to count products received on the product support member to determine the stock level. By some approaches, the method can further include sending a low stock signal with the control circuit in response to determining that the stock level indicates a number of products on the product support member is less than a predetermined number. Those skilled in the art will recognize that a wide variety of other modifications, alterations, and combinations can also be made with respect to the above described embodiments without departing from the scope of the invention, and that such modifications, alterations, and combinations are to be viewed as being within the ambit of the inventive concept. | <SOH> BACKGROUND <EOH>Retail stores often utilize modular shelving units to display products for sale. It can be important to maintain an accurate count of inventory during operation of the store. Pursuant to this, associates have to count products on the shelves. It can be difficult for associates to accurately determine a count of products on the shelves and, as such, one method to ensure an accurate count to remove all of the products from the shelves. Accordingly, the associates must then restock the products on the shelves. Prior attempts at automating the tracking of stock levels indirectly have been difficult to implement due to prohibitive costs and technical limitations. | <SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>Disclosed herein are embodiments of systems, apparatuses and methods pertaining to determining a stock level of products on a product display and creating workflow tasks in response to detecting a low stock level. This description includes drawings, wherein: FIG. 1 is a perspective view of an example merchandising unit in accordance with some embodiments. FIG. 2 is a diagrammatic side elevational view of a stock level detection system showing a convex mirror and a camera device in accordance with several embodiments. FIG. 3 is a diagrammatic side elevational view of a stock level detection system showing a segmented, stepped mirror and a scanner device in accordance with some embodiments. FIG. 4 is a flowchart in accordance with several embodiments. detailed-description description="Detailed Description" end="lead"? Elements in the figures are illustrated for simplicity and clarity and have not necessarily been drawn to scale. For example, the dimensions and/or relative positioning of some of the elements in the figures may be exaggerated relative to other elements to help to improve understanding of various embodiments of the present invention. Also, common but well-understood elements that are useful or necessary in a commercially feasible embodiment are often not depicted in order to facilitate a less obstructed view of these various embodiments of the present invention. Certain actions and/or steps may be described or depicted in a particular order of occurrence while those skilled in the art will understand that such specificity with respect to sequence is not actually required. The terms and expressions used herein have the ordinary technical meaning as is accorded to such terms and expressions by persons skilled in the technical field as set forth above except where different specific meanings have otherwise been set forth herein. | G06Q10087 | 20171006 | 20180426 | 66102.0 | G06Q1008 | 0 | WALKER, MICHAEL JARED | Stock Level Determination | UNDISCOUNTED | 0 | REJECTED | G06Q | 2,017 |
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15,727,490 | PENDING | SITE-SPECIFIC COVALENT CHEMICAL LIGATION TO MONOCLONAL AND POLYCLONAL IMMUNOGLOBULIN | Methods and compositions are described herein for covalently linking an antibody to a molecular payload. Compositions are described herein containing an antibody covalently linked to a molecular payload. | 1. A compound comprising: i) a targeting moiety that specifically binds a nucleotide binding pocket of an antibody; ii) a cross-linking agent; iii) an active agent or a conjugating agent; and iv) a linker, wherein the linker covalently links: a) the targeting moiety, b) the cross-linking agent, and c) the active agent or conjugating agent. 2.-4. (canceled) 5. The compound of claim 1, wherein the linker comprises an amino acid sequence. 6. The compound of claim 5, wherein the amino acid sequence comprises negatively charged amino acids. 7. The compound of claim 6, wherein the amino acid sequence has affinity for a nucleotide binding pocket of an antibody. 8. The compound of claim 1, wherein the linker comprises: i) an amino acid sequence; and ii) an ethylene glycol dimer or a PEG polymer. 9. The compound of claim 8, wherein the linker comprises a lysine-aspartate-serine amino acid sequence and the ethylene glycol dimer. 10. The compound of claim 9, wherein the compound has a formula of: wherein, R2 comprises the targeting moiety that specifically binds to the nucleotide binding pocket of an antibody; R2 comprises the cross-linking agent; and R3 comprises the active agent or conjugating agent. 11. The compound of claim 1, wherein the targeting moiety that specifically binds a nucleotide binding pocket of an antibody comprises a purine or a purine analogue. 12. The compound of claim 11, wherein the purine or purine analogue comprises an indole. 13. The compound of claim 11, wherein the purine or purine analogue is indole-3-butyrate. 14. The compound of claim 1, wherein the compound comprises a formula of: wherein L1 and L2 are independently a C1-C10 alkylene, and R4 is represented by the following formula: wherein R5 is an amino acid side chain, m and n are independently from 1 to 10, and R3 comprises the active agent or conjugating agent. 15. The compound of claim 1, wherein the compound comprises a formula of: wherein L1 and L2 are independently a C1-C10 alkylene, and R4 is represented by the following formula: wherein R5 is an amino acid side chain, m and n are independently from 1 to 10, and R3 comprises the active agent or conjugating agent. 16. The compound of claim 14, wherein m is at least 2, and the at least two amino acid side chains comprise a dipeptide affinity element that increases the affinity of the targeting moiety for the nucleotide binding pocket of the antibody. 17. The compound of claim 14, wherein the compound has a formula of: wherein R3 is the active agent or conjugating agent. 18. The compound of claim 15, wherein the compound has a formula of: wherein R3 is the active agent or conjugating agent. 19.-23. (canceled) 24. The compound of claim 1, wherein the compound comprises a formula of: 25. The compound of claim 1, wherein the compound comprises a formula selected from the group consisting of: 26. A method for covalently conjugating an antibody to a molecular payload, wherein the molecular payload comprises a compound of claim 1, the method comprising: a) forming a reaction mixture comprising the antibody and the molecular payload under conditions suitable to form a non-covalent binding interaction between a nucleotide binding pocket of the antibody and a targeting moiety of the molecular payload, wherein the reaction mixture is an aqueous solution having a pH of less than about 7.5; and b) raising the pH of the reaction mixture above about 8.0, under conditions suitable to form a covalent bond between the antibody and the cross-linking agent. 26.-39. (canceled) 40. The method of claim 26, wherein the method comprises a) forming the reaction mixture comprising the antibody, a 5-fold molar excess of the compound of claim 17 relative to nucleotide binding pockets of the antibody, and PBS 7.0 or PBS 7.5; b) incubating the reaction mixture of a) for at least about 0.25 h at a temperature of from about 4° C. to about 37° C.; c) removing unbound compound of claim 17 by dialysis or size exclusion chromatography; d) raising the pH of the reaction mixture to about 8.5, under conditions suitable to form a covalent bond between the antibody and the compound of claim 17 by adding a basic solution comprising 0.1 M sodium bicarbonate pH 8.5, 0.1 N NaOH or 0.1 N NH4OH; and e) incubating the reaction mixture of d) for at least about 0.25 h at a temperature of from about 4° C. to about 37° C. 41. The method of claim 40, wherein R3 of the compound of claim 17 comprises a conjugating agent comprising an alkyne or azide and the method further comprises: f) introducing into the reaction mixture a copper (I) catalyst and an active agent comprising an azide or alkyne that is reactive to the alkyne or azide of the conjugating agent, thereby conjugating the active agent to the conjugating agent. 42. The method of claim 40, wherein R3 of the compound of claim 17 comprises a conjugating agent comprising a 1,2-dihydroxybenzene moiety, and the method further comprises: f) introducing into the reaction mixture an active agent comprising a boronic acid moiety that is reactive to the 1,2-dihydroxybenzene moiety of the conjugating agent, thereby conjugating the active agent to the conjugating agent. 43. A compound comprising the following formula: wherein R6 is an antibody and R3 comprises an active agent or conjugating agent. 44. (canceled) 45. (canceled) 46. A compound comprising the following formula: wherein R6 is an antibody and R3 comprises an active agent or conjugating agent. 47. (canceled) 48. (canceled) | CROSS-REFERENCES TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62/144,710, filed Apr. 8, 2015, the contents of which are hereby incorporated in the entirety for all purposes. BACKGROUND OF THE INVENTION Non-specific ligation methods have been traditionally used to chemically modify immunoglobulins. Site-specific ligation of compounds (detectable labels, toxins, or ligands) to antibodies has become increasingly important in the fields of therapeutic antibody-drug conjugates and bispecific antibodies. BRIEF SUMMARY OF THE INVENTION In a first embodiment, the present invention provides a compound comprising: i) a targeting moiety that specifically binds a nucleotide binding pocket of an antibody; ii) a cross-linking agent; iii) an active agent or a conjugating agent; and iv) a linker, wherein the linker covalently links: a) the targeting moiety, b) the cross-linking agent, and c) the active agent or conjugating agent. In a second embodiment, the present invention provides a method for covalently conjugating an antibody to a molecular payload, wherein the molecular payload comprises any of the compounds described herein, the method comprising: a) forming a reaction mixture comprising the antibody and the molecular payload under conditions suitable to form a non-covalent binding interaction between a nucleotide binding pocket of the antibody and a targeting moiety of the molecular payload, wherein the reaction mixture is an aqueous solution having a pH of less than about 7.5; and b) raising the pH of the reaction mixture above about 8.0, under conditions suitable to form a covalent bond between the antibody and the cross-linking agent. Definitions As used herein, the following terms have the meanings ascribed to them unless specified otherwise. It is to be understood that this invention is not limited to the particular methodology, protocols, and reagents described, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which will be limited only by the appended claims. As used herein the singular forms “a,” “and,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a compound” includes a plurality of such compounds and reference to “the antibody” includes reference to one or more antibodies and equivalents thereof known to those skilled in the art, and so forth. All technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention belongs unless clearly indicated otherwise. An “antibody” refers to a polypeptide of the immunoglobulin family or a polypeptide comprising fragments of an immunoglobulin that is capable of noncovalently, reversibly, and in a specific manner binding a corresponding antigen. The antibodies referred to herein contain one or more nucleotide binding pockets as defined by Rajagopalan et al., 1999 or U.S. Pat. No. 5,693,764. An exemplary antibody structural unit comprises a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one light (about 25 kD) and one heavy chain (about 50-70 kD), connected through a disulfide bond. The recognized immunoglobulin genes include the κ, λ, α, 65 , δ, ϵ, and μ constant region genes, as well as the myriad immunoglobulin variable region genes. Light chains are classified as either κ or λ. Heavy chains are classified as γ, μ, α, δ, or ϵ, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD, and IgE, respectively. The N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The terms variable light chain (VL) and variable heavy chain (VH) refer to these regions of light and heavy chains respectively. As used herein, an “antibody” encompasses all variations of antibody and fragments thereof that possess a particular binding specificity. Thus, the term “antibody” includes full length antibodies, chimeric antibodies, and humanized antibodies, and multimeric versions of these fragments (e.g., multispecific (including bispecific) antibodies, multivalent antibodies, tetramers) with the same binding specificity. The term “antibody” also includes fragments, relative to a full-length antibody, that possess a particular binding specification. An “antibody fragment” as used in here encompasses all variations of antibody fragments that possess a particular binding specifically. Thus, this term includes are single chain antibodies (ScFv), Fab, Fab′, and multimeric versions of these fragments (e.g., F(ab′)2,) with the same binding specificity. While various antibody fragments, e.g., a Fab, may be defined in terms of the digestion of an intact antibody, one of skill will appreciate that such fragments may be synthesized de novo typically by using recombinant DNA methodology. The antibody can be a monoclonal antibody, Alternatively, the antibody can be a polyclonal antibody or a mixture of structurally different monoclonal antibodies. In some cases, the antibody is an antibody that binds an antigen associated with a disease or condition. For example, the antibody can be an anti-tumor-associated-antigen antibody, In some cases, the antibody is an antibody that binds an immune cell (e.g., B cell, macrophage, dendritic cell, natural killer cell, natural killer T cell, helper T cell, or cytotoxic T cell). In some cases, the antibody is a checkpoint inhibitor. In some cases, the checkpoint inhibitor binds PD-1, PD-L1, or CTLA-4. As used herein, the term “targeting moiety that specifically binds a nucleotide binding pocket of an antibody” refers to a moiety that forms a specific non-covalent interaction between the nucleotide binding pocket of an antibody—as defined by Rajagopalan et al., 1996 or U.S. Pat. No. 5,693,764 and the targeting moiety. Generally, the non-covalent interaction between the targeting moiety and the nucleotide binding pocket has dissociation constant (Kd) of better than (i.e., less than) about 8 μM., better than about 5 μM, better than about 1 μM, or about 1 μM. Such targeting moieties include purities, purine analogues, purine nucleotides, or purine nucleotide analogues. Exemplary targeting moieties include, but are not limited to, indole-3-butyric acid, methyl-indole-3-carboxaldehyde, fluorotryptamine, fluoroindole-3-carboxaldehyde, or methylindole-3-carboxyaldehyde. As used herein, the term “cross-linking agent” refers to an agent that is capable of forming a covalent bond with a protein. In some cases, the cross-linking agent forms a covalent bond with an amine (e.g., a primary amine, such as the epsilon amine of a lysine side chain) of the protein (e.g., antibody). In some cases, the cross-linking agent forms a covalent bond with a guanidinium group (e.g., a guanidinium group of an arginine) of a protein (e.g., antibody). In some cases, the cross-linking agent forms a covalent bond with a sulfhydryl group of the protein (e.g., a sulfhydryl group of a cysteine side chain of an antibody). In some cases, the cross-linking agent is a cryptic cross-linking agent that is capable of contacting a protein in a reaction mixture in a non-reactive (or crytpic) form. The cryptic cross-linking agent can then be triggered to form a covalent bond with the protein by changing the reaction mixture conditions. In some cases, the reaction mixture conditions are changed to cross-link the cross-linking agent and the protein by introduction of visible or ultraviolet light. In some cases, the reaction mixture conditions are changed to cross-link the cross-linking agent and the protein by raising the pH of the reaction mixture. In some cases, the reaction mixture conditions are changed to cross-link the cross-linking agent and the protein by introducing a catalyst to the reaction mixture. Exemplary cross-linking agents include, but are not limited to, photo-cross-linking agents, cross-linking agents comprising an acryloyl moiety, cross-linking agents comprising a maleimide moiety, cross-linking agents comprising a 1,5-difluoro-2,4-dinitrobenzene (DNDFB) moiety, or cross-linking agents derived from a 1,5-difluoro-2,4-dinitrobenzene (DNDFB) moiety, such as 5-fluoro-2,4-dinitrobenzene. As used herein, the term “active agent” refers to an agent that can be used as a detectable label or a biologically active agent. Detectable labels can include one or more of the following: a label, a dye, a radionuclide, an affinity label, a ligand, a reactive compound, a resin, a second protein or polypeptide or polypeptide analog, a polynucleotide, a metal chelator, or a small molecule (e.g., a drug). In some cases the active agent can be a ligand for a biologically active agent. A biologically active agent can include any cytotoxic, cytostatic or immunomodulatory drug. The biologically active agent can be a ligand to a cell. For example, the biologically active agent can be a ligand with affinity to an immune cell (e.g., B cell, macrophage, dendritic cell, natural killer cell, natural killer T cell, helper T cell, or cytotoxic T cell) or a tumor cell. Alternatively, the biologically active agent can be a ligand with affinity to a microbe. As used herein, the term “linker” refers to a chemical moiety that covalently links the targeting moiety, the cross-linking agent, and the active agent or conjugating agent. In some cases, the linker has affinity to the antibody. For example, in some cases, the linker can be, or contain, an affinity element that increases the affinity (e.g., as demonstrated by a lower Kd) of the molecular payload to the antibody beyond that provided by the targeting moiety. Exemplary linkers include linkers that contain an ethylene glycol dimer or a PEG moiety. Exemplary linkers include linkers that contain an amino acid or an amino acid polymer (e.g., linkers that contain a polypeptide). In some cases, the amino acid or amino acid polymer is an affinity element. In some cases, the combination of the linker (e.g., a linker that contains an amino acid or an amino acid polymer) and the targeting moiety has a higher affinity (e.g., lower Kd) or greater binding specificity (e.g., lower background binding) than the targeting moiety alone. Thus, for example, the targeting moiety and linker can be used in combination to obtain improved cross-linking of an active agent or conjugating agent to a target protein e.g., antibody). As used herein, the term “conjugating agent” refers to an agent that is covalently linked to a linker and contains a reactive moiety that can be used to covalently link the linker to an active agent. Exemplary conjugating agents contain 1,2-dihydroxybenzene. The 1,2-dihydroxybenzene can be used to covalently link an active agent containing a boronic acid. Other exemplary conjugating agents contain an alkyne or azide moiety. The alkyne or azide moiety can be used to covalently link an active agent containing a complementary alkyne or azide moiety to the conjugating agent via azide alkyne Huisgen cycloaddition or Copper (I)-catalyzed azide-alkyne cycloaddition. For example, if the conjugating agent contains an azide group, the active agent contains an alkyne. Conversely, if the conjugating agent contains an alkyne, the active agent contains an azide group. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1. (A, B) Depicted here is one of the F(ab) arms used in the Autodock studies. indole-3-butyric acid can be seen nestled within the nucleotide binding pocket (NBP). Cross-linking agent can be reacted with proximal lysines, cysteines, or arginines in or near the NBP, as indicated. (C) Based upon the top clusters generated from Autodock, several libraries were designed. X1X2X3X4 library with DNFB is shown. (D) Sample image of screening. Arrow indicates labeled bead. FIG. 2. Indole-3-butryic acid directs the peptide to the nucleotide binding pocket (NBP) where free amines reside. At slightly basic pH, DNFB reacts with the several free amines within this binding pocket which allows covalent ligation peptide to bind to the free amines located within the NBP. FIG. 3. (A) All of the hits identified in the library screen were resynthesized on TentaGel. Trastuzumab was added to the beads, washed, and allowed to crosslink by increasing the pH to pH 8.5. Nonbinding antibodies were washed away with acidic glycine buffer (pH 3.0). Anti-human Cy3 IgG was added to the beads to bind to trastuzumab. Beads were then imaged and quantified using Image J. Average intensity of beads were taken. (B) Describes the overall concept of the bead staining. (C) The DNFB on Asp-Ser beads were reacted with methylamine or methylpypridine prior to staining with antibodies. The 50% decrease in fluorescent intensity indicates the decreased ability for the quenched crosslinker to react with trastuzumab. * P<0.05. FIG. 4. (A) Structure of soluble peptides DS (1), Phe(2Cl)-T-Phe(2Cl)-Q (2, F(2Cl)), and Negative control (3) used in solution phase experiments. (B) Western blot analysis with solution phase peptides (DS—Lane 1 and 2, F(2Cl)—Lane 5 and 6, Neg—Lane 7 and 8). When pH was increased to 8.5, an increase in product for the DS sample was observed. Some product is still seen at pH 7.5 due to peptide specificity to the nucleotide binding pocket and mild reactivity at pH 7.5. No differences, however, were seen with Phe(2Cl). Same amount of product was observed in both pH 7,5 and 8.5. Free peptide and free trastuzumab, as predicted, was negatively stained. FIG. 5. Western blot analysis with DS was performed with bevacizumab (Bev). cetuximab (Cet), retuximab (Rit), and IVIG. When pH was increased to 8.5, we observed an increase in product for the DS sample. Some product is still seen at pH 7.5 due to peptide specificity to the nucleotide binding pocket and mild reactivity at pH 7.5. FIG. 6. (A) Papain digestion was performed on trastuzumab conjugated with DS, trastuzumab only, IVIG conjugated with DS, rituximab conjugated with DS, and cetuximab conjugated with DS. Samples were then reduced. In the western blot, only the Fab fragment was identified while both Fc and Fab fragments were seen in the coomassie blue gel. (B) The same experiment was done with sulfo-NHS-biotin where conjugation occurred with both Fab and Fc fragments. (C) Structure of sulfo-NHS-biotin. FIG. 7. (A) Western blot analysis of antibody peptide conjugate under nonreducing conditions. One band was found at 150 kDa indicating a homogenous product. (B) Antibody peptide conjugate was formed as previously mentioned. Conjugates were then digested with pepsin. It is noted that ligation occurred only at F(ab)2 fragment. (C) Western blot analysis of soluble DS peptide. At increasing molar ratio, increased product was observed at both pH 7.5 and pH 8.5. At ratios above 2.5:1 peptide: trastuzumab, no additional products were produced. (D) Differences in conjugation was seen when pH was increased, with most products identified at pH 8.5. FIG. 8. Size exclusion HPLC was used to estimate the conjugation efficiency of DS peptide to trastuzumab. After conjugating DS to the antibody (trastDS), the sample was dialyzed to remove unbound peptide. TrastDS was then incubated with neutravidin at different ratios, 4:1 (A), 10:1 (B), and 30:1 (C) for 1 hour and analyzed on a gel filtration column, (D) represents trastuzumab with no neutravidin. The percentage of peptide that is able to conjugate to trastuzumab was determined by analyzing the area under the curve. Percent of peptide conjugated=area of neutravidin conjugates/total area. Neutravidin conjugates include monomer, dimer, trimer, and tetramer. It was estimated that 79% of the trastuzumab was contain the conjugated peptide. FIG. 9. (A-C) Cells (A: SKBR3; B:MCF7; C:MDA-MB-468) were incubated with 40 ng/ml of Trast or Trast-DS. 40 ng/ml trastuzumab or trast-DS were applied to cells prior to secondary antibody labeling, Cy3-labeled anti-human IgG Fc secondary antibody. The fluorescent intensity of the secondary antibody was recorded through FACs on each cell lines. The binding of Trast-DS to the NBP did not affect binding affinity of trastuzumab to SKBR3 or MCF7 cells. As expected, no binding of trastuzumab or trast-DS was seen in MDA-MB-468 cells, (D-E) Similar FACS analysis was performed on TrastDS-MMAE conjugates. In SKBR and MCF7 cells, the immunotoxin conjugates did not affect binding affinity of trastuzumab to the Her2(+) cells. No binding of trastuzumab or trastDS-MMAE, was seen in Her2(−) cells, MDA-MB-468 cells. FIG. 10. Cells (A: SKBR3; B:MCF7; C:MDA-MB-468) were incubated with TrastDS conjugated with MMAE, at either 1:3 or 2:2 ratio. In cell lines with HER2 expression, SKBR3 and MCF7, a decreased in cell viability was seen in antibodies with MMAE conjugation. In the cell line lacking HER2 expression, MDA-MB-468 this effect was not as pronounced. FIG. 11. Bispecific binding abilities for both Her2 and α4β1 integrin are shown. Biotinylated DS peptide was conjugated to trastuzumab creating trast-DS. Trast-DS was dialyzed and crosslinked at pH 8.5. 3:1 ratio of trast-DS to biotinylated LLP2A was bound to streptavidin-PE (SAPE). Controls (trast-DS only and LLP2A only) were conjugated to SAPE at a 4:1 molar ratio. 750 μM trast-DS, 750 μM trast-DS: LLP2A, 250 μM LLP2a were incubated with SKBR-3 human mammary gland/breast adenocarcinoma (A) and Jurkat human T lymphocyte (B) cells for 1 hour. Cells were run through flow cytometry to quantify cells. FIG. 12. Test compounds used for computational modeling. FIG. 13. Libraries synthesized for combinatorial screens. FIG. 14. The crosslinking ability of an indole based photocrosslinker (A) without any additional cross-linking agent or affinity element was analyzed using clinically approved antibodies (rituximab and bevacizumab). This compound was conjugated to antibodies through UV light to initiate the photocrosslinking process. (B) The conjugation was observed only under 1:50 ratio between ligand and antibody at the highest energy level (1 J/cm2) among all the antibodies. FIG. 15. CryoEM images to depict site specific ligation to NBP. The dotted lines outlines the antibody. (A) represents trastuzumab labeled with nanogold, indicated by arrows. Inset represents the IgG structure (pdb code 3CM9.pdb). The gold particle is about 2-3 pixel in size. The IgG molecule appeared as three-domain structure with gold particle residing on top of the domain joint. Each domain is about 60 Å in length suggesting that the IgG molecule (65 Å) is in a slightly tilted orientation. Two nanogold particles are seen on each of the F(ab) arms. (B) represents an IgG antibody without any labeling. (C) TrastDS conjugate was digested with pepsin to obtain f(ab)2 fragments and labeled with nanogold. (D) represents an unlabeled fragment. FIG. 16. (A) Differences in conjugation were seen when pH was increased, with no differences in product seen at pH 8.5 or 9.5. (B) 10 μM DS peptide was incubated with 50 μM trastuzumab for 1 hour at 37° C. Different crosslinking times were tested. FIG. 17. (A) 30 μg protein from whole cell lysate (SKBr3, MCF7 and MDA-MB-468) were performed for Her2 expression level detection. (B) Band intensities were quantified through Image Lab 5.0 Software. FIG. 18. Depicts a boronic acid monomethyl auristatin E (MMAE) biologically active agent. FIG. 19. Depicts a compound described herein containing a maleimide cross-linking agent, an indole targeting moiety, a linker containing a lysine-aspartate-serine amino acid sequence, and a biotin active agent. FIG. 20. (TOP) Depicts a compound described herein containing a maleimide cross-linking agent, an indole targeting moiety, a linker containing a lysine-aspartate-serine amino acid sequence, and a dihyroxyphenylalanine active agent (MDS-1DOPA). (BOTTOM) Depicts mass spectrometry data confirming synthesis of the compound depicted above. FIG. 21. Depicts a conjugate formed between the compound depicted in FIG. 20, an antibody represented by R (e.g., trastuzumab), and the boronic acid MMAE biologically active agent (e.g., Trast-MDS-DOPA-BA-MMAE). FIG. 22. (TOP) Depicts a compound described herein containing a maleimide cross-linking agent, an indole targeting moiety, a linker containing a lysine-aspartate-serine amino acid sequence, and an active agent containing two dihyroxyphenylalanine moieties (MDS-2DOPA). (BOTTOM) Depicts mass spectrometry data confirming synthesis of the compound depicted above. FIG. 23. Depicts a conjugate formed between the compound depicted in FIG. 22, an antibody represented by R (e.g., trastuzumab), and two boronic acid MMAE biologically active agents (e.g., Trast-MDS-2DOPA-BA-MMAE). FIG. 24. (A) Western blot analysis of four different antibodies conjugated to the biotin compound depicted in FIG. 19 indicates that the compound conjugates to both the heavy and light chain of all four antibodies. (B) Western blot analysis of papain digested conjugated antibody indicates that conjugation occurs in the Fab fragment and not the Fc region. (C) Biotin quantification indicates that an approximately a 2:1 ratio of biotin to antibody in the conjugated antibody. FIG. 25. Illustrates conjugation efficiency between the compound of FIG. 19 and the antibody trastuzumab (TrastMDS). Lanes 2, 3, and 4 contain unmodified trastuzumab, and incubation with avidin agarose does not decrease the amount of antibody in solution. Lanes 5, 6, and 7 contain TrastMDS, and incubation with increasing amounts of avidin agarose decreases the amount of antibody in solution. Lanes 8, 9, and 10 contain avidin agarose and incubating the avidin agarose with decreasing amounts of TrastMDS decreases the amount of antibody in solution. FIG. 26. Illustrates the effect of an antibody drug conjugate (ADC) compound of FIGS. 21 and 23, where R is trastuzumab, (1DOPA and 2DOPA respectively), on viability of cancer cell lines SKBr3, MCF7, and SKOV3. The 4 DOPA compound is a trastuzumab-DOPA-boronic acid MMAE compound containing four dihydroxyphenylalanine moieties, each bound to a boronic acid MMAE moiety. The column labeled trastuzumab refers to unconjugated antibody. FIG. 27. Illustrates a schematic for a use of an antibody conjugate described herein for cross-linking activated T cells to target cancer cells. In the schematic depicted, the nivolumab antibody binds to and inhibits the T cell surface checkpoint antigen PD-1, and is conjugated to a compound containing: a maleimide cross-linking agent, an indole targeting moiety, a linker containing a lysine-aspartate-serine amino acid sequence, and an active agent containing an α3β1-integrin ligand LXY30 (Xiao et al., EJNMMI Res. 2016 December; 6(1):18), Binding of the antibody to the T cell and the ligand to a target cancer cell that expresses α3β1-integrin delivers an activated T cell to the target cancer cell, enhancing anti-tumor efficacy. FIG. 28. Depicts successful conjugation of nivolumab (N) to a compound described herein containing a maleimide cross-linking agent (M), an indole targeting moiety, a linker containing a lysine-aspartate-serine amino acid sequence (DS), and an active agent containing a biotinylated LYX30 peptide to generate a bi-functional antibody conjugate. “NMDS Only” refers to nivolumab (N) conjugated to the compound described herein containing a maleimide cross-linking agent (M), an indole targeting moiety, and a linker containing a lysine-aspartate-serine amino acid sequence (DS). Conjugation is confirmed by gel electrophoresis and fluorescence detection of streptavidin Alexa 488 labeling, as well as size exclusion chromatography. FIG. 29. Depicts binding of the bi-functional conjugate characterized in FIG. 28 to PD-1 and α3β1-integrin. FIG. 30. Depicts results of an in vitro T cell killing assay monitored and quantified by flow cytometry. Untreated target cells (SKOV3) showed little cytotoxicity. Target cells treated with activated T cells showed a moderate amount of cell killing. The addition of the checkpoint inhibitor nivolumab increased target cell killing. The use of the bifunctional nivolumab and LXV30 conjugate NMDS-LYX30 increased the number of dead and dying target cells by 14.4% as compared to nivolumab. FIG. 31. Depicts the improved T cell killing of target cells with the bifunctional NMDS-LYX30 immunoconjugate as measured by ELISA detection of cytokine (top: Granzyme B, bottom: perforin) release at multiple timepoints. FIG. 32. Depicts (TOP) Depicts a compound described herein containing a maleimide cross-linking agent, an indole targeting moiety, a linker containing a lysine-aspartate-serine amino acid sequence, and an active agent containing four dihyroxyphenylalanine moieties (MDS-4DOPA). (BOTTOM) Depicts mass spectrometry data confirming synthesis of the compound depicted above. FIG. 33. Depicts a conjugate formed between the compound depicted in FIG. 32, an antibody represented by R (e.g., trastuzumab), and two boronic acid MMAE biologically active agents (e.g., Trast-MDS-4DOPA-BA-MMAE). DETAILED DESCRIPTION I. Introduction Described herein are methods and compositions for utilizing the nucleotide-binding pocket in antibody F(ab) arms to target a compound for covalent attachment to the antibody. As described herein, nucleotide-based cross-linking agent-derivatized One Bead One Compound (OBOC) peptide libraries are developed for the identification of linkers that increase binding affinity of the cross-linking agent to the antibody and can be used as site-specific derivatization agents against both monoclonal and polyclonal antibodies. Immunoconjugates resulting from such linkers can be used as diagnostic agents and therapeutics against cancer or infectious agents. Targeted therapy using monoclonal antibodies (mAbs) has revolutionized the treatment of cancer by recognizing antigens expressed on cell surfaces1,2. The addition of cytotoxic drugs to these mAbs, creating antibody-drug conjugates (ADC) was a natural extension of this approach, and has achieved varying success in the clinic. These antibody drug conjugates combine the targeted specificity of mAbs with the enhanced tumor-killing power of toxic effector molecules permitting the sensitive discrimination between target and normal tissue, resulting in fewer toxic side effects than most conventional chemotherapeutic drugs3. Recently, trastuzumab emtansine (Kadcyla; Genentech/Roche), an anti-Her2 maytansine conjugate demonstrated an improved survival compared to standard treatment4. Similarly, Brentuximab Vedotin (Adcetris; Seattle Genetics) received accelerated approval for the treatment of relapsed Hodgkin lymphoma or relapse systemic anaplastic large cell lymphoma through the use of a CD30 directed antibody drug conjugated with a microtubule-disrupting agent monoomethyl auristatin E (MMAE)5. The first clinically approved ADC, gemtuzumab ozogamicin (Mylotarg; Wyeth/Pfizer) was removed from the market because of toxicity and lack of efficacy in larger clinical trials6. Although these approvals show great potential of ADCs to impact major unmet needs in oncology, the withdrawal of Mylotarg shows that further work is necessary to optimize this new class of drugs7. The cytotoxic drugs are generally conjugated to antibodies through nonspecific methods, including targeting (1) primary airlines from lysine or (2) free sulfhydryls from cysteines by reduction of the hinge and inter-strand disulfide bonds8. These modifications, however, creates heterogeneous products because of the reoccurrence of the same functional groups. These complex mixtures lead to variable in vivo pharmacokinetics, efficacy, and safety profiles8. The high abundance of lysine in each immunoglobulin molecule, for example, makes it difficult to control the stoichiometry and specificity of the chemical conjugates. Although there are fewer cysteines on an antibody, modification of the cysteines may alter the stability and function of the antibody9. Therefore, to create a homogenous product, extensive purification processes are needed. Many investigators have moved towards the development of site-specific modifications to create ADCs, providing complete control over the attachment thereby decreasing heterogeneity in the final clinical products. Current site-specific conjugation methods include both antibody engineering and chemical methods. Several research groups have engineered a cysteine residue on the surface of the antibody to introduce sulfhydryl groups for subsequent conjugation to a linker payload2,10. These methods have successfully created homogenous conjugates. However, the engineering of these antibodies require extensive optimization, therefore lengthening the time for these molecules to reach the clinic. A number of chemical methods have emerged by modifying N-terminal residues11,12 targeting tyrosine residues13,14, or adding recognition tags for enzymatic modification15-17. While these methods can site-specifically conjugate a payload to antibodies, many of these processes require the use of organic solvents which are often times too harsh to maintain folded protein structures18 or require very extensive conjugation times which may affect protein stability. Conjugation to the N-terminus, for example, can also be problematic as the conjugation of a cytotoxic payload or a ligand may affect epitope binding which is typically mediated by regions at or near the N-terminus. As a simple alternative, site-specific conjugation to clinically available antibodies can be done through the use of a ligand that binds directly to the Fab arm. Here, we propose to use of a novel site-specific affinity element to chemically modify antibodies with a wide array of different functional groups including peptides, detectable labels, small molecules, cytotoxic agents, etc. This blending of features of site-specific conjugated functional groups and mAbs, without antibody engineering, is economically attractive because it can utilize many existing clinically available antibodies, reducing production costs and shortening preclinical-to-clinical translation times19. Rajagopalan et al.20 have identified a nucleotide-binding pocket (NBP), which exists in all immunoglobulin Fab arms. This highly conserved pocket is located between the variable light (VL) and variable heavy (VH) domain of all antibody isotypes20-22. Through an in silica docking study, Handlogten et al.22 identified indole-3-butryic acid as a highly specific compound that binds to the NBP with Kds ranging between 1 μM to 8 μM, with binding affinity dependent on the antibody20,22. Alves et al23 has described a UV photocrosslinking method relying on the indole group to crosslink to specific residues within the NBP of IgG. This method requires the use of UV excitation to develop an indole radical used for crosslinking. This requirement for UV excitation increases the risk of impairing Fc recognition and creates a loss in the antibody's ability to recognize its antigen. Together, there is an increased need to discover enhanced small molecules that can take advantage of this nucleotide binding pocket for site specific ligation. We have taken advantage of the site specificity provided by indole-3-butryic acid and developed focused one-bead-one-compound (OBOC) combinatorial peptide libraries capped by indole-3-butyric acid to discover an affinity element capable of site-specific ligation to the nucleotide-binding site of immunoglobulin via proximity-ligation. For irreversible ligation to free amines and thiols at the nucleotide-binding site, we placed a 1,5-difluoro-2,4-dinitrobenzene (DNDFB) moiety24 or a maleimide moiety adjacent to the indole group of the OBOC library. This crosslinking agent (e.g., DNDFB or maleimide), in addition to our targeting ligand (e.g., indole and peptide containing linker), makes it a superior conjugate because of the mild conditions required to covalently crosslink to the antibody. From this library we have discovered several linkers that allow site-specific introduction of orthogonal functional groups that can be readily used for subsequent conjugation of a cytotoxic payload, detectable label, or ligand for generating a bispecific antibody. For example, this linker can be used for the ligation of toxin such as monomethyl auristatin E (MMAE) to make antibody-toxin conjugates for cancer therapy. This can be done through the use of existing clinically available mAbs such as Herceptin, Avastin, and Rituxan. In some cases, the conjugate can be used for site-specific introduction of a functional that can be used to form a further covalent bond to an active agent (e.g., biologically active agent). For example, the conjugate can introduce one or more (e.g., 2, 3, 4. 5, 6, or more) 1,2-dihydroxybenzne groups (e.g., in the form of dihydroxyphenylalanine). These dihydroxybenzne groups can each in turn be used to conjugate a boronic acid containing group and form a boronic ester under mild conditions. In some cases, the boronic acid containing group further contains a cytotoxic payload such as the MMAE derivative depicted in FIG. 18. As another example, the conjugate can introduce one or more (e.g., 2, 3, 4, 5, 6, or more) azide or alkyne functional groups. In addition, one may site-specifically introduce disease-specific targeting ligands onto readily available monoclonal or polyclonal human intravenous immunogobulins (IVIGs) without the need to reengineer an antibody, which can take months to years. This latter application is particularly useful for, e.g., rapid deployment of neutralizing antibodies against emerging pathogens in epidemics and pandemics, such as the recent Ebola outbreak. Alternatively, a monoclonal antibody conjugated to a disease-specific targeting ligand can be used for bringing effector and target cells into proximity to enhance the activity of effector cell induced cytotoxicity. For example, a checkpoint inhibitory antibody (e.g., anti-PD-1, anti-PD-L1, anti-CTLA4, etc.) can be conjugated to a disease-specific targeting ligand. Checkpoint inhibitory antibodies that bind an effector immune cell (e.g., T cell) antigen (e.g., PD-1) can be conjugated to a target cell specific ligand to increase effector cell cytotoxic activity against the target cell. In some cases, the target cell specific ligand is or contains an LXY30 peptide. Similarly, checkpoint inhibitory antibodies that bind a target cell antigen (e.g., PD-L1) can be conjugated to an effector immune cell specific ligand to increase effector cell cytotoxic activity against the target cell. The target cell can be a microbe, or a tumor cell. In some cases, the target cell is a tumor cell. II. Compositions Described herein is a compound comprising i) a targeting moiety that specifically binds a nucleotide binding pocket of an antibody; ii) a cross-linking agent; iii) an active agent or a conjugating agent; and iv) a linker, wherein the linker covalently links: a) the targeting moiety, b) the cross-linking agent, and c) the active agent or conjugating agent. In some cases, the cross-linking agent is an acryloyl functional group. In sonic cases, the cross-linking agent is a photo-crosslinking group. In sonic cases, the cross-linking agent is a cross-linking agent that can be activated to cross-link to (i.e., form a covalent bond to) a protein (e.g., antibody) by raising the pH of a reaction mixture in which the cross-linking agent is present to at least about 8.0 or 8.5. In some cases, the cross-linking agent is 5-fluoro-2,4-dinitrobenzene (DNFB). In some cases, the cross-linking agent is maleimide. The linker can be any compound capable of linking a targeting moiety, a cross-linking agent, and an active agent or conjugating agent. In some cases, the linker contains one or two ethylene glycol moieties. In some cases, the linker contains a polyethylene glycol (PEG) polymer. In some cases, the linker contains an ethylene glycol dimer or a PEG polymer. PEG is a well-known, water soluble polymer that is commercially available or can be prepared by ring-opening polymerization of ethylene glycol according to methods well known in the art (Sandler and Karo, Polymer Synthesis, Academic Press, New York, Vol. 3, pages 138-161). The term “PEG” is used broadly to encompass any polyethylene glycol molecule, without regard to size or to modification at an end of the PEG, and can be represented as linked to an amino acid by the formula: XO—(CH2CH2O)=n—CH2CH2—Y where n is 3 to 10,000 or more and X is H or a terminal modification, including but not limited to, a C1-4 alkyl. In some cases, a PEG used in the invention terminates on one end with hydroxy or methoxy, i.e., X is H or CH3 (“methoxy PEG”). In some cases, the linker contains an amino acid sequence. The amino acid sequence can contain negatively charged amino acids. In some cases, the negatively charged amino acids are aspartate, glutamate, or a combination thereof. In some cases, the linker contains an amino acid sequence and an ethylene glycol dimer or PEG polymer. In some cases, the linker contains a lysine-aspartate-serine amino acid sequence and an ethylene glycol dimer. In some cases, the linker contains an ethylene glycol dimer and an amino acid sequence selected from the group consisting of: Ile; Leu; Ser; Asp; His; Phe; Glu; Asn; Asp-Ser; Phe-Bpa; Asp-Leu; Asp-Gly; Trp-Glu; Bpa-Gln; Asp-Thr; Trp-Phe-Gln; Phe-Asp-His; Asp-Trp-Nva; Glu-Asp-Pro; Trp-Phe(2Cl)-Thr-Thr; Thr-HoCit-His-His; Phe(2Cl)-Thr-Phe(2Cl)-Gln; Glu-Leu-Gln-Nal2; Glu-HoPhe-Gln-His; Glu-Ala-Asn-Glu; and Asp-Gly-Phe(2Cl)-Thr. In some cases, the linker can contain an affinity element that increases the specificity or affinity of the targeting moiety to which it is linked to the nucleotide binding pocket of an antibody. In some cases, the affinity element is an amino acid sequence. For example, the affinity element can be an amino acid sequence that contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more negatively charged amino acids. As another example, the affinity element can be a water soluble or hydrophilic amino acid sequence. For instance, the affinity element can contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more polar amino acids. In some cases, the affinity element is a di- or tripeptide. In some cases, the affinity element contains a lysine, an aspartate, and a serine. In some cases, the affinity element contains a lysine-aspartate-serine amino acid sequence. In some cases, the affinity element contains an aspartate and a serine. In some cases, the affinity element contains an aspartate-serine amino acid sequence. The compound can have the following formula: where R1 contains the targeting moiety that specifically binds to the nucleotide binding pocket of an antibody; R2 contains the cross-linking agent; and R3 contains the active agent or conjugating agent. In some embodiments, the targeting moiety that specifically binds the nucleotide binding pocket of an antibody comprises a purine nucleotide or a purine nucleotide analogue. In some cases, the purine nucleotide or purine nucleotide analogue contains an indole. In some cases, the purine nucleotide or purine nucleotide analogue is indole-3-butyrate. Exemplary targeting moieties can further include sinefungin, methyl-indole-3-carboxaldehyde, fluorotryptamine, fluoroindole-3-carboxaldehyde, or methylindole-3-carboxyaldehyde. In some embodiments, the compound has the following formula: wherein L1 and L2 are independently a C1-C10 alkylene, and R4 is represented by the following formula: where R5 is an amino acid side chain, m and n are independently from 1 to 10, and R3 contains the active agent or conjugating agent. In some cases, the amino acid side chains of R5 are independently selected to include one or more negatively charged amino acids (e.g., aspartate or glutamate) or one or more polar amino acids (e.g., serine, threonine, histidine, glutamine, asparagine, tyrosine, cysteine, methionine, or tryptophan). In some cases, the amino acid side chains are independently selected to include an affinity element that increases the affinity of a targeting moiety to the nucleotide binding pocket of an antibody. Exemplary affinity elements include, but are not limited to, a di- or tripeptide, such as a di- or tripeptide that contains one or more negatively charged or one or more polar amino acids, or a combination thereof. Exemplary affinity elements can include affinity elements that contain lysine, aspartate, and serine. Exemplary affinity elements can include affinity elements that contain a lysine-aspartate-serine amino acid sequence. Exemplary affinity elements can include affinity elements that contain aspartate and serine. Exemplary affinity elements can include affinity elements that contain an aspartate-serine amino acid sequence. In some embodiments, the compound has the following formula: where R3 contains the active agent or conjugating agent. In some embodiments, the active agent contains a detectable label. The detectable label can be a label, a dye, a radionuclide, an affinity label, a photoaffinity label, a reactive compound, a resin, or a second protein or polypeptide or polypeptide analog. The second protein can or polypeptide can be an antibody or antibody fragment, an enzyme (e.g., horse radish peroxidase, alkaline phosphatase, etc.), or a protein ligand. The detectable label can be a metal chelator (e.g., 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DMA)), a polynucleotide, a DNA, an RNA, a nanoparticle, a spin label, a fluorophore, a metal-containing moiety, a group that covalently or noncovalently interacts with other molecules, a photocaged moiety, a photoisomerizable moiety, biotin, a derivative of biotin, a biotin analogue, avidin, streptavidin, a moiety incorporating a heavy atom, a chemically cleavable group, a photocleavable group, a redox-active agent, a biophysical probe, a phosphorescent group, a chemiluminescent group, an electron dense group, a magnetic group, an intercalating group, a chromophore, an energy transfer agent, or any combination of the foregoing. In some cases, the detectable label is a biotin molecule. In some cases, the active agent contains a biologically active agent. The biologically active agent can include any cytotoxic, cytostatic or immunomodulatory drug. The biologically active agent can be a ligand to a cell. For example, the biologically active agent can be a ligand with affinity to an immune cell (e.g., natural killer cell, natural killer T cell, or cytotoxic T cell). Alternatively, the biologically active agent can be a ligand with affinity to a microbe. In some cases, the biologically active agent is a cytotoxic or immunomodulatory agent. In some cases, the active agent is a chemotherapeutic agent. Useful classes of chemotherapeutic, cytotoxic or immunomodulatory agents include, for example, antitubulin agents, auristatins, DNA minor groove binders, DNA replication inhibitors, alkylating agents (e.g., platinum complexes such as cis-platin, mono(platinum), bis(platinum) and tri-nuclear platinum complexes and carboplatin), anthracyclines, antibiotics, antifolates, antimetabolites, calmodulin inhibitors, chemotherapy sensitizers, duocarmycins, etoposides, fluorinated pyrimidines, ionophores, lexitropsins, maytansinoids, nitrosoureas, platinols, pore-forming compounds, purine antimetabolites, puromycins, radiation sensitizers, rapamycins, steroids, taxanes, topoisomerase inhibitors, vinca alkaloids (e.g., vincristine, vinblastine, vindesine, and vinorelbine), radionuclides (e.g., Yt-99), or the like. In sonic cases, the active agent contains a cytotoxic agent. In some cases, the cytotoxic agent is monomethyl auristatin E. In some cases, the cytotoxic agent is vincristine. In some embodiments, the compound has the following formula: In some embodiments, the compound contains the following formula: wherein R6 is an antibody and R3 comprises an active agent or conjugating agent. The antibody can be any antibody known in the art, so long as it contains one or more nucleotide binding pockets. Nucleotide binding pockets can be located between the variable light and variable heavy chain domains of all antibody isotypes. Thus, in some cases, the nucleotide binding pocket contains a variable light chain domain and variable heavy chain domain. In some cases, the nucleotide binding pocket includes the CDR1 domain and at least a portion of the FR2 region of a variable light chain. In some cases, the nucleotide binding pocket includes the CDR3 domain and at least a portion of the FR4 region of the variable heavy chain. In some cases, the nucleotide binding pocket includes residues H100, H101, H103 L44, L36, or a combination thereof. In some cases, H100 is Glu. In some cases, H101 is Asp. In some cases, H103 is Trp. In some cases, L44 is Pro. In some cases, L36 is Tyr. In some cases, the antibody is a. polyclonal antibody. For example, the antibody can be immunoglobulin harvested from a donor. In some cases, the antibody is immunoglobulin harvested from a donor that is conjugated to a molecular payload compound described herein using a method described herein and administered to a subject (e.g., by intravenous administration). In some cases, the polyclonal antibody is Flebogamma, Gamunex, Privigen or Gammagard. In some embodiments, the conjugating agent contains an azide or alkyne. The use of a conjugating agent containing an azide or alkyne group can enable facile linkage to an active agent (e.g., detectable label or biologically active agent) via cycloaddition. For example copper catalyzed cycloaddition. Thus, when the conjugating agent contains an azide, an active agent containing an alkyne can be linked to the conjugating agent. Alternatively, when the conjugating agent contains an alkyne, an active agent containing an azide can be linked to the conjugating agent. III. Methods Described herein is a method for covalently conjugating one or more of the foregoing compounds to an antibody. In some embodiments, the method is for covalently conjugating an antibody to a molecular payload, where the molecular payload is comprised of any one of the foregoing compounds described herein that contains a cross-linking agent. In some cases, the method includes: a) forming a reaction mixture containing the antibody and the molecular payload under conditions suitable to form a non-covalent binding interaction between a nucleotide binding pocket of the antibody and a targeting moiety of the molecular payload; and b) triggering a cross-linking event between the antibody and the cross-linking agent of the molecular payload. The cross-linking event can be triggered by one or more of the following: raising the pH, lowering the pH, introducing an oxidant, introducing a reductant, irradiating the reaction mixture (e.g., with ultraviolet or visible light, or a combination thereof), or introducing a catalyst into the reaction mixture. In some cases, the method can include: a) forming a reaction mixture containing the antibody and the molecular payload under conditions suitable to form a non-covalent binding interaction between a nucleotide binding pocket of the antibody and a targeting moiety of the molecular payload, wherein the reaction mixture is an aqueous solution having a pH of less than about 7.5; and b) raising the pH of the reaction mixture above about 8.0, under conditions suitable to form a covalent bond between the antibody and the cross-linking agent. The pH of the reaction solution in a) can be about 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8.0. The raising the pH of b) can be raising the pH of the reaction mixture above about 8.0, 8.5, 9.0, 9.5, 10.0, or more. The pH can be raised by a variety of methods. In some cases, a base is added to the reaction mixture. In some cases, a basic solution is added to the reaction mixture. In some cases, a basic solution containing a primary amine is added to the reaction mixture. The use of a basic solution containing a primary amine can serve to raise the pH and thus trigger cross-linking and quench the cross-linking agents of any molecular payload that is not in a non-covalent interaction with the nucleotide binding pocket via the targeting moiety. Exemplary bases or basic solutions include, but are not limited to sodium bicarbonate, NaOH, NH4OH, 0.1 N NaOH, 0.1 M sodium bicarbonate (e.g., pH 8, 8.5, 9, 9.5, 10, 10.5, or higher), 0.1 N NH4OH, or 7 N NH4OH. In some cases, the basic solution contains 0.1 M sodium bicarbonate pH 8.5, 0.1 N NaOH or 0.1 N NH4OH. In some cases, the cross-linking forms a covalent bond between the cross-linking agent and a primary amine, a sulfhydryl, or a guanidinium group of the antibody. In some cases, the primary amine, sulfhydryl, or guanidinium group is within 8 Å of the nucleotide binding pocket. In some cases, the primary amine, sulfhydryl, or guanidinium group is within 6 Å of the nucleotide binding pocket of the antibody. In some cases, the primary amine, sulfhydryl, or guanidinium group is within 4 Å of the nucleotide binding pocket. In some cases, the primary amine, sulfhydryl, or guanidinium group is within an amino acid reside that forms the nucleotide binding pocket. Generally, the maximum distance between the nucleotide binding pocket and the antibody amino acid functional group that cross-links with the cross-linking agent is controlled by the distance between the targeting moiety and the cross-linking agent. In an exemplary embodiment, the targeting moiety and the cross-linking agent are linked by a lysine, and the distance between the targeting moiety and the cross-linking agent is less than about 8 Å, 6 Å, or 4 Å. In some cases, the cross-linking forms a covalent bond between the cross-linking agent and a primary amine of the antibody. In some cases, the cross-linking forms a covalent bond between the cross-linking agent and an epsilon amine of a lysine side chain of the antibody. In some cases, the cross-linking forms a covalent bond between the cross-linking agent and an epsilon amine of a lysine side chain of the antibody that is within less than about 8 Å, 6 Å, or 4 Å of the nucleotide binding pocket of the antibody. In some embodiments, the method includes incubating the reaction mixture containing the antibody and the molecular payload for at least about 0.25 h. The incubating can allow the non-covalent interaction between the targeting moiety of the molecular payload and the nucleotide binding pocket of the antibody to occur, at least partially occur, or to reach equilibrium. In some cases, the incubating the reaction mixture containing the antibody and the molecular payload is performed for 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 7, 8, 12, 18, 24 h, or more. In some embodiments, the conditions suitable to form the non-covalent binding interaction between the nucleotide binding pocket of the antibody and the targeting moiety of the molecular payload include a reaction mixture temperature of about 20° C. In some cases, the reaction mixture temperature during the non-covalent binding is from about 4° C. to about 45° C. In some cases, the reaction mixture temperature during the non-covalent binding is from about 4° C. to about 37° C. In some cases, the reaction mixture temperature during the non-covalent binding is from about 4° C. to about 30° C. In some cases, the reaction mixture temperature during the non-covalent binding is from about 4° C. to about 25° C. In some cases, the reaction mixture temperature during the non-covalent binding is about 4, 6, 8, 10, 12, 14, 18, 20, 25, 30, 35, 37, 40, or about 45° C. In some embodiments, the reaction mixture of a) contains phosphate buffered saline. In some cases, the reaction mixture of a) comprises phosphate buffered saline at a pH of about 7.0 (PBS 7.0) or phosphate buffered saline at a pH of about 7.5 (PBS 7.5). In some cases, the phosphate buffered saline contains sodium and potassium ions. In some cases, the phosphate buffered saline contains sodium ions. In some cases, the phosphate buffered saline contains calcium ions. In some cases, the phosphate buffered saline contains magnesium ions. In some cases, the phosphate buffered saline is calcium free. In some cases, the phosphate buffered saline is magnesium free. In some cases, the phosphate buffered saline is calcium and magnesium free. An exemplary phosphate buffered saline is prepared by introducing into water 137 mM NaCl, 2.7 mM KCl, 10 mM Na2HPO4, and 1.8 mM KH2PO4, and adjusting the pH to 7.0, 7.4, or 7.5. In some cases, the pH is adjusted with HCl. In some cases, the pH is adjusted with NaOH. In some cases, the reaction mixture of a) contains a molar excess of molecular payload relative to nucleotide binding pockets. In some cases, the reaction mixture of a) contains a molar excess of molecular payload relative to nucleotide binding pockets and the method further includes removing unbound molecular payload from the reaction mixture after forming the non-covalent interaction between the targeting moiety and the nucleotide binding pockets and before cross-linking. In some cases, the reaction mixture of a) contains a molar excess of molecular payload relative to nucleotide binding pockets and the method further includes removing unbound molecular payload from the reaction mixture after a) and before b). The unbound molecular payload can be removed from the reaction mixture by dialysis or size exclusion chromatography. In some cases, the size exclusion chromatography includes applying the reaction mixture to a desalting column and collecting the flow through fraction. In some cases, the size-exclusion chromatography includes high performance liquid chromatography (HPLC) or fast protein liquid chromatography (FPLC). For example, a gel filtration column can be used with an HPLC or FPLC system to separate bound and unbound molecular payload prior to the cross-linking step. In sonic cases, unbound molecular payload and/or unconjugated antibody, can be removed additionally, or alternatively, after the cross-linking step, e.g., by dialysis or size-exclusion chromatography. In some cases, the molecular payload contains a conjugating agent that includes an azide or alkyne, and after forming the covalent bond between the antibody and the cross-linking agent, the method further comprises conjugating an active agent to the azide or alkyne via azide alkyne Huisgen cycloaddition or Copper (I)-catalyzed azide-alkyne cycloaddition. In some cases, the molecular payload contains a conjugating agent that includes a boronic acid conjugating group (e.g., 1,2-dihydroxybenzene such as dihyroxyphenylalanine). The method further comprises conjugating an active agent to the boronic acid conjugating group via boronic ester synthesis. In some embodiments, the method includes a) forming the reaction mixture comprising PBS 7.0 or PBS 7.5, the antibody, and a 5-fold molar excess of the following molecular payload relative to nucleotide binding pockets of the antibody, b) incubating the reaction mixture of a) for at least about 0.25 h at a temperature of from about 4° C. to about 37° C.; c) removing unbound molecular payload by dialysis or size exclusion chromatography; d) raising the pH of the reaction mixture to about 8.5, under conditions suitable to form a covalent bond between the antibody and the molecular payload by adding a basic solution containing 0.1 M sodium bicarbonate pH 8.5, 0.1 N NaOH or 0.1 N NH4OH; and e) incubating the reaction mixture of d) for at least about 0.25 h at a temperature of from about 4° C. to about 37° C. In some cases, the molar excess of molecular payload to nucleotide binding pockets of the antibody is, or is about, 1.1-fold, 2-fold, 2.5-fold, 3-fold, 4-fold, 5-fold, or more. In some cases, the R3 of the molecular payload contains a conjugating agent that contains an alkyne or azide and the method further includes: f) introducing into the reaction mixture a copper (1) catalyst and an active agent comprising an azide or alkyne that is reactive to the alkyne or azide of the conjugating agent, thereby conjugating the active agent to the conjugating agent. In some cases, the R3 of the molecular payload contains a conjugating agent that contains a 1,2-dihydroxybenzene moiety, and the method further includes: f) introducing into the reaction mixture an active agent comprising a boronic acid that is reactive to the 1,2-dihydroxybenzene moiety of the conjugating agent, thereby conjugating the active agent to the conjugating agent. EXAMPLES The following examples are offered to illustrate, but not to limit the claimed invention. Example 1 Experimental Methods General Procedures The chemicals and solvents used were of analytical grade and were received from commercial sources. Fmoc-protected amino acids were purchased from Advanced ChemTech (Louisville, Ky.), EMD Chemicals Inc. (Gibbstown, N.J.), and Chem-Impex International, Inc. (Wood Dale, Ill.). TentaGel S NH2 (90 m, 0.27 mmol/g) was purchased from Rapp Polymere Gmbh (Tubingen, Germany). Indole-3-butyric acid and 1,5-difluoro-2,4-dinitrobenzene were from Sigma Aldrich (St. Louis, Mo.). Library Design and Synthesis To aid in the design of the library, computer-modeling studies were done. We started by performing molecular docking studies using Autodock v4.219 to understand the binding of indole-3-butyric acid to trastuzumab. The three-dimensional structure of human trastuzumab available in PDB (ID: 1N8Z) was used for all docking studies. From the low energy binding conformations calculated by the indole-trastuzumab docking, the spatial and charge properties were identified. This knowledge was used to design several virtual test ligands of varying lengths and charge properties. These ligands were docked with trastuzumab using Autodock v4.219. Trastuzumab and ligand structures were prepared for docking using Autodock Tools19 package. Partial atomic charges were assigned to the ligands using the Gasteiger-Marsili method, and after merging of non-polar hydrogens; rotatable bonds were assigned using Autodock Tools. Water molecules were removed from the trastuzumab structure; the missing hydrogen atoms and Kollman partial charges were added. Further, non-polar hydrogen atoms were merged to their corresponding carbons. A grid size of 60×60×60 with grid spacing of 0.375 Å for smaller ligands was used, and for larger ligands the grid size was increased proportionally to fit the whole ligand molecule. We used the Lamarckian Genetic Algorithm (Pseudo Solis-Wets Algorithm20) to perform 256 independent docking runs with default parameters in Autodock. Cluster analysis was performed on docked results using RMS tolerance of 2 Å. The results were analyzed to compare the lowest energy binding energy conformations. Further, to test for the binding specificity profile, blind docking runs were performed using these test ligands, and trastuzumab as the target protein. The SwissDock webservice21 was used to conduct these blind dockings. Energy optimized structure of the ligands was calculated using Merck Molecular Force Field (MMFF)22 as implemented in Marvin Suite v 5.11. Among the clusters generated by SwissDock, top clusters were analyzed and compared to check for convergence on the binding site. These top clusters were then used to design several one-bead-one-compound (OBOC) combinatorial libraries to identify an optimal crosslinking compound to the NBP. Library Screen/Confirmation Screen Approximately 100,000 library beads were immobilized onto 30 mm polystyrene dishes by using a series of 90% DMF washes. Beads were then washed and swelled in PBS. Nonspecific binding was inhibited with blocking buffer (0.1% BSA, 0.1% Tween, and 0.05% sodium azide) for one hour in room temperature. After several PBS washes, 1 ng/ml trastuzumab (Genentech, South San Francisco, Calif.) in PBS (pH 7.0) was added and was placed in a rotating incubator at 37° C. for 1 hour. Here, we used trastuzumab as the model monoclonal antibody. Excess antibody was removed, and beads were gently washed with PBS. To facilitate crosslinking of DNDFB to the antibody of the peptide library, we raised the pH to 8.5 for one hour. After crosslinking, beads were washed sequentially with PBS, 1.00 mM pH 3 glycine, and then pH 8 TBS. Anti-human IgG-alkaline phosphatase conjugate was then added at 1:1000 dilution. After washing, beads were then developed using BCIP (5-bromo-4-chloro-3′-indolyphosphate p-toluidine salt) solution. (NBT (nitro-blue tetrazolium chloride) was not used due to high background staining with TentaGel library beads.) Using a dissecting microscope, plates were imaged and positive beads were isolated. The isolated beads were then treated with 8M guanidine/HCl to remove all non-covalently linked proteins. The beads were further washed with PBS and water. Beads were decoded using Edman degradation chemistry (ABI Procise 494 Protein Sequencer). In the confirmation studies, hits were synthesized on TentaGel. Staining steps were the same except 1:30 anti-human IgG conjugated to Cy3 was used to allow for fluorescence quantification. Beads were imaged with Olympus IX2-IX2-UCB (Center Valley, Pa.) under 4× objective. Cy3 excitation and emission settings were used. Bead intensity was measured and quantified using Image J. Western Blot 50 μM DS peptide was incubated with 10 μM trastuzumab at 37° C. for 1 hr in a shaking incubator. Samples were then dialyzed to remove unbound peptides, with frequent water changes. Crosslinking occurred by increasing the sample to pH 8.5 and incubated for 1 hr at room temperature. 50 ng of each sample was loaded onto 10% SDS-PAGE gel with Laemelli loading buffer containing β-mercaptoethanol. Denatured, reduced samples were run @140V. Proteins were then transferred to PVDF membrane at 100V. Membranes were washed with TBST and were blocked with blocking buffer for 1 hr in room temperature. After a series of PBS washes, 1:500 streptavidin-alkaline phosphatase was added to the membrane and incubated for 1 hr. Blots were developed using BCIP/NBT (Promega, Madison, Wis.). Similar western blots were done using bevacizumab (Genentech/Roche, South San Francisco, Calif.), rituximab (Biogen IDEC, Cambridge, Mass.), cetuximab (Bristol-Myers Squibb, New York, N.Y.), and intravenous immunoglobulin (BDI Pharma, Columbia, S.C.). Papain Digestion The biotinlyated DS affinity element was conjugated with several FDA-approval therapeutic antibodies, including trastuzumab, IVIG, rituximab, and cetuximab. The affinity element and the antibody were incubated at 37° C. for an hour followed by room temperature incubation with 1.4 μL 7N ammonia hydroxide for 1 hour. These biotinylated immunoconjugates were then digested with papain to generate Fab and Fc fragments. Fragments were then separated on a 4% to 12% Tris-glycine gel (Life Technologies, Inc., Gaithersburg, Md.) and transferred to PVDF membranes. Blots were probed with streptavidin-Horseradish Peroxidase (HRP) (BioRad, Hercules, Calif.), which would have a strong binding affinity with biotinlyated affinity element. Blotting was carried out in 10% non-fat milk solution. Fragments were visualized using enhanced chemiluminescence reagents (GE health Care, Buckinghamshire, UK). Commassie Brilliant Blue G-250 (Thermo, UK) staining was performed at the same time on a separated gel with the same samples. HABA-Avidin Quantification Biotinylated antibody conjugates were prepared as described in previous sections. The absorbance of HABA/Avidin premix solution (pierce) was measured at 500 nm. The biotinylated proteins were mixed with HABA/Avidin premix solution for 30 minutes at room temperature. Absorbance measurements were measured again at the same wavelength. Calculations of moles of biotin per mole of protein used the following formula: Aλ=ϵλbC, (Beer's Law) where A is the absorbance of the sample at a particular wavelength (λ). The wavelength for the HABA assay is 500 nm. ϵ is the absorptivity or extinction coefficient at the wavelength (λ). For HABA/avidin samples at 500 nm, B is the cell path length of the microplate reader (Molecular Devices, Sunnyvale, Calif.) expressed in centimeters. C is the concentration of the sample expressed in molarity. Moles of biotin per mole of protein is calculated by: mmol biotin from the sample/mmol protein in original sample. Size-Exclusion HPLC Samples were prepared as mentioned for western analysis. Trastuzumab-biotinylated peptide conjugates were then incubated with neutravidin at different molar ratios (4:1, 10:1, 30:1 trastuzumab conjugate:neutravidin) for 1 hr. Samples were then run on Waters size exclusion HPLC (Milford, Mass.), with Superdex200 (10/300) column from GE Healthcare (Pittsburgh, Pa.). Area under the curve (AUC) was then measured to quantify the amount of successful conjugation. Peaks were compared to a known control sample. Cell Culture Jurkat human T-lymphocyte, SKBR-3 MCF-7, and MDA-MB-468 human mammary gland/breast adenocarcinoma cells were purchased from American Type Culture Collection (ATCC; Manassas, Va.). SKBR-3 cells were cultured McCoy5A. Medium with 10% fetal bovine serum (FBS), 100 U/ml penicillin G, and 100 μg/ml streptomycin. Jurkat, MCF-7 and MDA-MB-468 cells were cultured in RPMI-1640 Medium with 10% FBS 100 U/ml penicillin, 100 μg/ml streptomycin. All cells were cultured at 37° C. using a humidified 5% CO2 incubator. Flow Cytometry 10×105 cells (SKBR-3, MCF7, and MDA-MB-468) were plated. Trastuzumab-peptide crosslinker was prepared as previously mentioned. Trastuzumab-peptide conjugate and/or biotinylated MMAE were then conjugated to avidin at 1:3, 2:2, and 3:1 molar ratio. Cells were dosed with 40 ng/mL modified or naked antibodies for 2 hours at 37° C. Cells were trypsinized, washed with PBS, and incubated with anti-human IgG Fe Cy3 secondary antibody (Thermo, Waltham, Mass.) for 1 hour on ice in the dark. Cells were then washed with cold PBS and resuspended for flow cytometry analysis using a FACScan system (Becton Dickinson, San Jose, Calif.). Cells (breast carcinomas SKBR-3, trastuzumab insensitive breast cancer line MCF7 and antigen negative breast cancer cell line, MDA-MB-468 (100,000 cells per sample) were incubated at 37° C. with 40 ng/ml conventional or DS conjugated trastuzumab for 2 hrs in 2 mL total volume. After this incubation, cells were washed and then incubated with anti-human IgG Fc Cy3 secondary antibody (1 h on ice in dark). PBS+1% FBS+2 mM EDTA were used as dilution buffer for secondary antibody. Cells were then washed and analyzed by flow cytometry (Becton Dickinson, San Jose, Calif.). 3×104 cells (SKBR-3 and Jurkat) were plated in a 48 well plate. Trastuzumab-peptide crosslinker was prepared as previously mentioned. Trastuzumab-peptide conjugate and/or biotinylated. LLP2A were then conjugated to SAPE at 4:1 molar ratio. The bispecific samples were conjugated at 3:1:1 molar ratio (trastuzumab-peptide:LLP2A:SAPE). Cells were dosed with (1) 750 nM Trastuzumab-peptide, (2) 250 nM LLP2A, or (3) 750 nM Trastuzumab-peptide/LLP2A conjugate for 1 hr. SKBR-3 cells were trypsinized; Jurkat cells were removed. All cells were washed with cold PBS and resuspended in PBS for flow cytometry analysis using the FACScan system (Becton Dickinson, San Jose, Calif.). Cryo Electron Microscopy The Trastuzumab-peptide crosslinker conjugate was prepared as previously mentioned. Prior to crosslinking, the sample was dialyzed to remove any unbound peptide. Antibody-peptide conjugates were mixed with streptavidin nanogold (Nanoprobes, Yaphank, N.Y.) at 3:1 ratio for 20 min. After optimizing sample concentration, 3 μl of aliquot of specimen was applied on carbon-coated copper grids that had been glow discharged and then stained with 2% uranyl acetate. The specimen was examined under a JEM-2100 transmission electron microscope (JOEL, Peabody, Mass.) and images were recorded on a TVIPS 4×4 CCD camera TemCam-F415, Gauting, Germany) with a step size of 1.2 Å at the specimen space. Results and Discussion The increasing interest in antibody drug conjugates and bispecific antibodies presents great need for site specific linkers to control conjugation to antibodies. Here, we present a small molecule peptide crosslinker that has the ability to covalently conjugate to an amino acid within or near the nucleotide binding pocket located in the Fab portion of monoclonal and polyclonal antibodies (IgG, IgE, etc.). This simple conjugate allows for the addition of ligand or a toxic payload to be easily adapted for the emergence of antibody drug conjugates or bispecific antibodies. Design and Screening of a Peptide Library The design of a site-specific conjugation peptide is based on targeting the nucleotide-binding pocket (NBP) in IgG antibodies. In our studies, trastuzumab was used as the model monoclonal antibody. Based upon previous molecular modeling data22 and the Fab domain crystal structure of trastuzumab30, we located the NBP with H101, H103 and L36 as the amino acids interacting with indole-3-butyric acid. In this NBP, numerous lysine residues were found surrounding the indole-3-butryate binding site (FIGS. 1a, b). Based upon this structural characteristic, a small library of compounds was examined (Table 1, FIG. 12) by comparing the docking conformations and energies to the NBP. Taking advantage of the lysine residues located within this NBP, we expected to have enhanced affinity of indole-3-butryate to the NBP by including negatively charged amino acids in the library (Table 2). The energy characterizations obtained from Autodock25 indicated that the crosslinker located on the lysine directly next to indole-3-butryic acid was preferred over other conformations (Table 1). Compounds with amino acids between the indole-3-butryate and Lys(crosslinker) had less optimal mean cluster binding energies. Results of this in silico screen predicted that indole-3-butryate-Lys(acrylic acid)-Glu would bind with the highest affinity to the NBP. Using this knowledge, we designed eight OBOC libraries to screen for compounds with enhanced affinity and crosslinking ability to the NBP. TABLE 1 Energy calculations derived from computer modeling of test compounds used in Autodock. Lowest energy indicates the predicted binding energy by Autodock. All crosslinkers are located in ε-amine of lysine unless otherwise denoted. Structures of test compounds are depicted in FIG. 12 Mean Lowest Cluster Binding Binding Targeting Energy Energy compound X1 X2 X3 (kcal/mol) (kcal/mol) Indole K(xlinker) −6.69 −5.28 Indole K(xlinker −6.97 −5.82 (α-amine)) Indole P K(xlinker) −5.14 0.48 Indole G K(xlinker) −5.47 −1.99 Indole P G K(xlinker) −3.18 5.37 Indole K(xlinker) D −5.8 −4.86 Indole K(G-xlinker) G D −5.34 −1.78 Indole K(x-linker) E −6.68 −5.78 Indole K(xlinker) Aad −5.49 −2.81 Indole K(xlinker) G D −5.79 −2.42 Indole K(xlinker) G E −5.11 −3.61 TABLE 2 Amino acids used in the library Ala Phe Aic Nva Asn Pro Ana (Nov-1) Orn HCl Asp Ser Bpa Phe(3-Cl) Gln Thr Cha Phe(4-Me) Glu Trp Chg Phe(diCl) Gly Tyr Dpr Phg His Val HoCit Tyr(dil) Ile 4-Apc HoPhe Leu Acpc Nal-2 Met Alb Nle Libraries based on the results of the in silico screens were synthesized on TentaGel beads using a split-mix technique31. KX1, KX1X2, KX1X2X3, and KX1X2X3X1 libraries N-capped by “indole-butyrate-Lys(crosslinker)” were synthesized with the combination of unnatural and L-amino acids (FIGS. 1c, 13, Table 2). The variable portions of the libraries were synthesized using the split mix technique. Indole-3-butyric acid and 1,5-difluoro-2,4-dinitrobenzene (DNDFB) were then coupled to the lysine side chain. We first tried acrylic acid and cyanuric chloride as the covalent crosslinker; however, these crosslinkers resulted in very high background, which made screening difficult (data not shown). In lieu of these more traditionally used crosslinkers, Marquez24 showed that DNDFB is a mild electrophile that can be used to cross-link naturally occurring proteins via primary amines. With the displacement of the first fluorine with the compound to generate DNFB, the reactivity of the remaining fluorine is significantly lowered allowing for its efficient use in biological applications24. Covalent crosslinking of DNDFB or DNFB to a primary amine is very efficient under slightly basic conditions, making this crosslinker very easy to use and can be broadly used in various therapeutic immunoglobulin conjugates. In order to identify beads that covalently crosslink trastuzumab, we have modified our previously reported enzyme-linked colorimetric screening method32. After incubating trastuzumab with the DNDFB modified bead library at pH 8, we treated the beads with acidic glycine (pH 3.0) buffer to ensure that only covalently linked trastuzumab will remain on the bead. The covalently linked antibody was then detected with anti-human antibody-alkaline phosphatase conjugate followed by the BCIP substrate, Peptide-beads turned green and were physically isolated for microsequencing (FIGS. 1d, 3). All of the DNDFB modified libraries were screened multiple times, ensuring that ˜90% of the members in all forms of the libraries were screened. Several trends were observed from the positive hits (FIG. 3a). Asp and Phe (including its unnatural amino acid derivatives) appears frequently in all forms of the library. In the peptides without Asp, other negatively charged amino acids are found. Multiple Lys residues in the NBP favor the identification of negatively charged amino acids. Although our computational analysis concluded that negatively charged amino acids was the best fit for the NBP, our library included all natural amino acids. Despite this, most of the hits identified consisted of negatively charged amino acids, confirming our original hypothesis. The positive sequences were resynthesized in solid state on TentaGel beads to compare the crosslinking abilities between all of the positive hits (FIG. 3a,b). Similar incubation times and washes were performed as the screening process. After the acidic glycine wash, anti-human IgG conjugated to Cy3 was used to detect the crosslinked trastuzumab. From this assay, several indole-butyrate-Lys(DNFB)-derivatized dipeptides with Asp, Glu, and Phe(2Cl)-Thr-Phe(2Cl)-Gln were found to have superior crosslinking abilities compared to other hits and our negative control (indole-K(DNFB) without peptide). These results were consistent with the results found in the computer-modeling data. In order to understand if the indole-butyrate-peptides were merely a strong binding agent to the NBP or if DNFB was utilized to covalently crosslink with free amines in the NBP, indole-butyrate-peptides were reacted with methylamine and methyl-piperidine. These highly basic compounds react with the free fluorine in DNFB making the peptide compound unreactive and unable to crosslink to the NBP of the immunoglobulin (FIG. 3c). Using similar crosslinking incubation times and staining procedures as the reconfirmation assay, the beads displayed decreased Cy3 intensity when the indole-butyrate-Lys(DNFB)-Asp-Ser linker (DS affinity element) reacted with the highly basic compounds, indicating the crosslinking ability of the DS peptide to IgG. Peptide Crosslinker Characterization To understand the site specificity of our peptide to the NBP, the top two hits (DS affinity element 1 and F(2Cl)-T-F(2Cl)-Q affinity element 2) from the reconfirmation studies were resynthesized in soluble biotinylated form (FIG. 4a). Here, the affinity element is a part of the indole-K(DNFB)-peptide-peg linker-K(biotin) molecule. A negative control peptide (compound 3) without the amino acids peptide sequence was also synthesized. PEG linkers were added between the indole-peptide and biotin to maintain peptide binding and crosslinking ability. The peptide-linker reaction chemistry is shown in FIG. 2. Reducing, denaturing conditions were employed for Western blot analysis to confirm the covalent reactions and to obtain distinguishable bands between unreacted IgG and the cross-linked IgG (FIG. 4b). After 1 hour incubation of 50 μM of peptide crosslinker with 10 μM trastuzumab at pH 7.5, crosslinking was then introduced by raising the pH to 8.5. Biotin-tagged peptide-antibody conjugates were detected at 25 kDa and 50 kDa for all 3 affinity elements, representing covalent ligation to both the heavy and light chains (FIG. 4b). This is expected as residues from both chains form the NBP. Controls (antibody alone and peptide alone) did not show any bands at any molecular weight. The promising hit F(2Cl)-T-F(2Cl)-Q affinity element (2) showed similar results as our negative control (3) (FIG. 4b), Where no differences were observed among the different pH. The faint bands at pH 7.5 indicate some reactivity of DNDFB at neutral pH. DS affinity element (1), however, showed a surprising and dramatic increase of product at pH 8.5. This addition of Asp and Ser is thus proven to dramatically increase the amount of peptides capable of binding to NBP. These results indicate that affinity element is a superior peptide linker that adds superior binding specificity to the targeting moiety and that the addition of DNFB as a cross-linking agent can allow for optimal conjugation to the NBP. The same western blot analysis was performed with bevacizumab, cetuximab, rituximab, and IVIG. Similar results were seen with these antibodies when affinity element 1 was added (FIG. 5) indicating the broad application of our peptide linker. However, decreased activity was seen with cetuximab when compared to bevacizumab, rituximab and WIG suggesting that DS affinity element is not optimal for the NBP in cetuximab. Alves33,34 discovered a indole-3-butryic acid based linker that utilizes UV photocrosslinking to covalently conjugate to the NBP. Due to the lack of peptide sequence to improve specificity, this conjugate requires an increased ratio of linker to antibody for efficient crosslinking (FIG. 14). Site Specificity Characterization Classical peptide mapping techniques were first used to determine the linker conjugation site using trypsin and chymotrypsin for protein digestion of the separated heavy and light chain. Unlike other site specific conjugation linkers which modified one specific amino acid35,36, our peptide linker has the ability to ligate to several free amines that are located within or near the NBP. Similar to results previously found by Wang37, this was problematic for the identification of exact modifications sites since these peptides produced weak MS signals, which are not suitable for this type of analysis. In order to determine site specificity of the novel ligation strategy, we conjugated the DS peptide-biotin to several immunoglobulins, including trastuzumab, IVIG, rituximab, and cetuximab. These immunoconjugates were digested with papain and then further reduced to generate Fab and Fc fragments, which could be resolved on SDS-PAGE. In all of the antibody conjugates, only the Fab portion (FIG. 6a), but not the Fe portion was biotinylated. This is expected since indole-6-butyric acid has binding specificity against the Fab fragment. In a control experiment, we used a sulfa-NHS-biotin, a nonspecific amine reactive reagent (FIG. 6c), to derivatize the same set of antibodies and found that both Fab and Fc fragments were labeled (FIG. 6b). Together, this data prove that our ligation strategy is general, site-specific, ligates to the Fab portion of the immunoglobulin only, and can be applied even to polyclonal IVIG. This indicates the broad application of the DS peptide where it can be applied to site-specifically ligate directly to the Fab in many clinical antibodies without the need to reengineer an antibody and without the use of harsh chemical agent, which is a significant improvement to current site-specific crosslinking technology. Using cryo-electron microscopy, we further imaged our immunoconjugate (FIG. 15) by incubating the antibody conjugate with 5.6 nm streptavidin-nanogold and then performed cryo-electron microscopy. We were able to visualize nanogold (1.4 nm) binding to only the inner arms of IgG, at positions next to both Fab arms (FIG. 15a, b). It appeared that there were two residing sites for nanogold on each Fab arm. One of the nanogolds is localized to the variable domain, which is the known location of the NBP. The other nanogold was located near the constant domain. The distance between two resident sites is about 6 nm; suggesting the flexibility of the peptide and the multiple conjugation sites on streptavidin, as well as the difference of the binding orientation in respect to Fab arm, because the EM image is a two-dimensional projection. The second conjugation site, which appeared to be at the constant domain, can be bound to the NBP but its location in the EM image is a result of the flexibility of the peptide and streptavidin conjugation. It should be noted that no binding was seen in the Fc arm or on the outer portion of the Fab further demonstrating consistency of site-specific conjugation. These two sites were also observed when F(ab)2 fragments were imaged. The nanogold was again found at positions close to the variable domain (FIG. 15c,d). In all cases, the nanogold is at a distance equivalent to one streptavidin from the Fab arm again confirming the site specificity provided by the combination of the indole targeting moiety and the peptide affinity element. These imaging studies were repeated and similar results were obtained (data not shown). Our antibody-linker conjugate (trast-DS) produced a homogenous conjugate (FIG. 7a) on a nonreducing SDS-PAGE gel indicating no loss of interchain disulfide bonds through peptide conjugation as seen in some site specific conjugates. With the abundance of primary amines on IgG, DNDFB and DNFB can potentially randomly react with any of the primary airlines on the surface of the antibody. The absence of additional products indicates that conjugation did not occur randomly but was site-specific. The trast-DS conjugate was digested with pepsin and covalent ligation was maintained in the F(ab)2 arms (FIG. 7b). Again, a homogenous product was seen, further indicating the low probability of nonspecific binding. The reactivity of DS affinity element was further investigated to explore optimal conditions for the crosslinking reaction. The optimal pH of the reaction was studied as shown in FIG. 7d. After 1 h the bands had increasing intensity as the pH was increased from 7.5 to 8.5 with the most products seen in 8.5. Beyond pH 8.5, no additional products were found (FIG. 16a). We further analyzed the optimal time for conjugation. Within 15 minutes of increased pH there is no difference in the amount of product created (FIG. 16b). In order to understand the efficacy of our peptide, we used different ratios of DS peptide to trastuzumab to discover the most efficient combination (FIG. 7c). It was observed that at molar ratios above 2.5 DS peptide: 1 trastuzumab, no additional products were seen on the western blot analysis. This saturability of binding further proves the site specificity of the targeting moiety affinity element combination. Through these optimization steps, it was found that at a 2.5:1 molar ratio of compound to antibody is sufficient for efficient ligation at pH 8.5 in 15 minutes. We further analyzed our antibody conjugate by quantifying the number of peptide linker conjugated to each antibody. The antibodies conjugated to biotinylated DS affinity element were subjected to quantitative assay with a biotin quantification assay (Table 3). Free avidin was mixed with 4′-hydroxyazobenzene-2-carboxylic acid (HABA) that forms a complex that is a yellow chromophore with molar extinction coefficient 34000 M−1.cm−1 at 500 nm, However, biotin has much higher binding coefficient towards avidin than that of HABA. When biotin conjugated materials are mixed with the HABA-avidin complex, biotin replaces HABA to give a biotin-avidin complex that barely absorbs light at 500 nm. Thus, the chromophore concentration decreases. By measuring the absorbance difference at 500 nm using UV-Vis spectroscopy, the number of avidin-accessible biotin can be calculated. Using this method, we estimated that ˜2 DS affinity elements were attached to each antibody, which corresponds to the two NBP that are found within each monoclonal IgG antibody. This number of conjugates per antibody is similar to other known site-specific antibodies2,38,39,40. As expected, the nonspecific sulfo-NHS-biotin conjugate can randomly react with different lysine side chains on the surface of the antibodies tested. TABLE 3 This table indicates the number of the biotin per monoclonal antibody. Using a HABA-avidin complex with our conjugated biotinylated antibodies, the difference in absorbance at 500 nm is proportional to the number of biotin per antibody. Our DS peptide retains the site specificity that has an average biotin per antibody ratio between 1 and 3, whereas the positive control, NH2- reactive biotin to monoclonal antibodies, has an average of 5 to 8 biotin molecules conjugates to each antibody. mAb-NHS mAb-DS mAb avidin-HRP Bevacizumab # of biotin 4.47 2.3 0 1.401 Cetuximab # of biotin 7.98 2.77 0 1.401 Rituximab # of biotin 6.58 2.1 0 1.401 IVIG # of biotin 9.09 2.21 0 1.401 Trastuzumab # of biotin 6.33 1.6 0 1.401 An important factor to understand is the crosslinking efficiency of the indole:DS peptide:DNFB containing compound to trastuzumab. The tract-DS-biotin conjugate was generated as described above and incubated with neutravidin at 4:1, 10:1, and 30:1 ratios. Using size exclusion chromatography, the percentage of peptide that is able to conjugate to trastuzumab was determined. Comparing to a standard, we were able to determine the free trastuzumab, monomer (1 trastuzumab antibody, DS-biotin, and neutravidin), dimer/trimer (2-3 trastuzumab antibodies, 2-3 DS-biotins, and neutravidin), and tetramers (4 trastuzumab antibodies, 4 DS-biotins, and neutravidin) that were created by mixing trast-DS-biotin with neutravidin. Using area under the curve (AUC) to estimate the relative amount of each Ab-neutravidin complex, the number of free trastuzumab to the various conjugated forms was extrapolated. The reaction between affinity element and immunoglobulin was highly efficient with 79% of the antibodies crosslinked (FIG. 8a-d) when 5 molar excess of peptide to trastuzumab was used. The lack of absolute conjugation efficiency can result from peptides incorrectly oriented in the binding site thereby limiting the access of DNFB to the free amines within the NBP. In Vitro Characterization The site-specific ligation of a nucleotide binding pocket ligand targeting moiety in combination with a peptide affinity element containing linker and a cross-linking agent has broad utility. For example, cytotoxins can be easily conjugated to the C-terminus of the peptide affinity element, e.g., directly or through one or more ethylene glycol linker moieties, for the production of ADCs. As another example, ligands can be easily conjugated to the C-terminus of the peptide affinity element, e.g., directly or through one or more ethylene glycol linker moieties, to create bispecific antibodies. We demonstrated the ability of the targeting moiety, affinity element, cross-linking agent combination to be applied to other clinical antibodies thereby proving its application for many disease applications. Conjugation of a compound to the NBP which has close proximity of to the antigen binding site is a cause of concern. This proximity has the potential to affect the antigen binding ability. We tested the Trast-DS conjugate for binding to SKBR3, MCF7, and MDA-MB-468 cells. SKBR3 cells have a high expression of Her2 receptors, MCF7 cells have moderate Her2 expression, while MDA-MB-468 cells do not have Her2 expression (FIG. 17), The antigen binding ability of Trastuzumab and Trast-DS was confirmed using flow cytometry. (FIG. 9a-c). By detection with Cy3 labelled anti-human IgG secondary antibody, Trast-DS did not display any fluorescent shift. TrastDS-MMAE, an immunotoxin generated through our conjugation method also retained the antigen binding ability (FIG. 9d-f). Both Her2 expressing cell lines showed similar binding affinity and specificity to the unmodified antibody. In order to determine the ability of the DS affinity element to serve as a conjugate linker, trast-DS was conjugated with biotinlyated MMAE with neutravidin thereby creating a cytotoxic mAb (FIG. 10). Anti-Her2-trastuzumab conjugated with MMAE were tested on Her2-expressing breast cancer cells for cytotoxicity (MCF7 cells and SKBR3 cells) and Her2 negative cells (MDA-MB-458) for selectivity. Cell viability of the three cell lines was compared with controls (neutravidin-biotin-MMAE complex and Trast-DS) and TrastDS-MMAE conjugates. SKBR3 and MCF7 cells showed decreased cell viability in a dose dependent manner compared to MDA-MB-468 cells, which was not significantly affected by the MMAE conjugation. Due to the valine-citrulline linker attached to the biotin-MMAE, the free drug is released only when biotin-MMAE complex is internalized38. This was confirmed when severe cytotoxicity was not observed in all three cell lines with the avidin-biotin-MMAE control. However, trastDS conjugates showed increased cytotoxicity in SKBR3 and MCF7 cells proving that MMAE (an antineoplastic agent) is effectively entering the cell in the Her2(+) cells and inhibiting the assembly of microtubule. This difference is likely resulting from the increased binding of trastuzumab to Her2(+) cells and the internalization of the cytotoxic antibody conjugate. It should be noted, however, MDA-MB-468 displayed some levels of nonspecific cytotoxicity. The immunoconjugates depicted a certain extent of receptor dependent cytotoxicity and provides a proof of concept that our site-specific conjugation technique serves as a good platform for target delivery of cytotoxic reagents. This technology can be applied to other conjugates, such as radioactive ligand conjugates or immunomodulin molecule conjugates. We conjugated a ligand to the C-terminus of a compound containing a targeting moiety (e.g., indolyl), cross-linking agent (e.g., DNFB), and affinity element containing linker (e.g., DS-peptide), thereby creating a mAb that targets two antigens. In order to understand the multi-targeting ability of our IgG conjugate, trastDS was incubated with biotinylated LLP2A41 and streptavidin PE (SAPE) at 3:1:1 ratio (trastDS:LLP2A: SAPE), LLP2A is a peptidomimetic compound with the ability to bind to α4β1 integrin on Jurkat cells. We added this TrastDS/LLP2A conjugate at 750 μM to SKBR-3 and Jurkat cells (FIG. 11) for 1 hr. The TrastDS/LLP2A conjugate was able to bind to both Jurkat and SKBR-3 cells. No loss of affinity was seen with SKBR-3 cells but some binding affinity was lost with the Jurkat cells, which may have resulted from the steric hindrance created from the antibody as measured by flow cytometry. Meanwhile, the control trastuzumab peptide bound only to SKBR-3 cells and not Jurkat cells. Similarly, the control LLP2A only bound to Jurkat cells and saw no binding with SKBR-3 cells. Here we have confirmed the bispecific nature of our compound that through the use of the peptide can produce binding to streptavidin, The TrastDS:LLP2A compound can be utilized to facilitate delivery of NK cells and T-cells to the tumor site for immunotherapy. CONCLUSION With the increased interest in covalent conjugation to antibodies, much effort has been placed into this technology to site-specifically control conjugation of a therapeutic pay-load to monoclonal antibodies producing homogeneous products. Heterogeneity in conjugation to antibodies results in toxicity and antibody instability2. We exploited previous knowledge on NBP reported by Rajagopalan et al20 by employing OBOC combinatorial chemistry and novel screening strategy to develop NBP targeting compound that contains a targeting moiety and a linker containing a dipeptide affinity element in combination with a cross-linking agent. This targeting compound can site-specifically ligate therapeutic pay-load to the two NBPs on an antibody molecule, or an NBP containing antibody fragment. Through proximity ligation, the compound can be covalently linked to the immunoglobulin through the built-in dinitrofluorobenzene cross-linking agent, under very mild conditions, where 79% of antibodies are crosslinked within 15 minutes. This conjugation results in a homogenous product that does not affect the thiol stability of the antibody, which is unseen with other nonspecific chemical crosslinkers. Although the indole-Lys(DNFB)-Asp-Ser-containing compound can efficiently derivatize IVIG, it is less efficient with Centuximab. This indicates that more than one, and perhaps a few affinity elements and/or targeting moiety combinations may be needed to cover the NBPs of the entire spectrum of immunoglobulins. Therapeutic payloads can be introduced to the immunoglobulins via two general approaches: (i) direct site-specific ligation to antibody NBPs of a compound conjugated to a therapeutic payload, or (ii) site-specific ligation of azide-derivatized affinity element, followed by introduction of therapeutic payload via click chemistry13. Compared to other site-specific covalent modifications, this technique is mild, highly efficient, and can be used for many clinically available antibodies. This technique is simple and should be readily scalable, thereby shortening optimization time and can be quickly adapted for manufacturing antibody drug conjugates or bispecific antibodies. One unique feature of this antibody conjugation strategy is that it can be applied to polyclonal antibodies such as IVIG, making it possible to introduce pathogen-specific ligands to IVIG, generating neutralizing antibodies against infectious microbes, such as the Ebola virus. REFERENCES (1) Carter, P. 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G.; Abdiche, Y.; Zhou, D.; Chandrasekaran, R.; Samain, C.; Loo, C.; Rossi, A.; Rickert, M.; Krimm, S.; Wong, T.; Chin, S. M.; Yu, J.; Dilley, J.; Chaparro-Riggers, J.; Filzen, G. F.; O'Donnell, C. J.; Wang, F.; Myers, J. S.; Pons, J.; Shelton, D. L.; Rajpal, A. Chemistry & biology 2013, 20, 161. (41) Peng, L.; Liu, R. W.; Marik, J.; Wang, X. B.; Takada, Y.; Lam, K. S. Nat. Chem. Biol. 2006, 2, 381. Example 2 Synthesis and Characterization of Antibody Conjugates With Maleimide Cross-Linker Trastuzumab, bevacizumab, rituximab, and nivolumab were individually conjugated to a compound containing a maleimide (M) cross-linking agent, and an aspartate-serine-containing linker (DS), herein referred to as an MDS compound (e.g., FIG. 19). The MDS compound (50 μM) was incubated with 10 μM antibody at 37° C. (pH 7.5) for 1 h in a shaking incubator. Cross-linking occurred by increasing the pH of the sample to 8.5 and incubating for 1 h at room temperature, thereby forming Trast-MDS or TMDS, BMDS, RMDS, and NMDS, respectively. In some cases, the MDS compound contained a biotinylated active agent. Samples were then dialyzed overnight at 4° C. to remove unbound peptides, with frequent water changes. Compounds containing a maleimide cross-linking agent, an aspartate-serine-containing linker, and 1, 2, or 4 dihydroxyphenylalanine (DOPA) functional groups, herein referred to generically as MDS-DOPA and specifically as MDS-1DOPA, MDS-2DOPA, and MDS-4DOPA respectively. Successful synthesis was confirmed by mass-spectrometry (See, FIGS. 20, 22, and 32). Trastuzumab was conjugated to MDS-1DOPA, MDS-2DOPA, and MDS-4DOPA. MDS-DOPA compounds (50 μM) were independently incubated with 10 μM trastuzumab at 37° C. (pH 7.5) for 1 h in a shaking incubator. Cross-linking occurred by increasing the pH of the sample to 8.5 and incubating for 1 h at room temperature, thereby forming Trast-MDS-1DOPA, Trast-MDS-2DOPA, and Trast-MDS-4DOPA. Samples were then dialyzed overnight at 4° C. to remove unbound peptides, with frequent water changes. Trast-MDS-(DOPA, Trast-MDS-2DOPA, and Trast-MDS-4DOPA were individually incubated with BA-MMAE peptide (FIG. 18) at 1:10 ratio at pH 8.5 for 1 hour at room temperature, thereby forming Trast-MDS-1DOPA-BA-MMAE (FIG. 21, R represents trastuzumab), Trast-MDS-2DOPA-BA-MMAE (FIG. 23, R represents trastuzumab), and Trast-MDS-4DOPA-BA-MMAE (FIG. 33, R represents trastuzumab). Samples were then dialyzed overnight at 4° C. to remove unbound peptides, with frequent water changes. TMDS, BMDS, RMDS, and NMDS containing a biotin active agent were analyzed by western blotting with anti-biotin detection reagent, gel electrophoresis with coomassie blue detection reagent, and biotin quantification assay with HABA biotin complex (FIG. 24). The results indicated that the MDS compound retains site specificity and has an average biotin per antibody ratio approximately 2, whereas the positive control, NH2-reactive biotin to monoclonal antibodies, has an average of 5-10 biotin molecules conjugates to each antibody. Trast-MDS was analyzed to determine the efficiency of the maleimide cross-linking reaction (FIG. 25). Conjugation efficiency is determined by comparing the band intensity between lane 7/10 and lanes 2/3/4 of FIG. 25. The results indicated that greater than 90% of the MDS compound conjugated to trastuzumab under the experimental conditions. Trastuzumab-MDS-DOPA-BAMMAE conjugates were tested for in vitro cell killing (FIG. 26). Cells (A: SKBR3; B: MCF7; C: SKOV3) were incubated with Trast-MDS conjugated with Moronic Acid MMAE. In cell lines with HER2 triple positive expression (SKBR3 and SKOV3), decreased cell viability was seen for antibodies with MMAE conjugation. In the cell line that has lower HER2 expression (MCF7), this effect was not as pronounced. (D) IC50 values for Trastuzumab-1/2/4DOPA-BA-MMAE and Trastuzumab alone. Example 3 Synthesis and Characterization of Bi-Specific Antibody Conjugates The anti-PD-1 checkpoint inhibitor antibody Nivolumab was conjugated to a cancer cell targeting ligand LXY30 to generate NMDS bi-functional antibody conjugates for enhanced effector cell killing as depicted in the schematic illustrated in FIG. 27. NMDS preparation: MDS compound (50 μM) was incubated with 10 μM Nivolumab at 37° C. (pH 7.5) for 1 h in a shaking incubator. Cross-linking occurred by increasing the pH of the sample to 8.5 by 0.1 N ammonium solution and incubating for 1 h at room temperature, thereby generating NMDS. Samples were then dialyzed overnight at 4° C. to remove unbound peptides, with frequent water changes. NMDS-LXY30 preparation: Biotinlyated. LXY30 is synthesized, purified and lyophilized prior to complex formation in lam lab. Bi-functional NMDS-LXY30 immuno-conjugate is formed with 3:1:1 ratio between biotinlyted LXY30, Streptavidin-Alexa488 and NMDS or biotinlyted LXY30, NeutrAvidin and NMDS respectively in PBS at room temperature for 20 minutes. Electrophoresis: 5 μg biotinylated LXY3O, NMDS, Strepavidin Alexa 488, and generated bi-functional immunoconjugate were loaded onto a 4-12% Tris-glycine gel (Life Technologies, Inc., Gaithersburg, Md.) under non-reducing condition. Bands were detected later by Coomassie blue staining and GFP fluorescent channel. Size Exclusion Chromatography (SEC): 5 μg of each samples were subjected analysis on SEC chromatography. The results are depicted in FIG. 28. In FIG. 28, panel a., one homogeneous band under non reducing condition electrophoresis analysis in lane 4 is both detected by Coomassie blue staining and GFP fluorescent channel, demonstrating the successful generation of bi-functional NMDS-LXY30 immunoconjugate with biotinlyted LXV30, Streptavidin-Alexa488 and NMDS. In panel b. an extra peak found under size exclusion chromatography analysis with bi-functional NMDS-LXY30 sample comparing to nivolumab only. By calculating the peak retention time, the molecular size of extra peak yields 200 KDa, which is very close to the predicted MW for hi-functional NMDS-LXY30 immunoconjugate, 210 KDa. The extra shoulder peak on the bi-functional sample represents extra neutrAvidin in the complex, yields at 60 KDa. The NMDS-LXY30 immunoconjugate was tested for tumor targeting and in vitro cell killing. SKOV3, and U87 cells were plated in 48-well plates at 20000 cells per well and allowed to adhere overnight at 37° C. in a humidified atmosphere of 5% CO2. 4% PFA were then used to fix the cells for 20 minutes at room temperature after the seeding. Cell were stained with 1 μg/ml bi-functional conjugates and followed by 500 ng GST tagged PD-1 protein for one hour at room temperature. Anti-GST horseradish peroxidase (HRP) and 3,3′-diaminobenzidine (DAB) were incubated sequentially for color development. Similar immunohistochemistry was performed on SKOV3 cells with 1 mg/ml biotin-LXY30, followed by avidin-HRP and DAB as positive control. The results are depicted in FIG. 29. In FIG. 29, picture 1, and picture 2, the only color change is found in panel D, demonstrating that the generated hi-functional conjugates bind to PD-1 protein. The location of the color deposit demonstrates the in-functional conjugates also bind with integrin (α3β1) expressed on the target cell membrane. The table shows results of several control experiments designed to rule out false positive results from cross reactivity within the reagents. Picture 3 shows the color deposit preferentially located on the cell membrane, when target cells are incubated with biotin-LXY30 and detected with avidin HRP/DAB, as in the bi-functional conjugate experiment. In vitro cytotoxicity assays were performed to analyze the effect of the NMDS-LYX30 bi-functional immunoconjugate on T cell targeting of an α3β1 integrin expressing target cell. Target cells (SKOV3) were labeled with GFP. The labeled target cells were plated in 6-well plates at 30000 cells per well and allowed to adhere overnight at 37° C. in a humidified atmosphere of 5% CO2. PBMCs were isolated from healthy volunteer donor and activated with anti-CD3, anti-CD28 (1 g/ml) for 72 hours prior to co-incubation with target cells. The activated PBMCs were co-cultured with target cells at E:T=10:1 ratio for 12 hours at 37° C. in a humidified atmosphere of 5% CO2 with or without 100 ng/ml immunoconjugates contained medium. At the end of the incubation, the cells were lifted by trypsin and collected from the plate. The cells were resuspended in equal volume of PBS containing 2% FBS, 1 mmol/L EDTA, Propidium iodine (PI) and Annexin V-APC for 15 minutes. The fluorescent intensity of GFP, PI and APC were recorded by a FACs machine. 10000 events of target cells were recorded by gating GFP positive channel. The percentage of live/dead cells was calculated by the different cell population containing different amount of annexin V or PI. The number of dying target cells and dead target cells were increased by 14.4% with bi-functional immunoconjugate treatment comparing to nivolumab treatment alone, indicating that the bi-functional conjugates improved anti-tumor therapeutic effect. The results are depicted in FIG. 30. Soluble perforin (Cell Sciences), and granzyme B (eBioscience) were detected from growth media at three different incubation time, 4 hours, 12 hours and 24 hours by ELBA according to the manufacture's protocols. Effector cells:target cells ratio=10:1 with or without 100 ng/ml immunoconjugates contained medium. The results are depicted in FIG. 31. Elevated perforin and granzyme B level were detected from the media at all three different time points with bi-functional incubation indicating that the improved anti-tumor therapeutic effect is due to cytotoxic T cell killing pathway. It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes. | <SOH> BACKGROUND OF THE INVENTION <EOH>Non-specific ligation methods have been traditionally used to chemically modify immunoglobulins. Site-specific ligation of compounds (detectable labels, toxins, or ligands) to antibodies has become increasingly important in the fields of therapeutic antibody-drug conjugates and bispecific antibodies. | <SOH> BRIEF SUMMARY OF THE INVENTION <EOH>In a first embodiment, the present invention provides a compound comprising: i) a targeting moiety that specifically binds a nucleotide binding pocket of an antibody; ii) a cross-linking agent; iii) an active agent or a conjugating agent; and iv) a linker, wherein the linker covalently links: a) the targeting moiety, b) the cross-linking agent, and c) the active agent or conjugating agent. In a second embodiment, the present invention provides a method for covalently conjugating an antibody to a molecular payload, wherein the molecular payload comprises any of the compounds described herein, the method comprising: a) forming a reaction mixture comprising the antibody and the molecular payload under conditions suitable to form a non-covalent binding interaction between a nucleotide binding pocket of the antibody and a targeting moiety of the molecular payload, wherein the reaction mixture is an aqueous solution having a pH of less than about 7.5; and b) raising the pH of the reaction mixture above about 8.0, under conditions suitable to form a covalent bond between the antibody and the cross-linking agent. | A61K4765 | 20171006 | 20180524 | 90995.0 | A61K4765 | 0 | VAJDA, KRISTIN ANN | SITE-SPECIFIC COVALENT CHEMICAL LIGATION TO MONOCLONAL AND POLYCLONAL IMMUNOGLOBULIN | SMALL | 1 | CONT-ACCEPTED | A61K | 2,017 |
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15,727,820 | PENDING | POLYMER MATRIX COMPOSITIONS COMPRISING A HIGH CONCENTRATION OF BIO-FERMENTED SODIUM HYALURONATE AND USES THEREOF | The present invention relates to stable polymer matrix compositions comprising high concentrations (from about 1.5% w/w to about 3.5% w/w) sodium hyaluronate obtained from a Streptococcus zooepidemicus source and a non-ionic polymer. The polymer matrix composition further comprises polyethylene glycol and methylparaben, and utilizes ingredients that are of pharmaceutical or compendial grade. The polymer matrix compositions may optionally comprise an active ingredient. The present polymer matrix compositions may be used in the treatment of wounds, burns, certain dermatological conditions, vaginal dryness, and in topical, transdermal delivery and sustained release of active ingredients. | 1. A polymer matrix composition comprising: about 1.5% w/w to about 3.5% w/w bio-fermented sodium hyaluronate, about 0.1% w/w to about 2.0% w/w non-ionic polymer, and water; wherein the sodium hyaluronate in the gel is stable upon storage for at least 6 months at 40° C. and 75% relative humidity and/or for at least 18 months at 25° C. and 60% relative humidity. 2. The polymer matrix composition of claim 1, further comprising at least one active ingredient. 3. The polymer matrix composition of claim 2, wherein the at least one active ingredient is selected from the group consisting of pantothenic acid, diclofenac sodium, niacin and glycerin. 4. The polymer matrix composition of claim 1, wherein the bio-fermented sodium hyaluronate is of pharmaceutical grade according to the European Pharmacopoeia, has an average molecular weight between about 600,000 Daltons to about 800,000 Daltons, has nucleic acid content of less than or equal to 0.5%, has protein content of less than or equal to 0.3%, Total Combined Yeast and Mould Count (TYMC) of less than or equal to 10 cfu/g, Bacterial Endotoxin Test (BET) score of less than or equal to 0.5 IU/mg, and tests absent for Staphylococcus aureus, Pseudomonas aeruqinosa, Escherichia coli, and Salmonella sp. 5. The polymer matrix composition of claim 1, wherein the non-ionic polymer is selected from a group consisting of polyvinylpyrrolidone, poloxamer, copovidone, polyvinyl alcohol, cellulose derivatives, sorbitol based polymer, locus bean gum, guar gum, maltodextrin, vinyl pyrrolidone copolymer, polyacrylamide, polyethylene oxide copolymer, neutralized polyacrylic acid, polysorbate, ethoxylates, polyalcohols, polyethylene glycol, methoxy methoxypolyethylene glycol (MPEG) alpha, omega-dialkyl-ethoxylates, and mixtures thereof. 6. The polymer matrix composition of claim 1, wherein the non-ionic polymer is hydroxyethylcellulose. 7. The polymer matrix composition of claim 6, wherein the hydroxyethylcellulose is of pharmaceutical grade and has a Total Aerobic Microbial Count (TAMC) of less than 100 cfu/g. 8. The polymer matrix composition of claim 1, further comprising polyethylene glycol (PEG). 9. The polymer matrix composition of claim 8, wherein the PEG is present in an amount of from about 2% w/w to about 4% w/w, has a combined ethylene glycol and diethylene glycol content of less than or equal to 0.25% w/w, and/or wherein the amount of PEG having a molecular weight of at least 400 is less than 5 weight % by total weight of the PEG. 10. The polymer matrix composition of claim 9, wherein the PEG has a combined ethylene glycol and diethylene glycol content of less than or equal to 0.25%, TAMC of less than 100 cfu/mL and TYMC of less than or equal to 10 cfu/mL. 11. The polymer matrix composition of claim 8, wherein the bio-fermented sodium hyaluronate is present in an amount of 2.3 to 2.7% w/w, the non-ionic polymer is hydroxyethylcellulose and is present in an amount of 0.5 to 1.5% w/w, and the polyethylene glycol is present in an amount of 2 to 4% w/w. 12. The polymer matrix composition of claim 11, wherein the bio-fermented sodium hyaluronate is present in an amount of 2.5% w/w, the hydroxyethylcellulose is present in an amount of 1% w/w, and the polyethylene glycol is present in an amount of 3.0% w/w. 13. The polymer matrix composition of claim 8, wherein: the bio-fermented sodium hyaluronate is of pharmaceutical grade according to the European Pharmacopoeia, has an average molecular weight between about 600,000 Daltons to about 800,000 Daltons, has nucleic acid content of less than or equal to 0.5%, has protein content of less than or equal to 0.3%, Total Combined Yeast and Mould Count (TYMC) of less than or equal to 10 cfu/g, Bacterial Endotoxin Test (BET) score of less than or equal to 0.5 IU/mg, and tests absent for Staphylococcus aureus, Pseudomonas aeruqinosa, Escherichia coli, and Salmonella sp.; the non-ionic polymer is pharmaceutical grade hydroxyethylcellulose and has a Total Aerobic Microbial Count (TAMC) of less than 100 cfu/g; the polyethylene glycol (PEG) is of pharmaceutical grade, wherein the average molecular weight of the PEG is 200 and wherein the PEG has a combined ethylene glycol and diethylene glycol content of less than or equal to 0.25%, TAMC of less than 100 cfu/mL and TYMC of less than or equal to 10 cfu/mL; and the water is purified having a TAMC of less than 100 cfu/mL and a BET score of less than 0.25 EU/mL. 14. The polymer matrix composition of claim 13, further comprising an active ingredient is selected from the group consisting of pantothenic acid, diclofenac sodium, niacin and glycerin. 15. The polymer matrix composition of claim 3, wherein the active ingredient is diclofenac sodium. 16. A method of treatment comprising topically applying the polymer matrix composition of claim 3, thereby treating a condition selected from the group consisting of post-operative incisions, dermatological conditions, burns, damaged skin, atopic dermatitis, vaginal dryness, actinic keratosis and musculoskeletal pain. 17. The method of claim 16, wherein the active ingredient is delivered transdermally by the topically applying. 18. The method of claim 16, wherein the active ingredient is pantothenic acid and the condition is damaged skin or atopic dermatitis. 19. The method of claim 16, wherein the active ingredient comprises niacin and glycerin and the condition is vaginal dryness. 20. The method of claim 16, wherein the active ingredient is diclofenac sodium and the condition is actinic keratosis and musculoskeletal pain. | FIELD OF THE INVENTION The present invention relates to polymer matrix compositions comprising sodium hyaluronate. More particularly, the present invention relates to polymer matrix compositions comprising sodium hyaluronate obtained from a bacterial source and that are useful in the treatment of wounds and incisions, treatment of pain, transdermal delivery of active ingredients, sustained release of active ingredients, and preparation of personal lubricants. BACKGROUND OF THE INVENTION Hyaluronic acid (HA) is a naturally occurring mucopolysaccharide (also commonly referred to as glycosaminoglycan). It has been isolated by various methods from numerous tissue sources including vitreous humor, skin, synovial fluid, serum, chicken combs, shark skin, umbilical cords, tumors, hemolytic streptococci from pigskin, whale cartilage, and the walls of veins and arteries. HA may, however, also be synthesized artificially or made by recombinant technology. Moreover, it is known that HA may also be manufactured by fermentation of selected Streptococcus zooepidemicus bacterial strains (see U.S. Pat. No. 4,517,295 issued to Bracke et al.), and can readily be converted to its sodium salt. The repeating unit of the HA molecule is a disaccharide consisting of D-glucuronic acid and N-acetyl-D-glycosamine. Because HA has a negative charge at neutral pH, it is soluble in water, where it forms highly viscous solutions. Fractions of HA, including its sodium salt, are known to foul′ a stable polymer matrix when combined with a non-ionic polymer such as hydroxyethyl cellulose or hydroxypropyl cellulose. Such polymer matrix formulations are known to be useful in preparing compositions for various applications for human and animal use. For example, a formulation containing sodium hyaluronate and hydroxyethylcellulose was formerly marketed under the name of Ionic Polymer Matrix (IPM) Wound Gel for applying to wounds to promote wound healing. In addition, polymer matrices of HA formulated with other active ingredients are known to be useful as topical drug formulations for delivering the active ingredients to sites below the dermal level of the skin. HA polymer matrix topical active ingredient formulations for trans-dermal delivery of active ingredients are disclosed for example in U.S. Pat. No. 5,897,880, U.S. Pat. No. 6,120,804, U.S. Pat. No. 6,387,407, and U.S. Pat. No. 6,723,345. HA polymer matrices formulated with other active ingredients are also known to be useful as formulations for sustained release of the pharmaceutical agents. HA polymer matrix formulations for sustained release delivery of active ingredients are disclosed in U.S. Pat. No. 6,063,405, U.S. Pat. No. 6,335,035, and U.S. Pat. No. 6,007,843. Preparing sodium hyaluronate polymer matrix formulations presents many challenges. Initially, in the 1980s only HA obtained from animal sources was available commercially, and many of the formulations were delivered by injection, or used as drops in the eye, rather than for topical use for dermatological conditions. The natural HA used in various formulations has usually been obtained from rooster combs. The rooster comb (also known as a chicken comb) is an avian source and as such is of animal origin. As a result, sodium hyaluronate formulations manufactured using sodium hyaluronate from rooster combs have been known to cause allergies and carry other risks associated with products of animal origin, namely a risk of transmission of animal diseases to humans. Consequently, the currently approved topical products containing sodium hyaluronate formulations available on the market are contra-indicated for those patients who are hypersensitive to sodium hyaluronate of animal origin. Moreover, sodium hyaluronate is difficult to formulate in high concentrations above 1.5% w/w, due to the difficulty in manufacturing a formulation that maintains stability and is not too viscous for normal use when packaged in a tube. For this reason many of the commercial formulations on the market have a concentration of HA or sodium hyaluronate well below 1% w/w, and many in fact have a concentration at around 0.2% w/w. To the inventors' knowledge, there are no products currently on the market that contain more than 1.5% w/w sodium hyaluronate. When not mixed and manufactured properly, a high HA or sodium hyaluronate concentration formulation will quickly break down, and therefore the percentage of HA or sodium hyaluronate in the formulation will fall below the acceptable limit (+/−10% of original amount), resulting in a very short shelf life for the product. Formulations containing a high concentration of sodium hyaluronate therefore present a challenge due to the instability of the matrix. This results in inconsistencies in the matrix formulation and impairs the ability of sodium hyaluronate formulations to perform their functions. For example, when applied to wounds to promote healing, a sodium hyaluronate polymer matrix formulation helps to maintain a moist wound environment, an effect that is dependent on the formulation maintaining its high level of sodium hyaluronate concentration. The maintenance of a moist wound environment is widely recognized to positively contribute to wound healing. However, due to their instability and the resulting drop in the level of sodium hyaluronate that occurs as the formulation breaks down, high concentration sodium hyaluronate formulations are not effective in maintaining a moist environment. When formulated for the delivery of a drug, the inconsistency of high concentration sodium hyaluronate formulations reduces the ability of such formulations to allow the drug to diffuse through the tissue when administered, thereby impairing their ability to achieve the therapeutic dose. In addition, the sodium hyaluronate polymer matrix formulation product formerly marketed under the name of Ionic Polymer Matrix (IPM) Wound Gel was withdrawn from the market due to problems with the formulation. Therefore, a need exists for a method for formulating a sodium hyaluronate polymer matrix containing a high concentration of sodium hyaluronate that can be manufactured and sold commercially. SUMMARY OF THE INVENTION The present invention relates to stable polymer matrix compositions, preferably pharmaceutical compositions, comprising a high concentration (for example, from about 1.5% to about 3.5% w/w) of sodium hyaluronate obtained from a bacterial source such as Streptococcus zooepidemicus or Bacillus subtilis source. Sodium hyaluronate obtained from a bacterial source is referred to hereinafter as “bio-fermented” sodium hyaluronate. The compositions further comprise a non-ionic polymer optionally in an amount of from about 0.1% to about 2% w/w, polyethylene glycol, methylparaben and water. By “stable”, as used herein, it is meant that the amount of sodium hyaluronate in the formulation does not vary by more than +1-10% (w/w) relative to the original amount provided in the composition, at 40° C., 75% relative humidity (accelerated stability conditions) for a period of at least 6 months, and/or at 25° C., 60% relative humidity (long-term stability conditions) for a period of at least 18 months. The amount of sodium hyaluronate may be measured by HPLC techniques known in the art of pharmaceutical development. In one aspect of the present invention, the polymer matrix compositions of the present invention comprise components which are of compendial (USP or Ph. Eur.) and/or of pharmaceutical grade. These terms are discussed further below. Preferably, all the components of the compositions are of compendial and/or of pharmaceutical grade. In a further aspect of the invention, the polymer matrix compositions comprise components of certain specifications. In one aspect, polymer matrix compositions of the present invention may be used in the treatment of wounds, burns, and certain dermatological conditions. In another aspect of the present invention, the polymer matrix compositions comprise an active ingredient. In this aspect of the invention, the polymer matrix compositions may be used for trans-dermal delivery, topical delivery, and sustained release delivery of the active ingredient. In some aspects, the polymer matrix compositions may be used for the treatment of musculoskeletal pain. A further aspect of the present invention relates to the use of the polymer matrix compositions in the treatment of vaginal dryness. In a further aspect, the present invention relates to methods for preparing stable polymer matrix compositions of the present invention. DETAILED DESCRIPTION OF THE INVENTION The inventors determined that the product IPM Wound Gel could not be successfully formulated because the product was made from naturally sourced sodium hyaluronate (“natural sodium hyaluronate”) and because the testing regimen was not sufficient and raw materials were not of sufficient quality. The natural sodium hyaluronate was produced from rooster combs (which is an animal origin source) and was of cosmetic grade. The natural sodium hyaluronate was found to be more prone to microbiological contamination including that from the manufacturing facility and surrounding environment. This led to microbiological failure of the product rendering the product unsafe and not useful. Moreover, the product IPM Wound Gel used ingredients that were of insufficient or inconsistent grade. Also, testing to determine the quality of the IPM Wound Gel Product was insufficient to ensure a stable product of sufficient quality. The inventors unexpectedly discovered that sodium hyaluronate polymer matrix compositions can be advantageously formulated using bio-fermented sodium hyaluronate obtained from strains of Streptococcus zooepidemicus or Bacillus subtilis bacteria. The inventors further determined that sodium hyaluronate polymer matrix compositions can be advantageously formulated by using ingredients of sufficient quality, i.e., ingredients of compendial (USP or Ph. Eur.) and/or pharmaceutical grade, including bio-fermented sodium hyaluronate. An ingredient or component of pharmaceutical grade, as provided herein, may be defined as an ingredient or a component having at least 99% purity, preferably not containing binders, fillers, excipients, dyes, or unknown substances. In some embodiments, an ingredient of pharmaceutical grade additionally meets one or more of the following criteria: the ingredient has an endotoxin level of 0.5 EU/mg or less (or 0.5 EU/ml or less for liquid ingredients), the ingredient has a total aerobic microbial count (TAMC) of less than 100 cfu/g, (or less than 100 cfu/ml for liquid ingredients), the ingredient has a total yeast and mold count (TYMC) of less than 10 cfu/g (or less than 10 cfu/ml for liquid ingredients), the ingredient has a nucleic acid content of 0.5% w/w or less, and the ingredient has a protein content of 0.3% w/w or less. Methods of measuring endotoxin levels, TAMC, TYMC, nucleic acid levels and protein levels would be known to the person skilled in the art of pharmaceuticals. An ingredient or component of compendial grade refers to a grade of ingredient with full compendial testing as appropriate to the USP (US Pharmacopoeia), NF (National Formulary), BP (British Pharmacopeia) or Ph. Eur. (European Pharmacopeia), thus meeting chemical purity standards which are established by these recognized national or regional pharmacopeia authorities. Typically, an ingredient or component which is of compendial grade will also be of pharmaceutical grade. Validated assays methods for testing the amount of sodium hyaluronate and methylparaben in the formulations, as well as through compliance with Bacterial Endotoxin Test (“BET”), and microbiological test limits, including for Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, and Salmonella sp., as well as compliance with other parameters, have been used to confirm the quality of the formulations of the present invention. The present inventors have unexpectedly found that compositions according to the present invention have improved stability (i.e. the concentration of sodium hyaluronate in the formulation does not vary by more than +/−10% (w/w) relative to the original amount provided in the composition, at 40° C., 75% relative humidity (accelerated stability conditions) for a period of at least 6 months, and/or at 25° C., 60% relative humidity (long-term stability conditions) for a period of at least 18 months), improved wound-healing properties, and reduced cytotoxicity effects relative to comparable compositions comprising natural sodium hyaluronate which may be obtained from an avian source and non-pharmaceutical and/or non-compendial grade components (e.g. IPM Wound Gel). It is believed that the stability, wound-healing properties and cytotoxicity of the composition of the invention are improved with the use of bio-fermented sodium hyaluronate, and even further improved by the use of components which are of compendial and/or pharmaceutical grade. The inventors further developed a process for formulating a polymer matrix composition containing a high concentration (i.e., between about 1.5% w/w to about 3.5% w/w) of sodium hyaluronate and produced a stable polymer matrix composition containing a high concentration of sodium hyaluronate according to the present invention. Additionally, provided herein is a formulation obtained by the process. In some embodiments, the process comprises the steps: a) Adding methylparaben to water and mixing to produce a methylparaben solution, b) Adding bio-fermented sodium hyaluronate to the methylparaben solution and mixing to produce a sodium hyaluronate solution, c) Separately dissolving the non-ionic polymer, optionally hydroxycellulose, in water to produce a non-ionic polymer solution, d) Combining the sodium hyaluronate solution with the non-ionic polymer solution and mixing to produce a homogenous sodium hyaluronate non-ionic polymer solution, e) Adding polyethylene glycol to the sodium hyaluronate non-ionic polymer solution and mixing to form the polymer matrix composition. Typically, the polymer matrix composition obtained by the method comprises from about 1.5% w/w/to about 3.5% w/w bio-fermented sodium hyaluronate and from about 0.1% w/w to about 2.0% w/w non-ionic polymer, in addition to polyethylene glycol, methylparaben and water. The method may further comprise a step of adding at least one active ingredient selected from: pantothenic acid, diclofenac sodium, niacin and glycerin. Each of the components used in the process may be of compendial grade and/or pharmaceutical grade as defined herein. Preferably, all the components of the composition are of compendial grade and/or pharmaceutical grade. Each of the components may also be provided in the amounts defined herein and may have the properties (e.g. purity) defined herein. Sodium hyaluronate (CAS Number: 9067-32-7, molecular formula [C14H20N11Na]n) consists of a linear polysaccharide, whose basic unit is a disaccharide of D-glucuronic acid and N-acetyl-D-glucosamine linked by a glucuronidic (1-3) bond. The disaccharides units are linearly polymerized by hexosaminidic (1-4) linkages, as shown in Formula 1: Sodium hyaluronate is a white or almost white, very hygroscopic powder or fibrous aggregate. It is odorless and the pH of the 5% solution is in the range of 5.0-8.5. Sodium hyaluronate is easily soluble in cold water and insoluble in organic solvents. Sodium hyaluronate of high quality, i.e., BET≦0.5 EU/g microbial quality, may be obtained from commercial suppliers. The process of obtaining bio-fermented sodium hyaluronate can vary, but in general, the preparation involves the following steps: fermenting selected Streptococcus zooepidemicus bacterial strains; selecting the sodium hyaluronate crude product obtained from fermentation; purifying the crude product by filtration; precipitating sodium hyaluronate with an organic solvent; and drying. Bio-fermented sodium hyaluronate obtained from Streptococcus zooepidemicus is available commercially from suppliers such as QUFU, Freda, and Contipro. As an example, U.S. Pat. No. 4,517,295 to Bracke et al. discloses the preparation of hyaluronic acid in high yield from Streptococcus bacteria by fermenting the bacteria under anaerobic conditions in a CO2 enriched growth medium, separating the bacteria from the resulting broth and isolating the hyaluronic acid from the remaining constituents of the broth. Separation of the microorganisms from the hyaluronic acid is facilitated by killing the bacteria with trichloroacetic acid. After the removal of the bacteria cells and concentration of the higher molecular weight fermentation products, the hyaluronic acid is isolated and purified by precipitation, re-suspension and re-precipitation. One particular fraction of bio-fermented sodium hyaluronate that exhibits excellent matrix formation according to the present invention is sodium hyaluronate having an average molecular weight between about 600,000 Daltons to about 800,000 Daltons. Bio-fermented sodium hyaluronate having an average molecular weight of 500,000 to 1,000,000 Daltons has also been found to be acceptable in the formulations of the present invention. In addition to bio-fermented sodium hyaluronate, polymer matrix formulations of the present invention include a non-ionic polymer. Non-ionic polymers suitable for use in formulations of the present invention include polyvinylpyrrolidones, poloxamers, copovidone, polyvinyl alcohol, cellulose derivatives, sorbitol based polymers, locus bean gum, guar gum, maltodextrin, vinyl pyrrolidone copolymers, polyacrylamides, polyethylene oxide copolymers, neutralized polyacrylic acids, polysorbates, ethoxylates, polyalcohols, polyethylene glycol, methoxy methoxypolyethylene glycol (MPEG) and alpha, omega-dialkyl-ethoxylates, or mixtures thereof. Polyvinylpyrrolidones suitable for use with the present invention include PVP K-90, PVP K-17, and polyvinyl pyrrolidone-vinyl acetate (PVP-VA) copolymer. Cellulose derivatives suitable for use with the present invention include hydroxyethylcellulose, hydroxypropylmethylcellulose, ethyl(hydroxyethyl)cellulose, and methyl cellulose. Sorbitol based polymers suitable for use with the present invention include Neosorb. Polyacrylic acids suitable for use with the present invention include, but not limited to neutralized Carbopol 980, Carbopol 940 and Carbomer 981 (Old type Carbomer 941). Polysorbates suitable for use with the present invention include Polysorbate 20 (USP/Ph. Eur.), Polysorbate 21, Polysorbate 40 (USP/Ph. Eur.), Polysorbate 60 (USP/Ph. Eur.), Polysorbate 61, Polysorbate 65, Polysorbate 80 (USP/Ph. Eur.), Polysorbate 81, Polysorbate 85, and Polysorbate 120. Hydroxyethylcellulose (“HEC”) is a particularly preferred non-ionic polymer for use with the present invention. It is believed that there are many such non-ionic polymers that can be used to successfully form the polymer matrix formulations of the present invention. As such, included in the present invention are any non-ionic polymers that can successfully form a polymer matrix with sodium hyaluronate. Other suitable ingredients for use in the manufacture of the polymer matrix compositions of the present invention include stabilizers and fillers such as methylparaben, benzyl alcohol, polyethylene glycol, methoxypolyethylene glycol, and purified water. Preferably, ingredients used in the bio-fermented sodium hyaluronate polymer matrix compositions of the present invention conform to the compendial standards (USP or Ph. Eur.) In a preferred embodiment, the bio-fermented sodium hyaluronate used in the compositions of the present invention is of compendial or pharmaceutical grade quality. More preferably, all raw materials used in the formulations of the present invention are of high microbiological quality (i.e. of compendial and/or pharmaceutical grade). In contrast, in the IPM Wound Gel comprising sodium hyaluronate of animal origin, the individual components do not meet the compendial and/or pharmaceutical grade standards. The following Table 1 compares the changes made in specifications of raw materials from the formulation used in the product IPM Wound Gel to the formulation of the present invention. TABLE 1 Changes to specifications of raw materials used in the formulation of the present invention in comparison to those used in the product IPM Wound Gel. Sodium hyaluronate bio-fermented IPM Wound Gel formulation of the present invention Sodium hyaluronate Grade: Cosmetic grade Grade: Pharmaceutical grade (Ph. Eur.) Nucleic acid: ≦0.5% (Ph. Eur.) Protein content ≦5% Protein content ≦0.3% (Ph. Eur.) TYMC ≦50 cfu (colony TYMC ≦10 cfu/g (Ph. Eur.) forming units)/g E. coli: Negative Staphylococcus aureus: Absence (Ph. Eur.) Pseudonionas aeruginosa: Absence (Ph. Eur.) Escherichia coli: Absence (Ph. Eur.) Salmonella sp.: Absence (Ph. Eur.) Bacterial Endotoxin Test (BET) ≦0.5 IU/mg Hydroxyethylcellulose (HEC) TAMC (Total Aerobic TAMC <100 cfu/g (USP/Ph. Eur.) Microbial Count) <1000 cfu/g Polyethylene Glycol 200 (PEG 200) PEG 200 or PEG 400 PEG 200 Limit of ethylene glycol and diethylene glycol (combined): 5 0.25% w/w (USP) — TAMC <100 cfu/mL (USP) TYMC ≦10 cfu/mL (USP) Methylparaben TAMC <100 cfu/mL (USP/Ph. Eur.) TYMC ≦10 cfu/mL (USP/Ph. Eur.) Purified water TAMC <100 cfu/mL (USP/Ph. Eur.) BET <0.25 EU/mL (USP/Ph. Eur.) The grade of PEG used with IPM Wound Gel was intermittently PEG 400 which may have reduced the stability of the product. The matrix formed was less stable than the formulation of the present invention. The PEG used with the preferred embodiment of formulations of the present invention is of better purity in that the restricted substances, namely, ethylene glycol and diethylene glycol are well controlled. Optionally, the PEG used in formulations of the present invention and specifically, in the methods of preparing the formulations, comprises ethylene glycol and diethylene glycol in a combined amount of less than 0.25% w/w. Preferably, the average molecular weight (mass average and/or number average) of the PEG used in formulations of the present invention and in the methods of preparing the compositions, is 200 Da. (This is referred to hereinafter as “PEG 200 grade”.) In some embodiments, the average molecular weight (mass average and/or number average) of the PEG is not less than 190 or more than 210. In some embodiments, the amount of PEG having a molecular weight of at least 400 Da is less than 5, 4, 3, 2 or 1 weight % by total weight of the PEG. In some embodiments, the PEG is present in the formulations in an amount of from about 0.5% to about 10% w/w, or from about 1% to about 5% w/w, or from about 2% to about 4% w/w, or about 3% w/w. Sodium hyaluronate used with the IPM Wound Gel was of cosmetic grade and did not meet compendial and/or pharmaceutical grade requirements as defined herein. In the preferred embodiment, the present invention uses sodium hyaluronate of pharmaceutical grade and/or compendial grade with consistent quality. Preferably, the sodium hyaluronate has a low content of nucleic acid and protein (e.g. a nucleic acid content of 0.5% w/w/or less and/or a protein content of 0.3% w/w or less). In the preferred embodiment of the present invention, the TYMC microbial count is better controlled (e.g. 10 cfu/g or less), and all the specified microorganisms are tested for their absence. Additionally, in the preferred embodiment of the present invention, BET is tested and is 0.5 EU/mg or less, and the protein content of sodium hyaluronate has been significantly reduced (e.g. from 5% w/w or less for IPM Wound Gel to 0.3% w/w or less for the preferred embodiment of the present invention). In regard to HEC used in the preferred embodiment of the present invention, there is a better control of microbial count (e.g. the HEC has a TAMC of less than 100 cfu/g) than with the HEC used with IPM Wound Gel (e.g. the HEC has a TAMC of less than <1000 cfu/g) provided by the raw material supplier. Hence the formulation of the present invention in the preferred embodiment was found to be significantly better quality. In the preferred embodiment of the present invention, methylparaben raw material is tested for TAMC and TYMC tests to ensure that only good quality raw material is used in the manufacture of the formulation in the preferred embodiment of the present invention. For example, the TAMC and TYMC of the methylparaben is preferably 10 cfu/ml or less. The methylparaben may be present in the formulations of the present invention in an amount of from about from about 0.01 to about 0.3% w/w, from about 0.1 to about 0.3% w/w or about 0.2% w/w. Additionally, in the preferred embodiment of the present invention, purified water is better controlled microbiologically by performing additional tests TAMC and BET. For example, the TAMC of water is 100 cfu/ml or less, and/or the BET of water is 0.25 EU/ml or less. The bio-fermented sodium hyaluronate polymer matrix formulation is a clear viscous, odorless, aqueous gel composed principally of sodium hyaluronate, a derivative salt of hyaluronic acid. The formulation of bio-fermented sodium hyaluronate is a polymer matrix made up of negatively charged polymer, namely, sodium hyaluronate, and a non-ionic polymer, such as HEC. In other words, sodium hyaluronate (as a negatively charged polymer) forms part of the polymer matrix in combination with a non-ionic polymer, such as HEC, and it helps to maintain the moist environment through the matrix. The concentration of sodium hyaluronate in the polymer matrix is from about 1.5% to about 3.5% w/w, or from about 2% to about 3% w/w, or from about 2.3% to 2.7% w/w, or about 2.5% w/w. The concentration of the non-ionic polymer, other than HEC, is from about 0.1% w/w to about 2.0% w/w, preferably from about 0.5% to 1.5% w/w, and more preferably, from about 0.7% w/w to about 1.3% w/w. In some embodiments, the non-ionic polymer is present in an amount of about 1% w/w. The concentration of HEC may be from about 0.1% w/w to about 2.0% w/w, or from about 0.1% w/w to about 1.5% w/w, preferably from about 0.5% to 1.5% w/w, and more preferably, from about 0.7% w/w to about 1.3% w/w. Preferably, non-ionic polymers such as HEC are of compendial or pharmaceutical grade, as defined above. Where non-ionic polymers are not available in compendial or pharmaceutical grade, non-ionic polymers of best available quality should be used. The viscosity of bio-fermented sodium hyaluronate polymer matrix formulation should be in the acceptable limits or range so that the matrix is stable and is easy to apply on the skin, wound, or other tissue. The formulation should also have a viscosity that can be handled easily during manufacturing and filling. The viscosity range has been investigated. It was determined that the formulation of the present invention should have a viscosity of about 10,000 to 50,000 cps (cP) when tested at room temperature (23° C., 77° F.). The therapeutically useful pH range of the formulation was set at 5.0 to 7.0. In a preferred embodiment, the polymer matrix composition of the present invention may comprise bio-fermented sodium hyaluronate in an amount of from about 2.3 to about 2.7% w/w, non-ionic polymer, preferably hydroxycellulose, in an amount of from about 0.5 to about 1.5% w/w, polyethylene glycol in an amount of from about 1 to about 4% w/w, and methylparaben in an amount of from about 0.1 to about 0.3% w/w. Most preferably, the bio-fermented sodium hyaluronate polymer matrix formulation comprises sodium hyaluronate (2.5%, w/w), HEC (1% w/w), methylparaben (0.2% w/w), polyethylene glycol (3%, w/w) and purified water, USP (approx. 93%, w/w). In preferred embodiments, all the components/ingredients are of compendial grade and/or pharmaceutical grade as defined herein. The test results found that in a particular embodiment, the average viscosity of this bio-fermented sodium hyaluronate formulation is 30,000 cps, i.e. exactly in the middle of the range (10,000-50,000 cps), at room temperature. It is well known that molecular weight of sodium hyaluronate and concentration of sodium hyaluronate have a direct effect on the viscosity of the product. The solutions used to prepare the gels of the present invention may be prepared in a variety of ways. The non-ionic polymer such as HEC may be dissolved in water, mixed with anionic or negatively charged sodium hyaluronate solution to form the sodium hyaluronate/non-ionic polymer matrix, and then the optional active ingredient may be added or loaded to the system. The preparation procedure may involve dissolving a non-ionic polymer such as HEC in water at a low speed (from about 25 rpm to less than about 400 rpm) to medium speed (from about 400 rpm to less than about 2000 rpm) for a few hours (about 1 to about 2 hours). Separately, sodium hyaluronate may be slowly added to water while stirring at high speed, followed by stirring at medium speed (from about 400 rpm to less than about 2000 rpm) for a few hours (about 2 hours), followed by stirring at low speed from about 25 rpm to less than about 400 rpm for a long duration (overnight, or about 8 hours to about 15 hours) until all of the sodium hyaluronate polymer has dissolved into the mixture and a crystal-clear viscous solution has formed. The non-ionic polymer such as HEC solution may be added to the sodium hyaluronate solution and mixed at medium speed (from about 400 rpm to less than about 2000 rpm) followed by mixing at low to medium speed (from about 25 rpm to less than about 2000 rpm) for a long period (from about 4 hours to about 15 hours) until a homogenous solution is produced. Conventional pharmaceutically acceptable emulsifiers, suspending agents, solvents (such as polyethylene glycol 200), antioxidants (such as sodium meta-bisulfate) and preservatives (such as benzyl alcohol, methylparaben) may then be added to this system. When formulated with an active ingredient as a system for transdermal or sustained release of the active ingredient, using safe techniques, the active ingredient (e.g., 3% diclofenac sodium) may be slowly added to the above sodium hyaluronate/non-ionic polymer matrix mixture while increasing the speed to high speed (from about 2000 rpm to about 3000 rpm), and the addition of the entire quantity of the active ingredient should be completed within a short duration (about 15 minutes). Once all the components are blended together, such as by mixing at low speed (from about 25 rpm to less than about 400 rpm) to medium speed (from about 400 rpm to less than about 2000 rpm) for about 2 hours to about 20 hours, the system is filled into tubes. The resulting system is clear to slightly hazy, colourless, viscous, odorless gel which are found to be stable on storage for a few years (from 18 months to 4 years). Preferably, a No-fermented sodium hyaluronate polymer matrix formulation according to the invention is prepared as follows. First, add methylparaben to water in a suitable container and mix at medium speed (from about 400 rpm to less than about 2000 rpm) for few hours (about 2 hours). Ensure that methylparaben is completely dissolved. Then slowly add sodium hyaluronate in a steady flow to the mixture gradually increasing the stirring speed from medium speed (from about 400 rpm to less than about 2000 rpm) to high speed (from about 2000 rpm to less than about 3000 rpm) as the mixture thickens and the spin stays while charging sodium hyaluronate in a suitable container (for about 1 hour). Mix for few hours (about 2 hours) at medium speed (from about 400 rpm to less than about 2000 rpm). Continue the mixing at low speed (from about 25 rpm to less than about 400 rpm) for long duration (about 8 hours) until all of the sodium hyaluronate polymer has dissolved into the mixture and a crystal-clear viscous solution has formed. In a separate container dissolve the HEC (e.g. 1%) in purified water while stirring at medium speed (from about 400 rpm to less than about 2000 rpm) and mix well. Continue stirring for a few hours (from about 1 to about 2 hours). The resulting HEC solution is added to the sodium hyaluronate solution and mixed at medium speed (from about 400 rpm to less than about 2000 rpm) followed by low speed (from about 25 rpm to less than about 400 rpm) for a long period (about 4 hours) until a homogenous solution is produced. Add polyethylene glycol into the mixture while mixing at a medium speed (from about 400 rpm to less than about 2000 rpm). Continue mixing at medium speed for about 1 hour. Reduce the speed and continue mixing at low speed (from about 25 rpm to less than about 400 rpm) for a few hours (minimum of about 3 hours). The bulk gel may then be filled in tubes or bottles and capped. Further provided is a polymer matrix composition obtained by this method. In some embodiments, the formulations of the invention as defined herein further comprise an active ingredient. Thus, the methods of preparing the formulations defined herein may comprise a further step of adding an active ingredient. For example, specifically provided is a stable polymer matrix composition comprising 1.5% w/w bio-fermented sodium hyaluronate, 1.0% w/w hydroxyethylcellulose, 3.0% w/w polyethylene glycol, 0.2% w/w methylparaben, 1.5% w/w pantothenic acid, and water. Preferably, each component is of compendia) grade and/or of pharmaceutical grade. More preferably, the bio-fermented sodium hyaluronate is of pharmaceutical grade according to the European Pharmacopoeia, has nucleic acid content of less than or equal to 0.5%, has protein content of less than or equal to 0.3%, TYMC of less than or equal to 10 cfu/g, BET score of less than or equal to 0.5 IU/mg, and tests absent for Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, and Salmonella sp.; the hydroxyethylcellulose has a TAMC of less than 100 cfu/g; the polyethylene glycol is of PEG 200 grade and has a combined ethylene glycol and diethylene glycol content of less than or equal to 0.25%, TAMC of less than 100 cfu/mL and TYMC of less than or equal to 10 cfu/mL; the methylparaben has a TAMC of less than 100 cfu/mL and TYMC of less than or equal to 10 cfu/mL; and the water is purified having a TAMC of less than 100 cfu/mL and a BET score of less than 0.25 EU/mL. A method of making such a composition comprises the steps: Adding methylparaben to water and mixing at medium speed for about 2 hours until completely dissolved to produce a methylparaben solution; Adding bio-fermented sodium hyaluronate to the methylparaben solution in a steady flow gradually increasing the stirring speed from medium to high as the mixture thickens and the spin stays while charging sodium hyaluronate; Mixing for about 2 hours at medium speed followed by mixing at low speed about 8 hours to 15 hours; Separately, dissolving hydroxyethylcellulose in water while stirring at medium speed and mixing well; Stirring the hydroxyethylcellulose mixture for about 1 to about 2 hours to produce a hydroxyethylcellulose solution; Adding the hydroxyethylcellulose solution to the sodium hyaluronate solution; Mixing at medium speed until a homogenous solution is produced, followed by mixing at medium speed about 8 hours to 15 hours; Adding polyethylene glycol into the sodium hyaluronate hydroxyethylcellulose solution while mixing at a medium speed for about 1 hour; and Adding pantothenic acid and mixing well at medium speed for about 2 hours until dissolved and the gel is homogenous. “Low”, “medium” and “high” speeds are as defined above. Further provided is a polymer matrix composition obtained by this method. The stable polymer matrix composition comprising 1.5% w/w bio-fermented sodium hyaluronate, 1.0% w/w hydroxyethylcellulose, 3.0% w/w polyethylene glycol, 0.2% w/w methylparaben, 1.5% w/w pantothenic acid, and water as defined herein or obtained by the method described herein may be used in the treatment for damaged skin and/or in the treatment of atopic dermatitis. Further provided is a stable polymer matrix composition comprising: 2.3% w/w bio-fermented sodium hyaluronate, 0.7% w/w hydroxyethylcellulose, 10% w/w methoxypolyethylene glycol, 0.3% w/w methylparaben, 3.0% w/w diclofenac sodium, and water. Preferably, each component is of compendial grade or pharmaceutical grade. More preferably, the bio-fermented sodium hyaluronate is of pharmaceutical grade according to the European Pharmacopoeia, has nucleic acid content of less than or equal to 0.5%, has protein content of less than or equal to 0.3%, TYMC of less than or equal to 10 cfu/g, BET score of less than or equal to 0.5 IU/mg, and tests absent for Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, and Salmonella sp.; the hydroxyethylcellulose has a TAMC of less than 100 cfu/g; the methoxypolyethylene glycol is of USP compendial grade; the methylparaben has a TAMC of less than 100 cfu/mL and TYMC of less than or equal to 10 cfu/mL; and the water is purified having a TAMC of less than 100 cfu/mL and a BET score of less than 0.25 EU/mL. A method of making such a composition comprises the steps: Adding methylparaben to water and mixing at medium speed for about 2 hours until completely dissolved to produce a methylparaben solution; Adding bio-fermented sodium hyaluronate to the methylparaben solution in a steady flow gradually increasing the stirring speed from medium to high as the mixture thickens and the spin stays while charging sodium hyaluronate; Mixing for about 2 hours at medium speed followed by mixing at low speed for about 8 hours until all of the sodium hyaluronate has dissolved to produce a sodium hyaluronate solution; Separately, dissolving hydroxyethylcellulose in water while stirring at low to medium speed and mixing well; Stirring the hydroxyethylcellulose mixture for about 1 to 2 hours to produce a hydroxyethylcellulose solution; Adding the hydroxyethylcellulose solution to the sodium hyaluronate solution; Mixing at medium speed for about 10 to about 15 hours until a homogenous solution is produced; Adding methoxypolyethylene glycol into the sodium hyaluronate hydroxyethylcellulose solution while mixing at a high speed; Mixing at medium speed for about 3 to about 4 hours; and Over a period of about 15 minutes, slowly adding diclofenac sodium while mixing at high speed; and Mixing at medium speed for about 15 to 20 hours. “Low”, “medium” and “high” speeds are as defined above. Further provided is a polymer matrix composition obtained by this method. The stable polymer matrix composition comprising: 2.3% w/w bio-fermented sodium hyaluronate, 0.7% w/w hydroxyethylcellulose, 10% w/w methoxypolyethylene glycol, 0.3% w/w methylparaben, 3.0% w/w dicloflenac sodium, and water as defined herein or obtained by the method defined herein, may be used to treat actinic keratosis and/or to treat musculoskeletal pain. Further provided is a stable polymer matrix composition comprising: 1.5% w/w bio-fermented sodium hyaluronate, 0.7% w/w hydroxyethylcellulose, 3% w/w polyethylene glycol, 0.2% w/w methylparaben, 0.85% w/w niacin, 3% w/w glycerin, and water. Preferably, each component is of compendial grade or pharmaceutical grade. More preferably, the bio-fermented sodium hyaluronate is of pharmaceutical grade according to the European Pharmacopoeia, has nucleic acid content of less than or equal to 0.5%, has protein content of less than or equal to 0.3%, TYMC of less than or equal to 10 cfu/g, BET score of less than or equal to 0.5 IU/mg, and tests absent for Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, and Salmonella sp., the hydroxyethylcellulose has a TAMC of less than 100 cfu/g; the polyethylene glycol is of PEG 200 grade and has a combined ethylene glycol and diethylene glycol content of less than or equal to 0.25%, TAMC of less than 100 cfu/mL and TYMC of less than or equal to 10 cfu/mL; the methylparaben has a TAMC of less than 100 cfu/mL and TYMC of less than or equal to 10 cfu/mL; the water is purified having a TAMC of less than 100 cfu/mL and a BET score of less than 0.25 EU/mL. A method of making such a composition comprises the steps: Adding methylparaben to water and mixing at medium speed for about 2 hours until completely dissolved to produce a methylparaben solution; Slowly adding bio-fermented sodium hyaluronate to the methylparaben solution in a steady flow while gradually increasing the stirring speed from medium to high as the mixture thickens and the spin stays while charging sodium hyaluronate; Mixing for about 2 hours at medium speed following by mixing at low speed about 8 hours to 15 hours until all of the sodium hyaluronate has dissolved to produce a sodium hyaluronate solution; Separately, dissolving hydroxyethylcellulose in water while stirring at low to medium speed and mixing well; Stirring the hydroxyethylcellulose mixture for about 1 to about 2 hours to produce a hydroxyethylcellulose solution; Adding the hydroxyethylcellulose solution to the sodium hyaluronate solution; Mixing at medium speed about 8 hours to 15 hours to produce a homogenous sodium hyaluronate hydroxyethylcellulose solution; Adding polyethylene glycol into the sodium hyaluronate hydroxyethylcellulose solution; Mixing at medium speed for about 2.5 hours; Adding niacin and glycerin; and Stirring at low speed for about 2 hours. “Low”, “medium” and “high” speeds are as defined above. Further provided is a polymer matrix composition obtained by this method. The stable polymer matrix composition comprising 1.5% w/w bio-fermented sodium hyaluronate, 0.7% w/w hydroxyethylcellulose, 3% w/w polyethylene glycol, 0.2% w/w methylparaben, 0.85% w/w niacin, 3% w/w glycerin, and water, as defined herein or obtained by the method defined above may be used in the in the treatment of vaginal dryness. The polymer matrix compositions formulated with bio-fermented sodium hyaluronate of the present invention can be used in the manufacture of pharmaceutical compositions, medical device compositions, natural health product compositions, and dietary supplement compositions. In topical applications, the polymer matrix compositions of the present invention serve to maintain moist wound environment. The maintenance of a moist wound environment is widely recognized to positively contribute to wound healing process and relief from certain dermatological conditions. The polymer matrix compositions formulated with bio-fermented sodium hyaluronate of the present invention may be used for topical applications or transdermal applications. For example, the polymer matrix compositions formulated with bio-fermented sodium hyaluronate of the present invention may be used for topical application in the treatment of many types of ulcers (wounds), including venous stasis, diabetic wounds and diabetic ulcers, and post-operative incisions, and in anti-aging treatments. The invention has shown to be especially effective in hard-to-heal wounds. In particular, the compositions of the present invention are effective in promoting the healing of surgical incisions in diabetic patients. For example, the compositions of the present invention are effective in promoting the healing of surgical incisions in diabetic patients following digit amputations, particularly in diabetic patients suffering from osteomyelitis. More particularly, the polymer matrix compositions formulated in with bio-fermented hyaluronate of the present invention have been shown to be useful in topical applications for the management/treatment of dermatological conditions, burns (1″ degree burns), minor abrasions, minor cuts, and in helping to relieve dry waxy skin irritations association with dry skin conditions. Furthermore, the polymer matrix compositions formulated in with bio-fermented hyaluronate of the present invention have been shown be useful in topical applications for the management of exudating wounds such as leg ulcers, pressure ulcers, diabetic ulcers, surgical wounds (post-operative and donor sites), mechanically or surgically debrided wounds, second degree burns, and the management and relief of burning, itching and pain associated with various types of dermatoses, including atopic dermatitis, allergic contact dermatitis, and radio-dermatitis. In other aspects, the polymer matrix compositions formulated with bio-fermented sodium hyaluronate of the present invention may be also used in the manufacture of a system for a sustained release delivery of an active ingredient, and in the manufacture of a system for topical application, topical delivery or transdermal delivery of an active ingredient. In additional aspects, the polymer matrix compositions formulated with bio-fermented sodium hyaluronate of the present invention can be used in the manufacture of personal lubricants for use in the management of symptoms of female sexual dysfunction. When formulated with an active ingredient as a system for transdermal delivery of an active ingredient, the bio-formulated sodium hyaluronate polymer matrix formulation is believed to form a matrix which microencapsulates, suspends, and/or entraps the active ingredient such that when it is administered, it is slowly released into the systemic circulatory system or muscular tissue providing a method of delivering an active ingredient to an affected site in the body through the skin. The active ingredient may be added either directly to the homogenous solution or gel of sodium hyaluronate and a non-ionic polymer such as HEC or it may be separately dissolved or disbursed in water before addition to the homogenous solution or gel of sodium hyaluronate and a non-ionic polymer such as HEC and mixed well. The active ingredient must be solubilized in the polymer matrix solution in order to be topically administered. Conventional pharmaceutically acceptable excipients well known to those skilled in the art, such as surfactants, suspending agents, emulsifiers osmotic enhancers, extenders and dilutants, pH modifiers as well as fragrances, colors, flavors and other additives may be added to this system. One particularly non-limiting effective material for solubilizing water insoluble drugs is methoxypolyethylene glycol (MPEG). Once all the components are blended together, for medium speed for 1 to 4 hours, the system is filled into tubes or bottles, sterilized, if required, and stored for future use. The formulations of this invention formulated with an active ingredient for topical application, or for topical delivery of an active ingredient or trans-dermal delivery of an active ingredient may potentially be used to treat a variety of mammal and animal conditions and physical states. These systems may have a particular application to pain management, namely the treatment and alleviation of pain associated with any disease, condition or physical state. Without being limited to the specific pain being treated, the preparations of this invention formulated with an active ingredient for topical application/delivery or for transdermal delivery may treat the following non-limiting locations or sources of pain below the dermal level of the skin, including, but not limited to knees, ankles, hands, feet and neck. In addition to treating disorders associated with pain below the dermal level of the skin, the preparations of this invention formulated with an active ingredient for topical application/delivery or for transdermal delivery may be used to treat a wide variety of dermatologic disorders as well as many types of ulcers (wounds) including venous stasis and diabetic wounds. The invention has shown to be especially effective in hard to heal wounds. Exemplary, non-limiting disorders that may potentially be treated with the preparations of this invention formulated with an active ingredient for topical application or transdermal delivery include dermatitis conditions such as: Contact Dermatitis; Atopic Dermatitis; Radio Dermatitis; Seborrheic Dermatitis; Nummular Dermatitis; Chronic Dermatitis of Hands and Feet; Generalized Exfoliative Dermatitis; Stasis Dermatitis; and Localized Scratch Dermatitis; bacterial infections of the skin, such as: Staphylococcal Diseases of the Skin, Staphylococcal Scalded Skin Syndrome; Erysipelas; Folliculitis; Furuncles; Carbuncles; Hidradenitis Suppurativa; Paronychial Infections and Erythrasma; superficial fungal infections such as: Dermatophyte Infections; Yeast Infections; Candidiasis; and Tinea Versicolor; parasitic infections of the skin such as: Scabies; Pediculosis; and Creeping Eruption; disorders of hair follicles and sebaceous glands such as: Acne; Rosacea; Perioral Dermatitis; Hypertrichosis; Alopecia; Pseudofolliculitis Barbae; and Keratinous Cyst; scaling papular diseases, such as: Psoriasis; Pityriasis Rosea; and Lichen Planus; pressure sores; benign tumors and malignant tumors. A wide variety of active ingredients which may be administered topically may be used in the topical or transdermal delivery system according to this invention. These may include drugs from all major categories, and without limitation, for example, anesthetics including benzocaine, tetracaine, mepivacaine, prilocaine, etidocaine, bupivacaine and lidocaine; analgesics, such as acetaminophen, ibuprofen, fluriprofen, ketoprofen, voltaren (U.S. Pat. No. 3,652,762), phenacetin and salicylamide; nonsteroidal anti-inflammatories (NSAIDS) selected from the group consisting of naproxen, acetaminophen, ibuprofen, flurbiprofen, ketoprofen, phenacetin, salicylamide, and indomethacin; antibiotics including amebicides, broad and medium spectrum, fungal medications, monobactams and viral agents and specifically including such as erythromycin, penicillin and cephalosporins and their derivatives; central nervous system drugs such as thioridazine, diazepam, meclizine, ergoloid mesylates, chlorpromazine, carbidopa and levodopa; metal salts such as potassium chloride and lithium carbonate; minerals selected from the group consisting of iron, chromium, molybdenum and potassium; immunomodulators; immunosuppressives; thyroid preparations such as synthetic thyroid hormone, and thyroxine sodium; steroids and hormones including ACTH, anabolics, androgen and estrogen combinations, androgens, corticoids and analgesics, estrogens, glucocorticoid, gonadotropin, gonadotropin releasing, human growth hormone, hypocalcemic, menotropins, parathyroid, progesterone, progestogen, progestogen and estrogen combinations, somatostatis-like compounds, urofollitropin, vasopressin, and others; and vitamins selected from water-soluble vitamins such as B complex including vitamin B5 and B3 (Niacin), vitamin C, vitamin B12 and folic acid and veterinary formulations. Doses may vary from patient to patient depending on the type and severity of the condition being treated and the active ingredient being administered. Generally, doses of 1 ml to 75 ml may be administered with preferred doses using 2 to 25 ml of the gelled matrix system. When formulated with another active ingredient as a system for sustained release of an active ingredient, the bio-formulated sodium hyaluronate polymer matrix formulation may allow an effective therapeutic level of an active ingredient to be administered once over at least a 24 hour to several day interval. It is believed that the bio-formulated sodium hyaluronate polymer matrix formulation forms a matrix which microencapsulates, suspends and/or entraps the active ingredient such that when it is administered it is slowly released into the systemic circulatory system or muscular tissue providing a sustained and prolonged active ingredient release rate. A wide variety of active ingredients may be used in the sustained delivery system according to this invention. These may include drugs from all major categories, and without limitation, for example, anesthetics including those used in caudal, epidural, inhalation, injectable, retrobulbar, and spinal applications, such as bupivacaine and lidocaine; analgesics, such as acetaminophen, ibuprofen, fluriprofen, ketoprofen, voltaren (U.S. Pat. No. 3,652,762), phenacetin and salicylamide; anti-inflammatories selected from the group consisting of naproxen and indomethacin; antihistamines, such as chlorpheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, phenyltoloxamine citrate, diphenhydramine hydrochloride, promethazine, brompheniramine maleate, dexbrompheniramine maleate, clemastine fumarate and triprolidine; antitussive selected from the group consisting of dextromethorphan hydrobromide and guaifenesin; expectorants such as guaifenesin; decongestants, such as phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, ephedrine; antibiotics including amebicides, broad and medium spectrum, fungal medications, monobactams and viral agents and specifically including such as erythromycin, penicillin and cephalosporins and their derivatives; bronchodilators such as theophylline, albuterol and terbutaline; cardiovascular preparations such as diltiazem, propranolol, nifedepine and clonidine including alpha adrenoceptro agonist, alpha receptor blocking agent, alpha and beta receptor blocking agent, angiotensin converting enzyme inhibitors, beta blocking agents, calcium channel blocker, and cardiac glycosides; central nervous system drugs such as thioridazine, diazepam, meclizine, ergoloid mesylates, chlorpromazine, carbidopa and levodopa; metal salts such as potassium chloride and lithium carbonate; minerals selected from the group consisting of iron, chromium, molybdenum and potassium; immunomodulators; immunosuppressives; thyroid preparations such as synthetic thyroid hormone, and thyroxine sodium; steroids and hormones including ACTH, anabolics, androgen and estrogen combinations, androgens, corticoids and analgesics, estrogens, glucocorticoid, gonadotropin, gonadotropin releasing, human growth hormone, hypocalcemic, menotropins, parathyroid, progesterone, progestogen, progestogen and estrogen combinations, somatostatin-like compounds, urofollitropin, vasopressin, and others; and vitamins selected from water-soluble vitamins such as B complex, vitamin C, vitamin B12 and folic acid and veterinary formulations. Dosage forms may also involve the use of bupivacaine, lidocaine, vitamin B12, methyl prednisolone and adenosine-5-monophosphate sodium. The active ingredient may be added directly to the homogenous solution or gel of sodium hyaluronate and a non-ionic polymer such as HEC or else it may be separately dissolved or disbursed in water before addition to the homogenous solution or gel of sodium hyaluronate and a non-ionic polymer such as HEC. Conventional pharmaceutically acceptable excipients well known to those skilled in the art, such as surfactants, suspending agents, emulsifiers osmotic enhancers, extenders and dilutants, pH modifiers as well as fragrances, colors, flavors and other additives may be added to this system. Once all the components are blended together, for medium speed for 1 to 4 hours, the system is filled into tubes or bottles, sterilized, and stored for future use. The dosage form of this invention, in solution or suspension form, may be used topically or by injection intramuscularly, epidurally or subcutaneously. Dosages may vary from patient to patient depending on the type and severity of the condition being treated and drug being administered. The active ingredient must be solubilized in the polymer matrix solution in order to be topically administered. The formulations of this invention formulated with an active ingredient for sustained delivery of an active ingredient may potentially be used to treat a variety of animal conditions and physical states. These systems may potentially have particular application to pain management, namely the treatment and alleviation of pain associated with any disease condition or physical state. Without being limited to the specific pain being treated, the preparations of this invention when formulated with an active ingredient for sustained delivery of an active ingredient may potentially treat the following non-limiting locations or sources of pain: abdominal, such as in appendicitis, dysmenorrhea, musculoskeletal, pelvic, peptic ulcer, psychogenic, and urologic; acute; arm; backache; cancer; cardiac (myocardial ischemia); chest; dental; ear; esophageal; eye; face; head; and neck; in fibromyalgia; foot; and leg; heel; ischemic pain such as in myocardial, peripheral arterial, low back, in mitral valve prolapse, in myocardial infarction, myofascial pain syndrome (fibromyalgia, fibromyositis), neck, neuropathic, neurotransmitter abnormality, nociceptive, and nocturnal pain; pelvic; pericardial; in peripheral arterial disease; phantom limb; pleuritic; polyneuropathy; postmastectomy syndrome; postoperative; psychogenic; in pulmonary embolism; in renal disease, such as colic; root avulsions; shoulder; stump; thalamic; in toes; and toothache. Besides chronic and intractable pain where injections of the formulation of the present invention for sustained delivery of an active ingredient may be required, the present sustained delivery formulations may potentially be used to aid in post-surgical pain treatments. With regard to uses after surgery, the formulations may be used following abdominal, cervical, thoracic or cardiac surgery, whereby multiple layers of tissue, as being sewed back together, are treated with the system. Such treatments may aid in a patient's recovery by not only avoiding addictive drug use such as a morphine drip, but result in the immediate and long term relief of pain to enable rapid rehabilitation. The formulations of the present invention are formulated into pharmaceutically acceptable dosage forms by conventional methods known in the pharmaceutical art. An effective but nontoxic amount of the system is employed in treatment. The dose regimen for administering drugs or treating various conditions may be selected in accordance with a variety of factors including the type, age, weight, sex, and medical condition of the subject, the route of administration and the particular formulation or combination of active ingredients employed. Determination of the proper dose for a particular situation is within the skill of the art. Generally, amounts of the active ingredient may vary from 0.0001% to about 50% by weight of the system. The bio-fermented sodium hyaluronate polymer matrix formulation of the present invention was found to be stable and safer than that used in the known Ionic Polymer Matrix (IPM) Wound Gel based on various testing such as Bacterial Endotoxin Test (BET), biocompatibility tests (Example 1, Example 2, and Example 3) and microbial bio-burden test (Example 7), and is of better quality based on validated chemical test (Example 5 and 6) and stability data of the product at regular interval of time (Example 4). A new BET has been carried out in addition to the existing test methods used with the Ionic Polymer Matrix (IPM) Wound Gel product in order to ensure that the bio-fermented sodium hyaluronate polymer matrix formulation of the present invention meets the acceptable BET test limits and hence potentially reduces the incidence of pyrogenicity in the patients. Previously, there were no BET test limits set for the Ionic Polymer Matrix (IPM) Wound Gel product. Only positive or negative bacterial endotoxin test results were identified. The BET test results carried out with the bio-fermented sodium hyaluronate polymer matrix formulation product and bio-fermented sodium hyaluronate raw material indicated that the products pass the BET test. Both the raw material bio-fermented sodium hyaluronate and the finished bio-fermented sodium hyaluronate polymer matrix formulation product were tested for BET with stringent limits. The BET test were validated. In addition, no microbiological tests for specific microorganisms or the absence of specific microorganisms were previously performed on the Ionic Polymer Matrix (IPM) Wound Gel product. Microbiological testing performed on each batch or lot of the bio-fermented sodium hyaluronate polymer matrix formulation product included all the tests as per USP<61> (Total Aerobic Microbial Count (TAMC) and Total Combined Yeast and Mould Count (TYMC)) and USP<62> (Absence of Staphylococcus aureus, Pseudomonas aeruginosa, E. coli and Salmonella). The product passed these tests. The stability of the bio-fermented sodium hyaluronate polymer matrix formulation has now also been investigated and the product has demonstrated acceptable stability. Previous the test methods used for the determination of sodium hyaluronate and methylparaben in the Ionic Polymer Matrix (IPM) Wound Gel product were found to be not precise, accurate or linear since the test methods were not validated. Validated analytical test methods were also developed and applied to the determination of hyaluronic acid content (see Example 13 and Example 5) and also for the determination of methylparaben content (see Example 14 and Example 6) in the bio-fermented sodium hyaluronate polymer matrix formulation. Application of the bio-fermented sodium hyaluronate polymer matrix formulation was shown in a clinical study showing improvement in closure of incision lines in patients with toe amputations due to diabetes complications (Example 8). In summary, the disclosed process allows for preparing sodium hyaluronate polymer matrix concentration having a high concentration of sodium hyaluronate, i.e., from about 1.5% to about 3.5% w/w. There is a significant improvement in the quality and safety of bio-fermented sodium hyaluronate polymer matrix formulation from the known Ionic Polymer Matrix (IPM) Wound Gel due to the change in the source of sodium hyaluronate from avian (rooster comb) to a bio-fermented source obtained from a bacterial fermentation process. Specifically, the stability of the compositions of the present invention, and the wound-healing properties of the compositions of the present invention are significantly and unexpectedly improved, and the cytotoxicity of the compositions of the present invention is reduced, over compositions comprising natural sodium hyaluronate from avian sources. The use of compendial and/or or pharmaceutical grade raw materials has also been unexpectedly found to further improve the stability, reduce cytotoxicity, and improve wound-healing properties of the compositions. The improvements are evident from the development and application of additional quality testing such as BET and bioburden test (USP 62) and improved Biocompatability test (Cytoxicity test) results, the development and application of test methods for sodium hyaluronate and the preservative methylparaben. Table 2 below summarizes the testing regimen of the formulation of the present invention in comparison to the testing regimen of IPM Would Gel. TABLE 2 Summary of the testing regimen of the formulation of the present invention in comparison to the testing regimen of IPM Would Gel. Sodium hyaluronate bio-fermented IPM Wound Gel formulation of the present invention Bacterial Endotoxin Test BET: Negative BET test limits established. The test method was based old The test method is based on LAL test Rabbit Pyrogenicity test. (Limulus amebocyte lysate test) method which is better quantified. — BET method validated Test for Specified Microorganisms — Test for Specified Microorganisms including: Pseudomonas aeruginosa: Negative Staphylococcus aureus: Negative E. coil: Negative Salmonella: Negative Conducted per USP<62>/Ph. Eur. Validated Test Methods — Analytical test method validated for the determination of sodium hyaluronate content in the sodium hyaluronate bio- fermented formulation. Analytical test method validated for the determination of methylparaben content in the sodium hyaluronate biofermented formulation. Viscosity — Viscosity (η) = 10,000-50,000 cps (recorded). Anti-microbial Effectiveness Test (AET) — AET: Meets USP requirements (stability test) (USP <51>) Methylparahen test Methylparaben test (Limit 90-110%) (stability test) Biocompatibility Test Test for Skin Irritation, Test for Skin Irritation, Guinea pig Guinea pig Maximization Sensitization Test and Maximization Cytotoxicity Test were performed. Sensitization Test and However, Cytotoxicity test showed that Cytotoxicity Test the test article had a smaller zone of were performed. lysis (i.e. less cytotoxic) as compared to the IPM Wound Gel. Stability 1 year long-term stability tested, 18 months long-term stability tested. In the examples below, results of testing of bio-fermented sodium hyaluronate polymer matrix formulation comprising sodium hyaluronate (2.5%, w/w), hydroxyethyl cellulose (1% w/w), methylparaben (0.2% w/w), polyethylene glycol (3%, w/w) and purified water, USP (approx. 93%, w/w) made from raw materials of preferred grades and by preferred process of the present invention (referred to as the “test article”, also referred to “IPM Wound Gel Bio”) are presented. Example 1: Test for Skin Irritation The test article, bio-fermented sodium hyaluronate polymer matrix formulation was evaluated for primary skin irritation in accordance with the guidelines of ISO 10993-10, Biological evaluation of medical devices—Part 10: Tests for irritation and skin sensitization. Two 0.5 mL portions of the test article and control article (namely, saline solution, i.e., 0.9% Sodium chloride solution) were topically applied to the skin of each of three rabbits and left in place for 24 hours. The sites were graded for erythema and edema at 1, 24, 48 and 72 hours after removal of the single sample application. There was no erythema and no edema observed on the skin of the animals treated with the test article. The Primary Irritation Index for the test article was calculated to be 0.0. The response of the test article was categorized as negligible. Example 2: Guinea Pig Maximization Sensitization Test The test article was evaluated for the potential to cause delayed dermal contact sensitization in a guinea pig maximization test. This study was conducted based on the requirements of ISO 10993-10, Biological evaluation of medical devices—Part 10: Tests for irritation and skin sensitization. Dose determination was performed to determine a suitable test article concentration for testing. The test article solution was intradermally injected and occlusively patched to ten test guinea pigs. The control article was similarly injected and occlusively patched to five control guinea pigs. Following a recovery period, the test and control animals received challenge patches of the test solution and the vehicle control article. All sites were scored for dermal reactions at 24 and 48 hours after patch removal. The test article solution showed no evidence of causing delayed dermal contact sensitization in the guinea pig. The test article was not considered a sensitizer in the guinea pig maximization test. Example 3: Cytotoxicity Test The in-vitro cytotoxicity test showed that the test article had a smaller zone of lysis (i.e. less cytotoxic) as compared to the previous known Ionic Polymer Matrix (IPM) Wound Gel. The details of the test performed is provided below: The test article was evaluated to determine the potential for cytotoxicity based on the requirements of ISO 10993-5: Biological evaluation of medical devices—Part 5: Tests for in vitro cytotoxicity. Triplicate wells were dosed with 0.1 mL of the test article placed on a filter (test filter disc). Triplicate wells were dosed with 0.1 mL of 0.9% sodium chloride solution placed on a filter disc (filter disc control). Triplicate wells were dosed with a 1 cm length portion of high density polyethylene as a negative control. Triplicate wells were dosed with a 1 cm×1 cm portion of latex as a positive control. Each was placed on an agarose surface directly overlaying a sub confluent monolayer of L-929 mouse fibroblast cells. After incubating at 37° C. in the presence of 5% CO2 for 24 hours, the cultures were examined macroscopically and microscopically for any abnormal cell morphology and cell lysis. The in-vitro cytotoxicity test showed that the test article had a smaller zone of lysis (i.e., less cytotoxic) as compared to the previously known Ionic Polymer Matrix (IPM) Wound Gel, as shown in Table below. Zone of lysis (mm) Test article IPM Wound Gel Test Disc 1 1 4 Test Disc 2 1 4 Test Disc 2 1 4 Example 4: Stability of Bio-Fermented Sodium Hyaluronate Polymer Matrix Formulation Stability of the test article was studied after incubation at various temperatures and time-intervals. Methods: The concentrations of sodium hyaluronate were measured after incubation periods of various lengths. Other test parameters included appearance test, methylparaben assay, pH and viscosity. Results: Examples of test results for IPM Wound Gel Bio are shown in Table #3a. All concentrations of sodium hyaluronate are in % w/w. Sodium hyaluronate % (w/w) Temperature Month 0 Month 3 Month 6* 25° C. and 60% RH 2.48 2.51 2.52 30° C. and 65% RH 2.48 Not Scheduled 2.53 30° C. and 75% RH 2.48 2.47** 2.55 40° C. and 75% RH 2.48 2.52 2.46 *It has been seen that the response factor of the calibration curve increase during the stability study. This is probably due to absorption of water for the standard. The response factor has increased to 104% from the zero value to the six months value (103% from zero to three months). The results are therefore false higher. **% RSD for 2 in weights (4 injections) 4.25%. All other test parameters were all well within the stability test limits. Further exemplary long-term (18 month) stability test results relating to IPM Wound Gel Bio are provided in Table 1b. The concentration of sodium hyaluronate is expressed as a percentage of the original amount. The tests were performed under standard conditions (25° C. and 60% RH). TABLE 3b Time (months) 0 3 6 9 12 18 Amount of 96.7% 91.4% 93.1% 93.2% 93.4% 94.4% sodium hyaluronate Conclusions: It can be concluded from the results presented above that the test article is stable over a prolonged period as substantiated by the results from the accelerated stability tests at 40° C. and 75% RH, and by the results from the long-term stability tests. In contrast, the control product comprising avian sodium hyaluronate (IPM Wound Gel) failed stability tests conducted after 6 months. Example 5: Method Validation of Determination of Sodium Hyaluronate Content in the Test Article An HPLC method was developed and validated for the determination sodium hyaluronate in the test article. An HPLC System with a UV detector was used. Results and Discussion: The average assay obtained for sodium hyaluronate in the test article was 2.545% w/w and the % relative standard deviation was 0.32. Over a range of 1.14% (or 114 μg/mL) to 3.99% (or 399 μg/mL) the assay showed good linearity with a correlation coefficient greater than 0.999. A precision study showed that the % relative standard deviation was approximately 0.481 for the % Label claim of sodium hyaluronate. Hence the HPLC method used for the determination of sodium hyaluronate content (or assay) has been validated and verified. Example 6: Method Validation for the Determination of Methylparaben Content in the Test Article An HPLC method was validated for the determination methylparaben content in the test article was developed. An HPLC System with a UV detector was used. Results and Discussion: The average assay obtained for methylparaben was 103.3% and the % relative standard deviation was 0.56. Over a range of 0.06% to 0.18% the assay of methylparaben showed good linearity with a correlation coefficient greater than 0.999. A precision study showed that the % relative standard deviation was approximately 0.096 for the Label claim of methylparaben. Hence the HPLC method used for the determination of methylparaben content (or assay) has been validated and verified. Example 7: Antimicrobial Effectiveness Testing (AET) Antimicrobial efficacy testing (AET) measures the effectiveness of antimicrobial preservatives that are added to inhibit the growth of microorganisms that may be introduced inadvertently during the manufacturing process or during product use. Antimicrobial effectiveness testing should be performed on all aqueous-based products that are injectable, ophthalmic, otic, nasal, oral, and topical. The antimicrobial preservative in the test article is methylparaben at target concentration of 0.2% w/w. Methods: The AET was performed on the test article as per USP<51> compendial standard using the all five microorganisms—Escherichia coli (fermentative gram negative bacteria), Pseudomonas aeruginosa (non-fermentative gram negative bacteria), Staphylococcus aureus (gram positive bacteria), Aspergillus niger (mold or fungus) and Candida albicans (yeast). The Antimicrobial Effectiveness Testing was performed on three lots at 18 months' time-point Long-Term Stability Study. Results: The test results indicated that the proposed preservative system and concentration met the preservative effectiveness test requirements for Category 2 products (as per USP, topically used products made with aqueous bases or vehicles, non-sterile nasal products, and emulsions, including those applied to mucous membranes). Specifically, even at 18 months, the test article was negative for Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Aspergillus niger and Candida albicans. Furthermore, even at 18 months, the TYMC and TAMC were found to be less than 10 cfu/g. In contrast, the control product comprising avian sodium hyaluronate (IPM Wound Gel) failed microbial tests after 6 months. Conclusion: The preservative system has been demonstrated to be suitable and effective in protecting the test article from microbial growth or from inadvertently introduced microorganisms. Example 8: Closure of Incision Lines in Patients with Digit Amputations Study design: IPM Wound Gel Bio was used in the healing of incision lines after digit amputations. Over a period of 9 months, 116 amputations were performed on diabetic patients with non-healing, digital diabetic ulceration. Blood supply was never perfect in those patients, however, is also not profoundly impaired. The treatment protocol was to apply a thin film of IPM Wound Gel Bio along the incision line, on a daily basis, with the wound site covered with foam dressing. The patients were seen 1 week postoperatively and again 2 weeks later. Results: The results that 94 (81%) of those patients healed, with complete epithelialization of the incision line within 1-2 weeks. This is in contrast to a typical 4 week healing time that was observed prior to using IPM Wound Gel Bio. In addition, the complication rate was correspondingly low as there was no incision line dehiscence or infection. Conclusions: The overall experience with IPM Wound Gel Bio has been extremely positive. Particularly striking was the consistency in the healing times of the incision lines, given that the patients were very sick patients with profound underlying end organ damage. The healing mechanism in these individuals is grossly impaired and amputation with primary closure is frequently fraught with postoperative complications. The rate of these complications was reduced with the introduction of IPM Wound Gel Bio as a postoperative treatment protocol and as such the need for ongoing homecare was reduced as well the patient's return to work or normal activities of daily living was accelerated. The improved wound healing properties of IPM Wound Gel Bio may be attributable to the increased stability and reduced cytotoxicity of IPM Wound Gel Bio. Example 9: A Formulation Containing Sodium Hyaluronate for Application to Wounds TABLE 3 A preferred biofermented sodium hyaluronate formulation containing a high concentration sodium hyaluronate Ingredient Amounts (% w/w) Sodium hyaluronate 2.5 Hydroxyethylcellulose 1.0 Polyethylene glycol 3.0 Methylparaben 0.2 Water q.s.* Total 100 *quantum sufficit The above batch contained a sodium hyaluronate as a humectant and matrix forming agent, hydroxyethylcellulose is a thickening agent and helps in forming polymer matrix, polyethylene glycol is a solvent, methylparaben as preservative and water as a solvent. Several experiments were done and the optimum pH range was established to be 5.0 to 7.0. The optimum viscosity range of the solution was established to be in the range of 10,000-50,000 cps at room temperature (23° C.). The product is found to be stable. The formulation in Table 1 was prepared by adding methylparaben to water in a suitable container and mixing at a speed of from about 400 rpm to less than about 2000 rpm (“medium speed”) for a few hours (about 2 hours). Ensure that methylparaben is completely dissolved. Then slowly add sodium hyaluronate (having a molecular weight from 600,000-800,000 Daltons) in a steady flow to the mixture gradually increasing the stirring speed from medium speed as defined above to a speed of from about 2000 rpm to about 3000 rpm (“high speed”) as the mixture thickens and the spin stays while charging sodium hyaluronate in a suitable container (for about 1 hour). Mix for few hours (about 2 hours) at medium speed. Continue the mixing at a speed of from about 25 rpm to less than 400 rpm (“low speed”) for long duration (about 8 hours) until all of the sodium hyalorunate polymer has dissolved into the mixture and a crystal-clear viscous solution has formed. In a separate container dissolve 1% hydroxyethylcellulose in purified water while stirring at medium speed and mix well. Continue stirring for few hours (from about 1 to about 2 hours). The resulting hydroxyethylcellulose solution is added to the sodium hyaluronate solution and mixed at medium speed followed by low speed for long period (about 4 hours) until a homogenous solution is produced. Add polyethylene glycol into the mixture while mixing at a medium speed. Continue mixing at medium speed for about 1 hour. Reduce the speed and continue mixing at low speed for a few hours (minimum of about 3 hours). The bulk gel is then filled in tubes or bottles and capped. Example 10: A formulation containing sodium hyaluronate and pantothenic acid for topical use A formulation containing sodium hyaluronate and pantothenic acid may be used in the treatment of damaged skin and can be used in the treatment of atopic dermatitis. TABLE 4 A biofermented sodium hyaluronate formulation containing a high concentration sodium hyaluronate and pantothenic acid. Ingredient Amounts (% w/w) Sodium hyaluronate 1.5 Hydroxyethylcellulose 1.0 Polyethylene glycol 3.0 Pantothenic acid (Vitamin B5) 1.5 Methylparaben 0.2 Water q.s.* Total 100 *quantum sufficit The formulation in Table 2 was prepared as detailed below: First, add methylparaben to water in a suitable container and mix at medium speed for few hours (about 2 hours). Ensure that methylparaben is completely dissolved. Then add sodium hyaluronate slowly in a steady flow in water while gradually increasing the stirring speed from medium to high speed as the dissolvent thickens and the spin stays while charging sodium hyaluronate in a suitable container. Mix for few hours (about 2 hours) at medium speed. Continue the mixing at low speed for long duration (overnight, or about 8 hours to about 15 hours) until all of the sodium hyalorunate polymer has dissolved into the mixture and a crystal-clear viscous solution has formed. In a separate container dissolve 1.0% hydroxyethylcellulose in purified water while stirring at medium speed and mix well. Continue stirring for a few hours (from about 1 to about 2 hours). Next the hydroxyethylcellulose solution is added to the sodium hyaluronate solution and mixed at medium speed until a homogenous solution is produced. The resulting solution is mixed at medium speed for long period (overnight, or about 8 hours to about 15 hours) until a homogenous solution is produced. Add polyethylene glycol into the mixture while mixing at a medium speed for about 1 hour. This is followed by the addition of pantothenic acid and mixing well at medium speed for few hours (about 2 hours) until dissolved and the gel is homogeneous. The bulk gel is then filled in tubes or bottles and capped. Example 11: A Formulation Containing Sodium Hyaluronate and Diclofenac Sodium for Topical Use A formulation containing sodium hyaluronate and diclofenac sodium can be used to treat actinic keratosis and in the relief of musculoskeletal pain in areas affected by the pain. Such areas include, but are not limited to, knees, ankles, feet, back, neck, elbows and hips. TABLE 5 A biofermented sodium hyaluronate formulation containing a high concentration sodium hyaluronate and dicloflenac sodium. The formulation was found to be stable. Ingredient Amount (% w/w) Dicloflenac sodium 3 Sodium hyaluronate 2.3 Hydroxyethylcellulose 0.7 Methoxypolyethylenc glycol 10 Methylparaben 0.3 Water q.s* Total 100 *quantum sufficit The formulation in Table 3 was prepared as follows: First, add methylparaben to water in a suitable container and mix at medium speed for few hours (about 2 hours). Ensure that methylparaben is completely dissolved. Then slowly add sodium hyaluronate to it while gradually increasing the stirring speed from medium to high as the mixture thickens and the spin stays while charging sodium hyaluronate in a suitable container for about 1 hour. Mix for few hours (about 2 hours) at medium speed. Continue the mixing at low speed for long duration (about 8 hours) until all of the sodium hyaluronate polymer has dissolved into water and a crystal-clear viscous solution has formed. The gel should be homogenous. In a separate container dissolve 0.7% hydroxyethylcellulose in purified water while stirring at low to medium speed and mix well. Continue stirring for few hours (from about 1 to about 2 hours). The resulting hydroxyethylcellulose solution is added to the sodium hyaluronate solution and mixed at medium speed for a long period (from about 10 to about 15 hours) until a homogenous solution is produced. Add methoxypolyethylene glycol (MPEG) 10% into the mixture. The mixing speed should be increased for the mixture while this step is being performed to a high speed. The resulting mixture thus formed should be allowed to mix at medium speed for a few hours (from about 3 to about 4 hours). Using safe techniques, 3% diclofenac sodium should be slowly added to the mixture. Again the mixing speed for the purpose of addition of diclofenac should be increased to high speed, and the addition of entire quantity of diclofenac should be completed within a short duration (about 15 minutes). The final mixture is clear with a slight green tint following further mixing for long duration (about 15 to about 20 hours) at medium speed. The final product should be transferred, using aseptic technique, to a bulk storage container and then the bulk gel is filled in tubes or bottles and capped. Example 12: A Formulation Containing Sodium Hyaluronate for Treating Vaginal Dryness Containing Using Niacin and Glycerin TABLE 6 A biofermented sodium hyaluronate formulation containing a high concentration sodium hyaluronate and niacin and glycerin. Ingredient Amounts Niacin 0.85 Glycerin 3 Sodium hyaluronate 1.5 Hydroxyethylcellulose 0.7 Polyethylene glycol 3 Methylparaben 0.2 Water q.s.* Total 100 *quantum sufficit **Glycerin USP should be used [Not More Than 0.10% each for diethylene glycol and ethylene glycol is found in Glycerin as per USP] A transdermal preparation of niacin (0.85%) and glycerin (3%) formula for Table 4 is prepared in the following manner. First, add methylparaben to water in a suitable container and mix at medium speed for few hours (about 2 hours). Ensure that methylparaben is completely dissolved. Then add sodium hyaluronate slowly in a steady flow in water while gradually increasing the stirring speed from medium to high speed as the mixture thickens and the spin stays while charging sodium hyaluronate in a suitable container for about 1 hour. Mix for few hours (about 2 hours) at medium speed. Continue the mixing at low speed for long duration (overnight, or about 8 hours to about 15 hours) until all of the sodium hyaluronate polymer has dissolved into water and a crystal-clear viscous solution has formed. The gel should be homogenous. Next, a solution is prepared by adding 0.7% HEC to purified water while stirring at low to medium speed and mixing well. Continue stirring for few hours (from about 1 to about 2 hours). The resulting solution is then added to the above formed mixture of sodium hyaluronate and mixed at medium speed for a long period (overnight, or about 8 hours to about 15 hours) to form a sodium hyaluronate/HEC polymer matrix. To the resulting mixture PEG is added and stirred at medium speed for a few hours (about 2.5 hours). Then, niacin and glycerin is added to the HAJHEC polymer matrix. The mixture is stirred at low speed for few hours (about 2 hours). The bulk gel is either stored for filling or a 0.5 to 0.75 ml of the resulting gel is loaded into syringes and stored in a refrigerator. Example 13: Test Method for Determination of Sodium Hyaluronate An HPLC test method for the determination of sodium hyaluronate in the test article (sodium hyaluronate bio-fermented wound gel formulation) was developed. Column BioSep SEC-s2000, 300 mm × 7.8 mm, 5 μ Detection UV @205 nm Column Temp.: 40° C. Injection Volume: 10 μL Flow Rate: 1.3 mL/min Run Time: 20 min Mobile Phase: 50 mM KH2PO4, pH adjusted to 7.0 The assay is based on HPLC analysis with a size exclusion analytical column and UV detection at 205 nm. Example 14: Test method for determination of methylparaben An HPLC test method for the determination of methylparaben in the test article (sodium hyaluronate bio-fermented wound gel formulation) was developed. Column Kinetex, C8, 100 mm × 4.6 mm, 2.6 μ, 100 A Detection UV @254 nm Column Temp.: 35° C. Injection Volume: 20 μL Flow Rate: 1.4 mL per min Run Time: 2 min Mobile Phase: 60:40 (v/v) 0.1% TFA in Milli-Q Water; 0.1% TFA in Acetonitrile The assay is based on HPLC analysis with reverse phase C8 analytical column and UV detection at 254 nm. Although specific embodiments of the invention have been described, it will be apparent to one skilled in the art that variations and modifications to the embodiments may be made within the scope of the following claims. Example 15: Pharmacokinetics and Bioavailability of 3% Diclofenac IPM Matrix 2.3% Sodium Hyaluronate Gel An open label, single centre, single dose, single dose, one-treatment, one period, pharmacokinetic and bioavailability study was carried out. Six normal, healthy, non-smoking males between the ages of 18-45 were administered 3% diclofenac IPM matrix gel made with 2.3% avian sodium hyalorunate, which was applied once for a 24 hour period. A total of 4 cc was the applied to the anterior right knee of each subject. Pharmacokinetics and bioavailability of the single dose application was assessed. A total 18 blood samples and 8 urine samples were collected for each subject during the 24 hour period after administration. The concentration of diclofenac was assessed for each sample. Diclofenac plasma and urine concentrations are presented in Table 7 and 8. Diclofenac was found in samples from all subjects. Concentrations varied from subject to subject, but this was normal for diclofenac. TABLE 7 Diclofenac Plasma Concentration (ng/mL) Measured in Samples from Subjects Using 3% Diclofenac Gel Diclofenac Concentration Subject Hour Min Found [ng/ml] 1 0 0 BLQ 1 0 25 BLQ 1 0 5 BLQ 1 0 75 BLQ 1 1 0 0.074 1 1 5 0.228 1 2 0 0.385 1 2 5 0.487 1 3 0 0.655 1 3 5 0.859 1 4 0 0.807 1 5 0 0.944 1 6 0 1.40 1 7 0 1.53 1 8 0 1.75 1 12 0 1.57 1 16 0 1.93 1 24 0 2.33 2 0 0 BLQ 2 0 25 BLQ 2 0 5 BLQ 2 0 75 BLQ 2 1 0 0.042 2 1 5 0.191 2 2 0 0.369 2 2 5 0.403 2 3 0 0.471 2 3 5 0.410 2 4 0 0.496 2 5 0 0.814 2 6 0 1.03 2 7 0 1.01 2 8 0 1.33 2 12 0 1.25 2 16 0 1.98 2 24 0 2.44 3 0 0 BLQ 3 0 25 BLQ 3 0 5 BLQ 3 0 75 BLQ 3 1 0 BLQ 3 1 5 BLQ 3 2 0 0.049 3 9 5 0.184 3 3 0 0.118 3 3 5 0.184 3 4 0 0.232 3 5 0 0.244 3 6 0 0.377 3 7 0 0.489 3 8 0 0.532 3 12 0 0.944 3 16 0 1.64 3 24 0 2.92 4 0 0 BLQ 4 0 25 BLQ 4 0 5 BLQ 4 0 75 BLQ 4 1 0 BLQ 4 1 5 BLQ 4 2 0 BLQ 4 2 5 0.090 4 3 0 BLQ 4 3 5 0.053 4 4 0 0.045 4 5 0 0.084 4 6 0 0.107 4 7 0 0.312 4 8 0 0.383 4 12 0 0.563 4 16 0 0.940 4 24 0 0.429 5 0 0 BLQ 5 0 25 BLQ 5 0 5 BLQ 5 0 75 BLQ 5 1 0 BLQ 5 1 5 BLQ 5 2 0 BLQ 5 2 5 0.046 5 3 0 0.066 5 3 5 0.081 5 4 0 0.150 5 5 0 0.367 5 6 0 0.448 5 7 0 0.742 5 8 0 1.07 5 12 0 3.04 5 16 0 3.65 5 24 0 2.17 6 0 0 BLQ 6 0 25 BLQ 6 0 5 BLQ 6 0 75 BLQ 6 1 0 BLQ 6 1 5 0.023 6 2 0 0.072 6 2 5 0.109 6 3 0 0.215 6 3 5 0.287 6 4 0 0.385 6 5 0 0.772 6 6 0 1.23 6 7 0 1.60 6 8 0 1.98 6 12 0 1.34 6 16 0 1.63 6 24 0 1.31 *BLQ = below the lower limit of quantification (0.02 ng/ml) TABLE 8 Diclofenac Urine Concentration (ng/mL) Measured in Samples from Subjects Using 3% Diclofenac Gel Diclofenac Concentration Subject Hour Found [ng/ml] 1 pre 0.0 hr BLQ 1 0.0-2.0 hr 0.012 1 2.0-4.0 hr 0.117 1 4.0-6.0 hr 0.704 1 6.0-8.0 hr 3.58 1 8.0-10.0 hr 3.98 1 10.0-12.0 hr 3.83 1 12.0-24.0 hr 2.81 2 pre 0.0 hr BLQ 2 0.0-2.0 hr 0.042 2 2.0-4.0 hr 0.434 2 4.0-6.0 hr 0.428 2 6.0-8.0 hr 0.724 2 8.0-10.0 hr 2.59 2 10.0-12.0 hr 0.785 2 12.0-24.0 hr 2.67 3 pre 0.0 hr BLQ 3 0.0-2.0 hr BLQ 3 2.0-4.0 hr BLQ 3 4.0-6.0 hr 0.144 3 6.0-8.0 hr 0.315 3 8.0-10.0 hr 0.748 3 10.0-12.0 hr 0.427 3 12.0-24.0 hr 6.04 4 pre 0.0 hr BLQ 4 0.0-2.0 hr BLQ 4 2.0-4.0 hr 0.051 4 4.0-6.0 hr 0.120 4 6.0-8.0 hr 0.356 4 8.0-10.0 hr 0.654 4 10.0-12.0 hr 4.95 4 12.0-24.0 hr 2.24 5 pre 0.0 hr BLQ 5 0.0-2.0 hr 0.595 5 2.0-4.0 hr 0.097 5 4.0-6.0 hr 0.804 5 6.0-8.0 hr 2.29 5 8.0-10.0 hr 0.763 5 10.0-12.0 hr 3.28 5 12.0-24.0 hr 7.76 6 pre 0.0 hr BLQ 6 0.0-2.0 hr BLQ 6 2.0-4.0 hr 0.384 6 4.0-6.0 hr 3.52 6 6.0-8.0 hr 13.9 6 8.0-10.0 hr 11.0 6 10.0-12.0 hr 2.71 6 12.0-24.0 hr 2.27 *BLQ = below the lower limit of quantification (0.01 ng/ml) Example 16: Efficacy of 3% Diclofenac IPM 2.3% Sodium Hyalorunate Matrix Gel by Topical Application in Treating Painful Musculoskeletal Conditions, Principally Involving the Relief of Pain and Muscle Spasm 23 patients with musculoskeletal pain, at a pain clinic, were asked to volunteer to test 3% diclofenac IPM 2.3% sodium hyalorunate matrix gel made with avian sodium hyalorunate. The gel was applied liberally on the skin four times a day over the area with the musculoskeletal problem causing the pain. The patients were asked to assess 34 criteria to estimate their musculoskeletal pain or stiffness on a visual analogue scale, graded 0-10 at the first visit. 17 patients were assessed on only one criterion but five patients were assessed on two criteria as follows: right and left ankle, neck pain and stiffness, headache and neck pain and shoulder and neck pain to make a total of 34 criteria. They were then given a supply of diclofenac gel to apply to painful area and asked to grade the change in the pain on a nine point scale from very much worse through no change to very much better. The patients were then given a further one week supply of gel and they did a second self assessment at the end of the second week's treatment. After one week's treatment, of 23 patients' 27 criteria, eight criteria reported no change, 19 reported an improvement varying between somewhat better and no pain and no one had worse pain. The improved group consisted of ten, one, six and two patients being respectively somewhat better, better, much better and having no pain. No patient had worse pain. After two week's treatment, which essentially are similar to the results at one week, but one patient's criterion reported being somewhat worse, six showed no change and twenty patients' criteria reported improvement with feeling better. Combining the results at one and two weeks produced a similar result to each of them. Using a visual analogue scale with only one criterion for each patient, the average figure falls after diclofenac and rises when it is discontinued In conclusion, diclofenac gel is an effective preparation for the transcutaneous relief of arthritis and musculoskeletal pain. It has good patient acceptance, is easily administered, causes no serious side-effects, and avoids the gastrointestinal upset that so often accompanies oral NSAID use. There would be an expected improvement in the above-mentioned clinical behavior of ionic polymer matrix gel manufactured with sodium hyaluronate from a bacterial source in accordance with the present invention, compared with that manufactured with hyaluronate from an avian source used in example 15 and 16 since the formulations of the present invention have reduced cytotoxicity effects and improved stability. | <SOH> BACKGROUND OF THE INVENTION <EOH>Hyaluronic acid (HA) is a naturally occurring mucopolysaccharide (also commonly referred to as glycosaminoglycan). It has been isolated by various methods from numerous tissue sources including vitreous humor, skin, synovial fluid, serum, chicken combs, shark skin, umbilical cords, tumors, hemolytic streptococci from pigskin, whale cartilage, and the walls of veins and arteries. HA may, however, also be synthesized artificially or made by recombinant technology. Moreover, it is known that HA may also be manufactured by fermentation of selected Streptococcus zooepidemicus bacterial strains (see U.S. Pat. No. 4,517,295 issued to Bracke et al.), and can readily be converted to its sodium salt. The repeating unit of the HA molecule is a disaccharide consisting of D-glucuronic acid and N-acetyl-D-glycosamine. Because HA has a negative charge at neutral pH, it is soluble in water, where it forms highly viscous solutions. Fractions of HA, including its sodium salt, are known to foul′ a stable polymer matrix when combined with a non-ionic polymer such as hydroxyethyl cellulose or hydroxypropyl cellulose. Such polymer matrix formulations are known to be useful in preparing compositions for various applications for human and animal use. For example, a formulation containing sodium hyaluronate and hydroxyethylcellulose was formerly marketed under the name of Ionic Polymer Matrix (IPM) Wound Gel for applying to wounds to promote wound healing. In addition, polymer matrices of HA formulated with other active ingredients are known to be useful as topical drug formulations for delivering the active ingredients to sites below the dermal level of the skin. HA polymer matrix topical active ingredient formulations for trans-dermal delivery of active ingredients are disclosed for example in U.S. Pat. No. 5,897,880, U.S. Pat. No. 6,120,804, U.S. Pat. No. 6,387,407, and U.S. Pat. No. 6,723,345. HA polymer matrices formulated with other active ingredients are also known to be useful as formulations for sustained release of the pharmaceutical agents. HA polymer matrix formulations for sustained release delivery of active ingredients are disclosed in U.S. Pat. No. 6,063,405, U.S. Pat. No. 6,335,035, and U.S. Pat. No. 6,007,843. Preparing sodium hyaluronate polymer matrix formulations presents many challenges. Initially, in the 1980s only HA obtained from animal sources was available commercially, and many of the formulations were delivered by injection, or used as drops in the eye, rather than for topical use for dermatological conditions. The natural HA used in various formulations has usually been obtained from rooster combs. The rooster comb (also known as a chicken comb) is an avian source and as such is of animal origin. As a result, sodium hyaluronate formulations manufactured using sodium hyaluronate from rooster combs have been known to cause allergies and carry other risks associated with products of animal origin, namely a risk of transmission of animal diseases to humans. Consequently, the currently approved topical products containing sodium hyaluronate formulations available on the market are contra-indicated for those patients who are hypersensitive to sodium hyaluronate of animal origin. Moreover, sodium hyaluronate is difficult to formulate in high concentrations above 1.5% w/w, due to the difficulty in manufacturing a formulation that maintains stability and is not too viscous for normal use when packaged in a tube. For this reason many of the commercial formulations on the market have a concentration of HA or sodium hyaluronate well below 1% w/w, and many in fact have a concentration at around 0.2% w/w. To the inventors' knowledge, there are no products currently on the market that contain more than 1.5% w/w sodium hyaluronate. When not mixed and manufactured properly, a high HA or sodium hyaluronate concentration formulation will quickly break down, and therefore the percentage of HA or sodium hyaluronate in the formulation will fall below the acceptable limit (+/−10% of original amount), resulting in a very short shelf life for the product. Formulations containing a high concentration of sodium hyaluronate therefore present a challenge due to the instability of the matrix. This results in inconsistencies in the matrix formulation and impairs the ability of sodium hyaluronate formulations to perform their functions. For example, when applied to wounds to promote healing, a sodium hyaluronate polymer matrix formulation helps to maintain a moist wound environment, an effect that is dependent on the formulation maintaining its high level of sodium hyaluronate concentration. The maintenance of a moist wound environment is widely recognized to positively contribute to wound healing. However, due to their instability and the resulting drop in the level of sodium hyaluronate that occurs as the formulation breaks down, high concentration sodium hyaluronate formulations are not effective in maintaining a moist environment. When formulated for the delivery of a drug, the inconsistency of high concentration sodium hyaluronate formulations reduces the ability of such formulations to allow the drug to diffuse through the tissue when administered, thereby impairing their ability to achieve the therapeutic dose. In addition, the sodium hyaluronate polymer matrix formulation product formerly marketed under the name of Ionic Polymer Matrix (IPM) Wound Gel was withdrawn from the market due to problems with the formulation. Therefore, a need exists for a method for formulating a sodium hyaluronate polymer matrix containing a high concentration of sodium hyaluronate that can be manufactured and sold commercially. | <SOH> SUMMARY OF THE INVENTION <EOH>The present invention relates to stable polymer matrix compositions, preferably pharmaceutical compositions, comprising a high concentration (for example, from about 1.5% to about 3.5% w/w) of sodium hyaluronate obtained from a bacterial source such as Streptococcus zooepidemicus or Bacillus subtilis source. Sodium hyaluronate obtained from a bacterial source is referred to hereinafter as “bio-fermented” sodium hyaluronate. The compositions further comprise a non-ionic polymer optionally in an amount of from about 0.1% to about 2% w/w, polyethylene glycol, methylparaben and water. By “stable”, as used herein, it is meant that the amount of sodium hyaluronate in the formulation does not vary by more than +1-10% (w/w) relative to the original amount provided in the composition, at 40° C., 75% relative humidity (accelerated stability conditions) for a period of at least 6 months, and/or at 25° C., 60% relative humidity (long-term stability conditions) for a period of at least 18 months. The amount of sodium hyaluronate may be measured by HPLC techniques known in the art of pharmaceutical development. In one aspect of the present invention, the polymer matrix compositions of the present invention comprise components which are of compendial (USP or Ph. Eur.) and/or of pharmaceutical grade. These terms are discussed further below. Preferably, all the components of the compositions are of compendial and/or of pharmaceutical grade. In a further aspect of the invention, the polymer matrix compositions comprise components of certain specifications. In one aspect, polymer matrix compositions of the present invention may be used in the treatment of wounds, burns, and certain dermatological conditions. In another aspect of the present invention, the polymer matrix compositions comprise an active ingredient. In this aspect of the invention, the polymer matrix compositions may be used for trans-dermal delivery, topical delivery, and sustained release delivery of the active ingredient. In some aspects, the polymer matrix compositions may be used for the treatment of musculoskeletal pain. A further aspect of the present invention relates to the use of the polymer matrix compositions in the treatment of vaginal dryness. In a further aspect, the present invention relates to methods for preparing stable polymer matrix compositions of the present invention. detailed-description description="Detailed Description" end="lead"? | A61K31728 | 20171009 | 20180215 | 65614.0 | A61K31728 | 1 | LAU, JONATHAN S | POLYMER MATRIX COMPOSITIONS COMPRISING A HIGH CONCENTRATION OF BIO-FERMENTED SODIUM HYALURONATE AND USES THEREOF | SMALL | 1 | CONT-ACCEPTED | A61K | 2,017 |
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15,728,228 | PENDING | MEDIA ECHOING AND SOCIAL NETWORKING DEVICE AND METHOD | A method and apparatus for echoing media via a mobile device are disclosed herein. According to an embodiment, the method can include displaying automatically to a user, on the mobile device, a list of one or more respective identifiers of one or more other users experiencing respective media within a selectable geographic area. The user is then allowed to select whether to play one or more of the respective media on the mobile device, and can connect with the one or more other users via a social networking site. As a result, the user can network with previously unknown people, based on a common taste in music or other media, for example, as well as a geographic location. | 1. A method, comprising: displaying to a user, on a mobile device, one or more geographic locations and respective identifiers of one or more other users experiencing respective media within a geographic area, wherein the geographic area is automatically determined based on a set radius from the mobile device; displaying automatically to the user an experience identifier corresponding, respectively, to each of the one or more other users, wherein the experience identifier is alterable at least in part when one experiences respective media in real time while each of the one or more other users currently experiences the respective media, wherein the experience identifier is displayed concurrently with the one or more respective identifiers of the one or more other users determined to be within the geographic area, along with an indication that the one or more other users are within the geographic area; allowing the user to select whether to experience one or more of the respective media on the mobile device; and causing a processor to transmit a signal to a second user to display to the second user a changeable identifier of the user of the mobile device after the user of the mobile device selects to experience the media being experienced by the second user, wherein when the user selects to experience one or more of the respective media on the mobile device, the respective media is streamed such that the respective media is synchronized in real time with the respective media experienced by the second user. 2. The method of claim 1, further comprising: providing an option to request a connection with one or more of the one or more other users via a social networking website. 3. The method of claim 1, wherein the respective media initiated by the second user is previously stored on a server before being initiated. 4. The method of claim 1, further comprising: displaying one or more advertisements on the mobile device of the user or the one or more other users. 5. The method of claim 4, wherein the one or more advertisements are related to the one or more geographic locations or at least one establishment within a set distance from the one or more geographic locations. 6. The method of claim 1, wherein the mobile device is incorporated as part of a virtual reality viewing device. 7. The method of claim 1, wherein at least one of an indication of the one or more geographic locations or the respective identifiers are provided in order of their distance from the mobile device. 8. The method of claim 1, further comprising: allowing the user to purchase a good or service at the one or more displayed geographic locations using the mobile device. 9. The method of claim 1, wherein the one or more geographic locations are displayed in an order of their distance from the mobile device. 10. A mobile device, comprising: a display to display to a user, on a mobile device, one or more geographic locations and respective identifiers of one or more other users experiencing respective media within a geographic area, wherein the geographic area is automatically determined based on a set radius from the mobile device, wherein the display further displays automatically to the user an experience identifier corresponding, respectively, to each of the one or more other users, wherein the experience identifier is alterable at least in part when one experiences respective media in real time while each of the one or more other users currently experiences the respective media, wherein the experience identifier is displayed concurrently with the one or more respective identifiers of the one or more other users determined to be within the geographic area, along with an indication that the one or more other users are within the geographic area, and the display is further configured to display a selection icon configured to allow the user to select whether to experience one or more of the respective media on the mobile device; and a transmitter including circuitry causing a processor to transmit a signal to a second user to display to the second user a changeable identifier of the user of the mobile device after the user of the mobile device selects to experience the media being experienced by the second user, wherein when the user selects to experience one or more of the respective media on the mobile device, the respective media is streamed such that the respective media is synchronized in real-time with the respective media experienced by the second user. 11. The mobile device of claim 10, the display further displays an icon which, when selected by the user, allows the user to request a connection with one or more of the one or more other users via a social networking website. 12. The mobile device of claim 10, wherein the respective media initiated by the second user is previously stored on a server before being initiated. 13. The mobile device of claim 10, wherein the display further displays one or more advertisements on the mobile device of the user or the one or more other users. 14. The mobile device of claim 13, wherein the one or more advertisements are related to the one or more geographic locations or at least one establishment within a set distance from the one or more geographic locations. 15. The mobile device of claim 10 wherein the mobile device is incorporated as part of a virtual reality viewing device. 16. The mobile device of claim 10, wherein at least one of an indication of the one or more geographic locations or the respective identifiers are provided in order of their distance from the mobile device. 17. The mobile device of claim 10, wherein the display further displays one or more icons, when selected by the user, allowing the user to conduct a business transaction at the one or more displayed geographic locations using the mobile device. 18. A non-transitory computer-readable medium storing instructions thereon for, when executed by one or more processors, causing a mobile device to: display to a user, on the mobile device, one or more geographic locations and respective identifiers of one or more other users experiencing respective media within a geographic area, wherein the geographic area is automatically determined based on a set radius from the mobile device; display automatically to the user an, experience identifier corresponding, respectively, to each of the one or more other users, wherein the experience identifier is alterable at least in part when one experiences respective media in real time while each of the one or more other users currently experiences the respective media, wherein the experience identifier is displayed concurrently with the one or more respective identifiers of the one or more other users determined to be within the geographic area, along with an indication that the one or more other users are within the geographic area; allow the user to select whether to experience one or more of the respective media on the mobile device; and cause a processor to transmit a signal to a second user to display to the second user a changeable identifier of the user of the mobile device after the user of the mobile device selects to experience the media being experienced by the second user, wherein when the user selects to experience one or more of the respective media on the mobile device, the respective media is streamed such that the respective media is synchronized in real time with the respective media experienced by the second user. 18. The computer-readable medium of claim 17, wherein the respective media initiated by the second user is previously stored on a server before being initiated. 19. The computer-readable medium of claim 18, further causing one or more advertisements to be displayed on the mobile device of the user or the one or more other users. 20. The computer-readable medium of claim 19, wherein the one or more advertisements are related to the one or more geographic locations or at least one establishment within a set distance from the one or more geographic locations. | CROSS REFERENCE TO RELATED APPLICATIONS This application claims the priority of, and is a continuation in part of, U.S. patent application Ser. No. 15/355,265 (U.S. Pub. 2017/0070872), filed Nov. 18, 2016 and Ser. No. 13/454,546 (U.S. Pub. 2013/0282809 issued as U.S. Pat. No. 9,501,760), filed Apr. 24, 2012, the contents of both of which are incorporated herein by reference in their entirety. FIELD OF THE INVENTION This relates generally to media echoing and social networking methods and devices, for use with mobile systems. BACKGROUND OF THE INVENTION Existing media providers, such as Pandora, Google Play and Spotify, Ltd., allow listeners to wirelessly stream music on mobile devices. In the case of Spotify, Ltd., for example, a user can choose to display his or her music selections on social networking websites, such as Facebook®, and can instantly share music with his or her Facebook “friends” who also subscribe to the media provider. However, the existing media providers fail to support a mechanism for allowing a user to share, or echo, music, or otherwise connect to other users, who are not currently “friends” via social networking. That is, the existing technology lacks the ability to allow users to establish social interactions with strangers within a predetermined, selectable geographic area, based on a shared interest in chosen media. Therefore, there exists a need for methods and systems capable of allowing a user to designate a geographic area within which a list of identifiers of other users playing media can be displayed on a user's device, such that the user can select to play (e.g., stream), the same media as one or more of the listed other users. Accordingly, the user can network with previously unknown people, based on a common taste in music, for example. SUMMARY OF THE INVENTION The presently disclosed embodiments are directed to solving one or more of the problems presented in the prior art, described above, as well as providing additional features that will become readily apparent by reference to the following detailed description when taken in conjunction with the accompanying drawings. One embodiment is directed to a method of echoing media via a mobile device. The method can include displaying automatically to a user, on the mobile device, a list of one or more respective identifiers of one or more other users experiencing respective media within a selectable geographic area; and allowing the user to select whether to play one or more of the respective media on the mobile device. Another embodiment is directed to an apparatus for echoing media. The apparatus includes a display configured to display automatically to a user, on a mobile device, a list of one or more respective identifiers of one or more other users experiencing respective media within a geographic area defined by the user; and a section unit configured to allow the user to select whether to play one or more of the respective media on the mobile device. Yet another embodiment is directed to a system configured to echo media on a mobile device. The system includes a positioning unit configured to determine respective distances of a plurality of mobile device, with respect to a first mobile device; a processor configured to compare the distances between each of the plurality of mobile devices and the first mobile device to a preselected distance selected by a first user of the first mobile device; and transmitter configured to transmit, to the first mobile device, a list of one or more other of the plurality of mobile devices, automatically when any one of the one or more other of the plurality of mobile devices moves within the preselected distance form the first mobile device used by the first user. According to certain embodiments, the list includes personalized and reconfigurable identifiers, respectively, of each user of the one or more other of the plurality of mobile devices that moves within the preselected distance, and the list includes respective media currently being streamed from a centralized server by each user of the one or more other of the plurality of mobile devices that moves within the preselected distance. The system further includes a display unit configured to display automatically, to the first user, the list such that the first user selects whether to stream one or more of the respective media from the centralized server; and a transmitter configured to transmit an indication to the centralized server indicating that the first user has selected to stream one or more of the respective media. According to certain embodiments, the centralized server is further configured to indicate to at least one of the one or more other of the plurality of mobile devices that the first user has se3lected to stream one or more of the respective media. The indication from the centralized server can include a personalized identifier designated by the first user. It is to be understood that both the foregoing general description and the following detailed description are exemplary and are intended to provide further explanation of the claimed subject matter. BRIEF DESCRIPTION OF THE DRAWINGS The present disclosure, in accordance with one or more various embodiments, is described in detail with reference to the following Figures. The drawings are provided for purposes of illustration only and merely depict exemplary embodiments of the disclosure. These drawings are provided to facilitate the reader's understanding of the disclosure and should not be considered limiting of the breadth, scope, or applicability of the disclosure. It should be noted that for clarity and ease of illustration these drawings are not necessarily made to scale. FIG. 1 illustrates an exemplary operating environment including wireless mobile devices, according to various embodiments of the present disclosure. FIG. 2 illustrates an exemplary communication system including a mobile device and a base station, according to various embodiments of the present disclosure. FIG. 3 illustrates an exemplary mobile device displaying various features of the present technology, according to various embodiments of the present disclosure. FIG. 4 illustrates an exemplary mobile device displaying various features of the present technology, according to various embodiments of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS In the following description of embodiments, reference is made to the accompanying drawings which form a part hereof, and in which it is shown by way of illustration specific embodiments in which the invention can be practiced. It is to be understood that other embodiments can be used and structural changes can be made without departing from the scope of the disclosed embodiments. FIG. 1 illustrates a mobile radio channel operating environment, according to one embodiment of the present invention. The mobile radio channel operating environment may include a base station (BS) 102, one or more mobile stations (also referred to as MS, mobile device, or the like) 100, and global positioning system (GPS) satellites 120. As described in further detail below, the respective locations of the mobile devices 100 can be determined based on GPS satellites 120 or other known mechanisms and systems for detecting relative proximities of mobile devices 100, performed by hardware and software within mobile devices 100 themselves. The exemplary mobile station 100 in FIG. 1 is a mobile phone; however, alternately, mobile station 100 may be an automobile, MP3 player or other similar portable device. According to some embodiments, mobile station 100 may be a personal wireless computer such as a wireless notebook computer, a wireless palmtop computer, tablet, or other mobile computer devices. Similarly, a mobile station 100 can include virtual reality (VR)-style goggles or glasses, which may or may not be configured to incorporate a separate wireless device. For example, the VR goggles could use the screen and/or the GPS functionality of the separate wireless device in order to be worn by a user and display a VR-type presentation to the user. Of course, various configurations may be implemented within the scope of the present disclosure. The base station 102 can be a centralized server unit having a memory module, processor module and transceiver module, configured to store and distribute media to mobile stations 100. According to an embodiment, base station 102 can be another mobile device 100, as would be understood by one of ordinary skill in the art. Mobile stations 100 can include any conventional GPS receiver modules, which are not depicted. FIG. 2 shows an exemplary wireless communication system for transmitting and receiving data between mobile station 100 and base station 102, in accordance with one embodiment of the present invention. The mechanism may include components and elements configured to support known or conventional operating features that need not be described in detail herein. This system generally comprises a base station 102 with a base station transceiver module 202, a base station antenna 206, a base station processor module 216 and a base station memory module 218. System 200 generally comprises a mobile station 100 with a mobile station transceiver module 208, a mobile station antenna 212, a mobile station memory module 220, a mobile station processor module 222, and a network communication module 226. Of course both BS 102 and MS 100 may include additional or alternative hardware and software modules without departing from the scope of the present disclosure, as would be apparent to one of ordinary skill in the art. Furthermore, these and other elements of the system may be interconnected together using a data communication bus (e.g., 228, 230), or any suitable interconnection arrangement. Such interconnection facilitates communication between the various elements of the wireless system. Those skilled in the art will understand that the various illustrative blocks, modules, circuits, and processing logic described in connection with the embodiments disclosed herein may be implemented in hardware, computer-readable software, firmware, or any practical combination thereof. To clearly illustrate this interchangeability and compatibility of hardware, firmware, and software, various illustrative components, blocks, modules, circuits, and steps are described generally in terms of their functionality. Whether such functionality is implemented as hardware, firmware, or software depends upon the particular application and design constraints imposed on the overall system. Those familiar with the concepts described herein may implement such functionality in a suitable manner for each particular application, but such implementation decisions should not be interpreted as causing a departure from the scope of the present invention. In the exemplary system, the base station transceiver 202 and the mobile station transceiver 208 each comprise a transmitter module and a receiver module (not shown). Additionally, although not shown in this figure, those skilled in the art will recognize that a transmitter may transmit to more than one receiver, and that multiple transmitters may transmit to the same receiver. The mobile station transceiver 208 and the base station transceiver 202 are configured to communicate via a wireless data communication link 214. The mobile station transceiver 208 and the base station transceiver 202 cooperate with a suitably configured RF antenna arrangement 206/212 that can support a particular wireless communication protocol and modulation scheme. In the exemplary embodiment, the mobile station transceiver 208 and the base station transceiver 202 can be configured to support industry standards such as the Third or Fourth Generation Partnership Project Long Term Evolution (3GPP or 4GPP LTE), Time Division-Synchronous Code Division Multiple Access (TD-SCDMA), Wi-Fi, and the like. The mobile station transceiver 208 and the base station transceiver 202 may be configured to support alternate, or additional, wireless data communication protocols, including future variations of IEEE 802.16, such as 802.16e, 802.16m, and so on. Processor modules 216/222 may be implemented, or realized, with a general purpose processor, a content addressable memory, a digital signal processor, an application specific integrated circuit, a field programmable gate array, any suitable programmable logic device, discrete gate or transistor logic, discrete hardware components, or any combination thereof, designed to perform the functions described herein. In this manner, a processor may be realized as a microprocessor, a controller, a microcontroller, a state machine, or the like. A processor may also be implemented as a combination of computing devices, e.g., a combination of a digital signal processor and a microprocessor, a plurality of microprocessors, one or more microprocessors in conjunction with a digital signal processor core, or any other such configuration. In practical embodiments the processing logic may be resident in the base station and/or may be part of a network architecture that communicates with the base station transceiver 202. The steps of a method or algorithm described in connection with the embodiments disclosed herein may be embodied directly in hardware, in firmware, in a software module executed by processor modules 216/222, or in any practical combination thereof. A software module may reside in memory modules 218/220, which may be realized as RAM memory, flash memory, ROM memory, EPROM memory, EEPROM memory, registers, a hard disk, a removable disk, a CD-ROM, or any other form of storage medium known in the art. In this regard, memory modules 218/220 may be coupled to the processor modules 218/222 respectively such that the processors modules 216/220 can read information from, and write information to, memory modules 618/620. As an example, processor module 216, and memory modules 218, processor module 222, and memory module 220 may reside in their respective ASICs. The memory modules 218/220 may also be integrated into the processor modules 216/220. In an embodiment, the memory module 218/220 may include a cache memory for storing temporary variables or other intermediate information during execution of instructions to be executed by processor modules 216/222. Memory modules 218/220 may also include non-volatile memory for storing instructions to be executed by the processor modules 216/220. Memory modules 218/220 may include a frame structure database (not shown) in accordance with an exemplary embodiment of the invention. Frame structure parameter databases may be configured to store, maintain, and provide data as needed to support the functionality of system 200 in the manner described below. Moreover, a frame structure database may be a local database coupled to the processors 216/222, or may be a remote database, for example, a central network database, and the like. A frame structure database may be configured to maintain, without limitation, frame structure parameters as explained below. In this manner, a frame structure database may include a lookup table for purposes of storing frame structure parameters. The network communication module 226 generally represents the hardware, software, firmware, processing logic, and/or other components of the system that enable bi-directional communication between base station transceiver 202, and network components to which the base station transceiver 202 is connected. For example, network communication module 226 may be configured to support internet or Wi-Fi traffic. In a typical deployment, without limitation, network communication module 226 provides an 802.3 Ethernet interface such that base station transceiver 202 can communicate with a conventional Ethernet based computer network. In this manner, the network communication module 226 may include a physical interface for connection to the computer network (e.g., Mobile Switching Center (MSC)). FIG. 3 shows an exemplary mobile device 100, according to an embodiment of the present disclosure. For exemplary purposes, the mobile device 100 is depicted as a wireless telephone; however, any mobile device may be incorporated without departing from the scope of the invention. For example, according to an embodiment, the mobile device 100 can be an on-board computing system within an automobile. As shown in FIG. 3, a list is displayed in display area 310, which includes identifiers of three other mobile device 100 users who are currently playing media and are within a preselected geographic area selected by the user of the depicted mobile device 100. According to certain embodiments, GPS satellites 120 can provide an exact position to each mobile device 100, which in turn transmit their respective positions to a centralized server (e.g., base station 102). The centralized server can also store the preselected geographic area determined by the user (e.g., a radius of 100 yards), and can compare the distances between the depicted mobile device 100 and other mobile devices 100 who are playing media and are logged on to a particular web site or application, for example. If any of the other mobile devices 100 are logged on and within the user's defined area, then the centralized server can automatically incorporate the identifiers of the users of those other mobile devices 100 into the list displayed in display area 310 of the depicted mobile device 100. The user of the depicted mobile device 100 can change the desired geographic area within which to locate other users, via the “CHANGE AREA” icon 320, which can allow the user to customize the searchable area. In this exemplary scenario, three other mobile devices have been determined to be within the bounds set by the user of the depicted mobile device 100 (e.g., “Blond with Red Sweatshirt,” 312 “Silver Pickup Truck,” 314 and “Jill S.” 316). The identifiers are respectively designated by each of the users of the mobile devices 100. Of course, one of ordinary skill in the art would realize that the users could change their respective identifiers at any time (e.g., via their own “OPTIONS” icon 330), depending on what car they are driving, where they are located, what they are wearing, their appearance, a nickname, or any other identifying features they wish to show up on the other users' lists. According to one embodiment, the list can include an identifier of what type of media is being experienced by the respective other users (e.g., “Jill S.” 316 is listening to song “ABC” by Band 2). Alternatively, the other users may experience audio and/or video via YouTube, for example, like “Silver Pickup Truck” 314. The user of the depicted mobile device 100 can select to play (or echo) any of the media that is being experienced by the other users on the list. According to the depicted example, the user can select a “PLAY” icon, which will transmit a signal to the centralized server to request streaming of the identified media. The streaming can begin from the start of the particular song or video, for example, or can begin at a middle point in the song or video where the identified other user is currently at in real time. In the depicted example, the number of times other users who are identified on the list have been “echoed” (i.e., the number of times other users have decided to experience the same media that they are currently experiencing) can be provided to the user of the depicted mobile device 100. In this case, “Jill S.” 316 is identified as having 75 echoes in real time (i.e., 75 other users have decided to experience what “Jill S.” is currently experiencing at that time). Any other experience indication(s) or indicator(s) or identifier(s) (e.g., points and/or levels and/or color codes and/or any other visual or audible indication) could be displayed or played for each user as well. In such a case, each user could have an overall experience total displayed, which may indicate how active the user has been on the application in the past (e.g., not currently in real time, but a total of overall usage or overall media experienced cumulatively). Any experience indication could be altered in real time, based on real-time activity as the media originator or echoing other users. An algorithm stored at a server, for example, could be implemented to determine what experience indication/identifier should be displayed, depending on the amount and type of usage of the application. According to certain embodiments, predetermined geographic areas can be set at a central server, or obtained and gathered from any number of servers (e.g., selected by any user or any network administrator), such that the predetermined geographic areas can be set to provide various activities or other options to the user of the mobile device 100 when mobile device 100 arrives within the predetermined geographic area. Or, a user can select a geographic area, including a selectable radius from the user's mobile device, for example, so that another user can interact with the user only within the user's selected radius. In such a case, the need for presetting an area or distance at a centralized server is unnecessary. A desired geographic area could be determined by user's being capable of accessing a particular cellular base station for example. In such a case, any mobile device accessing a particular base station could be considered acceptably within the selected geographic area, according to one embodiment. In such an embodiment, processing circuitry, communicatively coupled to memory, would be capable of accessing user data from any particular base station in order to determine which user devices are served thereby. According to an example, when a mobile device 100 is within a predetermined distance (e.g., set at the central server) from a predetermined geographic location, the user of mobile device 100 may be see a display on mobile device 100 showing an option to purchase or otherwise obtain (e.g., trade) digital media to be streamed or downloaded to mobile device 100. For example, users may be determined to be within a predetermined geographic area (or even at a particular geographic location) if their respective devices are within a predetermined threshold distance (e.g., a 50′ radius) from a virtual marker, such as predetermined geographic coordinates, or any other manner of assigning a marker to any particular location. Mobile device 100 may provide a visual or audio indication thereon to indicate where such a predetermined geographic area is (e.g., a station provided on a map, via augmented or virtual reality, or any visual or audible indication). A predetermined geographic locations could be any point of interest or establishment, like a physical store, place of business, home or other landmarks, according to various embodiments, which could be indicated to the user when the user searches geographic areas on the mobile device 100 (e.g., zooming in or out on a map to search for markers or other indications of such a predetermined geographic area, or simply moves into a new geographic area with establishments of points of interests at designated geographic locations). In other words, a geographic area could be an area selectable by any user which could include one or more particular geographic locations of interest. According to an embodiment, when two or more users are simultaneously at or within a predetermined geographic location or area, as determined by the central server, for example, the two or more users may be allowed and able to transfer and receive digital media from each other. Such a transfer of media could be device-to-device, or via a central server system (including one or more servers and/or processors). Such a transfer of digital media could be performed by any mechanisms, as would be apparent to one of ordinary skill in the art. The digital media could be then stored on each mobile device 100 (or one or the other), or saved on a centralized memory (e.g., cloud storage) for streaming and/or downloading later. Such digital media to be transferred and/or received can include digital coupons, tradable pictures (e.g., drawings, photos, etc.), videos or any other type of media. According to one embodiment, if a user was determined to be within a participating store, for example, the mobile device 100 of the user could be automatically sent a digital coupon or other advertisement, which could relate to the store's business for example. The digital media could be pre-stored on a centralized server/memory and transmitted to the mobile device 100, or could be stored at a memory at the store and transmitted to mobile device 100 directly (device-to-device) or via a centralized server. Further, the user could be prompted to purchase physical or virtual items upon being determined to be at the geographic location. It should be appreciated that various revenue streams could be realized using the features described herein. For example, a participating store at a predetermined physical location could pay a fee or subscription in order to have a virtual marker located at its physical location, in order to attract users to their physical location. Various other advertisement revenues could be generated by displaying advertisements dependent upon the determined geographic location of the user of mobile device 100. Moreover, the physical store or any online store could generate revenue by offering add-on purchases (either additional digital media and/or actual items at the store) for sale to the user. Further, various conventional techniques could be used in order to determine which advertisements or other digital content to push to the user, and ultimately displayed on the mobile device, based on various other criteria (e.g., user data or other user preferences), to determine what digital media to push to the user. Revenue could be generated by each other user experiencing media based on a number of echoes their media has generated in real time, if the user is the creator of the media, for example, as in the case where the user experiencing media is the originator of said media via YouTube Live, for example. Of course, the layout of the features and information presented on the list is merely one example, and is not intended to limit the scope of the disclosure in any way. One of ordinary skill in the art would realize that various additional information and combinations thereof could be depicted in various ways. Moreover, a touchscreen cellular phone is depicted with icons that can execute various functions via the user's touch. However, any display device could be implemented with any type of scroll, highlight and/or selection mechanisms in conventional mobile devices. Furthermore, it is not necessary for GPS satellites to be utilized in obtaining exact coordinates of each mobile device 100. Using known techniques of detecting the presence of other mobile devices within a defined radius, each mobile device 100 could determine on its own that another mobile device 100 is within an acceptable range. That is, it would not be necessary for the centralized server to make the comparison between the respective distances and the desired area preselected by the user of the mobile device 100. Within certain distances, mobile devices 100 could identify themselves are concurrently running an echoing application or logged on to a particular website, and could transfer identifiers and media information automatically via any conventional technique, such as Bluetooth®, etc. Then, if the user of the mobile device 100 depicted in FIG. 3 decided to select one or more media on the list to play, a signal would be transmitted to the centralized server requesting to stream the particular media. FIG. 4 is an exemplary mobile device 100, according to an embodiment of the present disclosure. In the depicted embodiment, display area 310 shows a layout of the screen if the user decides to select identifier “Jill S.” 316 for additional options, but does not immediately decide to echo the media by selecting “PLAY.” In FIG. 4, display area 310 shows the precise distance that between “Jill S.” and the depicted mobile device 100 (e.g., 100 ft.). The exemplary display area provides an option for the user to play the media (i.e., “PLAY” 400) or purchase the song, for example (i.e., “PURCHASE” 402). If the user selects to purchase the media, the mobile device 100 can automatically direct the user to a media distributer, such as iTunes, Amazon, etc. According to the exemplary embodiment, the user of the depicted mobile device 100 can select “LINK REQUEST” 410, which can send a signal to the centralized server, instructing the centralized server to send a friend request, for example, for connecting via social networking (e.g., a friend request via Facebook for Google+, or any other social networking outlet). Of course, it is possible that the request can be sent directly to the user of the other device (i.e., “Jill S.”) directly, if contact information is exchanged beforehand, using any conventional technique. According to the exemplary embodiment, the user of the depicted mobile device 100 can select “SEND I.D.” 420, which can send a signal to the centralized server, instructing the centralized server to send an identification message to the mobile device of one or more of the other users, which was echoed by the depicted mobile device 100. Of course, the user of the depicted mobile device 100 can designate and personalize any identifier of his or her choosing to be displayed to the user of the echoed device. In this manner, the user of the echoed device can become aware that another user has echoed the media being played on his or her device, and can receive an identifier of the user who has echoed the media. In accordance with the present disclosure, a user may be allowed to designate a geographic area within which a list of identifiers of other users playing media can be displayed on a user's device, such that the user can select to play (e.g., stream), the same media as one or more of the listed other users (a.k.a. echo). Therefore, as one exemplary advantage to embodiments described herein, the user can network with previously unknown people, based on a common taste in music or other media, for example, as well as a geographic location. While various embodiments of the invention have been described above, it should be understood that they have been presented by way of example only, and not by way of limitation. Likewise, the various diagrams may depict an example architectural or other configuration for the disclosure, which is done to aid in understanding the features and functionality that can be included in the disclosure. The disclosure is not restricted to the illustrated example architectures or configurations, but can be implemented using a variety of alternative architectures and configurations. Additionally, although the disclosure is described above in terms of various exemplary embodiments and implementations, it should be understood that the various features and functionality described in one or more of the individual embodiments are not limited in their applicability to the particular embodiment with which they are described. They instead can be applied alone or in some combination, to one or more of the other embodiments of the disclosure, whether or not such embodiments are described, and whether or not such features are presented as being a part of a described embodiment. Thus the breadth and scope of the present disclosure should not be limited by any of the above-described exemplary embodiments. In this document, the terms “computer program product”, “computer-readable medium”, and the like, may be used generally to refer to media such as, memory storage devices, or storage unit. These, and other forms of computer-readable media, may be involved in storing one or more instructions for use by processor to cause the processor to perform specified operations. Such instructions, generally referred to as “computer program code” (which may be grouped in the form of computer programs or other groupings), when executed, enable the computing system. It will be appreciated that, for clarity purposes, the above description has described embodiments of the invention with reference to different functional units and processors. However, it will be apparent that any suitable distribution of functionality between different functional units, processors or domains may be used without detracting from the invention. For example, functionality illustrated to be performed by separate processors or controllers may be performed by the same processor or controller. Hence, references to specific functional units are only to be seen as references to suitable means for providing the described functionality, rather than indicative of a strict logical or physical structure or organization. Terms and phrases used in this document, and variations thereof, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing: the term “including” should be read as meaning “including, without limitation” or the like; the term “example” is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; and adjectives such as “conventional,” “traditional,” “normal,” “standard,” “known”, and terms of similar meaning, should not be construed as limiting the item described to a given time period, or to an item available as of a given time. But instead these terms should be read to encompass conventional, traditional, normal, or standard technologies that may be available, known now, or at any time in the future. Likewise, a group of items linked with the conjunction “and” should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as “and/or” unless expressly stated otherwise. Similarly, a group of items linked with the conjunction “or” should not be read as requiring mutual exclusivity among that group, but rather should also be read as “and/or” unless expressly stated otherwise. Furthermore, although items, elements or components of the disclosure may be described or claimed in the singular, the plural is contemplated to be within the scope thereof unless limitation to the singular is explicitly stated. The presence of broadening words and phrases such as “one or more,” “at least,” “but not limited to”, or other like phrases in some instances shall not be read to mean that the narrower case is intended or required in instances where such broadening phrases may be absent. Furthermore, although individually listed, a plurality of means, elements or method steps may be implemented by, for example, a single unit or processing logic element. Additionally, although individual features may be included in different claims, these may possibly be advantageously combined. The inclusion in different claims does not imply that a combination of features is not feasible and/or advantageous. Also, the inclusion of a feature in one category of claims does not imply a limitation to this category, but rather the feature may be equally applicable to other claim categories, as appropriate. | <SOH> BACKGROUND OF THE INVENTION <EOH>Existing media providers, such as Pandora, Google Play and Spotify, Ltd., allow listeners to wirelessly stream music on mobile devices. In the case of Spotify, Ltd., for example, a user can choose to display his or her music selections on social networking websites, such as Facebook®, and can instantly share music with his or her Facebook “friends” who also subscribe to the media provider. However, the existing media providers fail to support a mechanism for allowing a user to share, or echo, music, or otherwise connect to other users, who are not currently “friends” via social networking. That is, the existing technology lacks the ability to allow users to establish social interactions with strangers within a predetermined, selectable geographic area, based on a shared interest in chosen media. Therefore, there exists a need for methods and systems capable of allowing a user to designate a geographic area within which a list of identifiers of other users playing media can be displayed on a user's device, such that the user can select to play (e.g., stream), the same media as one or more of the listed other users. Accordingly, the user can network with previously unknown people, based on a common taste in music, for example. | <SOH> SUMMARY OF THE INVENTION <EOH>The presently disclosed embodiments are directed to solving one or more of the problems presented in the prior art, described above, as well as providing additional features that will become readily apparent by reference to the following detailed description when taken in conjunction with the accompanying drawings. One embodiment is directed to a method of echoing media via a mobile device. The method can include displaying automatically to a user, on the mobile device, a list of one or more respective identifiers of one or more other users experiencing respective media within a selectable geographic area; and allowing the user to select whether to play one or more of the respective media on the mobile device. Another embodiment is directed to an apparatus for echoing media. The apparatus includes a display configured to display automatically to a user, on a mobile device, a list of one or more respective identifiers of one or more other users experiencing respective media within a geographic area defined by the user; and a section unit configured to allow the user to select whether to play one or more of the respective media on the mobile device. Yet another embodiment is directed to a system configured to echo media on a mobile device. The system includes a positioning unit configured to determine respective distances of a plurality of mobile device, with respect to a first mobile device; a processor configured to compare the distances between each of the plurality of mobile devices and the first mobile device to a preselected distance selected by a first user of the first mobile device; and transmitter configured to transmit, to the first mobile device, a list of one or more other of the plurality of mobile devices, automatically when any one of the one or more other of the plurality of mobile devices moves within the preselected distance form the first mobile device used by the first user. According to certain embodiments, the list includes personalized and reconfigurable identifiers, respectively, of each user of the one or more other of the plurality of mobile devices that moves within the preselected distance, and the list includes respective media currently being streamed from a centralized server by each user of the one or more other of the plurality of mobile devices that moves within the preselected distance. The system further includes a display unit configured to display automatically, to the first user, the list such that the first user selects whether to stream one or more of the respective media from the centralized server; and a transmitter configured to transmit an indication to the centralized server indicating that the first user has selected to stream one or more of the respective media. According to certain embodiments, the centralized server is further configured to indicate to at least one of the one or more other of the plurality of mobile devices that the first user has se3lected to stream one or more of the respective media. The indication from the centralized server can include a personalized identifier designated by the first user. It is to be understood that both the foregoing general description and the following detailed description are exemplary and are intended to provide further explanation of the claimed subject matter. | H04W4206 | 20171009 | 20180201 | 60363.0 | H04W420 | 1 | MACILWINEN, JOHN MOORE JAIN | MEDIA ECHOING AND SOCIAL NETWORKING DEVICE AND METHOD | SMALL | 1 | CONT-ACCEPTED | H04W | 2,017 |
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15,728,405 | PENDING | MULTI-WALLED PLACEHOLDER | A placeholder for vertebrae or vertebral discs includes a tubular body, which along its jacket surface has a plurality of breakthroughs or openings for over-growth with adjacent tissue. The placeholder includes at least a second tubular body provided with a plurality of breakthroughs and openings at least partially inside the first tubular body. The first and second tubular bodies can have different cross-sectional shapes, can be are arranged inside one another by press fit or force fit or can be connected to each other via connecting pins and arranged side by side to one another in the first body. | 1-52. (canceled) 53. A placeholder for implantation in a human or animal body, the placeholder having a first end, a second end, and a longitudinal axis extending through the first and second ends, the placeholder comprising: an inner wall defining an inner cavity extending along the longitudinal axis, wherein a plurality of openings are defined by and extend through the inner wall; an outer wall positioned around the inner wall, wherein a plurality of openings are defined by and extend through the outer wall; and a connecting portion connecting the inner and outer walls and keeping the inner and outer walls spaced apart from one another in a direction transverse to the longitudinal axis, wherein the openings in the outer wall extend into the space between the inner and outer walls, and the openings in the inner wall connect the space between the inner and outer walls with the inner cavity, to promote in-growth of body tissue; wherein the connecting portions is separable from the inner and outer walls, and wherein when the inner and outer walls are connected to one another by the connecting portion, the connecting portion extends into both the inner and outer walls and has a widened portion positioned in the inner cavity. 54. The placeholder of claim 53, wherein the connecting portion comprises a screw or a rivet. 55. The placeholder of claim 53, wherein the widened portion of the connecting portion forms a stop configured to abut the inner wall when the inner and outer walls are connected to one another by the connecting portion. 56. The placeholder of claim 55, wherein the connecting portion comprises a second stop configured to abut the outer wall to maintain a constant spacing between the inner and outer walls. 57. The placeholder of claim 53, wherein the outer wall comprises an engagement structure for engaging the connecting portion when the inner and outer walls are connected to one another by the connecting portion. 58. The placeholder of claim 57, wherein the engagement structure comprises a threaded hole in the outer wall. 59. The placeholder of claim 53, wherein when the inner and outer walls are connected to one another by the connecting portion, the widened portion is positioned in the inner cavity, while an opposite end of the connecting portion extends entirely through the outer wall and past an outer surface of the outer wall. 60. The placeholder of claim 53, wherein the placeholder comprises a plurality of the connecting portions to connect the inner and outer walls to one another. 61. The placeholder of claim 53, wherein the outer wall is spaced apart equidistantly from the inner wall along at least a portion of a perimeter of the inner wall. 62. The placeholder of claim 53, wherein the placeholder comprises a vertebral implant, where the first and second ends are configured to contact vertebrae. 63. The placeholder of claim 53, wherein the inner and outer walls each comprises titanium. 64. A placeholder for implantation in a human or animal body, the placeholder having a first end, a second end, and a longitudinal axis extending through the first and second ends, the placeholder comprising: an inner wall defining an inner cavity extending along the longitudinal axis, wherein a plurality of diamond-shaped openings are defined by and extend through the inner wall; an outer wall positioned around the inner wall, wherein a plurality of diamond-shaped openings are defined by and extend through the outer wall; and a plurality of connecting portions arranged at a plurality of different axial positions along the longitudinal axis to connect the inner and outer walls and to keep the inner and outer walls spaced apart from one another in a direction transverse to the longitudinal axis, wherein the openings in the outer wall extend into the space between the inner and outer walls, and the openings in the inner wall connect the space between the inner and outer walls with the inner cavity, to promote in-growth of body tissue; wherein at least one of the openings in the inner wall is aligned with one of the openings in the outer wall, such that a pathway having a diamond-shaped profile corresponding to the at least one opening in the inner wall extends entirely unobstructed from the inner cavity through the inner and outer walls to an outside of the placeholder. 65. The placeholder of claim 64, wherein a plurality of pathways having diamond-shaped profiles corresponding to respective ones of the openings in the inner wall extend entirely unobstructed from the inner cavity through the inner and outer walls to the outside of the placeholder. 66. The placeholder of claim 64, further comprising a third wall positioned around the outer wall, wherein a plurality of diamond-shaped openings are defined by and extend through the third wall, and wherein the pathway having the diamond-shaped profile extends unobstructed from the inner cavity through the inner wall, the outer wall, and the third wall to the outside of the placeholder. 67. The placeholder of claim 64, wherein at least two of the openings in the outer wall are aligned laterally at a same axial position along the longitudinal axis, and wherein at least two of the openings in the outer wall are at different axial positions. 68. The placeholder of claim 64, wherein in a plane transverse to the longitudinal axis, the outer wall has an oblong cross-sectional shape. 69. The placeholder of claim 64, wherein the inner cavity is open at both the first and second ends of the placeholder. 70. The placeholder of claim 64, wherein the space between the inner and outer walls is open at both the first and second ends of the placeholder. 71. The placeholder of claim 70, wherein at least part of the space between the inner and outer walls extends unobstructed between the first and second ends of the placeholder. 72. The placeholder of claim 64, wherein the outer wall is spaced apart equidistantly from the inner wall along at least a portion of a perimeter of the inner wall. 73. The placeholder of claim 64, wherein the placeholder comprises a vertebral implant, where the first and second ends are configured to contact vertebrae. 74. The placeholder of claim 64, wherein the inner and outer walls each comprises titanium. | CROSS-REFERENCE TO RELATED APPLICATION(S) This application is a continuation of U.S. patent application Ser. No. 15/012,827, filed Feb. 1, 2016, which is a continuation of U.S. patent application Ser. No. 13/914,471, filed Jun. 10, 2013, now U.S. Pat. No. 9,254,199, which is a continuation of U.S. patent application Ser. No. 11/645,228, filed Dec. 22, 2006, now abandoned, which claims the benefit of and priority from U.S. Provisional Patent Application Ser. No. 60/753,854, filed Dec. 23, 2005, and the benefit of and priority from U.S. Provisional Patent Application Ser. No. 60/808,028, filed May 23, 2006, the disclosures of all of which are incorporated herein by reference. BACKGROUND The present invention refers to a placeholder for implantation into a human or animal body, especially as a placeholder for vertebrae or vertebral discs, a method for manufacturing such a placeholder, and a modular system for such a placeholder. Placeholders, especially for vertebrae or vertebral discs are known. For example, DE 19504867 C1 discloses a placeholder in the shape of a cylindrical-tubular body with a plurality of rhombic or diamond-shaped openings that are arranged in rows and columns. At the ends of the cylindrical tube are provided projecting serrations and recesses in correspondence with the rhombi that serve for engaging with adjacent vertebrae or adjacent tissue. The diamond-shaped openings facilitate in-growth of the tissue into the implant, such that the latter may knit well with the body. Moreover, an implant is known from US 2005/0015154 which has a scaffold-like structure in which the latticework extends over the full body or through the entire body of the implant. Such integral latticework structures are intended for use especially in replacement implants for joints, such as hips, knee joints, shoulder joints and the like. However, such integral latticework structures are difficult to manufacture and have to be adjusted and manufactured individually to suit every application case. DE 101 38 079 AI discloses a placeholder of adjustable axial length in which two sleeve-like parts are arranged adjustably inside one another, more precisely via a lever arrangement over which the parts are connected. Although this device facilitates very precise length adjustment, the lever arrangement is complicated to manufacture. DE 198 04 765 C2 discloses a placeholder for insertion between two vertebrae with an adjustable axial length. The total length is adjusted by moving an external tube relative to an internal tube. The length adjustment proceeds stepwise by means of catches. DE 697 19 431 T2 describes a longitudinally adjustable vertebral disc placeholder in which two sleeve bodies arranged telescopically inside one another are adjusted relative to each other and are lockable via screw arrangements. However, this arrangement does not uniformly distribute the load across the screw connections and does not effectively allow in-growth by the surrounding tissue because of the close arrangement of the sleeve bodies. US 2003/0078660 discloses an implant that may be used as a placeholder in which the implant has a sleeve-like body that is corrugated. This corrugated body may in turn be arranged inside a further sleeve body. However, the corrugated form of the one implant part again makes for complicated manufacture. EP 09 047 51 AI describes a tubular support body for vertebrae having two cages guided in one another which may be connected to each other by a projecting stud on the jacket surface of the one cage and axial feed channels in the jacket of the other cage. With this arrangement, facilitating of latching positions at different depths is provided. However, the support body is limited in variability by the feed channels. Based on the above, there is a need for an implant which is easy to manufacture and versatile in use, can provide load dissipation, allows in-growth into human or animal tissue, and is suitable for use as placeholder in the spine, that is, for vertebral discs and vertebrae, but also for tubular bones of the upper and lower extremities. SUMMARY According to one aspect of the present invention, several tubular bodies, namely a first tubular body and at least a second tubular body, are provided at least partially one inside the other, such that a multi-wall placeholder is formed which not only provides load-absorbing properties but also is suitable for allowing in-growth of adjacent tissue. The cross-sectional shapes of the first and the second bodies in a cross-sectional plane transverse to the longitudinal axis of the placeholder can be different. In particular, the second body arranged in the first body can have a simple or basic geometric shape, namely, a shape which is easy to manufacture. Such shapes include cylindrical or cuboid shapes with round, oval, rectangular or triangular cross-sections. In addition, a shape having a constant cross-section along its length may be used. Such simple geometrical basic shapes for the first and second bodies may be used to generate suitable mechanical properties, yet are affordable and easy to manufacture. The multi-wall placeholder described herein also provides a large contact surface with the bone at the front face of the placeholder. In addition, with a preassembled multi-wall placeholder, a better adjustment to the bone is possible. Consequently, subsidence of the placeholder may be considerably reduced, if not completely prevented. This can be important for weak osteoporotic vertebrae. The placeholder according to the present invention may also include a plurality of second tubular bodies nested inside each other, all of which are at least partially disposed in the first tubular body. In one embodiment, the first body may have a circular cross-sectional shape, while the second body or bodies may have a triangular, square, hexagonal, octagonal or generally polygonal, oval or kidney cross-sectional shape. In a further embodiment, the first tubular body, i.e., the external body may have a cross-sectional shape other than that of a circle, such as an oval or kidney cross-sectional shape, in which case the second body may have a correspondingly adjusted different cross-sectional shape, as described above or a similar shape. According to another aspect of the present invention, which is also applicable to all disclosed aspects of the invention, several second bodies may be arranged alongside each other in the first body. Accordingly, this arrangement can also achieve mechanical stability and/or ease of in-growth by the surrounding tissue into the placeholder. In addition, the wall thicknesses of the individual components, i.e. of the tubular bodies, may be kept small so as to facilitate in-growth of the tissue into the tubular bodies and thus into the implant. By providing several second bodies in the first body, e.g., two or three second bodies, the wall thickness of the individual tubular bodies can be reduced, while the overall loading capacity can be improved. The arrangement of two, three or several second bodies in the first body is applicable to all disclosed aspects of the invention. The second bodies can be spaced from each other and/or from the first body to promote in-growth of body tissue between the bodies. This also allows for more precise adjustment relative to the adjacent bone or to a placeholder end plate. Moreover, the spacing between the bodies will result in better in-growth and a more homogeneous distribution of the load across the cross-section of the implant. In the case of the arrangement of several second bodies in the first body, the arrangement of the second bodies may be such that their longitudinal axes are offset parallel to the tubular longitudinal axis of the first body. The result of this is that greater stability can be obtained for certain instances of mechanical loading. For example, the offset arrangement of the bodies may lead to greater stability in the case of flexural stress. Overall, the cross-sectional shape of the first and/or second bodies may assume diverse shapes, namely circles, triangles, oblongs, rectangles, squares, diamonds, (rhombi), polygons, hexagons, octagons, especially with rounded corners, ovals, kidney shapes or any free-form shapes. However, the shape can be restricted to certain basic shapes as this simplifies manufacturability. Among the basic shapes are especially circles, triangles, oblongs, rectangles, squares, diamonds, hexagons, all angular shapes including those with rounded corners and ovals and kidney shapes. According to a further aspect of the present invention, which is also applicable to all disclosed aspects of the invention, the second body or bodies can be accommodated in the first body by means of a press fit or force fit. For example, the outer dimension of the second body or bodies is larger than the inner dimension of the first body. This results in an elastic deformation of the bodies in the case of a force fit or an additional plastic deformation in the case of press fit. Alternatively, a connecting element or retaining element between the bodies can be a force fit or press fit. The press fit or force fit may thus be directly affected by contact between the first body and the second body/bodies or by the connecting elements. Alternatively, according to a further aspect of the invention, the connections between the bodies and/or connecting elements may take place by means of friction, a material or a positive connection (form-fit). According to another aspect of the present invention, which is also applicable to all disclosed aspects of the invention, the placeholder comprises a first tubular body having a jacket surface with a plurality of openings for over-growth with adjacent tissue and a second tubular body having a jacket surface with a plurality of openings, the second tubular body disposed at least partially inside the first tubular body. At least one spacer may be used wherein the second tubular body is spaced apart with the at least one spacer from the first tubular body. The spacer may also take the form of a connecting element configured to connect the first tubular body to the second tubular body. In particular, the connecting elements may comprise retaining plates and/or connecting pins. The retaining plates may be formed as plates or rings arranged transversely to the tubular longitudinal axis that are held by press fit or force fit or screw or rivet connections or generally by means of friction, a material or a positive connection (form-fit) in the first body. The second bodies may preferably also be held by press fit or force fit or again by connecting pins or generally by means of friction, a material or a positive connection. This means that the second bodies, for example may form a structural unit with the connecting elements, which is then held overall by means of a press fit or force fit in the first body. The connecting pins may be formed as rivets, screws and/or bars, which are welded, for example. For arranging the second bodies in the first body, at least one, but preferably several, and especially two retaining plates may be provided. The arrangement of the retaining plates may occur at the ends of the tubular bodies as end plates or distributed along the length of the tubular bodies as intermediate plates. The retaining plates may have a plurality of openings as well, more precisely in addition to the receivers, by means of which the second bodies are received and held. The plurality of openings again serves the purpose of in-growth of adjacent tissue. In addition or as an alternative to the retaining plates, connecting pins may be provided, which are formed especially as rivets, screws and/or bars, which are, for example, welded. The connecting pins preferably have stop faces for spaced retention of the bodies, for example a stop face may be provided by a corresponding rivet or screw head, while a second stop face may be provided in the vicinity of the thread or of the end of the rivet opposite the head. The connecting pins may be arranged in the openings or breakthroughs in the jacket surface of the tubular bodies which are provided for knitting with adjacent tissue. Alternatively, separate connecting openings may be provided for receiving the connecting elements in the tubular bodies or other components of the implant, such as the retaining plates. In the case of screw connections, preferably the thread holes are provided in the first outer body, such that the screw with its screw head lies on the inside. This results in a smooth external side without projections parallel to the tubular longitudinal axis. According to a further aspect of the invention, which is also applicable to all disclosed aspects of the invention, the tubular bodies can be arranged at least partially inside each other and may be connected by means of detachable connecting means or connecting means attachable or connectable directly at the point of use, such that a modular system is created, which facilitates in simple fashion individual adjustment to requirements. Accordingly, a modular system of several tubular bodies and corresponding connecting means may be provided, with the surgeon composing the corresponding placeholders to suit individual needs directly at the point of use. Naturally, however, the placeholders may also be supplied ready-made. But, even here, changes may still be made in the case of detachable connecting means. Additionally, a connection of the tubular bodies can be provided merely at a few sites on the jacket surface and/or in the vicinity of the front faces, such that, when viewed along the full length of the placeholder, free space that is available for in-growth of tissue is created in wide areas between the placeholders. For example, the connecting elements may be restricted to a total of 2 to 24, preferably 2 to 12 elements, and/or 2 to 4, especially 3. In another embodiment, three connecting elements may be assigned to each row of openings or breakthroughs in the jacket surface. The connecting elements may cooperate with the breakthroughs themselves or with further receivers, recesses or holes, such as thread holes. In a further embodiment, the tubular bodies may be arranged concentrically, such that parallel wall areas are formed, especially in the case of the same cross-sectional shapes. In yet another embodiment also applicable to all disclosed aspects of the invention, the connecting elements may preferably be variably attached in the openings of the jacket surface of the tubular bodies, such that the tubular bodies may be arbitrarily aligned and arranged relative to each other. For example, the bodies can be arranged such that they are not completely inside each other, but to, for example, leave them projecting out in the longitudinal direction. This means that the length or height of the placeholders may be adjusted, since the different tubular placeholders arranged inside one another may be retracted telescopically from each other or, conversely, pushed into each other in order for them to be subsequently fixed in this position. This is especially possible continuously or in steps. Additionally, the tubular bodies may also be rotated against each other, such that the openings provided in the jacket surfaces are in alignment or staggered relative to, for example, one or two adjacent bodies or all bodies. Also, the tubular bodies may have different forms, especially different wall thicknesses, such that, for example, the external tubular body may be very thin in order to facilitate rapid over-growth or in-growth by the surrounding tissue through the openings, while the internal body or bodies have a greater wall thickness to impart stability to the placeholder. The different shapes which are possible for the cross-sectional shapes are also conceivable for the openings or breakthroughs in the jacket surface of the tubular bodies, such that their external contour, too, may have the shape of a circle, a triangle, an oblong, a rectangle, a square, a hexagon, an octagon, generally a polygon with or without rounded corners, a diamond or similar. In all aspects, the tubular bodies may be arranged spaced apart from each other, with this space either provided by the connecting elements that connect the tubular bodies and/or separate spacers that may be provided, especially on the inside and/or outside of the jacket surface, preferably in the shape of bars or plates projecting at right angles towards the outside or the inside. On account of the spacing of the tubular bodies, sufficient space is available for in-growing tissue. Furthermore, on account of the spaced arrangement of tubular bodies, correspondingly broad contact surfaces may form at the ends or front faces that render separate attachment of end plates or similar unnecessary. The tubular bodies may also have, at least on one end, or on both ends, projections and/or recesses which enable engagement with adjacent vertebrae or other tissue and facilitate in-growth. The connecting elements, which may be formed by pins, bolts, catches, screws, end plates and similar, may be variably accommodated, especially at the openings or breakthroughs of the jacket surface, such that no additional separate receivers need to be provided for the connecting elements. This can reduce outlay and simplifies manufacturability. Nonetheless, corresponding separate receivers may be provided at the jacket surfaces of the tubular bodies. In a further embodiment, the placeholders have, at the front faces of the tubular bodies, at least one, preferably two end plates, which simultaneously serve as connecting means. The end plates, which, for example, are annular, have for this purpose cut-outs and/or recesses into which the projections at the ends of the tubular bodies may engage, especially positively and/or non-positively. The annular end plate may function as a tensioning or spring-loaded ring that has a separating gap or slit, such that the projections provided in the cut-outs or recesses of the tubular bodies are held by means of friction by the end plate. Correspondingly, the intermediate plates or retaining plates may also be formed generally as tensioning or spring-loaded rings. Alternatively or additionally, it is naturally also possible to have a bonded (material) connection of end plates or retaining plates and tubular bodies, such as by means of welding, especially laser welding, as also applies to the other connecting means, especially those provided in the vicinity of the jacket surfaces, The tubular bodies and/or the connecting elements may be coated or have received a surface treatment. For example, coatings to be mentioned in this regard are hydroxy apatite or plasma treatments, which, for example, may lead to a rough titanium surface if titanium or titanium alloys are used as material. Overall, all suitable biocompatible materials having the corresponding properties may be used for the various components, such as tubular bodies and connecting elements. Preferred are biocompatible polymers or metals, such as titanium or titanium alloys, or also nitinol, a nickel-titanium alloy. Especially, different materials may also be used for the various components. According to a further aspect, the placeholder has at least two different tubular bodies, for example, one body differing in diameter from the other. These bodies are arranged at least partially inside each other, and the bodies are then connected to each other, preferably detachably, by means of at least one connecting element. In this regard, the arrangement of the tubular bodies may be varied relative to each other, e.g., along the longitudinal axis. This is especially true if the connecting elements may be used at many locations along the tubular bodies. Additionally, the angle arrangement between bodies may be varied. Through the structure of the tubular bodies of the invention, which is described in detail especially in the following embodiments, it is also possible to adjust the length and/or the alignment of the ends of the tubular bodies by means of cutting to length at any site, The result is a further increase in the variability of use. Additionally, the placeholders may be coated or subjected to surface treatment not only altogether following assembly, but also individually before the components are assembled. Accordingly, even in the case of parts on the inside, such as a cylindrical tubular body arranged lying on the inside, said body may be coated or surface treated prior to assembly, such that complete coating or surface treatment here may occur. In another embodiment, the present invention provides a modular, individually usable system for placeholders, e.g., through the use of individual components, which can be used alone, preassembled or selectively assembled. The corresponding placeholder has an extremely large surface area due to its many walls and construction from several tubular bodies, and thus markedly facilitates in-growth and on-growth. Additionally, despite the very large surface area, manufacturability is improved and, in particular, coatability and surface treatability are improved. This also results in improved in-growth properties. In particular, the modular assembly allows for individual surface treatment of the single components. Thus, different coating of the individual components may take place, i.e., of the various cylindrical-tubular bodies located in the different positions. This results in an implant having good mechanical stability and improved in-growth characteristics, which is especially suitable for vertebral discs or placeholders. An optimum fusion element for orthopedics is thus achieved. BRIEF DESCRIPTION OF THE DRAWINGS Further, characteristics and features of the invention are apparent from the following description of preferred embodiments using the enclosed drawings. The drawings show in purely schematic form, in FIG. 1 a first embodiment of a placeholder of the invention; FIG. 2 a plan view of the placeholder from FIG. 1; FIG. 3 a three-dimensional representation of a further placeholder of the invention with a detailed representation of the jacket surface; FIG. 4 a plan view of the placeholder from FIG. 3; FIG. 5 a three-dimensional representation of a third embodiment of a placeholder of the invention; FIG. 6 a plan view of the placeholder from FIG. 5; FIG. 7 a perspective representation of the placeholder from FIG. 5 without end plate; FIG. 8 a plan view of the placeholder from FIG. 7; FIG. 9 perspective representations of two individual tubular bodies and the placeholder in the assembled state and plan views of the respective tubular bodies; FIG. 10 a perspective view of a further embodiment of a placeholder of the invention with a detailed view of the jacket surface; FIG. 11 a perspective representation of a further embodiment of a placeholder of the invention with a detailed view of the jacket surface; FIG. 12 a perspective representation and a plan view of a further embodiment of a placeholder of the invention; FIGS. 13 (a)-(c) a perspective representation, a lateral view and a plan view, respectively, of a further placeholder of the invention; FIG. 14 perspective representation of a further embodiment of a placeholder of the invention; FIG. 15 perspective representation of the embodiment of the placeholder from FIG. 14 in a shorter variant; FIG. 16 a plan view of the placeholder in accordance with FIG. 15; FIG. 17 a perspective representation of a further embodiment of the placeholder of the invention; FIG. 18 a plan view of the placeholder from FIG. 17; FIG. 19 a perspective representation of a further embodiment of a placeholder of the invention; FIG. 20 a plan view of the placeholder from FIG. 19; FIG. 21 a perspective representation of a further embodiment of a placeholder of the invention; FIG. 22 a plan view of the placeholder from FIG. 20; FIG. 23 a perspective representation of a further embodiment of a placeholder of the invention; FIG. 24 a plan view of the placeholder from FIG. 23; FIGS. 25 to 29 representations of cross-sectional shapes of tubular bodies for the present invention; FIGS. 30 to 35 representations of the shapes of breakthroughs or openings in the jacket surface of a placeholder or tubular body of the invention; FIG. 36 a perspective representation of a screw connection; FIG. 37 a cross-sectional view of the screw connection from FIG. 36; FIG. 38 a perspective view of a connecting pin as screw; FIG. 39 a perspective view of a rivet connection; FIG. 40 a cross-sectional view of the rivet connection from FIG. 39; FIG. 41 a perspective representation of the rivet from FIGS. 39 and 40 in the un-riveted state; FIG. 42 a perspective representation of the rivet from FIG. 41 in the riveted state; FIG. 43 a first example of a use of a placeholder of the invention in a schematic lateral representation; FIG. 44 a further schematic lateral representation of a further embodiment for the use of a placeholder of the invention; and FIG. 45 a lateral view of a third application example for the present invention. DETAILED DESCRIPTION FIG. 1 shows a perspective representation of a first embodiment of a placeholder 1 of the invention in which the tubular bodies 2, 3 and 4 are partially arranged inside each other. The tubular body 4, which has the largest diameter, accommodates the tubular bodies 2 and 3 of smaller diameter. Tubular body 3, which has the next largest diameter, accommodates the tubular body 2 of the smallest diameter. The tubular body 3 is arranged in the tubular body 4, such that it projects over the edge 5 of the tubular body 4 in the direction of the longitudinal axis of the placeholder 1. Similarly, the tubular body 2 is arranged in the tubular body 3, such that it projects over the edge 6 of the tubular body 3. The tubular bodies 2, 3 and 4 are connected to each other via pins 8 (see FIG. 2), which are detachably inserted by press fit through cut-outs or holes 25 (see FIG. 3) of the tubular bodies 2, 3, 4. Accordingly, it is possible, when the pins 8 have been removed, to adjust the length or height of the placeholder 1 by mutually pushing the tubular bodies 2, 3, 4 against each other along the longitudinal axis of the placeholder 1. At the desired length or height, the tubular bodies 2, 3, 4 may be attached to each other and fixed in the corresponding position by inserting the corresponding pins 8 into the holes 25. The pins 8 may have corresponding stopping and/or catching means at their ends, such as hooks (not shown), to ensure that pins 8 are secured in the holes 25. Additionally, other connecting means, such as screws with threaded holes and the like, are conceivable. The tubular bodies 2, 3, 4 have at their jacket surface 10 a plurality of openings 9, which in the embodiment shown in FIG. 1, have a hexagonal shape and are uniformly arranged in rows and columns, such that a generally honeycomb structure is produced. On account of this honeycomb structure, simple in-growth of tissue is ensured combined with simultaneous stability and strength of the placeholder 1. Additionally, the weight of the placeholder 1 is reduced. Due to the multiple wall formation on account of the arrangement of tubular bodies 2, 3 and 4 inside each other, in-growth of tissue is not hampered at least in the overlapping regions despite increased stability and strength. FIGS. 3 and 4 are a perspective representation (FIG. 3) and a plan view (FIG. 4) of a further embodiment of a placeholder 1 in accordance with the invention, in which similar or identical parts are provided with the same numerals. The embodiment of FIGS. 3 and 4 differs from that of FIGS. 1 and 2 essentially in that the tubular bodies 2, 3 and 4 are completely accommodated inside each other such that the tubular bodies 2 and 3 do not project beyond the upper edge 5 of the tubular body 4. As a result, the edges 7, 6, 5 of the tubular bodies 2, 3 and 4 form a common contact plane for, e.g., an adjacent vertebra. Due to the three tubular bodies 2, 3 and 4 being arranged inside each other, and being spaced apart from each other, the result as compared to a single tubular body, is a much greater contact surface in the form of a ring, without the need to provide additional end plates or the like. The ends of the tubular bodies 2, 3 and 4 of the embodiments of FIGS. 1 to 4 each have projections in the form of projecting bars or spikes 11 (referred to herein as projections 11) and indentations 12, such that overall corrugated edges 7, 6 and 5 result. The projections 11 and the indentations 12 can be made by cutting off or cutting to length the structure of the tubular bodies 2, 3 and 4 perpendicular to the longitudinal axis, and more precisely approximately in the middle of a series of openings 9. Correspondingly, each indentation 12 has a shape with parallel wall sections formed by the projections 11 and a triangular bottom, which connects the parallel wall sections. The projections 11 and the indentations 12 engage with adjacent body parts, such as vertebrae or adjacent tissue and permit over-growth with corresponding tissue. Moreover, the detailed representation of FIG. 3 shows the holes 25 or receivers for the pins 8 for connection of the tubular bodies 2, 3, 4. Instead of the pins 8 and holes 25, screws and threaded holes could also be used. In FIG. 4, it may be seen that the concentrically arranged tubular bodies 2, 3 and 4, which are each formed as a cylinder in the embodiments of FIGS. 1 to 4, are spaced apart from each other and held by individual, thin bars 13, which, in turn, are radially spaced apart from each other by a certain angle. In the embodiment shown in FIG. 4, the bars 13 are radially spaced apart from each other by an angle of 120°. In contrast to the pins 8, which may be detachable and/or attachable directly during the surgery involving the placeholder 1 of the embodiments of FIGS. 1 and 2, the bars 13 may have a solid bonded connection (material connection) for example by means of laser welding, with the tubular bodies 2, 3 and 4, such that the placeholder is ready-made. FIGS. 5 to 8 show in various representations a further embodiment of a placeholder 1 in accordance with the invention, which, like the embodiments of FIGS. 1 to 4, may especially be used as placeholders for vertebrae. Here, too, identical or similar components are provided with the same reference numerals. The embodiment of FIGS. 5 to 8 has, as especially shown by FIG. 8, two tubular bodies 3 and 4, which are arranged with tubular body 3 completely accommodated in the tubular body 4. The embodiment of FIGS. 5 to 8 differs from the embodiments of FIGS. 1 to 4 in that, at each of the upper and lower ends, an end plate 14 in the shape of an annular disc is provided, which is subdivided by a slit or gap 16. Moreover, several rectangular cut-outs 15 are arranged annularly in the end plate 14. Accordingly, as particularly shown from the plan view of FIG. 6, the cut-outs 15 accommodate the projections 11 of the tubular bodies 4 and 3. Due to the slit 16, the annular end plate 14 functions as a tensioning or spring-loaded ring. For example, the width of the gap 16 can be elastically reduced by squeezing the ends 17 and 18 together when the end plate 14 is arranged. Due to the elastic recovery forces of the annular end plate 14, on being released after placement on the tubular bodies 3 and 4 and the insertion of the projections 11 into the cut-outs 15, the end plate 14 relaxes, with the projections 11 being squeezed and pressed against the edges of the cut-outs 15. Thus, the end plate 14 is held against the projections 11 non-positively or by friction. Support of this kind is also possible for retaining plates that are not arranged at the ends of the tubular bodies but positioned along the length of the tubular bodies at locations intermediate the ends of the tubular bodies. FIGS. 7 and 8 show the placeholder 1 of FIGS. 5 and 6 in a representation without the end plates 14. Here it may be seen that the tubular bodies 3 and 4 are kept spaced apart merely on account of the end plates, without the need for additional connecting elements or spacers. FIG. 9 shows a further embodiment of a placeholder 1 in accordance with the invention, with the tubular bodies 3 and 4 initially shown individually and, in the right sub-figure, in the assembled state. Aside from the perspective representations, the lower part of FIG. 9 shows the plan views of the tubular bodies 3 and 4. Again, identical or similar components are provided with the same numerals, as in the previous embodiments. While the external tubular body 4 essentially corresponds to the previous embodiments, the inner tubular body 3 additionally has spacers 19 in the form of plates, which project perpendicularly outwards in several rows on the jacket surface 10 of the tubular body 3. The spacers 19 may either be formed integrally with the cylindrical body 3 or attached to it by means of bonded (material), positive (form-fit) or non-positive (frictional) connection, Naturally, it is also conceivable for the spacers 19 to be similarly provided on the inside of the external tubular body 4 or on both tubular bodies 3 and 4. The individual spacers 19 are radially spaced around the circumference of the tubular body 3 at a specific angle, more precisely, in the embodiment shown in FIG. 9, each at an angle of 40°. Naturally, more or fewer spacers 19 may be arranged around the circumference or in a row, more or fewer rows and also at different distances. In the embodiment shown, the spacers 19 may also be used simultaneously as connecting elements between the tubular bodies 3 and 4, for example by corresponding catch, interlocking or clip connections. This is possible, for example, if corresponding cut-outs are provided on the inside of the tubular body 4 into which the spacers 19 may engage. For example, the dimensions of the inner diameter of the tubular body 4 and the outer diameter of the tubular body 3 with the spacers 19 may be designed such that the outer diameter of the tubular body 3 with the spacers 19 is slightly greater than the inner diameter of the tubular body 4, such that one or both of the bodies 3 and 4 is elastically extended or compressed, respectively, during assembly and relaxation then occurs when the spacers 19 engage with the corresponding cut-outs or recesses (not shown) on the inside of the tubular body 4 in order to simultaneously act as connecting elements. FIGS. 10 and 11 show further embodiments of placeholders in accordance with the invention, and find application, for example, in the case of or for replacing vertebral discs. Here again, identical or similar parts are provided with the same numerals. FIGS. 10 and 11 illustrate especially by way of the enlarged detailed views of the jacket surface 10 that the tubular bodies 3 and 4 may be aligned differently, more precisely on the one hand such that the openings 9 are flush or aligned with each other, as shown in FIG. 11, or, offset, as shown in FIG. 10. In an offset arrangement of the openings 9, the bar-like regions of the mantle jacket I0 of the inner tubular body 3 may be seen behind the opening 9 of the external tubular body 4, whereas the bar-like regions of the jacket surface I04 of the external tubular body 4 partially cover the opening of the tubular body 3. In contrast, in the case of the flush alignment of openings 9 of the tubular bodies 3 and 4, the jacket surface region I03 of the inner tubular body 3 is arranged behind the jacket surface region I04 of the external tubular body 4 and a through-opening 9 is created in the jacket surfaces 10 of the bodies 3 and 4. FIG. 12, in turn, shows a placeholder for vertebrae that essentially corresponds to the previous embodiments and thus has the same numerals for identical or similar components. In the placeholder 1 of FIG. 12, the tubular bodies 2, 3 and 4 are again inserted in each other, the particular feature here being that the tubular bodies 2, 3 and 4 have different wall strengths or thicknesses, as is especially evident in the plan view in the right sub-figure of FIG. 12. Thus, the inner and outer tubular bodies 2 and 4 are thinner than the central tubular body 3. Thus, the central tubular body 3 contributes the most to strength and stability, while the outer and inner tubular bodies 4 and 2 facilitate rapid in-growth and over-growth due to the low wall thickness. Spacers, such as pins 8 or bars 13, are not shown herein for illustration purposes. FIG. 13 shows in the three sub-views (a) to (c), a perspective view (a), a lateral view (b) and a plan view (c) of a placeholder 1 for a vertebral disc. Here, again, identical or similar components are provided with the same numerals, as in the previous embodiments. The embodiment of FIG. 13 corresponds to the placeholder 1 of FIG. 3, the difference being that just two tubular bodies 3 and 4 are provided and that only a single row of completely formed openings 9 is provided. Correspondingly, the height or length of the placeholder 1 of FIG. 13 is markedly reduced relative to that of the placeholder 1 from FIG. 3. This corresponds to the different use purposes, namely on one hand to serve as placeholder for vertebrae (FIG. 3) and on the other to be used as placeholder for a vertebral disc (FIG. 13). FIG. 14 shows in a further embodiment a perspective view of a placeholder in accordance with the invention in which again identical numerals are used for the same or similar components, as in the previous embodiments. The placeholder 1 in FIG. 14 has a first, tubular body 4 with a cylindrical tubular shape, which in turn possesses a plurality of diamond-shaped openings 9, which are arranged in rows and columns to form a honeycomb structure. The diamond-shaped openings 9 are limited by bars 10, which, as in the previous embodiments, form projections 11 and recesses 12 at the upper and lower edge at the ends of the cylindrical tubular body 4. In the external tubular body two retaining plates 30 are arranged, that are provided in the end regions of the tubular body 4. The retaining plates 30 are completely accommodated in the tubular body 4 and are held there by press fit or force fit. Correspondingly, the outer diameter of the retaining plates 30 is chosen somewhat larger than the inner diameter of the tubular body 4, such that the parts are elastically tensioned. Other suitable means to secure the retaining plates may also be used. The circular, disc-shaped retaining plates 30 have a plurality of openings 31, which facilitate in-growth and permeation by tissue. Additionally, receiving openings 32 are provided in which second, cylindrical-tubular shaped bodies 3′, 3″ and 3′″ are accommodated, which in their shape and form correspond to that of the external tubular body 4. However, the second tubular bodies 3′, 3″ and 3′″ differ with regards to their dimensions, i.e. the diameter of the second tubular bodies 3′, 3″ and 3′″ is chosen much smaller than that of the external tubular body 4. The receiving openings 32 of the retaining plates 30 are arranged at the corner points of an imaginary triangle (shown in FIG. 16 with dashed lines), such that the second tubular bodies 3′, 3″ and 3′″ are accommodated side by side to each other in the interior space of the external tubular body 4. The tubular longitudinal axes of the second tubular bodies 3′, 3″ and 3″, which run through the center of the circular cross-section of the second tubular bodies 3′, 3″ and 3″, are therefore offset parallel to the longitudinal axis of the external tubular body 4. The second tubular bodies 3′, 3″ and 3′″ are also accommodated by press fit or force fit in the receivers 32 of the retaining plates 30. The outer diameter of the second tubular bodies 3′, 3″ and 3′ is thus again chosen somewhat greater than the diameter of the receiving openings 32, such that, on insertion of the second tubular bodies 3′, 3″ and 3″, elastic deformation of the second tubular bodies 3′, 3″ and 3′″ and of the retaining plates 30 occurs, which effects the press fit of the tubular bodies 3′, 3″ and 3′″ in the receiving openings 32. While the embodiment of FIG. 14 may be used as a placeholder for vertebrae, the variant shown in FIG. 15, also in a perspective representation, is intended as a replacement for vertebral discs. Correspondingly, the placeholder 1 of FIG. 15, in which again identical or similar components are provided with identical numerals as in the previous embodiments, is chosen much smaller in length. Correspondingly, only a single retaining plate 30 is provided, instead of the two retaining plates of the embodiment of FIG. 14. The retaining plate 30 in the embodiment of FIG. 15 is arranged approximately in the middle of the height of the placeholder. Other than the differences described herein, the embodiment of FIG. 15 does not differ from that of FIG. 14. FIG. 16 shows a plan view of the embodiment of FIG. 15 in which the arrangement of the external tubular body 4 and of the second, inner tubular bodies 3′, 3″ and 3′″ is clearly shown. Further, the openings 31, which are provided in the retaining plates 30 for in-growth and permeation by tissue, are shown. The openings 31 may have different sizes as shown. Overall, with the embodiments of FIGS. 14 to 16, an implant or placeholder is provided which, on account of the chosen press fit or force fit arrangement, is readily manufacturable and whose components facilitate simple and variable arrangement. Additionally, sufficient free space for in-growth by tissue to the external tubular body 4 is provided by the arrangement of the tubular bodies 3′, 3″, and 3′″. At the same time, however, sufficiently large contact surfaces on the ends of the placeholder 1 are provided for accommodating and dissipating load. FIGS. 17 to 24 show different embodiments in which, without use of a retaining plate, several or individual second tubular bodies 3 of different shapes are accommodated in differently shaped external tubular bodies 4, again by press fit or force fit. In the embodiment which, in FIGS. 17 and 18, is shown in perspective and plan view representations, respectively, the external tubular body 4 has, in a cross-sectional plane perpendicular to the tubular longitudinal axis, i.e. perpendicular to the jacket surface, a kidney shape, whereas the second tubular bodies 3′, 3″ and 3′″ accommodated in the external tubular body 4 have a circular cross-section. Correspondingly, the second tubular bodies 3′, 3″ and 3′″ are accommodated side by side to each other in the external tubular body 4. In the case of the placeholder 1, which, in FIGS. 19 and 20, is shown in perspective and plan view representations, respectively, two cylindrical tubular bodies 3′ and 3″ which have a circular cross-section are arranged, also by press fit or force fit, in an external tubular body 4 with an oval shaped cross-section, whereas, in the embodiment of FIGS. 21 and 22, three second bodies 3′, 3″ and 3′″ with cylindrical tubular shape, i.e. circular cross-section, are arranged in an external tubular body 4 having a cylindrical-tubular shape and thus also circular cross-section. In FIGS. 23 and 24 is shown a further embodiment of a placeholder 1 in accordance with the invention in which, again, only two tubular bodies are arranged inside each other. In the embodiment shown in FIGS. 23 and 24, the inner tubular body 3 has a triangular shape in a cross-section running perpendicular to the tubular longitudinal axis, whereas the external tubular body 4, in turn, possesses a cylindrical tubular shape with circular cross-section. In the embodiment shown in FIGS. 23 and 24, thus only one tubular body 3 is accommodated by press fit or force fit in the tubular body 4. In the variant shown in embodiments of FIGS. 17 to 24, it would also be possible, instead of press fit or force fit, to provide a connection for the first and second tubular bodies 4 and 3 at their contact surfaces by means of connecting elements, such as connecting pins in the form of screws or bonded (material) connections, such as welding. FIGS. 25 to 29 show different cross-sectional forms of tubular bodies 2, 3, 4 of the kind that may be used in the present invention. Aside from a circular or annular cross-section, such as shown in FIG. 25, oblong, especially rectangular and preferably square shapes (FIG. 26), hexagonal shapes (FIG. 27), oval shapes (FIG. 28) or kidney shapes (FIG. 29) are conceivable. Additionally, there is the possibility of using other shapes, such as octagonal base shapes or totally free-form shapes. Preferred, however, are simple base shapes. Especially, it is also possible to combine cylindrical tubular bodies having different cross-sectional shapes with each other. FIGS. 30 to 35 show different shapes of openings 9 and their mutual arrangement in the jacket surfaces 10 of the tubular bodies 2, 3 and 4. Aside from the diamond shape (rhombus) of FIG. 30, circular shapes (FIG. 31), oblong shapes, especially square and rectangular (FIG. 32), hexagonal shapes (FIG. 33), oval shapes (FIG. 34) or octagonal shapes (FIG. 35) are conceivable. Additionally, other suitable shapes are conceivable that facilitate a large area for the openings 9 combined with simultaneous stability of the interlaying framework. As far as the mutual arrangement of the openings 9 is concerned, these may either be arranged in rows, in which the openings 9 are totally spaced apart in rows, such as in FIGS. 32 and 35, or the openings are arranged in the rows such that they project into the corresponding cavities formed by openings 9 of adjacent rows, as is particularly pronounced in the FIGS. 30 and 33. This also shows that the openings 9 in the columns in which they are arranged may be provided directly beneath each other or, preferably, offset from each other, such that axial load dissipation, especially, improves. As FIGS. 30 to 35 further show, the columns with openings 9 arranged under each other may be each offset essentially from each other by the half-width of an opening. FIGS. 36 to 42 show in different views embodiments of connections by means of connecting pins, such as rivets and screw connections. FIG. 36 shows a partial section of the jacket surface 10 or of the bars forming the jacket surface 10 of tubular bodies 3 and 4, in which a screw connection is provided. The screw 13 has a screw head 40 which, as shown in a cross sectional view in FIG. 37, with a contact surface 43 makes contact with the inner surface of the tubular body 3, while the shaft 45 of the screw 13 projects through an opening in the wall of the tubular body 3 and with its screw end 41 opposite the head 40 engages with the threaded hole 42 of the external tubular body 4. In this connection, the contact surface 44, which limits the screw thread 41, makes contact with the inside of the external tubular body 4. The screw connection is designed such that preferably the outside of the tubular body 4 flushes with the thread-side end of the screw 13. FIG. 38 shows the screw 13 in a perspective representation. Although not shown, the screw head may be configured to provide engagement with an actuating tool, such as a screw driver. In similar representations as the screw connection, FIGS. 39 to 42 illustrate a rivet connection. Here, too, the rivet connection represents the connection between the tubular body 3 and the tubular body 4, as may especially be seen in the perspective representation of FIG. 39. With its contact surface 56, the head of the rivet 50 touches, as may be seen in FIG. 40, the inside of the tubular body 3, while the contact surface 57, which limits the rivet section at the end of the rivet 50 opposite the head 51, touches the inside of the external tubular body 4. The tubular bodies 3 and 4 each have one through-hole opening, through which rivet 50 with the rivet shaft 52 is inserted. The rivet area 53 has a cylindrically shaped cut-out 55, such that, following insertion of the rivet 50 through the through-hole opening of the tubular body 4, the edge 54 may be crimped such that a reliable connection is afforded and the rivet is prevented from leaving the through-hole opening of the tubular body 4. FIGS. 41 and 42, each show the rivet 50 in the unriveted state (FIG. 41) and riveted state (FIG. 42) with edge 54. FIGS. 43 to 44 are schematic lateral or sectional representations of applications for placeholders in accordance with the invention, with the placeholder 1 in FIG. 43 serving as a replacement vertebral disc and the placeholder 1 in FIG. 44 serving as a replacement vertebra. The placeholders 1 in the applications of FIGS. 43 and 44 are part of a spinal column stabilization system, in which pedicle screws 20, especially polyaxial screws, are arranged in vertebrae, which accommodate between them a connecting rod 21 to mutually align and stabilize the spine. Because of the arrangement in the spine, the placeholders 1 for the spine or vertebral discs are exposed to stresses, especially dynamic stress. The placeholder 1 according to the present invention, and in particular, the multi-wall configuration and/or the multi-component formation thereof, provides a solution for dealing with the noted stresses. Additionally, the placeholder in accordance with the invention may also be used for clinical applications, such as long bones, e.g. following a break, as shown in FIG. 45, in which in case of destruction of the bone 22 in its central area, the arrangement of a corresponding placeholder 1 of the invention and stabilization with a nail 23 and a screw 24 may serve to reproduce the bone structure. | <SOH> BACKGROUND <EOH>The present invention refers to a placeholder for implantation into a human or animal body, especially as a placeholder for vertebrae or vertebral discs, a method for manufacturing such a placeholder, and a modular system for such a placeholder. Placeholders, especially for vertebrae or vertebral discs are known. For example, DE 19504867 C1 discloses a placeholder in the shape of a cylindrical-tubular body with a plurality of rhombic or diamond-shaped openings that are arranged in rows and columns. At the ends of the cylindrical tube are provided projecting serrations and recesses in correspondence with the rhombi that serve for engaging with adjacent vertebrae or adjacent tissue. The diamond-shaped openings facilitate in-growth of the tissue into the implant, such that the latter may knit well with the body. Moreover, an implant is known from US 2005/0015154 which has a scaffold-like structure in which the latticework extends over the full body or through the entire body of the implant. Such integral latticework structures are intended for use especially in replacement implants for joints, such as hips, knee joints, shoulder joints and the like. However, such integral latticework structures are difficult to manufacture and have to be adjusted and manufactured individually to suit every application case. DE 101 38 079 AI discloses a placeholder of adjustable axial length in which two sleeve-like parts are arranged adjustably inside one another, more precisely via a lever arrangement over which the parts are connected. Although this device facilitates very precise length adjustment, the lever arrangement is complicated to manufacture. DE 198 04 765 C2 discloses a placeholder for insertion between two vertebrae with an adjustable axial length. The total length is adjusted by moving an external tube relative to an internal tube. The length adjustment proceeds stepwise by means of catches. DE 697 19 431 T2 describes a longitudinally adjustable vertebral disc placeholder in which two sleeve bodies arranged telescopically inside one another are adjusted relative to each other and are lockable via screw arrangements. However, this arrangement does not uniformly distribute the load across the screw connections and does not effectively allow in-growth by the surrounding tissue because of the close arrangement of the sleeve bodies. US 2003/0078660 discloses an implant that may be used as a placeholder in which the implant has a sleeve-like body that is corrugated. This corrugated body may in turn be arranged inside a further sleeve body. However, the corrugated form of the one implant part again makes for complicated manufacture. EP 09 047 51 AI describes a tubular support body for vertebrae having two cages guided in one another which may be connected to each other by a projecting stud on the jacket surface of the one cage and axial feed channels in the jacket of the other cage. With this arrangement, facilitating of latching positions at different depths is provided. However, the support body is limited in variability by the feed channels. Based on the above, there is a need for an implant which is easy to manufacture and versatile in use, can provide load dissipation, allows in-growth into human or animal tissue, and is suitable for use as placeholder in the spine, that is, for vertebral discs and vertebrae, but also for tubular bones of the upper and lower extremities. | <SOH> SUMMARY <EOH>According to one aspect of the present invention, several tubular bodies, namely a first tubular body and at least a second tubular body, are provided at least partially one inside the other, such that a multi-wall placeholder is formed which not only provides load-absorbing properties but also is suitable for allowing in-growth of adjacent tissue. The cross-sectional shapes of the first and the second bodies in a cross-sectional plane transverse to the longitudinal axis of the placeholder can be different. In particular, the second body arranged in the first body can have a simple or basic geometric shape, namely, a shape which is easy to manufacture. Such shapes include cylindrical or cuboid shapes with round, oval, rectangular or triangular cross-sections. In addition, a shape having a constant cross-section along its length may be used. Such simple geometrical basic shapes for the first and second bodies may be used to generate suitable mechanical properties, yet are affordable and easy to manufacture. The multi-wall placeholder described herein also provides a large contact surface with the bone at the front face of the placeholder. In addition, with a preassembled multi-wall placeholder, a better adjustment to the bone is possible. Consequently, subsidence of the placeholder may be considerably reduced, if not completely prevented. This can be important for weak osteoporotic vertebrae. The placeholder according to the present invention may also include a plurality of second tubular bodies nested inside each other, all of which are at least partially disposed in the first tubular body. In one embodiment, the first body may have a circular cross-sectional shape, while the second body or bodies may have a triangular, square, hexagonal, octagonal or generally polygonal, oval or kidney cross-sectional shape. In a further embodiment, the first tubular body, i.e., the external body may have a cross-sectional shape other than that of a circle, such as an oval or kidney cross-sectional shape, in which case the second body may have a correspondingly adjusted different cross-sectional shape, as described above or a similar shape. According to another aspect of the present invention, which is also applicable to all disclosed aspects of the invention, several second bodies may be arranged alongside each other in the first body. Accordingly, this arrangement can also achieve mechanical stability and/or ease of in-growth by the surrounding tissue into the placeholder. In addition, the wall thicknesses of the individual components, i.e. of the tubular bodies, may be kept small so as to facilitate in-growth of the tissue into the tubular bodies and thus into the implant. By providing several second bodies in the first body, e.g., two or three second bodies, the wall thickness of the individual tubular bodies can be reduced, while the overall loading capacity can be improved. The arrangement of two, three or several second bodies in the first body is applicable to all disclosed aspects of the invention. The second bodies can be spaced from each other and/or from the first body to promote in-growth of body tissue between the bodies. This also allows for more precise adjustment relative to the adjacent bone or to a placeholder end plate. Moreover, the spacing between the bodies will result in better in-growth and a more homogeneous distribution of the load across the cross-section of the implant. In the case of the arrangement of several second bodies in the first body, the arrangement of the second bodies may be such that their longitudinal axes are offset parallel to the tubular longitudinal axis of the first body. The result of this is that greater stability can be obtained for certain instances of mechanical loading. For example, the offset arrangement of the bodies may lead to greater stability in the case of flexural stress. Overall, the cross-sectional shape of the first and/or second bodies may assume diverse shapes, namely circles, triangles, oblongs, rectangles, squares, diamonds, (rhombi), polygons, hexagons, octagons, especially with rounded corners, ovals, kidney shapes or any free-form shapes. However, the shape can be restricted to certain basic shapes as this simplifies manufacturability. Among the basic shapes are especially circles, triangles, oblongs, rectangles, squares, diamonds, hexagons, all angular shapes including those with rounded corners and ovals and kidney shapes. According to a further aspect of the present invention, which is also applicable to all disclosed aspects of the invention, the second body or bodies can be accommodated in the first body by means of a press fit or force fit. For example, the outer dimension of the second body or bodies is larger than the inner dimension of the first body. This results in an elastic deformation of the bodies in the case of a force fit or an additional plastic deformation in the case of press fit. Alternatively, a connecting element or retaining element between the bodies can be a force fit or press fit. The press fit or force fit may thus be directly affected by contact between the first body and the second body/bodies or by the connecting elements. Alternatively, according to a further aspect of the invention, the connections between the bodies and/or connecting elements may take place by means of friction, a material or a positive connection (form-fit). According to another aspect of the present invention, which is also applicable to all disclosed aspects of the invention, the placeholder comprises a first tubular body having a jacket surface with a plurality of openings for over-growth with adjacent tissue and a second tubular body having a jacket surface with a plurality of openings, the second tubular body disposed at least partially inside the first tubular body. At least one spacer may be used wherein the second tubular body is spaced apart with the at least one spacer from the first tubular body. The spacer may also take the form of a connecting element configured to connect the first tubular body to the second tubular body. In particular, the connecting elements may comprise retaining plates and/or connecting pins. The retaining plates may be formed as plates or rings arranged transversely to the tubular longitudinal axis that are held by press fit or force fit or screw or rivet connections or generally by means of friction, a material or a positive connection (form-fit) in the first body. The second bodies may preferably also be held by press fit or force fit or again by connecting pins or generally by means of friction, a material or a positive connection. This means that the second bodies, for example may form a structural unit with the connecting elements, which is then held overall by means of a press fit or force fit in the first body. The connecting pins may be formed as rivets, screws and/or bars, which are welded, for example. For arranging the second bodies in the first body, at least one, but preferably several, and especially two retaining plates may be provided. The arrangement of the retaining plates may occur at the ends of the tubular bodies as end plates or distributed along the length of the tubular bodies as intermediate plates. The retaining plates may have a plurality of openings as well, more precisely in addition to the receivers, by means of which the second bodies are received and held. The plurality of openings again serves the purpose of in-growth of adjacent tissue. In addition or as an alternative to the retaining plates, connecting pins may be provided, which are formed especially as rivets, screws and/or bars, which are, for example, welded. The connecting pins preferably have stop faces for spaced retention of the bodies, for example a stop face may be provided by a corresponding rivet or screw head, while a second stop face may be provided in the vicinity of the thread or of the end of the rivet opposite the head. The connecting pins may be arranged in the openings or breakthroughs in the jacket surface of the tubular bodies which are provided for knitting with adjacent tissue. Alternatively, separate connecting openings may be provided for receiving the connecting elements in the tubular bodies or other components of the implant, such as the retaining plates. In the case of screw connections, preferably the thread holes are provided in the first outer body, such that the screw with its screw head lies on the inside. This results in a smooth external side without projections parallel to the tubular longitudinal axis. According to a further aspect of the invention, which is also applicable to all disclosed aspects of the invention, the tubular bodies can be arranged at least partially inside each other and may be connected by means of detachable connecting means or connecting means attachable or connectable directly at the point of use, such that a modular system is created, which facilitates in simple fashion individual adjustment to requirements. Accordingly, a modular system of several tubular bodies and corresponding connecting means may be provided, with the surgeon composing the corresponding placeholders to suit individual needs directly at the point of use. Naturally, however, the placeholders may also be supplied ready-made. But, even here, changes may still be made in the case of detachable connecting means. Additionally, a connection of the tubular bodies can be provided merely at a few sites on the jacket surface and/or in the vicinity of the front faces, such that, when viewed along the full length of the placeholder, free space that is available for in-growth of tissue is created in wide areas between the placeholders. For example, the connecting elements may be restricted to a total of 2 to 24, preferably 2 to 12 elements, and/or 2 to 4, especially 3. In another embodiment, three connecting elements may be assigned to each row of openings or breakthroughs in the jacket surface. The connecting elements may cooperate with the breakthroughs themselves or with further receivers, recesses or holes, such as thread holes. In a further embodiment, the tubular bodies may be arranged concentrically, such that parallel wall areas are formed, especially in the case of the same cross-sectional shapes. In yet another embodiment also applicable to all disclosed aspects of the invention, the connecting elements may preferably be variably attached in the openings of the jacket surface of the tubular bodies, such that the tubular bodies may be arbitrarily aligned and arranged relative to each other. For example, the bodies can be arranged such that they are not completely inside each other, but to, for example, leave them projecting out in the longitudinal direction. This means that the length or height of the placeholders may be adjusted, since the different tubular placeholders arranged inside one another may be retracted telescopically from each other or, conversely, pushed into each other in order for them to be subsequently fixed in this position. This is especially possible continuously or in steps. Additionally, the tubular bodies may also be rotated against each other, such that the openings provided in the jacket surfaces are in alignment or staggered relative to, for example, one or two adjacent bodies or all bodies. Also, the tubular bodies may have different forms, especially different wall thicknesses, such that, for example, the external tubular body may be very thin in order to facilitate rapid over-growth or in-growth by the surrounding tissue through the openings, while the internal body or bodies have a greater wall thickness to impart stability to the placeholder. The different shapes which are possible for the cross-sectional shapes are also conceivable for the openings or breakthroughs in the jacket surface of the tubular bodies, such that their external contour, too, may have the shape of a circle, a triangle, an oblong, a rectangle, a square, a hexagon, an octagon, generally a polygon with or without rounded corners, a diamond or similar. In all aspects, the tubular bodies may be arranged spaced apart from each other, with this space either provided by the connecting elements that connect the tubular bodies and/or separate spacers that may be provided, especially on the inside and/or outside of the jacket surface, preferably in the shape of bars or plates projecting at right angles towards the outside or the inside. On account of the spacing of the tubular bodies, sufficient space is available for in-growing tissue. Furthermore, on account of the spaced arrangement of tubular bodies, correspondingly broad contact surfaces may form at the ends or front faces that render separate attachment of end plates or similar unnecessary. The tubular bodies may also have, at least on one end, or on both ends, projections and/or recesses which enable engagement with adjacent vertebrae or other tissue and facilitate in-growth. The connecting elements, which may be formed by pins, bolts, catches, screws, end plates and similar, may be variably accommodated, especially at the openings or breakthroughs of the jacket surface, such that no additional separate receivers need to be provided for the connecting elements. This can reduce outlay and simplifies manufacturability. Nonetheless, corresponding separate receivers may be provided at the jacket surfaces of the tubular bodies. In a further embodiment, the placeholders have, at the front faces of the tubular bodies, at least one, preferably two end plates, which simultaneously serve as connecting means. The end plates, which, for example, are annular, have for this purpose cut-outs and/or recesses into which the projections at the ends of the tubular bodies may engage, especially positively and/or non-positively. The annular end plate may function as a tensioning or spring-loaded ring that has a separating gap or slit, such that the projections provided in the cut-outs or recesses of the tubular bodies are held by means of friction by the end plate. Correspondingly, the intermediate plates or retaining plates may also be formed generally as tensioning or spring-loaded rings. Alternatively or additionally, it is naturally also possible to have a bonded (material) connection of end plates or retaining plates and tubular bodies, such as by means of welding, especially laser welding, as also applies to the other connecting means, especially those provided in the vicinity of the jacket surfaces, The tubular bodies and/or the connecting elements may be coated or have received a surface treatment. For example, coatings to be mentioned in this regard are hydroxy apatite or plasma treatments, which, for example, may lead to a rough titanium surface if titanium or titanium alloys are used as material. Overall, all suitable biocompatible materials having the corresponding properties may be used for the various components, such as tubular bodies and connecting elements. Preferred are biocompatible polymers or metals, such as titanium or titanium alloys, or also nitinol, a nickel-titanium alloy. Especially, different materials may also be used for the various components. According to a further aspect, the placeholder has at least two different tubular bodies, for example, one body differing in diameter from the other. These bodies are arranged at least partially inside each other, and the bodies are then connected to each other, preferably detachably, by means of at least one connecting element. In this regard, the arrangement of the tubular bodies may be varied relative to each other, e.g., along the longitudinal axis. This is especially true if the connecting elements may be used at many locations along the tubular bodies. Additionally, the angle arrangement between bodies may be varied. Through the structure of the tubular bodies of the invention, which is described in detail especially in the following embodiments, it is also possible to adjust the length and/or the alignment of the ends of the tubular bodies by means of cutting to length at any site, The result is a further increase in the variability of use. Additionally, the placeholders may be coated or subjected to surface treatment not only altogether following assembly, but also individually before the components are assembled. Accordingly, even in the case of parts on the inside, such as a cylindrical tubular body arranged lying on the inside, said body may be coated or surface treated prior to assembly, such that complete coating or surface treatment here may occur. In another embodiment, the present invention provides a modular, individually usable system for placeholders, e.g., through the use of individual components, which can be used alone, preassembled or selectively assembled. The corresponding placeholder has an extremely large surface area due to its many walls and construction from several tubular bodies, and thus markedly facilitates in-growth and on-growth. Additionally, despite the very large surface area, manufacturability is improved and, in particular, coatability and surface treatability are improved. This also results in improved in-growth properties. In particular, the modular assembly allows for individual surface treatment of the single components. Thus, different coating of the individual components may take place, i.e., of the various cylindrical-tubular bodies located in the different positions. This results in an implant having good mechanical stability and improved in-growth characteristics, which is especially suitable for vertebral discs or placeholders. An optimum fusion element for orthopedics is thus achieved. | A61F2442 | 20171009 | 20180405 | 97508.0 | A61F244 | 1 | LAWSON, MATTHEW JAMES | MULTI-WALLED PLACEHOLDER | UNDISCOUNTED | 1 | CONT-ACCEPTED | A61F | 2,017 |
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15,728,451 | PENDING | SYSTEM AND METHOD FOR PRESENTING MULTIPLE PICTURES ON A TELEVISION | A device provides multiple video streams from a plurality of video streams to a display. The device includes an input interface, a frame controller, and an output interface. The input interface is configured to receive a plurality of video streams and to transfer the plurality of video streams to the frame controller. The frame controller is configured to generate frame signals including multiple subframe signals corresponding to a video stream of the plurality of video streams. The output interface is configured to output the frame signals to the display. The frame signals are configured to cause video from multiple video streams of the plurality of video streams to be displayed in separate non-overlapping portions on the display. | 1. A device comprising: an input interface configured to receive a plurality of video streams and to provide the plurality of video streams to a frame controller, wherein each video stream of the plurality of video streams corresponds to a video channel of a plurality of video channels; the frame controller configured to generate a first frame signal including: a first subframe signal corresponding to a first video stream of the plurality of video streams; a second subframe signal corresponding to a second video stream of the plurality of video streams; and a third subframe signal corresponding to a third video stream of the plurality of video streams; an output interface configured to output the first frame signal to a display, wherein the first frame signal is configured to cause the display to simultaneously display first video corresponding to the first video stream in a first portion of the display, second video corresponding to the second video stream in a second portion of the display, and third video corresponding to the third video stream in a third portion of the display and to output first audio corresponding to the first video stream, wherein the first portion, the second portion, and the third portion of the display are non-overlapping, and wherein the first portion is larger than the second portion; the frame controller further configured to generate a second frame signal responsive to receiving a swap command, the second frame signal including: a fourth subframe signal corresponding to the first video stream of the plurality of video streams; a fifth subframe signal corresponding to the second video stream of the plurality of video streams; and a sixth subframe signal corresponding to the third video stream of the plurality of video streams; and the output interface further configured to output the second frame signal to the display, wherein the second frame signal is configured to cause the display to simultaneously display video corresponding to the second video stream in the first portion of the display, video corresponding to the first video stream in the second portion of the display, and video corresponding to the third video stream in the third portion of the display and to output second audio corresponding to the second video stream. 2. The device of claim 1, the frame controller including a plurality of tuners, each tuner configured to generate a subframe signal. 3. The device of claim 1, wherein the input interface is configured to receive the plurality of video streams via a coaxial cable. 4. The device of claim 1, wherein the input interface is configured to receive the plurality of video streams via an Ethernet cable. 5. The device of claim 1, wherein the input interface is configured to receive at least one video stream of the plurality of video streams via a coaxial cable. 6. The device of claim 5, wherein the input interface is configured to receive another video stream of the plurality of video streams via a component cable, a composite cable, a high-definition multimedia interface (HDMI) cable, or via an Internet connection. 7. The device of claim 1, wherein the input interface comprises a wireless interface configured to receive the plurality of video streams wirelessly. 8. The device of claim 1, wherein the first frame signal is further configured cause the display to display each subframe in a corresponding area of the display separate from an area occupied by any other subframe. 9. The device of claim 1, the frame controller further configured to generate a third frame signal responsive to a channel change command, the third frame signal comprising: a seventh subframe signal corresponding to a fourth video stream of the plurality of video streams; a eight subframe signal corresponding to the second video stream of the plurality of video streams; and a ninth subframe signal corresponding to the third video stream of the plurality of video streams, wherein the third frame signal is configured to cause the display to simultaneously display video corresponding to the second video stream in the first portion of the display, video corresponding to the fourth video stream in the second portion of the display, and video corresponding to the third video stream in the third portion of the display and to output third audio corresponding to the fourth video stream. 10. The device of claim 1, the frame controller further configured to generate a third frame signal responsive to a channel change command, the third frame signal comprising: a seventh subframe signal corresponding to the first video stream of the plurality of video streams; a eight subframe signal corresponding to a fourth video stream of the plurality of video streams; and a ninth subframe signal corresponding to the third video stream of the plurality of video streams, wherein the third frame signal is configured to cause the display to simultaneously display video corresponding to the fourth video stream in the first portion of the display, video corresponding to the first video stream in the second portion of the display, and video corresponding to the third video stream in the third portion of the display and to output third audio corresponding to the fourth video stream. 11. The device of claim 1, the frame controller further configured to generate a third frame signal responsive to a pause command, the third frame signal comprising: a seventh subframe signal corresponding to the first video stream of the plurality of video streams, wherein the seventh subframe contains the same video data as the fourth subframe signal; an eight subframe signal corresponding to the second video stream of the plurality of video streams; and a ninth subframe signal corresponding to the third video stream of the plurality of video streams, wherein the third frame signal is configured to cause the display to simultaneously display video corresponding to the second video stream in the first portion of the display, video corresponding to the first video stream in the second portion of the display, and video corresponding to the third video stream in the third portion of the display and to output third audio corresponding to the second video stream. 12. The device of claim 1, further comprising a memory configured to store video data of at least one video stream of the plurality of video streams responsive to receiving a record command. 13. The device of claim 1, the frame controller further configured to adjust a size of at least one of the subframes of a third frame signal responsive to one or more inputs. 14. The device of claim 1, wherein a first aspect ratio of the first video comprises a 16×9 aspect ratio. 15. The device of claim 14, wherein the first aspect ratio of the first video is the same as an input aspect ratio of the first video stream. 16. The device of claim 1, further comprising display, wherein the output interface corresponds to an internal bus of the display. 17. The device of claim 16, wherein the display corresponds to a television. 18. The device of claim 16, wherein the display corresponds to a mobile display device. 19. A method comprising: receiving a plurality of video streams and to provide the plurality of video streams to a frame controller, wherein each video stream of the plurality of video streams corresponds to a video channel of a plurality of video channels; generate a first frame signal including: a first subframe signal corresponding to a first video stream of the plurality of video streams; a second subframe signal corresponding to a second video stream of the plurality of video streams; and a third subframe signal corresponding to a third video stream of the plurality of video streams; outputting the first frame signal to a display, wherein the first frame signal is configured to cause the display to simultaneously display first video corresponding to the first video stream in a first portion of the display, second video corresponding to the second video stream in a second portion of the display, and third video corresponding to the third video stream in a third portion of the display and to output first audio corresponding to the first video stream, wherein the first portion, the second portion, and the third portion of the display are non-overlapping, and wherein the first portion is larger than the second portion; generating a second frame signal responsive to receiving a swap command, the second frame signal including: a fourth subframe signal corresponding to the first video stream of the plurality of video streams; a fifth subframe signal corresponding to the second video stream of the plurality of video streams; and a sixth subframe signal corresponding to the third video stream of the plurality of video streams; and outputting the second frame signal to the display, wherein the second frame signal is configured to cause the display to simultaneously display video corresponding to the second video stream in the first portion of the display, video corresponding to the first video stream in the second portion of the display, and video corresponding to the third video stream in the third portion of the display and to output second audio corresponding to the second video stream. 20. The method of claim 19, further comprising outputting a third frame signal to the display responsive to a sound swap command, wherein the third frame signal is configured to cause the display to simultaneously display video corresponding to the second video stream in the first portion of the display, video corresponding to the first video stream in the second portion of the display, and video corresponding to the third video stream in the third portion of the display and to output third audio corresponding to the first video stream. | CROSS-REFERENCE TO RELATED APPLICATIONS The present application is a continuation of and claims priority to U.S. patent application Ser. No. 15/065,960, filed Mar. 10, 2016, which is a continuation of U.S. patent application Ser. No. 14/480,595, filed Sep. 8, 2014, now issued as U.S. Pat. No. 9,319,619, which is a continuation of U.S. patent application Ser. No. 11/731,461, filed Apr. 2, 2007, now issued as U.S. Pat. No. 8,863,187, the content of each of which is incorporated by reference herein in its entirety. FIELD OF THE INVENTION This invention generally relates to television, and more particularly, to a system and method to display multiple pictures on a television set. BACKGROUND OF THE INVENTION The introduction of High Definition Television (HDTV) and the flat panel display has led to new and pleasant experience in watching television. The slimness of a flat panel television set saves space and allows a consumer to place a larger television in a room of limited size. HDTV sets support high resolution and better picture quality. Many HDTV sets sold today are flat panel television sets. Along with the improved resolution and picture quality, the trend in HDTV sales has been towards a general increase in the size of the average television display. For example, in United States, the average size of a HDTV set sold is now approximately 30 inches, diagonal. In some Asian countries, the average size is even larger than 32 inches. A large screen allows a consumer to more comfortably view multiple pictures. For example, a consumer may watch the Super Bowl on a large picture on the display screen, while simultaneously viewing an NBA game between the Sacramento Kings and the LA Lakers on a smaller picture, a local college basketball between Stanford and Berkeley on a third picture, and a hockey game between New York Islanders and Anaheim Ducks on a fourth picture on the television display. Not to miss any important news, the consumer may view CNN or FOX on a fifth picture. Last but not least, they may also view a sixth picture, such as from a baby monitor their 8-month old baby's room, at the same time. On a traditional smaller television screen, having six picture frames displaying simultaneously on the screen would necessitate that at least some of the picture frames would be so small as to be difficult to view at an average or normal viewing distance. With the large screen, however, more the larger display area allows for more picture detail to be discerned at the same distance than with a smaller television screen. Currently, there are several ways to view multiple pictures simultaneously on a television set. Picture in picture (PIP) allows two pictures to be shown on a television set at the same time, with a smaller picture displayed on top of, or overlaying, a larger picture. Since the smaller picture overlays the larger picture, the larger picture is not entirely visible. This is often extremely inconvenient, as the overlaid picture may cover a portion of the larger picture of interest to the viewer. For example, the overlaid portion might cover the end zone of a football game. Moreover, conventional PIP often does not display the overlaid pictures in their intended resolution or aspect ratio. Also, there are PC television cards that can generate and present for display thumb-nail size pictures of many channels, and allow a user to select a channel to view from the small pictures. These small pictures are intended for channel selection purposes. They are small and difficult to be watched over a long period of time. Moreover, the PC television card can only tune to one channel at a time, thus the television channels are scanned one at a time to refresh the pictures. Due to limited processing speed, not all images and sounds of a given television channel are captured by the PC television card. The scanning and tuning speed may be so slow such that the pictures are effectively displayed as still images, or at best in a slow motion manner. When going from a relatively small conventional television display to a larger and flatter display having improved resolution, consumers expect a major change in their enjoyment of the television viewing experience, especially after they have invested in a good quality large screen HDTV set. Thus, there is a need to display multiple pictures on a high resolution large screen television set without overlaying another picture, while preserving the high resolution of the displayed pictures. BRIEF SUMMARY OF THE INVENTION An aspect of the present invention provides a television system including an input interface for receiving video data from a plurality of video streams and transferring the video data to a frame controller in communication with a television display. Each of the plurality of video streams has a display aspect ratio, and the frame controller causes the video data from each of the plurality of different video streams to be displayed in a separate frame on the television display. Each frame occupies an area of the television display separate from an area occupied by any other frame. In another aspect of the invention, the input interface receives video data from one or more sources selected from the list including broadcast television, cable television, satellite television, video cassette player (VCR), and digital versatile disk (DVD). In one aspect of the invention, the input interface receives video data in one or more of the following formats: NTSC, PAL, and HDTV. In another aspect of the invention, the input interface includes one or more of a coaxial interface, a radio frequency (RF) interface, a high-definition multimedia interface (HDMI), component interface, composite interface, an Ethernet interface, or a wireless network interface. In one aspect of the invention, the input interface includes a wireless network. Any wireless network may be used, including a Wireless Local Area Network (WLAN), a Worldwide Interoperability for Microwave Access (WiMax) network, or and Ultra-wideband (UWB) network. In another aspect of the invention, the frame controller includes a plurality of tuners, each configured to generate a sub-frame signal from the video data from one of the video streams, with each sub-frame signal corresponding to one of the separate display frames. The frame controller is further configured to combine the sub-frame signals into a frame signal for display on the television display. Another aspect of the invention also includes a control device for communicating instructions to the frame controller. The communicated instructions include what video streams are to be displayed in which frames. In another aspect of the invention, the frame controller communicates with the control device by infrared signals, radio signals, or a data network. If a data network is used, it may be any of Ethernet, WLAN, WiMAX, or any other data network. In another aspect of the invention, the control device is a remote control, a cell phone, a personal computer or a laptop computer. Another aspect of the present invention provides a method for of displaying video from a plurality of video streams on a television display. The method includes inputting video data from the plurality of video streams to a frame controller, each video stream having a display aspect ratio, causing the video data from each of the plurality of video streams to be displayed in a separate frame on the television display. Each display frame occupies an area of the television display separate from the area occupied by any other frame. Another aspect of the present invention provides a television system including an input interface for receiving high definition television (HDTV) video data from a plurality of video streams and transferring the HDTV video data to a frame controller in communication with a television display. Each of the plurality of video streams has a display aspect ratio, and the frame controller causes the HDTV video data from each of the plurality of different video streams to be displayed in high resolution a separate frame on the television display. At least one of the video streams is displayed in a frame having a height and a width in proportion to the video stream's aspect ratio. Furthermore, each frame further occupies an area of the television display separate from an area occupied by any other frame BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE FIGURES FIG. 1 is a schematic diagram illustrating a television set with a multi-picture frame; FIG. 1a is a schematic diagram illustrating a picture and a frame controller in accordance with an embodiment of the present invention; FIG. 2 is a schematic diagram illustrating controlling operations of a multi-picture frame, in accordance with an embodiment of the present invention; FIG. 2a is a schematic diagram depicting a process to swap the television channel of two displayed pictures, in accordance with an embodiment of the present invention; FIG. 2b is a schematic diagram depicting a process to change a television channel of a display picture, in accordance with an embodiment of the present invention; FIG. 3a is a schematic diagram depicting the use of a television channel selection list for selecting a television channel to display, in accordance with an embodiment of the present invention; and FIG. 3b is a schematic diagram depicting the use of a television channel name list for selecting a television channel to display, in accordance with an embodiment of the present invention. DETAILED DESCRIPTION OF THE INVENTION In the following description, for purposes of explanation, specific numbers, materials and configurations are set forth in order to provide a thorough understanding of the invention. It will be apparent, however, to one having ordinary skill in the art, that the invention may be practiced without these specific details. In some instances, well-known features may be omitted or simplified so as not to obscure the present invention. Furthermore, reference in the specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the invention. The appearances of the phrase “in an embodiment” in various places in the specification are not necessarily all referring to the same embodiment. The term “video data” referred to in the descriptions of various embodiments of the invention herein described is intended to generally describe electronic audio and video signals containing or incorporating video for display on a television or other video display device. This term is used in the broadest sense as known in the electronic arts, and may include analog and/or digital signals. Likewise, the term “video stream” is used in a non-limiting fashion and generally refers to the collection of video data, together with any carrier signals, data headers or other electronic information, which singularly or taken together allow the described embodiments to operate. For example, a digital video stream from a given video source might include multiple packets of compressed video data, each packet or group thereof having one or more packet headers. Typically, one or more of the headers includes information relating to the video data, such as the compression algorithm used, the aspect ratio, etc. The term “aspect ratio” referred to in the descriptions of the various embodiments of the invention herein described refers to the ratio of the width of the video display image to the height of the video display image. For most NTSC television display images, the current aspect ratio is 4:3. High-definition Television (HDTV) uses an aspect ratio of 16:9, which is similar to the aspect ratio used by motion pictures. Reference herein to displaying a video stream in a frame having a height and a width proportional to the video stream's aspect ratio means that an HDTV video stream is displayed filling a frame having a width:height ratio of 16:9. Similarly, a standard NTSC television video stream would be displayed filling a frame having a width:height ration of 4:3. As used herein, the terms “picture frame” and “frame” refer to the borders of a displayed picture. Unless otherwise specified, a picture frame does not necessarily have a border of any particular width, i.e., a displayed picture might occupy the entire area of the picture frame, or the picture frame may include a border. Reference to locations on a display device may be made by referring to either the location of the picture frame or to the location of displayed picture itself, without limitation. Reference to the size of a picture frame refers to the height and width of the frame, and frames of differing width and/or differing height are referred to as being of different sizes. As used herein, the term “picture” refers to the whole of the display image and its picture frame, unless otherwise indicated, without limitation. An embodiment of the present invention advantageously provides for the display of multiple pictures on a high resolution large screen television set without overlaying another picture, while preserving the high resolution and aspect ratio of the displayed pictures. FIG. 1 is a block diagram of a television set 100 displaying a multi-picture frame and a frame controller 150. Television set 100 is an electronic device that receives and displays images and sounds. In one embodiment, television set 100 receives images and sounds as video data or a video stream from a television channel 131, which may originate from a broadcast television network, a cable television network, a satellite television network, or Internet Protocol television (IPTV) network. Alternatively, the video data may originate from a VCR, a DVD player, a digital video recorder (DVR), a set top box, or any other video source. In an embodiment, television set 100 includes a screen capable of displaying a multi-picture frame 120 large enough for a user to comfortably watch multiple pictures from 6 feet away. In one embodiment television set 100 has a screen size of at least 32 inches, or 80 cm. In another embodiment, a user watches television set 100 from 15 feet away, and the screen size is at least 60 inches or 150 cm. Multi-picture frame 120 includes multiple pictures 121, 123, 125, 127, 128, 129. Picture 128 is a major picture having a display size larger than the smaller pictures 121, 123, 125, 127 and 129. Multi-picture frame 120 differs from picture-in-picture (PIP) in that a small picture does not overlay over the large picture 128 in multi-picture frame 120. Moreover, the large picture 128 does not occupy the full screen, as in a conventional PIP. In an exemplary embodiment, television set 100 has a screen size of 32 inches diagonal, picture 128 has a size of 22 inches diagonal, and picture 121 has a size of 9 inches diagonal. In another exemplary embodiment, television set 100 has a screen size of 40 inches diagonal, picture 128 has a size of 27 inches diagonal, and picture 121 has a size of 12 inches diagonal. In still another exemplary embodiment, television set 100 has a screen size of 60 inches diagonal, picture 128 has a size of 42 inches diagonal, and picture 121 has a size of 16 inches diagonal. In various embodiments, picture 128 may have a picture resolution and aspect ratios of NTSC standard, defined by National Television System Committee, Phase Alternating Line (PAL), DVD video, or HDTV. In one embodiment, picture 128 has a better picture resolution than NTSC, PAL or HDTV. The layout of the multiple pictures depicted in FIG. 1 is exemplary in nature. In various embodiments the number, dimensions and positions of the various pictures or picture frames may differ. For example, in one embodiment the size of large picture 128 is as depicted, but the sizes of the small pictures are different. FIG. 1a is a block diagram depicting a picture 124 and a frame controller 150. Picture 124 can be a larger picture 128 or smaller picture 127, as depicted in FIG. 1. In an embodiment, picture 124 displays images and sounds, i.e., the video signal of television channel 134. In one embodiment, picture 124 displays cable television channel 34, or video from a DVD player. Typically, different pictures such as picture 123 and picture 129 display different television channels 133 and 139. For example, in one embodiment, picture 123 displays cable television channel 34, picture 129 displays broadcast television channel 48, picture 123 displays satellite television channel 93, and picture 127 displays a movie from a VCR. Referring once again to FIG. 1, in an embodiment of the invention, pictures 121, 123, 125, 127, 128, and 129 display television channels 131, 133, 135, 137, 138 and 139, respectively. In one embodiment, television 120 displays the sounds of the largest picture 128 and not of other pictures. Alternatively, in another embodiment, television 120 may display the sounds of picture 129 or of another picture as selected by the user. Frame controller 150 controls multi-picture frame 120. In an embodiment, frame controller 150 includes input interface 192 connecting to television channels 131, 133, 135, 137, 138 and 139. Input interface 192 may include any of a coaxial interface, a Radio Frequency (RF) interface, a High-Definition Multimedia interface (HDMI), a component interface such as YPbPr or YCbCr interface, a composite interface, an Ethernet interface, or a wireless network interface. Frame controller 150 receives video streams of the said television channels from the input interface 192. Frame controller 150 connects to television set 100. In one embodiment, frame controller 150 includes an output interface 195 connecting to television set 100. Frame controller 150 sends frame signal 180 for multi-picture frame 120 over output interface 195 to television set 100. In one embodiment, output interface 195 may include an RF interface, an HDMI interface, an S-video interface, a component interface, or a composite interface. Output interface 195 may include a wireless network such as a Wireless Local Area Network (WLAN), a Worldwide Interoperability for Microwave Access (WiMax), or an Ultra-Wideband (UWB) network. Referring back to Figure la, frame controller 150 includes a tuner 154 handling a video stream or signal for picture 124. Based on television channel 134 of picture 124, tuner 154 selects television channel 134 from input interface 192, receives the video stream or signal 164 of television channel 134, transforms channel video stream or signal 164 to sub-frame signal 184. In FIG. 1, frame controller 150 includes multiple tuners 151, 153, 155, 157, 158, 159 corresponding to multiple pictures 121, 123, 125, 127, 128, and 129, accordingly. Tuners 151, 153, 155, 157, 158 and 159 generate sub-frame signals 181, 183, 185, 187, 188 and 189. Frame controller 150 combines sub-frame signals 181, 183, 185, 187, 188 and 189 into frame signal 180, and transmits frame signal 180 over output interface 195 to television set 100. Television set 100 subsequently displays frame signal 180. In one embodiment, television set 100 includes the frame controller 150. In such an embodiment the output interface 195 may be an internal bus or other connection within the television set 100. FIG. 2 illustrates controlling operations of a multi-picture frame 120. In an embodiment of the invention, frame controller 150 controls operations of the multi-picture frame 120, and a user 104 uses a controlling device 106 to instruct frame controller 150. Frame controller 150 connects to the controlling device 106 through, for example infrared signals, radio signals, or a data network such as Ethernet, WLAN, or WiMax. In alternative embodiments, the controlling device 106 is a remote control, a mobile device such as a cell phone, a personal computer or a laptop. FIGS. 2a and 2b are block diagrams illustrating picture swapping and changing operations, respectively, in an exemplary embodiment of the invention. In FIG. 2a, frame controller 150 provides a swap operation 115a swapping picture 121 with picture 128. User 104 selects, using controlling device 106, picture 121 and picture 128. The user 104 then selects swap operation 115a. In response to receiving the swap operation 115a signal from the controlling device 106, frame controller 150 informs tuner 151 to transform channel signal 161 to sub-frame signal 181 using a large picture resolution of picture 128. Frame controller 150 informs tuner 158 to transform channel signal 168 to sub-frame signal 188 using a small picture resolution of picture 121. When frame controller 150 composes sub-frame signals 181, 183, 185, 187, 188 and 189, frame controller 150 places sub-frame signal 188 to the location of picture 121 and sub-frame signal 181 to the location of picture 128. The replacement of picture 128 by picture 121 may be performed in several ways. In an embodiment, frame controller 150 informs tuner 158 to select television channel 131. Tuner 158 receives channel signals 168 from television channel 131, transforms channel signals 168 to sub-frame signal 188. In another embodiment, frame controller 150 informs tuner 158 not to transform channel signal 168. Frame controller 150 informs tuner 151 to transform channel signal 161 to sub-frame signal 188 using picture resolution of picture 128, in addition to sub-frame signal 181 using current small picture resolution of picture 121. Frame controller places sub-frame signal 188 to the location of picture 128. A user 104 may swap two small pictures, such as picture 123 and picture 125, rather than swapping a small picture and a large picture. As depicted in FIG. 2b, in an embodiment, frame controller 150 provides a change operation 115b to change a television channel of a displayed picture. In exemplary operation, a user 104 selects picture 125, which is displaying television channel 135. Next, user 104 selects the change channel operation 115b using the controlling device 106, and further selects another television channel to display. In one embodiment, the user 104 selects the new television channel directly, whereas, in an alternative embodiment, the user 104 selects the next channel in a sequence of channels, or the previous channel, or another video source altogether, such as DVD player. In one embodiment, the user 104 keys in a television channel number or name. Frame controller 150 determines television channel 235 and informs tuner 155 to switch to television channel 235. FIGS. 3a and 3b illustrate the use of a television channel selection list and a television channel name list, respectively, for selecting a television channel to display. In one embodiment, frame controller 150 determines the second television channel 235 based on picture 125. For example, picture 125 may be associated with a pre-determined television channel list 205 for picture 125. FIG. 3a illustrates television channel list 205 for picture 125. Picture 125 is currently displaying television channel 135. When the user 104 selects the next television channel, frame controller 150 determines the second television channel 235 from television channel list 205 to be cable channel 57. In another, frame controller 150 connects to a datastore 220 that includes television channel list 205. Frame controller 150 matches picture 125 against datastore 220 and retrieves television channel list 205. In another embodiment, frame controller 150 queries a network computing device 222 that includes television channel list 205. Frame controller 150 sends picture 125 and television channel 135 to computing device 222. Frame controller 150 obtains television channel 235 from computing device 222. In an embodiment, the user 104 specifies television channel 235 by channel name 215, as depicted in FIG. 3b. Frame controller 150 matches channel name 215 against television channel name list 207 and retrieves the corresponding television channel 235. In one embodiment, frame controller 150 connects a datastore 220 that includes television channel name list 207. Frame controller 150 matches picture 125 against datastore 220 and retrieves television channel name list 207. In another embodiment, frame controller 150 queries a network computing device 222 that includes television channel name list 207. Frame controller 150 sends picture 125 and channel name 215 to computing device 222. Frame controller 150 obtains television channel 235 from computing device 222. Numerous other operations may be performed by the frame controller 150 as directed by a user 104. For example, operation 115 can be used to increase or reduce the size of picture 128. In one embodiment, operation 115 can be to swap the picture whose sounds are audible between picture 123 and picture 128. In another embodiment, frame controller 150 connects to a recorder such as a DVD recorder, and operation 115 can be used to record television channel 135 of picture 125. In yet another embodiment, operation 115 can be used to restart a television program of television channel 137 of picture 127, or to pause, fast forward or fast backward television channel 137 of picture 127. Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as defined by the appended claims. | <SOH> BACKGROUND OF THE INVENTION <EOH>The introduction of High Definition Television (HDTV) and the flat panel display has led to new and pleasant experience in watching television. The slimness of a flat panel television set saves space and allows a consumer to place a larger television in a room of limited size. HDTV sets support high resolution and better picture quality. Many HDTV sets sold today are flat panel television sets. Along with the improved resolution and picture quality, the trend in HDTV sales has been towards a general increase in the size of the average television display. For example, in United States, the average size of a HDTV set sold is now approximately 30 inches, diagonal. In some Asian countries, the average size is even larger than 32 inches. A large screen allows a consumer to more comfortably view multiple pictures. For example, a consumer may watch the Super Bowl on a large picture on the display screen, while simultaneously viewing an NBA game between the Sacramento Kings and the LA Lakers on a smaller picture, a local college basketball between Stanford and Berkeley on a third picture, and a hockey game between New York Islanders and Anaheim Ducks on a fourth picture on the television display. Not to miss any important news, the consumer may view CNN or FOX on a fifth picture. Last but not least, they may also view a sixth picture, such as from a baby monitor their 8-month old baby's room, at the same time. On a traditional smaller television screen, having six picture frames displaying simultaneously on the screen would necessitate that at least some of the picture frames would be so small as to be difficult to view at an average or normal viewing distance. With the large screen, however, more the larger display area allows for more picture detail to be discerned at the same distance than with a smaller television screen. Currently, there are several ways to view multiple pictures simultaneously on a television set. Picture in picture (PIP) allows two pictures to be shown on a television set at the same time, with a smaller picture displayed on top of, or overlaying, a larger picture. Since the smaller picture overlays the larger picture, the larger picture is not entirely visible. This is often extremely inconvenient, as the overlaid picture may cover a portion of the larger picture of interest to the viewer. For example, the overlaid portion might cover the end zone of a football game. Moreover, conventional PIP often does not display the overlaid pictures in their intended resolution or aspect ratio. Also, there are PC television cards that can generate and present for display thumb-nail size pictures of many channels, and allow a user to select a channel to view from the small pictures. These small pictures are intended for channel selection purposes. They are small and difficult to be watched over a long period of time. Moreover, the PC television card can only tune to one channel at a time, thus the television channels are scanned one at a time to refresh the pictures. Due to limited processing speed, not all images and sounds of a given television channel are captured by the PC television card. The scanning and tuning speed may be so slow such that the pictures are effectively displayed as still images, or at best in a slow motion manner. When going from a relatively small conventional television display to a larger and flatter display having improved resolution, consumers expect a major change in their enjoyment of the television viewing experience, especially after they have invested in a good quality large screen HDTV set. Thus, there is a need to display multiple pictures on a high resolution large screen television set without overlaying another picture, while preserving the high resolution of the displayed pictures. | <SOH> BRIEF SUMMARY OF THE INVENTION <EOH>An aspect of the present invention provides a television system including an input interface for receiving video data from a plurality of video streams and transferring the video data to a frame controller in communication with a television display. Each of the plurality of video streams has a display aspect ratio, and the frame controller causes the video data from each of the plurality of different video streams to be displayed in a separate frame on the television display. Each frame occupies an area of the television display separate from an area occupied by any other frame. In another aspect of the invention, the input interface receives video data from one or more sources selected from the list including broadcast television, cable television, satellite television, video cassette player (VCR), and digital versatile disk (DVD). In one aspect of the invention, the input interface receives video data in one or more of the following formats: NTSC, PAL, and HDTV. In another aspect of the invention, the input interface includes one or more of a coaxial interface, a radio frequency (RF) interface, a high-definition multimedia interface (HDMI), component interface, composite interface, an Ethernet interface, or a wireless network interface. In one aspect of the invention, the input interface includes a wireless network. Any wireless network may be used, including a Wireless Local Area Network (WLAN), a Worldwide Interoperability for Microwave Access (WiMax) network, or and Ultra-wideband (UWB) network. In another aspect of the invention, the frame controller includes a plurality of tuners, each configured to generate a sub-frame signal from the video data from one of the video streams, with each sub-frame signal corresponding to one of the separate display frames. The frame controller is further configured to combine the sub-frame signals into a frame signal for display on the television display. Another aspect of the invention also includes a control device for communicating instructions to the frame controller. The communicated instructions include what video streams are to be displayed in which frames. In another aspect of the invention, the frame controller communicates with the control device by infrared signals, radio signals, or a data network. If a data network is used, it may be any of Ethernet, WLAN, WiMAX, or any other data network. In another aspect of the invention, the control device is a remote control, a cell phone, a personal computer or a laptop computer. Another aspect of the present invention provides a method for of displaying video from a plurality of video streams on a television display. The method includes inputting video data from the plurality of video streams to a frame controller, each video stream having a display aspect ratio, causing the video data from each of the plurality of video streams to be displayed in a separate frame on the television display. Each display frame occupies an area of the television display separate from the area occupied by any other frame. Another aspect of the present invention provides a television system including an input interface for receiving high definition television (HDTV) video data from a plurality of video streams and transferring the HDTV video data to a frame controller in communication with a television display. Each of the plurality of video streams has a display aspect ratio, and the frame controller causes the HDTV video data from each of the plurality of different video streams to be displayed in high resolution a separate frame on the television display. At least one of the video streams is displayed in a frame having a height and a width in proportion to the video stream's aspect ratio. Furthermore, each frame further occupies an area of the television display separate from an area occupied by any other frame | H04N544591 | 20171009 | 20180322 | 69213.0 | H04N5445 | 3 | TILAHUN, ALAZAR | SYSTEM AND METHOD FOR PRESENTING MULTIPLE PICTURES ON A TELEVISION | SMALL | 1 | CONT-ACCEPTED | H04N | 2,017 |
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15,729,512 | PENDING | SYNTHETIC GLUCOPYRANOSYL LIPID ADJUVANTS | Compounds, particularly, glucopyranosyl lipid adjuvant (GLA) compounds, having the following structure (I) are provided: or a pharmaceutically acceptable salt thereof, wherein L1. L2, L3, L4, L5, L6, L7, L8, L9, L10, Y1,Y2, Y3, Y4, R1, R2, R3 , R4, R5, R6, are as defined herein. Pharmaceutical compositions, vaccine compositions, and related methods for inducing or enhancing immune responses, are also provided. | 1. A GLA compound having the following structure (I): or a pharmaceutically acceptable salt thereof, wherein: L1, L2, L3, L4, L5 and L6 are the same or different and independently —O—, —NH— or —(CH2)—; L7, L8, L9, and L10 are the same or different and independently absent or —C(═O)—; Y1 is an acid functional group; Y2 and Y3 are the same or different and independently —OH, —SH, or an acid functional group; Y4 is —OH or —SH; R1, R3, R5 and R6 are the same or different and independently C8-13 alkyl; and R2 and R4 are the same or different and independently C6-11 alkyl. 2. A GLA compound according to claim 1, wherein L5 and L6 are both —O—, L7, L8, L9, and L10 are each —C(═O)—, and the GLA compound has the following formula (II): 3. A GLA compound according to claim 2, wherein R1, R3, R5 and R6 are each Cx alkyl, where x is constant and is selected from an integer from 8-13, and R2 and R4 are both Cx-2 alkyl, and the GLA compound has the following formula (III): 4. A GLA compound according to claim 3, wherein x is selected from an integer from 10-12. 5. A GLA compound according to claim 4, wherein x is 11, and the GLA compound has the following structure (IV): 6. A GLA compound according to claim 2, wherein Y1 is —OP(═O)(OH)2 and Y2, Y3 and Y4 are each —OH, and the GLA compounds have the following formula (V): 7. A GLA compound according to claim 2, wherein L1 and L3 are both —O— and L2 and L4 are both —NH—, and the GLA compound has the following formula (VI): 8. A GLA compound according to claim 2, wherein Y1 is —OP(O)(OH)2, Y2, Y3 and Y4 are each —OH, L1 and L3 are both —O—, and L2 and L4 are both —N—, and the GLA compound has the following formula (VII): 9. A GLA compound according to claim 2, wherein Y1 is —OP(O)(OH)2, Y2, Y3 and Y4 are each —OH, L1 and L3 are both —O—, L2 and L4 are both —NH—, R1, R3, R5 and R6 each are Cx alkyl where x is constant and is selected from an integer from 8-13, and R2 and R4 are both Cx-2 alkyl, and the GLA compound has the following formula (VIII): 10. A GLA compound according to claim 9, wherein x is 11, and the GLA compound has the following structure (IX): 11. A vaccine composition comprising a compound of any one of claims 1-10 in combination with an antigen or a recombinant expression vector encoding an antigen. 12. The vaccine composition of claim 11 wherein the recombinant expression construct is viral vector. 13. The vaccine composition of claim 12 wherein the viral vector is selected from the group consisting of an adenovirus vector, an adeno-associated virus vector, a herpesvirus vector, a lentivirus vector, a poxvirus vector and a retrovirus vector. 14. A method of eliciting or enhancing an antigen-specific immune response in a subject, the method comprising administering to the subject a vaccine composition of claim 11. 15. A pharmaceutical composition comprising a compound of any one of claims 1-10 and pharmaceutically acceptable carrier or excipient. 16. A method for stimulating a non-specific immune response in a subject comprising administering to the subject a pharmaceutical composition of claim 15. | CROSS-REFERENCE TO RELATED APPLICATION This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 61/184,703 filed Jun. 5, 2009, which is incorporated herein by reference in its entirety. BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to the field of pharmaceutical and vaccine compositions. More specifically, embodiments described herein relate to pharmaceutical and vaccine compositions, as well as related prophylactic and therapeutic methods, wherein the compositions comprise a glucopyranosyl lipid adjuvant (GLA) as described herein. Description of the Related Art The immune system of higher organisms has been characterized as distinguishing foreign agents (or “non-self”) agents from familiar or “self” components, such that foreign agents elicit immune responses while “self” components are ignored or tolerated. Immune responses have traditionally been characterized as either humoral responses, in which antibodies specific for antigens are produced by differentiated B lymphocytes known as plasma cells, or cell mediated responses, in which various types of T lymphocytes act to eliminate antigens by a number of mechanisms. For example, CD4+ helper T cells that are capable of recognizing specific antigens may respond by releasing soluble mediators such as cytokines to recruit additional cells of the immune system to participate in an immune response. Also, CD8+ cytotoxic T cells that are also capable of specific antigen recognition may respond by binding to and destroying or damaging an antigen-bearing cell or particle. It is known in the immunological arts to provide certain vaccines according to a variety of formulations, usually for the purpose of inducing a desired immune response in a host. Several strategies for eliciting specific immune responses through the administration of a vaccine to a host include immunization with heat-killed or with live, attenuated infectious pathogens such as viruses, bacteria or certain eukaryotic pathogens; immunization with a non-virulent infective agent capable of directing the expression of genetic material encoding the antigen(s) to which an immune response is desired; and immunization with subunit vaccines that contain isolated immunogens (such as proteins) from a particular pathogen in order to induce immunity against the pathogen. (See, e.g., Liu, 1998 Nature Medicine 4(5 suppl.):515.) For certain antigens there may be one or more types of desirable immunity for which none of these approaches has been particularly effective, including the development of vaccines that are effective in protecting a host immunologically against human immunodeficiency viruses or other infectious pathogens, cancer, autoimmune disease, or other clinical conditions. It has long been known that enterobacterial lipopolysaccharide (LPS) is a potent stimulator of the immune system, although its use in adjuvants has been curtailed by its toxic effects. A non-toxic derivative of LPS, monophosphoryl lipid A (MPL), produced by removal of the core carbohydrate group and the phosphate from the reducing-end glucosamine, has been described by Ribi et al (1986, Immunology and Immunopharmacology of Bacterial Endotoxins, Plenum Publ. Corp., NY, p 407-419). A further detoxified version of MPL results from the removal of the acyl chain from the 3-position of the disaccharide backbone, and is called 3-O-deacylated monophosphoryl lipid A (3D-MPL). It can be purified and prepared by the methods taught in GB 2122204B, which reference also discloses the preparation of diphosphoryl lipid A, and 3-O-deacylated variants thereof. For example, 3D-MPL has been prepared in the form of an emulsion having a small particle size less than 0.2 μm in diameter, and its method of manufacture is disclosed in WO 94/21292. Aqueous formulations comprising monophosphoryl lipid A and a surfactant have been described in WO9843670A2. Bacterial lipopolysaccharide-derived adjuvants to be formulated in adjuvant combinations may be purified and processed from bacterial sources, or alternatively they may be synthetic. For example, purified monophosphoryl lipid A is described in Ribi et at 1986 (supra), and 3-O-deacylated monophosphoryl or diphosphoryl lipid A derived from Salmonella sp. is described in GB 2220211 and U.S. Pat. No. 4,912,094. 3D-MPL and the β(1-6) glucosamine disaccharides as well as other purified and synthetic lipopolysaccharides have been described (WO 98/01139; U.S. Pat. No. 6,005,099 and EP 0 729 473 B1, Hilgers et al., 1986 Int. Arch. Allergy Immunol., 79(4):392-6; Hilgers et at., 1987, Immunology, 60(1); 141-6; and EP 0 549 074 B1). Combinations of 3D-MPL and saponin adjuvants derived from the bark of Quillaja Saponaria molina have been described in EP 0 761 231B. WO 95/17210 discloses an adjuvant emulsion system based on squalene, α-tocopherol, and polyoxyethylene sorbitan monooleate (TWEEN™-80), formulated with the immunostimulant QS21, and optionally including 3D-MPL. Despite the accessibility of such combinations, the use of adjuvants derived from natural products is accompanied by high production costs, inconsistency from lot to lot, difficulties associated with large-scale production, and uncertainty with respect to the presence of impurities in the compositional make-up of any given preparation. Accordingly, there is a need for improved vaccines, and in particular for vaccines that beneficially contain high-purity, chemically defined adjuvant components that exhibit lot-to-lot consistency and that can be manufactured efficiently on an industrial scale without introducing unwanted or structurally undefined contaminants. The present invention provides compositions and methods for such vaccines, and offers other related advantages. BRIEF SUMMARY OF THE INVENTION The present invention in its several aspects is directed to compounds, compositions and methods that advantageously employ certain synthetic glucopyranosyl lipid adjuvants (GLA) as immunomodulators or adjuvants. Therefore, according to one aspect of the invention described herein, there are provided GLA compounds having a structure according to the following formula (I): or a pharmaceutically acceptable salt thereof, wherein L1, L2. L3, L4, L5, L6, L7, L8, L9, L10, Y1,Y2, Y3, Y4, R1, R2, R3, R4, R5, R6, are as defined herein. The GLA compounds of the present invention have utility over a broad range of therapeutic applications where induction of specific or non-specific immune responses is desired. For example, in certain aspects of the invention, there are provided vaccine compositions comprising one or more GLA compounds as set forth herein in combination with an antigen. Such vaccine compositions may be advantageously used in methods for stimulating antigen-specific immune responses in subjects in need thereof. In other aspects of the invention, there are provided pharmaceutical compositions comprising one or more GLA compounds as set forth herein, wherein the compositions are substantially devoid of antigen. Such pharmaceutical compositions may be advantageously used in methods for stimulating non-specific immune responses in subjects in need thereof, for example in the treatment of infection, seasonal rhinitis and the like. These and other aspects of the present invention will become evident upon reference to the following detailed description and attached drawings. In addition, various references are set forth herein which describe in more detail certain aspects of this invention, and are therefore incorporated by reference in their entireties. BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S) FIG. 1 demonstrates IFN-y cytokine production induced in vivo following vaccination of mice with compositions of the invention comprising antigen and GLA, FIGS. 2A-2F show antibody responses induced in vivo following vaccination of mice with compositions of the invention comprising antigen and GLA. FIG. 3 shows the NF-kB enhancement observed at different concentrations of an illustrative GLA compound of the invention (Compound IX). FIGS. 4A-4D show the induction of immunostimulatory cytokines (MIP-1b and TNFa) at different concentrations of an illustrative GLA compound of the invention (Compound IX). DETAILED DESCRIPTION OF THE INVENTION Monophosphoryl lipid A (MPL) and other related adjuvants are known to mediate their effects, at least in part, by acting as agonists of Toll-like receptors (TLR). The glucopyranosyl lipid adjuvant (GLA) compounds of the present invention were rationally designed based upon 3D structural considerations in relation to TLR receptor stimulation. More specifically, according to the present invention, by selectively defining the acyl chain lengths of the GLA compounds of the invention such that they achieve a “flat” bottom in the three dimensional structure of the compounds, an improved fit may be achieved within the binding site of a TLR receptor, thereby resulting in enhanced TLR stimulation and enhanced immunostimulatory properties. In addition, the solubility of the GLA compounds of the invention (e.g., in aqueous solutions) is advantageously improved due to the shortened acyl chain lengths, thereby facilitating efficient and effective compound formulation. Furthermore, because the acyl chain lengths are tailored to make the molecule three dimensionally “flat” along the bottom of the molecule, the compounds can be more effectively incorporated within vesicles, e.g., for liposomal formulations. Further still, compounds of the invention provide advantageous profiles of potency relative to toxicity. For example, the compounds of the invention may be used over a broad and relatively high range of dosages for achieving a desired level of activity (e.g., adjuvant activity), while nevertheless remaining substantially non-toxic to human cells and to human patients, as assayed, for example, by the levels of tumor necrosis factor produced from human cells over a range of concentrations, which quickly rises and levels off unlike other more toxic TLR4 agonists such as lipopolysaccharide. This cell based assay should be predictive of lower inflammatory markers like C-reactive protein involved in adverse events in human pharmacology. The favorable potency vs. toxicity profile for the compounds of the invention may be particularly important, for example, when administering to children whose tolerance to cytokines may be lower, or when the compounds are used in formulations targeted at a large population where more leveled responses will translate into more consistent clinical outcomes for people with a varied responsiveness to TLR agonism. Similarly, regulatory approval will be simplified since target dosing will be more forgiving and manufacturing simplified when the range of active pharmaceutical ingredient need not be controlled at as strict a tolerance level. Therefore, the present invention in its many embodiments provides compounds, vaccine compositions, adjuvant compositions, pharmaceutical compositions and related formulations and methods that include synthetic GLA compounds as described herein. The GLA compounds represent synthetic immunomodulators which, advantageously relative to adjuvants of the prior art, and in particular, relative to natural product adjuvants, can be prepared in substantially homogeneous form. Moreover, the GLA compounds of the invention can be prepared efficiently and economically through large-scale synthetic chemical manufacturing, unlike natural product-derived adjuvants. Because a synthetic adjuvant that is chemically synthesized from defined starting materials to obtain a chemically defined product exhibits qualitative and quantitative batch-to-batch consistency, the GLA compounds of the invention offer benefits including improved product quality control. As described herein, GLA compounds, compositions and methods for their use include in some embodiments the use of GLA by itself with a pharmaceutically acceptable carrier or excipient for immunological adjuvant activity (e.g., non-specific immunostimulatory activity), including “adjuvanting” in which GLA administration to a subject may be wholly independent of, and/or separated temporally and/or spatially from, administration to the subject of one or more antigens against which elicitation or enhancement of an immune response (e.g., an antigen-specific response) in the subject is desired. Other embodiments include the use of GLA in a vaccine composition that also includes one or a plurality of antigens to which an immune response elicited or enhanced by such a vaccine is desired. As described herein, these vaccine compositions may in certain related embodiments also include one or more toll-like receptor (TLR) agonist and/or one or a plurality of one or more of a co-adjuvant, an imidazoquinoline immune response modifier, and a double stem loop immune modifier (dSLIM). In other related embodiments, a vaccine composition as provided herein may comprise GLA and one or more recombinant expression constructs each comprising a promoter operably linked to a nucleic acid sequence encoding the antigen against which elicitation or enhancement of an immune response (e.g., an antigen-specific response) in the subject is desired. GLA As noted above, because GLA is a chemically synthesized adjuvant it can be prepared in substantially homogeneous form, which refers to a GLA preparation that is at least 80%, preferably at least 85%, more preferably at least 90%, more preferably at least 95% and still more preferably at least 96%, 97%, 98% or 99% pure with respect to the GLA molecule. GLA compounds of the present invention have the following formula (I): or a pharmaceutically acceptable salt thereof, wherein: L1, L2, L3, L4, L5 and L6 are the same or different and independently —O—, —NH— or —(CH2)—; L7, L8, L9, and L10 are the same or different and independently absent or —C(═O)—; Y1 is an acid functional group; Y2 and Y3 are the same or different and independently —OH, —SH, or an acid functional group; Y4 is —OH or —SH; R1, R3, R5 and R6 are the same or different and independently C8-13 alkyl; and R2 and R4 are the same or different and independently C6-11 alley As used herein, the above terms have the following meaning: “Alkyl” means a straight chain or branched, noncyclic or cyclic, unsaturated or saturated aliphatic hydrocarbon containing from 1 to 20 carbon atoms, and in certain preferred embodiments containing from 11 to 20 carbon atoms. Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and the like, including undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, etc.; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like. Representative saturated cyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; while unsaturated cyclic alkyls include cyclopentenyl and cyclohexenyl, and the like. Cyclic alkyls are also referred to herein as “homocycles” or “homocyclic rings.” Unsaturated alkyls contain at least one double or triple bond between adjacent carbon atoms (referred to as an “alkenyl” or “alkynyl”, respectively). Representative straight chain and branched alkenyls include ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, and the like; while representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, and the like. “C8-13alkyl” and “C6-11alkyl” mean an alkyl as defined above, containing from 8-13 or 6-11 carbon atoms, respectively. “Acid functional group” means a functional group capable of donating a proton in aqueous media (i.e. a Bronsied-Lowry acid). After donating a proton, the acid functional group becomes a negatively charged species (i.e. the conjugate base of the acid functional group). Examples of acid functional groups include, but are not limited to: —OP(═O)(OH)2 (phosphate), —OS(═O)(OH)2 (sulfate), —OS(OH)2 (sulfite), —C(═O)OH (carboxylate), —OC(═O)CH(NH2)CH2C(═O)OH (aspartate), —OC(═O)CH2CH2C(═O)OH (succinate). and —OC(═O)CH2OP(═O)(OH)2 (carboxymethylphosphate). In more specific embodiments, the present invention provides GLA compounds of formula (I), wherein L5 and L6 are both —O— and L7, L8, L9, and L10 are each —C(═O)—, and the GLA compounds have the following formula (II): In more specific embodiments, the present invention provides GLA compounds of formula (II), wherein R1, R3, R5 and R6 are each Cx alkyl, where x is constant and is selected from an integer from 8-13, and R2 and R4 are both Cx-2 alkyl, and the GLA compounds have the following formula (III): In other more specific embodiments, the present invention provides GLA compounds of formula (III), wherein x is selected from an integer from 10-12. In other more specific embodiments, the present invention provides GLA compounds of formula (III), wherein x is 11, and the GLA compounds have the following structure (IV): In still other specific embodiments, the invention provides GLA compounds of formula (II), wherein Y1 is —OP(═O)(OH)2 and Y2, Y3 and Y4 are each —OH, and the GLA compounds have the following formula (V): In other specific embodiments, the invention provides GLA compounds of formula (II), wherein L1 and L3 are both —O— and L2 and L4 are both —NH—, and the GLA compounds have the following formula (VI): In yet more specific embodiments, the invention provides GLA compounds of formula (II), wherein Y1 is —OP(O)(OH)2, Y2, Y3 and Y4 are each —OH, L1 and L3 are both —O—, and L2 and L4 are both —NH—, and the GLA compounds have the following formula (VII): In still other specific embodiments, the present invention provides GLA compounds of formula (II), wherein Y1 is —OP(O)(OH)2, Y2, Y3 and Y4 are each —OH, L1 and L3 are both —O—, L2 and L4 are both —NH—, R1, R3, R5 and R6 each are Cx alkyl where x is constant and is selected from an integer from 8-13, and R2 and R4 are both Cx-2 alkyl, and the GLA compounds have the following formula (VIII): In a more specific embodiments of formula (VIII), x is 11, and the invention provides a GLA compound having the following structure (IX): GLA Compounds As mentioned above, the present invention provides GLA compounds. The GLA compounds of the present invention may be prepared by known organic synthesis techniques, including the methods described in more detail in the Examples. In general, the GLA compounds of structure (I) may be prepared by the following Reaction Schemes, wherein all substituents are as defined above unless indicated otherwise. The sugar backbone of representative GLA compounds can be prepared generally according to Reaction Scheme 1, wherein G1, G2, G3, G4, G5, G6, G7, G8, G9, and G10 are either the same or different and independently an appropriate protecting group or hydrogen. An appropriate sugar, such as (i), can be purchased or prepared according to methods known to those skilled in the art. The functional groups of sugar (i) can then be fully protected using methods known to those skilled in the art to obtain (ii). In this respect, one skilled in the art will recognize that an appropriate orthogonal protecting group strategy which allows for selective deprotection of the sugar functional groups may be employed. Suitable protecting groups include, but are not limited to silylethers, benzyl ethers, allyloxycarbonyl, acetals, Fmoc, azide, and the like. Deprotection of G1 results in free alcohol (iii) which can then be coupled with protected sugar (iv) using appropriate coupling conditions, for example CCl3CN/NaH, to obtain the desired sugar backbone (v). Representative GLA compound tail pieces, wherein L5 and L6 are both —O— and L7, L8, L9, and L10 are each —C(═O)—, can be prepared generally according to Reaction Scheme 2, wherein G11 represents an appropriate protecting group. Acid compounds of structure (vi) can be purchased or prepared according to methods known to those skilled in the art. Reaction of (vi) with an appropriate reagent, such as methyl hydrogen malonate, yields ketoester (vii). Reduction of (vii) yields alcohol (viii). One skilled in the art will recognize that under appropriate conditions the keto group of (vii) may be reduced stereospecifically as exemplified in the Examples. Saponification of (viii) yields acid (ix) which can be subsequently protected to yield (x). Treatment of (x) with acid chloride (xi) yields (xii) which upon deprotection yields (xiii). Compounds (ix) and (xiii) may both be converted to a suitably protected acid chloride derivative by methods known to those skilled in the art and attached to the GLA compound sugar backbone as shown in Reaction Scheme 3 below. Although Reaction Scheme 2 depicts synthesis of a GLA compound tail piece comprising R1 and R2, it should be understood that other tail pieces comprising other alkyl groups (e.g. R3, R4, R5, and R6) may also be prepared by an analogous method. Other tail pieces with different L5, L6, L7, L8, L9, and L10 groups may also be prepared by analogous methods. Representative GLA compounds can be prepared generally according to Reaction Scheme 3, wherein G12 and G13 are the same or different and independently represent an appropriate protecting group. Removal of the G5 protecting group of (v) followed by reaction with acid chloride (xiv) produces (xv). Similarly, removal of the G8 protecting group from (xv) followed by reaction with acid chloride (xvi) results in (xvii). Deprotection of (xvii) and reaction with acid chloride (xviii) yields (xix). Removal of G9 and reaction with (xx) then produces the protected GLA compound (xxi). Global deprotection of (xxi) results in a compound of structure (II). Although Reaction Scheme 3 depicts the synthesis of a compound of structure (II), one skilled in the art will recognize that analogous methods may be employed to produce any compound of structure (i). In addition, one skilled in the art will also recognize that with selection of the appropriate protecting groups, the final deprotection results in the desired compound. The compounds of the present invention may generally be utilized as the free base or free acid. Alternatively, the compounds of this invention may be used in the form of acid or base addition salts. Acid addition salts of the free amino compounds of the present invention may be prepared by methods well known in the art, and may be formed from organic and inorganic acids. Suitable organic acids include maleic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, acetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic, glycolic, glutamic, and benzenesulfonic acids. Suitable inorganic acids include hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids. Similarly, base addition salts of the acid compounds of the present invention may be prepared by methods well known in the art, and may be formed from organic and inorganic bases. Suitable organic bases include, but are not limited to, triethylamine and pyridine. Suitable inorganic bases include, but are not limited to, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and ammonia. Thus, the term “pharmaceutically acceptable salt” of structure (I) is intended to encompass any and all acceptable salt forms. In addition, prodrugs are also included within the context of this invention. Prodrugs are any covalently bonded carriers that release a compound of structure (I) in vivo when such prodrug is administered to a patient. Prodrugs are generally prepared by modifying functional groups in a way such that the modification is cleaved, either by routine manipulation or in vivo, yielding the parent compound. Prodrugs include, for example, compounds of this invention wherein hydroxy, amine or sulfhydryl groups are bonded to any group that, when administered to a patient, cleaves to form the hydroxy, amine or sulfhydryl groups. Thus, representative examples of prodrugs include (but are not limited to) acetate, formate and benzoate derivatives of alcohol and amine functional groups of the compounds of structure (I). Further, in the case of a carboxylic acid (COOH), esters may be employed, such as methyl esters, ethyl esters, and the like. With regard to stereoisomers, the compounds of structure (I) may have chiral centers and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof. Furthermore, some of the crystalline forms of the compounds of structure (I) may exist as polymorphs, which are included in the present invention. In addition, some of the compounds of structure (I) may also form solvates with water or other organic solvents. Such solvates are similarly included within the scope of this invention. Antigen An antigen, for use in certain embodiments of the herein described vaccine compositions and methods employing GLA, may be any target epitope, molecule (including a biomolecule), molecular complex (including molecular complexes that contain biomolecules), subcellular assembly, cell or tissue against which elicitation or enhancement of immunreactivity in a subject is desired. Frequently, the term antigen will refer to a polypeptide antigen of interest. However, antigen, as used herein, may also refer to a recombinant construct which encodes a polypeptide antigen of interest (e.g, an expression construct). In certain preferred embodiments the antigen may be, or may be derived from, or may be immunologically cross-reactive with, an infectious pathogen and/or an epitope, biomolecule, cell or tissue that is associated with infection, cancer, autoimmune disease, allergy, asthma, or any other condition where stimulation of an antigen-specific immune response would be desirable or beneficial. Preferably and in certain embodiments the vaccine formulations of the present invention contain an antigen or antigenic composition capable of eliciting an immune response against a human or other mammalian pathogen, which antigen or antigenic composition may include a composition derived from a virus such as from HIV-1, (such as tat, nef, gp120 or gp160), human herpes viruses, such as gD or derivatives thereof or Immediate Early protein such as ICP27 from HSV1 or HSV2, cytomegalovirus ((esp. Human)(such as gB or derivatives thereof), Rotavirus (including live-attenuated viruses), Epstein Barr virus (such as gp350 or derivatives thereof), Varicella Zoster Virus (such as gpI, II and IE63), or from a hepatitis virus such as hepatitis B virus (for example Hepatitis B Surface antigen or a derivative thereof), hepatitis A virus, hepatitis C virus and hepatitis E virus, or from other viral pathogens, such as paramyxoviruses: Respiratory Syncytial virus (such as F and G proteins or derivatives thereof), parainfluenza virus, measles virus, mumps virus, human papilloma viruses (for example HPV6, 11, 16, 18, etc.), flaviviruses (e.g., Yellow Fever Virus, Dengue Virus, Tick-borne encephalitis virus, Japanese Encephalitis Virus) or Influenza virus (whole live or inactivated virus, split influenza virus, grown in eggs or MDCK cells, or whole flu virosomes (as described by Gluck, Vaccine, 1992, 10, 915-920) or purified or recombinant proteins thereof, such as HA, NP. NA, or M proteins, or combinations thereof). In certain other preferred embodiments the vaccine formulations of the present invention contain an antigen or antigenic composition capable of eliciting an immune response against a human or other mammlian pathogen, which antigen or antigenic composition may include a composition derived from one or more bacterial pathogens such as Neisseria spp, including N. gonorrhea and N. meningitidis (for example capsular polysaccharides and conjugates thereof, transferrin-binding proteins, lactoferrin binding proteins, PilC, adhesins); S. pyogenes (for example M proteins or fragments thereof, C5A protease, lipoteichoic acids), S. agalactiae, S. mutans: H. ducreyi; Moraxella spp, including M catarrhalis, also known as Branhamella catarrhalis (for example high and low molecular weight adhesins and invasins); Bordetella spp, including B. pertussis (for example pertactin, pertussis toxin or derivatives thereof, filamentous hemagglutinin, adenylate cyclase, fimbriae), B. parapertussis and B. bronchiseptica; Mycobacterium spp., including M. tuberculosis (for example ESAT6, Antigen 85A, -B or -C), M. bovis, M. leprae, M. avium, M. paratuberculosis, M. smegmatis; Legionella spp, including L. pneumophila; Escherichia spp, including enterotoxic E. coli (for example colonization factors, heat-labile toxin or derivatives thereof, heat-stable toxin or derivatives thereof), enterohemorragic E. coli, enteropathogenic E. coli (for example Shiga toxin-like toxin or derivatives thereof); Vibrio spp, including V. cholera (for example cholera toxin or derivatives thereof); Shigella spp, including S. sonnei, S. dysenteriae, S. flexnerii; Yersinia spp, including Y. enterocolitica (for example a Yop protein), Y. pestis, Y. pseudotuberculosis; Campylobacter spp, including C. jejuni (for example toxins, adhesins and invasins) and C. coli; Salmonella spp, including S. typhi, S. paratyphi, S. choleraesuis, S. enteritidis; Listeria spp., including L. monocytogenes; Helicobacter spp, including H. pylori (for example urease, catalase, vacuolating toxin); Pseudomonas spp, including P. aeruginosa; Staphylococcus spp., including S. aureus, S. epidermidis; Enterococcus spp., including E. faecalis, E. faecium; Clostridium spp., including C. tetani (for example tetanus toxin and derivative thereof), C. botulinum (for example botulinum toxin and derivative thereof), C. difficile (for example clostridium toxins A or B and derivatives thereof); Bacillus spp., including B. anthracis (for example botulinum toxin and derivatives thereof); Corynebacterium spp., including C. diphtheriae (for example diphtheria toxin and derivatives thereof); Borrelia spp. including B. burgdorferi (for example OspA, OspC, DbpA, DbpB), B. garinii (for example OspA, OspC, DbpA, DbpB), B. afzelii (for example OspA, OspC, DbpA, DbpB), B. andersonii (for example OspA, OspC, DbpA, DbpB), B. hermsii; Ehrlichia spp., including E. equi and the agent of the Human Granulocytic Ehrlichiosis; Rickettsia spp, including R. rickettsii; Chlamydia spp. including C. trachomatis (for example MOMP, heparin-binding proteins), C. pneumoniae (for example MOMP, heparin-binding proteins), C. psittaci; Leptospira spp., including L. interrogans; Treponema spp., including T. pallidum (for example the rare outer membrane proteins), T. denticola, T. hyodysenteriae; or other bacterial pathogens. In certain other preferred embodiments the vaccine formulations of the present invention contain an antigen or antigenic composition capable of eliciting an immune response against a human or other mammalian pathogen, which antigen or antigenic composition may include a composition derived from one or more parasites (See, e.g., John, D. T. and Petri, W. A., Markell and Voge's Medical Parasitology-9th Ed., 2006, WB Saunders, Philadelphia; Bowman, D. D., Georgis' Parasitology for Veterinarians-8th Ed., 2002, WB Saunders, Philadelphia) such as Plasmodium spp., including P. falciparum; Toxoplasma spp., including T. gondii (for example SAG2, SAG3, Tg34); Entamoeba spp., including E. histolytica; Babesia spp., including B. microti; Trypanosoma spp., including T. cruzi; Giardia spp., including G. lamblia; Leishmania spp., including L. major; Pneumocystis spp., including P. carinii; Trichomonas spp., including T. vaginalis; or from a helminth capable of infecting a mammal, such as: (i) nematode infections (including, but not limited to, Enterobius vermicularis, Ascaris lumbricoides, Trichuris trichuria, Necator americanus, Ancylostoma duodenale, Wuchereria bancrofti, Brugia malayi, Onchocerca volvulus, Dracanculus medinensis, Trichinella spiralis, and Strongyloides stercoralis); (ii) trematode infections (including, but not limited to, Schistosoma mansoni, Schistosoma haematobium, Schistosoma japonicum, Schistosoma mekongi, Opisthorchis sinensis, Paragonimus sp, Fasciola hepatica, Fasciola magna, Fasciola gigantica); and (iii) cestode infections (including, but not limited to, Taenia saginata and Taenia solium). Certain embodiments may therefore contemplate vaccine compositions that include an antigen derived from Schisostoma spp., Schistosoma mansonii, Schistosoma haematobium, and/or Schistosoma japonicum, or derived from yeast such as Candida spp., including C. albicans; Cryptococcus spp., including C. neoformans. Other preferred specific antigens for M. tuberculosis are for example Th Ra12, Tb H9, Tb Ra35, Tb38-1, Erd 14, DPV, MTI, MSL, mTTC2 and hTCC1 (WO 99/51748). Proteins for M. tuberculosis also include fusion proteins and variants thereof where at least two, preferably three polypeptides of M. tuberculosis are fused into a larger protein. Preferred fusions include Ra12-TbH9-Ra35, Erd14-DPV-MTI, DPV-MTI-MSL, Erd14DPV-MTI-MSL-mTCC2, Erd14-DPV-MTI-MSL, DPV-MTI-MSL-mTCC2, TbH9-DPV-MTI (WO 99151748). Certain preferred antigens for Chlamydia include for example the High Molecular Weight Protein (HWMP) (WO 99/17741), ORF3 (EP 366 412), CT622, CT610, pmpD, UVEB and putative membrane proteins (Props). Other Chlamydia antigens of the vaccine formulation can be selected from the group described in WO 99128475. Preferred bacterial vaccines comprise antigens derived from Streptococcus spp, including S. pneumoniae (for example capsular polysaccharides and conjugates thereof, PsaA, PspA, PdB, streptolysin, choline-binding proteins) and the protein antigen Pneumolysin (Biochem Biophys Acta, 1989, 67, 1007; Rubins et al., Microbial Pathogenesis, 25, 337-342), and mutant detoxified derivatives thereof (WO 90/06951; WO 99/03884). Other preferred bacterial vaccines comprise antigens derived from Haemophilus spp., including H. influenzae type B (for example PRP and conjugates thereof), nontypeable H. influenzae, for example OMP26, high molecular weight adhesins, P5, P6, protein D and lipoprotein D, and fimbrin and fimbrin derived peptides (U.S. Pat. No. 5,843,464) or multiple copy variants or fusion proteins thereof. Derivatives of Hepatitis B Surface antigen are well known in the art and include, inter alia, those PreS1, Pars2 S antigens set forth described in European Patent applications EP-A414 374; EP-A-0304 578, and EP 198474. In one preferred aspect the vaccine formulation of the invention comprises the HIV-1 antigen, gp120, especially when expressed in CHO cells. In a further embodiment, the vaccine formulation of the invention comprises gD2t as hereinabove defined. In a preferred embodiment of the present invention vaccines containing the claimed adjuvant comprise antigen derived from the Human Papilloma Virus (HPV) considered to be responsible for genital warts (HPV 6 or HPV 11 and others), and the HPV viruses responsible for cervical cancer (HPV16, HPV18 and others). Particularly preferred forms of genital wart prophylactic, or therapeutic, vaccine comprise L1 particles or capsomers, and fusion proteins comprising one or more antigens selected from the HPV 6 and HPV 11 proteins E6, E7, L1, and L2. Certain preferred forms of fusion protein include L2E7 as disclosed in WO 96/26277, and proteinD(1/3)-E7 disclosed in GB 9717953.5 (PCT/EP98/05285). A preferred HPV cervical infection or cancer, prophylaxis or therapeutic vaccine, composition may comprise HPV 16 or 18 antigens. For example, L1 or L2 antigen monomers, or L1 or L2 antigens presented together as a virus like particle (VLP) or the L1 alone protein presented alone in a VLP or capsomer structure. Such antigens, virus like particles and capsomer are per se known. See for example WO94/00152, WO94/20137, WO94/05792, and WO93/02184. Additional early proteins may be included alone or as fusion proteins such as E7, E2 or preferably F5 for example; particularly preferred embodiments include a VLP comprising L1E7 fusion proteins (WO 96/11272). Particularly preferred HPV 16 antigens comprise the early proteins E6 or F7 in fusion with a protein D carrier to form Protein D-E6 or E7 fusions from HPV 16, or combinations thereof; or combinations of E6 or E7 with L2 (WO 96/26277). Alternatively the HPV 16 or 18 early proteins E6 and E7, may be presented in a single molecule, preferably a Protein D-E6/E7 fusion. Such vaccine may optionally contain either or both E6 and E7 proteins front HPV 18, preferably in the form of a Protein D-E6 or Protein D-E7 fusion protein or Protein D E6/E7 fusion protein. The vaccine of the present invention may additionally comprise antigens from other HPV strains, preferably from strains HPV 31 or 33. Vaccines of the present invention further comprise antigens derived from parasites that cause Malaria. For example, preferred antigens from Plasmodia falciparum include RTS,S and TRAP. RTS is a hybrid protein comprising substantially all the C-terminal portion of the circumsporozoite (CS) protein of P. falciparum linked via four amino acids of the preS2 portion of Hepatitis B surface antigen to the surface (S) antigen of hepatitis B virus. Its full structure is disclosed in the International Patent Application No. PCT/EP92/02591, published as WO 93/10152 claiming priority from UK patent application No.9124390.7. When expressed in yeast RTS is produced as a lipoprotein particle, and when it is co-expressed with the S antigen from HBV it produces a mixed particle known as RTS,S. TRAP antigens are described in the International Patent Application No. PCT/GB89/00895 published as WO 90/01496. A preferred embodiment of the present invention is a Malaria vaccine wherein the antigenic preparation comprises a combination of the RTS,S and TRAP antigens. Other plasmodia antigens that are likely candidates to be components of a multistage Malaria vaccine are P. faciparum MSP1, AMA1, MSP3, EBA, GLURP, RAP1, RAP2, Sequestrin, PfEMP1, Pf332, LSA1, LSA3, STARP, SALSA, PfEXP1, Pfs25, Pfs28, PFS27125, Pfs16, Pfs48/45, Pfs230 and their analogues in Plasmodium spp. Accordingly, certain herein disclosed embodiment contemplate an antigen that is derived from at least one infectious pathogen such as a bacterium, a virus or a fungus, including an Actinobacterium such as M. tuberculosis or M. leprae or another mycobacterium; a bacterium such as a member of the genus Salmonella, Neisseria, Borrelia, Chlamydia or Bordetella; a virus such as a herpes simplex virus, a human immunodeficiency virus (HIV), a feline immunodeficiency virus (FIV), cytomegalovirus, Varicella Zoster Virus, hepatitis virus, Epstein Barr Virus (EBV), respiratory syncytial virus, human papilloma virus (HPV) and a cytomegalovirus; HIV such as HIV-1 or HIV-2; a fungus such as Aspergillus, Blastomyces, Coccidioides and Pneumocysti or a yeast, including Candida species such as C. albicans, C. glabrata, C. krusei, C. lusitaniae, C. tropicalis and C. parapsilosis; a parasite such as a protozoan, for example, a Plasmodium species including P. falciparum, P. vivax, P. malariae and P. ovale; or another parasite such as one or more of Acanthamoeba, Entamoeba histolytica, Angiostrongylus, Schistosoma mansonii, Schistosoma haematobium, Schistosoma japonicum, Cryptosporidium, Ancylostoma, Entamoeba histolytica, Entamoeba coli, Entamoeba dispar, Entamoeba hartmanni, Entamoeba polecki, Wuchereria bancrofti, Giardia, and Leishmania. For example, in GLA-containing vaccine embodiments containing antigens derived from Borrelia sp., the antigens may include nucleic acid, pathogen derived antigen or antigenic preparations, recombinantly produced protein or peptides, and chimeric fusion proteins. One such antigen is OspA. The OspA may be a full mature protein in a lipidated form by virtue of its biosynthesis in a host cell (Lipo-OspA) or may alternatively be a non-lipidated derivative. Such non-lipidated derivatives include the non-lipidated NS1-OspA fusion protein which has the first 81 N-terminal amino acids of the non-structural protein (NS1) of the influenza virus, and the complete OspA protein, and another, MDP-OspA is a non-lipidated form of OspA carrying 3 additional N-terminal amino acids. Compositions and methods are known in the art for identifying subjects having, or suspected of being at risk for having, an infection with an infectious pathogen as described herein. For example, the bacterium Mycobacterium tuberculosis cases tuberculosis (TB). The bacteria usually attack the lungs but can also attack the kidney, spine, and brain. If not treated properly, TB disease can be fatal. The disease is spread from one person to another in the air when an infected person sneezes or coughs. In 2003, more than 14,000 cases of TB were reported in the United States. Although tuberculosis can generally be controlled using extended antibiotic therapy, such treatment is not sufficient to prevent the spread of the disease and concerns exist regarding the potential selection for antibiotic-resistant strains. Infected individuals may be asymptomatic, but contagious, for some time. In addition, although compliance with the treatment regimen is critical, patient behavior is difficult to monitor. Some patients do not complete the course of treatment, which can lead to ineffective treatment and the development of drug resistance. (e.g., U.S. Pat. No. 7,087,713) Currently, vaccination with live bacteria is the most efficient method for inducing protective immunity against tuberculosis. The most common Mycobacterium employed for this purpose is Bacillus Calmette-Guerin (BCG), an avirulent strain of Mycobacterium Bovis. However, the safety and efficacy of BCG is a source of controversy and some countries, such as the United States, do not vaccinate the general public. Diagnosis is commonly achieved using a skin test, which involves intradermal exposure to tuberculin PPD (protein-purified derivative). Antigen-specific T cell responses result in measurable induration at the injection site by 48 72 hours after injection, which indicates exposure to Mycobacterial antigens. Sensitivity and specificity have, however, been a problem with this test, and individuals vaccinated with BCG cannot be distinguished from infected individuals. (e.g., U.S. Pat. No. 7,087,713) While macrophages have been shown to act as the principal effectors of M. tuberculosis immunity, T cells are the predominant inducers of such immunity. The essential role of T cells in protection against M. tuberculosis infection is illustrated by the frequent occurrence of M. tuberculosis in AIDS patients, due to the depletion of CD4 T cells associated with human immunodeficiency virus (HIV) infection. Mycobacterium-reactive CD4 T cells have been shown to be potent producers of gamma-interferon (IFN-gamma), which, in turn, has been shown to trigger the anti-mycobacterial effects of macrophages in mice. While the role of IFN-gamma in humans is less clear, studies have shown that 1,25-dihydroxy-vitamin D3, either alone or in combination with IFN-gamma or tumor necrosis factor-alpha, activates human macrophages to inhibit M. tuberculosis infection. Furthermore, it is known that IFN-gamma stimulates human macrophages to make 1,25-dihydroxy-vitamin D3. Similarly, IL-12 has been shown to play a role in stimulating resistance to M. tuberculosis infection. For a review of the immunology of M. tuberculosis infection, see Chan and Kaufmann, in Tuberculosis: Pathogenesis, Protection and Control, Bloom (ed.), ASM Press. Washington, D.C. (1994). Existing compounds and methods for diagnosing tuberculosis or for inducing protective immunity against tuberculosis include the use of polypeptides that contain at least one immunogenic portion of one or more Mycobacterium proteins and DNA molecules encoding such polypeptides. Diagnostic kits containing such polypeptides or DNA sequences and a suitable detection reagent may be used for the detection of Mycobacterium infection in patients and biological samples. Antibodies directed against such polypeptides are also provided. In addition, such compounds may be formulated into vaccines andior pharmaceutical compositions for immunization against Mycobacterium infection. (U.S. Pat. Nos. 6,949,246 and 6,555,653). Malaria was eliminated in many parts of the world in the 1960s, but the disease still persists and new strains of the disease are emerging that are resistant to existing drugs. Malaria is a major public health problem in more than 90 countries. Nine out of ten cases of malaria occur in sub-Saharan Africa. More than one third of the world's population is at risk, and between 350 and 500 million people are infected with malaria each year. Forty-five million pregnant women are at risk of contracting malaria this year. Of those individuals already infected, more than 1 million of those infected die each year from what is a preventable disease. The majority of those deaths are children in Africa. Malaria is usually transmitted when a person is bitten by an infected female Anopheles mosquito. To transmit the mosquito must have been infected by having drawn blood from a person already infected with malaria. Malaria is caused by a parasite and the clinical symptoms of the disease include fever and flu-like illness, such as chills, headache, muscle aches, and tiredness. These symptoms may be accompanied by nausea, vomiting, and diarrhea. Malaria can also cause anemia and jaundice because of the loss of red blood cells. Infection with one type of malaria, Plasmodium falciparum, if not promptly treated, may cause kidney failure, seizures, mental confusion, coma, and death. An in vitro diagnostic method for malaria in an individual is known, comprising placing a tissue or a biological fluid taken from an individual in contact with a molecule or polypeptide composition, wherein said molecule or polypeptide composition comprises one or more peptide sequences bearing all or part of one or more T epitopes of the proteins resulting from the infectious activity of P. falciparum, under conditions allowing an in vitro immunological reaction to occur between said composition and the antibodies that may be present in the tissue or biological fluid, and in vitro detection of the antigen-antibody complexes formed (see, e.g., U.S. Pat. No. 7,087,231). Expression and purification of a recombinant Plasmodium falciparum (3D7) AMA-1 ectodomain have been described. Previous methods have produced a highly purified protein which retains folding and disulfide bridging of the native molecule. The recombinant AMA-1 is useful as a diagnostic reagentas well as in antibody production, and as a protein for use alone, or as part of, a vaccine to prevent malaria. (U.S. Pat. No. 7,029,685) Polynucleotides have been described in the art that encode species-specific P. vivax malarial peptide antigens which are proteins or fragments of proteins secreted into the plasma of a susceptible mammalian host after infection, as have monoclonal or polyclonal antibodies directed against these antigens. The peptide antigens, monoclonal antibodies, and/or polyclonal antibodies are utilized in assays used to diagnose malaria, as well as to determine whether Plasmodium vivax is the species responsible for the infection. (U.S. Pat. No. 6,706,872) Species-specific P. vivax malarial peptide antigens have also been reported which are proteins or fragments of proteins secreted into the plasma of a susceptible mammalian host after infection, as have monoclonal or polyclonal antibodies directed against these antigens. The peptide antigens, monoclonal antibodies, and/or polyclonal antibodies are utilized in assays used to diagnose malaria, as well as to determine whether Plasmodium vivax is the species responsible for the infection (see, e.g., U.S. Pat. No. 6,231,861). A recombinant Plasmodium falciparum (3D7) AMA-1 ectodomain has also been expressed by a method that produces a highly purified protein which retains folding and disulfide bridging of the native molecule. The recombinant AMA-1 is useful as a diagnostic reagent, for use in antibody production, and as a vaccine. (U.S. Pat. No. 7,060,276) Similarly known are the expression and purification of a recombinant Plasmodium falciparum (3D7) MSP-142, which retains folding and disulfide bridging of the native molecule. The recombinant MSP-142 7 is useful as a diagnostic reagent, for use in antibody production, and as a vaccine. (U.S. Pat. No. 6,855,322) Diagnostic methods for the detection of human malaria infections to identify a subject having or suspected of being at risk for having an infection with a malaria infectious pathogen are thus known according to these and related disclosures. Specifically, for example, blood samples are combined with a reagent containing 3-acetyl pyridine adenine dinucleotide (APAD), a substrate (e.g. a lactate salt or lactic acid), and a buffer. The reagent is designed to detect the presence of a unique glycolytic enzyme produced by the malaria parasite. This enzyme is known as parasite lactic acid dehydrogenase (PLDH). PLDH is readily distinguishable from host LDH using the above-described reagent. Combination of the reagent with a parasitized blood sample results in the reduction of APAD. However, APAD is not reduced by host LDH. The reduced APAD may then be detected by various techniques, including spectral, fluorimetric, electrophoretic, or colorimetric analysis. Detection of the reduced APAD in the foregoing manner provides a positive indication of malaria infection (e.g., U.S. Pat. No. 5,124,141). In another methodology for diagnosing malaria, a polypeptide comprising a characteristic amino acid sequence derived from the Plasmodium falciparum antigen GLURP, is recognized in a test sample by a specific antibody raised against or reactive with the polypeptide. (U.S. Pat. No. 5,231,168) Leishmaniasis is a widespread parasitic disease with frequent epidemics in the Indian subcontinent, Africa, and Latin America and is a World Health Organization priority for vaccine development. A complex of different diseases, Leishmania parasites cause fatal infections of internal organs, as well as serious skin disease. One of the most devastating forms of leishmaniasis is a disfiguring infection of the nose and mouth. The number of cases of leishmaniasis is increasing, and it is now out of control in many areas. Leishmaniasis is also on the rise in some developed countries, specifically southern Europe as a result of HIV infection. Available drugs are toxic, expensive, and require long-term daily injections. Leishmania are protozoan parasites that inhabit macrophages or the white blood cells of the immune system. The parasites are transmitted by the bite of small blood sucking insects (sand flies), which are difficult to control, as they inhabit vast areas of the planet. Visceral leishmaniasis is the most dangerous of the three manifestations of the disease. It is estimated that about 500,000 new cases of the visceral form (kala-azar or “the killing disease”) occur each year. More than 200 million people are currently at risk for contracting visceral leishmaniasis. Over 90 percent of visceral leishmaniasis cases occur in India, Bangladesh, Sudan, Brazil, and Nepal. Most of the deaths occur in children. Those with the cutaneous forms are often left permanently disfigured. Leishmania infections are difficult to diagnose and typically involve histopathologic analysis of tissue biopsy specimens. Several serological and immunological diagnostic assays have, however, been developed. (U.S. Pat. No. 7,008,774; Senaldi et al., (1996) J. Immunol. Methods 193:9 5; Zijlstra, et al., (1997) Trans. R. Soc. Trap. Med. Hyg. 91:671 673; Badaro, et al., (1996) J. Inf. Dis. 173:758 761; Choudhary, S., et al., (1992) J. Comm. Dis. 24:32 36; Badaro, R., et al., (1986) Am. J. Trap. Med. Hyg. 35:72 78; Choudhary, A., et al., (1990) Trans. R. Soc. Trap. Med. Hyg. 84:363 366; and Reed, S. G., et al., (1990) Am. J. Trap. Med. Hyg. 43:632 639). The promastigotes release metabolic products into the culture medium to produce conditioned medium. These metabolic products are immunogenic to the host. See Schnur, L. F., et al., (1972) Isrl. J. Med. Sci. 8:932 942; Sergeiev, V. P., et al., (1969) Med. Parasitol. 38:208 212; El-On, J., et al., (1979) Exper. Parasitol. 47:254 269; and Bray, R. S., et al., (1966) Trans. R. Soc. Trop. Med. Hyg. 60:605 609; U.S. Pat. No. 6.846,648, U.S. Pat. No. 5,912,166; U.S. Pat. No. 5,719,263; U.S. Pat. No. 5,411,865). About 40 million people around the world are infected with HIV, the virus that causes AIDS. Around 3 million people die of the disease each year, 95 percent of them in the developing world. Each year, close to 5 million people become infected with HIV. Currently, sub-Saharan African carries the highest burden of disease, but it is quickly spreading to other countries such as India, China, and Russia. The epidemic is growing most rapidly among minority populations. In the United States there have been more than 950,000 cases of AIDS reported since 1981. AIDS hits people during their most productive years. Women, for both biological and social reasons, have an increased risk for HIV/AIDS. AIDS is caused by human immunodeficiency virus (HIV), which kills and damages cells of the body's immune system and progressively destroys the body's ability to fight infections and certain cancers. HIV is spread most commonly by having unprotected sex with an infected partner. The most robust solution to the problem is preventing the virus from spreading. Making a safe, effective, and affordable HIV vaccine is one way to reach this goal. Across the world, fewer than one in five people at high risk for HIV infection have access to effective prevention. Methods for diagnosing HIV infections are known, including by virus culture, PCR of definitive nucleic acid sequences from patient specimens, and antibody tests for the presence of anti-HIV antibodies in patient sera, (see e.g., U.S. Pat. Nos. 6,979,535, 6,544,728, 6,316,183, 6,261,762, 4,743,540.) According to certain other embodiments as disclosed herein, the vaccine compositions and related formulations and methods of use may include an antigen that is derived from a cancer cell, as may be useful for the immunotherapeutic treatment of cancers. For example, the adjuvant formulation may finds utility with tumor rejection antigens such as those for prostate, breast, colorectal, lung, pancreatic, renal or melanoma cancers. Exemplary cancer or cancer cell-derived antigens include MACE 1, 3 and MACE 4 or other MACE antigens such as those disclosed in WO99/40188, PRAME, BADE, Lage (also known as NY Eos 1) SAGE and HAGE (WO 99/53061) or GAGE (Robbins and Kawakami, 1996 Current Opinions in Immunology 8, pps 628-636; Van den Eynde et al., International Journal of Clinical & Laboratory Research (1997 & 1998); Correale et al. (1997), Journal of the National Cancer Institute 89, p. 293. These non-limiting examples of cancer antigens are expressed in a wide range of tumor types such as melanoma, lung carcinoma, sarcoma and bladder carcinoma. See, e.g., U.S. Pat, No. 6,544,518. Other tumor-specific antigens are suitable for use with GLA according to certain presently disclosed embodiments include, but are not restricted to, tumor-specific or tumor-associated gangliosides such as GM2, and GM3 or conjugates thereof to carrier proteins; or an antigen for use in a GLA vaccine composition for eliciting or enhancing an anti-cancer immune response may be a self peptide hormone such as whole length Gonadotrophin hormone releasing hormone (GnRH, WO 95/20600), a short 10 amino acid long peptide, useful in the treatment of many cancers. In another embodiment prostate antigens are used, such as Prostate specific antigen (PSA), PAP, PSCA (e.g., Proc. Nat. Acad. Sci. USA 95(4) 1735-1740 1998), PSMA or, in a preferred embodiment an antigen known as Prostase. (e.g., Nelson, et al., Proc. Natl. Acad. Sci. USA (1999) 96: 3114-3119; Ferguson, et al. Proc. Natl. Acad. Sci. USA 1999. 96, 3114-3119; WO 98/12302; U.S. Pat. No. 5,955,306; WO 98/20117; U.S. Pat. Nos. 5,840,871 and 5,786,148; WO 00/04149. Other prostate specific antigens are known from WO 98/137418, and WO1004149. Another is STEAP (PNAS 96 14523 14528 7-12 1999). Other tumor associated antigens useful in the context of the present invention include: Plu-1 (J Biol. Chem 274 (22) 15633 -15645, 1999), HASH -1, HasH-2, Cripto (Salomon et al Bioessays 199, 21:61-70, U.S. Pat. No. 5,654,140) and Criptin (U.S. Pat. No. 5,981,215). Additionally, antigens particularly relevant for vaccines in the therapy of cancer also comprise tyrosinase and survivin. The herein disclosed embodiments pertaining to GLA-containing vaccine compositions comprising a cancer antigen will be useful against any cancer characterized by tumor associated antigen expression, such as HER-2/neu expression or other cancer-specific or cancer-associated antigens. Diagnosis of cancer in a subject having or suspected of being at risk for having cancer may be accomplished by any of a wide range of art-accepted methodologies, which may vary depending on a variety of factors including clinical presentation, degree of progression of the cancer, the type of cancer, and other factors. Examples of cancer diagnostics include histopathological, histocytochemical, immunohistocytochemical and immunohistopathological examination of patient samples (e.g., blood, skin biopsy, other tissue biopsy, surgical specimens, etc.), PCR tests for defined genetic (e.g., nucleic acid) markers, serological tests for circulating cancer-associated antigens or cells bearing such antigens, or for antibodies of defined specificity, or other methodologies with which those skilled in the art will be familiar. See, e.g., U.S. Pat. Nos. 6,734,172; 6,770,445; 6,893,820; 6,979,730; 7,060,802; 7,030,232; 6,933,123; 6,682,901; 6,587,792; 6,512,102; 7,078,180; 7,070,931; JP5-328975; Waslylyk et al., 1993 Eur. J Bloch. 211(7):18. Vaccine compositions and methods according to certain embodiments of the present invention may also be used for the prophylaxis or therapy of autoimmune diseases, which include diseases, conditions or disorders wherein a host's or subject's immune system detrimentally mediates an immune response that is directed against “self” tissues, cells, biomolecules (e.g., peptides, polypeptides, proteins, glycoproteins, lipoproteins, proteolipids, lipids, glycolipids, nucleic acids such as RNA and DNA, oligosaccharides, polysaccharides, proteoglycans, glycosaminoglycans, or the like, and other molecular components of the subjects cells and tissues) or epitopes (e.g., specific immunologically defined recognition structures such as those recognized by an antibody variable region complementarity determining region (CDR) or by a T cell receptor CDR. Autoimmune diseases are thus characterized by an abnormal immune response involving either cells or antibodies, that are in either case directed against normal autologous tissues. Autoimmune diseases in mammals can generally be classified in one of two different categories: cell-mediated disease (i.e., T-cell) or antibody-mediated disorders. Non-limiting examples of cell-mediated autoimmune diseases include multiple sclerosis, rheumatoid arthritis, Hashimoto thyroiditis, type I diabetes mellitus (Juvenile onset diabetes) and autoimmune uvoretinitis. Antibody-mediated autoimmune disorders include, but are not limited to, myasthenia gravis, systemic lupus erythematosus (or SLE), Graves' disease, autoimmune hemolytic anemia, autoimmune thrombocytopenia, autoimmune asthma, cryoglobulinemia, thrombic thrombocytopenic purpura, primary biliary sclerosis and pernicious anemia. The antigen(s) associated with: systemic lupus erythematosus is small nuclear ribonucleic acid proteins (snRNP); Graves' disease is the thyrotropin receptor, thyroglobulin and other components of thyroid epithelial cells (Akamizu et al., 1996; Kellerman et al., 1995; Raju et al., 1997; and Texier et al., 1992); pemphigus is cadherin-like pemphigus antigens such as desmoglein 3 and other adhesion molecules (Memar et al., 1996: Stanley, 1995; Plott et al., 1994; and Hashimoto, 1993); and thrombic thrombocytopenic purpura is antigens of platelets. (See, e.g., U.S. Pat. No. 6,929,796; Gorski et al. (Eds.), Autoimmunity, 2001, Kluwer Academic Publishers, Norwell, M A; Radbruch and Lipsky, P. E. (Eds.) Current Concepts in Autoimmunity and Chronic Inflammation (Curr. Top. Microbial. and Immunol.) 2001, Springer, NY.) Autoimmunity plays a role in more than 80 different diseases, including type 1 diabetes, multiple sclerosis, lupus, rheumatoid arthritis, scleroderma, and thyroid diseases. Vigorous quantitative estimates of morbidity for most autoimmune diseases are lacking. Most recent studies done in the late 1990s reveal that autoimmune diseases are the third most common major illness in the United States; and the most common autoimmune diseases affect more than 8.5 million Americans. Current estimates of the prevalence of the disease range from 5 to 8 percent of the United States population. Most autoimmune diseases disproportionately affect women. Women are 2.7 times more likely than men to acquire an autoimmune disease. Women are more susceptible to autoimmune diseases; men appear to have higher levels of natural killer cell activity than do women. (Jacobsen et al, Clinical Immunology and Immunopathology, 84:223-243, 1997.) Autoimmune diseases occur when the immune system mistakes self tissues for nonself and mounts an inappropriate attack. The body can be affected in different ways from autoimmune diseases, including, for example, the gut (Crohn's disease) and the brain (multiple sclerosis). It is known that an autoantibody attacks self-cells or self-tissues to injure their function and as a result causes autoimmune diseases, and that the autoantibody may be detected in the patient's serum prior to the actual occurrence of an autoimmune disease (e.g., appearance of clinical signs and symptoms). Detection of an autoantibody thus permits early discovery or recognition of presence or risk for developing an autoimmune disease. Based on these findings, a variety of autoantibodies against autoantigens have been discovered and the autoantibodies against autoantigens have been measured in clinical tests (e.g., U.S. Pat. Nos. 6,919,210, 6,596,501, 7,012,134, 6,919,078) while other autoimmune diagnostics may involve detection of a relevant metabolite (e.g., U.S. Pat. No. 4,659,659) or immunological reactivity (e.g., U.S. Pat. Nos. 4,614,722 and 5,147,785, 4,420,558, 5,298,396, 5,162,990, 4,420,461, 4,595,654, 5,846,758, 6,660,487). In certain embodiments, the compositions of the invention will be particularly applicable in treatment of the elderly and/or the immunosuppressed, including subjects on kidney dialysis, subjects on chemo-therapy and/or radiation therapy, transplant recipients, and the like. Such individuals generally exhibit diminished immune responses to vaccines and therefore use of the compositions of the invention can enhance the immune responses achieved in these subjects. In other embodiments, the antigen or antigens used in the compositions of the invention include antigens associated with respiratory diseases, such as those caused or exacerbated by bacterial infection (e.g. pneumococcal), for the prophylaxis and therapy of conditions such as chronic obstructive pulmonary disease (COPD). COPD is defined physiologically by the presence of irreversible or partially reversible airway obstruction in patients with chronic bronchitis and/or emphysema (Am J Respir Crit Care Med. 1995 November; 152(5 Pt 2):S77-121). Exacerbations of COPD are often caused by bacterial (e.g. pneumococcal) infection (Clin Microbiol Rev. 2001 April; 14(2):336-63). In a particular embodiment, a composition of the invention comprises a GLA adjuvant, as described herein, in combination with the Pneumococcal vaccine Prevnar® (Wyeth). In still other embodiments, the compositions of the invention, comprising GLA as described herein, are used in the treatment of allergic conditions. For example, in a particular embodiment, the compositions are used in allergy desensitization therapy. Such therapy involves the stimulation of the immune system with gradually increasing doses of the substances to which a person is allergic, wherein the substances are formulated in compositions comprising GLA. In specific embodiments, the compositions are used in the treatment of allergies to food products, pollen, mites, cats or stinging insects (e.g., bees, hornets, yellow jackets, wasps, velvet ants, fire ants). TLR As described herein, certain embodiments of the present invention contemplate vaccine compositions and immunological adjuvant compositions, including pharmaceutical compositions, that include, in addition to the GLA compound(s) of the invention, one or more toll-like receptor agonist (TLR agonist). Toll-like receptors (TLR) include cell surface transmembrane receptors of the innate immune system that confer early-phase recognition capability to host cells for a variety of conserved microbial molecular structures such as may be present in or on a large number of infectious pathogens. (e.g., Armant et al., 2002 Genome Biol. 3(8):reviews 3011.1-3011.6; Fearon et al., 1996 Science 272:50; Medzhitov et al., 1997 Curr. Opin. Immunol. 9:4; Luster 2002 Curr. Opin. Immunol. 14:129; Lien et al. 2003 Nat. Immunol. 4:1162; Medzhitov, 2001 Nat. Rev. Immunol. 1:135; Takeda et al., 2003 Ann Rev Immunol. 21:335: Takeda et al. 2005 Int. Immunol. 17:1; Kaisho et al., 2004 Microbes Infect. 6:1388; Datta et al., 2003 J. Immunol. 170:4102). Induction of TLR-mediated signal transduction to potentiate the initiation of immune responses via the innate immune system may be effected by TLR agonists, which engage cell surface TLR. For example, lipopolysaccharide (LPS) may be a TLR agonist through TLR2 or TLR4 (Tsan et al., 2004 J. Leuk. Biol. 76:514; Tsan et al., 2004 Am. J. Physiol. Cell Physiol. 286:C739; Lin et al., 2005 Shock 24:206); poly(inosine-cytidine) (polyl:C) may be a TLR agonist through TLR3 (Salem et al., 2006 Vaccine 24:5119); CpG sequences (oligodeoxynucleotides containing unmethylated cytosine-guanosine or “CpG” dinucleotide motifs, e.g., CpG 7909, Cooper et al., 2005 ADS 19:1473; CpG 10101 Bayes et al. Methods Find Exp Clin Pharmacol 27:193; Vollmer et al. Expert Opinion on Biological Therapy 5:673; Vollmer et al., 2004 Antimicrob. Agents Chemother. 48:2314; Deng et al., 2004 J. Immunol. 173:5148) may be TLR agonists through TLR9 (Andaloussi et a., 2006 Glia 54:526; Chen et al., 2006 J. lmmunol. 177:2373); peptidoglycans may be TLR2 and/or TLR6 agonists (Saboll et al., 2006 Biol. Reprod. 75:131; Nakao et al., 2005 J. Immunol. 174:1566); 3M003 (4-amino-2-(ethoxymethyl)-α,α-dimethyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline-1-ethanol hydrate, Mol. Wt. 318 Da from 3M Pharmaceuticals, St. Paul, Minn., which is also a source of the related compounds 3M001 and 3M002; Gorden et al., 2005 J. Immunol. 174:1259) may be a TLR7 agonist (Johansen 2005 Clin. Exp. Allerg. 35:1591) and/or a TLR8 agonist (Johansen 2005); flagellin may be a TLRS agonist (Feuillet et al., 2006 Proc. Nat. Acad. Sci. USA 103:12487); and hepatitis C antigens may act as TLR agonists through TLR7 and/or TLR9 (Lee et al., 2006 Proc. Nat. Acad. Sci. USA 103:1828; Horsmans et al., 2005 Hepatol. 42:724). Other TLR agonists are known (e.g., Schirmbeck et al., 2003 J. Immunol. 171:5198) and may be used according to certain of the presently described embodiments. For example, and by way of background (see, e.g., U.S. Pat. No. 6,544,518) immunostimulatory oligonucleotides containing unmethylated CpG dinucleotides (“CpG”) are known as being adjuvants when administered by both systemic and mucosal routes (WO 96/02555, EP 468520, Davis et al., J. Immunol, 1998. 160(2):870-876; McCluskie and Davis, J. Immunol., 1998, 161(9):4463-6). CpG is an abbreviation for cytosine-guanosine dinucleotide motifs present in DNA. The central role of the CG motif in immunostimulation was elucidated by Krieg, Nature 374, p546 1995. Detailed analysis has shown that the CG motif has to be in a certain sequence context, and that such sequences are common in bacterial DNA but are rare in vertebrate DNA. The immunostimulatory sequence is often: Purine, Purine, C, G, pyrimidine, pyrimidine; wherein the dinucleotide CG motif is not methylated, but other unmethylated CpG sequences are known to be immunostimulatory and may be used in certain embodiments of the present invention. CpG when formulated into vaccines, may be administered in free solution together with free antigen (WO 96/02555; McCluskie and Davis, supra) or covalently conjugated to an antigen (POT Publication No. WO 98/16247), or formulated with a carrier such as aluminium hydroxide (e.g., Davis et al. supra, Brazolot-Millan et al., Proc. Nati. Acad. Sci., USA, 1998, 95(26), 15553-8). The preferred oligonucleotides for use in adjuvants or vaccines of the present invention preferably contain two or more dinucleotide CpG motifs separated by at least three, more preferably at least six or more nucleotides. The oligonucleotides of the present invention are typically deoxynucleotides. In a preferred embodiment the internucleotide in the oligonucleotide is phosphorodithioate, or more preferably a phosphorothioate bond, although phosphodiester and other internucleotide bonds are within the scope of the invention including oligonucleotides with mixed internucleotide linkages. Methods for producing phosphorothioate oligonucleotides or phosphorodithioate are described in U.S. Pat. Nos. 5,666,153, 5,278,302 and WO95/26204. Examples of preferred oligonucleotides have sequences that are disclosed in the following publications; for certain herein disclosed embodiments the sequences preferably contain phosphorothioate modified internucleotide linkages: CPG 7909: Cooper et al., “CPG 7909 adjuvant improves hepatitis B virus vaccine seroprotection in antiretroviral-treated HIV-infected adults.” AIDS, 2005 Sep. 23; 19(14):1473-9. CpG 10101: Bayes et al., “Gateways to clinical trials.” Methods Find. Exp. Clin. Pharmacal. 2005 April; 27(3):193-219. Vollmer J., “Progress in drug development of immunostimulatory CpG oligodeoxynucleotide ligands for TLR9.” Expert Opinion on Biological Therapy. 2005 May; 5(5): 673-682 Alternative CpG oligonucleotides may comprise variants of the preferred sequences described in the above-cited publications that differ in that they have inconsequential nucleotide sequence substitutions, insertions, deletions and/or additions thereto. The CpG oligonucleotides utilized in certain embodiments of the present invention may be synthesized by any method known in the art (e.g., EP 468520). Conveniently, such oligonucleotides may be synthesized utilizing an automated synthesizer. The oligonucleotides are typically deoxynucleotides. In a preferred embodiment the internucleotide bond in the oligonucleotide is phosphorodithioate, or more preferably phosphorothioate bond, although phosphodiesters are also within the scope of the presently contemplated embodiments. Oligonucleotides comprising different internucleotide linkages are also contemplated, e.g., mixed phosphorothioate phosphodiesters. Other internucleotide bonds which stabilize the oligonucleotide may also be used. Co-Adjuvant Certain embodiments as provided herein include vaccine compositions and immunological adjuvant compositions, including pharmaceutical compositions, that contain, in addition to GLA compound(s), at least one co-adjuvant, which refers to a component of such compositions that has adjuvant activity but that is other than GLA. A co-adjuvant having such adjuvant activity includes a composition that, when administered to a subject such as a human (e.g., a human patient), a non-human primate, a mammal or another higher eukaryotic organism having a recognized immune system, is capable of altering (i.e., increasing or decreasing in a statistically significant manner, and in certain preferred embodiments, enhancing or increasing) the potency and/or longevity of an immune response. (See, e.g., Powell and Newman, “Vaccine design—The Subunit and Adjuvant Approach”, 1995, Plenum Press, New York) In certain embodiments disclosed herein GLA and a desired antigen, and optionally one or more co-adjuvants, may so alter, e.g., elicit or enhance, an immune response that is directed against the desired antigen which may be administered at the same time as GLA or may be separated in time and/or space (e.g., at a different anatomic site) in its administration, but certain invention embodiments are not intended to be so limited and thus also contemplate administration of GLA in a composition that does not include a specified antigen but which may also include one or more of a TLR agonist, a co-adjuvant, an imidazoquinline immune response modifier, and a double stem loop immune modifier (dSLIM). Accordingly and as noted above, co-adjuvants include compositions other than GLA that have adjuvant effects, such as saponins and saponin mimetics, including QS21 and QS21 mimetics (see, e.g., U.S. Pat. No. 5,057,540; EP 0 362 279 Bl; WO 95/17210), alum, plant alkaloids such as tomatine, detergents such as (but not limited to) saponin, polysorbate 80, Span 85 and stearyl tyrosine, one or more cytokines (e.g., GM-CSF, IL-2, IL-7, IL-12, TNF-alpha, IFN-gamma), an imidazoquinoline immune response modifier, and a double stem loop immune modifier (dSLIM, e.g., Weeratna et al., 2005 Vaccine 23:5263). Detergents including saponins are taught in, e.g., U.S. Pat. No. 6,544,518; Lacaille-Dubois, M and Wagner H. (1996 Phytomedicine 2:363-386), U.S. Pat. No. 5,057,540 , Kensil, Crit Rev Ther Drug Carrier Syst, 1996, 12 (1-2):1-55, and EP 0 362 279 B1. Particulate structures, termed Immune Stimulating Complexes (ISCOMS), comprising fractions of Quil A (saponin) are haemolytic and have been used in the manufacture of vaccines (Morein, B., EP 0 109 942 B1). These structures have been reported to have adjuvant activity (EP 0 109 942 B1; WO 96/11711). The haemolytic saponins QS21 and QS17 (HPLC purified fractions of Quil A) have been described as potent systemic adjuvants, and the method of their production is disclosed in U.S. Pat. No.5,057,540 and EP 0 362 279 B1. Also described in these references is the use of QS7 (a non-haemolytic fraction of Quil-A) which acts as a potent adjuvant for systemic vaccines. Use of QS21 is further described in Kensil et al. (1991. J. Immunology 146:431-437). Combinations of QS21 and polysorbate or cyclodextrin are also known (WO 99/10008). Particulate adjuvant systems comprising fractions of QuilA, such as QS21 and QS7 are described in WO 96/33739 and WO 96/11711. Other saponins which have been used in systemic vaccination studies include those derived from other plant species such as Gypsophila and Saponaria (Bomford et al., Vaccine, 10(9):572-577, 1992). Escin is another detergent related to the saponins for use in the adjuvant compositions of the embodiments herein disclosed. Escin is described in the Merck index (12th Ed.: entry 3737) as a mixture of saponin occurring in the seed of the horse chestnut tree, Aesculus hippocastanum. Its isolation is described by chromatography and purification (Fiedler, Arzneimittel-Forsch. 4, 213 (1953)), and by ion-exchange resins (Erbring et al., U.S. Pat. No. 3,238,190). Fractions of escin (also known as aescin) have been purified and shown to be biologically active (Yoshikawa M, et al. (Chem Pharm Bull (Tokyo) 1996 August; 44(8): 1454-1464)). Digitonin is another detergent, also being described in the Merck index (12th Ed., entry 3204) as a saponin, being derived from the seeds of Digitalis purpurea and purified according to the procedure described by Gisvold et al., J. Am. Pharm.Assoc., 1934, 23, 664; and Rubenstroth-Bauer, Physiol. Chem., 1955, 301, 621. Other co-adjuvants for use according to certain herein disclosed embodiments include a block co-polymer or biodegradable polymer, which refers to a class of polymeric compounds with which those in the relevant art will be familiar. Examples of a block co-polymer or biodegradable polymer that may be included in a GLA vaccine composition or a GLA immunological adjuvant include Pluronic® L121 (BASF Corp., Mount Olive, N.J.; see, e.g., Yeh et al., 1996 Pharm. Res. 13:1693; U.S. Pat. No. 5,565,209), CRL1005 (e.g., Triozzi et al., 1997 Clin Canc. Res. 3:2355), poly(lactic-co-glycolic acid) (PLGA), poly(lactic acid) (PLA), poly-(D,L-lactide-co-glycolide) (PLG), and polyl:C. (See, e.g., Powell and Newman, “Vaccine design—The Subunit and Adjuvant Approach”, 1995, Plenum Press, New York) Certain embodiments contemplate GLA vaccines and GLA immunological adjuvants that include an oil, which in some such embodiments may contribute co-adjuvant activity and in other such embodiments may additionally or alternatively provide a pharmaceutically acceptable carrier or excipient. Any number of suitable oils are known and may be selected for inclusion in vaccine compositions and immunological adjuvant compositions based on the present disclosure. Examples of such oils, by way of illustration and not limitation, include squalene, squalane, mineral oil, olive oil, cholesterol, and a mannide monooleate. Immune response modifiers such as imidazoquinoline immune response modifiers are also known in the art and may also be included as co-adjuvants in certain presently disclosed embodiments. Certain preferred imidazoquinoline immune response modifiers include, by way of non-limiting example, resiquimod (R848), imiquimod and gardiquimod (Hemmi et al., 2002 Nat. Immunol. 3:196; Gibson et al., 2002 Cell. Immunol. 218:74; Gorden et al., 2005 J. Immunol. 174:1259); these and other imidazoquinoline immune response modifiers may, under appropriate conditions, also have TLR agonist activity as described herein. Other immune response modifiers are the nucleic acid-based double stem loop immune modifiers (dSLIM). Specific examples of dSLIM that are contemplated for use in certain of the presently disclosed embodiments can be found in Schmidt et al., 2006 Allergy 61:56; Weihrauch et al. 2005 Clin Cancer Res. 11(16):5993-6001; Modern Biopharmaceuticals, J. Knäblein (Editor). John Wiley & Sons, Dec. 6, 2005. (dSLIM discussed on pages 183 to ˜200), and from Mologen AG (Berlin, FRG: [retrieved online on Aug. 18, 2006 at http://www.mologen.com/English/04.20-dSLIM.shtml]. As also noted above, one type of co-adjuvant for use with GLA as described herein may be the aluminum co-adjuvants, which are generally referred to as “alum.” Alum co-adjuvants are based on the following: aluminum oxyhydroxide; aluminum hydroxyphosphoate; or various proprietary salts. Vaccines that use alum co-adjuvants may include vaccines for tetanus strains, HPV, hepatitis A, inactivated polio virus, and other antigens as described herein. Alum co-adjuvants are advantageous because they have a good safety record, augment antibody responses, stabilize antigens, and are relatively simple for large-scale production. (Edelman 2002 Mol. Biotechnol. 21:129-148; Edelman, R. 1980 Rev. Infect. Dis. 2:370-383.) Other co-adjuvants that may be combined with GLA for effective immune stimulation include saponins and saponin mimetics, including QS21 and structurally related compounds conferring similar effects and referred to herein as QS21 mimetics. QS21 has been recognized as a preferred co-adjuvant. QS21 may comprise an HPLC purified non-toxic fraction derived from the bark of Quillaja Saponaria Molina. The production of QS21 is disclosed in U.S. Pat. No. 5,057,540. (See also U.S. Pat. Nos. 6,936,255, 7,029,678 and 6,932,972.) GLA may also in certain embodiments be combined with immunostimulatory complexes” known as ISCOMS (e.g., U.S. Pat. Nos. 6,869,607, 6,846,489, 6,027,732, 4,981,684), including saponin-derived ISCOMATRIX®, which is commercially available, for example, from Iscotec (Stockholm, Sweden) and CSL Ltd. (Parkville, Victoria, Australia). Recombinant Expression Construct According to certain herein disclosed embodiments, the GLA vaccine composition may contain at least one recombinant expression construct which comprises a promoter operably linked to a nucleic acid sequence encoding an antigen. In certain further embodiments the recombinant expression construct is present in a viral vector, such as an adenovirus, adeno-associated virus, herpesvirus, lentivirus, poxvirus or retrovirus vector. Compositions and methods for making and using such expression constructs and vectors are known in the art, for the expression of polypeptide antigens as provided herein, for example, according to Ausubel et al. (Eds.), Current Protocols in Molecular Biology, 2006 John Wiley & Sons, NY. Non-limiting examples of recombinant expression constructs generally can be found, for instance, in U.S. Pat. Nos. 6,844,192; 7,037,712; 7,052,904; 7,001,770; 6,106,824; 5,693,531; 6,613,892; 6,875,610; 7,067,310; 6,218,186; 6.783,981; 7,052,904; 6,783,981; 6,734.172; 6,713,068; 5,795,577 and 6,770,445 and elsewhere, with teachings that can be adapted to the expression of polypeptide antigens as provided herein, for use in certain presently disclosed embodiments. Immune Response The invention thus provides compositions for altering (i.e., increasing or decreasing in a statistically significant manner, for example, relative to an appropriate control as will be familiar to persons skilled in the art) immune responses in a host capable of mounting an immune response. As will be known to persons having ordinary skill in the art, an immune response may be any active alteration of the immune status of a host, which may include any alteration in the structure or function of one or more tissues, organs, cells or molecules that participate in maintenance and/or regulation of host immune status. Typically, immune responses may be detected by any of a variety of well known parameters, including but not limited to in vivo or in vitro determination of: soluble immunoglobulins or antibodies; soluble mediators such as cytokines, lymphokines, chemokines, hormones, growth factors and the like as well as other soluble small peptide, carbohydrate, nucleotide and/or lipid mediators; cellular activation state changes as determined by altered functional or structural properties of cells of the immune system, for example cell proliferation, altered motility, induction of specialized activities such as specific gene expression or cytolytic behavior; cellular differentiation by cells of the immune system, including altered surface antigen expression profiles or the onset of apoptosis (programmed cell death); or any other criterion by which the presence of an immune response may be detected. Immune responses may often be regarded, for instance, as discrimination between self and non-self structures by the cells and tissues of a host's immune system at the molecular and cellular levels, but the invention should not be so limited. For example, immune responses may also include immune system state changes that result from immune recognition of self molecules, cells or tissues, as may accompany any number of normal conditions such as typical regulation of immune system components, or as may be present in pathological conditions such as the inappropriate autoimmune responses observed in autoimmune and degenerative diseases. As another example, in addition to induction by up-regulation of particular immune system activities (such as antibody and/or cytokine production, or activation of cell mediated immunity) immune responses may also include suppression, attenuation or any other down-regulation of detectable immunity, which may be the consequence of the antigen selected, the route of antigen administration, specific tolerance induction or other factors. Determination of the induction of an immune response by the vaccines of the present invention may be established by any of a number of well known immunological assays with which those having ordinary skill in the art will be readily familiar. Such assays include, but need not be limited to, to in vivo or in vitro determination of: soluble antibodies; soluble mediators such as cytokines, lymphokines, chemokines, hormones, growth factors and the like as well as other soluble small peptide, carbohydrate, nucleotide and/or lipid mediators; cellular activation state changes as determined by altered functional or structural properties of cells of the immune system, for example cell proliferation, altered motility, induction of specialized activities such as specific gene expression or cytolytic behavior; cellular differentiation by cells of the immune system, including altered surface antigen expression profiles or the onset of apoptosis (programmed cell death). Procedures for performing these and similar assays are widely known and may be found, for example in Lefkovits (Immunology Methods Manual: The Comprehensive Sourcebook of Techniques, 1998; see also Current Protocols in Immunology; see also, e.g., Weir, Handbook of Experimental Immunology, 1986 Blackwell Scientific, Boston, Mass.; Mishell and Shigii (eds.) Selected Methods in Cellular Immunology, 1979 Freeman Publishing, San Francisco, Calif.; Green and Reed, 1998 Science 281:1309 and references cited therein.). Detection of the proliferation of antigen-reactive T cells may be accomplished by a variety of known techniques. For example, T cell proliferation can be detected by measuring the rate of DNA synthesis, and antigen specificity can be determined by controlling the stimuli (such as, for example, a specific desired antigen- or a control antigen-pulsed antigen presenting cells) to which candidate antigen-reactive T cells are exposed. T cells which have been stimulated to proliferate exhibit an increased rate of DNA synthesis. A typical way to measure the rate of DNA synthesis is, for example, by pulse-labeling cultures of T cells with tritiated thymidine, a nucleoside precursor which is incorporated into newly synthesized DNA. The amount of tritiated thymidine incorporated can be determined using a liquid scintillation spectrophotometer. Other ways to detect T cell proliferation include measuring increases in interleukin-2 (IL-2) production, Ca2+ flux, or dye uptake, such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium. Alternatively, synthesis of lymphokines (such as interferon-gamma) can be measured or the relative number of T cells that can respond to a particular antigen may be quantified. Detection of antigen-specific antibody production may be achieved, for example, by assaying a sample (e.g., an immunoglobulin containing sample such as serum, plasma or blood) from a host treated with a vaccine according to the present invention using in vitro methodologies such as radioimmunoassay (RIA), enzyme linked immunosorbent assays (ELISA), equilibrium dialysis or solid phase immunoblotting including Western blotting. In preferred embodiments ELISA assays may further include antigen-capture immobilization of the target antigen with a solid phase monoclonal antibody specific for the antigen, for example, to enhance the sensitivity of the assay. Elaboration of soluble mediators (e.g., cytokines, chemokines, lymphokines, prostaglandins, etc.) may also be readily determined by enzyme-linked immunosorbent assay (ELISA), for example, using methods, apparatus and reagents that are readily available from commercial sources (e.g., Sigma, St. Louis, Mo.; see also R & D Systems 2006 Catalog, R & Systems, Minneapolis, Minn.). Any number of other immunological parameters may be monitored using routine assays that are well known in the art. These may include, for example, antibody dependent cell-mediated cytotoxicity (ADCC) assays, secondary in vitro antibody responses, flow immunocytofluorimetric analysis of various peripheral blood or lymphoid mononuclear cell subpopulations using well established marker antigen systems, immunohistochemistry or other relevant assays. These and other assays may be found, for example, in Rose et al. (Eds.), Manual of Clinical Laboratory Immunology, 5th Ed., 1997 American Society of Microbiology, Washington, D.C. Accordingly it is contemplated that the vaccine and adjuvant compositions provided herein will be capable of eliciting or enhancing in a host at least one immune response that is selected from a TH1-type T lymphocyte response, a TH2-type T lymphocyte response, a cytotoxic T lymphocyte (CTL) response, an antibody response, a cytokine response, a lymphokine response, a chemokine response, and an inflammatory response. In certain embodiments the immune response may comprise at least one of production of one or a plurality of cytokines wherein the cytokine is selected from interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), production of one or a plurality of interleukins wherein the interleukin is selected from IL-1, IL-2, IL-3, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, IL-16, IL-18 and IL-23, production one or a plurality of chemokines wherein the chemokine is selected from MIP-1α, MIP-1β, RANTES, CCL4 and CCL5, and a lymphocyte response that is selected from a memory T cell response, a memory B cell response, an effector T cell response, a cytotoxic T cell response and an effector B cell response. See, e.g., WO 94/00153; WO 95/17209; WO 96/02555; U.S. Pat. No. 6,692,752; U.S. Pat. No. 7,084,256; U.S. Pat. No. 6,977,073; U.S. Pat. No. 6,749,856; U.S. Pat. No. 6,733,763; U.S. Pat. No. 6,797,276; U.S. Pat. No. 6,752,995; U.S. Pat. No. 6,057,427; U.S. Pat. No. 6,472,515; U.S. Pat. No. 6,309,847; U.S. Pat. No. 6,969,704; U.S. Pat. No. 6,120,769; U.S. Pat. No. 5,993,800; U.S. Pat. No. 5.595,888; Smith et al., 1987 J Biol Chem. 262:6951; Kriegler et al., 1988 Cell 53:45 53; Beutler et al., 1986 Nature 320:584; U.S. Pat. No. 6,991,791; U.S. Pat. No. 6,654,462; U.S. Pat. No. 6,375,944. Pharmaceutical Compositions Pharmaceutical compositions generally comprise at least one GLA compound of the invention, and may further comprise one or more components as provided herein that are selected, for example, from antigen, TLR agonist, co-adjuvant (including optionally a cytokine, an imidazoquinoline immune response modifier and/or a dSLIM), and/or a recombinant expression construct, in combination with a pharmaceutically acceptable carrier, excipient or diluent. Therefore, in certain aspects, the present invention is drawn to GLA “monotherapy” wherein GLA, as described herein, is formulated in a composition that is substantially devoid of other antigens, and is administered to a subject in order to stimulate an immune e response, e.g., a non-specific immune response, for the purpose of treating or preventing a disease or other condition, such as for treating an infection by an organism, for treating seasonal rhinitis, or the like. In one embodiment, for example, the compositions and methods of the invention employ a GLA compound for stimulating an immune response in a subject. In another embodiment, the GLA is in the form of a spray, optionally provided in a kit. The GLA may be preferably formulated in a stable emulsion. In one particular embodiment, for example, a composition is provided comprising a GLA compound of the invention in a stable emulsion substantially devoid of other antigens. In certain other embodiments, the pharmaceutical composition is a vaccine composition that comprises both GLA and an antigen and may further comprise one or more components, as provided herein, that are selected from TLR agonist, co-adjuvant (including, e.g., a cytokine, an imidazoquinoline immune response modifier and/or a dSLIM) and the like and/or a recombinant expression construct, in combination with a pharmaceutically acceptable carrier, excipient or diluent. Illustrative carriers will be nontoxic to recipients at the dosages and concentrations employed. For GLA-plus-nucleic acid-based vaccines, or for vaccines comprising GLA plus an antigen, about 0.001 μg/kg to about 100 mg/kg body weight will generally be administered, typically by the intradermal, subcutaneous, intramuscular or intravenous route, or by other routes. In a more specific embodiment, the dosage is about 0.001 μg/kg to about 1 mg/kg. In another specific embodiment, the dosage is about 0.001 to about 50 μg/kg. In another specific embodiment, the dosage is about 0.001 to about 15 μg/kg. In another specific embodiment, the amount of GLA administered is about 0.01 μg/dose to about 5 mg/dose. In another specific embodiment, the amount of GLA administered is about 0.1 μg/dose to about 1 mg/dose. In another specific embodiment, the amount of GLA administered is about 0.1 μg/dose to about 100 μg/dose. In another specific embodiment, the GLA administered is about 0.1 μg/dose to about 10 μg/close. It will be evident to those skilled in the art that the number and frequency of administration will be dependent upon the response of the host. “Pharmaceutically acceptable carriers” for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remingtons Pharmaceutical Sciences, Mack Publishing Co. (A.R. Gennaro edit. 1985). For example, sterile saline and phosphate-buffered saline at physiological pH may be used. Preservatives, stabilizers, dyes and even flavoring agents may be provided in the pharmaceutical composition. For example, sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid may be added as preservatives. Id. at 1449. In addition, antioxidants and suspending agents may be used. Id. “Pharmaceutically acceptable salt” refers to salts of the compounds of the present invention derived from the combination of such compounds and an organic or inorganic acid (acid addition salts) or an organic or inorganic base (base addition salts). The compositions of the present invention may be used in either the free base or salt forms, with both forms being considered as being within the scope of the present invention. The pharmaceutical compositions may be in any form which allows for the composition to be administered to a patient. For example, the composition may be in the form of a solid, liquid or gas (aerosol). Typical routes of administration include, without limitation, oral, topical, parenteral (e.g., sublingually or buccally), sublingual, rectal, vaginal, and intranasal (e.g., as a spray). The term parenteral as used herein includes iontophoretic (e.g., U.S. Pat. Nos. 7,033,598; 7,018,345; 6,970,739), sonophoretic (e.g., U.S. Pat. Nos. 4,780,212; 4,767,402; 4,948,587; 5,618,275; 5,656,016; 5,722,397; 6,322,532; 6,018,678), thermal (e.g., U.S. Pat. Nos. 5,885,211; 6,685,699), passive transdermal (e.g., U.S. Pat. Nos. 3,598,122; 3,598,123; 4,286,592; 4,314,557; 4,379,454; 4,568,343; 5,464,387; UK Pat. Spec. No. 2232892; U.S. Pat. Nos. 6,871,477; 6,974,588; 6,676,961), microneedle (e.g., U.S. Pat. Nos. 6,908,453; 5,457,041; 5,591,139; 6,033,928) administration and also subcutaneous injections, intravenous, intramuscular, intrasternal, intracavernous, intrathecal, intrameatal, intraurethral injection or infusion techniques. In a particular embodiment, a composition as described herein (including vaccine and pharmaceutical compositions) is administered intradermally by a technique selected from iontophoresis, microcavitation, sonophoresis or microneedles. The pharmaceutical composition is formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient. Compositions that will be administered to a patient take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of one or more compounds of the invention in aerosol form may hold a plurality of dosage units. For oral administration, an excipient and/or binder may be present. Examples are sucrose, kaolin, glycerin, starch dextrins, sodium alginate, carboxymethylcellulose and ethyl cellulose. Coloring and/or flavoring agents may be present. A coating shell may be employed. The composition may be in the form of a liquid, e.g., an elixir, syrup, solution, emulsion or suspension. The liquid may be for oral administration or for delivery by injection, as two examples. When intended for oral administration, preferred compositions contain one or more of a sweetening agent, preservatives, dye/colorant and flavor enhancer. In a composition intended to be administered by injection, one or more of a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent may be included. A liquid pharmaceutical composition as used herein, whether in the form of a solution, suspension or other like form, may include one or more of the following carriers or excipients: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils such as squalene, squalene, mineral oil, a mannide monooleate, cholesterol, and/or synthetic mono or digylcerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. An injectable pharmaceutical composition is preferably sterile. In a particular embodiment, a pharmaceutical or vaccine composition of the invention comprises a stable aqueous suspension of less than 0.2 um and further comprises at least one component selected from the group consisting of phospholipids, fatty acids, surfactants, detergents, saponins, fluorodated lipids, and the like. In another embodiment, a composition of the invention is formulated in a manner which can be aerosolized. It may also be desirable to include other components in a vaccine or pharmaceutical composition, such as delivery vehicles including but not limited to aluminum salts, water-in-oil emulsions, biodegradable oil vehicles, oil-in-water emulsions, biodegradable microcapsules, and liposomes. Examples of additional immunostimulatory substances (co-adjuvants) for use in such vehicles are also described above and may include N-acetylmuramyl-L-alanine-D-isoglutamine (MDP), glucan, IL-12, GM-CSF, gamma interferon and IL-12. While any suitable carrier known to those of ordinary skill in the art may be employed in the pharmaceutical compositions of this invention, the type of carrier will vary depending on the mode of administration and whether a sustained release is desired. For parenteral administration, such as subcutaneous injection, the carrier preferably comprises water, saline, alcohol, a fat, a wax or a buffer. For oral administration, any of the above carriers or a solid carrier, such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, sucrose, and magnesium carbonate, may be employed. Biodegradable microspheres (e.g., polylactic galactide) may also be employed as carriers for the pharmaceutical compositions of this invention. Suitable biodegradable microspheres are disclosed, for example, in U.S. Pat. Nos. 4,897,268 and 5,075,109. In this regard, it is preferable that the microsphere be larger than approximately 25 microns. Pharmaceutical compositions (including GLA vaccines and GLA immunological adjuvants) may also contain diluents such as buffers, antioxidants such as ascorbic acid, low molecular weight (less than about 10 residues) polypeptides, proteins, amino acids, carbohydrates including glucose, sucrose or dextrins, chelating agents such as EDTA, glutathione and other stabilizers and excipients. Neutral buffered saline or saline mixed with nonspecific serum albumin are exemplary appropriate diluents. Preferably, product may be formulated as a lyophilizate using appropriate excipient solutions (e.g., sucrose) as diluents. As described above, in certain embodiments the subject invention includes compositions capable of delivering nucleic acid molecules encoding desired antigens. Such compositions include recombinant viral vectors (e.g., retroviruses (see WO 90/07936, WO 91/02805, WO 93/25234, WO 93/25698, and WO 94/03622), adenovirus (see Berkner, Biotechniques 6:616-627, 1988; Li et al., Hum. Gene Ther. 4:403-409, 1993; Vincent et al., Nat. Genet. 5:130-134, 1993; and Kolls et al., Proc. Natl. Acad. Sci. USA 91:215-219, 1994), pox virus (see U.S. Pat. No. 4,769,330; U.S. Pat. No. 5,017,487; and WO 89/01973)), recombinant expression construct nucleic acid molecules complexed to a polycationic molecule (see WO 93/03709), and nucleic acids associated with liposomes (see Wang et al., Proc. Natl. Acad. Sci. USA 84:7851, 1987). In certain embodiments, the DNA may be linked to killed or inactivated adenovirus (see Curiel et al., Hum. Gene Ther. 3:147-154, 1992; Cotton et al., Proc. Natl. Acad. Sci. USA 89:6094, 1992). Other suitable compositions include DNA-ligand (see Wu et al., J. Biol. Chem. 264:16985-16987, 1989) and lipid-DNA combinations (see Feigner et al., Proc. Natl. Acad. Sci. USA 84:7413-7417, 1989). In addition to direct in vivo procedures, ex vivo procedures may be used in which cells are removed from a host, modified, and placed into the same or another host animal. it will be evident that one can utilize any of the compositions noted above for introduction of antigen-encoding nucleic acid molecules into tissue cells in an ex vivo context. Protocols for viral, physical and chemical methods of uptake are well known in the art. Accordingly, the present invention is useful for enhancing or eliciting, in a host, a patient or in cell culture, an immune response. As used herein, the term “patient” refers to any warm-blooded animal, preferably a human. A patient may be afflicted with an infectious disease, cancer, such as breast cancer, or an autoimmune disease, or may be normal (i.e., free of detectable disease and/or infection). A “cell culture” is any preparation containing immunocompetent cells or isolated cells of the immune system (including, but not limited to, T cells, macrophages, monocytes, B cells and dendritic cells). Such cells may be isolated by any of a variety of techniques well known to those of ordinary skill in the art (e.g., Ficoll-hypaque density centrifugation). The cells may (but need not) have been isolated from a patient afflicted with cancer, and may be reintroduced into a patient after treatment. In certain embodiments a liquid composition intended for either parenteral or oral administration should contain an amount of GLA vaccine composition such that a suitable dosage will be obtained. Typically, this amount is at least 0.01 wt % of an antigen in the composition. When intended for oral administration, this amount may be varied to be between 0.1 and about 70% of the weight of the composition. Preferred oral compositions contain between about 4% and about 50% of the antigen. Preferred compositions and preparations are prepared so that a parenteral dosage unit contains between 0.01 to 1% by weight of active composition. The pharmaceutical composition may be intended for topical administration, in which case the carrier may suitably comprise a solution, emulsion, ointment or gel base. The base, for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, beeswax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Thickening agents may be present in a pharmaceutical composition for topical administration. If intended for transdermal administration, the composition may include a transdermal patch or iontophoresis device. Topical formulations may contain a concentration of the antigen (e.g., GLA-antigen vaccine composition) or GLA (e.g., immunological adjuvant composition; GLA is available from Avanti Polar Lipids, Inc., Alabaster, Ala.; e.g., product number 699800) of from about 0.1 to about 10% w/v (weight per unit volume). The composition may be intended for rectal administration, in the form, e.g., of a suppository which will melt in the rectum and release the drug. The composition for rectal administration may contain an oleaginous base as a suitable nonirritating excipient. Such bases include, without limitation, lanolin, cocoa butter and polyethylene glycol. In the methods of the invention, the vaccine compositions/ adjuvants may be administered through use of insert(s), bead(s), timed-release formulation(s), patch(es) or fast-release formulation(s). Also contemplated in certain embodiments are kits comprising the herein described GLA vaccine compositions and/or GLA immunological adjuvant compositions, which may be provided in one or more containers. In one embodiment all components of the GLA vaccine compositions and/or GLA immunological adjuvant compositions are present together in a single container, but the invention embodiments are not intended to be so limited and also contemplate two or more containers in which, for example, a GLA immunological adjuvant composition is separate from, and not in contact with, the antigen component. By way of non-limiting theory, it is believed that in some cases administration only of the GLA immunological adjuvant composition may be performed beneficially, whilst in other cases such administration may beneficially be separated temporally and/or spatially (e.g., at a different anatomical site) from administration of the antigen, whilst in still other cases administration to the subject is beneficially conducted of a GLA vaccine composition as described herein and containing both antigen and GLA, and optionally other herein described components as well. A container according to such kit embodiments may be any suitable container, vessel, vial, ampule, tube, cup, box, bottle, flask, jar, dish, well of a single-well or multi-well apparatus, reservoir, tank, or the like, or other device in which the herein disclosed compositions may be placed, stored and/or transported, and accessed to remove the contents. Typically such a container may be made of a material that is compatible with the intended use and from which recovery of the contained contents can be readily achieved. Preferred examples of such containers include glass and/or plastic sealed or re-sealable tubes and ampules, including those having a rubber septum or other sealing means that is compatible with withdrawal of the contents using a needle and syringe. Such containers may, for instance, by made of glass or a chemically compatible plastic or resin, which may be made of, or may be coated with, a material that permits efficient recovery of material from the container and/or protects the material from, e.g., degradative conditions such as ultraviolet light or temperature extremes, or from the introduction of unwanted contaminants including microbial contaminants. The containers are preferably sterile or sterilizable, and made of materials that will be compatible with any carrier, excipient, solvent, vehicle or the like, such as may be used to suspend or dissolve the herein described vaccine compositions and/or immunological adjuvant compositions and/or antigens and/or recombinant expression constructs, etc. Emulsion systems may also be used in formulating compositions of the present invention. For example, many single or multiphase emulsion systems have been described. Oil in water emulsion adjuvants per se have been suggested to be useful as adjuvant composition (EP 0 399 843B), also combinations of oil in water emulsions and other active agents have been described as adjuvants for vaccines (WO 95/17210; WO 98/56414; WO 99/12565; WO 99/11241). Other oil emulsion adjuvants have been described, such as water in oil emulsions (U.S. Pat. No. 5,422,109; EP 0 480 982 B2) and water in oil in water emulsions (U.S. Pat. No. 5.424,067; EP 0 480 981 B). The oil emulsion adjuvants for use in the present invention may be natural or synthetic, and may be mineral or organic. Examples of mineral and organic oils will be readily apparent to the man skilled in the art. In a particular embodiment, a composition of the invention comprises an emulsion of oil in water wherein the GLA is incorporated in the oil phase. In another embodiment, a composition of the invention comprises an emulsion of oil in water wherein the GLA is incorporated in the oil phase and wherein an additional component is present, such as a co-adjuvant, TLR agonist, or the like, as described herein. In order for any oil in water composition to be suitable for human administration, the oil phase of the emulsion system preferably comprises a metabolizable oil. The meaning of the term metabolizable oil is well known in the art. Metabolizable can be defined as “being capable of being transformed by metabolism” (Dorland's illustrated Medical Dictionary, W. B. Saunders Company, 25th edition (1974)). The oil may be any vegetable oil, fish oil, animal oil or synthetic oil, which is not toxic to the recipient and is capable of being transformed by metabolism. Nuts (such as peanut oil), seeds, and grains are common sources of vegetable oils. Synthetic oils are also part of this invention and can include commercially available oils such as NEOBEE® and others. Squalene (2,6,10,15,19,23-Hexamethyl-2,6,10,14,18,22-tetracosahexaene), for example, is an unsaturated oil which is found in large quantities in shark-liver oil, and in lower quantities in olive oil, wheat germ nil, rice bran oil, and yeast, and is a particularly preferred oil for use in this invention. Squalene is a metabolizable oil virtue of the fact that it is an intermediate in the biosynthesis of cholesterol (Merck index, 10th Edition, entry no. 8619). Particularly preferred oil emulsions are oil in water emulsions, and in particular squalene in water emulsions. In addition, the most preferred oil emulsion adjuvants of the present invention comprise an antioxidant, which is preferably the oil .alpha.-tocopherol (vitamin E. EP 0 382 271 B1). WO 95/17210 and WO 99/11241 disclose emulsion adjuvants based on squalene, alpha-tocopherol, and TWEEN® 80, optionally formulated with the immunostimulants QS21 and/or 3D-MPL (which are discussed above). WO 99/12565 discloses an improvement to these squalene emulsions with the addition of a sterol into the oil phase. Additionally, a triglyceride, such as tricaprylin (C27H50O6), may be added to the oil phase in order to stabilize the emulsion (WO 98/56414). The size of the oil droplets found within the stable oil in water emulsion are preferably less than 1 micron, may be in the range of substantially 30-600 nm, preferably substantially around 30-500 nm in diameter, and most preferably substantially 150-500 nm in diameter, and in particular about 150 nm in diameter as measured by photon correlation spectroscopy. In this regard, 80% of the oil droplets by number should be within the preferred ranges, more preferably more than 90% and most preferably more than 95% of the oil droplets by number are within the defined size ranges The amounts of the components present in the oil emulsions of the present invention are conventionally in the range of from 2 to 10% oil, such as squalene; and when present, from 2 to 10% alpha tocopherol; and from 0.3 to 3% surfactant, such as polyoxyethylene sorbitan monooleate. Preferably the ratio of oil: alpha tocopherol is equal or less than 1 as this provides a more stable emulsion. Span 85 may also be present at a level of about 10, In some cases it may be advantageous that the vaccines of the present invention will further contain a stabilizer. The method of producing oil in water emulsions is well known to the person skilled in the art. Commonly, the method comprises the mixing the oil phase with a surfactant such as a PBS/TWEEN80® solution, followed by homogenization using a homogenizer. For instance, a method that comprises passing the mixture once, twice or more times through a syringe needle would be suitable for homogenizing small volumes of liquid. Equally, the emulsification process in a microfluidizer (M110S microfluidics machine, maximum of 50 passes, for a period of 2 minutes at maximum pressure input of 6 bar (output pressure of about 850 bar)) could be adapted to produce smaller or larger volumes of emulsion. This adaptation could be achieved by routine experimentation comprising the measurement of the resultant emulsion until a preparation was achieved with oil droplets of the required diameter. The following Examples are offered by way of illustration and not by way of limitation. EXAMPLES Example 1 2-AZIDO-2-DEOXY-D-GLUCOPYRANOSIDE (2) Sodium azide (2.78 g, 42.7 mmol) was dissolved in water (7 mL) and toluene (7 mL). The mixture was cooled to 0° C. under vigorous stirring. Triflic anhydride (4.57 mL, 27.2 mmol) was added dropwise, and the mixture was stirred for 30 min at 0° C. The temperature was raised to 10° C. and the biphasic mixture was stirred for 2 h. A saturated aqueous solution of sodium hydrogencarbonate was added dropwise until gas evolution had ceased. The two phases were separated, and the aqueous layer was extracted with toluene (2×7 mL). The combined organic layers were used in the subsequent diazo transfer reaction. Glucose amine 1 (2.04 g, 9.45 mmol), sodium hydrogencarbonate (3.21 g, 38.22 mmol), and copper(II) sulfate pentahydrate (90.5 mg, 0.362 mmol) were dissolved in water (12.3 mL). The triflic azide stock solution prepared above (21 mL) was added, followed by the addition of methanol (81 mL) to yield a homogeneous system. The blue mixture was stirred vigorously at room temperature. Complete consumption of the amine was monitored by TLC (ninhydrin stain) and is also indicated by a color change of the mixture from blue to green. The solvents were removed in vacuo with a rotary evaporator keeping the temperature strictly below 25° C. The residue was purified by chromatography on silica gel (120 g RediSep column, eluting with a gradient of 0% through 40% methanol/dichloromethane over 50 min, 85 mL/min) to give product 2 (1.93 g, 99%) as a colorless liquid. 1H NMR (300 MHz, CD3OD) (mixture of diastereomers 1/1) δ 5.18 (d, J=3.4 Hz, 0.5H), 4.51 (d, J=8.0 Hz, 0.5H), 3.89-3.63 (m, 3H), 3.32-3.26 (m, 2H), 3.11-3.06 (m, 1H). Example 2 2-AZIDO-2-DEOXY-4,6-O-BENZYLIDENE-D-GLUCOPYRANOSIDE (3) To a solution of compound 2 (2.00 g, 9.75 mmol) in DMF (40 mL) was added benzaldehyde dimethyl acetal (1.65 g, 10.8 mmol) and camphorsulfonic acid (90 mg). The flask was connected to a vacuum system, and the mixture was heated at 50° C. in an oil bath. After 3 h, the mixture was concentrated using a rotary evaporator. The residue was re-dissolved in diethyl ether (50 mL) and Et3N (2 mL) followed by saturated sodium bicarbonate (50 mL). The aqueous layer was extracted with diethyl ether (3×50 mL). The combined organic extracts were dried over sodium sulfate and filtered. After the removal of solvents using a rotary evaporator, the residue was purified by chromatography on silica gel (120 g RediSep column, eluting with a gradient of 0% through 100% ethyl acetate/hexanes over 50 min, 85 mL/min) to give product 3 (2.58 g, 90%) as a colorless liquid. 1H NMR (300 MHz, CD3OD) δ 7.49-7.32 (m, 5H), 5.58 (s, 1H), 4.64 (d, J=3.8 Hz, 1H), 4.25-341 (m, 5H), 3.23-3.20 (m, 1H). Example 3 TERT-BUTYLDIMETHYLSILYL-2-AZIDO-4,6-O-BENZYLIDENE-2-DEOXY-β-D-GLUCOPYRANOSIDE (4) t-Butyidimethylsilyi chloride (820 mg, 5.44 mmol) was added to a mixture of compound 3 (1.45 g, 4.94 mmol) and imidazole (768 mg, 11.3 mmol) in CH2Cl2 (40 mL) at 0° C. After the solution was stirred overnight, saturated sodium bicarbonate (20 mL) was added, and the mixture was extracted with diethyl ether (3×30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (80 g RediSep column, eluting with a gradient of 0% through 70% ethyl acetate/hexanes over 40 min, 60 mL/min) to yield product 4 (1.5 g, 74%) as a colorless solid. 1H NMR (300 MHz, CDCl3) δ 7.46-7.43 (m, 2H), 7.35-7.32 (m, 3H), 5.48 (s. 1H), 4.59 (d, J=7.6 Hz, 1H), 4.23 (dd, J=10.2, 5.0 Hz, 1H), 3.73 (t, J=10.2 Hz, 1H), 3.56-3.51 (m, 2H), 3.31-3.28 (m, 2H), 2.72 (d, J=2.2 Hz, 1H), 0.91 (s, 9H), 0.14 (s, 3H), 0.13 (s, 3H). Example 4 TERT-BUTYLDIMETHYLSILYL-3-O-ALLYLOXYCARBONYL-2-AZIDO-4,6-O-BENZYLDIDINE-2-DEOXY-D-GLUCOPYRANOSIDE (5) To a solution of compound 4 (1.50 g, 3.68 mmol) and tetramethyle hylenediamine (TMEDA) (0.78 mL, 5.2 mmol) in dichloromethane (DCM) (50 mL) at 0° C. was added allyl chloroformaie (0.78 mL, 7.3 mmol) dropwise. The mixture was allowed to warm to room temperature, and the mixture was stirred at room temperature for 10 h. The mixture was diluted with DCM (50 mL) and washed with saturated aqueous NaHCO3 (2×100 mL) and brine (2×50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (80 g RediSep column, eluting with a gradient of 0% through 50% ethyl acetate/hexanes over 40 min, 60 mL/min) to yield product 5 (1.57 g, 87%) as a colorless solid. Rf=0.40 (hexanes/ethyl acetate, 3/1, v/v). 1H NMR (300 MHz, CDCl3) δ 7.44-7.41 (m, 2H). 7.35-7.32 (m, 3H), 5.98-5.85 (m, 1H), 5.48 (s, 1H), 5.38-5.22 (m, 2H), 4.88 (t, J=11.4 Hz, 1H), 4.72-4.64 (m, 3H), 4.32-4.27 (m, 1H), 3.81-3.65 (m, 2H), 3.50-3.42 (m, 2H), 0.94 (s, 9H) , 0.18 (s, 3H), 0.17 (s, 3H). Example 5 TERT-BUTYLDIMETHYLSILYL-3-O-ALLYLOXYCARBONYL-2-AZIDO-6-O-BENZYL-2-DEOXY-D-GLUCOPYRANOSIDE (6) A suspension of compound 5 (320 mg, 0.651 mmol) and molecular sieves (4 Å, 200 mg) in THF (5 mL) was stirred at room temperature for 1 h, and then NaCNBH3 (246 mg, 3.91 mmol) was added. A solution of hydrogen chloride (2 M in diethyl ether) was added dropwise to this mixture until the mixture became acidic (˜5 mL, pH=5). After being stirred another 0.5 h, the reaction mixture was quenched with solid NaHCO3, diluted with diethyl ether (100 mL), and washed with saturated aqueous NaHCO3 (2×100 mL) and brine (2×50 mL). The organic layer was dried over Na2SO4, filtered, concentrated in vacuo, and the residue was purified by flash column chromatography (40 g RediSep column, eluting with a gradient of 0% through 100% ethyl acetate/hexanes over 40 min, 40 mL/min) to yield product 6 (273 mg, 85%) as a colorless solid. Rf=0.42 (hexanes/ethyl acetate, 4/1, v/v). 1H NMR (300 MHz, CDCl3) δ 7.39-7.34 (m, 5H), 5.99-5.89 (m, 1H), 5.40-5.26 (m, 2H), 4.67-4.56 (m, 5H), 3.72-3.70 (m, 3H), 3.48-3.46 (m, 2H), 3.37 (dd, J=9.6, 8.4 Hz, 1H), 3.01 (broad s, 1H), 0.94 (s, 9H), 0.17 (s, 6H). Example 6 TERT-BUTYLDIMETHYLSILYL-3-O-ALLYLOXYCARBONYL-2-AZIDO-6-O-BENZYL-2-DEOXY-4-O-(1,5-DIHYDRO-3-OXO-3λ5-3H-2,4,3-BENZODIOXAPHOSPHEPIN-3-YL)-D-GLUCOPYRANOSIDE (7) To a solution of compound 6 (5.47 g, 11.1 mmol) and 1H-tetrazole (3 wt % in acetonitrile, 35.5 mmol, 104 mL) was added N,N-diethyl-1,5-dihydro-3H-2,4,3-benzodioxaphosphepin-3-amine (5.3 g. 22 mmol). After the reaction mixture was stirred at room temperature for 15 min, it was cooled to −20° C., stirred for another 10 min at that temperature, and then mCPBA (8.40 g, 50-55 wt %, 24.4 mmol) was added. The reaction mixture was stirred at −20° C. for 20 min, and concentrated in vacuo. The residue was redissolved in DCM (30 mL) and washed with saturated aqueous NaHCO3 (40 mL). The aqueous layer was extracted with DCM (3×50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (120 g RediSep column, eluting with a gradient of 0% through 100% ethyl acetate/hexanes over 60 min, 85 mL/min) to yield product 7 (4.85 g, 65%) as a pale yellow oil. Rf=0.40 (hexanes/ethyl acetate, 1/1, v/v). 1H NMR (300 MHz. CDCl3) δ 7.35-7.18 (m, 9H), 5.98-5.85 (m. 1H), 5.41-5.05 (m, 6H), 4.64 (t, J=10.1 Hz, 1H), 4.58-4.52 (m, 6H), 3.83 (d, J=9.0 Hz, 1H), 3.72-3.61 (m, 2H), 3.41 (dd, J=10.5, 7.4 Hz, 1H), 0.92 (s, 9H), 0.16 (s, 3H), 0.15 (s, 3H). Example 7 TERT-BUTYLDIMETHYLSILYL-3-O-ALLYLOXYCARBONY -6-O-BENZYL-2-DEOXY-4-O-(1,5-DIHYDRO-3-OXO-3λ5-3H-2,4,3-BENZODIOXAPHOSPHEPIN-3-YL)-2-(9-FLUORENYLMETHOXYCARBONYLAMINO)-D-GLUCOPYRANOSIDE (8) Acetic acid (0.30 mL, 5.2 mmol) was added dropwise to a stirred suspension of 7 (700 mg, 1.04 mmol) and zinc powder (676 mg, 10.4 mmol) in DCM (15 mL). The reaction mixture was stirred at room temperature for 4 h, after which it was diluted with ethyl acetate (50 mL). The solids were removed by filtration and washed with ethyl acetate (2×10 mL). The combined filtrates were washed with saturated aqueous NaHCO3 (2×40 mL) and brine (2×40 mL). The organic phase was dried (MgSO4) and filtered, and the filtrate was concentrated in vacuo to afford the crude intermediate amine as a pale yellow oil. Rf=0.21 (hexanes/ethyl acetate, 1/1, v/v). 9-Fluorenylmethyloxycarbonyl chloride (Fmoc-CI) (323 mg, 1.25 mmol) was added to a stirred solution of the crude amine and diisopropylethylamine (DIPEA) (0.22 mL, 1.3 mmol) in DCM (15 mL) at 0° C. The reaction mixture was warmed and stirred at room temperature for 5 h, after which it was diluted with DCM (40 mL) and washed with brine (2×50 mL). The organic phase was dried (MgSO4) and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (40 g RediSep column, eluting with a gradient of 0% through 100% ethyl acetate/hexanes over 30 min, 40 mL/min) to give product 8 (337 mg, 73% over two steps) as a white solid. Rf=0.54 (hexanes/ethyl acetate, 1/1, v/v). 1H NMR (300 MHz, CDCl3) δ 7.78-7.20 (m, 17H), 5.92-5.82 (m, 1H), 5.49-5.16 (m, 8H), 4.69-4.06 (m, 5H), 4.49-4.28 (m, 2H), 3.88-3.61 (m, 3H), 3.60-3.51 (m, 2H), 3.32 (broad s, 1H), 0.94 (s, 9H), 0.14 (s, 3H), 0.10 (s, 3H). Example 8 3-O-ALLYLOXYCARBONYL-6-O-BENZYL-2-DEOXY-4-O-(1,5-DIHYDRO-3-OXO-3λ5-3H-2,4,3-BENZODIOXAPHOSPHEPIN-3-YL)-2-(9-FLUORENYLMETHOXYCARBONYLAMINO)-D-GLUCOPYRANOSIDE (9) Hydrogen fluoride/pyridine (6 mL, 0.2 mol) was added dropwise to a stirred solution of 8 (6.00 g, 6.88 mmol) in THF (50 mL). The reaction mixture was stirred at room temperature for 12 h, after which it was diluted with diethyl ether (100 mL), and then washed with saturated aqueous NaHCO3 (2×40 mL) and brine (2×40 mL). The organic phase was dried (MgSO4) and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (120 g RediSep column, eluting with a gradient of 0% through 80% ethyl acetate/hexanes over 60 min, 85 mL./min) to give product 9 (4.34 g, 83%) as a pale yellow oil. 1H NMR (300 MHz. CDCl3) δ 7.75-7.20 (m, 17H), 5.92-5.82 (m, 1H), 5.27-5.06 (m, 9H). 4.59-4.55 (m, 5H), 4.41-4.39 (m, 1H), 4.25-4.01 (m, 5H), 3.85-3.65 (m, 2H). Example 9 TERT-BUTYLDIMETHYLSILYL-6-O-{3-O-ALLYLOXYCARBONYL-6-O-BENZYL-2-DEOXY-4-O-(1,5-DIHYDRO-3-OXO-3λ5-3H-2,4,3-BENZODIOXAPHOSPHEPIN-3-YL)-2-[(R)-3-DODECANOYLOXY-TETRADECANOYLAMINO]-β-D-GLUCOPYRANOSYL}-2-AZIDO-4-O-BENZYL-3-O-[(R)-3-BENZYLOXY-DODECANOYL]-2-DEOXY-β-D-GLUCOPYRANOSIDE (11) A suspension of 10 (see preparation below) (350 mg, 0.172 mmol), zinc (1.3 g, 21 mmol), and acetic acid (0.70 mL, 12 mmol) in DCM (20 mL) was stirred at room temperature for 12 h. The mixture was diluted with diethyl ether. The solids were removed by filtration, and the residue was washed with diethyl ether (2×10 mL). The combined filtrates were washed with saturated aqueous NaHCO3 (2×15 mL) and brine (2×15 mL). The organic phase was dried (MgSO4) and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (12 g RediSep column, eluting with a gradient of 0% through 60% ethyl acetate/hexanes over 35 min, 30 mL/min) to afford product 11 (220 mg, 64%) as a pale yellow syrup. Rf=0.29 (hexanes/ethyl acetate, 5/2, v/v). 1H NMR (300 MHz, CDCl3) δ 7.37-7.24 (m, 20H), 6.20 (d, J=7.2 Hz, 1H), 5.59 (t, J=9.6 Hz, 1H), 5.31 (m, 1H), 5.12-4.97 (m, 6H), 4.62-4.44 (m, 7H), 4.05-3.24 (m, 9H), 2.68-2.12 (m. 9H), 1.64-1.59 (m, 13H), 1.27 (broad m, 95H), 0.94 (m, 25H), 0.13 (s, 6H). HRMS (m/z) (pos) calcd for C117H193N2O20PSi, 2005.37; found, 2006.3729 [M+H]+. Example 10 TERT-BUTYLDIMETHYLSILYL-6-O-{3-O-ALLYLOXYCARBONYL-6-O-BENZYL-2-DEOXY-4-O-(1,5-DIHYDRO-3-OXO-3λ5-3H-2,4,3-BENZODIOXAPHOSPHEPIN-3-YL)-2-[(R)-3-DODECANOYLOXY-TETRADECANOYLAMINO]-β-D-GLUCOPYRANOSYL}-4-O-BENZYL-3-O-[(R)-3-BENZYLOXY-DODECANOYL]-2-[(R)-3-4-METHOXYBENZYLOXY-TETRADECANOYL]-2-DEOXY-β-D-GLUCOPYRANOSIDE (12) To a solution of amine 11 (93 mg, 0.046 mmol) in DCM (10 mL) was added pyridine (21 mg, 0.27 mmol), (R)-3-(4-methoxybenzyloxy)tetradecanoyl chloride (see preparation below, compound 35) (40 mg, 0.12 mmol), and 4-dimethylaminopyridine (DMAP) (1 mg) at room temperature, and the mixture was stirred overnight. The mixture was transferred to a separatory funnel and diluted with diethyl ether (20 mL) and saturated sodium bicarbonate (20 mL). The aqueous layer was extracted with diethyl ether (3×20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (12 g RediSep column, eluting with a gradient of 0% through 80% ethyl acetate/hexanes over 35 min, 30 mL/min) to give the product 12 (81 mg, 74%) as a colorless liquid. Rf=0.34 (hexanes/ethyl acetate, 3/2, v/v). 1H NMR (300 MHz, CDCl3) δ 7.34-7.20 (m, 20H), 6.89-6.86 (m, 4H), 6.15 (t, J=9.0 Hz, 1H), 5.57-5.55 (m, 1H), 5.31-4.99 (m, 8H), 4.57-4.44 (m, 11H), 4.06-3.33 (m, 15H), 2.63-2.57 (m, 5H), 2.33-2.27 (m, 9H), 1.57 (m, 8H), 1.27 (broad m, 112H), 0.88-0.82 (m, 27H), 0.08 (s, 3H), 0.04 (s, 3H). HRMS (m/z) (pos) calcd for C139H227N2O23PSi, 2351.62; found, 2352.6343 [M+H]+. Example 11 LIPID A (13a) A suspension of 12 (10 mg, 0.0042 mmol) and Pd-black (15.0 mg) in anhydrous THF (5 mL) was shaken under an atmosphere of H2 (50 psi) at room temperature for 30 h. The catalyst was removed by filtration. The residue was washed with THF (2×1 mL). The solution was cooled to −40° C. and neutralized with ammonia in methanol (0.1 mL, 7 M) and concentrated without heating in vacuo. The residue was purified by chromatography (12 g RediSep column, eluting with chloroform/methanol/water 8/2/0.1 for 30 min, 30 mL/min) to afford 13a (4 mg, 54%) as a colorless film. The product was re-dissolved in water and methanol (v/v, 1/1, 2 mL) and lyophilized to obtain the product 13a as a white powder. 1H NMR (500 MHz, CDCl3) δ 6.00-5.00 (m, 1H), 4.50-3.50 (m, 2H), 3.00-2.00 (m, 3H), 2.00-1.00 (m, 50H), 0.81 (m, 18H). MS (Multimode, neg) calcd for C96H181N2O22P, 1745.28; found, 1745.0 [M−H]−. Example 12 LIPID A (13b) A suspension of 12 (27 mg, 0.011 mmol) and Pd-black (41.0 mg) in anhydrous THF (12 mL) was shaken under an atmosphere of H2 (50 psi) at room temperature for 30 h. The catalyst was removed by filtration. The residue was washed with THF (2×3 mL). The solution was neutralized with triethylamine (TEA) (0.1 mL) and concentrated without heating in vacuo. The combined filtrates were concentrated in vacuo and purified by chromatography on silica (12 g RediSep column, eluting with chloroform/methanol/water 8/2/0.1 30 min, 30 mL/min) to afford 13b (5 mg, 25%) as a colorless film. The product was re-dissolved in water and methanol (v/v. 1/1, 2 mL) and lyophilized to obtain the product 13b as a white powder. 1H NMR (500 MHz, CDCl3) δ 5.17 (broad, 2H), 4.23-3.62 (m, 5H), 3.11-3.07 (q, J=2.8 Hz, 2H), 2.51-2.12 (m, 6H), 1.56-1.00 (m, 69H), 0.92-0.84 (m, 18H). MS (Multimode, neg) calcd for C96H181N2O22P, 1745.28; found, 1744.1 [M−H]. Example 13 TERT-BUTYLDIMETHYLSILYL-6-O-[3-O-ALLYLOXYCARBONYL-6-O-BENZYL-2-DEOXY-4-O-(1,5-DIHYDRO-3-OXO-3λ5-3H-2,4,3-BENZODIOXAPHOSPHEPIN-3-YL)-2-(9-FLUORENYLMETHOXYCARBONYLAMINO)-β-D-GLUCOPYRANOSYL]-2-AZIDO-4-O-BENZYL-2-DEOXY-β-D-GLUCOPYRANOSIDE (15) Compound 9 (89 mg, 0.12 mmol) was dissolved in anhydrous DCM (3 mL). Trichloroacetonitrile (1.0 mL) was added followed by sodium hydride (1.0 mg, 60% in mineral oil). After 15 min, TLC indicated the presence of 9, so an additional quantity of sodium hydride (1 mg, 60% in mineral oil) was added. After 15 min, TLC indicated that the reaction was complete. The mixture was concentrated under vacuum and loaded onto a SiO2 column which was pretreated with Et3N and eluted with 50% ethyl acetatelhexanes to provide the trichloroacetimidate intermediate (76.9 mg, 71%) which was used without further purification. A suspension of trichloroacetimidate (76.9 mg, 0.0852 mmol), acceptor 14 (see preparation below) (52.34 mg, 0.1277 mmol), and molecular sieves (4 Å, 500 mg) in DCM (5.0 mL) was stirred at room temperature for 1 h. The mixture was cooled (−60° C.), and TMSOTf (1.54 μL, 0.0851 mmol) was added. After the reaction mixture was stirred for 30 min, it was quenched with solid NaHCO3. The solids were removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (hexanes/ethyl acetate, 2:1 (v/v)) to give 15 (55 mg, 40%) as a colorless solid. 1H NMR (500 MHz, CD3COCD3) δ 7.86-7.22 (m, 22H), 6.98 (d, J=9.0 Hz, 1H), 5.85 (m, 1H), 5.41 (t, J=9.0 Hz, 1H), 5.38-5.21 (m, 3H), 5.10-5.02 (m, 3H), 4.91 (d, J=11.0 Hz, 2H), 4.72-4.46 (m, 7H), 4.23-4.15 (m. 4H), 3.93-3.80 (m, 4H), 3.69-3.66 (m, 1H), 3.54 (br s, 3H), 3.20 (dd, J1=8.0 Hz, J2=8.0 Hz, 1H), 0.95 (s, 9H), 0.17 (s, 6H); 13C NMR (125 MHz, CD3COCD3) δ 207.00, 156.61, 155.51, 145.22, 144.82, 142.06, 142.01, 139.98, 139.57, 136.68, 136.62, 133.02, 132.94, 129.85, 129.83, 129.15, 129.05, 128.95, 128.91, 128.82, 128.61, 128.49, 128.41, 128.21, 128.17, 128.0, 127.92, 126.19, 126.09, 125.98, 120.79, 118.60, 118.52, 101.41, 97.57, 78.78, 78.10, 76.84, 75.98, 75.88, 75.43, 75.30, 75.17, 74.70, 74.07, 70.63, 69.76, 69.64, 69.27, 69.15, 69.10, 69.02, 68.97, 67.73, 67.17, 57.29, 54.94, 26.11, 18.51; HR MS (m!z) calcd for C59H69N4O16PSi [M+H]+, 1149.4293; found, 1149.4238. Example 14 TERT-BUTYLDIMETHYLSILYL-6-O-{3-O-ALLYLOXYCARBONYL-6-O-BENZYL-2-DEOXY-4-O-(1,5-DIHYDRO-3-OXO-3λ5-3H-2,4,3-BENZODIOXAPHOSPHEPIN-3-YL)-2-[(R)-3-DODECANOYLOXY-TETRADECANOYLAMINO]-β-D-GLUCOPYRANOSYL}-2-AZIDO-4-O-BENZYL-2-DEOXY-β-D-GLUCOPYRANOSIDE (16) 1,8-Diazabicylco[5.4.0]undec-7-ene (220 μL, 1.47 mmol) was added dropwise to a solution of 15 (800 mg, 0.696 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 1 h, after which it was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/methanol, 100:1 through 100:3 (v/v)) to afford the free amine (648 mg, 99%) as a colorless syrup. 1H NMR (500 MHz, CDCl3) δ 7.36-7.17 (m. 14H). 5.96-5.88 (m, 1H), 5.40-5.06 (m, 7H), 4.84-4.50 (m, 9H), 4.21 (d, J=13.5 Hz, 1H), 4.15-4.11 (m, 1H), 3.82 (m, 1H), 3.79-3.42 (m, 5H), 3.34-3.19 (m, 2H), 2.96-2.90 (m, 1H), 2.34 (d, J=4.5 Hz, 1H), 0.90 (s, 9H), 0.13 (s, 6H). HRMS (m/z) calcd for C44H59N4O14PSi [M+H]+, 927.3613; found, 927.3569. N,N-Dicyclohexylcarbodiimide (DCC) (230 mg, 1.11 mmol) was added to a stirred solution of (R)-3-dodecanoyl-tetradecanoic acid (see preparation below, compound 40) (381 mg, 0.81 mmol) in DCM (10 mL). After the reaction mixture was stirred for 10 min, the free amine (648 mg, 0.699 mmol) in DCM (10 mL) was added, and stirring was continued for another 12 h. The insoluble materials were removed by filtration, and the residue was washed with DCM (2×2 mL). The combined filtrates were concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexanes/ethyl acetate, 2:1 (v/v)) to give 16 (450 mg, 47%) as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.35-7.17 (m, 14H), 5.94-5.86 (m, 2H), 5.47 (t, J=9.0, 10.5 Hz, 1H), 5.37 (d, J=2.5 Hz, 1H), 5.34 (d, J=2.5 Hz, 1H), 5.24 (d, J=13.5 Hz. 1H), 5.13-4.97 (m, 6H), 4.75 (d, J=11.0 Hz, 1H), 4.66-4.49 (m, 7H), 4.00 (d, J=17.0 Hz, 2H), 3.83 (d, J=10.5 Hz, 1H), 3.75-3.56 (m, 4H). 3.49-3.36 (m, 5H), 3.20 (m, 1H), 2.42-2.17 (m, 4H). 1.93 (d, J=11.5 Hz, 1H), 1.70 (m, 2H), 1.23 (br s, 36H), 0.92 (s, 9H), 0.89-0.86 (m, 6H), 0.14 (s, 6H); HRMS (m/z) calcd for C72H111N4O17PSi [M+H]+, 1363.7529; found. 1363.7487. Example 15 TERT-BUTYLDIMETHYLSILYL-6-O-{3-O-ALLYLOXYCARBONYL-6-O-BENZYL-2-DEOXY-4-O-(1,5-DIHYDRO-3-OXO-3λ5-3H-2,4,3-BENZODIOXAPHOSPHEPIN-3-YL)-2-[(R)-3-DODECANOYLOXY-TETRADECANOYLAMINO]-β-D-GLUCOPYRANOSYL}-2-AZIDO-4-O-BENZYL-3-O-[(R)-3-BENZYLOXY-TETRADECANOYL]-2-DEOXY-β-D-GLUCOPYRANOSIDE (17) A mixture of (R)-3-benzyloxytetradecanoic acid (see preparation below, compound 33) (120 mg, 0.540 mmol) and DCC (171 mg, 0.830 mmol) in DCM (5 mL) was stirred at room temperature for 10 min, and then disaccharide 16 (451 mg, 0.331 mmol) in DCM (5 mL) and DMAP (25 mg, 0.21 mmol) were added. The reaction mixture was stirred at room temperature for 14 h, after which the solids were removed by filtration. The residue was washed with DCM (2×4 mL). The combined filtrates were concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexanes/ethyl acetate, 4:1(v/v)) to give 17 (540 mg, 97%) as a white solid. Rf=0.41 (hexanes/ethyl acetate, 2:1(v/v)). 1H NMR (500 MHz. CDCl3) δ 7.33-7.15 (m, 19H), 5.94-5.85 (m, 2H), 5.47(t, J=9.5 Hz, 1H), 5.37 (d, J=17.5 Hz, 1H), 5.22 (d, J=10.0 Hz, 1H), 5.10-4.95 (m, 7H), 4.62-4.43 (m, 10H), 4.0-3.96 (m, 3H), 3.90-3.81 (m, 2H). 3.74-3.67 (m, 3H), 3.56-3.42 (m, 6H), 3.33-3.27 (m, 1H), 2.60-2.21 (m, 6H), 1.24 (br s, 54H), 0.91 (s, 9H), 0.87-0.84 (m, 9H), 0.14 (s. 6H). HRMS (m/z) calcd for C93H143N4O19PSi [M+H]+, 1679.9931; found, 1679.9934. Example 16 TERT-BUTYLDIMETHYLSILYL-6-O-{6-O-BENZYL-2-DEOXY-4-O-(1,5-DIHYDRO-3-OXO-3λ5-3H-2,4,3-BENZODIOXAPHOSPHEPIN-3-YL)-2-[(R)-3-DODECANOYLOXY-TETRADECANOYLAMINO]-β-D-GLUCOPYRANOSYLI-2-AZIDO-4-O-BENZYL-3-O-[(R)-3-BENZYLOXY-TETRADECANOYL]-2-DEOXY-β-D-GLUCOPYRANOSIDE (18) Tetrakis(triphenylphosphine)palladium (228 mg, 0.198 mmol) was added to a solution of 17 (1.66 g, 0.980 mmol), n-BuNH2 (0.19 mL, 1.97 mmol), and HCOOH (74.5 μL, 1.98 mmol) in THF (20 mL). After the reaction mixture was stirred at room temperature for 20 min, it was diluted with DCM (40 mL), and washed successively with water (40 mL), saturated aqueous NaHCO3 (2×40 mL), and brine (40 mL). The organic phase was dried (MgSO4) and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (hexanesiethyl acetate, 4:3 (v/v)) to give compound 18 (1.43 g, 91%). Rf=0.5 (hexanes/ethyl acetate, 1:1 (v/v)). 1H NMR (500 MHz, CDCl3) δ 7.33-7.11 (m, 19H), 6.2 (d, J=7.5 Hz, 1H), 5.46 (t, J=9.0 Hz, 1H), 5.04-4.90 (m, 9H), 4.55-4.38 (m, 8H), 3.92 (d, J=10.0 Hz, 1H), 3.84-3.76 (m, 1H), 3.75-3.7 (m, 4H), 3.53-3.44 (m, 2H), 3.43-3.32 (m, 2H), 3.25-3.20 (m, 1H), 2.61-2.10 (m, 12H). 1.23 (br s, 54H), 0.90 (s, 9H), 0.88-0.84 (m, 9H), 0.12 (s, 6H). HRMS (m/z) calcd for C89H139N4O17PSi [M+H]+, 1595.972; found, 1595.9713. Example 17 TERT-BUTYLDIMETHYLSIYL-6-O-{6-O-BENZYL-2-DEOXY-4-O-(1,5-DIHYDRO-3-OXO-3λ5-3H-2,4,3-BENZODIOXAPHOSPHEPIN-3YL)-2-[(R)-3-DODECANOYLOXY-TETRADECANOYLAMINO)-3-O-[(R)-3-(P-METHOXY)BENZYLOXYTETRADECANOYL]-β-D-GLUCOPYRANOSYL}-2-AZIDO-4-O-BENZYL-3-O-[(R)-3-BENZYLOXY-TETRADECANOYL]-2-DEOXY-β-D-GLUCOPYRANOSIDE (19) A solution of (R)-3-(p-meihoxy)benzyloxy-tetradecanoic acid (see preparation below, compound 34, 424 mg, 1.16 mmol) and DCC (369 mg, 1.79 mmol) in DCM (15 mL) was stirred at room temperature for 10 min, and the alcohol 18 (1.43 g, 0.896 mmol)in DCM (10 mL) and DMAP (54.72 mg, 0.4479 mmol) were added. The reaction mixture was stirred for another 14 h, after which the solids were removed by filtration and washed with DCM (2×5 mL). The combined filtrates were concentrated in vacuo. The residue was purified by silica gel column chromatography (hexanes/ethyl acetate, 4:1 (v/v)) to afford 19 (1.15 g, 66%) as a white solid. Rf=0.46 (hexanesiethyl acetate, 2:1 (v/v)). 1H NMR (500 MHz, CDCl3) δ 7.38-6.79 (m, 23H). 5.73 (d, J=8.0 Hz, 1H), 5.55 (t, J=9.5 Hz, 1H), 5.20-4.88 (m, 8H), 4.66-4.47 (m, 12H), 4.33 (d, J=12.5 Hz, 1H), 4.0-3.66 (m, 12H), 3.61-3.40 (m, 5H), 3.36-3.27 (m, 3H), 2.67 (d, J=6.0 Hz, 2H). 2.60-2.22 (m, 6H), 1.27 (br s, 72H), 0.93 (s, 9H), 0.92-0.87 (m, 12H), 0.16 (s, 6H). HRMS (m/z) calcd for C111H173N4O20PSi [M+H]+, 1942.2228; found, 1942.2289. Example 18 TERT-BUTYLDIMETHYLSIYL-6-O-{6-O-BENZYL-2-DEOXY-4-O-(1,5-DIHYDRO-3-OXO-3λ5-3H-2,4,3-BENZODIOXAPHOSPHEPIN-3YL)-2[(R)-3-DODECANOYLOXY-TETRADECANOYLAMINO]-3-O-[(R)-3-TETRADECANOYLOXY-TETRADECANOYL]-β-D-GLUCOPYRANOSYL}-2-AZIDO-4-O-BENZYL-3-O-[(R)-3-BENZYLOXY-TETRADECANOYL]-2-DEOXY-β-D-GLUCOPYRANOSIDE (10) To a stirred solution of 19 (1.15 g, 0.592 mmol) in a mixture of DCM and H2O (11 mL, 10:1 (viv)) was added 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (202 mg, 0.890 mmol). The reaction mixture was stirred at room temperature for 1 h, after which it was diluted with DCM. The mixture was washed with brine (20 mL), dried (MgSO4), and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexanesiethyl acetate, 3:1 (v/v)) to give the alcohol as a colorless syrup (1.01 g, 94%). Rf=0.50 (hexanes/ethyl acetate, 5:3 (v/v)). Myristoyl chloride (0.74 mL, 2.7 mmol) was added to a solution of the alcohol (1.01 g, 0.554 mmol), and pyridine (0.35 mL, 4.33 mmol) in DCM (20 mL). After the reaction mixture was stirred at room temperature for 12 h, it was diluted with DCM and washed with saturated aqueous NaHCO3 (2×40 mL) and brine (40 mL). The organic phase was dried (MgSO4) and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (hexanes/ethyl acetate, 4:1 (v/v)) to afford 10 (680 mg, 57%) as a white solid. Rf=0.46 (hexanes/ethyl acetate, 5:2 (v/v)). 1H NMR (500 MHz, CDCl3) δ 7.37-7.24 (m, 19H), 6.23 (d, J=7.5 Hz, 1H), 5.58 (t, J1=9.5 Hz, 1H), 5.32-5.27 (m, 1H), 5.16-4.99 (m, 6H), 4.78-4.44 (m, 7H), 4.03 (d. J=10.5 Hz, 1H), 3.99-3.20 (m, 10H), 2.65-2.21 (m, 10H), 1.61-1.51 (m, 10H), 1.27 (br s, 94H), 1.21 (br s, 25H), 0.12 (s, 6H). Example 19 TERT-BUTYLDIMETHYLSILYL-6-O-{3-O-ALLYLOXYCARBONYL-6-O-BENZYL-2-DEOXY-4-O-(1,5-DIHYDRO-3-OXO-3λ5-3H-2,4,3-BENZODIOXAPHOSPHEPIN-3-YL)-2-[(R)-3-DECANOYLOXY-TETRADECANOYLAMINO]-5-D-GLUCOPYRANOSYL}-2-AZIDO-4-O-BENZYL-2-DEOXY-β-D-GLUCOPYRANOSIDE (20) Compound 15 (1.23 g, 1.07 mmol) was acylated in a manner similar to the synthesis of compound 16 (Example 14) using (DCC, 430 mg, 2.08 mmol), required lipid (Compound 40, Example 36, 630 mg, 1.59 mmol), and triethylamine (161 mg, 1.59 mmol) to provide 20 (1.05 g, 81%) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.35-7.17 (m, 14H), 5.91-5.86 (m, 2H), 5.47 (t, J=9.0, 10.5 Hz, 1H), 5.34 (d, J=17 Hz, 1H), 5.24 (d, J=10.5 Hz, 1H), 5.10-4.98 (m, 8H), 4.75 (d, J=11.5 Hz, 1H), 4.66-4.49 (m, 8H), 4.00 (d, J=11.0 Hz, 2H), 3.83 (d, J=11.0 Hz, 1H), 3.75-3.69 (m, 2H), 3.49-3.36 (m, 4H), 3.20 (m. 1H), 2.40-2.26 (m, 4H), 1.24 (br s, 32H), 0.92 (s, 9H), 0.89-0.86 (m, 6H), 0.14 (s, 6H); MS (Multimode, pos) m/z=1307 [M+H]+. Example 20 TERT-BUTYLDIMETHYLSILYL-6-O-{3-O-ALLYLOXYCARBONYL-6-O-BENZYL-2-DEOXY-4-O-(1,5-DIHYDRO-3-OXO-3λ5-3H -2,4,3-BENZODIOXAPHOSPHEPIN-3-YL)-2-[(R)-3-DECANOYLOXY-TETRADECANOYLAMINO]-β-D-GLUCOPYRANOSYL}-2-AZIDO-4-O-BENZYL-3-O-[(3-BENZYLOXY-TETRADECANOYL]-2-DEOXY-β-D-GLUCOPYRANOSIDE (21) Compound 20 (1.43 g, 1.18 mmol) was acylated in a manner similar to the synthesis of compound 17 (Example 15) using (DCC, 453 mg, 2.20 mmol), required lipid (477 mg, 1.43 mmol), and N,N-dimethyl-4-aminopyridine (67 mg, 0.548 mmol) to provide 21 (1.60 g, 83%) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.33-7.15 (m, 19H), 5.94-5.85 (m, 2H), 5.48 (t, J=9.0 Hz, 1H), 5.34 (d, J=17.5 Hz, 1H), 5.22 (d, J=10.0 Hz, 1H), 5.12-4.96 (m, 7H), 4.63-4.46 (m, 11H), 3.97 (d, J=10.5 Hz, 1H), 3.89-3.85 (m, 2H), 3.74-3.68 (m, 3H), 3.55-3.52 (m, 2H), 3.47-3.41 (m, 1H), 3.28 (m, 1H), 2.61-2.22 (m, 8H), 1.59-1.52 (m, 6H), 1.98 (m, 2H), 1.23 (br s, 44H), 0.90 (s, 9H), 0.88-0.84 (m, 9H), 0.12 (s, 6H); MS (Multimode, pos) m/z=1625 [M+H]+. Example 21 TERT-BUTYLDIMETHYLSILYL-6-O-{6-O-BENZYL-2-DEOXY-4-O-(1,5-DIHYDRO-3-OXO-3λ5-3H -2,4,3-BENZODIOXAPHOSPHEPIN-3-YL)-2-[(R)-3-DODECANOYLOXY-TETRADECANOYLAMINO]-β-D-GLUCOPYRANOSYL}-2-AZIDO-4-O-BENZYL-3-O-[(R)-3-BENZYLOXY-TETRADECANOYL]-2-DEOXY-β-D-GLUCOPYRANOSIDE (22) Compound 21 (1.60 g, 0.985 mmol) was reacted in a manner analagous to the synthesis of compound 18 (Example 16). Accordingly, tetrakis(triphenylphosphine)palladium, (227 mg, 0.196 mmol), formic acid (74 μL, 1.97 mmol), and n-butylamine (144 mg, 1.97 mmol) to provide 22 (1.25 g, 82%) as a yellow solid. 1H NMR (500 MHz, CDCl3) δ 7.33-7.15 (m, 19H), 6.20 (d, J=7.5 Hz, 1H), 5.38-4.95 (m, 6H), 4.86 (d, J=8.0 Hz, 1H), 4.60-4.46 (m, 10H), 3.97-3.71 (m, 8H), 3.68-3.48 (m, 5H), 3.31-3.27 (m, 3H), 2.62-2.55 (m, 2H), 2.50-2.42 (m, 3H), 2.40-2.22 (m, 5H), 1.23 (br s, 44H), 0.90 (s, 9H), 0.88-0.84 (m, 9H). 0.12 (s, 6H); MS (Multimode, pos) m/z=1539 [M+H]+. Example 22 TERT-BUTYLDIMETHYLSILYL-6-O-{6-BENZYL-2-DEOXY-4-O-(1,5-DIHYDRO-3-OXO-3λ5-3H-2,4,3-BENZODIOXAPHOSPHEPIN-3-YL)-2-[(R)-3-DECANOYLOXY-TETRADECANOYLAMINO]-3-O-[(R)-3-(P-METHOXY)BENZYLOXYTETRADECANOYL]-β-D-GLUCOPYRANOSYL}-2-AZIDO-4-O-BENZYL-3-O-[(R)-3-BENZYLOXY-TETRADECANOYL]-2-DEOXY-β-D-GLUCOPYRANOSIDE (23) Compound 22 (1.25 g, 0.811 mmol) was acylated in a manner similar to the synthesis of compound 19 (Example 17) using (DCC, 335 mg, 1.62 mmol), required lipid (Compound 34, Example 32, 386 mg, 1.06 mmol), and N,N-dimethyl-4-aminopyridine (50 mg, 0.41 mmol) to provide 23 (440 mg, 29%) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.38-6.79 (m, 23H), 5.71 (d, J=7.5 Hz. 1H), 5.55 (t, J=9.5 Hz, 1H), 5.06-4.85 (m. 9H), 4.66-4.45 (m, 12H), 3.97 (d, J=11.0 Hz, 1H), 3.90-3.69 (m, 9H), 3.60-3.55 (m, 3H), 3.37-3.29 (m, 2H), 2.65 (d, J=7.5 Hz, 2H), 2.61-2.55 (m, 1H), 2.48-2.42 (m, 1H), 2.35-2.21 (m, 3H), 2.11-2.05 (m, 1H),1.62-1.59 (m, 8H), 1.27 (br s, 62H), 0.93 (s, 9H), 0.92-0.87 (m, 12H), 0.16 (s, 6H); MS (Multimode, pos) m/z=1886 [M+H]+. Example 23 TERT-BUTYLDIMETHYLSILYL-6-O-{6-O-BENZYL-2-DEOXY-4-O-(1,5-DIHYDRO-3-OXO-3λ5-3H-2,4,3-BENZODIOXAPHOSPHEPIN-3-YL)-2-[(R)-3-DECANOYLOXY-TETRADECANOYLAMINO]-3-O-[(R)-3-DECANOYLOXY-TETRADECANOYL]-β-D-GLUCOPYRANOSYL}-2-AZIDO-4-O-BENZYL-3-O-[(R)-BENZYLOXY-TETRADECANOYL]-2-DEOXY-β-D-GLUCOPYRANOSIDE (24) Compound 23 (446 mg, 0.236 mmol) was first deprotected using DDQ (80 mg, 0.35 mmol) following the procedure for intermediate 10 for Target A. This intermediate (343 mg, 0.194 mmol) was then acylated in a manner similar to the synthesis of compound 10 for Target A using decanoyl chloride (185 mg, 0.970 mmol) and pyridine (123 mg, 1.55 mmol) to provide 24 (343 mg, 76%) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.39-7.22 (m, 14H), 6.15 (d, J=7.5 Hz, 1H), 5.54 (t, J=9.5 Hz, 1H), 5.28-5.24 (m. 1H), 5.14-4.96 (m, 8H), 4.60-4.45 (m, 10H), 3.99 (d, J=10.5 Hz, 1H), 3.90-3.85 (m, 1H), 3.80-3.65 (m, 4H), 3.55 (m, 3H), 3.46-3.39 (m, 1H), 3.32-3.27 (m, 1H), 2.66-2.53 (m, 3H), 2.46-2.41 (m, 1H), 2.35-2.18 (m, 7H), 1.61-1.51 (m, 10H), 1.26 (br s, 78H), 0.95 (s, 9H), 0.92-0.90 (m, 15H), 0.19 (5, 3H), 0.18 (s, 3H). Example 24 TERT-BUTYLDIMETHYLSILYL-6-O-{6-O-BENZYL-2-DEOXY-4-O-(1,5-DIHYDRO-3-OXO-3λ5-3H-2,4,3-BENZODIOXAPHOSPHEPIN-3-YL)-2-[(R)-3-DECANOYLOXY-TETRADECANOYLAMINO]-3-O-[(R)-3-DECANOYLOXY-TETRADECANOYL]-β-D-GLUCOPYRANOSYL}-4-O-BENZYL-3-O-[(R)-3-BENZYLOXYTETRADECANOYL]-2-[(R)-3-BENZYLOXY-TETRADECANOYLAMINO]-2-DEOXY-β-D-GLUCOPYRANOSIDE (25) A suspension of 24 (296 mg, 0.154 mmol), zinc (100 mg, 1.52 mmol), and acetic acid (53 μL, 0.93 mmol) in DCM (10 mL) was stirred at room temperature for 12 h, after which it was diluted with ethyl acetate (25 mL). The solids were removed by filtration and washed with ethyl acetate (2×25 mL), and the combined filtrates were washed with saturated aqueous NaHCO3 (2×100 mL) and brine (200 mL). The organic phase was dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (hexanes/ethyl acetate, 2.5:1 (v/v)) to afford the amine as a pale yellow syrup (245 mg, 84%). 1H NMR (500 MHz, CDCl3) δ 7.39-7.22 (m, 14H), 6.15 (d, J=7.5 Hz, 1H), 5.54 (t, J=9.5 Hz, 1H), 5.29-5.23 (m, 1H), 5.13-4.93 (m, 8H). 4.62-4.30 (m, 9H), 4.00 (d, J=10.5 Hz, 1H), 3.88-3.65 (m, 6H), 3.56-3.53 (m, 2H), 3.46-3.41 (m, 1H), 2.66-2.58 (m, 4H), 2.54-2.45 (m, 2H), 2.35-2.17 (m, 7H), 1.64-1.42 (m, 12H), 1.26 (br s, 78H), 0.87 (s, 24H), 0.13 (s, 6H). The amine was added to a stirred solution of (R)-3-benzyloxytetradecanoyl chloride (228 mg, 0.646 mmol), DMAP (15.79 mg, 0.1292 mmol), and pyridine (83 μL, 1.0 mmol) in DCM (5.0 mL). The reaction mixture was stirred for 14 h. The mixture was diluted with CH2Cl2 and was washed with saturated NaHCO3/brine dried under Na2SO4 and concentrated under vacuum. The residue was purified by silica gel TLC chromatography (hexanes/ethyl acetate, 3.5:1 (v/v)) to give 25 (450 mg, >100%) as a white solid. Rf=0.54 (hexanes/ethyl acetate, 2:1 (v/v)). 1H NMR (500 MHz, CDCl3) δ 7.39-7.22 (m, 19H), 6.14-6.10 (m, 2H), 5.57 (I, J=9.5 Hz, 1H), 5.29-5.24 (m, 1H), 5.13-4.93 (m, 7H). 4.61-4.41 (m, 10H), 4.00 (d, J=10.5 Hz, 1H), 3.89-3.79 (m, 8H), 3.72-3.66 (m, 4H), 3.57-3.35 (m, 3H), 2.73-2.57 (m, 10H), 2.39-2.15 (m, 10H), 1.71-1.64 (m, 7H), 1.26 (br s, 93H), 0.88 (s, 24H), 0.83 (s, 9H). Example 25 6-O-{6-O-BENZYL-2-DEOXY-4-O-(1,5-DIHYDRO-3-OXO-3λ5-3H-2,4,3-BENZODIOXAPHOSPHEPIN-3-YL)-2-[(R)-3-DECANOYLOXY-TETRADECANOYLAMINO]-3-O-KR)-[(3-DECANOYLOXY-TETRADECANL]-β-D-GLUCOPYRANOSYL}-4-O-BENZYL-3-O-[(R)-3-BENZYLOXY-TETRADECANOYL]-2-[(R)-3-BENZYLOXY-TETRADECANOYLAMINO]-2-DEOXY-α-D-GLUCOPYRANOSE (26) Hydrogen fluoride/pyridine (1.12 mL, 43.1 mmol) was added dropwise to a stirred solution of 25 (450 mg, 0.204 mmol) in THF (5 mL). The reaction mixture was stirred at room temperature for 14 h. The mixture was diluted with ethyl acetate (100 mL) and washed with saturated aqueous NaHCO3 (2×80 mL) and brine. The organic phase was dried (Na2SO4) and filtered. The filtrate was concentrated in vacua. The residue was purified by silica gel column chromatography (hexanes/ethyl acetate, 3:1 through 4:3 (v/v)) to give 26 (180 mg, 42%) as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.39-7.19 (m, 19H), 6.31 (d, J=7.0 Hz. 1H), 6.24 (d, J=9.5 Hz, 1H), 5.57-5.48 (m, 2H), 5.40 (t, J=9.5 Hz, 1H), 5.28-5.21 (m, 1H), 5.14-4.96 (m, 8H), 4.68-4.41 (m, 12H). 4.23-4.19 (m, 1H), 4.13-4.06 (m, 1H), 3.94-3.66 (m, 9H), 3.38-3.28 (m, 2H), 2.67-2.58 (m, 3H), 2.44-2.20 (m, 11H), 1.58 (br s, 12H), 1.26 (br s, 93H), 0.91-0.81 (m, 18H). Example 26 (3R)-((2R,3S,4R,5S)-3-((R)-3-(DECANOYLOXY)TETRADECANAMIDO)-2-(((3S,4R,5S)-3,6-DIHYDROXY-5-((R)-3-HYDROXYTETRADECANAMIDO)-4-((R)-3-HYDROXYTETRADECANOYLOXY)TETRAHYDRO-2H-PYRAN-2-Y)ETHOXY)-6-(HYDROXYMETHYL)-5-(PHOSPHONOOXY)TETRAHYDRO-2H-PYRAN-4-YL) 3-(DECANOYLOXY)TETRADECANOATE (IX) Compound 26 (180 mg, 0.0858 mmol) was dissolved in anhydrous THF (15 mL). Palladium black (0.225 g) was added to the mixture and was hydrogenated under 50 psi hydrogen atmosphere overnight. The mixture was filtered through a bed of diatomaceous earth. The filtrate was cooled to −40° C. and a solution of ammonia in methanol (1.8 mL, 4 M) was added. The mixture was concentrated under vacuum without heating. The residue was purified by silica gel chromatography eluting with a mixture of chloroform/methanol/water, 80:20:1 (v/v) to give the desired compound (IX) (102 mg, 73%). Analysis by TLC and 1H NMR showed the presence of grease and a faint close running spot (TLC in CH2Cl2/CMA, 4:1). The residue was subjected to chromatography (12 g RediSep column, eluted with a gradient of isocratic CH2Cl2 for 5 column volumes (CVs), a gradient through 25% CMA over 10 CVs, isocratic for 10 CVs, a gradient though 100% CMA over 10 CVs, isocratic at 100% CMA for 10 CVs, 20 mL/min) to give the desired product (57 mg, 25%). TLC analysis of the combined and concentrated fractions still indicated a very small amount of impurity running just above the desired product. The residue was re-purified by silica gel chromatography (two 12 g RediSep columns in series, same gradient as above) to provide 8.9 mg of the desired product pure by TLC and 11.9 mg of slightly impure product after dissolving in methanol/water/chloroform and freeze-drying. Total yield (20.8 mg, 14%) as an off white solid. Rf=0.40 CMA. 1H NMR (500 MHz, CDCl3) δ 5.40-5.30 (br s, 2H), 4.10-4.00 (m, 4H), 3.70-3.60 (m, 4H), 2.83-2.76 (m, 1H), 2.75-2.20 (m, 13H), 2.10-1.90 (broad, 9H), 1.40-1.00 (broad, 106H), 0.90-0.70 (broad, 18H). MS (Multimode, Neg) m/z=1632 [M−H]−. Example 27 METHYL 3-OXOTETRADECANOATE (29) To a suspension of magnesium ethoxide (10.82 g, 94.61 mmol) in 1,4-dioxane (100 mL) was added methyl hydrogen malonate (25.0 g, 189 mmol) in 1,4-dioxane (100 mL). The resulting slurry was stirred overnight. The mixture was concentrated in vacuo. In a separate flask, lauric acid (28, 20.85 g, 104.1 mmol) was dissolved in 1,4-dioxane (50 mL) and a solution of CDI (16.88 g, 104.1 mmol) in 1,4-dioxane (150 mL) was added at room temperature. The resulting solution was stirred overnight. The mixture was then transferred to the methyl magnesium malonate flask. The resulting suspension was refluxed overnight. The mixture was concentrated in vacuo. The residue was redissolved in DCM (300 mL) and filtered through a silica plug (10 g). The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (360 g RediSep column, eluting with a gradient of 0% through 30% ethyl acetate/hexanes over 80 min, 100 mL/min) to afford product 29 (17 g, 61%) as a pale yellow syrup. Example 28 (R)-METHYL 3-HYDROXYTETRADECANOATE (30) A slurry of methyl 3-oxotetradecanoate (29, 29.0 g, 113 mmol) in methanol (120 mL) was purged in a 300 mL high pressure reactor glass sleeve with N2 for 10 minutes. Dichloro-R-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl ruthenium (897 mg, 1.10 mmol) was added. The mixture was placed in a Parr 5500 series compact reactor. The reactor was charged with H2 (60 psi) and vented 3 times. The reactor was charged with H2 (60 psi) and stirred (1200 rpm) and heated to 50° C. for 20 h. The reactor was cooled to room temperature, and the resulting orange solution was concentrated in vacuo. The residue was purified by silica gel chromatography (120 g RediSep column, eluting with a gradient of 0% through 40% ethyl acetate/hexanes over 60 min, 85 ml/min) to provide product 30 (28.5 g, 97% yield) as a white solid. Example 29 (R)-METHYL 3-(BENZYLOXY)TETRADECANOATE (31) To a solution of compound 30 (2.8 g, 10.83 mmol) and benzyl trichloroacetimidate (3.4 g, 14 mmol) in DCM (100 mL) was added trifluoromethanesulfonic acid (0.24 mL, 2.7 mmol) dropwise at 0° C. The resulting mixture was stirred at 0° C. for 6 h and warmed to room temperature. The mixture was washed with a saturated solution of NaHCO3 (300 mL) and water (300 mL) and the organic layer dried over Na2SO4. The drying agent was removed by filtration, and the solvents removed using a rotary evaporator. The residue was purified by chromatography on silica gel (80 g RediSep column, eluting with a gradient of 0% through 30% ethyl acetate/hexanes over 60 min, 60 mL/min) to give the product 31 (1.2 g, 32%) as a colorless liquid. 1H NMR (300 MHz, CDCl3) δ 7.30-7.05 (m, 5H), 4.51 (s, 2H), 3.90-3.80 (m, 1H), 3.70 (s, 3H), 2.58-2.45 (m, 2H), 1.80-1.60 (m, 2H), 1.50-1.20 (m, 18H), 0.85 (t, J=5.8 Hz, 3H). Example 30 (R)-3-(BENZYLOXY)TETRADECANOIC ACID (33) Ester 31 (1.3 g, 3.73 mmol) was dissolved in THF/MeOH/CH3CN mixture (v/v/v, 1/1/1, 90 mL). Lithium hydroxide monohydrate (235 mg, 5.6 mmol) as a solution in water (30 mL) was added, and the mixture stirred overnight. The solvent amount was reduced in vacuo to about 30 mL. To the remaining aqueous solution was added 1 M hydrochloric acid to bring the pH down to 3. The aqueous layer was extracted with diethyl ether (3×40 mL). The combined organic extracts were dried over sodium sulfate. The drying agent was removed by filtration, and the solvents removed using a rotary evaporator. The residue was purified by chromatography on silica gel (40 g RediSep column, eluting with a gradient of 0% through 50% ethyl acetate/hexanes over 40 min, 40 mL/min) to give the product 33 (990 mg, 79%) as a colorless liquid. 1H NMR (300 MHz, CDCl3) δ 7.30-7.05 (m, 5H), 4.51 (s, 2H), 3.90-3.80 (m, 1H), 2.58-2.45 (m, 2H), 1.80-1.60 (m, 2H), 1.50-1.20 (m, 18H), 0.85 (t, J=5.8 Hz, 3H). Example 31 (R)-METHYL 3-(4-METHOXYBENZYLOXY)TETRADECANOATE (32) To a solution of compound 30 (3.50 g, 12.9 mmol) and 4-methoxybenzyl trichloroacetimidate (4.65 g, 17.3 mmol) in DCM (100 mL) was added camphorsulfonic acid (450 mg, 1.92 mmol). The mixture was stirred overnight at room temperature. The mixture was washed with a saturated solution of NaHCO3 (300 mL) and water (300 mL) and dried over Na2SO4. The drying agent was removed by filtration and the solvents removed using a rotary evaporator. The residue was purified by chromatography on silica gel (120 g RediSep column, eluting with a gradient of 0% through 30% ethyl acetatethexanes over 70 min, 85 mL/min) to give the product 32 (4.01 g, 81%) as a colorless liquid. Example 32 (R)-3-(4-METHOXYBENZYLOXY)TETRADECANOIC ACID (34) Ester 32 (4.01 g, 10.4 mmol) was dissolved in THF/MeOH/CH3CN mixture (v/v/v, 1/1/1, 90 mL). Lithium hydroxide monohydrate (874 mg, 20.8 mmol) as a solution in water (30 mL) was added, and the mixture stirred overnight. The solvent amount was reduced in vacuo to about 30 mL. To the remaining aqueous solution was added hydrochloric acid (1 M) to bring the pH down to 3. The aqueous layer was extracted with diethyl ether (3×40 mL). The combined organic extracts were dried over sodium sulfate. The drying agent was removed by filtration and the solvents removed using a rotary evaporator. The residue was purified by chromatography on silica gel (120 g RediSep column, eluting with a gradient of 0% through 50% ethyl acetate/hexanes over 60 min, 85 mL/min) to give the product 34 (3.37 g, 89%) as a colorless liquid. 1H NMR (300 MHz, CDCl3) δ 7.22 (d, J=6.1 Hz, 2H), 6.82 (d, J=6.1 Hz, 2H), 4.46 (s, 2H), 3.81 (m, 1H), 3.75 (s, 3H), 2.65-2.49 (m, 2H), 1.80-1.60 (m, 2H), 1.50-1.20 (m, 18 H), 0.85 (t, J=5.8 Hz, 3H). Example 33 (R)-3-(4-METHOXYBENZYLOXY)TETRADECANOYL CHLORIDE (35) To a solution of acid 34 (500 mg, 1.37 mmol) in DCM (5 mL) was added dimethylformamide (DMF) (100 mg, 1.37 mmol), and the resulting mixture was cooled to −10° C. Oxalyl chloride (174 mg, 1.37 mmol) in DCM (5 mL) was added dropwise. The solution was allowed to warm to room temperature over 1 h. After TLC analysis showed no acid present, the mixture was concentrated in vacuo and used without further purification. Example 34 (R)-2-OXO-2-PHENYLETHYL 3-HYDROXYTETRADECANOATE (37) To a solution of (R)-3-hydroxytetradecanoic acid (36, see preparation below) (9.55 g, 39.1 mmol) and triethylamine (5.90 g, 58.6 mmol) in ethyl acetate (500 mL) was added 2-bromoacetophenone (7.90 g, 39.1 mmol) at room temperature. The mixture was stirred at room temperature for 14 h. The precipitate was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (120 g RediSep column, eluting with a gradient of 0% through 30% ethyl acetate/hexanes over 50 min, 85 mL/min) to give the product 37 (10.2 g, 72% yield) as a white solid. Example 35 (R)-2-OXO-2-PHENYLETHYL-3-DECANOYLOXYTETRADECANOATE (39) To a solution of 37 (4.80 g, 13.2 mmol) and pyridine (2.10 g, 26.5 mmol) in DCM (100 mL) at 0° C. was added decanoyl chloride (38, 2.8 g, 4.8 mmol). The mixture was stirred for 14 h allowing the temperature of the mixture to rise to room temperature. The mixture was washed with a saturated solution of NaHCO3 (100 mL) and brine (100 mL) and dried over Na2SO4. The drying agent was removed by filtration and the solvents removed using a rotary evaporator. The residue was purified by chromatography on silica gel (120 g RediSep column, eluting with a gradient of 0% through 40% ethyl acetate/hexanes over 50 min, 85 mL(min) to give the product 39 (6.68 g, 97%) as a colorless liquid. Example 36 (R)-3-(DECANOYLOXY)TETRADECANOIC ACID (40) Ester 39 (10.15 g, 20.77 mmol) was dissolved in acetic acid (100 mL). Zinc (15.5 g, 237 mmol) was added, and the mixture heated to reflux for 4 h. The acetic acid was removed under vacuum and the residue azeotroped with toluene to dryness. The residue was purified by chromatography on silica gel (120 g RediSep column, eluting with a gradient of 0% through 60% ethyl acetatelhexanes over 50 min, 85 ml/min) to give the product 40 (7.2 g, 89%) as a colorless liquid. 1H NMR (300 MHz, CDCl3) δ 5.23-5.19 (m. 1H), 2.62-2.55 (m, 2H), 2.34-2.25 (m, 2H), 1.65-1.58 (m, 2H), 1.28-1.20 (m, 32H). 0.85 (m, 6H). Example 37 (R)-METHYL 3-HYDROXYTETRADECANOATE (39) A slurry of methyl 3-oxotetradecanoate (41, 5.27 g, 20.6 mmol) in methanol (30 mL) in a 300 mL high pressure reactor glass sleeve was sparged with N2 for 10 minutes. Dichloro-R-2,2′-bis(diphenylphosphino)-1,1′-binaphthylruthenium (142 mg, 1.1 mmol) was added and the mixture was placed in a Parr 5500 series compact reactor. The reactor was charged with H2 (60 psi) and vented three times. The reactor was then charged with a final portion of H2 (60 psi) stirred (600 rpm) and heated to 50° C. for 20 h. The reactor was then cooled to room temperature and the mixture concentrated in vacuo. The resulting residue was purified by silica gel chromatography, eluting with a gradient of 0% through 50% ethyl acetate/hexanes to provide 42 (3.97 g, 74%) as an off-white solid. 1H NMR (CDCl3) δ 4.00-3.98 (m, 1H), 3.71 (s, 3H), 2.82 (d, J=6.5 Hz, 1H), 2.62-2.30 (m, 2H), 1.54-1.39 (m, 3H), 1.27 (br s, 17H), (m, 20H), 0.86 (t, J=7.0 Hz, 3H). Example 38 (R)-3-HYDROXYTETRADECANOIC ACID (36) Lithium hydroxide monohydrate (1.98 g, 47.2 mmol) was added to a solution of (R)-methyl 3-hydroxytetradecanoate (42, 8.17 g, 31.5 mmol) in THF (66 mL) and water (66 mL) and stirred at room temperature for 2 h. The mixture was then diluted with diethyl ether (1 L) and the pH adjusted to ˜3 with a solution of hydrochloric acid (1 N). The solution was then extracted with diethyl ether (200 mL), and the organic fractions were combined and dried over Na2SO4. Na2SO4 was removed by filtration and the filtrate was concentrated in vacuo to provide (R)-3-hydroxytetradecanoic acid (36, 7.59 g, 98%) as an off-white solid. 1H NMR (CDCl3) δ 3.99-3.94 (m, 1H), 2.45-2.39 (m, 2H), 1.47 (br s, 3H), 1.29 (br s, 17H), 0.89 (t, J=7.0 Hz, 3H). Example 39 (R)-2-OXO-2-PHENYLETHYL-3-TETRADECANOYLOXYTETRADECANOATE (46) Myristoyl chloride (45, 8.83 g, 35.8 mmol) was added to a solution of (R)-2-oxo-2-phenylethyl 3-hydroxytetradecanoate (37, prepared according to Example 34, 10.8 g, 29.8 mmol) in pyridine (40 mL). The reaction mixture was stirred at room temperature for 14 h. The mixture was then concentrated in vacua, and the residual pyridine removed by dissolving the residue in toluene (100 mL) and concentrating in vacuo. The resulting residue was purified by silica gel chromatography, eluting with a gradient of 0% through 20% ethyl acetate/hexanes, to provide 46 (16.31 g, 83%) as a colorless oil. 1H NMR (CDCl3) δ 7.90 (m, 2H), 7.64-7.57 (m, 1H), 7.50-7.45 (m, 2H), 5.33 (s, 2H), 5.31-5.27 (m, 1H), 2.80-2.70 (m, 2H), 2.33-2.26 (t, J=4.5 Hz, 2H), 1.65-1.58 (m, 2H), 1.31-1.21 (m, 40 H), 0.85 (t, J=10.0 Hz. 6H). Example 40 (R)-3-(TETRADECANOYLOXY)TETRADECANOIC ACID (47) Zinc dust (24.42 g, 373.3 mmol) was added to a solution of 46 (16.28 g, 28.42 mmol) in acetic acid (150 mL). The mixture was then heated to reflux (115° C.) for 3 h. The mixture was then concentrated in vacuo, and the residual pyridine removed by dissolving the residue in toluene (100 mL) and concentrating in vacuo. The resulting residue was by silica gel chromatography, eluting with a gradient of 0% through 30% ethyl acetate/hexanes to provide (R)-benzyl 3-(tetradecanoyloxy)tetradecanoic acid (47, 11.14 g, 86% yield) as a colorless oil. 1H NMR (CDCl3) δ 5.29-5.18 (m, 1H), 2.62-2.55 (m, 2H), 2.34-2.25 (m, 2H), 1.65-1.58 (m, 3H), 1.28-1.20 (m, 40 H), 0.85 (m, 6H). Example 41 TERT-BUTYLDIMETHYLSILYL-2-AZIDO-4-O-BENZYL-2-DEOXY-O-D-GLUCOPYRANOSIDE (47) Compound 4 (prepared according to Example 3, 1.32 g, 3.36 mmol) was dissolved in a solution of BH2 (1 M) in THF (18.1 mL, 18.1 mmol). After the mixture was stirred at 0° C. for 5 min, dibutylboron triflate (1 M in DCM, 3.62 mL, 3.62 mmol) was added dropwise, and the reaction mixture was stirred at 0° C. for another 1 h. Subsequently, triethylamine (0.5 mL) and methanol (-0.5 mL) were added until the evolution of H2 gas had ceased. The solvents were evaporated in vacuo, and the residue was co-evaporated with methanol (3×50 mL). The residue was purified by silica gel column chromatography (hexanes/ethyl acetate, 8:1 (v/v)) to give 14 (0.67 g, 49%) as a colorless oil. Rf=0.40 (hexanes/ethyl acetate, 3:1 (v/v)). 1H NMR (500 MHz, CDCl3) δ 7.32-7.31 (m, 5H), 4.81 (d, J=11.4 Hz, 1H), 4.70 (d, J=11.4 Hz, 1H), 4.55 (d, J=7.5 Hz, 1H), 3.84 (m, 1H), 3.70 (dd, 1H, J=12.0, 1.5 Hz, 1H), 3.49-3.43 (m, 2H), 3.33 (br s, 1H), 3.22-3.17 (m, 1H), 0.92 (s, 9H), 0.14 (s, 6H). Example 42 INDUCTION OF TH1-TYPE IMMUNE RESPONSE IN VIVO This example demonstrates in vivo Th1-type immunostimulant activity for an illustrative GLA compound of the invention having the following structure (IX): Compound IX was used in a vaccine containing a Mycobacterium tuberculosis antigenic polypeptide referred to as ID83. Standard immunological methodologies and reagents were employed (Current Protocols in Immunology, Coligan et al. (Eds.) 2006 John Wiley & Sons, NY). Mice (four C57BL16 animals per group) were immunized three times at three-week intervals with ID83 antigen (8 μg per animal for each immunization) in water, ID83 antigen (8 μg per animal for each immunization) formulated in a stable emulsion vehicle, or ID83 antigen (8 μg per animal for each immunization) formulated in a stable emulsion containing (i) GLA-SE (10 μg per animal for each immunization), or (ii) Compound IX (10 μg per animal for each immunization). One week after each injection, mice were bled to evaluate antigen-specific antibody (IgG1 and IgG2c) responses. Three weeks after the last immunization mice were sacrificed and spleens collected to analyze T cell-dependent IFN-γ cytokine responses to in vitro antigen stimulation by ELISPOT according to published methods (Id.). IFN-γ cytokine responses have been associated with a TH1 protective phenotype against M. tuberculosis infection. FIG. 1 shows ELISPOT data of anti-ID83 IFN-γ cytokine production induced in mice three weeks after the third immunization using ID83 antigen and ID83 component antigens (Rv2608, Rv1813 and Rv3620) formulated with a stable emulsion (SE) of 10 μg Compound IX, compared to ID83 formulated in GLA-SE, SE or water. Means and SEM of IFN-γ secreting cells per million of splenocytes in each group are shown. “GLA-SE”, as used in the Examples herein refers to a stable emulsion of a compound as described in co-owned U.S. Patent Publication No. 20080131466, wherein R1, R3, R5 and R6 are C11 linear alkyl; and R2 and R4 are C13 linear alkyl. All animals responded equivalently to ConA, a potent cell activator and mitogen. ID83+Compound IX vaccination induced robust ID83 antigen-specific cytokine responses, while little or no such responses were observed in the ID83+water or ID83+SE control groups. Similar levels of IFN-γ secreting cells were elicited in splenocytes purified from mice immunized with ID83+Compound IX or ID83+GLA-SE upon restimulation with the ID83 component antigens, Rv2608, Rv1813 and Rv3620. In conclusion, Compound IX in a stable oil formulation with M. tuberculosis vaccine antigen candidate ID83 induced predominantly antigen-specific immune responses of the cellular type (T cell) associated with the protective TH1 phenotype. Example 43 INDUCTION OF TH1- AND TH2-TYPE IMMUNE RESPONSES IN VIVO This example demonstrates in vivo Th1- and Th2-type immunostimulant activity of Compound IX in a vaccine containing a Mycobacterium tuberculosis antigen referred to as ID83. Standard immunological methodologies and reagents were employed (Current Protocols in Immunology, Coligan et al. (Eds.) 2006 John Wiley & Sons, NY). Mice (four C57BL/6 animals per group) were immunized three times at three-week intervals with the ID83 antigen (8 μg per animal for each immunization) used alone or formulated in a stable emulsion containing Compound IX (10 μg per animal for each immunization). Sera were collected by bleeding animals one week after each immunization, and serum levels of IgG1 and IgG2c antibodies specific for ID83 were examined by ELISA according to published methods (Id.) Predominance of either IgG1 or IgG2c antibody isotype is associated with TH2 or TH1 responses, respectively. It has been demonstrated that a TH1 response is necessary for protection against Mycobacterium tuberculosis infection. As shown in FIG. 2, vaccination with ID83 in water induced predominantly antigen-specific IgG1 antibody. In contrast, ID83+SE, ID83+Compound IX-SE or ID83 GLA-SE vaccination induced higher IgG2c antibody titers, and converted the phenotype to a mixed IgG1:IgG2c antigen-specific antibody response. Example 44 INDUCTION OF TLR4-DEPENDENT IMMUNOSTIMULATION IN HUMAN CELLS This example demonstrates the immunostimulatory activity of Compound IX in human cells. Compound IX was tested in vitro using HEK 293 cells (InvivoGen) with expression vectors encoding 1) TLR4, MD-2, and CD14, or 2) TLR2 and TLR6 to define compound activity and dependence on TLR4, and to exclude activation of TLR2. These HEK 293 cell lines were further stably transfected with the NF-kB reporter vector pNifty-2 such that alkaline phosphatase is secreted into the growth media upon activation of the TLR signaling pathway. Transfected cell lines were plated at 5×104 cells per well in a 96-well plates and stimulated for 16-24 hours cultured in medium containing serial dilutions of Compound IX and other adjuvants. Secreted alkaline phosphatase activity was measured in the culture media using QUANTIBlue® assay (InvivoGen). The data was measured as enhancement of NF-kB above the PBS negative control. Using this assay, Compound IX showed greater than two-fold enhancement of NF-kB at concentrations as low as 0.1 μg/ml (FIG. 3). The results of these experiments demonstrated clear TLR4 agonist activity for Compound IX that did not appear to be associated with induction of TLR2. Compound IX was designed based on structural considerations of the reported atomic structure of MD2 and TLR4. As such, the fact that it binds and elicits a profile that is similar to that of a commercially approved TLR4 agonist (MPL®) is a surprising and unexpected result. More specifically, the profile for Compound IX advantageously plateaus rapidly as concentrations are increased, before one would expect the cytokine levels to rise to a point where negative side effects may exert themselves. Thus, it is expected that Compound IX and other illustrative compounds of the invention can be safely administered over a broad range of concentrations, which is highly desirable in the context of reproducibility of clinical outcomes among patients and for the safety in ranging a dose for adults and children. In this respect, the lower cytokine activity for Compound IX is a surprising and desirable result that will further facilitate its safe use in clinical formulations. Example 45 INDUCTION OF IMMUNOSTIMULATORY CYTOKINES IN HUMAN BLOOD CELLS In this example, human whole blood cells were stimulated with Compound IX and ELISA assays were performed to detect the induction of immunostimulatory cytokines. Serial dilutions (1:5) of Compound IX and other adjuvants were performed with phosphate buffered saline in a 96 well plate for a total of 7 dilutions. 100 μl of freshly drawn human blood from two different donors were mixed and incubated with 100 μl of adjuvant dilutions. Following a 20 hour incubation, plates were centrifuged and supernatants (˜70 μl) were collected, avoiding red blood cells, and stored at −20° C. prior performing MIP-1-α and TNF-═ ELISAs using standard biochemical procedures. The results of these experiments further confirmed that Compound IX has immunostimulatory activity in primary human blood cells (FIG. 4). Additionally, these primary donor results mimicked the results seen in human cell lines and extend these important findings in relation to the possible dose ranges and safety profiles for this compound. All of the above U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet, are incorporated herein by reference, in their entirety. From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims. | <SOH> BACKGROUND OF THE INVENTION <EOH> | <SOH> BRIEF SUMMARY OF THE INVENTION <EOH>The present invention in its several aspects is directed to compounds, compositions and methods that advantageously employ certain synthetic glucopyranosyl lipid adjuvants (GLA) as immunomodulators or adjuvants. Therefore, according to one aspect of the invention described herein, there are provided GLA compounds having a structure according to the following formula (I): or a pharmaceutically acceptable salt thereof, wherein L 1 , L 2 . L 3 , L 4 , L 5 , L 6 , L 7 , L 8 , L 9 , L 10 , Y 1 ,Y 2 , Y 3 , Y 4 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , are as defined herein. The GLA compounds of the present invention have utility over a broad range of therapeutic applications where induction of specific or non-specific immune responses is desired. For example, in certain aspects of the invention, there are provided vaccine compositions comprising one or more GLA compounds as set forth herein in combination with an antigen. Such vaccine compositions may be advantageously used in methods for stimulating antigen-specific immune responses in subjects in need thereof. In other aspects of the invention, there are provided pharmaceutical compositions comprising one or more GLA compounds as set forth herein, wherein the compositions are substantially devoid of antigen. Such pharmaceutical compositions may be advantageously used in methods for stimulating non-specific immune responses in subjects in need thereof, for example in the treatment of infection, seasonal rhinitis and the like. These and other aspects of the present invention will become evident upon reference to the following detailed description and attached drawings. In addition, various references are set forth herein which describe in more detail certain aspects of this invention, and are therefore incorporated by reference in their entireties. | A61K3939 | 20171010 | 20180201 | 92440.0 | A61K3939 | 0 | MCINTOSH III, TRAVISS C | SYNTHETIC GLUCOPYRANOSYL LIPID ADJUVANTS | UNDISCOUNTED | 1 | CONT-ACCEPTED | A61K | 2,017 |
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15,731,543 | PENDING | System for managing web-based swipe module tool and software for scrolling and paging through content data and applications | A cloud-based computer system and architecture for managing and migrating through web-based content data and content applications from multiple content data sources or service providers in real time is disclosed. The cloud-based computing system and architecture of the present invention includes a log-in or master server that acts as a single point access and supports a single user interface. The single user interface is preferably an icon-based master web-page with a slide tool that allows a user to scroll or page through the content data and/or content applications from the multiple content data sources or service providers in real time from a logged in remote computer device. | 1. A cloud-based computer system comprising: a) master server accessible over the internet/Intranet from remote computer devices; and b) a master application that runs on the master server and includes software coded for organizing content data and content applications from multiple content sources or service providers viewable from the remote computer devices through the cloud-based master server, wherein master content application programs the remote computer devices to operate a slide tool capable of scrolling or paging through the content data or the content applications in real time from a master web-page. 2. The cloud-based computer system of claim 1, wherein the content sources or service providers include one or more personal content account. 3. The cloud-based computer system of claim 2, wherein the personal content account is an e-mail account. 4. The cloud-based computer system of claim 1, wherein the master application includes tools for enabling security features that limits access to one or more of the content sources or service providers based a user log-in. 5. The cloud-based computer system of claim 1, wherein the master server collects and stores history analytics based content data and content applications viewed by a user. 6. The cloud-based computer system of claim 5, wherein the history analytics are used to select content data and content applications viewable from master web-page. 7. A computer system with a user interface that includes a slide tool for scrolling or paging through content data or content applications from multiple content data sources or service providers in real time from a remote computer. 8. The computer system of claim 7, further comprising a cloud-based master server in communication with the multiple content data sources or service providers. 9. The computer system of claim 8, wherein the cloud-based master server runs a master application that codes the remote computer with software for enabling the slide tool. 10. The computer system of claim 8, wherein the cloud-based master server collects and stores history analytics based on usage of the remote computer. 11. The computer system of claim 10, wherein the cloud-based master server uses the history analytics to select content data or the content applications based on a log-in user. 12. The computer system of claim 7, wherein the user interface is an icon-based master web-page. 13. The computer system of claim 7, wherein one of the content sources or service providers includes is an e-mail web-site. 14. A method of managing content data and/or content application from the multiple content sources or service providers through a user interface, the method comprising: a) setting up an account on a cloud-based log-in or master server which streams the content data and/or content applications from the multiple content sources or service providers; and b) constructing the user interface via a tool box on cloud-based log-in or master server that is accessible from a remote computer, wherein the user interface is capable of migrating through the content data and/or content applications from the multiple content sources or service providers through the user interface in real time. 15. The method of claim 14, wherein setting up the account includes one or more of enabling security features and selecting personal settings. 16. The method of claim 14, wherein one of the multiple content sources or service providers is and e-mail content source or service provider. 17. The method of claim 14, wherein the user interface is an icon-base web-page. 18. The method of claim 17, further comprising logging the cloud-based log-in or master server from a remote computer, wherein the cloud-based log-in or master server initiates a down load of software on to the remote computer that enables a slide tool. 19. The method of claim 18, further comprising selectively viewing the content data and/or content applications from the multiple content sources or service providers by scrolling or paging through the content data and/or content applications using the slide tool. 20. The method of claim 19, further comprising storing user history analytics based content data and/or content applications viewed. | RELATED APPLICATIONS This patent application claims priority under 35 U.S.C. 119 (e) of the U.S. Provisional Patent Application Ser. No. 61/404,860 filed Oct. 12, 2010, and titled “COMPUTER NETWORK SYSTEM FOR MANAGING WEB-BASED CONTENT DATA” and the U.S. Provisional Patent Application Ser. No. 61/463,539 filed Feb. 22, 2011, and titled “SYSTEM FOR MANAGING WEB-BASED SWIPE MODULE TOOL AND SOFTWARE FOR SCROLLING AND PAGING THROUGH CONTENT DATA AND APPLICATIONS”. The U.S. Provisional Patent Application Ser. No. 61/404,860 filed Oct. 12, 2010, and titled “COMPUTER NETWORK SYSTEM FOR MANAGING WEB-BASED CONTENT DATA” and the U.S. Provisional Patent Application Ser. No. 61/463,539 filed Feb. 22, 2011, and titled “SYSTEM FOR MANAGING WEB-BASED SWIPE MODULE TOOL AND SOFTWARE FOR SCROLLING AND PAGING THROUGH CONTENT DATA AND APPLICATIONS” are both hereby incorporated by reference. FIELD OF THE INVENTION This invention relates to computer systems for managing web-based content data in a cloud-based computing environment. More particularly, the present invention relates to computer systems for managing and migrating through web-based content data in a cloud-based computing environment from multiple content data sources through a single point of access and/or user interface from a remote computing device. BACKGROUND OF THE INVENTION Cloud-based computing provides computation, software, data access, and storage services that do not require a user to have knowledge of the physical location and configuration of the system and architecture that delivers the content data and/or services. Cloud-based computing can include the delivery of any kind of content data and/or services in real-time, which extend the capabilities to a remote computing device, typically over the internet. Most cloud-based computing systems and architectures include a master sever that networks to other service provider servers and streams content data to the master server that is then accessed through the remote computing device. Cloud-based computing provides for the ability to expand a user's ability to access the multiple sources of content data and/or services through the master server. However, currently available computing systems requires multiple log-in procedures for accessing the multiple sources of content data and/or services and/or do not provide for the ability to manage the content data and/or services from multiple sources through a single user interface. Accordingly, the present invention is directed to a cloud-based computing system and architecture for managing the content data and/or services from multiple sources through a single user interface in real time. SUMMARY OF THE INVENTION There are a few known computer systems and architectures that allow you to migrate through content data using a scrolling-type feature or tool, hereafter a scrolling application. The first example of a scrolling application, includes a scrolling software that typically runs on mobile computing devices, such as smart phones, computer tablets and the like. In this scrolling application, a user swipes through content data contained in different files that are stored directly on the mobile device. The content data is then displayed the on a screen of the mobile computing device. The user can then initiated a call, play, send or execute function by, for example, selecting an icon which instructs the mobile computing device to accesses additional content data over the internet. In this scrolling application, the user is paging or migrating through content data in files that have been downloaded and stored on the mobile computing device itself. A second type of scrolling application includes a “plug-in and play” software that is operated from a computing device, such as a lap-top or desk-top computer. In a plug-in and play environment, a user downloads the plug-in and play software from their computing device and the plug-in and play software then allows the user to execute functions for scrolling or migrating through various web-pages of content data displayed on a web-site interface in a “slide-like” presentation. In this case, the computing device must be compatible with the plug-in and play software and the plug-in and play software is not capable of being integrating directly into web-based application, such as to allow the user to migrates through content data from multiple content data sources through a single user interface in real time. The present invention is directed to a cloud-based computer system and architecture for managing and migrating through web-based content data and content applications from multiple content data sources or service providers in real time. The cloud-based computing system and architecture of the present invention includes a log-in or master server that acts as a single point access and supports a user interface. Preferably, the log-in or master server that is in communication with the multiple content data sources or service providers via servers. The user interface is preferably an icon-based master web-page viewable over the master server from a remote computing device. In further embodiments of the invention, the master web-page includes features for displaying and migrating through personal content data, such as those provided by networking web-sites and e-mail web-sites. In operation, a user logs into the log-in or master server over the internet/intranet from a remote computing device. The server accesses the multiple content data sources or provider through their respective servers in the cloud-based computing environment based on enabled user or account preferences. The log-in or master server is programmed to run and execute a master content application software that is coded for organizing content data and content applications from the multiple content sources or service providers on a single master web-page. The master web-page is a “dynamic” in the sense that the master web-page displays streaming content data and content applications from the multiple content data sources in real time. The master content application software, hereafter master program, is further configured to program the remote computing device with code to operate a slide tool. The slide tool allows a user to scroll or page through the content data and/or content applications in real time from master server on a master web-page from the remote computer device. Unlike prior art cloud-based computing system and architectures, the present invention is capable of being integrated directly into the content applications from the multiple content data sources or service providers and, thus, is capable of providing for the ability to migrate through the content data on the dynamic master web-page in real time. Further, the present invention allows for the capability to add or subtract any number of content data sources or service providers. For example a user's log-in account can be customized to allow for only selected content data sources and application to run at any giving time. Also, the present invention allows for content data to be selected and copied from one or mole of the content data sources or service providers and saved to the user's master web-page, the user's personal setting and, in some cases, to another content data source or service provider. The operations and activities of the user over the master web-page via the remote computing device is capable of being recorded and stored to provide user history analytics. The user history analytics can then be used select promotions, advertisement, news and other information that targets the user based on the operations performed and/or the content data sources or service providers that are used. These promotions, advertisement, news and other information can then be directed to the master web-page or the viewable content data can be modified to represent the user's apparent interests. A master web-page, in accordance with the embodiment of the invention includes lock-out controls for security or for controlling user activity. For example, the master web-pages in further embodiments includes subsets of content data that are accessible depending on which user is logged into the master web-page. For example, a remote tool is configured deliver a subset of content data or applications to a third party enabled remote computing device to allow access only to the content data and/or applications that match an authorized user and/or a target audience. The present invention provides a unique web-based database, user interface, remote slide tool and the user history analytics which is used as a comprehensive solution to manage content data and/or applications from multiple content data sources. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic representation of a cloud-based computer architecture for managing web-based content data, in accordance with the embodiments of the invention. FIG. 2A shows a representation dynamic user web-page or master web-page for simultaneously displaying content data and/or content applications from multiple content sources simultaneously, in accordance with the embodiments of the invention. FIG. 2B shows a representation dynamic user web-page for displaying and scrolling or paging through content data and/or content application from multiple content sources in real-time with a slide tool, in accordance with the embodiments of the invention. FIG. 2C shows a representation dynamic user page that further includes personal account features, in accordance with the embodiments of the invention. FIGS. 3A-B shows block-flow diagrams outlining steps for managing the content data or applications from the multiple content sources or service providers through a single point of access and user interface, in accordance with the method of the present invention. DETAILED DESCRIPTION OF THE INVENTION To facilitate the clarity of the ensuing description, words and phrases listed below have been ascribed the following meanings: 1) Content data is any data or information that is stored remotely on servers that are generally accessible over the internet/intranet via a service provider servers. 2) Content applications are software applications that accesses display and organized content data, generally from a web sites. 3) A log-in server or master server is a dedicated server for supporting a master program and user interface to access and view content data and applications from multiple content data sources or providers through a single user interface. 4) A tool is a feature that is usually represent by an icon, that are viewable and/or selectable from a from a computing device; selecting the tool will generally initiate one or more software sequences to access, display and/or organize content data on a web-page. 5) A tool-box is a set of sub-features, generally accessible through an administrator account or password, that allow a web-page layout and/or operation to be customized by linking tools with content applications. 6) A dynamic user web-page or master web-page is a web-page viewable remotely from a remote computing device via log-in server or master server and which displays a slide tool that scrolls or pages through content data and/or content application from multiple content data sources and/or service providers in real time. 7) Cloud-based computer system or architecture includes multiple content data sources or service provider servers that are linked to a log-in server or master server via the internet/intranet. 8) A remote computing device is an electronic device that is capable of accessing the log-in server or master server over the internet/intranet and displaying or viewing a master web-page and content data therefrom. FIG. 1 shows a schematic representation of a cloud-based computer system and architecture 100 for managing web-based content data, in accordance with the embodiments of the invention. The cloud-based computer system and architecture 100 includes a log-in server or master server 105 that acts a single point of access for a plurality of content data sources or service provider servers 101, 103, and 105. The plurality of content data sources or service provider servers 101, 103, and 105 are in communication or linked to the log-in server or master server 105 via a communication network, such as the internet or intranet represented by the arrows 133, 135 and 137. The log-in server or master server 105 supports a program to run and execute a master content application software, hereafter master application, represented by the box 107. The master application 107 is coded for organizing content data and content applications from the multiple content sources or service provider servers 101, 103 and 105 on a master web-page 201, 201′ and 201″ (FIGS. 2A-C), such as described below. In operation, a user (not shown) logs into the log-in server or master server 105 over the internet/intranet, represented by the arrow 131 from a suitable remote computing devices 111. A suitable remote computing device 111 is for example, a desk top computer 125 with a monitor or display 127 and a keyboard 123 and mouse 121 for entering information and executing functions. Alternatively, a suitable computing device is a laptop computer, a tablet computer, a smart phone or any other electronic device that is capable of accessing the log-in server or master server 105 over the internet/intranet and displaying or viewing content data therefrom on a master web-page a 201, 201′ and 201″ (FIGS. 2A-C), such as described below. FIG. 2A shows a representation of a dynamic user web-page or master web-page 201 for simultaneously displaying content data and/or content application 101′, 103 and 105′ from the corresponding set of content sources or service provider servers 101, 103 and 105 through a log-in server or master server 105, in accordance with the embodiments of the invention. Referring now to FIG. 2B, in accordance with a preferred embodiment of the invention a master web-page 201′ includes a slide tool or scrolling tool indicated by the arrow 226 operable from the computing device 111 (FIG. 1). In operation, when the remote computing device 111 logs into the log-in server or master server 105 over the internet/intranet, for at least the first time, the log-in server or master server 105 and the master application 107 initiates a down load of software on to the remote computing device 111 that enables the slide tool or scrolling tool 226 to operable from an user input interface, such as a keyboard 123, a mouse 121, a touch screen (not shown) or any other suitable user interface on the remote computing device 111. With the remote computing device 111 enabled with the slide tool or scrolling tool 126, a user can view his or her master web-page 201′ and scroll through or page through content data and content applications 101′, 103 and 105′ from corresponding set of content data sources or service provider servers 101, 103, and 105 in real time. In accordance with further embodiments of the invention, a master web-page 201″ includes a slide tool or scrolling tool indicated by the arrow 227 operable from any suitable user interface on the remote computing device 111, such as describe above. In addition, the master application 107 is equipped with a tool box that allows an authorized user or administrator to build the master web-page 201″ and include features for displaying and migrating through personal content data, such as those provided by a networking web-site or an e-mail web-site 233. In operation, portions of content data and/or portions of content applications 101′, 103 and 105′ from the corresponding set of content sources or service provider servers 101, 103 and 105 are capable of being selected and copied using the computing device 111 and saved to the user's master web-page 201″ or one or more of the user's personal accounts. Also, the master web-page 201″ preferably includes a search tool or function 231 that allows a user to search for selected content data and content applications 101′, 103 and 105′ from each content data sources or service provider servers 101, 103, and 105 individually or simultaneously. As described above, the The cloud-based computer system and architecture 100, the master application 107 and corresponding tool box provides for the capability to include lock-out controls, collect history analytics and have subsets of accessible content data or content applications. FIG. 3A shows a block-flow diagram 300 outlining steps, in accordance with the method of the present invention. In the step 301, a personal account is set up from on a cloud-based log-in or master server 105 (FIG. 1) from the remote computing device 111 (FIG. 1). The account set up procedure includes establishing a user name and password. In the step 303, an administrator or authorized user selects which security features are enabled, which content sources or service providers are accessible, which personal setting or features are accessible and constructs the general layout of a master web-page via the tool box on the master application 107 (FIG. 1). After the personal account is set up and the master web-page is constructed in the steps 301 and 303, in the step 305 the master application 107 initiates a down load of software on to the remote computing device 111 that enables a the slide tool or scrolling tool 226 and 227 (FIGS. 2B-C) to operable from a user input interface on the remote computing device 111. FIG. 3B shows a block-flow diagram 350 outlining steps, in accordance with a further method of the present invention. After a user personal account has been established, the content sources or service providers have been selected and the scrolling tool software has been down loaded, such as described above with reference to FIG. 3A, in the step 351 the user is capable of logging into the log-in or master server 105 (FIG. 1) using the remote computing device 111 (FIG. 1). After the user logs into the log-in or master server in the step 351, in the step 353 the user accesses his or her personal or shared master-web-page and views or manages content data and/or content applications 101′, 103′ and 105′ (FIGS. 2A-C) from the corresponding content sources or service providers 101, 103 and 105 (FIG. 1). While logged into the log-in server or master server 105, in the step 355 the user is capable of using the slide tool or scrolling tool 226 and 227 (FIGS. 2B-C) to page through and manage content data and/or content applications 101′, 103′ and 105′ from the multiple content sources or service providers 101, 103 and 105 and search for selected content data and content applications 101′, 103 and 105′ from each content data sources or service provider servers 101, 103, and 105 using the search tool 231. As described previously, the user is also capable of accessing personal content providers enabled during the set-up procedure described above. Also, the user is capable of selecting content data and/or content applications and coping the selected content data and/or content applications to the user's master web-page or the user's personal content data account. The present invention provides an expandable solution for managing content data in a cloud-based computing environment which is capable of being integrated into applications from multiple sources. The invention provides users with a highly interactive experience and the ability migrate through the content data and applications on the dynamic master web-page in real time. The dynamic master web-page preferably includes an icon-based interface and is capable delivering a broad spectrum of content data such as marketing data, sales data, operations data, manufacturing data, financial data, documents, spreadsheets, presentations, audio data, video data, database listings, custom or off the shelf business applications, games, or any other content data or application data. | <SOH> BACKGROUND OF THE INVENTION <EOH>Cloud-based computing provides computation, software, data access, and storage services that do not require a user to have knowledge of the physical location and configuration of the system and architecture that delivers the content data and/or services. Cloud-based computing can include the delivery of any kind of content data and/or services in real-time, which extend the capabilities to a remote computing device, typically over the internet. Most cloud-based computing systems and architectures include a master sever that networks to other service provider servers and streams content data to the master server that is then accessed through the remote computing device. Cloud-based computing provides for the ability to expand a user's ability to access the multiple sources of content data and/or services through the master server. However, currently available computing systems requires multiple log-in procedures for accessing the multiple sources of content data and/or services and/or do not provide for the ability to manage the content data and/or services from multiple sources through a single user interface. Accordingly, the present invention is directed to a cloud-based computing system and architecture for managing the content data and/or services from multiple sources through a single user interface in real time. | <SOH> SUMMARY OF THE INVENTION <EOH>There are a few known computer systems and architectures that allow you to migrate through content data using a scrolling-type feature or tool, hereafter a scrolling application. The first example of a scrolling application, includes a scrolling software that typically runs on mobile computing devices, such as smart phones, computer tablets and the like. In this scrolling application, a user swipes through content data contained in different files that are stored directly on the mobile device. The content data is then displayed the on a screen of the mobile computing device. The user can then initiated a call, play, send or execute function by, for example, selecting an icon which instructs the mobile computing device to accesses additional content data over the internet. In this scrolling application, the user is paging or migrating through content data in files that have been downloaded and stored on the mobile computing device itself. A second type of scrolling application includes a “plug-in and play” software that is operated from a computing device, such as a lap-top or desk-top computer. In a plug-in and play environment, a user downloads the plug-in and play software from their computing device and the plug-in and play software then allows the user to execute functions for scrolling or migrating through various web-pages of content data displayed on a web-site interface in a “slide-like” presentation. In this case, the computing device must be compatible with the plug-in and play software and the plug-in and play software is not capable of being integrating directly into web-based application, such as to allow the user to migrates through content data from multiple content data sources through a single user interface in real time. The present invention is directed to a cloud-based computer system and architecture for managing and migrating through web-based content data and content applications from multiple content data sources or service providers in real time. The cloud-based computing system and architecture of the present invention includes a log-in or master server that acts as a single point access and supports a user interface. Preferably, the log-in or master server that is in communication with the multiple content data sources or service providers via servers. The user interface is preferably an icon-based master web-page viewable over the master server from a remote computing device. In further embodiments of the invention, the master web-page includes features for displaying and migrating through personal content data, such as those provided by networking web-sites and e-mail web-sites. In operation, a user logs into the log-in or master server over the internet/intranet from a remote computing device. The server accesses the multiple content data sources or provider through their respective servers in the cloud-based computing environment based on enabled user or account preferences. The log-in or master server is programmed to run and execute a master content application software that is coded for organizing content data and content applications from the multiple content sources or service providers on a single master web-page. The master web-page is a “dynamic” in the sense that the master web-page displays streaming content data and content applications from the multiple content data sources in real time. The master content application software, hereafter master program, is further configured to program the remote computing device with code to operate a slide tool. The slide tool allows a user to scroll or page through the content data and/or content applications in real time from master server on a master web-page from the remote computer device. Unlike prior art cloud-based computing system and architectures, the present invention is capable of being integrated directly into the content applications from the multiple content data sources or service providers and, thus, is capable of providing for the ability to migrate through the content data on the dynamic master web-page in real time. Further, the present invention allows for the capability to add or subtract any number of content data sources or service providers. For example a user's log-in account can be customized to allow for only selected content data sources and application to run at any giving time. Also, the present invention allows for content data to be selected and copied from one or mole of the content data sources or service providers and saved to the user's master web-page, the user's personal setting and, in some cases, to another content data source or service provider. The operations and activities of the user over the master web-page via the remote computing device is capable of being recorded and stored to provide user history analytics. The user history analytics can then be used select promotions, advertisement, news and other information that targets the user based on the operations performed and/or the content data sources or service providers that are used. These promotions, advertisement, news and other information can then be directed to the master web-page or the viewable content data can be modified to represent the user's apparent interests. A master web-page, in accordance with the embodiment of the invention includes lock-out controls for security or for controlling user activity. For example, the master web-pages in further embodiments includes subsets of content data that are accessible depending on which user is logged into the master web-page. For example, a remote tool is configured deliver a subset of content data or applications to a third party enabled remote computing device to allow access only to the content data and/or applications that match an authorized user and/or a target audience. The present invention provides a unique web-based database, user interface, remote slide tool and the user history analytics which is used as a comprehensive solution to manage content data and/or applications from multiple content data sources. | H04L672838 | 20170626 | 20171026 | 70840.0 | H04L2908 | 3 | TRAN, JIMMY H | System for managing web-based swipe module tool and software for scrolling and paging through content data and applications | SMALL | 1 | CONT-ACCEPTED | H04L | 2,017 |
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15,735,725 | PENDING | AQUEOUS DENTAL GLASS IONOMER COMPOSITION | The present invention relates to an aqueous dental glass ionomer composition comprising (A) a reactive particulate glass, (B) a water-soluble, polymerizable polymer comprising acidic groups, which is reactive with the particulate glass in a cement reaction, whereby the polymerizable polymer has a polymer backbone and hydrolysis-stable pendant groups having one or more polymerizable carbon-carbon double bonds, wherein the polymerizable polymer is obtainable by a process comprising a) a step of copolymerizing a mixture comprising (i) a first copolymerizable monomer comprising at least one optionally protected carboxylic acid group and a first polymerizable organic moiety, and (ii) a second copolymerizable monomer comprising one or more optionally protected primary and/or secondary amino groups and a second polymerizable organic moiety, for obtaining an amino group containing copolymer; b) a step of coupling to the amino group containing copolymer a compound having a polymerizable moiety and a functional group reactive with an amino group of repeating units derived from the second copolymerizable monomer in the amino group containing copolymer obtained in the first step, wherein the optionally protected amino group is deprotected, so that polymerizable pendant groups are linked to the backbone by hydrolysis-stable linking groups, and, optionally, a step of deprotecting the protected carboxylic acid group after step a) or step b), for obtaining a polymerizable polymer; (C) a hydrolysis-stable, water-soluble monomer having one polymerizable double bond and optionally a carboxylic acid group, said monomer having a molecular weight of at most 200 Da; (D) a polymerization initiator system; and (E) a polymerizable hydrolysis-stable crosslinker having at least two polymerizable carbon-carbon double bonds. | 1. An aqueous dental glass ionomer composition comprising (A) a reactive particulate glass, (B) a water-soluble, polymerizable polymer comprising acidic groups, which is reactive with the particulate glass in a cement reaction, whereby the polymerizable polymer has a polymer backbone and hydrolysis-stable pendant groups having one or more polymerizable carbon-carbon double bonds, wherein the polymerizable polymer is obtainable by a process comprising a) a step of copolymerizing a mixture comprising (i) a first copolymerizable monomer comprising at least one optionally protected carboxylic acid group and a first polymerizable organic moiety, and (ii) a second copolymerizable monomer comprising one or more optionally protected primary and/or secondary amino groups and a second polymerizable organic moiety, for obtaining an amino group containing copolymer; b) a step of coupling to the amino group containing copolymer a compound having a polymerizable moiety and a functional group reactive with an amino group of repeating units derived from the second copolymerizable monomer in the amino group containing copolymer obtained in the first step, wherein the optionally protected amino group is deprotected, so that polymerizable pendant groups are linked to the backbone by hydrolysis-stable linking groups, and, optionally, a step of deprotecting the protected carboxylic acid group after step a) or step b), for obtaining a polymerizable polymer; (C) a hydrolysis-stable, water-soluble monomer having one polymerizable double bond and optionally a carboxylic acid group, said monomer having a molecular weight of at most 200 Da; (D) a polymerization initiator system; and (E) a polymerizable hydrolysis-stable crosslinker having at least two polymerizable carbon-carbon double bonds. 2. The aqueous dental glass ionomer composition according to claim 1, wherein the hydrolysis-stable, water-soluble monomer according to (C) is contained in an amount of from 5 to 30 percent by weight based on the total weight of the aqueous dental glass ionomer composition. 3. The aqueous dental glass ionomer composition according to claim 1, which further comprises (F) a non-reactive filler; 4. The aqueous dental glass ionomer composition according to claim 1, wherein the molar ratio of first copolymerizable monomer to second copolymerizable monomer in the mixture copolymerized in step a) (mol first copolymerizable monomer/mol second copolymerizable monomer) is in the range of from 100:1 to 100:50. 5. The aqueous dental glass ionomer composition according to claim 1, wherein the coupling reaction in step b) is an addition reaction or a condensation reaction forming a bond selected from a group consisting of an amide bond, a urea bond and a thiourea bond. 6. The aqueous dental glass ionomer composition according claim 1, wherein the first copolymerizable monomer is represented by the general formula (1): wherein R1 is a hydrogen atom, a —COOZ group or a straight chain or branched C1-6 alkyl group which may be substituted by a —COOZ group; R2 is a hydrogen atom, a —COOZ group or a straight-chain or branched C1-6 alkyl group which may be substituted by a —COOZ group; A is a single bond or a straight-chain or branched C1-6 alkylene group which group may contain 1 to 3 heteroatoms in between two carbon atoms of the alkylene carbon chain, which heteroatoms are selected from an oxygen atom, nitrogen atom, and sulfur atom, and/or which alkylene group may contain in between two carbon atoms of the alkylene carbon chain 1 to 3 groups selected from an amide bond or a urethane bond; Z which may be the same or different, independently represents a hydrogen atom, a metal ion, a protecting group for a carboxylic acid group, or the Z forms with a further —COOZ group present in the molecule an intramolecular anhydride group. 7. The aqueous dental glass ionomer composition according claim 1, wherein the second copolymerizable monomer is represented by the general formula (2): wherein R3 is a hydrogen atom or a straight chain or branched C1-6 alkyl group which may be substituted by a —COOZ′ group; X is a protected amino group or a hydrocarbon group having 1 to 20 carbon atoms, which is substituted with an amino group which may carry a protecting group, wherein the hydrocarbon group may contain 1 to 6 heteroatoms, which heteroatoms are selected from an oxygen atom, nitrogen atom, and sulfur atom, and/or which hydrocarbon group may contain a group selected from an amide bond or a urethane bond and which hydrocarbon group may further be substituted with up to 6 groups selected from —COOZ′, amino groups, hydroxyl groups and thiol groups; Y is a hydrogen atom, a —COOZ′ group, or a hydrocarbon group having 1 to 20 carbon atoms, wherein the hydrocarbon group may contain 1 to 6 heteroatoms, which heteroatoms are selected from an oxygen atom, nitrogen atom, and sulfur atom, and/or which hydrocarbon group may contain a group selected from an amide bond or a urethane bond and which hydrocarbon group may further be substituted with up to 6 groups selected from —COOZ′, amino groups, hydroxyl groups and thiol groups; Z′ which may be the same or different, independently represents a hydrogen atom, a metal ion, a protecting group for a carboxylic acid group, or the Z′ forms with a further —COOZ′ group present in the molecule an intramolecular anhydride group. 8. The aqueous dental glass ionomer composition according to claim 1, wherein the compound having a polymerizable moiety and a functional group reactive with an amino group of repeating units derived from the second copolymerizable monomer is a compound represented by the general formula (3): wherein R4 is a hydrogen atom or a straight chain or branched C1-6 alkyl group which may be substituted by a —COOZ″ group; R5 is a hydrogen atom or a straight-chain or branched C1-6 alkyl group which may be substituted by a —COOZ″ group; Z″ which may be same or different, independently represents a hydrogen atom, a metal ion, a protecting group for a carboxylic acid group, or the Z″ forms with a further —COOZ″ group present in the molecule an intramolecular anhydride group; and LG is a leaving group, or wherein LG may replace Z″ and form with R4 or R5 an intramolecular carboxylic acid anhydride group, or wherein two molecules of formula (3) form an intermolecular carboxylic acid anhydride group by condensation of LG and/or —COOZ″, wherein LG is an oxygen atom. 9. The aqueous dental glass ionomer composition according claim 1, wherein the water-soluble monomer having one polymerizable double bond has a carboxylic acid group, wherein said one polymerizable double bond is a carbon-carbon double bond; said monomer is a compound represented by the general formula (4): wherein R6 is a hydrogen atom or a straight chain or branched C1-3 alkyl group, R7 is a hydrogen atom or a C1-6 group optionally substituted with a —COOH group, wherein R6 and R7 are selected with the proviso that the molecular weight of compound of formula (4) is at most 200 Da. 10. The aqueous dental glass ionomer composition according to claim 9, wherein the water-soluble monomer having one polymerizable carbon-carbon double bond and a carboxylic acid group is a compound represented by the general formula (4′): wherein R6′ is a hydrogen atom or a straight chain or branched C1-3 alkyl group, and R7′ is a hydrogen atom or a straight-chain or branched C1-3 alkyl group which may be substituted by a —COOH group, wherein R6′ and R7′ are selected with the proviso that the molecular weight of the compound of formula (4) is at most 200 Da. 11. The aqueous dental glass ionomer composition according to claim 1, wherein the polymerizable polymer comprising acidic groups has a molecular weight Mw in the range of from 103 Da to 106 Da. 12. The aqueous dental glass ionomer composition according to claim 1, wherein the particulate glass comprises 1) 20 to 45% by weight of silica, 2) 20 to 40% by weight of alumina, 3) 20 to 40% by weight of strontium oxide, 4) 1 to 10% by weight of P2O5, and 5) 3 to 25% by weight of fluoride. 13. The aqueous dental glass ionomer composition according to claim 1, comprising 20 to 80 percent by weight of the reactive particulate glass, based on the total weight of the composition and/or comprising 10 to 80 percent by weight of the polymer comprising acidic groups, based on the total weight of the composition, and/or comprising up to 75 percent by weight of dispersed nanoparticles based on the total weight of the composition. 14. The aqueous dental glass ionomer composition according to claim 1, which, when cured, has at least one of the following mechanical characteristics: an adhesive bond strength to dentin of at least 5 MPa as measured according to ISO 29022:2013; and/or a flexural strength of at least 80 MPa as measured according to ISO 4049. 15. A dental composition comprising a mixture comprising a water-soluble, polymerizable polymer comprising acidic groups, which is reactive with the particulate glass in a cement reaction, whereby the polymerizable polymer has a polymer backbone and hydrolysis-stable pendant groups having one or more polymerizable carbon-carbon double bonds, wherein the polymerizable polymer is obtainable by a process comprising a) a step of copolymerizing a mixture comprising (i) a first copolymerizable monomer comprising at least one optionally protected carboxylic acid group and a first polymerizable organic moiety, and (ii) a second copolymerizable monomer comprising one or more optionally protected primary and/or secondary amino groups and a second polymerizable organic moiety, for obtaining an amino group containing copolymer; b) a step of coupling to the amino group containing copolymer a compound having a polymerizable moiety and a functional group reactive with an amino group of repeating units derived from the second copolymerizable monomer in the amino group containing copolymer obtained in the first step, wherein the optionally protected amino group is deprotected, so that polymerizable pendant groups are linked to the backbone by hydrolysis-stable linking groups, and, optionally, a step of deprotecting the protected carboxylic acid group after step a) or step b), for obtaining a polymerizable polymer; and said mixture further comprises a hydrolysis-stable, water-soluble monomer having one polymerizable double bond and optionally a carboxylic acid group, said monomer having a molecular weight of at most 200 Da. | FIELD OF THE INVENTION The present invention relates to an aqueous dental glass ionomer composition. Furthermore, the present invention relates to the use of a mixture comprising a specific water-soluble, polymerizable polymer comprising acidic groups and a specific water-soluble, polymerizable monomer for the preparation of a dental composition. The aqueous dental glass ionomer composition according to the present invention provides an acid-resistant cured glass ionomer composition having excellent mechanical properties and long-term mechanical and chemical resistance. BACKGROUND OF THE INVENTION Dental restorative materials are known for restoring the function, morphology and integrity of dental structures damaged by physical damage or caries-related decay of enamel and/or dentin. Dental restorative materials are required to have high biocompatibility, good mechanical properties and mechanical and chemical resistance over a long period of time given the harsh conditions for a restorative material in the buccal cavity. Dental restorative materials include glass ionomer cements having good biocompatibility and good adhesion to the dental hard tissues. Moreover, glass ionomer cements may provide cariostatic properties through the release of fluoride ions. Glass ionomer cements are cured by an acid-base reaction between a reactive glass powder and a polyalkenoic acid. However, conventional glass ionomer cements have a relatively low flexural strength and are brittle due to salt-like structures between the polyacid and the basic glass. The mechanical properties of glass ionomer cements may be improved by the selection of the polyacidic polymer. For example, a polymer having polymerizable moieties as pendant groups can be crosslinked in order to increase the mechanical resistance of the resulting glass ionomer cement. Japanese Patent Publication No. 2005-65902A discloses a dental adhesive composition comprising, as a polymerizable monomer containing a particular carboxylic acid, a carboxylic acid compound having a (meth)acryloyl group and a carboxyl group which are bound to an aromatic group. However, such a polymerizable monomer having an ester group quickly degrades in an acidic medium. Chen et al. and Nesterova et al. (Chen et al., J. Appl. Polym. Sci., 109 (2008) 2802-2807; Nesterova et al., Russian Journal of Applied Chemistry, 82 (2009) 618-621) disclose copolymers of N-vinylformamide with acrylic acid and/or methacrylic acid, respectively. However, none of these documents mentions the introduction of a further polymerizable moiety into the copolymer. WO2003/011232 discloses water-based medical and dental glass ionomer cements that can be post-polymerized after the cement reaction. The dental glass ionomer cements consist of two separate polymers, wherein one of the polymers has a pendant post-polymerizable moiety linked to the polymer through an ester bond. However, this ester bond between the polymer and the polymerizable moieties is again prone to hydrolytic cleavage in acidic media. Moreover, crosslinking of the glass ionomer may lead to the shrinkage of the dental composition in particular when the molecular weight of the crosslinking polymer is low. WO2012/084206 A1 discloses a polymer for a dental glass ionomer cement. However, WO2012/084206 does not disclose a specific combination of components for a composition of a dental glass ionomer cement. SUMMARY OF THE INVENTION It is an object of the present invention to provide an aqueous dental glass ionomer composition providing improved mechanical properties including high flexural strength and a clinically relevant adhesion to tooth structure after curing, as well as hydrolysis-stability in an aqueous medium before and after curing, in particular in an acidic medium. The present invention provides an aqueous dental glass ionomer composition comprising: (A) a reactive particulate glass, (B) a water-soluble, polymerizable polymer comprising acidic groups, which is reactive with the particulate glass in a cement reaction, whereby the polymerizable polymer has a polymer backbone and hydrolysis-stable pendant groups having one or more polymerizable carbon-carbon double bonds, wherein the polymerizable polymer is obtainable by a process comprising a) a step of copolymerizing a mixture comprising (i) a first copolymerizable monomer comprising at least one optionally protected carboxylic acid group and a first polymerizable organic moiety, and (ii) a second copolymerizable monomer comprising one or more optionally protected primary and/or secondary amino groups and a second polymerizable organic moiety, for obtaining an amino group containing copolymer; b) a step of coupling to the amino group containing copolymer a compound having a polymerizable moiety and a functional group reactive with an amino group of repeating units derived from the second copolymerizable monomer in the amino group containing copolymer obtained in the first step, wherein the optionally protected amino group is deprotected, so that polymerizable pendant groups are linked to the backbone by hydrolysis-stable linking groups, and, optionally, a step of deprotecting the protected carboxylic acid group after step a) or step b), for obtaining a polymerizable polymer; (C) a hydrolysis-stable, water-soluble monomer having one polymerizable double bond and optionally a carboxylic acid group, said monomer having a molecular weight of at most 200 Da; and (D) a polymerization initiator system; and (E) a polymerizable hydrolysis-stable crosslinker having at least two polymerizable carbon-carbon double bonds. Specifically, in the coupling step b), the polymerizable pendant groups are linked to the backbone by hydrolysis-stable linking groups. The linkage preferably does not involve an ester group. Furthermore, the present invention provides a use of a mixture comprising: a water-soluble, polymerizable polymer comprising acidic groups, which is reactive with the particulate glass in a cement reaction, whereby the polymerizable polymer has a polymer backbone and hydrolysis-stable pendant groups having one or more polymerizable carbon-carbon double bonds, wherein the polymerizable polymer is obtainable by a process comprising a) a step of copolymerizing a mixture comprising (i) a first copolymerizable monomer comprising at least one optionally protected carboxylic acid group and a first polymerizable organic moiety, and (ii) a second copolymerizable monomer comprising one or more optionally protected primary and/or secondary amino groups and a second polymerizable organic moiety, for obtaining an amino group containing copolymer; b) a step of coupling to the amino group containing copolymer a compound having a polymerizable moiety and a functional group reactive with an amino group of repeating units derived from the second copolymerizable monomer in the amino group containing copolymer obtained in the first step, wherein the optionally protected amino group is deprotected, so that polymerizable pendant groups are linked to the backbone by hydrolysis-stable linking groups, and, optionally, a step of deprotecting the protected carboxylic acid group after step a) or step b), for obtaining a polymerizable polymer; said mixture further comprising a hydrolysis-stable, water-soluble monomer having one polymerizable double bond and optionally a carboxylic acid group, said monomer having a molecular weight of at most 200 Da, for the preparation of a dental composition. Preferably, the hydrolysis-stable, water-soluble monomer having one polymerizable double bond and optionally a carboxylic acid group includes acrylic acid. A cured aqueous dental glass ionomer composition according to the present invention is hydrolysis-stable and has excellent mechanical properties based on the specific combination of the polymerizable polymer according to (B) and the monomer having one polymerizable double bond according to (C). After polymerization of the polymerizable polymer according to (B) and the monomer having one polymerizable double bond according to (C), the polymer may contain an increased number of acidic groups when the monomer having one polymerizable double bond according to (C) contains a carboxylic acid group. Accordingly, crosslinking by a cement reaction and adhesion to dental hard tissue may be improved. The inventors have recognized that resin reinforced dental glass ionomer cements are subject to deterioration during storage or after curing in the mouth of the patient. The inventors have further recognized that the deterioration includes hydrolytic degradation of the resin component conventionally containing hydrolyzable moieties. The inventors have then recognized that by using a specific process for the preparation of a polymer, an improved water-soluble, hydrolysis-stable, polymerizable polymer according to (B) may be prepared at a high molecular weight which overcomes the drawbacks of conventional resin reinforced glass ionomer cements known from the prior art. In said polymerizable polymer according to (B), the introduction of amino group containing repeating units into the backbone of the polymer allows to provide high molecular weight copolymers having polymerizable pendant groups linked to the backbone by hydrolysis stable linking groups. Thereby, the disadvantages of conventional polymerizable resin components may be avoided. The polymerizable pendant groups of the polymerizable polymer according to (B) may react with the monomer having one polymerizable double bond according to (C) whereby a graft polymer is formed. The grafted side-chains may contain additional carboxylic acid groups which can take part in a cement reaction, thereby further increasing the strength of the cured composition. A crosslinked polymer may be obtained by a polymerizable hydrolysis-stable crosslinker having at least two polymerizable carbon-carbon double bonds which crosslinks polymerizable polymers according to (B) and grafted side-chains obtained based on monomer having one polymerizable double bond according to (C). DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS In the following, sometimes components (A), (B), (C) and (D) of the present aqueous dental glass ionomer composition are referred to by the terms “(reactive particulate) glass according to (A)”, “(water-soluble) polymerizable polymer according to (B)”, “(hydrolysis-stable, water-soluble) monomer (having one polymerizable double bond) according to (C)” and “polymerization initiator system according to (D)” respectively. The term “(co)polymerizable” as used with the terms “first copolymerizable monomer” having a “first polymerizable organic moiety”, “second copolymerizable monomer” having a “second polymerizable organic moiety”, “compound having a polymerizable moiety” having “polymerizable pendant groups” and the crosslinker as well as the hydrolysis-stable, water-soluble monomer having “polymerizable (carbon-carbon) double bond” respectively mean compounds capable of combining by covalent bonding in an addition polymerization to form a polymer. Said “polymerizable polymer” may be combined with a crosslinker as well as with the hydrolysis-stable, water-soluble monomer having “polymerizable (carbon-carbon) double bond” respectively to form graft polymers and/or crosslinked polymers when curing the aqueous dental glass ionomer composition. The terms “first polymerizable organic moiety”, “second polymerizable organic moiety”, “polymerizable pendant groups” and “polymerizable (carbon-carbon) double bond” as used herein in connection components (B), (C) and (E) of the present aqueous dental glass ionomer composition mean any double bond capable of addition polymerization, in particular free radical polymerization, preferably a carbon-carbon double bond. The term “curing” means the polymerization of functional oligomers and monomers, or even polymers, into a polymer network. Curing is the polymerization of unsaturated monomers or oligomers in the presence of crosslinking agents. The term “curable” refers to a aqueous dental glass ionomer composition that will polymerize into a crosslinked polymer network when irradiated for example with actinic radiation such as ultraviolet (UV), visible, or infrared radiation, or when reacted with polymerisation initiators. The present aqueous dental glass ionomer composition provides a cured dental glass-ionomer composition/cement. Said cured dental glass ionomer composition/cement is formed based on a reaction between (A) the reactive particulate glass, the above described components polymerizable polymer according to (B), monomer according to (C) and polymerization initiator system according to (D) in a cement reaction and a polyaddition reaction. (A) The Reactive Particulate Glass The term “reactive particulate glass” refers to a solid mixture of mainly metal oxides transformed by a thermal melt process into a glass and crushed by various processes, which glass is capable of reacting with a polymer containing acidic groups in a cement reaction. The glass is in particulate form Moreover, the reactive particulate glass may be surface modified, e.g. by silanation or acid treatment. Any conventional reactive dental glass may be used for the purpose of the present invention. Specific examples of particulate reactive glasses are selected from calcium alumino silicate glass, calcium alumino fluorosilicate glass, calcium aluminumfluoroborosilicate glass, strontium aluminosilicate glass, strontium aluminofluorosilicate glass, strontium aluminofluoroborosilicate glass. Suitable particulate reactive glasses may be in the form of metal oxides such as zinc oxide and/or magnesium oxide, and/or in the form of ion-leachable glasses, e.g., as described in U.S. Pat. No. 3,655,605, U.S. Pat. No. 3,814,717, U.S. Pat. No. 4,143,018, U.S. Pat. No. 4,209,434, U.S. Pat. No. 4,360,605 and U.S. Pat. No. 4,376,835. Preferably, the reactive particulate glass according to (A) is a reactive particulate glass comprising: 1) 20 to 45% by weight of silica, 2) 20 to 40% by weight of alumina, 3) 20 to 40% by weight of strontium oxide, 4) 1 to 10% by weight of P2O5, and 5) 3 to 25% by weight of fluoride. The present aqueous dental glass ionomer composition preferably comprises 20 to 90 percent by weight of the reactive particulate glass, more preferably 30 to 80 percent by weight, based on the total weight of the composition. The reactive particulate glass usually has an average particle size of from 0.005 to 100 μm, preferably of from 0.01 to 40 μm as measured, for example, by electron microscopy or by using a conventional laser diffraction particle sizing method as embodied by a MALVERN Mastersizer S or MALVERN Mastersizer 2000 apparatus. The reactive particulate glass may have a unimodal or multimodal (e.g., bimodal) particle size distribution, wherein a multimodal reactive particulate glass represents a mixture of two or more particulate fractions having different average particle sizes. The reactive particulate glass may be a an agglomerated reactive particulate glass which is obtainable by agglomerating a reactive particulate glass in the presence of a modified polyacid and/or polymerizable (meth)acrylate resins. The particle size of the agglomerated reactive particulate glass may be adjusted by suitable size-reduction processes such as milling. The reactive particulate glass may be surface modified by a component according to (B), (C) and/or (D). In particular, the reactive particulate glass may be surface modified by one or more components of the polymerization initiator system (D) in order to avoid contact of the one or more components of the polymerization initiator system (D) with an acid under aqueous conditions. The reactive particulate glass may alternatively or additionally be surface modified by a surface modifying agent. Preferably, the surface modifying agent is a silane. A silane provides a suitable hydrophobicity to the reactive particulate glass, which allows for an advantageous, homogeneous admixture with the organic components according to (B), (C) and (D) of the aqueous dental glass ionomer composition. (B) The Water-Soluble, Polymerizable Polymer Comprising Acidic Groups The water-soluble, polymerizable polymer comprising acidic groups is an organic polymeric compound comprising ionizable pendant groups, such as carboxylic acid groups. The carboxylic acid groups of the polymer are capable of reacting with a reactive particulate glass in a cement reaction to form a glass ionomer cement. The water-soluble, polymerizable polymer comprising acidic groups according to (B) is obtainable by a process comprising the copolymerization step a), the coupling step b), and an optional deprotection step. The term “polymerizable polymer” used in connection with item (B) means a polymer containing one or more polymerizable moieties capable of polymerizing and crosslinking of the polymer for improving the mechanical properties and the long-term mechanical and chemical resistance of the cured aqueous dental glass ionomer composition. The term “water-soluble” used in connection with the term “polymerizable polymer” means that at least 0.1 g, preferably 0.5 g of the polymerizable polymer dissolves in 100 g of water at 20° C. The water-soluble polymerizable polymer according to (B) is hydrolysis-stable, which means that the polymer is stable to hydrolysis in an acidic medium, such as in a dental composition. Specifically, the polymer does not contain groups such as ester groups which hydrolyze in aqueous media at pH 3 at room temperature within one month. The water-soluble, polymerizable polymer comprising acidic groups according to (B) is obtainable by a process comprising step a) of copolymerizing a mixture comprising (i) a first copolymerizable monomer comprising at least one optionally protected carboxylic acid group and a first polymerizable organic moiety and (ii) a second copolymerizable monomer comprising one or more optionally protected primary and/or secondary amino groups and a second polymerizable organic moiety for obtaining an amino group containing copolymer. The mixture may also contain further monomers. The first copolymerizable monomer to be used in step a) comprises at least one, preferably one to three, more preferably one or two, most preferably one optionally protected carboxylic acid group(s). The protecting group of an optionally protected carboxylic acid group is not particularly limited as long as it is a carboxyl-protecting group known to those of ordinary skill in the art of organic chemistry (cf. P.G.M. Wuts and T.W. Greene, Greene's Protective Groups in Organic Synthesis, 4th Edition, John Wiley and Sons Inc., 2007). Preferably, the carboxyl-protecting group is selected from a trialkylsilyl group, an alkyl group and an arylalkyl group. More preferably, the carboxyl-protecting group is selected from an alkyl group or an arylalkyl group. Most preferably, the carboxyl-protecting group is selected from a tert-butyl group and a benzyl group. In one preferred embodiment, the carboxyl-protecting group is a tert-butyl group. The term “polymerizable organic moiety” as used herein means an organic moiety of a molecule which can be used to covalently link this molecule in a chemical reaction (polymerization) to other molecules reactive with this moiety to form a macromolecule of repeating or alternating structural units. Preferably, this polymerizable organic moiety is a carbon-carbon double bond as in the case of an ethylenically unsaturated moiety. In a preferred embodiment of the aqueous dental glass ionomer composition of the present invention, the first copolymerizable monomer is represented by the general formula (1): In formula (1), R1 is a hydrogen atom, a —COOZ group or a straight chain or branched C1-6 alkyl group which may be substituted by a —COOZ group. Preferably, R1 is a hydrogen atom, a —COOZ group or a methyl group. More preferably, R1 is a hydrogen atom or a methyl group. In formula (1), R2 is a hydrogen atom, a —COOZ group or a straight-chain or branched C1-6 alkyl group which may be substituted by a —COOZ group. Preferably, R2 is a hydrogen atom or a —COOZ group. More preferably, R2 is a hydrogen atom. In formula (1), the dotted line indicates that R2 may be in either the cis or trans orientation. In formula (1), A is a single bond or a straight-chain or branched C1-6 alkylene group which group may contain 1 to 3 heteroatoms in between two carbon atoms of the alkylene carbon chain, which heteroatoms are selected from an oxygen atom, nitrogen atom, and sulfur atom, and/or which alkylene group may contain in between two carbon atoms of the alkylene carbon chain 1 to 3 groups selected from an amide bond or a urethane bond. Preferably, A is a single bond or a straight-chain or branched C1-6 alkylene group which group may contain a heteroatom in between two carbon atoms of the alkylene carbon chain, which heteroatom is selected from an oxygen atom or a nitrogen atom, and/or which alkylene group may contain in between two carbon atoms of the alkylene carbon chain a group selected from an amide bond or a urethane bond. More preferably, A is a single bond or a straight-chain C1-6 alkylene group. Most preferably, A is a single bond. In formula (1), Z which may be the same or different independently represents a hydrogen atom, a metal ion, a protecting group for a carboxylic acid group, or the Z forms with a further —COOZ group present in the molecule an intramolecular anhydride group. The metal ion may be a monovalent metal ion such as an alkali metal ion. In one embodiment, Z is a protecting group for a carboxylic acid group. In another embodiment, Z is a hydrogen atom. When Z forms with a further —COOZ group present in the molecule an intramolecular anhydride group (—C(O)OC(O)—), the further —COOZ group may be preferably present on R1 such as in case of itaconic acid anhydride. In a preferred embodiment, Z is a hydrogen atom and the polymerization reaction is conducted in an alkaline environment. In an alternative preferred embodiment, Z is a hydrogen atom and the amino groups of the first copolymerizable monomer and of the second copolymerizable monomer carry a protecting group. Preferably, the first copolymerizable monomer is a protected (meth)acrylic acid monomer. More preferably, a first polymerizable monomer is selected from tert-butyl acrylate and benzyl acrylate. Most preferably, a first polymerizable monomer is tert-butyl acrylate. In a preferred embodiment of the aqueous dental glass ionomer composition of the present invention, the second copolymerizable monomer is represented by the general formula (2): In formula (2), R3 is a hydrogen atom or a straight chain or branched C1-6 alkyl group which may be substituted by a —COOZ′ group. Preferably, R3 is a hydrogen atom. In formula (2), the dotted line indicates that R3 may be in either the cis or trans orientation. In formula (2), X is a protected amino group or a hydrocarbon group having 1 to 20 carbon atoms, which is substituted with an amino group which may carry a protecting group, wherein the hydrocarbon group may contain 1 to 6 heteroatoms, which heteroatoms are selected from an oxygen atom, nitrogen atom, and sulfur atom, and/or which hydrocarbon group may contain a group selected from an amide bond or a urethane bond and which hydrocarbon group may further be substituted with up to 6 groups selected from —COOZ′, amino groups, hydroxyl groups and thiol groups. Preferably, X is a hydrocarbon group having 1 to 20 carbon atoms, which is substituted with an amino group which may carry a protecting group, wherein the hydrocarbon group may contain a heteroatom, which heteroatom is selected from an oxygen atom and a nitrogen atom, and/or which hydrocarbon group may contain a group selected from an amide bond or a urethane bond and which hydrocarbon group may further be substituted with a —COOZ′ group. More preferably, X is a hydrocarbon group having 1 to 20 carbon atoms, even more preferably 1 to 6 carbon atoms, which is substituted with an amino group which may carry a protecting group, wherein the hydrocarbon group may contain an oxygen atom and/or which hydrocarbon group may contain an amide bond and which hydrocarbon group may further be substituted with a —COOZ′ group. In as specific embodiment wherein X is a protected amino group, the compound of formula (2) is allyl amine, wherein the amino group carries a protecting group. The protecting group of a protected amino group or an optionally protected amino group is not particularly limited and may be any conventional protecting group for an amino group as, for example, described in P.G.M. Wuts and T.W. Greene, Greene's Protective Groups in Organic Synthesis, 4th Edition, John Wiley and Sons Inc., 2007. Preferably, the amino-protecting group is selected from an acyl group, an arylalkyl group, an alkoxy carbonyl group, and an aryloxycarbonyl group. More preferably, the amino-protecting group is an acyl group. Most preferably, the amino-protecting group is a formyl group. In formula (2), Y is a hydrogen atom or a hydrocarbon group having 1 to 20 carbon atoms, wherein the hydrocarbon group may contain 1 to 6 heteroatoms, which heteroatoms are selected from an oxygen atom, nitrogen atom, and sulfur atom, and/or which hydrocarbon group may contain a group selected from an amide bond or a urethane bond and which hydrocarbon group may further be substituted with up to 6 groups selected from —COOZ′, amino groups, hydroxyl groups and thiol groups. Preferably, Y is a hydrogen atom or a hydrocarbon group having 1 to 20 carbon atoms, wherein the hydrocarbon group may contain a heteroatom, which heteroatom is selected from an oxygen atom and a nitrogen atom, and/or which hydrocarbon group may contain a group selected from an amide bond or a urethane bond and which hydrocarbon group may further be substituted with a —COOZ′ group. More preferably, Y is a hydrogen atom or a hydrocarbon group having 1 to 20 carbon atoms, even more preferably 1 to 6 carbon atoms, wherein the hydrocarbon group may contain an oxygen atom and/or which hydrocarbon group may contain an amide bond and which hydrocarbon group may further be substituted with a —COOZ′ group. In one preferred embodiment, Y is a hydrogen atom. In formula (2), Z′ which may be the same or different, independently represents a hydrogen atom, a metal ion, a protecting group for a carboxylic acid group, or the Z′ forms with a further —COOZ′ group present in the molecule an intramolecular anhydride group. In one embodiment, Z′ is a protecting group for a carboxylic acid group. In another embodiment, Z′ is a hydrogen atom. The metal ion may be a monovalent metal ion such as an alkali metal ion. In another embodiment, Z′ is a hydrogen atom. When Z forms with a further —COOZ′ group present in the molecule an intramolecular anhydride group (—C(O)OC(O)—). In a preferred embodiment, Z′ is a hydrogen atom and the polymerization reaction is conducted in an alkaline environment. In an alternative preferred embodiment, Z′ is a hydrogen atom and the amino groups of the second copolymerizable monomer carry a protecting group. In one embodiment, the second copolymerizable monomer comprises a second copolymerizable organic moiety selected from the group of (meth)acrylamide moieties which may be substituted and substituted (meth)acrylic acid which may be protected. In another embodiment, the second copolymerizable monomer is selected from allyl amine, aminopropyl vinyl ether, aminoethyl vinyl ether, N-vinyl formamide and 2-aminomethyl acrylic acid. In a preferred embodiment, the second copolymerizable monomer is aminopropyl vinyl ether. The amino group may be in the form of an ammonium salt such as a ammonium chloride. Preferred structures wherein the amino group may also carry a protecting group are depicted in Scheme 1 below. The molar ratio of first copolymerizable monomer to second copolymerizable monomer in the mixture copolymerized in step a) (mol first copolymerizable monomer/mol second copolymerizable monomer) is preferably in the range of from 100:1 to 100:50, more preferably in the range from 100:2 to 100:20, still more preferably in a range from 100:3 to 100:10. The further copolymerizable monomers optionally to be used in step a) comprise at least one, preferably one to three, more preferably one or two, most preferably one optionally protected acidic group(s) which are not carboxylic acid groups. Specific examples of acidic groups are sulfonic acid groups (—SO3M), phosphonic acid groups (—PO3M2) or phosphoric acid ester groups (—OPO3M2), or salts thereof, wherein M may independently be a hydrogen atom or a monovalent ion such as an alkali metal or an ammonium ion. Specific examples of the optional further monomers are selected from 2-acrylamido-2-methylpropane sulfonic acid, vinyl phosphonate, and vinyl sulfonic acid. In a preferred embodiment, the solutions containing the first copolymerizable monomer and the second copolymerizable monomer are separately saturated with nitrogen before combining them for copolymerization to minimize possible side-products of a competitive Aza-Michael addition. Step a) of the aqueous dental glass ionomer composition proceeds as a chain-growth polymerization. In one embodiment, step a) comprises radical copolymerization. The type of copolymer formed by step a) of the present invention may be a statistical copolymer, a random copolymer, an alternating copolymer, a block copolymer or a combination thereof. A copolymer obtained by step a) of the present invention is an amino group containing copolymer, such as, for example, a copolymer obtainable by copolymerization of acrylate and aminopropyl vinyl ether. The reaction conditions of the polymerization reaction according to step a) of the present invention are not particularly limited. Accordingly, it is possible to carry out the reaction in the presence or absence of a solvent. A suitable solvent may be selected from the group of water, dimethyl formamide (DMF), tetrahydrofurane (THF), and dioxane. The reaction temperature is not particularly limited. Preferably, the reaction is carried out at a temperature of between −10° C. to the boiling point of the solvent. Preferably, the reaction temperature is in the range of from 0° C. to 80° C. The reaction time is not particularly limited. Preferably the reaction time is in the range of from 10 minutes to 48 hours, more preferably 1 hour to 36 hours. The reaction is preferably carried out in the presence of a polymerization initiator. In a preferred embodiment of the aqueous dental glass ionomer composition, the polymerization initiator is selected from azobisisobutyronitrile (AlBN), 2,2-azobis(2-amidinopropane)dihydrochloride, 2,2′-azobis(2-methylbutyronitrile), 2,2′-azobis(N,N′-dimethyleneisobutyramidine) dihydrochloride, and 4,4′-azobis(4-cyano pentanoic acid). The amount of the polymerization initiator is not particularly limited. Suitably, the amount is in the range of from 0.001 to 5 mol % based on the total amount of the monomers. The reaction product obtained in step a) may be isolated by precipitation and filtration, or lyophilization. The product may be purified according to conventional methods. Step b) of the aqueous dental glass ionomer composition is a step of coupling a compound having a polymerizable moiety and a functional group reactive with an amino group of repeating units derived from the second copolymerizable monomer in the amino group containing copolymer obtained in the first step wherein the optionally protected amino group is deprotected. Preferably, the coupling reaction in step b) is an addition reaction or a condensation reaction forming a bond selected from an amide bond, a urea bond or a thiourea bond. The term “functional group reactive with an amino group” as used herein means any group which can form a covalent bond with an amino group of the amino group containing copolymer. Preferably, a functional group reactive with an amino group is a carboxylic acid group or a derivative thereof such as an ester group or an anhydride thereof, an isocyanate group or an isothiocyanate group. More preferably, a functional group reactive with an amino group is a carboxylic acid group or a derivative thereof. If the amino group of repeating units derived from the second copolymerizable monomer in the amino group containing copolymer obtained in the first step is protected, the amino group can be deprotected prior to step b) or concomitant with step b). The conditions for deprotection of an optionally protected amino group are selected according to the protecting group used. Preferably, the protected amino group is deprotected by hydrogenolysis or treatment with acid or base. If the deprotection of a protected amino group is carried out concomitantly with step b), it will be understood by a person skilled in the art that the deprotection conditions and the conditions for step b) have to be selected so that both reactions can proceed efficiently. In a preferred embodiment of the aqueous dental glass ionomer composition, the compound having a polymerizable moiety and a functional group reactive with an amino group of repeating units derived from the second copolymerizable monomer is a compound represented by the general formula (3): In formula (3), R4 is a hydrogen atom or a straight chain or branched C1-6 alkyl group which may be substituted by a —COOZ″ group, and R5 is a hydrogen atom or a straight-chain or branched C1-6 alkyl group which may be substituted by a —COOZ″ group. Preferably, R4 is a hydrogen atom, and R5 is a hydrogen atom or a methyl group. More preferably, R4 is a hydrogen atom, and R5 is a methyl group. In formula (3), the dotted line indicates that R4 may be in either the cis or trans orientation. In formula (3), Z″ which may be same or different, independently represents a hydrogen atom, a metal ion, a protecting group for a carboxylic acid group, or the Z″ forms with a further —COOZ″ group present in the molecule an intramolecular anhydride group. In one embodiment, Z″ is a protecting group for a carboxylic acid group. In another embodiment, Z″ is a hydrogen atom. In a preferred embodiment, Z″ is a hydrogen atom and the polymerization reaction is conducted in an alkaline environment. In an alternative preferred embodiment, Z″s a hydrogen atom and the amino groups of the second copolymerizable monomer carry a protecting group. In one embodiment, in formula (3), LG is a leaving group. Preferably, LG is a chlorine atom or a bromine atom, or forms with the adjacent carbonyl group a carboxylic acid anhydride moiety. More preferably, LG is a group which is suitable for reacting the compound of formula (3) in a Schotten-Baumann type reaction. In another embodiment, LG may replace Z″ and form with R4 or R5 an intramolecular carboxylic acid anhydride group. In yet another embodiment two molecules of formula (3) form an intermolecular carboxylic acid anhydride group by sharing a common LG, wherein LG is an oxygen atom. It is particularly preferred that the compound of formula (3) is acrylic acid, (meth)acrylic acid, crotonic acid, isocrotonic acid, tiglic acid, angelic acid, or an anhydride of the aforementioned acids formed of two identical or different acids; more preferably an anhydride of the aforementioned acids formed of two identical acids. Most preferably, the compound of formula (3) is (meth)acrylic anhydride. The coupling according to step b) of the present invention serves to introduce one or more polymerizable moieties into the amino group containing copolymer, which moieties can be post-polymerized to provide additional covalent and advantageously also ionic crosslinking, imparting additional strength to the dental material. In one embodiment of the aqueous dental glass ionomer composition, the carboxylic acid groups of the copolymer obtained in step b) are not protected and the copolymer can be used as a polymer according to the present invention without further treatment. In an alternative embodiment, the carboxylic acid groups of the copolymer obtained in step b) are protected and the carboxylic acid groups have to be deprotected before the copolymer exhibits the features of a polymer according to the present invention. The reaction conditions of the reaction according to step b) of the present invention are not particularly limited. Accordingly, it is possible to carry out the reaction in the presence or absence of a solvent. A suitable solvent may be selected from the group of dimethyl formamide (DMF), tetrahydrofurane (THF), and dioxane. The reaction temperature is not particularly limited. Preferably, the reaction is carried out at a temperature of between −10° C. to the boiling point of the solvent. Preferably, the reaction temperature is in the range of from 0° C. to 80° C. The reaction time is not particularly limited. Preferably the reaction time is in the range of from 10 minutes to 48 hours, more preferably 1 hour to 36 hours. The reaction product obtained in step b) may be isolated by precipitation and filtration. The product may be purified. The aqueous dental glass ionomer composition optionally includes a step of deprotecting the protected carboxylic acid group after step a) or step b), for obtaining a polymerizable polymer. In a preferred embodiment, the aqueous dental glass ionomer composition includes a step of deprotecting the protected carboxylic acid group for obtaining a polymerizable polymer. In a further preferred embodiment, the aqueous dental glass ionomer composition includes a step of deprotecting the protected carboxylic acid group after step b). The conditions for deprotection of an optionally protected carboxyl group are selected according to the protecting group used. Preferably, the protected carboxyl group is deprotected by hydrogenolysis or treatment with acid or base. A first embodiment of the polymerizable polymer according to (B) is illustrated by the following Scheme 2, wherein a amino group protected vinyl amine is reacted with acrylic acid for obtaining a polymer backbone having a protected amino group. The copolymer is preferably a random copolymer. In a further step, the protected amino groups of the polymer backbone are liberated and coupled to a polymerizable group containing moiety, whereby a polymer of the invention is obtained having acidic groups reactive in a cement reaction wherein ionic bonds are formed, and having polymerizable groups reactive in a crosslinking reaction wherein covalent bonds are formed. In above Scheme 2, any acrylamide group may be replaced by a methacrylamide group. A second embodiment of the polymerizable polymer according to (B) is illustrated by the following Scheme 3, wherein protected acrylic acid is reacted with an amino group containing polymerizable vinyl ether derivative for obtaining an amino group containing polymer backbone. In a further step, the amino groups of the polymer backbone are couples to a polymerizable group containing moiety. Finally, the carboxylic acid groups are liberated whereby a polymer of the invention is obtained having acidic groups reactive in a cement reaction wherein ionic bonds are formed, and having polymerizable groups reactive in a crosslinking reaction wherein covalent bonds are formed. In the above Scheme 3, any acrylamide group may be replaced by a methacrylamide group The polymerizable polymer obtained in step b) may be exemplified by the following preferred structures depicted in Scheme 4 below. In the structures illustrated in Scheme 4, the numbers refer to the number of additional carbon atoms introduced by each of the side chain as compared to a corresponding polyacrylic acid. Since a polymer having (a+b) repeating units contains b times the number of additional carbon atoms in addition to the number of carbon atoms in a polyacrylic acid having (a+b) carboxylic acid groups, but b times less carboxylic acid groups, the water solubility may be reduced. On the other hand, the introduction of an additional ionic group such as a —COOH group is capable of compensating the decrease in water solubility, and is also indicated above. Preferably, the number of side chains b, the number of additional carbon atoms and the number of additional carboxylic acid groups are adjusted so as to provide a useful water solubility of the polymer of the present invention. Accordingly, in a preferred embodiment, the side chains of the polymer which are linked to the polymer backbone via an amide bond, urea bond or thio urea bond contain one or more additional acidic groups, preferably carboxylic acid groups. The polymerizable polymer according to (B) preferably has an average molecular weight Mw in the range of from 103, in particular 104 to 106 Da. More preferably, the average molecular weight Mw is in the range of from 105 to 7·105 Da, or 3·104 to 2.5·105 Da. The polymerizable polymers according to (B) must be sufficient in number or percent by weight of carboxylic acid groups to bring about the setting or curing reaction in the presence of the reactive particulate glass according to (A) or any further unmodified or modified particulate reactive(s) and/or non-reactive filler(s). Preferably, the polymerizable polymer according to (B) is present in the aqueous dental glass ionomer composition in an amount of from 5 to 80 percent by weight, more preferably 10 to 50 percent by weight, still more preferably 15 to 40 percent by weight, based on the total weight of the composition. (C) The Monomer Having One Polymerizable Double Bond According to (C), the monomer having one polymerizable double bond is hydrolysis-stable and water-soluble. The term “hydrolysis-stable” used in this connection means that the monomer according to (C) is stable to hydrolysis in an acidic medium, such as in a dental composition. In particular, the monomer according to (C) does not contain groups, e.g. as ester groups, which hydrolyze in aqueous media at pH 3 at room temperature within one month. Further, the term “water-soluble” used in this connection means that at least 0.1 g, preferably 0.5 g of the monomer according to (C) dissolves in 100 g of water at 20° C. The hydrolysis-stable, water-soluble monomer according to (C) is an essential component of the aqueous dental glass ionomer composition according to the invention, since the monomer according to (C) polymerizes together with the polymerizable polymer according to (B) in the presence of the polymerization initiator system according to (D). Thereby, the monomer according to (C) may polymerize with itself and/or with the polymerizable pendant groups of the polymerizable compound according to (B). Hence, besides of the formation of a polymer formed of the monomer according to (C), there is a graft polymerization wherein monomer(s) according to (C) react with the polymerizable pendant groups of the polymerizable compound according to (B), whereby a graft polymer is formed. Furthermore, the graft side chains formed of the monomer according to (C) may additionally react with the pendant polymerizable groups of another polymerizable polymer according to (B), whereby a crosslinked polymer may be obtained. In the following Scheme 5, graft polymerisation by means of the monomer according to (C) is exemplary depicted for the polymerizable polymer according to (B) illustrated in Scheme 3 above, wherein acrylic acid is merely exemplary selected as a monomer according to (C). The letter “m” denotes an integer of at least 1. According to the present invention, one or a mixture of two or more monomers according to (C) may be used as component (C). A suitable monomer according to (C) does not contain groups hydrolysing at pH 3 within one month. In particular, a suitable monomer according to (C) does not contain any ester group. Furthermore, a suitable monomer according to (C) contains one polymerizable double bond. Suitable polymerizable double bonds are carbon-carbon double bonds such as alkenyl groups and vinyl groups. In a preferred embodiment of the aqueous dental glass ionomer composition, the hydrolysis-stable, water-soluble monomer having one polymerizable double bond has a carboxylic acid group and is a compound represented by the general formula (4): In formula (4), R6 is a hydrogen atom or a straight chain or branched C1-3 alkyl group, and R7 is a hydrogen atom or a straight-chain or branched C1-6 alkyl group which may be substituted by a —COOH group. In formula (4), the dotted line indicates that R6 may be in either the cis or trans orientation. Preferably, R6 is a hydrogen atom, and R7 is a hydrogen atom or a C1-3 alkyl group optionally substituted with a —COOH group. More preferably, R6 is a hydrogen atom, and R7 is a hydrogen atom or a methyl group substituted with a —COOH group, that is compound of formula (4) is acrylic acid or itaconic acid. Most preferably, the compound of formula (4) is acrylic acid. In formula (4), residues R6 and R7 are selected with the proviso that the molecular weight of the monomer having one polymerizable double bond according to (C) is at most 200 Da, preferably at most 150 Da, more preferably at most 100 Da. Furthermore, the hydrolysis-stable, water-soluble monomer having one polymerizable double bond may be 2-hydroxyethyl methacrylate (HEMA), hydroxypropyl methacrylate, 2-hydroxyethyl acrylamide (HEAA), N,N-dimethyl(meth)acrylamide, N,N-diethyl(meth)acrylamide, N,N-di-n-propyl(meth)acrylamide, and N-ethyl-N-methyl(meth)acrylamide. The monomer according to (C) is preferably selected in view of a good processability and applicability of the final aqueous dental glass ionomer composition, in particular in terms of viscosity. Therefore, the viscosity of the monomer according to (C) is preferably in the range of 0.1 to 100 mPa·s, more preferably 0.3 to 50 mPa·s, even more preferably 0.5 to 25 mPa·s, yet even more preferably 0.8 to 10 mPa·s, in particular 0.9 to 3 mPa·s. Monomers according to (C) comprising a carboxylic acid group are particularly advantageous, since such monomers introduce additional carboxylic acid groups into the acidic polymer in the aqueous dental glass ionomer composition, which can undergo a cement reaction resulting in a further improved setting or curing reaction in the presence of the reactive particulate glass according to (A). Preferably, the monomer according to (C) is contained in the aqueous dental glass ionomer composition in an amount of from 0.1 to 20, more preferably 1 to 15 even more preferably 2 to 10 percent by weight based on the total weight of the aqueous dental glass ionomer composition. When the monomer according to (C) is absent, a long-term mechanical resistance may be low. On the other hand, when the amount monomer according to (C) exceeds 20 percent of weight, shrinkage of the dental glass ionomer cement obtained from the present aqueous dental glass ionomer composition may occur. (D) The Polymerization Initiator System As a polymerization initiator system according to (D), any compound or system, capable of initiating the copolymerization reaction according to the present invention may be suitably used. The polymerization initiator according to (D) may be a photoinitiator or a redox initiator or a mixture thereof. A suitable redox initiator comprises an reducing and oxidizing agents, which typically react with or otherwise cooperate with one another to produce free-radicals capable of initiating polymerization of polymerizable double bonds in components (B) and (C) in a dark reaction, independent from the presence of light. The reducing and oxidizing agents are selected so that the polymerization initiator system is sufficiently storage-stable and free of undesirable colorization to permit storage and use under typical dental conditions. Moreover, the reducing and oxidizing agents are selected so that the polymerization initiator system is sufficiently miscible with the resin system to permit dissolution of the polymerization initiator system in the composition. Useful reducing agents include ascorbic acid, ascorbic acid derivatives, and metal complexed ascorbic acid compounds as described in U.S. Pat. No. 5,501,727; amines, namely tertiary amines, such as 4-tert-butyl dimethylaniline; aromatic sulfinic salts, such as p-toluenesulfinic salts and benzenesulfinic salts; thioureas, such as 1-ethyl-2-thiourea, tetraethyl thiourea, tetramethyl thiourea, 1,1-dibutyl thiourea, and 1,3-dibutyl thiourea; and mixtures thereof. Other secondary reducing agents may include cobalt (II) chloride, ferrous chloride, ferrous sulfate, hydrazine, hydroxylamine, salts of a dithionite or sulfite anion, and mixtures thereof. Suitable oxidizing agents include persulfuric acid and salts thereof, such as ammonium, sodium, potassium, cesium, and alkyl ammonium salts. Additional oxidizing agents include peroxides such as benzoyl peroxides, hydroperoxides such as cumyl hydroperoxide, t-butyl hydroperoxide, and amyl hydroperoxide, as well as salts of transition metals such as cobalt (III) chloride and ferric chloride, cerium (IV) sulfate, perboric acid and salts thereof, permanganic acid and salts thereof, perphosphoric acid and salts thereof, and mixtures thereof. One or more different oxidizing agents or one or more different reducing agent may be used in the polymerization initiator system. Small quantities of transition metal compounds may also be added to accelerate the rate of redox cure. The reducing and oxidizing agents are present in amounts sufficient to permit an adequate free-radical reaction rate. The reducing or oxidizing agents may be microencapsulated for enhancing shelf stability of the composition, and if necessary permitting packaging the reducing and oxidizing agents together (U.S. Pat. No. 5,154,762). Appropriate selection of an encapsulant may allow combination of the oxidizing and reducing agents and even of an acid-functional component and optional filler in a storage-stable state. Moreover, appropriate selection of a water-insoluble encapsulant allows combination of the reducing and oxidizing agents with the particulate reactive glass and water in a storage-stable state. Suitable photoinitiators for polymerizing free radically photopolymerizable compositions may include binary and tertiary systems. Tertiary photoinitiators may include an iodonium salt, a photosensitizer, and an electron donor compound as described in U.S. Pat. No. 5,545,676. Suitable iodonium salts include the diaryl iodonium salts, e.g., diphenyliodonium chloride, diphenyliodonium hexafluorophosphate, diphenyl-iodonium tetrafluoroborate, and tolylcumyliodonium tetrakis(pentafluorophenyl)borate. Suitable photosensitizers are monoketones and diketones that absorb some light within a range of about 400 nm to about 520 nm (preferably, about 450 nm to about 500 nm). Particularly suitable compounds include alpha diketones that have some light absorption within a range of about 400 nm to about 520 nm (even more preferably, about 450 to about 500 nm). Examples include camphorquinone, benzil, furil, 3,3,6,6-tetramethylcyclo-hexanedione, phenanthraquinone, 1-phenyl-1,2-propanedione and other 1-aryl-2-alkyl-1,2-ethanediones, and cyclic alpha diketones. Suitable electron donor compounds include substituted amines, e.g., ethyl dimethylaminobenzoate. Suitable photoinitiators may also include phosphine oxides typically having a functional wavelength range of about 380 nm to about 1200 nm. Examples of phosphine oxide free radical initiators with a functional wavelength range of about 380 nm to about 450 nm include acyl and bisacyl phosphine oxides such as those described in U.S. Pat. No. 4,298,738, U.S. Pat. No. 4,324,744 and U.S. Pat. No. 4,385,109 and EP 0 173 567. Specific examples of the acylphosphine oxides include 2,4,6-trimethylbenzoyldiphenylphosphine oxide, bis(2,4,6-trimethylbenzoyl)phenylphosphine oxide, dibenzoylphenylphosphine oxide, bis(2,6-dimethoxybenzoyl)phenylphosphine oxide, tris(2,4-dimethylbenzoyl)phosphine oxide, tris(2-methoxybenzoyl)phosphine oxide, 2,6-dimethoxybenzoyldiphenylphosphine oxide, 2,6-dichlorobenzoyldiphenyl phosphine oxide, 2,3,5,6-tetramethylbenzoyldiphenylphosphine oxide, benzoyl-bis(2,6-dimethylphenyl)phosphonate, and 2,4,6-trimethylbenzoylethoxyphenylphosphine oxide. Commercially available phosphine oxide photoinitiators capable of free-radical initiation when irradiated at wavelength ranges of greater than about 380 nm to about 450 nm include bis(2,4,6-trimethylbenzoyl)phenyl phosphine oxide (IRGACURE 819), bis(2,6-dimethoxybenzoyl)-(2,4,4-trimethylpentyl) phosphine oxide (CGI 403), a 25:75 mixture, by weight, of bis(2,6-dimethoxybenzoyl)-2,4,4-trimethylpentyl phosphine oxide and 2-hydroxy-2-methyl-1-phenylpropan-1-one (IRGACURE 1700), a 1:1 mixture, by weight, of bis(2,4,6-trimethylbenzoyl)phenyl phosphine oxide and 2-hydroxy-2-methyl-1-phenylpropane-1-one (DAROCUR 4265), and ethyl 2,4,6-trimethylbenzylphenyl phosphinate (LUCIRIN LR8893X). Typically, the phosphine oxide initiator is present in the composition in catalytically effective amounts, such as from 0.1 percent by weight to 5.0 percent by weight, based on the total weight of the composition. Tertiary amine reducing agents may be used in combination with an acylphosphine oxide Examples of suitable aromatic tertiary amine include N,N-dimethylaniline, N,N-dimethyl-p-toluidine, N,N-dimethyl-m-toluidine, N,N-diethyl-p-toluidine, N,N-dimethyl-3,5-dimethylaniline, N,N-dimethyl-3,4-dimethylaniline, N,N-dimethyl-4-ethylaniline, N,N-dimethyl-4-isopropylaniline, N,N-dimethyl-4-t-butylaniline, N,N-dimethyl-3,5-di-t-butylaniline, N,N-bis(2-hydroxyethyl)-3,5-dimethylaniline, N,N-bis(2-hydroxyethyl)-p-toluidine, N,N-bis(2-hydroxyethyl)-3,4-dimethylaniline, N,N-bis(2-hydroxyethyl)-4-ethylaniline, N,N-bis(2-hydroxyethyl)-4-isopropylaniline, N,N-bis(2-hydroxyethyl)-4-t-butylaniline, N,N-bis(2-hydroxyethyl)-3,5-di-isopropylaniline, N,N-bis(2-hydroxyethyl)-3,5-di-t-butylaniline, 4-N,N-dimethylaminobenzoic acid ethyl ester, 4-N,N-dimethylaminobenzoic acid methyl ester, 4-N,N-dimethylaminobenzoic acid n-butoxyethyl ester, 4-N,N-dimethylaminobenzoic acid 2-(methacryloyloxy) ethyl ester, 4-N,N-dimethylaminobenzophenone ethyl 4-(N,N-dimethylamino)benzoate and N,N-dimethylaminoethyl methacrylate. Examples of an aliphatic tertiary amine include trimethylamine, triethylamine, N-methyldiethanolamine, N-ethyldiethanolamine, N-n-butyldiethanolamine, N-lauryldiethanolamine, triethanolamine, 2-(dimethylamino) ethyl methacrylate, N-methyldiethanolamine dimethacrylate, N-ethyldiethanolamine dimethacrylate, triethanolamine monomethacrylate, triethanolamine dimethacrylate, and triethanolamine trimethacrylate. The amine reducing agent may be present in the composition in an amount from 0.1 percent by weight to 5.0 percent by weight, based on the total weight of the composition. The amount of active species of the polymerization initiator is not particularly limited. Suitably, the amount of polymerization initiator in the polymerization system according to (D) is in the range of from 0.001 to 5 mol % based on the total amount of the monomers. (E) The Polymerizable Crosslinker Having at Least Two Polymerizable C═C Double Bonds The aqueous dental glass ionomer composition according to the present invention contains a crosslinker, which is: (E) a polymerizable hydrolysis-stable crosslinker having at least two polymerizable carbon-carbon double bonds. The crosslinker according to (E) may be an alkylenediol dimethylacrylate such as 1,3-butanediol dimethacrylate, 1,4-butanediol dimethacrylate, an alkylenediol divinyl ether such as 1,4-butanediol divinyl ether, di(ethylene glycol) dimethacrylate, di(ethylene glycol) divinyl ether, pentaerythritol diacrylate monostearate, ethylene glycol dimethacrylate, trimetylolpropane trimethacrylate, pentaerythritol triacrylate or triallyl ether, pentaerythritol tetraacrylate and trimetylolpropane triacrylate. The crosslinker according to (E) may also be 1,3-Bis(acrylamido)-N,N″-diethylpropane, N,N-Di(cyclopropyl acrylamido) propane. Preferably, the crosslinker is a polymerizable compound of the following formula (5), which is disclosed in EP2705827 and WO2014040729: A″-L(B)n′ (5) wherein A″ is a group of the following formula (6) X10 is CO, CS, CH2, or a group [X100Z10]k, wherein X100 is an oxygen atom, a sulfur atom or NH, Z10 is a straight chain or branched C1-4 alkylene group, and k is an integer of from 1 to 10; R10 is a hydrogen atom, —COOM10, a straight chain or branched C1-16 alkyl group which may be substituted by a C3-6 cycloalkyl group, a C6-14 aryl or C3-14 heteroaryl group, —COOM10, —PO3M10, —O—PO3M102 or —SO3M10, a C3-6 cycloalkyl group which may be substituted by a C1-16 alkyl group, a C6-14 aryl or C3-14 heteroaryl group, —COOM10, —PO3M10, —O—PO3M102 or —SO3M10, a C6-14 aryl or C3-14 heteroaryl group which may be substituted by —COOM10, —PO3M10, —O—PO3M102 or —SO3M10, R20 is a hydrogen atom, —COOM10 a straight chain or branched C1-16 alkyl group which may be substituted by a C6-14 aryl or C3-14 heteroaryl group, —COOM10, —PO3M10, —O—PO3M102 and —SO3M10, a C3-6 cycloalkyl group which may be substituted by a C1-16 alkyl group, a C6-14 aryl or C3-14 heteroaryl group, —COOM10, —PO3M10, —O—PO3M102 or —SO3M10, or a C6-14 aryl or C3-14 heteroaryl group which may be substituted by —COOM10, —PO3M10, —O—PO3M102 and —SO3M10, L is a single bond or a linker group; B independently is a group according to the definition of A″, a group of the following formula (7) wherein X20 independently has the same meaning as defined for X1 in formula (6), R10 and R20 are independent from each other and independently have the same meaning as defined for formula (6), Ro is a hydrogen atom, a straight chain or branched C1-16 alkyl group which may be substituted by a C3-6 cycloalkyl group, a C6-14 aryl or C3-14 heteroaryl group, —COOM10, —PO3M10, —O—PO3M102 or —SO3M10, a C3-6 cycloalkyl group which may be substituted by a C1-16 alkyl group, a C6-14 aryl or C3-14 heteroaryl group, —COOM10, —PO3M10, —O—PO3M102 or —SO3M10, a C6-14 aryl group which may be substituted by —COOM10, —PO3M10, —O—PO3M102 or —SO3M10, a group of the following formula (IV) wherein X30 is CO, —CH2CO—, CS, or —CH2CS—, R10 and R20 which are independent from each other and independently have the same meaning as defined for formula (6), or a group [X40Z200]pE, wherein Z200 is a straight chain or branched C1-4 alkylene group, X40 is an oxygen atom, a sulfur atom or NH, E is a hydrogen atom, PO3M2, a straight chain or branched C1-16 alkyl group which may be substituted by a C3-6 cycloalkyl group, a C6-14 aryl or C3-14 heteroaryl group, —COOM10, —PO3M10, —O—PO3M102 or —SO3M10, a C3-6 cycloalkyl group which may be substituted by a C1-16 alkyl group, a C6-14 aryl or C3-14 heteroaryl group, —COOM10, —PO3M10, —O—PO3M102 or —SO3M10, a C6-14 aryl or C3-14 heteroaryl group which may be substituted by —COOM10, —PO3M10, —O—PO3M102 or —SO3M10, and p is an integer of from 1 to 10; and n′ is an integer of from from 1 to 4; wherein M10 which are independent from each other each represent a hydrogen atom or a metal atom. Preferably, when L is a single bond, B cannot be a group according to the definition of A″ or a group of the formula (7). The following groups are preferred groups of formula (6), wherein M is a hydrogen atom or a metal atom: Preferred divalent linker groups may be selected from methylene, ethylene, propylene, butylene and the following divalent groups: N,N′-(2E)-but-2-en-1,4-diallylbis-[(N-prop-2-en-1) amide and N,N-di(allyl acrylamido) propane are preferred. The aqueous dental glass ionomer composition according to the present invention may contain a non-reactive filler and/or further components such as an inhibitor or a sensitizer. The Cured Aqueous Dental Glass Ionomer Composition The present aqueous dental glass ionomer composition is a curable dental composition, that is a cured dental glass ionomer composition/cement can be obtained therefrom by polymerizing the polymerizable polymer according to (B) and the monomer according to (C) in the presence of the reactive particulate glass (A) and the polymerization initiator system according to (D). It was surprisingly found that when cured, the present dental glass ionomer composition has particularly advantageous mechanical properties: Said composition's adhesive bond strength to dentin is of at least 5 MPa as measured according to ISO 29022:2013; and said composition's flexural strength is of at least 80 MPa as measured according to ISO 4049. Particularly Preferred Embodiments of the Aqueous Dental Glass Ionomer Composition According to a particularly preferred embodiment, the aqueous dental glass ionomer composition according to the invention comprises (A) a reactive particulate glass comprising 1) 20 to 45% by weight of silica, 2) 20 to 40% by weight of alumina, 3) 20 to 40% by weight of strontium oxide, 4) 1 to 10% by weight of P2O5, and 5) 3 to 25% by weight of fluoride, (B) a water-soluble, polymerizable polymer comprising acidic groups, which is reactive with the particulate glass in a cement reaction, whereby the polymerizable polymer has a polymer backbone and hydrolysis-stable pendant groups having one or more polymerizable carbon-carbon double bonds, wherein the polymerizable polymer is obtainable by a process comprising a) a step of copolymerizing a mixture comprising (i) a first copolymerizable monomer is represented by the general formula (1′): wherein R1′ is a hydrogen atom, a —COOZ# group or a methyl group; R2′ is a hydrogen atom or a —COOZ# group; A′ is a single bond or a straight-chain or branched C1-6 alkylene group; Z# which may be the same or different, independently represents a hydrogen atom or a protecting group for a carboxylic acid group. (ii) a second copolymerizable monomer represented by the general formula (2′): wherein R3 is a hydrogen atom; X′ is a protected amino group or a hydrocarbon group having 1 to 6 carbon atoms, which is substituted with an amino group which may carry a protecting group, wherein the hydrocarbon group may contain a nitrogen atom; Y′ is a hydrogen atom or a hydrocarbon group having 1 to 6 carbon atoms, wherein the hydrocarbon group may contain an oxygen atom or an amide bond, and which hydrocarbon group may further be substituted with a —COOZ## group; Z## which may be the same or different, independently represents a hydrogen atom or a protecting group for a carboxylic acid group, for obtaining an amino group containing copolymer; b) a step of coupling to the amino group containing copolymer a compound having a polymerizable moiety and a functional group represented by the general formula (3′): wherein R4′ is a hydrogen atom or a methyl group; R5′ is a hydrogen atom or a methyl group; LG′ is a chlorine atom or a bromine atom, or forms with the adjacent carbonyl group a carboxylic acid anhydride moiety, or wherein two molecules of formula (3) form an intermolecular carboxylic acid anhydride group by condensation of LG′, wherein LG′ is an oxygen atom, wherein the optionally protected amino group is deprotected, so that polymerizable pendant groups are linked to the backbone by hydrolysis-stable linking groups, and, optionally, a step of deprotecting the protected carboxylic acid group after step a) or step b), for obtaining a polymerizable polymer having an average molecular weight Mw in the range of from 3·104 to 2.5·106 Da; (C) a hydrolysis-stable, water-soluble monomer having one polymerizable double bond and a carboxylic acid group, said monomer having a molecular weight of at most 200 Da is a compound represented by the general formula (4′): wherein R6′ is a hydrogen atom or a straight chain or branched C1-3 alkyl group, and R7′ is a hydrogen atom or a straight-chain or branched C1-3 alkyl group which may be substituted by a —COOH group, wherein R6′ and R7′ are selected with the proviso that the molecular weight of the compound of formula (4) is at most 200 Da; preferably, R6′ is a hydrogen atom, and R7′ is a hydrogen atom or a C1-3 group optionally substituted with a —COOH group; more preferably, R6′ is a hydrogen atom, and R7′ is hydrogen atom or a methyl group substituted with a —COOH group; (D) a polymerization initiator system being based on a radical initiator in the form of a photoinitiator or a redox initiator or a mixture thereof, and (E) a polymerizable hydrolysis-stable crosslinker having at least two polymerizable carbon-carbon double bonds. In this particularly preferred embodiment, it is preferred to select the first copolymerizable monomer represented by the general formula (1/1′), the second copolymerizable monomer represented by the general formula (2/2′), the compound having a polymerizable moiety and a functional group reactive with an amino group of repeating units derived from the second copolymerizable monomer represented by the general formula (3/3′) and the hydrolysis-stable, water-soluble monomer having one polymerizable double bond represented by the general formula (4/4′) as follows: the first copolymerizable monomer: is a protected (meth)acrylic acid monomer, more preferably tert-butyl acrylate or benzyl acrylate, most preferably tert-butyl acrylate; the second copolymerizable monomer: is an aminopropyl vinyl ether wherein the amino group may be in the form of an ammonium salt such as ammonium chloride, more preferably a compound selected from the following, wherein the amino group may also carry a protecting group: the compound having a polymerizable moiety and a functional group reactive with an amino group of repeating units derived from the second copolymerizable monomer: is acrylic acid, (meth)acrylic acid, crotonic acid, isocrotonic acid, tiglic acid, angelic acid, or an anhydride of the aforementioned acids formed of two identical or different acids; more preferably an anyhydride of the aforementioned acids formed of two identical acids; most preferably, the anhydride of acrylic acid; and the hydrolysis-stable, water-soluble monomer having one polymerizable double bond and a carboxylic acid group: is itaconic acid or acrylic acid, preferably acrylic acid. In the last mentioned particularly preferred embodiment, most preferably, the polymerizable polymer obtained in step b) has one of the following structures: (F) The non-reactive filler The present aqueous dental glass ionomer composition may further comprise (F) a non-reactive filler, which do not undergo a cement reaction with the polyacid polymer. Non-reactive fillers may be included in the present aqueous dental glass composition for changing the appearance of the composition, for controlling viscosity of the composition, for further improving mechanical strength of a dental glass ionomer cement obtained from the composition, and e.g. for imparting radiopacity. The non-reactive filler should be non-toxic and suitable for use in the mouth. The filler may be in the form of an inorganic material. It can also be a crosslinked organic material that is insoluble in the polymerizable polymer according to (B) comprised in the present aqueous dental glass ionomer composition, and is optionally filled with inorganic filler. For example, suitable non-reactive inorganic fillers may be quartz, nitrides such as silicon nitride, colloidal silica, submicron silica such as pyrogenic silicas, colloidal zirconia, feldspar, borosilicate glass, kaolin, talc or a metallic powder comprising one or more metals or metal alloys. Examples of suitable non-reactive organic fillers include filled or unfilled particulate polycarbonates or polyepoxides. Preferably the surface of the non-reactive organic filler particles is treated with a coupling agent in order to enhance the bond between the filler and the matrix. Suitable coupling agents include silane compounds such as gamma-methacryloxypropyltrimethoxysilane, gamma-mercaptopropyltriethoxysilane and gamma-aminopropyltrimethoxysilane. The non-reactive filler may have a unimodal or polymodal (e.g., bimodal) particle size distribution, wherein the particulate filler preferably has an average particle size of from 0.005 to 100 μm, preferably of from 0.01 to 40 μm. The particle size may be measured, for example, by electron microscopy or by using a conventional laser diffraction particle sizing method as embodied by a MALVERN Mastersizer S or MALVERN Mastersizer 2000 apparatus. The particulate filler may be a multimodal particulate non-reactive filler representing a mixture of two or more particulate fractions having different average particle sizes. The particulate reactive filler may also be a mixture of particles of different chemical composition. The particulate non-reactive filler may be surface modified by a surface modifying agent. Further Optional Components The aqueous dental glass ionomer composition according to the present invention may, besides of optional component (F), comprise additional optional components. For example, the aqueous dental glass ionomer composition according to the present invention may also include further components to improve the radio-opacity, such as CaWO4, ZrO2, YF3 or to increase the fluoride release such as YF3. For example, the aqueous dental glass ionomer composition according to the present invention may also include a modifying agent such as tartaric acid. Such modifying agent provides for adjusting the working time and a setting time of the glass ionomer cement reaction, respectively, when preparing the cement as described in U.S. Pat. No. 4,089,830, U.S. Pat. No. 4,209,434, U.S. Pat. No. 4,317,681 and U.S. Pat. No. 4,374,936. In general, an increase in working time results in an increase in setting time as well. The “working time” is the time between the beginning of the setting reaction when the polymer and modified particulate reactive filler are combined in the presence of water, and the time the setting reaction proceeds to the point when it is no longer practical to perform further physical work upon the system, e.g. spatulate it or reshape it, for its intended dental or medical application. The “setting time” is the time measured from the beginning of the setting reaction in a restoration to the time sufficient hardening has occurred to allow subsequent clinical or surgical procedures to be performed on the surface of the restoration. In a setting reaction, due to the presence of polymerizable double bonds, a polymerization reaction takes place. The aqueous dental glass ionomer composition according to the present invention may contain further components such as solvents, pigments, nonvitreous fillers, free radical scavengers, polymerization inhibitors, reactive and nonreactive diluents e.g. bisacrylamides such as N,N′-diethyl-1,3-bisacrylamido-propan (BADEP), 1,3-bisacrylamido-propan (BAP), and 1,3-bisacrylamido-2-ethyl-propan (BAPEN), surfactants (such as to enhance solubility of an inhibitor e.g., polyoxyethylene), coupling agents to enhance reactivity of fillers e.g., 3-(trimethoxysilyl) propyl methacrylate, and rheology modifiers. Suitable solvents or nonreactive diluents include alcohols such as ethanol and propanol. Suitable reactive diluents are alpha,beta unsaturated monomers for providing altered properties such as toughness, adhesion, and set time. Such alpha,beta-unsaturated monomers may be acrylates and methacrylates such as methyl acrylate, methyl methacrylate, ethyl acrylate, ethyl methacrylate, propyl acrylate, propyl methacrylate, isopropyl acrylate, isopropyl methacrylate, 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate (HEMA), hydroxypropyl acrylate, hydroxypropyl methacrylate, tetrahydrofurfuryl acrylate, tetrahydrofurfuryl methacrylate, glycidyl acrylate, glycidyl methacrylate, the diglycidyl methacrylate of bis-phenol A (“bis-GMA”), glycerol mono- and di-acrylate, glycerol mono- and di-methacrylate, ethyleneglycol diacrylate, ethyleneglycol dimethacrylate, polyethyleneglycol diacrylate (where the number of repeating ethylene oxide units vary from 2 to 30), polyethyleneglycol dimethacrylate (where the number of repeating ethylene oxide units vary from 2 to 30 especially triethylene glycol dimethacrylate (“TEGDMA”), neopentyl glycol diacrylate, neopentylglycol dimethacrylate, trimethylolpropane triacrylate, trimethylol propane trimethacrylate, mono-, di-, tri-, and tetra-acrylates and methacrylates of pentaerythritol and dipentaerythritol, 1,3-butanediol diacrylate, 1,3-butanediol dimethacrylate, 1,4-butanedioldiacrylate, 1,4-butanediol dimethacrylate, 1,6-hexane diol diacrylate, 1,6-hexanediol dimethacrylate, di-2-methacryloyloxethyl hexamethylene dicarbamate, di-2-methacryloyloxyethyl trimethylhexanethylene dicarbamate, di-2-methacryloyl oxyethyl dimethylbenzene dicarbamate, methylene-bis-2-methacryloxyethyl-4-cyclohexyl carbamate, di-2-methacryloxyethyl-dimethylcyclohexane dicarbamate, methylene-bis-2-methacryloxyethyl-4-cyclohexyl carbamate, di-1-methyl-2-methacryloxyethyl-trimethyl-hexamethylene dicarbamate, di-1-methyl-2-methacryloxyethyl-dimethylbenzene dicarbamate, di-1-methyl-2-methacryloxyethyl-dimethylcyclohexane dicarbamate, methylene-bis-1-methyl-2-methacryloxyethyl-4-cyclohexyl carbamate, di-1-chloromethyl-2-methacryloxyethyl-hexamethylene dicarbamate, di-1-chloromethyl-2-methacryloxyethyl-trimethylhexamethylene dicarbamate, di-1-chloromethyl-2-methacryloxyethyl-dimethylbenzene dicarbamate, di-1-chloromethyl-2-methacryloxyethyl-dimethylcyclohexane dicarbamate, methylene-bis-2-methacryloxyethyl-4-cyclohexyl carbamate, di-1-methyl-2-methacryloxyethyl-hexamethylene dicarbamate, di-1-methyl-2-methacryloxyethyl-trimethylhexamethylene dicarbamate, di-1-methyl-2-methacryloxyethyl-dimethylbenzene dicarbamate, di-1-methyl-2-metha-cryloxyethyl-dimethylcyclohexane dicarbamate, methylene-bis-1-methyl-2-methacryloxyethyl-4-cyclohexyl carbamate, di-1-chloromethyl-2-methacryloxyethyl-hexamethylene dicarbamate, di-1-chloromethyl-2-methacryloxyethyl-trimethylhexamethylene dicarbamate, di-1-chloromethyl-2-methacryloxyethyl-dimethylbenzene dicarbamate, di-1-chloromethyl-2-methacryloxyethyl-dimethylcyclohexane dicarbamate, methylene-bis-1-chloromethyl-2-methacryloxyethyl4-cyclohexyl carbamate, 2,2′-bis(4-methacryloxyphenyl)propane, 2,2′bis(4-acryloxyphenyl)propane, 2,2′-bis[4(2-hydroxy-3-methacryloxy-phenyl)]propane, 2,2′-bis[4(2-hydroxy-3-acryloxy-phenyl)propane, 2,2′-bis(4-methacryloxyethoxyphenyl)propane, 2,2′-bis(4-acryloxyethoxyphenyl)propane, 2,2′-bis(4-methacryloxypropoxyphenyl)propane, 2,2′-bis(4-acryloxypropoxyphenyl)propane, 2,2′-bis(4-methacryloxydiethoxyphenyl)propane, 2,2′-bis(4-acryloxydiethoxyphenyl)propane, 2,2′-bis[3(4-phenoxy)-2-hydroxypropane-1-methacrylate]propane, and 2,2′-bis[3(4-phenoxy)-2-hydroxypropane-1-acryalte]propane, may be mentioned. Other suitable examples of polymerizable components are isopropenyl oxazoline, vinyl azalactone, vinyl pyrrolidone, styrene, divinylbenzene, urethane acrylates or methacrylates, epoxy acrylates or methacrylates and polyol acrylates or methacrylates. Mixtures of alpha,beta-unsaturated monomers can be added if desired. Preferably, the mixed but unset dental compositions of the invention will contain a combined weight of about 0.5 to about 40%, more preferably about 1 to about 30%, and most preferably about 5 to 20% water, solvents, diluents and alpha,beta-unsaturated monomers, based on the total weight (including such water, solvents, diluents and alpha,beta-unsaturated monomers) of the mixed but unset aqueous dental glass ionomer composition components. An example of a suitable free radical scavenger is 4-methoxyphenol. An example of a suitable inhibitor is tert.-butyl hydroquinone (TBHQ), hydroxytoluene or butylated hydroxytoluene (BHT). The amount of inhibitor may be selected from 0.001 to 2% and preferably from 0.02 to 0.5% based on the total weight of the polymerizable polymer according to (B)/monomer according to (C)/water mixture. A mixture comprising the polymerizable polymer according to (B) and the monomer according to (C) may be used for the preparation of a dental composition, preferably for the preparation of a cured dental composition, more preferably for the preparation of a cured aqueous dental glass ionomer composition. The dental composition may be a dental material to be used in the oral cavity. Dental compositions for use according to the present inventive concept represent useful restorative and filling materials, luting cements, adhesive cements, base or orthodontic cements, cavity liners and bases, pit and fissure sealants. Preferably, the mixture comprising the polymerizable polymer according to (B) and the monomer according to (C) for use for the preparation of a dental composition in the form of an aqueous dental glass ionomer composition further comprises a reactive particulate glass according to (A) and/or a polymerization initiator system according to (D). More preferably, said mixture is an aqueous dental glass ionomer composition as defined in claim 1, wherein further preferred embodiments are set forth in subclaims 2 to 14 The invention will now be further illustrated by the following Examples. EXAMPLES In the following Examples 1 to 7, the preparation of preferred polymerizable polymers according to (B) is described. Example 1 1. Copolymerisation of tert.-Butylacrylat (tButA) and 3-Aminopropylvinylether (APVE) to poly(tButA-co-APVE) 5.0 g (39 mmol) tButA, 0.99 g (9.8 mmol, 20 mol-%) APVE and 0.16 g (2 mol-%) AIBN were separately dissolved in DMF and the solutions were saturated with N2. Then the solutions were combined and stirred for 24 h at 70° C. After the polymerization the cooled solution was diluted with DMF to 30 wt-% polymer solutions and precipitated in water/methanol (9:1). The separated solid was dried in vacuum. The obtained copolymer had a molecular weight Mn=18 kDa, an Mw=51 kDa and a PD of 2.8. IR-spectroscopy of the product showed no vinylether-vibrations while 1H-NMR showed broadened peaks for the aliphatic protons and no peaks for possible remaining double bond protons. 1H-NMR (500 MHz, DMSO-d6): δ (ppm)=3.5 (2H, 4), 2.7 (2H, 6), 2.2 (2H, 2), 1.8 (1H, 1), 1.6 (2H, 5), 1.44 (9H, 3). 2. Methacrylation of the Poly(tButA-Co-APVE) To a solution of 5 g (33.7 mmol) copolymer poly(tButA-co-APVE) dissolved in 31.5 g dichloromethane were added 1.3 g (8.42 mmol) methacrylic acid anhydride. After stirring the solution for 24 h at ambient temperature, the solvent was removed and the crude product was dissolved in 30 mL methanol. From this solution the polymer was precipitated in water, filtered off and dried in vacuum. FT-IR: νmax [cm−1]=2976, 2932, 1785, 1722 (Ester), 1670 (Amid I), 1626 (C═C), 1526 (Amid II), 1479, 1448, 1392, 1366, 1143, 844. 3. Hydrolysis of Ester Moieties To a solution of 1.0 g (8.15 mmol) of the methacrylated poly(tButA-co-APVE) in 5 mL chloroform were added 20 wt-% trifluoro acetic acid. After stirring the solution for 5 h at 60° C. the crude precipitated polymer was separated from the solvent. The polymer was washed with chloroform, dissolved in methanol and re-precipitated in chloroform. Then the yellow polymer was dried in vacuum. 1H-NMR (500 MHz, DMSO-d6): δ (ppm)=12.2 (1H, —COOH), 7.8 (1H, —NH—), 5.6 (1H, —C═C—H), 5.3 (1H, C═C—H), 2.2 (2H, —CH2-backbone), 1.8 (3H, —CH3), 1.8 (1H, —CH—, backbone), 1.5 (2H, O—CH2CH2), 1.4 (9H, C—(CH3)3, residual ester moieties). Example 2 1. Copolymerization of tert butyl acrylate (t-BA) and 3-aminopropyl vinylether (APVE) to poly(AA-co-APVE) In a three necked round bottom flask, equipped with a cooler, 2.34 mL (0.0206 mol) APVE and 8.97 mL (0.0618 mol) t-BA were mixed with 20 mL dioxane. 278 mg AIBN (2 mol-% regarding the total monomers) were dissolved, too. The reaction mixture was instantaneously flushed with Argon for about 20 min. Meanwhile a metal bath was preheated to 90° C. The polymerization was instantaneously started by placing the bath below the flask. After 1 h of stirring the reaction was complete. A sample of 5 mL was withdrawn and diluted with dioxane to 20 mL. The polymer was precipitated by adding this solution to an excess of 150 mL water. The polymer was dried at the vacuum pump. The molecular weight was determined by using SEC with DMF as eluent. Mn=11500 g/mol, Mw=38100 g/mol, PD=3.32 2. Modification of Poly(AA-Co-APVE) with Methacrylic Anhydride To the residue of the reaction mixture from synthetic step 1 cooled down to room temperature were added 26 mg tert.-butyl hydroquinone (TBHQ) to deactivate the residual initiator. Than 0.0309 mol methacrylic anhydride were added. After stirring the mixture for 2 h at room temperature, the solvent was removed at the rotary evaporator (30° C.) and afterwards the sample was dried at the vacuum pump. The NMR-spectra shows broadened peaks at 5.30 ppm and 5.64 ppm of double bonds indicating that the modification was successful. 3. Hydrolysis of Tert.-Butyl Ester Moieties 20 g of a polymer with 5 mol-% APVE incorporated were modified with methacrylic anhydride as described above. After removing the solvents at the rotary evaporator the crude product was dissolved in 50 mL of trifluoroacetic acid. The mixture was cooled in an ice bath which was slowly dissolving and stirred for 24 h. Over night the polymer precipitated. The suspension was decanted and the polymer was dissolved in 100 mL of dioxane. It was precipitated in a fivefold excess of acetone. The precipitate was dissolved again in dioxane and precipitated again. Afterwards the polymer was first dried at the rotary evaporator and afterwards at the vacuum pump. The NMR-spectra shows that the peak of the tert-butyl group at 1.38 ppm has nearly vanished. This corresponds to a degree of hydrolysis of 98 mol-%. Example 3 Copolymerisation of tert.-Butylacrylate and 3-Aminopropylvinylether —P(tBu-co-APVE) A solution of 15 g (117 mmol) tert.-Butylacrylat in 38 g DMF was saturated under ice cooling with nitrogen. 3 g (29 mmol) 3-Amino-propylvinylether were added to this solution after 15 minutes. Further 5 minutes later were added 480 mg (2 mol-%) AIBN in nitrogen counter flow. Then the solution was stirred for 24 h at 70° C. After the polymerization the cooled solution was diluted with DMF to 33 wt-% polymer solutions and precipitated in the 20-fold quantity of water. The solid was filtered off, washed with water and dried in vacuum. FT-IR: νmax [cm−1]=2977 (—CH2—), 1723 (ester), 1481, 1449, 1392, 1366, 1255, 1144, 845. 1H-NMR (500 MHz, CDCl3): δ (ppm)=3.5 (2H, —O—CH2—), 2.7 (2H, —CH2—NH2), 2.2 (2H, backbone), 1.8 (1H, backbone), 1.6 (2H, —O—CH2—CH2—), 1.44 (9H, -tbutyl). GPC (DMF): Mn=26 kDa, Mw=70 kDa, Mz=124 kDa, PD=2.7. The following table shows typical molecular masses for different polymerization samples using a ratio of eq(tBA):eq(APVE)=3:1: c(AIBN) tterm. Batch # [mol-%] [min.] Mn Mw Mz PD 044-020 4 10 35.600 81.000 137.000 2.3 30 40.000 64.200 94.000 1.6 60 40.400 60.700 85.100 1.5 1440 36.000 65.200 97.300 1.8 044-022 1 10 14.900 37.400 72.900 1.9 30 14.800 39.200 71.700 1.8 60 150.800 160.200 166.400 1.0 044-023 0, 1 30 69.700 106.900 146.400 1.5 Itaconic Amide Modified P(tBA-co-APVE-IA) To a clear solution of 3.0 g p(tBA-co-APVE) in 10 mL dichloro methane were added portion wise under stirring 0.4 g (3.6 mmol) itaconic acid anhydride, whereby the solution discolorates red and then yellowish. Then the solution was stirred for 24 h at room temperature prior to evaporate dichloro methane. FT-IR: νmax [cm−1]=2977 (—CH2—), 1718 (ester), 1668 (amide I), 1559 (amide II), 1476, 1437, 1392, 1367, 1252, 1146, 1100, 945, 843. Hydrolysis of Ester Moieties to P(AA-co-APVE-IA) The modified polymer was added portionwise under stirring to 10 mL trifluoroacetic acid, and stirred some hours at room temperature prior to evaporate the trifluoroacetic acid in vacuum. The obtained high viscous polymer was dissolved in water and dialyzed for 4 days (MWCO=1000 g/mol). After frieze drying a reddish solid was received. FT-IR: νmax [cm−1]=3392, 2932 (—CH2—), 1699 (acid), 1625 (—C═C), 1546 (amide II), 1447, 1407, 1230, 1164, 1094, 934, 798, 610 1H-NMR (300 MHz, D2O): δ (ppm)=8.0 (1H, —NH—), 6.4 (1H, —C═C—H), 5.6 (1H, —C═C—H), 3.5 (2H, —O—CH2—), 3.4 (2H, —NH—CH2—), 3.3 (2H, —NH—CO—CH2), 2.4 (1H, backbone), 2.0-1.5 (2H, backbone), 1.6 (2H, —O—CH2—CH2—). Example 4 Methacrylamide Modified P(tBA-co-APVE-MA) To a clear solution of 3.0 g p(tBA-co-APVE) of example 2 dissolved in 10 mL dichloromethane, 0.6 g (4.1 mmol) methacrylic acid anhydride was added dropwise. Then the solution was stirred for 24 h at room temperature prior to evaporation of dichloromethane. The obtained raw product was applied for further reactions without purification. FT-IR: νmax [cm−1]=3351, 2977 (—CH2—), 1721 (ester), 1668 (amide I), 1622 (—C═C), 1531 (amide II), 1452, 1392, 1366, 1255, 1146, 1089, 940, 845. Hydrolysis of Ester Moieties to P(AA-co-APVE-MA) The modified polymer was added portion wise under stirring to 10 mL trifluoro acetic acid, and stirred some hours at room temperature prior to evaporate the trifluoro acetic acid in vacuum. The obtained high viscous polymer was dissolved in water and dialyzed for 4 days (MWCO=1000 g/mol). After frieze drying a colorless solid was received. FT-IR: νmax [cm−1]=3180, 2934 (—CH2—), 2613, 1701 (acid), 1650 (amide I), 1597, 1537 (amide II), 1449, 1408, 1211, 1162, 1110, 919, 797, 611 1H-NMR (300 MHz, D2O): δ (ppm)=8.0 (1H, —NH—), 5.7 (1H, —C═C—H), 5.4 (1H, —C═C—H), 3.5 (2H, —O—CH2—), 3.5 (2H, —NH—CH2—), 2.2 (1H, backbone), 1.8-1.6 (2H, backbone), 1.6 (2H, —O—CH2—CH2—). Example 5 Acrylamide Modified P(tBA-co-APVE-AA) To a solution of 5.0 g p(tBA-co-APVE) of example 4 dissolved in 30 mL THF were added under ice cooling drop wise 0.76 g (6.7 mmol) acryloyl chloride, whereby immediately a white solid precipitates. The reaction mixture was stirred for further 24 h at room temperature. The solid was filtered off and the solvent was evaporated. The crude raw material was used for hydrolysis without further purification. FT-IR: νmax [cm−1]=3289, 2976 (—CH2—), 1722 (ester), 1659 (amide I), 1628 (—C═C), 1544 (amide II), 1480, 1448, 1366, 1254, 1143, 844. Hydrolysis of Ester Moieties to P(AA-co-APVE-AA) 3 g of the modified polymer was added portion wise under stirring to 10 mL trifluoro acetic acid, and stirred some hours at room temperature prior to evaporate the trifluoro acetic acid in vacuum. The obtained high viscous polymer was dissolved in water and adjusted to pH 2 by addition of aqueous NaOH. Then the solution was dialyzed for 4 days (MWCO=1000 g/mol). After frieze drying a colorless solid was received. FT-IR: νmax [cm−1]=3361, 2930 (—CH2—), 1707 (acid), 1654 (amide I), 1620 (—C═C), 1544 (amide II), 1447, 1407, 1242, 1179, 1097, 980, 801. 1H-NMR (300 MHz, D2O): δ (ppm)=6.3 (1H, —C═C—H), 6.2 (1H, —C═C—H), 5.8 (1H, —CH═C<), 3.6 (2H, —O—CH2—), 3.3 (2H, —NH—CH2—), 2.2 (1H, backbone), 1.9-1.4 (2H, backbone), 1.6 (2H, —O—CH2—CH2—). Example 6 Copolymerisation of Acrylic Acid and N-vinyl Formamide1 to P(AA-NVFA) 1N. A. Nesterova et alter, Russian Journal of Applied Chemistry 2008, Vol. 82, No. 4, pp. 618-621 3 g (41.6 mmol) acrylic acid and 590 mg (8.9 mmol) N-Vinylformamide were dissolved in 10.88 g distillated isopropanol and aerated with nitrogen for 30 minutes. Then 164 mg (2 mol-%) AIBN were added in the nitrogen counter flow and aerated with nitrogen for further 15 minutes. Then the solution was stirred for 24 h at 70° C., whereby a colorless solid precipitated. The solid was filtered off and washed repeatedly with acetone and dried under reduced vacuum. One obtained a colorless, fine dispersed solid. FT-IR: νmax [cm−1]=3272 (—NH2), 3054 (—CH2—), 2922, 1708 (acid), 1643 (amide I), 1532 (amide II), 1444, 1385 (—CH2—), 1244, 1178. 1H-NMR (300 MHz, DMSO-d6): δ (ppm)=12.2 (1H, —COOH), 7.9 (1H, —NH—COH), 4.3 (1H, —CH—NH), 2.2 (1H, —CH—COOH), 1.7 (2H, —CH2—CH—NH—), 1.5 (2H, CH2—CHCOOH). GPC (H2O): Mn=10 kDa, Mw=49 kDa, Mz=126 kDa, PD=5.0. Conversion of P(AA-co-NVFA) into P(AA-co-VAm) (based on the hydrolysis of pure p(VFA) to provide p(VAm), in K. Yamamoto et alter, Journal of Applied Polymer Science 2002, Vol. 89, pp. 1277-1283. 200 mg of the copolymer p(AA-co-NVFA) were dissolved in 10 mL 2 N NaOH and stirred for 2 h at 100° C. Then the solution was neutralized by HCl and dialyzed for 3 days (MWCO=1000 g/mol). After freeze drying a fleece-like colorless solid was obtained. FT-IR: □max [cm−1]=3274 (—NH2), 2919 (—CH2-), 1666 (—COONa), 1559 (—NH2), 1448, 1408 (—CH2—), 1188 (—C—O—). 1H-NMR (300 MHz, D2O): δ (ppm)=2.5 (1H, —CH—NH2), 2.0 (1H, —CH—COOH), 1.4 (2H, —CH2—CH—NH2), 1.3 (2H, —CH2—CH—COOH). Acrylamide Modified P(AA-co-VAm-MA) 0.5 g of the hydrolyzed copolymer P(AA-co-VAm) were added to a round bottom flask and an excess of 1.0 g methacrylic anhydride were added. The mixture was heated to 60° C. for 4 hours. Then the product was diluted in water and the polymer was precipitated in methanol twice. The final polymer was analyzed for functionalization with double bonds by 1H-NMR (C═C bonds at 5.51 ppm and 5.31 ppm). The polymer is soluble in water after stirring for 24 hours. The degree of functionalization reaches 4.0 mol-%. Example 7 Copolymerisation of Acrylic Acid and N-(2-Amino Ethyl)Methacryl Amide Hydrochloride 0.2 g (3 mmol) acrylic acid and 0.5 g (3 mmol) N-(2-amino ethyl)methacryl amide hydrochloride were dissolved in 1.4 g DMF and aerated with nitrogen for 15 minutes. Then 20 mg (2 mol-%) VA-044 were added in the nitrogen counter flow and aerated with nitrogen for further 5 minutes. Then the solution was stirred for 2 h at 70° C., whereby a colorless solid precipitates. The solid was filtered off and washed repeatedly with acetone and dried under reduced vacuum. One obtained a colorless, fine dispersed solid. FT-IR: νmax [cm−1]=3350 (—NH2), 2926, 1705 (acid), 1629 (amide I), 1527 (amide II), 1482, 1456, 1393, 1365, 1232, 1166, 837. 1H-NMR (300 MHz, DMSO-d6): δ (ppm)=12.3 (1H, —OH), 8.3 (1H, —NH—), 7.9 (2H, —NH2), 4.2 (1H, CH3-CH<), 2.9 (2H, —NH—CH2—), 2.6 (2H, —NH—CH2—CH2—), 1.5 (1H, backbone), 1.2 (3H, —CH3), 1.0 (2H, backbone). Example 7 The composition of the liquids 1 to 11 and of comparison liquids A, B and C are summarized in Table 1. For preparing the resin modified glass ionomer (RMGI) test specimens, the liquid was always mixed with silanated reactive glass in the form of fluoro-aluminium-silicate glass in a powder/liquid ratio of 2.8/1. The resulting mixture was filled in a transparent mold and cured for 20 s at each site with LicuLite® (from Dentsply DeTrey GmbH, Germany). The flexural strength of the glass ionomer composition based on liquids of example 1 to 11 and of comparison example 1 and 2 are given in Table 1. The flexural strength was tested according to ISO 4049, with the only difference that the specimens were stored after irradiation for 1 h in 100% humidity at 37° C., and thereafter for 23 h in water at 37° C. TABLE 1 Composition of the liquids 1 to 11 and of comparison liquids A and B and flexural strength of the glass ionomer compositions modified unmodified DCP- PAA PAA BADEP BAABE DAAP BAP AA DEAA Liquid wt % wt % wt % wt % wt % wt % wt % wt % 1 33.0 0.0 17.4 0.0 0.0 0.0 6.6 12.0 2 35.0 0.0 14.5 0.0 0.0 0.0 7.8 0.0 3 35.0 0.0 12.0 0.0 0.0 0.0 1.3 12.7 4 35.0 0.0 16.4 0.0 0.0 0.0 0.6 13.0 5 35.0 0.0 12.0 0.0 0.0 0.0 7.7 3.2 6 35.0 0.0 18.0 0.0 0.0 0.0 3.5 4.2 7 35.0 0.0 12.0 0.0 0.0 0.0 0.0 18.0 8 35.0 0.0 12.3 0.0 0.0 0.0 0.0 9.1 9 35.0 0.0 0.0 15.0 0.0 0.0 15.0 0.0 10 35.0 0.0 0.0 0.0 15.0 0.0 15.0 0.0 11 35.0 0.0 0.0 0.0 0.0 15.0 15.0 0.0 A 0.0 35.0 15.0 0.0 0.0 0.0 15.0 0.0 B 43.1 0.0 17.3 0.0 0.0 0.0 0.0 0.0 C 35.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 D 43.2 0.0 0.0 0.0 0.0 0.0 17.2 0.0 maleic Initiator/ Flexural HEAA MAA acid water Inhibitor strength Liquid wt % wt % wt % wt % wt % total Example MPa 1 0.0 0.0 0.0 30.7 0.3 100.0 1 91.8 2 7.7 0.0 0.0 33.7 1.3 100.0 2 90.1 3 4.0 0.0 0.0 33.8 1.1 100.0 3 83.7 4 0.0 0.0 0.0 33.7 1.3 100.0 4 86.9 5 3.4 3.7 0.0 33.7 1.3 100.0 5 93.7 6 0.0 1.6 2.6 33.8 1.2 100.0 6 81.2 7 0.0 0.0 0.0 33.9 1.1 100.0 7 88.5 8 0.0 8.6 0.0 33.8 1.3 100.0 8 81.6 9 0.0 0.0 0.0 33.9 1.1 100.0 9 96.0 10 0.0 0.0 0.0 33.9 1.1 100.0 10 83.5 11 0.0 0.0 0.0 33.9 1.1 100.0 11 95.9 A 0.0 0.0 0.0 33.8 1.2 100.0 Comparative 83.4 example 1 B 0.0 0.0 0.0 38.4 1.2 100.0 Comparative 64.6 example 2 C 0.0 0.0 0.0 63.8 1.2 100.0 Comparative 21.0 example 3 D 0.0 0.0 0.0 38.4 1.2 100.0 Comparative 37.7 example 4 modified PAA methacrylated poly-(acrylic acid-co-3-aminopropylvinylether) (p(AA-co-APVE-AA); MOPOS) unmodified PAA poly(acrylic acid-co-itaconic acid) (p(AA-co-IA)) BADEP 1,3-Bis(acrylamido)-N,N′-diethylpropane BAABE N,N′-(2E)-but-2-en-1,4-diallylbis-[(N-prop-2-en-1) amide DAAP N,N-Di(allyl acrylamido) propane DCP-BAP N,N-Di(cyclopropyl acrylamido) propane AA Acrylic acid DEAA Diethylacrylamide HEAA Hydroxyethylacryl amide MAA Methacrylic acid CQ Camphorquinone initiator DMABN Dimethylamino benzonitril initiator TBHQ tert.-Butylhydroquinone inhibitor | <SOH> BACKGROUND OF THE INVENTION <EOH>Dental restorative materials are known for restoring the function, morphology and integrity of dental structures damaged by physical damage or caries-related decay of enamel and/or dentin. Dental restorative materials are required to have high biocompatibility, good mechanical properties and mechanical and chemical resistance over a long period of time given the harsh conditions for a restorative material in the buccal cavity. Dental restorative materials include glass ionomer cements having good biocompatibility and good adhesion to the dental hard tissues. Moreover, glass ionomer cements may provide cariostatic properties through the release of fluoride ions. Glass ionomer cements are cured by an acid-base reaction between a reactive glass powder and a polyalkenoic acid. However, conventional glass ionomer cements have a relatively low flexural strength and are brittle due to salt-like structures between the polyacid and the basic glass. The mechanical properties of glass ionomer cements may be improved by the selection of the polyacidic polymer. For example, a polymer having polymerizable moieties as pendant groups can be crosslinked in order to increase the mechanical resistance of the resulting glass ionomer cement. Japanese Patent Publication No. 2005-65902A discloses a dental adhesive composition comprising, as a polymerizable monomer containing a particular carboxylic acid, a carboxylic acid compound having a (meth)acryloyl group and a carboxyl group which are bound to an aromatic group. However, such a polymerizable monomer having an ester group quickly degrades in an acidic medium. Chen et al. and Nesterova et al. (Chen et al., J. Appl. Polym. Sci., 109 (2008) 2802-2807; Nesterova et al., Russian Journal of Applied Chemistry, 82 (2009) 618-621) disclose copolymers of N-vinylformamide with acrylic acid and/or methacrylic acid, respectively. However, none of these documents mentions the introduction of a further polymerizable moiety into the copolymer. WO2003/011232 discloses water-based medical and dental glass ionomer cements that can be post-polymerized after the cement reaction. The dental glass ionomer cements consist of two separate polymers, wherein one of the polymers has a pendant post-polymerizable moiety linked to the polymer through an ester bond. However, this ester bond between the polymer and the polymerizable moieties is again prone to hydrolytic cleavage in acidic media. Moreover, crosslinking of the glass ionomer may lead to the shrinkage of the dental composition in particular when the molecular weight of the crosslinking polymer is low. WO2012/084206 A1 discloses a polymer for a dental glass ionomer cement. However, WO2012/084206 does not disclose a specific combination of components for a composition of a dental glass ionomer cement. | <SOH> SUMMARY OF THE INVENTION <EOH>It is an object of the present invention to provide an aqueous dental glass ionomer composition providing improved mechanical properties including high flexural strength and a clinically relevant adhesion to tooth structure after curing, as well as hydrolysis-stability in an aqueous medium before and after curing, in particular in an acidic medium. The present invention provides an aqueous dental glass ionomer composition comprising: (A) a reactive particulate glass, (B) a water-soluble, polymerizable polymer comprising acidic groups, which is reactive with the particulate glass in a cement reaction, whereby the polymerizable polymer has a polymer backbone and hydrolysis-stable pendant groups having one or more polymerizable carbon-carbon double bonds, wherein the polymerizable polymer is obtainable by a process comprising a) a step of copolymerizing a mixture comprising (i) a first copolymerizable monomer comprising at least one optionally protected carboxylic acid group and a first polymerizable organic moiety, and (ii) a second copolymerizable monomer comprising one or more optionally protected primary and/or secondary amino groups and a second polymerizable organic moiety, for obtaining an amino group containing copolymer; b) a step of coupling to the amino group containing copolymer a compound having a polymerizable moiety and a functional group reactive with an amino group of repeating units derived from the second copolymerizable monomer in the amino group containing copolymer obtained in the first step, wherein the optionally protected amino group is deprotected, so that polymerizable pendant groups are linked to the backbone by hydrolysis-stable linking groups, and, optionally, a step of deprotecting the protected carboxylic acid group after step a) or step b), for obtaining a polymerizable polymer; (C) a hydrolysis-stable, water-soluble monomer having one polymerizable double bond and optionally a carboxylic acid group, said monomer having a molecular weight of at most 200 Da; and (D) a polymerization initiator system; and (E) a polymerizable hydrolysis-stable crosslinker having at least two polymerizable carbon-carbon double bonds. Specifically, in the coupling step b), the polymerizable pendant groups are linked to the backbone by hydrolysis-stable linking groups. The linkage preferably does not involve an ester group. Furthermore, the present invention provides a use of a mixture comprising: a water-soluble, polymerizable polymer comprising acidic groups, which is reactive with the particulate glass in a cement reaction, whereby the polymerizable polymer has a polymer backbone and hydrolysis-stable pendant groups having one or more polymerizable carbon-carbon double bonds, wherein the polymerizable polymer is obtainable by a process comprising a) a step of copolymerizing a mixture comprising (i) a first copolymerizable monomer comprising at least one optionally protected carboxylic acid group and a first polymerizable organic moiety, and (ii) a second copolymerizable monomer comprising one or more optionally protected primary and/or secondary amino groups and a second polymerizable organic moiety, for obtaining an amino group containing copolymer; b) a step of coupling to the amino group containing copolymer a compound having a polymerizable moiety and a functional group reactive with an amino group of repeating units derived from the second copolymerizable monomer in the amino group containing copolymer obtained in the first step, wherein the optionally protected amino group is deprotected, so that polymerizable pendant groups are linked to the backbone by hydrolysis-stable linking groups, and, optionally, a step of deprotecting the protected carboxylic acid group after step a) or step b), for obtaining a polymerizable polymer; said mixture further comprising a hydrolysis-stable, water-soluble monomer having one polymerizable double bond and optionally a carboxylic acid group, said monomer having a molecular weight of at most 200 Da, for the preparation of a dental composition. Preferably, the hydrolysis-stable, water-soluble monomer having one polymerizable double bond and optionally a carboxylic acid group includes acrylic acid. A cured aqueous dental glass ionomer composition according to the present invention is hydrolysis-stable and has excellent mechanical properties based on the specific combination of the polymerizable polymer according to (B) and the monomer having one polymerizable double bond according to (C). After polymerization of the polymerizable polymer according to (B) and the monomer having one polymerizable double bond according to (C), the polymer may contain an increased number of acidic groups when the monomer having one polymerizable double bond according to (C) contains a carboxylic acid group. Accordingly, crosslinking by a cement reaction and adhesion to dental hard tissue may be improved. The inventors have recognized that resin reinforced dental glass ionomer cements are subject to deterioration during storage or after curing in the mouth of the patient. The inventors have further recognized that the deterioration includes hydrolytic degradation of the resin component conventionally containing hydrolyzable moieties. The inventors have then recognized that by using a specific process for the preparation of a polymer, an improved water-soluble, hydrolysis-stable, polymerizable polymer according to (B) may be prepared at a high molecular weight which overcomes the drawbacks of conventional resin reinforced glass ionomer cements known from the prior art. In said polymerizable polymer according to (B), the introduction of amino group containing repeating units into the backbone of the polymer allows to provide high molecular weight copolymers having polymerizable pendant groups linked to the backbone by hydrolysis stable linking groups. Thereby, the disadvantages of conventional polymerizable resin components may be avoided. The polymerizable pendant groups of the polymerizable polymer according to (B) may react with the monomer having one polymerizable double bond according to (C) whereby a graft polymer is formed. The grafted side-chains may contain additional carboxylic acid groups which can take part in a cement reaction, thereby further increasing the strength of the cured composition. A crosslinked polymer may be obtained by a polymerizable hydrolysis-stable crosslinker having at least two polymerizable carbon-carbon double bonds which crosslinks polymerizable polymers according to (B) and grafted side-chains obtained based on monomer having one polymerizable double bond according to (C). detailed-description description="Detailed Description" end="lead"? | A61K60835 | 20171212 | 20181213 | A61K6083 | 0 | SALAMON, PETER A | AQUEOUS DENTAL GLASS IONOMER COMPOSITION | UNDISCOUNTED | 0 | ACCEPTED | A61K | 2,017 |
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15,735,736 | PENDING | Fluid Retaining Structure | A fluid retaining structure comprising an electronic leak detection and location, ELDL, system, wherein the fluid retaining structure comprises inner and outer liners (18, 16) that form electrical isolation layers of the ELDL system, wherein an electrically conductive signal layer (10, 12) of the ELDL system provides structural rigidity to the fluid retaining structure. | 1.-22. (canceled) 23. A fluid retaining structure having an electronic leak detection and location (ELDL) system, the fluid retaining structure comprising: inner and outer liners adapted to form electrical isolation layers for the ELDL system; and an electrically conductive signal layer located between the inner and outer liners; wherein the electrically conductive signal layer is configured to provide structural rigidity to the fluid retaining structure. 24. The fluid retaining structure of claim 23, wherein the electrical isolation layers are further adapted to perform fluid retention and ingress prevention functions of the fluid retaining structure. 25. The fluid retaining structure of claim 23, wherein the inner and outer liners are waterproof. 26. The fluid retaining structure of claim 23, wherein the electrically conductive signal layer is made of a concrete-based material. 27. The fluid retaining structure of claim 23, wherein: the outer liner includes an outer liner floor section; and the electrically conductive signal layer includes an electrically conductive signal layer floor section; and the outer liner floor section is located beneath the electrically conductive signal layer floor section. 28. The fluid retaining structure of claim 27, wherein the electrically conductive signal layer of the floor section is constructed of interlocking precast concrete units. 29. The fluid retaining structure of claim 27, wherein: the outer liner includes outer liner wall sections; and the outer liner wall sections are continuous with the outer liner floor section. 30. The fluid retaining structure of claim 29, wherein: the electrically conductive signal layer includes electrically conductive signal layer wall sections; and the outer liner wall sections are wrapped around the electrically conductive signal layer wall sections. 31. The fluid retaining structure of claim 30, wherein the electrically conductive signal layer wall sections are constructed of steel reinforced concrete. 32. The fluid retaining structure of claim 30, wherein the wall sections and/or the floor sections of the electrically conductive signal layer are electrically isolated from each other. 33. The fluid retaining structure of claim 30, wherein at least one of the electrically conductive signal layer wall sections incorporates lightening cavities. 34. The fluid retaining structure of claim 23, wherein the outer liner is welded to the inner liner such that the outer liner passes through a wall-roof joint of the electrically conductive signal layer. 35. The fluid retaining structure of claim 23, further comprising: internal column supports; and cover elements for the internal column supports; wherein the internal column supports are located inside the cover elements. 36. The fluid retaining structure of claim 35, wherein the cover elements comprise sleeves placed over the column supports. 37. The fluid retaining structure of claim 35, wherein the cover elements are joined to or part of a floor section of the inner liner. 38. The fluid retaining structure of claim 23, which presents only the inner liner to any contents of the fluid retaining structure. 39. The fluid retaining structure of claim 23, further comprising sensors for the ELDL system, wherein the sensors are located between the inner liner and the outer liner. 40. A two-layer electronic leak detection and location (ELDL) system, comprising: an inner liner; an outer liner; an electrically conductive signal layer; and sensors in electrical contact with the electronically conductive signal layer; wherein the electrically conductive signal layer is configured to provide structural rigidity to the ELDL system. 41. A method of retaining a fluid in a structure with an electronic leak detection and location (ELDL) system, comprising: providing inner and outer liners to act as electrical isolation layers for the ELDL system; placing an electrically conductive signal layer between the inner and outer liners, the electrically conductive signal layer being configured to provide structural rigidity for the fluid retaining structure; and retaining the fluid inside the inner liner of the ELDL system. 42. A kit of parts for a fluid retaining structure having an electronic leak detection and location (ELDL) system, comprising: inner and outer liners adapted for forming electrical isolation layers for the ELDL system; and an electrically conductive signal layer to place between the inner and outer liners, the electrically conductive signal layer being configured to provide structural rigidity to the fluid retaining structure. 43. A liner for a fluid retaining structure having an electronic leak detection and location (ELDL) system, wherein the liner is adapted to form an electrical isolation layer of the ELDL system. 44. A fluid retaining structure adapted to incorporate an electronic leak detection and location (ELDL) system, wherein structural elements of the fluid retaining structure are adapted to form an electrically conductive signal layer of the ELDL system. | This invention relates to a fluid retaining structure, a leak detection system for a fluid retaining structure and methods of constructing the same. BACKGROUND Within the construction industry there has been a drive for many years to increase offsite manufacturing whilst reducing the amount of site work required as a result. This allows for reductions in site costs and reductions in the risk of injury to site workers on multi-trade sites. This has led to the concept of using prefabricated structural elements that by their nature are then difficult to waterproof due to the arrangement of joints between sections and the potential for differential movement causing connections to become unsound at some future point. It is an object of the present invention to address the abovementioned disadvantages. In order to address the disadvantages identified above, the approach has been developed to produce a composite tank incorporating movement tolerant lining materials with prefabricated structural elements. This combination means that all waterproofing requirements for the structural element design including crack width calculations, movement and general waterproofness can be omitted as design considerations in relation to those structural elements. Furthermore the introduction of electronic leak detection and location systems into the design allows any future leakage both in or out of the fluid retaining structure to be detected, located and repaired without wholesale replacement of the waterproofing layers. According to the present invention there is provided an apparatus and method as set forth in the appended claims. Other features of the invention will be apparent from the dependent claims, and the description which follows. According to a first aspect of the present invention, there is provided a fluid retaining structure having an electronic leak detection and location, ELDL, system, wherein the fluid retaining structure comprises inner and outer liners that form electrical isolation layers of the ELDL system, wherein an electrically conductive signal layer of the ELDL system provides structural rigidity to the fluid retaining structure. Preferably, the electrical isolation layers are adapted to perform fluid retention and ingress prevention functions of the fluid retaining structure. Preferably the liners are waterproofing liners. The electrically conductive signal layer may be made of a concrete-based material. The electrically conductive signal layer may be reinforced with a metal, such as steel or other materials that enhance structural capacity of the concrete. The electrically conductive signal layer may be reinforced with a plurality of metal or other elements that are in electrical contact with each other. Advantageously the concrete provides both an electrically conducting layer for the ELDL system and the structural integrity to support the fluid retaining structure whilst the electrical isolation layers retain fluid therein and prevent fluid from outside entering the structure. A floor section of the outer liner may be located beneath a floor section of the electrically conductive signal layer. The floor section of the electrically conductive signal layer may be a steel reinforced concrete floor. Uniquely the floor section of the electrically conductive signal layer of the fluid retaining structure may be entirely, or substantially, constructed of interlocking precast concrete units that may or may not require tying together with structural ties, equally for the purposes of the ELDL system the floor section of the electrically conductive signal layer could be in situ cast concrete. Wall sections of the outer liner are preferably continuous with the floor section thereof. The wall sections of the outer liner are preferably wrapped around wall sections of the electrically conductive signal layer. The wall sections of the electrically conductive signal layer may be steel reinforced concrete wall sections and may be the structural element of fluid retaining walls. The wall sections of the electrically conductive signal layer may be electrically isolated from each other. One wall section of the electrically conductive signal layer may be electrically isolated from an adjacent wall section of the electrically conductive signal layer. The electrical isolation is to sufficient allow signals from adjacent wall sections of the electrically conductive signal layer to be distinguished from each other. At least one of the wall sections of the electrically conductive signal layer may incorporate cavities, preferably introduced during manufacture. The cavities may be side cavities that preferably extend inwards from side edges of the wall sections of the electrically conductive signal layer. The cavities may be longitudinally tapered. The cavities may be rectilinear, preferably square, in cross-section. The cavities may have the advantageous effect of reducing an amount of concrete used in the wall sections. The wall sections of the electrically conductive signal layer may advantageously incorporate gaps therebetween to allow for the drainage of a leachate. Electrical connections to the control means of the ELDL system may also pass between the wall sections. The wall sections of the outer liner preferably extend and/or wrap over an upper edge or wall plate of the wall section of the electrically conductive signal layer. The outer liner is preferably welded to the inner liner such that it passes through a wall roof joint of the electrically conductive signal layer. However there are other configurations possible where the inner liner is not connected to the outer liner and instead remains separate. The fluid retaining structure may include internal column supports. The internal column supports may be located inside cover elements of the inner liner. The cover elements may be sleeves placed over the column supports. The cover elements may be joined to or part of a floor section of the inner liner. The floor section of the inner liner is preferably located over a floor section of the fluid retaining structure. The cover elements may be welded to the floor section of the inner liner. The fluid retaining structure may include a roof. The roof may be supported by the internal column supports and the wall sections. The roof may or may not also be an element of the electrically conductive signal layer. The outer liner may be wrapped over the roof, whereupon it would be necessary to line the soffit of the roof with the inner liner in the same way as the floor. Alternatively the roof liner may have a dual liner system with conductive medium and sensors between where the lower and upper liners would preferably be welded to the outer liner below the wall roof joint, forming a separate ELDL zone. The fluid retaining structure preferably presents only the inner liner to any contents of the fluid retaining structure. The inner liner preferably prevents any fluid held in the fluid retaining structure from contacting the electrically conductive signal layer in the absence of a leak. Sensors of the ELDL system are preferably located between the inner and outer liners. The sensors may be located in electrical contact with the electrically conductive signal layer. The sensors may be located in openings in the electrically conductive signal layer. Wiring of the ELDL system preferably exits the electrically conductive signal layer at an upper section of the fluid retaining structure. The inner and/or outer liners may be made of sections of non-electrically conducting liner material that are secured together, preferably by welding. According to another aspect of the present invention there is provided a two layer electronic leak detection and location, ELDL, system comprising inner and outer liners and an electrically conductive signal layer comprising sensors, wherein the electrically conductive signal layer provides structural rigidity to allow the ELDL system. Preferably, the electrically conductive signal layer provides the electrical conductivity between the two liners necessary to allow the ELDL system to function. The ELDL system may include control means and a plurality of sensors, wherein the sensors are electrically isolated from each other and in electrical communication to the control means, wherein the sensors have a sheet form. In this case, each sensor may be a wall section of the electrically conductive signal layer. The sensors may be block sensors or tile sensors. The sensors may be physically connected to each other, albeit electrically isolated from each other. The sensors may be physically joined by a non-conducting material, which may form a welded joint between sensors. The sensors may be spaced from each other to leave a gap therebetween, which gap is electrically non-conducting. The electrical communication with the control means may be a wired or wireless communication. According to a another aspect of the present invention, there is provided a method of retaining a fluid in a structure, the structure having an electronic leak detection and location, ELDL, system, wherein the fluid is retained by an inner liner that forms an electrical isolation layer of the ELDL system, wherein an electrically conductive signal layer of the ELDL system provides structural rigidity to the fluid retaining structure. According to another aspect of the present invention, there is provided kit of parts for a fluid retaining structure having an electronic leak detection and location, ELDL, system, wherein the fluid retaining structure comprises inner and outer liners for forming electrical isolation layers of the ELDL system, wherein an electrically conductive signal layer of the ELDL system provides structural rigidity to the fluid retaining structure. According to another aspect of the present invention, there is provided a liner for a fluid retaining structure having an electronic leak detection and location, ELDL, system, wherein the liner is adapted to form an electrical isolation layer of the ELDL system. According to another aspect of the present invention, there is provided a fluid retaining structure adapted to incorporate an electronic leak detection and location, ELDL, system, wherein structural elements of the fluid retaining structure are adapted to form an electrically conductive signal layer of the ELDL system. The references to service reservoir herein should be interpreted to include waste water tanks also. All of the features described herein may be combined with any of the above aspects, in any combination. For a better understanding of the invention, and to show how embodiments of the same may be carried into effect, reference will now be made, by way of example, to the accompanying diagrammatic drawings in which: FIG. 1 is a schematic perspective view of a water impermeable outer geomembrane with a service reservoir floor slab structure laid thereon; FIG. 2 is a schematic perspective view of geomembrane and floor slab with some wall units of the service reservoir in position; FIG. 3 is a schematic perspective view of the structure of FIG. 2 with metal tie bars in position, with the geomembrane omitted for clarity; FIG. 4 is a schematic perspective view of the structure of FIG. 3 with a second layer of floor slabs in position; FIG. 5 is a schematic perspective view of the structure of FIG. 4 with support columns of the service reservoir in position; FIG. 6 is a schematic perspective view of the structure of FIG. 5 with beams located on the support columns of the service reservoir; FIG. 7 is a schematic perspective view of the structure of FIG. 6 with metal roof ties of the service reservoir in position; FIG. 8 is a schematic perspective view of the structure of FIG. 7 with some roof slabs of the service reservoir in position; FIG. 9 is a schematic perspective view of the structure of FIG. 8 with additional roof slabs of the service reservoir in position and the outer geomembrane in position; FIG. 10 is a schematic partial perspective view of the floor slab showing positions of the columns; FIG. 11 is a schematic partial perspective view showing roof/wall joints of the service reservoir; FIG. 12 is a schematic partial perspective cut-away view showing the wall/roof structure; FIG. 13 is schematic partial perspective cut-away view showing a corner of the service reservoir; FIG. 14 is a schematic partial eye level perspective view of the service reservoir; FIG. 15 is a schematic partial perspective cut-away view showing ends of the beams; FIG. 16 is schematic partial perspective cut-away view showing details of the floor slabs and tie bars; FIGS. 17a-c show schematic front, rear and cross-sectional views of an embodiment of wall section for the service reservoir. The fluid retaining structures described herein are exemplified with respect to a service reservoir for drinking water as an example. Other fluid retaining structures are eminently suited to the invention, including slurry tanks, waste water reservoirs, water treatment reservoirs and generally tanks or retaining structures to keep fluids isolated from a surrounding environment. In addition it is conceived that the fluid retaining structure might also be used to create dry storage environment or dry underground accommodation where watertightness of the structure is paramount and monitorable, for example underground data centres or dry storage of contaminated wastes, such as nuclear wastes. A service reservoir incorporating an electronic leak detection and location (ELDL) system is described herein. As shown partially in FIG. 9, the service reservoir has the following features: a precast interlocking structure using a double stretcher bond configuration, with precast floor 10 made of sub units 10a (i.e. no in situ cast floor), wall units, or sections, 12 and a roof structure 14 made including lintels 13 and roof units 14a; ingress leak monitoring of the precast interlocking structure; egress leak monitoring of the precast interlocking structure; corrosion monitoring and/or cathodic protection of metallic components within the precast concrete units; an outer waterproofing liner 16 outside and beneath the precast concrete structure and a protective geotextile inner waterproofing liner 18 (see FIG. 15, not shown in other Figures for clarity, but takes the form of a flexible liner laid out in the tank to retain water, further details below) inside the interlocking structure. The sub units 10a of the floor are laid in a double layer stretcher bond configuration. The method of constructing the service reservoir will now be described with reference to the Figures. FIG. 1 shows the outer liner 16 placed on a prepared site. A first layer of floor sub-units 10a is then laid in a grid pattern on the outer liner 16. FIG. 2 shows a plurality of wall units 12 placed around the first layer of floor sub-units 10a. The wall units 12 are shown only partially surrounding the first layer of floor sub-units 10a for clarity, but the wall units 12 will form a complete tank shape. The wall units in this example include an inner foot 12a that extends horizontally to support the wall unit 12 in an upright orientation. The wall units also have outer feet 12b, although these are not essential and may be omitted. FIG. 3 shows tie bars 20 laid across the top of the first layer of floor sub-units 10a for optional reinforcement. FIG. 4 shows a second layer of floor sub-units 10b having been placed in position over the first layer of sub-units 10a and inner feet 12a of the wall sections 12, thereby locking the wall units 12 in position. FIG. 5 shows support columns 22 being place in position on top of the second layer of floor sub-units 10b. FIG. 6 shows lintels 13 being placed in position between tops of the columns 12. FIG. 7 shows optional tie bars 21 being place in position over the tops of the lintels 13. FIG. 8 shows roof units 14a being placed in position on top of the lintels 13. FIG. 9 shows edge roof units 14b being placed in position. Various methods of electronic leak detection and location have been disclosed previously. Some of the methods involve the use of a highly resistive plastic geomembrane being installed with electric poles at either side of the membrane. When a fault occurs in the geomembrane an electric connection occurs, which is detected as a current flow. In one system for electronic leak detection and location a single pole on one side of the geomembrane is used and an operator with another pole being connected to earth outside the geomembrane. The operator carries a pair of sensors and when he passes a hole in the geomembrane a polarity shift is detected, leading to the detection and location of the leak. In a more sophisticated system, as described in EP0962754, often referred to as a fixed or permanent leak detection system, a network/grid of point sensors is installed beneath the geomembrane to allow for more accurate detection of a leak. For example, sensors may be spaced on a grid of approximately 3 m×3 m, which spacing can lead to a sensitivity of approximately 300 mm. Other grid spacings are possible, for example at intervals of between 3 and 10 metres. In this installation the sensors are located outside the geomembrane, leaks from which are to be detected. A further improvement of this type of system is to use two layers of geomembrane with the sensors and a conductive geotextile (acting as an electrically conductive signal layer) being located between the two layers of geomembrane (acting as electrical isolation layers) and source electrodes being located outside the two layers of geomembrane in the earth or covering above and below the two geomembranes. The use of two membranes with sensors in between allows an alarm type of detection and location system to be provided, because the sensors are isolated from currents within the material being retained by the geomembrane and also from stray or environmental currents in the earth outside the geomembrane. Thus, when a leak does occur and the moisture leaks into the space between the two geomembranes this allows the electrical signal current to flow with the moisture into the encapsulated conductive textile between the two layers of membrane, the point sensors can detect the increase in current, allowing an alarm condition to be raised if a suitable monitoring system is installed and connected to the point sensors. Such systems exist for both online/permanent monitoring of membrane with suitable monitoring equipment being installed permanently on site and offline systems where only connectors are installed on site requiring power sources and testing equipment to be brought to site in order to test the installed point sensor system manually. In the embodiment described the ingress and egress leak monitoring is achieved by using the concrete structural members as an electrically isolated conductive signal layer between inner and outer geomembranes made of plastics material. Electrical Isolation Layer An electrical isolation layer is used in ELDL systems that are to be completely buried around the periphery. The purpose is to create an environment within an interstitial space between two geomembranes 16, 18 that is electrically isolated from the outside earth and the internal environment inside the reservoir. An upper 18 of the two geomembranes is often known as the ‘primary waterproofing liner’ and it is the primary waterproofing liner 18 that is normally the ‘service facing’ waterproofing liner. The waterproofing systems that are deployed for the purpose of electrical isolation are electrically non-conductive as is the primary waterproofing liner 18. In this description, the term liner or waterproofing liner will occasionally be used to refer to the geomembrane and vice versa. In the case of the service reservoir described herein the electrical isolation layer will need to be completely wrapped in the geomembranes 16, 18. The outer geomembrane 16 will be split into three sections: i. Below the precast floor 10 ii. External to the wall units 12 iii. Across the roof structure 14 The purpose of the electrical isolation layer is to ensure that in the event of damage to either of the geomembranes 16, 18 that an electrical signal current follows any moisture through a hole in the geomembrane 16/18, rather than (in accordance with Ohm's law) where there is a single lining system the signal may simply pass around the edge of the waterproofing liners 16/18 (or, go through a water pipe, or pass through metallic structures/fixings/ladders/railings bolted through the waterproofing liner) if this is the path of least resistance for electricity to travel. In prior art ELDL systems, where there is a double lining system having inner and outer geomembranes between, there is provided a conductive medium to augment the passage of an electrical signal from a hole in one of the geomembranes to one or more sensors surrounding it. In such prior art systems there would normally be a conductive signal layer (for example non-woven fabric based). Primary Waterproofing Liner The primary waterproofing liner is the ‘service facing’ part of the geomembrane construction and as the name would suggest this waterproofing liner has the primary responsibility for integrity of the waterproofing system. In reality both the inner (primary) 18 and outer 16 waterproofing liners are equally important in terms of electrical isolation enabling integrity monitoring, and in the context of service reservoir described herein one will protect from water/contaminant ingress the other from water egress. The primary waterproofing liner 18 in respect of the service reservoir would be the face of the waterproofing liner to: i. Internal tank floor ii. Internal tank walls iii. External upper roof waterproofing liner Service Reservoir Configuration In the context of service reservoirs it has been realised that it is possible to eliminate the need for any conductive signal layer within the interstitial space between waterproofing liners 16, 18, by placing the precast concrete units within this interstitial space. This has two advantages: i. The Electrical Isolation Layer forms the ingress prevention against positive water pressure from outside that tank; ii. The precast units become the conductive signal layer for the purposes of the ELDL system. The conductivity of the precast concrete for the floor 10, wall units 12 and roof 14 is controlled to ensure the proposed mix of concrete and steel reinforcement sits within the necessary band of compatibility required by the ELDL system. Also plasticisers are known to significantly decrease the electrical conductivity of concrete and so their use is monitored accordingly. Therefore, a suitable method would be to test the conductivity of the precast concrete itself to ensure the proposed mix of concrete sits within the necessary band of compatibility required by the ELDL system. In the event that the concrete cannot be manufactured effectively with sufficient electro-conductive properties to suit an ELDL system, then some material can be incorporated into the casting process, perhaps fixed to the face of the shuttering on either side of the precast unit or added to the concrete mix such as carbon, graphene or steel filings. The roof can either be constructed using a traditional double lined ELDL system complete with conductive signal layer between within the interstitial space both running over the top face of the roof or the soffit of the roof could be lined with a single liner utilising the structural elements of the roof as a conductive signal layer with a single liner over the top face of the roof. Alternatively, the roof may not be constructed of concrete and instead could be a floating cover roof incorporating a double-lined ELDL system utilising a tile system approach as described in WO2016/001639, the contents of which are incorporated herein by reference. In drinking water service reservoirs floating covers protect the water from contamination, evaporation, and the loss of water treatment chemicals (such as chlorine). In waste water tanks floating covers prevent odours, collect biogas, and prevent the build-up of algae. FIGS. 17a-c show an embodiment of a structure of the wall units 12 that provides weight saving (and cost saving). In themselves (even without the weight saving design) the wall units 12 design is unusual, because a gap between the adjacent wall units 12 is not filled. This is because in the service reservoir described herein, the concrete of the floor 10, wall units 12 and roof 14 are not directly providing a waterproofing function as is the manner of conventional concrete tank construction. In the service reservoir described herein the concrete is only required for structural strength/rigidity and to detect leaks through the waterproofing liners 16,18 either side. Given that the concrete of the floor 10, wall units 12 and roof 14 is not used in any way to waterproof the tank the concrete is free of design constraints that require very high grade concrete with crack width control measures to minimise cracking by introducing very complicated structural design and large quantities of steel reinforcing bars. It is also not necessary for the wall units 12 to be interconnected on site by pouring in-situ concrete and connecting reinforcing cages together with the protruding bars from the edges of each precast units; this mean that gaps can be left between the wall units 12 and those gaps (20-50 mm wide) between the individual wall panels can be used as drainage in case of a leak, whereby any water that might collecting between the liners 16,18 during a leak alert can freely drain out via weep tubes to a waste drain. In addition, as shown in FIGS. 17a-c and described below, it is possible to use formers that are pulled out after casting of the wall units 12 to leave cavities 12e in the edges of the concrete wall units 12, which saves weight, concrete cost, shipping cost and reduces the size of crane required to lift the wall units 12 into position. The precast concrete wall panels can be produced with ‘pull-out formers’ (not shown), either tapered or split for ease of extraction. The ‘pull-out formers’ are initially fixed to each side of the shuttering (concrete formwork) during production of the wall units 12; this has the effect of excluding concrete from spreading and forms a ‘shear panel’ 12d within the main body of the wall 12 see FIG. 17c). The purpose of the modification to the wall units 12 is to save on weight, whilst maintaining full structural adequacy. The wall units 12 incorporate a foot section 12a, shown in FIGS. 17a and 17b. This allows the preformed wall units 12 to stand unsupported when delivered to a site. Also, the foot section 12a is laid to abut an edge of adjacent first layer sub-units 10a of the lower layer of the floor. The second, upper layer of sub-units 10b is then laid over the abutting foot section 12a and lower layer sub-units 10a to lock the wall units 12 into position. The weight of the second layer of sub-units 10b in the double layer stretcher bond floor 10 therefore prevents the wall units 12 tipping backwards when the service reservoir is filled. The structure of this embodiment of wall unit is only possible because of the way the service reservoir is constructed. The ‘pull-out formers’ are the novel part of the design because normally a designer would not be able to create a water retaining structure with the cross-section shown in FIG. 17c. There would be no back to the jointing system necessitated by traditional/conventional design, whether this jointing was hydrophilic sealant or a water-bar for example, but in the embodiment described above uses an ‘open’ joint, so it does not matter. Therefore, the advantageous transfer of waterproofing functions to the liners 16 and 18 allows for innovative design of the wall units 12 for this service reservoir. ELDL Components With the possible exception of the roofing system (assuming the sufficient electro-conductive properties of the precast concrete units can be achieved, see above) in order to provide a composite construction incorporating ELDL functionality, the sensors, anodes and reference electrodes are deployed within the precast concrete units 10a, 12 themselves. The best method for this is to cast in a tubular hollow perhaps using a prepared timber dowel that when removed will allow the insertion of a flowable grout and sensors/anodes/reference electrodes on site. The sensors/anodes/reference electrodes of course have a tail of cable attached that needs to exit from the precast units in a common geometrical positions that allows them to be run to a valve house (not shown) of the service reservoir. The best position for the cables to exit is via a booted connection through the roof waterproofing liner inside a HDPE duct that can be bonded to the waterproofing liner itself. The top edge of the precast concrete roof units 14a has a rebate 14c on the inside face below the roof slab but above the waterproofing liner termination where the cables run around the perimeter of the tank (see FIG. 11). It is in the top face of this rebate that there are ‘cast in tubes’ running vertically parallel to the internal face of the precast concrete. Other alternatives for placement of sensors in the floor 10 &/or the wall 12 would be to leave slots/rebates in the face where sensors can be placed on site then filled with mortar before the waterproofing liner is installed. For the ELDL of water leaks out of the service reservoir there would need to be a connection to the water inside the tank. One option is to connect onto the metallic valves which themselves have a direct connection to the water inside the HDPE inlet and outlet pipes. For the detection of a leak into the tank/through the electrical isolation layer then source electrodes must to be placed beneath the lower waterproofing liner and outside the waterproofing liner in contact with the covering material/soil. The roof 14 could be constructed in a more orthodox fashion with sources above and below the upper and lower waterproofing liners respectively, with the sensors and conductive textile encapsulated between the two. Or alternatively monitoring of the primary liner only could be offered in the event that liner is deployed to the soffit of the roof with source electrodes being placed in the soil/sand/gravel or other covering above the roof. Electrical Continuity of Reinforcing Bar Given that the precast 10a, 12, 14a units effectively have a dual purpose in the service reservoir described, it is advisable that steel reinforcing bars 20 are installed carefully (perhaps pre-welded/tied together into cages) such that within each individual unit 10a, 12, 14a there is electrical continuity of all the steel 20 and additionally a cable, or other connector, should be provided from the cage in each unit 10a, 12, 14a that can then be connected to the adjacent units 10a, 12, 14a. In addition, advantageously the electrical continuity of the steel reinforcing bars inside each unit and to each other, also allows the functionality of corrosion monitoring via installed reference electrodes connected to the necessary control equipment and even cathodic protection of the steel within the precast units via installed anodes connected to the necessary control equipment. For the purposes of electrical continuity between the precast units and all the steel reinforcement contained therein. The same result can be achieved using protruding stainless steel threaded bar to enable electrical bonding straps to connect the units 10a, 12, 14a together. An additional option for the construction of the wall units 12 and floor sub-units 10a is to electrically isolate adjacent wall units 12 and/or floor sub-units 10a from each other and allow each entire wall unit 12/floor sub-unit 10a to act as a tile-type sensor, as described in WO2016/001639, the contents of which are incorporated herein by reference. The leak detection may be implemented by using the reinforcing steel of the wall units 12 and floor sub-units 10a as tile sensors. In this way, the separate wall units 12 and floor sub-units 10a are individually electrically connected to a control unit of the ELDL system, where the control unit analyses signals received from the wall units 12 and floor sub-units 10a to detect leaks from the service reservoir, in particular from the inner lining 18. The reinforcing bars 20 are not used in this configuration. In this way, breach of either of the inner or outer liners 18,16 will result in triggering of a sensor adjacent to the breach, which identifies a specified location, defined by the area of the wall unit 12, in the service reservoir that has been breached. The area corresponds to the area of the wall unit 12 that has been triggered. Thus, a plurality of defined zones is separately monitored, with each zone being defined by one of the wall units 12 or floor sub-units 10a. The wall units 12 are isolated from each other by the gaps between them, whereas uniquely the floor sub-units 10a can be isolated from each other by using concrete with a higher electrical resistivity achieved by using plasticiser additives, plastic fibres, or resin in the joints between discrete floor sub-units 10a, or by painting the three non-sensing surfaces of the concrete in an electrically non-conductive paint or coating. Waterproofing Internal Waterproofing of the Service Reservoir Waterproofing the service reservoir is of course the main concern and there are various systems available that could achieve the required goal: i. Studded cast-in types of liner cast into the concrete surface during production of the precast units ii. Spray applied polyurea coatings iii. Loose laid There are a number of considerations to take into account in the material selection process: i. Movement tolerance ii. Electrical conductivity iii. Regulation 31 approval (primary) for contact with potable water in the UK or other potable water contact approvals that may be required for such an applications in other geographical locations around the world iv. Internal finish & slip resistance for personnel entering tank intermittently (primary) v. Internal durability/resistance to chlorinated water & water jet cleaning (primary) vi. External durability (electrical isolation layer) The abovementioned criteria swiftly reduce the attractive options for water proofing on a practical level whilst all would provide the necessary waterproofing and electrical isolation properties required by the concept. There is a danger that anything bonded to the precast units will potentially fail in the event of quite small lateral or vertical movement. Movement, or the possibility of it, makes both studded cast-in types liner and spray applied systems less attractive, because they are likely to fail. In the interests of completeness however we would also point the other problems with studded cast-in types of liners in relation to the abovementioned criteria which are: lack of Regulation 31 approval; can look scruffy after the casting process; very expensive to purchase; requires a lot of onsite extrusion welding to complete the surfaces between units which can further add to the poor visual appeal of the completed waterproofing system as well the higher cost of extrusion welding over that of fusion/wedge welding. Polyurea spray applied system suffer none of the issues relating to Reg 31 approval or visual appeal, there is no extrusion welding necessary, but it is likely to crack in the event of movement and it remains a highly expensive option given the thicknesses that will need to be applied to achieve an electrically non-conductive finish which would need to be carefully verified using an ASTM D7953 arc test. Loose laid waterproofing liner is therefore the most favoured approach and one that could achieve the desired result effectively so long as due consideration is given to the complexity of producing a loose laid waterproofing liner system that provides neat and tidy finish and also the sensitivity to damage by site carelessness of following trades, with particular reference to the waterproofing liner beneath the structure that will be inaccessible once the structure is in place above it. The most appropriate waterproofing liners for a loose laid waterproofing liner approach are: i. Polypropylene ii. Butyl rubber iii. Polyethylene iv. PVC The selection criteria that must be considered here are as follows: i. Regulation 31 approval (primary) or other geographically required regulatory approval for contact with potable water ii. Cross compatibility for welding with external/roof waterproofing liner iii. Electrical conductivity iv. Weld compatibility with regulation 31 approved pipes or other geographically required regulatory approved pipework for contact with potable water v. Durability The first criteria of Regulation 31 approval immediately disadvantages the use of butyl rubber and PVC, in addition these products would struggle with cross compatibility, pipe connections (butyl) and electrical conductivity (butyl) and durability (PVC). This leaves polyethylene and polypropylene, both materials types are present in materials approved within the Regulation 31 approved list. Polypropylene is an excellent material but one which is really designed around ease of installation making it soft and easily workable, it can also be welded without extrusion reinforcement but this relies on great skill because if polypropylene is overheated in the welding process it release oils that make the weld seem good but allows it to simply fail sometime after the initial installation. Polypropylene's Achilles heel is the very flexibility which is it most beneficial property, this makes it extremely easy to damage both during and after the installation and with particular reference to high pressure cleaning. Another consideration with polypropylene is that it is not cross compatible with any form of pipework currently on the market. This leaves us with polyethylene and in turn the Regulation 31 Approval means that we have only HDPE to work with. HDPE is a stiff and very durable material that will last an extremely long time, the problems with it relate to its installation due to its stiffness but those who are used to working with it have no reservation about lining a tank with it. The question of neatness is still an issue. In order to create a neat installation it will be necessary to try to design and install the tank in a manner that suits the lining of it, rather than the normal position which is that a leaking tank not designed to be lined is fitted with a liner ‘bag’. One consideration under the Construction Design and Management Regulations in the UK with regard to the operation and maintenance of the tank is the slipperiness of wet HDPE waterproofing liner where the designers would need to consider the risk to the end users or maintenance crews. Slipperiness of the floor liner could be a major issue during the cleaning and inspection of tanks in service which we would overcome by the use of a structured/textured finish for the floor waterproofing liner. Optimum Tank Geometry for Internal Lining The optimum geometry for the tank on plan would be lozenge shaped or a square/rectangular shape with curved internal corners. The inner waterproofing liner 18 covers an upper layer of floor units 10b, the interior of the wall units 12 and the exterior of internal columns 22. It is also desirable to minimise or eliminate any angular detailing such as column thrust blocks, ideally the columns 22 will be circular and dropped into ‘sockets’ in the floor 10 in order to keep the floor waterproofing liner as flat as possible with only the scour/sump and the wall 12 to floor 10 joint necessitating changes in the direction of the waterproofing liner. The roof 14 includes lintels 13 that are laid across the tops of the columns 22, as shown in FIG. 6. Steel reinforcing bars 21 are then located (see FIG. 7) in a grid pattern through openings in the lintels 13 and at upper parts of the wall units 12 (or possibly in lintels 13 laid on top of the wall units 12). After that the roof units 14a are placed on the lintels (see FIGS. 8 and 9). Detailed views are shown in FIGS. 10 to 13, showing the rebate 14c in the roof units 14a. FIG. 14 shows a view without the inner liner 18 from eye level to show the internal detail. FIG. 16 shows the inner liner 18 only schematically, particularly showing the joins, given the transparent nature of the liner 18. FIG. 16 shows chamfered lower edges of the upper floor units 10b to show how the reinforcing bars 20 are received. Columns One option for the lining of the columns 22 is to use HDPE pipes as permanent external sleeves for precast concrete columns 22, although if we use these pipes as ‘formwork’ in fact the HDPE pipe will need to be retained by a rigid metal shutter whilst the concrete cures inside to ensure that the HDPE pipe does not deform with the warmth of the concrete's chemical curing process. It is envisaged that if this technique could be developed (using Regulation 31 Approved pipe) then it would vastly simplify both the lining and the connection between floor waterproofing liner 16 and column 22, where the waterproofing liner 16 could be welded directly to the foot of the column sleeve. Another alternative could be to use precast concrete columns 22 to suit the internal diameter of available HDPE pipe and drop the pipes over the concrete columns 22 to form a cover, although this option does then require a further operation on site. Although in the alternative this might improve the ability to place sensors within the columns 22 or get floor sensor cables out of the tank waterproofing liner 18 more easily through cast in channels in the face of the columns 22. Again electrical continuity of the columns 22 with the reinforcing bars 20 in the remaining units 10a, 12, 14a would need to be considered and connections made to the floor and roof to make the entire structure electrically continuous. Along the centreline of a row of columns 22 we could envisage using an HDPE casting in termination profile being deployed, cast into the floor units. This would allow the neat termination of the floor waterproofing liner with an extrusion weld running along the aforementioned column centreline. This would avoid the necessity to have holes in the waterproofing liner before and after each column in order to remove a fusion welding machine after forming the wedge weld between liners at junctions between horizontal and vertical structural elements, which would then have to be patched with unsightly round sections of geomembrane with extrusion weld around. It is important that during the casting process the cast in HDPE profile is installed carefully, straight and allowing enough overhang within a shutter (perhaps bulked with polystyrene either side to allow slight protrusion of the plastic profile, thereby allowing the casting profile itself to be butt welded to the adjacent profile in the next/adjacent precast unit. Wall Floor Junction Adapting further sections of Regulation 31 Approved HDPE pipework for use in the service reservoir by cutting some pipes lengthways into quarter segments and using this as a ‘skirting’ detail around the perimeters as an alternative to a filleted concrete wall/floor detail. The idea would be to form skirting from the quarter segments and then weld them together in the same way as fusion butt welding full pipes (except by hand). This would provide an excellent termination detail for both the wall waterproofing liner and the floor waterproofing liner, where geomembrane can be extrusion welded to the ‘cove skirting’. The reverse approach could be used around the edge of the scour, which is a drain in the floor where the outer curve of the pipe could be used, to change lining direction and similarly at the foot of the scour the same detail as the floor wall joint could be created where the inner curve of the pipe could be used as a ‘cove skirting’ to change direction of the liner as described above. Even where the corners of the tank are rounded internally it will be possible to create this ‘cove skirting’ detail by cutting out lateral segments of the quarter section and welding them back together to form the curved skirting detail, or simply using geometry cut out of standard pipe bend and t-junction sections. Finally all the cove skirting can be fixed with bolts countersunk sealed with hot extrudate from an extrusion welding machine. Wall Fixing Details At the top of the wall units there may be cast in HDPE profiles where the waterproofing liner will be extrusion welded in order to secure the leading edge of the waterproofing liner. Alternatively the outer liner can pass through the wall roof joint allowing the inner liner to be welded to it by extrusion or fusion welding techniques. It should be an aim to minimise the vertical fusion weld between geomembrane sheets mainly for aesthetic purposes. Rolls of geomembrane are approximately 5.5 m wide or 7.2 m wide this would represent the lined depth of the service reservoir offering and we would intend to try and deploy the waterproofing liner vertically from an articulated dispenser perhaps from a crane. We envisage temporarily bolting a number of modified geomembrane installer's mole cramps to some cast in sockets aligned vertically on one precast unit that would represent the starting point to temporarily pin the end of the geomembrane to the wall allowing the crane to pull out the membrane along the wall. As the process proceeds at regular intervals (to be determined e.g. 1.00 m centres, or less both vertically and horizontally) the geomembrane installer will secure the waterproofing liner to the walls using ‘tabs’ of the waterproofing liner material (e.g. 150 mm×150 mm) welded vertically to the rear of the geomembrane one side only. Then the flap that has been created can be fastened/bolted/shotfired to the wall before the other vertical side of the flap is also welded to the back of the geomembrane (if working space permits). As work on the tabs proceeds in the mid-sheet area of the waterproofing liner it can also be extrusion welded at the top to the cast in profile and at the bottom to the cove skirting detail. Alternatives to this process may exist but do need further investigation and testing: i. Clip together discs for ‘temporarily’ clipping membrane to soffits of tunnels. Increasing the recommended number of these discs per m2 and the fact they are installed on a wall not a soffit may enable their permanent installation on site. ii. Velcro discs for ‘temporary’ securing membrane in tunnels. Again increasing the recommended number may allow these to be relied upon permanently with sufficient testing. iii. Casting in 150×150 tabs of studded cast-in types of liner then ‘gluing’ the back of the wall waterproofing liner to it as it deploys may be an option but again this would require some testing to look at the sort of strength that could be achieved with this method. iv. Casting in 150 mm long ‘tabs’ of HDPE casting profile may also be an option fixed as described in (3) above, again subject to laboratory bond testing. v. Holes cast though the wall units at regular centres would allow coach bolt fixed through a ‘tab’ of waterproofing liner and extrusion welded to the rear face of the waterproofing liner would effectively allow the waterproofing liner to be secured from the outside of the tank. External Waterproofing of Service Reservoir We envisage laying source electrodes, 1000 g conductive geotextile and waterproofing liner directly to the excavated site before the delivery of the precast units and MIT will be carried out. The waterproofing liner would then be protected by a further layer of 1000 g conductive geotextile before either the precast units are placed directly on it, or concrete blinding is poured on top of it. The waterproofing liner can be tested for integrity after the blinding is poured and in the unlikely event of damage any isolated repairs can still be carried out by breaking out areas of damage repairing and recasting before placing of the precast units. Once the internal works are complete with all inlet and outlet pipes installed and the precast roof in place, the lower waterproofing liner can be laid across the roof on top of a layer of source electrodes and conductive textile. The lower roof waterproofing liner is then welded to form a continuous sheet before being ballasted and having further sheets of waterproofing liner extension fitted to its perimeter that can the pass down the sides of the tank and be connected to the waterproofing liner beneath the precast units/concrete blinding layer. Sensors and conductive textile are fitted to the roof area then the primary roof waterproofing liner is fitted over the top secured at the perimeter to the lower waterproofing liner around the perimeter of the tank below the wall joint. Source electrodes can be fixed to the side walls of the service reservoir before the drainage geocomposite is placed over the waterproofing liner on the roof and all the way down the sides of the reservoir. Then final source electrodes for the roof can then be placed on top of the drainage geocomposite. The continuous or remote leak monitoring electronics should already be wired commissioned and running before commencement of the backfilling to the sides or roof. This will allow the testing process to occur as the backfilling progresses with alarms occurring in the event of any damage as the work proceeds. Advantages Structural Design Requirement By encasing the structure in smart membranes, the design eliminates normal concrete (reservoir) code requirements for crack-width control, durability and hygiene. The structure may allowably flex more, have less concrete cover and less prefect surface finishes than would pertain to normal structures exposed to earth and stored water. Precast Slab on Grade Conventionally, precast concrete slabs are not used in ground slab construction due to the difficulty in preparing a bed of sufficient flatness to eliminate excessive stress as a result of high points and low points in the sub-grade. These would conventionally result a rocking action and indeterminate flexural forces with excessive strains which may compromise durability, hygiene and serviceability. Although a self-levelling screed is used to top the sub-base for the protection of the geomembrane, moderate differential settlements do not compromise this structure. The precast concrete slab design consists of two layers of concrete tile strategically overlapped at the joints. This creates a stretcher bond effect to enhance the distribution of load and is so located that the internal columns land centrally on the upper units and never on their joints. This design feature protects the membrane beneath the column and ensures the proper distribution of load to the substrate. Essentially the overlapping tile design eliminates differential shear forces either side of the lower joint lines, which would otherwise result in differential settlement capable of damaging the outer membrane. Placement of Structural Ties in the Slab on Grade. By adapting the edges of the precast floor tiles a void is created for the integration of the structural tie grid required to resist water pressure forces at the base of the perimeter wall units. This avoids any compromise to the membrane by their presence and places the tie forces centrally in the floor plate thus avoiding the potential development of eccentric moment. Waterproofing Component Although a concrete reservoir, the concrete components have no function in the waterproofing integrity of the system. This is a unique feature eliminating dependence on sealant-bond and concrete properties. Demountable Components of an installation may be demounted for use in part, in whole, or as part of larger installations elsewhere. Adaptable The system can be easily enlarged (or reduced) to accommodate future demand requirements. Constructability The innovation brings less reliance on fair weather during construction. Thermal Design The innovation eliminates the requirement for thermal steel design and thermal steel provision as required by the design of large conventional in-situ floor slabs, walls and suspended structures. Construction Impact Significantly fewer personnel are required for less time than with normal construction. Significantly fewer traffic movements are required with less dust, noise, disturbance and impact on neighbours. Transport is optimised by designing elements to realise the load-carrying capabilities of the delivery vehicles. Export Capabilities Complete reservoir assemblies are highly transport efficient—for export, disaster relief and overseas infrastructural development projects. Membrane Continuity The design includes a cantilever perimeter roof beam device which facilitates proper detailing of the membrane. Attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. Each feature disclosed in this specification (including any accompanying claims, abstract and drawings) may be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features. The invention is not restricted to the details of the foregoing embodiment(s). The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed. | <SOH> BACKGROUND <EOH>Within the construction industry there has been a drive for many years to increase offsite manufacturing whilst reducing the amount of site work required as a result. This allows for reductions in site costs and reductions in the risk of injury to site workers on multi-trade sites. This has led to the concept of using prefabricated structural elements that by their nature are then difficult to waterproof due to the arrangement of joints between sections and the potential for differential movement causing connections to become unsound at some future point. It is an object of the present invention to address the abovementioned disadvantages. In order to address the disadvantages identified above, the approach has been developed to produce a composite tank incorporating movement tolerant lining materials with prefabricated structural elements. This combination means that all waterproofing requirements for the structural element design including crack width calculations, movement and general waterproofness can be omitted as design considerations in relation to those structural elements. Furthermore the introduction of electronic leak detection and location systems into the design allows any future leakage both in or out of the fluid retaining structure to be detected, located and repaired without wholesale replacement of the waterproofing layers. According to the present invention there is provided an apparatus and method as set forth in the appended claims. Other features of the invention will be apparent from the dependent claims, and the description which follows. According to a first aspect of the present invention, there is provided a fluid retaining structure having an electronic leak detection and location, ELDL, system, wherein the fluid retaining structure comprises inner and outer liners that form electrical isolation layers of the ELDL system, wherein an electrically conductive signal layer of the ELDL system provides structural rigidity to the fluid retaining structure. Preferably, the electrical isolation layers are adapted to perform fluid retention and ingress prevention functions of the fluid retaining structure. Preferably the liners are waterproofing liners. The electrically conductive signal layer may be made of a concrete-based material. The electrically conductive signal layer may be reinforced with a metal, such as steel or other materials that enhance structural capacity of the concrete. The electrically conductive signal layer may be reinforced with a plurality of metal or other elements that are in electrical contact with each other. Advantageously the concrete provides both an electrically conducting layer for the ELDL system and the structural integrity to support the fluid retaining structure whilst the electrical isolation layers retain fluid therein and prevent fluid from outside entering the structure. A floor section of the outer liner may be located beneath a floor section of the electrically conductive signal layer. The floor section of the electrically conductive signal layer may be a steel reinforced concrete floor. Uniquely the floor section of the electrically conductive signal layer of the fluid retaining structure may be entirely, or substantially, constructed of interlocking precast concrete units that may or may not require tying together with structural ties, equally for the purposes of the ELDL system the floor section of the electrically conductive signal layer could be in situ cast concrete. Wall sections of the outer liner are preferably continuous with the floor section thereof. The wall sections of the outer liner are preferably wrapped around wall sections of the electrically conductive signal layer. The wall sections of the electrically conductive signal layer may be steel reinforced concrete wall sections and may be the structural element of fluid retaining walls. The wall sections of the electrically conductive signal layer may be electrically isolated from each other. One wall section of the electrically conductive signal layer may be electrically isolated from an adjacent wall section of the electrically conductive signal layer. The electrical isolation is to sufficient allow signals from adjacent wall sections of the electrically conductive signal layer to be distinguished from each other. At least one of the wall sections of the electrically conductive signal layer may incorporate cavities, preferably introduced during manufacture. The cavities may be side cavities that preferably extend inwards from side edges of the wall sections of the electrically conductive signal layer. The cavities may be longitudinally tapered. The cavities may be rectilinear, preferably square, in cross-section. The cavities may have the advantageous effect of reducing an amount of concrete used in the wall sections. The wall sections of the electrically conductive signal layer may advantageously incorporate gaps therebetween to allow for the drainage of a leachate. Electrical connections to the control means of the ELDL system may also pass between the wall sections. The wall sections of the outer liner preferably extend and/or wrap over an upper edge or wall plate of the wall section of the electrically conductive signal layer. The outer liner is preferably welded to the inner liner such that it passes through a wall roof joint of the electrically conductive signal layer. However there are other configurations possible where the inner liner is not connected to the outer liner and instead remains separate. The fluid retaining structure may include internal column supports. The internal column supports may be located inside cover elements of the inner liner. The cover elements may be sleeves placed over the column supports. The cover elements may be joined to or part of a floor section of the inner liner. The floor section of the inner liner is preferably located over a floor section of the fluid retaining structure. The cover elements may be welded to the floor section of the inner liner. The fluid retaining structure may include a roof. The roof may be supported by the internal column supports and the wall sections. The roof may or may not also be an element of the electrically conductive signal layer. The outer liner may be wrapped over the roof, whereupon it would be necessary to line the soffit of the roof with the inner liner in the same way as the floor. Alternatively the roof liner may have a dual liner system with conductive medium and sensors between where the lower and upper liners would preferably be welded to the outer liner below the wall roof joint, forming a separate ELDL zone. The fluid retaining structure preferably presents only the inner liner to any contents of the fluid retaining structure. The inner liner preferably prevents any fluid held in the fluid retaining structure from contacting the electrically conductive signal layer in the absence of a leak. Sensors of the ELDL system are preferably located between the inner and outer liners. The sensors may be located in electrical contact with the electrically conductive signal layer. The sensors may be located in openings in the electrically conductive signal layer. Wiring of the ELDL system preferably exits the electrically conductive signal layer at an upper section of the fluid retaining structure. The inner and/or outer liners may be made of sections of non-electrically conducting liner material that are secured together, preferably by welding. According to another aspect of the present invention there is provided a two layer electronic leak detection and location, ELDL, system comprising inner and outer liners and an electrically conductive signal layer comprising sensors, wherein the electrically conductive signal layer provides structural rigidity to allow the ELDL system. Preferably, the electrically conductive signal layer provides the electrical conductivity between the two liners necessary to allow the ELDL system to function. The ELDL system may include control means and a plurality of sensors, wherein the sensors are electrically isolated from each other and in electrical communication to the control means, wherein the sensors have a sheet form. In this case, each sensor may be a wall section of the electrically conductive signal layer. The sensors may be block sensors or tile sensors. The sensors may be physically connected to each other, albeit electrically isolated from each other. The sensors may be physically joined by a non-conducting material, which may form a welded joint between sensors. The sensors may be spaced from each other to leave a gap therebetween, which gap is electrically non-conducting. The electrical communication with the control means may be a wired or wireless communication. According to a another aspect of the present invention, there is provided a method of retaining a fluid in a structure, the structure having an electronic leak detection and location, ELDL, system, wherein the fluid is retained by an inner liner that forms an electrical isolation layer of the ELDL system, wherein an electrically conductive signal layer of the ELDL system provides structural rigidity to the fluid retaining structure. According to another aspect of the present invention, there is provided kit of parts for a fluid retaining structure having an electronic leak detection and location, ELDL, system, wherein the fluid retaining structure comprises inner and outer liners for forming electrical isolation layers of the ELDL system, wherein an electrically conductive signal layer of the ELDL system provides structural rigidity to the fluid retaining structure. According to another aspect of the present invention, there is provided a liner for a fluid retaining structure having an electronic leak detection and location, ELDL, system, wherein the liner is adapted to form an electrical isolation layer of the ELDL system. According to another aspect of the present invention, there is provided a fluid retaining structure adapted to incorporate an electronic leak detection and location, ELDL, system, wherein structural elements of the fluid retaining structure are adapted to form an electrically conductive signal layer of the ELDL system. The references to service reservoir herein should be interpreted to include waste water tanks also. All of the features described herein may be combined with any of the above aspects, in any combination. For a better understanding of the invention, and to show how embodiments of the same may be carried into effect, reference will now be made, by way of example, to the accompanying diagrammatic drawings in which: FIG. 1 is a schematic perspective view of a water impermeable outer geomembrane with a service reservoir floor slab structure laid thereon; FIG. 2 is a schematic perspective view of geomembrane and floor slab with some wall units of the service reservoir in position; FIG. 3 is a schematic perspective view of the structure of FIG. 2 with metal tie bars in position, with the geomembrane omitted for clarity; FIG. 4 is a schematic perspective view of the structure of FIG. 3 with a second layer of floor slabs in position; FIG. 5 is a schematic perspective view of the structure of FIG. 4 with support columns of the service reservoir in position; FIG. 6 is a schematic perspective view of the structure of FIG. 5 with beams located on the support columns of the service reservoir; FIG. 7 is a schematic perspective view of the structure of FIG. 6 with metal roof ties of the service reservoir in position; FIG. 8 is a schematic perspective view of the structure of FIG. 7 with some roof slabs of the service reservoir in position; FIG. 9 is a schematic perspective view of the structure of FIG. 8 with additional roof slabs of the service reservoir in position and the outer geomembrane in position; FIG. 10 is a schematic partial perspective view of the floor slab showing positions of the columns; FIG. 11 is a schematic partial perspective view showing roof/wall joints of the service reservoir; FIG. 12 is a schematic partial perspective cut-away view showing the wall/roof structure; FIG. 13 is schematic partial perspective cut-away view showing a corner of the service reservoir; FIG. 14 is a schematic partial eye level perspective view of the service reservoir; FIG. 15 is a schematic partial perspective cut-away view showing ends of the beams; FIG. 16 is schematic partial perspective cut-away view showing details of the floor slabs and tie bars; FIGS. 17 a - c show schematic front, rear and cross-sectional views of an embodiment of wall section for the service reservoir. detailed-description description="Detailed Description" end="lead"? The fluid retaining structures described herein are exemplified with respect to a service reservoir for drinking water as an example. Other fluid retaining structures are eminently suited to the invention, including slurry tanks, waste water reservoirs, water treatment reservoirs and generally tanks or retaining structures to keep fluids isolated from a surrounding environment. In addition it is conceived that the fluid retaining structure might also be used to create dry storage environment or dry underground accommodation where watertightness of the structure is paramount and monitorable, for example underground data centres or dry storage of contaminated wastes, such as nuclear wastes. A service reservoir incorporating an electronic leak detection and location (ELDL) system is described herein. As shown partially in FIG. 9 , the service reservoir has the following features: a precast interlocking structure using a double stretcher bond configuration, with precast floor 10 made of sub units 10 a (i.e. no in situ cast floor), wall units, or sections, 12 and a roof structure 14 made including lintels 13 and roof units 14 a; ingress leak monitoring of the precast interlocking structure; egress leak monitoring of the precast interlocking structure; corrosion monitoring and/or cathodic protection of metallic components within the precast concrete units; an outer waterproofing liner 16 outside and beneath the precast concrete structure and a protective geotextile inner waterproofing liner 18 (see FIG. 15 , not shown in other Figures for clarity, but takes the form of a flexible liner laid out in the tank to retain water, further details below) inside the interlocking structure. The sub units 10 a of the floor are laid in a double layer stretcher bond configuration. The method of constructing the service reservoir will now be described with reference to the Figures. FIG. 1 shows the outer liner 16 placed on a prepared site. A first layer of floor sub-units 10 a is then laid in a grid pattern on the outer liner 16 . FIG. 2 shows a plurality of wall units 12 placed around the first layer of floor sub-units 10 a . The wall units 12 are shown only partially surrounding the first layer of floor sub-units 10 a for clarity, but the wall units 12 will form a complete tank shape. The wall units in this example include an inner foot 12 a that extends horizontally to support the wall unit 12 in an upright orientation. The wall units also have outer feet 12 b , although these are not essential and may be omitted. FIG. 3 shows tie bars 20 laid across the top of the first layer of floor sub-units 10 a for optional reinforcement. FIG. 4 shows a second layer of floor sub-units 10 b having been placed in position over the first layer of sub-units 10 a and inner feet 12 a of the wall sections 12 , thereby locking the wall units 12 in position. FIG. 5 shows support columns 22 being place in position on top of the second layer of floor sub-units 10 b. FIG. 6 shows lintels 13 being placed in position between tops of the columns 12 . FIG. 7 shows optional tie bars 21 being place in position over the tops of the lintels 13 . FIG. 8 shows roof units 14 a being placed in position on top of the lintels 13 . FIG. 9 shows edge roof units 14 b being placed in position. Various methods of electronic leak detection and location have been disclosed previously. Some of the methods involve the use of a highly resistive plastic geomembrane being installed with electric poles at either side of the membrane. When a fault occurs in the geomembrane an electric connection occurs, which is detected as a current flow. In one system for electronic leak detection and location a single pole on one side of the geomembrane is used and an operator with another pole being connected to earth outside the geomembrane. The operator carries a pair of sensors and when he passes a hole in the geomembrane a polarity shift is detected, leading to the detection and location of the leak. In a more sophisticated system, as described in EP0962754, often referred to as a fixed or permanent leak detection system, a network/grid of point sensors is installed beneath the geomembrane to allow for more accurate detection of a leak. For example, sensors may be spaced on a grid of approximately 3 m×3 m, which spacing can lead to a sensitivity of approximately 300 mm. Other grid spacings are possible, for example at intervals of between 3 and 10 metres. In this installation the sensors are located outside the geomembrane, leaks from which are to be detected. A further improvement of this type of system is to use two layers of geomembrane with the sensors and a conductive geotextile (acting as an electrically conductive signal layer) being located between the two layers of geomembrane (acting as electrical isolation layers) and source electrodes being located outside the two layers of geomembrane in the earth or covering above and below the two geomembranes. The use of two membranes with sensors in between allows an alarm type of detection and location system to be provided, because the sensors are isolated from currents within the material being retained by the geomembrane and also from stray or environmental currents in the earth outside the geomembrane. Thus, when a leak does occur and the moisture leaks into the space between the two geomembranes this allows the electrical signal current to flow with the moisture into the encapsulated conductive textile between the two layers of membrane, the point sensors can detect the increase in current, allowing an alarm condition to be raised if a suitable monitoring system is installed and connected to the point sensors. Such systems exist for both online/permanent monitoring of membrane with suitable monitoring equipment being installed permanently on site and offline systems where only connectors are installed on site requiring power sources and testing equipment to be brought to site in order to test the installed point sensor system manually. In the embodiment described the ingress and egress leak monitoring is achieved by using the concrete structural members as an electrically isolated conductive signal layer between inner and outer geomembranes made of plastics material. | B65D90508 | 20171212 | 20180628 | 58051.0 | B65D9050 | 0 | IHEZIE, JOSHUA K | FLUID RETAINING STRUCTURE | UNDISCOUNTED | 0 | ACCEPTED | B65D | 2,017 |
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15,735,940 | PENDING | Stormwater Biofiltration System and Method | A stormwater treatment system and method for removing sediment, chemical pollutants, and debris from stormwater runoff by utilizing bioretention practices including physical, chemical and biological processes. Stormwater is directed into a primarily open-bottomed, multi-dimensional container whereby entrained sediment and other transportable materials are filtered and treated through a media filter layer consisting of inorganic and/or organic materials. A live plant (preferably a tree) situated within the container with roots resident in the media filter layer with the ability for expansion beyond the perimeter of the container through openings in one or more sidewalls The treated water may be further conveyed beyond the perimeter of the container by additional openings and/or piping. A vertically positioned overflow/bypass/clean out piping apparatus may be included within the stormwater treatment system to provide additional water conveyance. Additional ancillary conveyance, filtration and storage facilities may be connected to the described stormwater treatment system as conditions warrant. | 1. A stormwater treatment system with bioretention functionality comprising at least four vertical sidewalls and a partial horizontal top sidewall affixed to one or more of said sidewalls, wherein when said system is partially buried in the ground, said partial horizontal top sidewall exposes the interior of the system to the atmosphere; further wherein said system contains discrete layers of organic and inorganic material; provided said system does not have a bottom sidewall. 2-4. (canceled) 5. The stormwater treatment system according to claim 1, wherein said organic and inorganic material is confined to the interior of the system. 6. The stormwater treatment system according to claim 1, wherein said organic and inorganic material extends under and out of said system. 7-15. (canceled) 16. The stormwater treatment system according to claim 1, wherein said inorganic material is an aggregate media. 17. The stormwater treatment system according to claim 16, wherein said aggregate media comprises sand, gravel, stone or any combination thereof. 18. The stormwater treatment system according to claim 17, wherein said inorganic media further comprises organic material, provided said inorganic media can filter stormwater entering the system while maintaining moisture to support vegetation growth. 19. The stormwater treatment system according to claim 18, wherein said inorganic media further comprises an additive comprised of iron or aluminum oxide, an expanded ceramic, or a water treatment residual no greater than 20% (±5%) by volume or any combination thereof. 20. The stormwater treatment system according to claim 19, wherein said system contains a third discrete layer of material situated below the organic and inorganic layers comprising stone or aggregate or a combination thereof. 21-23. (canceled) 24. The stormwater treatment system according to claim 20, further comprising a separating layer situated below said third discrete layer. 25. The stormwater treatment system according to claim 24, wherein said separating layer comprises a manufactured geotextile fabric material and/or dimensional stone, provided said dimensional stone is different from the stone comprising the third layer immediately above the separating layer. 26. The stormwater treatment system according to claim 20, further comprising a base situated above or embedded within said separating layer. 27. The stormwater treatment system according to claim 24, wherein soil is located below said separating layer. 28. The stormwater treatment system according to claim 27, further comprising a horizontal under drain pipe embedded with said base and/or separating layer wherein when said drain pipe directs filtered stormwater out of the system into the surrounding ground or to a receiving facility. 29. The stormwater treatment system according to claim 28, wherein said horizontal under drain pipe contains a plurality of openings. 30. (canceled) 31. The stormwater treatment system according to claim 28, further comprising a vertical pipe extending through the opening in the partial horizontal top sidewall wherein said vertical pipe is a clean out access pipe or an overflow or internal bypass conduit or both which directs excess stormwater that enters the system and accumulates at the top of said system out of the system. 32-83. (canceled) | CROSS-REFERENCE TO RELATED APPLICATION This application claims priority to and the benefit of U.S. Provisional Patent Application No. 62/203,618 filed Aug. 11, 2015, U.S. Provisional Patent Application No. 62/253,752, which was filed on Nov. 11, 2015, and U.S. Provisional Patent Application No. 62/314,622 filed Mar. 29, 2016, the entire contents of each are incorporated by reference herein. FIELD OF THE INVENTION The application relates to a filtration system, method, and device to manage and improve the quality of stormwater runoff by removing and remediating pollutant constituents entrained in the water by way of physical, chemical, and biological processes. The invention intended to collect and process stormwater emanating from paved and unpaved surfaces, underground utilities, as well as from building roof drain structures. BACKGROUND OF THE INVENTION Stormwater runoff transports varying quantities of pollutants such as oil/grease, phosphorous, nitrogen, bacteria, heavy metals, pesticides, sediments, and other inorganic and organic constituents with the potential to impair surficial water bodies, infiltrate groundwater and impact aquifer systems. The systemic sources of these pollutants are referred to as either ‘point’ or ‘nonpoint’ (sources). Point source pollution is typically associated with a release such as a spill, or “end of pipe” release from a chemical plant. These are considered releases that can be tracked to a single location. Nonpoint source pollution is not readily discernible with respect to a single location, but is associated with combined pollutant loading and deposition from many sources spread out over a large area including a variety of human activities on land (e.g., excess fertilizer runoff), vehicle emissions (e.g., oil, grease, antifreeze), vehicle material wear (e.g., brake pads, metal on metal rubbing, corrosion), as well as natural characteristics of the soil and erosion, climate, and topography. Sediment transport is the most common form of nonpoint source pollution as it can contain a myriad of soluble and insoluble pollutants, comingled and concentrated and easily transported over impervious and pervious surfaces. Nonpoint source pollution via stormwater runoff is considered to be the primary contributing factor in water degradation. Over the past three decades, many studies have been performed to identify the major pollutant constituents typically found in stormwater, and their relative concentrations found in both urban and suburban runoff. Studies have consistently concluded that pollutant levels, particularly in urban runoff, contain concentrations of nutrients and other pollutants, with the potential to significantly impact receiving waters such as streams, lakes, rivers, as well as our underground groundwater aquifer system. Pollutants in both soluble and insoluble forms such as nitrogen, phosphorous, zinc, copper, petroleum hydrocarbons, and pesticides at various concentrations are commonly found in the stormwater profile. These constituents maintain varying degrees of solubility and transport with some being more mobile than others. Some constituents have a chemical affinity to “sorb” (adsorb/absorb) and collect, or, “hitch a ride,” onto sand particles, sediment, or other non-aqueous matter entrained in the stormwater during transport, thereby increasing the mass of concentration. Sediment laden pollution can also impair waterways due to increased levels of turbidity thereby decreasing sunlight penetration within water bodies, and impairing aquatic life. Historically, stormwater management systems have relied on collection and conveyance via a network of catchments and underground piping that typically transfer and discharge stormwater to a downgradient water body. Additionally, the practice of stormwater detention and/or retention which relies on the collection or transfer of stormwater to surficial ponds or holding areas whereby infiltration takes place, has been a preferred management technique. Both of these management techniques are commonly referred to as “centralized” techniques which were designed primarily to move stormwater from paved areas, without consideration of the pollutant loading effect. Beginning in the early 1980's, academia, municipalities, state and federal environmental regulatory agencies began looking at ways to best mitigate problems associated with nonpoint source pollution and stormwater runoff. Instead of relying solely on centralized stormwater collection and conveyance, a more “decentralized” approach to stormwater management began to evolve. Such traditional physical factors in determining stormwater control practices as site topography soil percolation rates, and degree of impervious cover were integrated with strategic land planning in an attempt to best replicate pre-development conditions and preserve the natural process of direct subsurface infiltration of precipitation. The focus turned to ways in which innovative engineering, and systems design and construction practices in new development and redevelopment could best be employed to reduce the impact from increasing the impervious “footprint” thereby minimizing site impact. The term “best management practices” (BMPs) was used to collectively identify various stormwater control practices and methodologies to achieve decentralized versus centralized management by treating water at its source, instead of at the end of the pipe. Low impact development (LID) is a term used to described a land planning, engineering, and building design approach to managing stormwater runoff. LID emphasizes conservation and use of on-site natural features to protect water quality. This approach implements engineered small-scale hydrologic controls to replicate or mimic the pre-development hydrologic regime of watersheds through infiltrating, filtering, storing, evaporating and detaining runoff close to its source. The LID concept began in Prince George's County, Md. around 1990 by municipal officials as an alternative to traditional centralized control measures. These officials found that traditional practices of detention and retention and associated maintenance were not cost-effective, and many cases, did not meet stormwater management goals, particularly with respect to water quality goals. Today, LID stormwater management practices have shown in many cases to reduce development costs through the reduction or elimination of conventional storm water conveyance and collection systems and infrastructure. Furthermore, LID systems may reduce need for paving, curb and gutter fixtures, piping, inlet structures, and stormwater ponds by treating water at its source instead of at the end of the pipe. Although up-front costs for LID practices can be higher than traditional controls, developers often recoup these expenditures in the form of enhanced community marketability, and higher lot yields. Developers are not the only parties to benefit from the use of LID atom water management techniques, municipalities also benefit in the long term through reduced maintenance costs. Of particular interest in regard to the present invention is a BMP practice based on the principals of “bioretention.” Bioretention is typically defined as the filtering of stormwater runoff through a plant/soil complex to capture, remove, and cycle pollutants by a variety of physical, chemical, and biological processes. Bioretention is a practice that relies on gravity to allow stormwater to infiltrate through natural soil or engineered filter “media” complexes while providing some degree of sediment collection/separation, and encouraging microbial degradation of entrained pollutants. Such bioretention practices as “rain gardens” and “sand filters” which rely on infiltration and natural pollutant attenuation began to be incorporated as part of LID practices beginning in the 1990's. In these systems, the ability and rate of water movement is not based upon structural controls, but more a function of the composition of the media and/or soils and the infiltration capacity. Although sand filters provide some degree of bioretention efficacy, more importantly, rain gardens rely on plant systems to further enhance microbial activity, and assimilate and uptake pollutant constituents such as phosphorous, nitrogen, and various metals in their soluble form. Accumulated test data of pollutant removal rates for bioretention practices have consistency shown high levels of control and attenuation. Federal and state environmental protection agencies recognize infiltration practices as the preferred means for returning rainwater runoff to the natural aquifer system, as opposed to piping and discharging collected stormwater to a downgradient water body location such as a river, lake, or the ocean. Within the past decade, another BMP practice/system which relies on infiltration and bioretention to achieve pollutant removal goals has emerged. This system typically integrates a landscape tree or other plant material with stormwater collection and remediation through an engineered filter media. The system is commonly referred to as a “tree box filter” system. The University of Hampshire Stormwater Center (UNHSC) was one of the earliest institutions to construct and test a tree box filter system. In 2007, UNHSC installed a tree box filter system at their campus test center. The system as designed was an approximately six-foot diameter, three-foot deep, round concrete vault resembling a large inverted concrete pipe. It was filled with a bioretention soil mix composed of approximately 80 percent sand and 20 percent compost. It was underlain horizontally by a perforated “underdrain” pipe at the base of the vault that was connected to, and discharged infiltrated stormwater to an existing stormwater drainage system. The system also contained an open-topped, vertical bypass pipe near the surface to accommodate heavy stormwater events which would otherwise overwhelm the concrete vault. The vault was open-bottomed to provide some direct infiltration to the underlying soils. The filter media was approximately three feet deep and was designed to maximize permeability while providing organic content by the incorporation of compost and native soils to sustain the tree. The vault was designed to be integrated with a street curb opening to collect surface runoff. During a rain event, stormwater migrating along a street curb would enter the curb cut opening and the vault system. The water then infiltrated through the media and was primarily conveyed through the sub drain pipe to the existing (separate) stormwater drainage system. Although the device had the capability of infiltrating stormwater to the surrounding environment through the open bottom, it principally relied on the sub drain pipe to convey stormwater to the existing drainage system. Most recently several proprietary tree box filter systems, and other structural bioretention systems, have been introduced for commercial use and are currently marketed as stormwater treatment devices, for the collection, filtration, and discharge of (treated) stormwater. As with the previously described UNHSC system, these systems are primarily vault systems with enclosed walls. They typically are constructed as a water impermeable precast concrete container with four side walls with a perforated horizontal underdrain pipe located at the base of the container. However, in contrast to the aforementioned UNHSC design system, these proprietary systems typically have a water impermeable bottom wall essentially forming a five-sided container, with a partially open top sidewall to allow for plant growth. They are designed to be integrated with street curbside collection with stormwater entering the system via an opening (throat) on one side of the container. The container typically contains a filter media of specific composition, with an overlying organic mulch media layer. The drain pipe collects and conveys filtered stormwater to an outlet point exterior of the container that is typically connected to a downgradient catch basin or other existing stormwater drainage system structure. The drain pipe is typically embedded in a layer of stone to facilitate collection and transport of all infiltrating water to the outlet point. The collection and treatment capacity of these close sided systems are defined by the horizontal and vertical interior dimensions of the container. Plant material is resident in the container with root growth confined within the container. These systems are designed to collect and infiltrate stormwater emanating from aboveground surfaces, underground storm drains, and building roof runoff. Based on third party evaluation and testing data, these systems have proven to provide effective stormwater quality treatment with the capacity to provide substantial pollutant removal rates. Although tree box filters and other closed box systems have proven to be an effective pollutant removal technology, several perceived deficiencies to their long term efficacy have been identified, which are inspiration and basis of the present invention. Since tree box filter systems inherently closed systems, both the filter media and plant root systems are contained within a five-sided box, therefore, their identifying name. Not unlike a “pot bound” potted plant, the roots of the plant (particularly trees) within a tree box filter are confined and restricted normally developing and freely migrating beyond the walls of the container. It is common knowledge that the majority of tree root growth is in a horizontal versus vertical direction. Roots primarily grow and spread laterally outward, and away from the tree trunk in search of nourishment to include water, nutrients and oxygen. Based on documented studies and an accepted understanding of tree root growth by the arboriculture and horticulture community, as well as an evaluation of tree root systems following disturbance or “wind throw”, as much as 80% of a mature tree's root system typically resides in the top 12 inches of soil. Therefore, a tree's root mass exists, and growth takes place, within a shallow horizontal matrix. It is also understood that a tree's roots normally grow to and beyond the distance of its canopy, or outer perimeter of leaf growth, typically by a factor of two or three times the distance between the trunk and outer edge of the canopy. Therefore, a healthy and thriving tree would require an extensive and unobstructed horizontal dimension to develop properly. A majority of commercial proprietary tree box system containers encompass less than 40 square feet in horizontal dimension. Due to the aforementioned discussion of root growth requirements, an actively growing containerized tree, as typified by a tree box system, would be expected to “outgrow” its horizontal dimension prior to attaining maturity. The negative consequences from the exhaustion of growing area, and the adverse effects of restricting a tree's root system from expanding normally could be the stunting of growth, decline in health, and potential susceptibility to disease and insect infestation. Furthermore, actively growing roots will be deflected in opposing directions following contact with an impenetrable obstacle such as the wall(s) of a tree box container. These roots have the potential to encircle the tree's trunk causing a condition called “girdling” whereby the encircling roots can strangle the tree's trunk as well as other developing roots, choking off nourishment. These debilitating factors could potentially lead to the premature death of the tree. If the tree in a tree box system requires removal and replacement due to decline or premature death, significant labor and material costs would be incurred. To facilitate tree removal, presumably most, if not all of the media within the container would also require removal. This associated cost and labor burden could further be exacerbated due to the potential need to remove existing stone surrounding the aforementioned underdrain piping at the base of the container of the typical tree filter system. Another perceived deficiency due to the effect of the “consumption” of media space by the ever increasing mass of root growth within the confined space of a tree box system would be the eventual reduction of stormwater movement and infiltration through the media filter. Most commercial tree box filter systems depend on rapid stormwater infiltration through the media to achieve treatment goals. The typical tree box filter media is purposely engineered to be of a highly porous open structure composition, primarily consisting of larger particle gravelly sands, thus providing rapid infiltration, as opposed to common landscape or garden soils that typically contain finer particles of sands, silts, and clay that inhibit rapid infiltration. A lesser percentage of the media mix is typically made up of these latter constituents as well as organic materials such as peat moss or compost that have the ability to absorb and retain water. These constituents are critical in providing irrigation for the tree and to sustain root growth, as well as promoting microbial growth for the degradation of some pollutants. However, it is apparent that the ever expanding network of roots of a maturing tree confined within a tree box would be expected (in time) to interfere with and slow down the infiltration of stormwater, thus reducing operational efficiency of the system. An additional perceived deficiency with a conventional commercial tree box filter is that since these systems are primarily closed bottomed, the only means to discharge infiltrated stormwater outside of the tree box is by way of the underdrain pipe. Since this pipe is typically connected a downgradient catch basin, or other closed stormwater management system, there is little opportunity to directly infiltrate quantities of this filtered water to surrounding soils and the groundwater system. If the surrounding soils are sufficiently permeable, as previously explained, direct infiltration is the preferred mode for returning rain water, in the form of treated stormwater, to the groundwater system. Therefore, an open bottomed tree filter system could allow quantities of filtered stormwater to be returned to surrounding subsurface soils and ultimately the groundwater system. Additionally, commercial tree box filter systems typically utilize a four or six-inch diameter drain pipe as the sole means to discharge filtered water from the system container. The quantity of water, and speed for which water could be evacuated from the container, are therefore severely limited due to the use of a small diameter outlet pipe as opposed to an open bottomed system such as the present invention. As previously discussed, tree box filter systems (and other enclosed bioretention based structures) rely on an engineered media of high porosity that allows for the rapid infiltration of stormwater that is entering the system. These medias are composed of inorganic materials to allow for rapid infiltration, and organic materials which retain water within the media to provide irrigation for the plant material. When both inorganic and organic constituents are blended in correct proportions, the resulting engineered media provides a proper balance of high infiltration capacity coupled with sufficient water holding capacity. Recent studies have determined that the incorporation of specific manufactured products or reconstituted rock-based materials formed by expanding specific minerals under intense heat, often referred to as “ceramics”, into an engineered media that has the capacity to adsorb and absorb (sorption) nutrients commonly found in stormwater runoff. Excessive concentrations of specific nutrients such as nitrogen, phosphorus, and soluble metals are known to pollute soils and water bodies. Sorption occurs as a chemical or physical bonding process where nutrients become “attached” to a material as it passes in aqueous solution. Manufactured products such as activated aluminum and activated iron have shown a great affinity for the sorption of soluble phosphorus and other minerals in the aqueous stage. The incorporation of these materials in an engineered media have shown to provide a measurable reduction in soluble phosphorus in stormwater runoff influent. Ceramics such as expanded shale and expanded clay have also shown a propensity for adsorbing minerals such as phosphorus and nitrogen. The mechanism for this sorption reaction is due mainly in part to the presence of tiny holes and fissures within the lattice of the ceramic structure. These holes and fissures are the result of the artificially induced intense heating of the expanded rock during the manufacturing process that causes the material to “pop”, forming these openings. Water treatment plant processes employ manufactured products such as coagulants to remove inorganic and organic matter suspended in the untreated source water. Coagulants have the ability to bind small contaminant particles that are suspended in water which otherwise would avoid initial treatment. Water Treatment Residuals (WTRs) are the products produced following this coagulation process, and treatment process. This resulting product may be a thickened liquid or a dewatered solid, in the solid form, these coagulant residual materials may be either aluminum or iron base oxides and are known to have a strong capacity to retain soluble phosphorus. It has been determined that aluminum and iron based WTRs, when exposed to stormwater influent can continue to capture and retain over 90% of soluble phosphorus, even after several years of continued contact. Incorporating any of these manufactured products including, reconstituted rock, and/or WTRs at no greater than 20% (±5%) by volume with a high infiltrating engineered media achieving an infiltration capacity of greater than 50 (±5 inches per hours would be expected to provide a pollutant removal benefit in systems such as the present invention. Manufactured tree box filter systems and other enclosed bioretention based structures are currently being used in many parts of the country in both commercial and residential applications where a stormwater management system is essential to mitigate non-point source pollution. These systems are typically manufactured of precast concrete by concrete manufacturers or their affiliates. They are customarily delivered pre-filled with filter media and arrive at a site ready for installation and the incorporation of the final plant product. The primary intent of a closed box system design prefilled with media is to be one of a “packaged” and “drop in place” product, uniform in construction, thereby expediting installation and reducing handling time and associated costs. Essentially closed-bottomed and closed-sided pre-cast concrete water impermeable treatment containers are described in U.S. Pat. Nos. 8,333,885, 6,277,274, 6,569,321, and 8,771,515. Several advantages to the present invention as to be detailed in the following description are designed to rectify the perceived deficiencies in current tree box filter systems, as well as provide additional benefit. Some of these advantages include, an open sided and open bottomed design to allow for direct infiltration; incorporating an engineered media amended with a manufactured product(s) or reconstituted rock-based materials to provide greater nutrient pollutant removal efficacy; the ability to service street, and building roof runoff; allow for multiple subsurface pipe openings; and, the ability to use a flexible, impermeable or substantially permeable subsurface liner to provide an enclosed treatment area. These, and other advantages will become apparent from a consideration of the following description and accompanying drawings. BRIEF SUMMARY OF THE INVENTION The present invention is intended to be a stormwater treatment system with bioretention functionality and is designed to treat stormwater runoff emanating from either previous or impervious surfaces (e.g., streets, parking lots, grassed areas, roof tops). An embodiment consists of a primarily open-bottomed container with a top sidewall at least partially open to the atmosphere, and side walls of varying vertical dimension. The container contains a filter media consisting of a mixture of organic and non-organic materials. Portions of the filter media on one or more sides of the container may maintain contact or otherwise communicate with the surrounding native or existing soil. Plant material will be located within the container with vegetative growth emanating through a central opening(s) in the top sidewall portion of the container, with at least partial, or free expression of the attended root system beyond the exterior “footprint” of the container. This and other embodiments and features of the present invention will become apparent from the following detailed description, accompanying illustrative drawings, and appended claims. Definitions The following terms are defined to aid the reader in fully understanding the operation, function, and utility of the present invention. “Accumulating stormwater” as used herein, refers to conditions when the system is inundated with a large volume of stormwater due to a severe storm, such as a hurricane, or a long and/or intense period of rain. “Affixed” as used herein, refers to the possibility that one or more things may be connected, by a variety of means, including, but not limited to a fastening device, such as a hinge, bolt, screw, rebar or the like, and adhesive, such as an epoxy, or a preformed interlocking groove or cutout. Affixed also takes into consideration joining two parts during the manufacturing process wherein the two claimed parts are manufactured as one complete part. “And/or” as used herein, refers to the possibility that both items or one or the other are claimed. For instance, A and/or B refers to the possibility of A only, B only or both A and B are present in the claimed invention. “Aggregate media” as used herein, refers to a sum, mass, or assemblage of various loose particles of inorganic and/or organic matter. “Base” refers to the bottom or lowest part of something; the part on which something rests or is supported. “Bioretention functionality” as used herein, refers to the functioning process in which nutrients, contaminants and aggregate media particles are removed from stormwater runoff through a combination of physical, chemical and biological processes as the water infiltrates and passes through the media layers within the stormwater treatment system. “Clean out access pipe” as used herein, refers to that pipe which is within the container and is positioned in a vertical orientation and connected to the horizontally positioned underdrain pipe. This pipe may also serve the dual purpose as the overflow/bypass pipe which evacuates accumulated water within the container which cannot otherwise infiltrate through the layer(s) of inorganic and/or organic materials of the stormwater treatment system. “Dimensional stone” as used herein, refers to a stone, or rock of a specific size and shape. “Discrete layer” as used herein, refers to an individual layer which is separate and different from any and all other layers. “Elevation” refers to a geographic location and its height above or below a fixed reference point. That which is a “raised elevation” rises above its surrounding elevation. “Filtering media” as used herein, refers to those layers either discrete or in combination of inorganic and/or organic material which have been introduced to and are resident within the container, and potentially exterior of the container. The filtering media allows for the infiltration and flow thru of incoming stormwater and is designed to provide treatment for nutrients and contaminants entrained in the water. “Fittings” as used herein, refer to those fixtures and furnishings used to connect and interconnect plastic pipe in combination with plumbing and drain systems allowing for multi directional positioning both vertically and horizontal. Fittings could include, but are not limited, to such items as known in the commercial trade as valves, elbows, tees, wyes, and unions, and the like. “Geotextile fabric material” as used herein, refers to permeable fabrics which have the ability to separate and maintain segregation between two discrete layers of inorganic or organic materials while still allowing for the infiltration of water between the two layers. Geotextile fabrics are typically constructed of fiberglass, polypropylene, polyester, or the like. “Impermeable material” as used herein, refers to those materials whether natural or synthetic which restrict a thing or force from penetrating said material. Impermeability is the resistance to that potential penetration. “Impervious subsurface membrane liner” as used herein, refers to a synthetic, flexible material which acts as a barrier to separate and maintain segregation between two discrete layers of inorganic and/or organic materials thus preventing the infiltration of water between the two layers. “In contact with” as used herein, refers to conditions when an action with one element causes a secondary action in a second element. For instance, when two pipes are “in contact with” each other, stormwater may flow from one pipe to a second pipe when said pipes are “in contact with” each other. “Interior” refers to the space created when all sidewalls are affixed to each other. “Inorganic material” refers to matter which is not derived from living organisms and contains no organically produced carbon. It includes rocks, minerals and metals. Inorganic matter can be formally defined with reference to what they are not: organic compounds. “Manifold pipes” refers to a combination of one or more smaller pipes or channels which lead out from a bigger pipe, typically in a perpendicular radius from the bigger pipe. A manifold is a component that is used to regulate fluid flow in a hydraulic system, thus controlling the transfer of water. “Open public area” to those areas that are open for public access and use. These areas may be owned by a national or local government body, ‘public’ body (e.g. a not-for-profit organization) and held in trust for the public, or owned by a private individual or organization but made available for public use or available public access “Organic material” refers to matter that was once alive and is in various states of decomposition. Dead plants, animals, bacteria and fungi are all examples of organic material. “Overflow or internal bypass conduit” as used herein, refers to a vertical pipe and passage by which to evacuate and convey excess stormwater that enters the container and then rises above the surface of the media and otherwise inundate the container. This condition typically arises when the rate and volume of water entering the container is greater than the ability of the media to infiltrate and transfer the water. “Partial horizontal top sidewall” as used herein, refers to the top portion of the container, either separate or affixed to the container, which is at least partially open to the surrounding environment. “Receiving facility” as used herein, refers to those structures or land masses either natural or man-made which receive incoming stormwater from another so defined facility. “Separating layer” as used herein, refers to an individual layer which is separate and different in characteristics and/or properties from that of the overlying and underlying layers. “Stormwater” refers to water that originates during precipitation events and snow/ice melt. Stormwater can soak into the soil (infiltrate), be held on the surface and evaporate, or runoff and end up in nearby streams, rivers, or other water bodies (surface water). “Stormwater receiving receptor” as used herein, refers to those bodies of land or water which receive stormwater from upgradient location associated with the stormwater management system of the present invention. The receptor may be sensitive to and/or otherwise impacted by the receiving waters and potential contaminant load. “Stormwater treatment system” as used herein, refer to the interior and exterior components of the present invention. “Straight line pipes” as used herein, refers to those pipes that traverse or travel across a surface in one continuous direction. “Vertical sidewall” as used herein, refers to one of four sides that form the vertical dimension of the container. “Watertight”'refers to a material or thing that is closely sealed, fastened, or fitted so that no water enters or passes through it. “Water treatment residual” refers to the waste by-product that is produced as part of water treatment processes to contaminants. These residuals form when suspended solids in the target water react with chemicals (e.g., coagulants) added in the treatment processes and associated process control chemicals (e.g., lime). These residuals have the ability to adsorb or otherwise attract and bind nutrients such as phosphorus to its surface. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a cutaway perspective various aspects of a stormwater treatment system of the present invention. FIG. 2 is a cutaway cross-sectional view of the first embodiment of the stormwater management system of the present invention with internal collection and discharge piping. FIGS. 3(a), 3(b), and 3(c) is a cutaway perspective view, plan view, and cutaway perspective view, respectively, of a second embodiment of a stormwater management system of the present invention. FIG. 4 is a cutaway perspective view of a third embodiment of a stormwater management system of the present invention with a separate top slab. FIGS. 5(a) and 5(b) is a cutaway cross-sectional view, and plan view, respectively, of a fourth embodiment of inflow and outflow pipes and openings of a stormwater management system of the present invention. FIG. 6 is a cutaway cross-sectional view of a fifth embodiment of a stormwater management system of the present invention. FIGS. 7(a) and 7(b) is a cutaway perspective view, and plan view, respectively, of a sixth embodiment of a stormwater management system of the present invention. These renderings are included for illustrative and interpretive purposes relative to specific embodiments and applications and should not be construed as the sole positioning, configurations, or singular use of the present invention. DESCRIPTION OF PREFERRED EMBODIMENTS The present invention is designed to be a stormwater management system hereby stormwater combined with mixed debris, sands, sediment, entrained and dissolved chemical and biological pollutants are separated, treated and/or remediated via physical, chemical, and biological processes prior to being infiltrated to the subsurface environment, and/or discharged to a separate drainage system. Referring now to the drawings, and specifically to FIG. 1, the present invention is comprised of a substantially water impermeable open bottomed container 1 of various dimensions and configurations with an open bottom and vertical sidewalls 10, 11, 12, 13, of various height and enclosure, and horizontal (top) sidewall 2 at least partially open to the environment. The container contains a mixture and/or discreet layer(s) of both organic and inorganic materials (media) which may or may not extend beyond the outside perimeter of the container. The container maintains vegetative plant(s) 5 whose roots 8 are resident in the media and are able to communicate unrestricted with the surrounding native soils or introduced soils 9. While continuing to reference FIG. 1, and also FIG. 2, the following description includes the preferred embodiment, manner of operation, and pollutant removal function(s). Stormwater enters the substantially water impermeable open-bottomed container 1 through one or more openings located on the container or through an opening 3 on a sidewall that abuts a street or impervious surface 4 with associated curbing 7. The preferred embodiment of the container is of a water tight concrete, metal, or plastic (or other impermeable substance) fabrication. The configuration, horizontal dimensions and shape of this container is primarily determined based on site logistics, and the size of the appropriate media dimensions to accommodate the flow emanating from the contribution area that makes up the incoming stormwater flow. Incoming stormwater flows immediately into the container 1, quantities of sand, sediment, and other floatable or non-floatable matter entrained within the stormwater flow also enters the container and accumulate on the surface of the media 6. As the water infiltrates through the media, additional quantities of sands and sediment may either become resident in the media or continue entrained with the water flow. Additionally, organic nutrients such as nitrogen and phosphorus, amongst others, and metals such as zinc and copper, amongst others, within the stormwater flow may adhere to the aggregate media and/or continue to pass through the media. The media is comprised of a mixture of aggregates (e.g., sand, gravel, stone), and organics, to achieve a substantial rate of infiltration, while maintaining moisture holding capacity to maintain biological activity and support plant growth. An embodiment would be the incorporation of an additive in the aggregate media that would contain an iron or aluminum oxide product, an expanded ceramic, and/or a water treatment residual of no greater than 20% (±5%) by volume to enhance the nutrient removal potential of the non-amended media. The water infiltrates through, and then exits the media layer of the container. The infiltrating water than typically communicates with an underlying layer of stone or other aggregate 14. A preferred embodiment would be a “separating” layer 19 consisting of either or both a manufactured geotextile fabric material, and a dimensional stone differing from that of the aforementioned underlying layer of stone/aggregate. The base of the container is envisioned to either rest on top of this stone/aggregate layer, or be partially embedded within this layer. It is envisioned that native soils or introduced soils 9 would be resident below this layer of stone. Depending upon the infiltration capacity of these soils, water would be allowed to freely migrate and/or infiltrate both vertically and horizontally. A preferred embodiment would be that an underdrain pipe 15 is provided adjacent to the bottom of the container within the stone layer 14 having a plurality of openings 16 that receive the infiltrating stormwater as it flows through the overlying media. This stormwater may then be transferred outside the footprint of the container and directed to another receiving facility. Associated with the underdrain pipe is a vertical pipe 17 which serves as either a cleanout access pipe, or as an overflow or internal bypass conduit to collect and transfer incoming stormwater that enters the container and then rises above the surface of the media. This vertical pipe is accessible through an opening(s) in the top sidewall 2. A plastic, fiberglass or metal-based fabricated grate or plate 50 may enclose portions of the top sidewall of the container. An opening 20 within the grate would allow the plant's trunk to extend through the grate and the top sidewall. The grate may be fixed or secured to the top sidewall of the container by way of fastening devices or other appurtenances. FIGS. 3(a), 3(b) and 3(c) depicts the first embodiment of the present invention which incorporates one or more openings 21, 22, 23, 24 on one or more sidewalls 10, 11, 12, 13 of the container to service one or more incoming and/or outgoing pipes 42, 43, 44 of predetermined dimension and length either straight line or manifold 41 with fittings 45 to receive and/or discharge stormwater communication with the container 1 of the present invention. These pipes could be accessed through the top sidewall 2 of the container, or through a surface grate or plate 50. The ability to connect piping in a multi-directional configuration allows for more flexibility in positioning the stormwater treatment system for both receiving incoming stormwater and discharging outgoing stormwater. Now referring specifically to FIG. 3(c), this embodiment incorporates one or more openings 91, 92 on one or more sidewalls of the container 1 to allow for the free movement of water that has accumulated above the media within the container to flow horizontally beyond the exterior walls of the container, and thereby further communicate with the media 6, and adjoining soil 9, providing a more expansive infiltration area. Now referring to FIG. 4 of a stormwater management system of the present invention, another embodiment of the invention would be that the container would be fabricated in two or more sections with a separate top slab 60 that would rest on or be affixed to the four sides, 61, 62 63, 64 of the container. Having a separate top slab would allow for making slight surficial elevational and side-to-side adjustments if site conditions require such adjustment. A separate top slab would also lessen the overall filling weight of the structure at time of installation particularly for large dimension containers. FIGS. 5a, and 5b depict another embodiment of the present invention which allows for incoming pipes from deeper elevations to enter the container. Often times, due to the location and elevation of upgradient catch basins or other facilities that collect stormwater for discharge to a stormwater management system such as the present invention, the point of entry to the container must be several feet below surface grade. Such factors as existing site conditions, drainage layout plans, and natural or artificial slopes, stormwater conveyance pipes must traverse a subject site at elevations several feet below ground surface 70. In this embodiment one or more incoming pipes 71 would enter the container at a depth below ground surface. Incoming water would discharge into a closed bottomed four-sided chamber 72 which is monolithic or attached to the container and would be composed of concrete, metal, or a plastic material. As the water rises within this chamber, it would flow over the interior top sidewall 73 of the chamber, and/or flow through one or more pipes 74 that have been cast in, or are otherwise traversing through the interior sidewall of the chamber. The water would then flow onto the media 6 within the container, and infiltrate through the media, as detailed in the present invention of FIGS. 1 & 2. FIG. 6 depicts another embodiment which illustrates a particular piping schematic of the present invention as a stormwater management system that accepts incoming water from an underground pipe emanating from either a building's roof, or an upgradient source or location such as an underground pipe, catch basin and/or other storm water receiving receptor. Water enters the container from an inlet pipe 80 situated on a primarily horizontal plane. Water passing over one or more openings 81 located on the inlet pipe, would have the ability to flow through the openings and make contact with the surface of the media 6 within the container. Water which is not able to flow through the aforementioned openings, would continue to flow through the pipe before connecting with a separate underdrain pipe 82 with a plurality of openings that is collecting infiltrating water flow. Both flows would then combine and continue on a primarily horizontal plane and then exit through one or more sides of the container. An embodiment would be that a vertical riser pipe 83 with an open or closed top 84 may be connected to the horizontal underdrain pipe. The purpose of this pipe would be to collect water that rises above the surface of the media within the container for evacuation through the underdrain pipe, or another outlet point; and/or to serve as a cleanout port to be accessed through an opening in the top 85 of the container or through an associated grate, plate or other removable fixture 86. FIGS. 7a and 7b depicts still another embodiment with similar configuration to previous figures represented of the present invention. In this embodiment, a flexible impervious or semi-impervious subsurface membrane liner 55 surrounds a substantial portion of the container 1. The purpose of this liner would be to provide a barrier between the container and media 6 associated with the container, and that of native or adjoining soils 56. Inlet and outlet piping of various diameter would be able to penetrate and otherwise traverse the wall of the liner. Such circumstances which may include this embodiment would be if the stormwater management system of the present invention was located proximal to identified sensitive environmental receptors which require protection or segregation. Such examples of these receptors could be water bodies 57, wetlands, drinking water protection areas and other examples. Another circumstance where the embodiment of a liner and/or barrier would be beneficial would be if contaminated soil or groundwater was present proximal to the stormwater management system, whereby infiltrating water associated with the stormwater management system could potentially comingle with or otherwise make contact with contaminated soil or groundwater thereby spreading the contamination further. The use of a flexible liner would also allow for the expansion of the collection and treatment area beyond the “foot print” of the container, and therefore not be constrained by the dimensions of the container, allowing for the maximization of the filtrating media area. The flexible impervious or semi-impervious subsurface membrane liner is envisioned to be composed of rubber, polyethylene, or other material(s) either unique or in composite and typically designed to be a barrier to separate one physical area from another physical area. Several of the embodiments of the invention may be connected to a sump pump. A sump pump is a pump used to remove water that has accumulated in a water collecting sump basin, commonly found in the basement of homes. The water may enter the perimeter drains of a basement waterproofing system, funneling into the basin or because of rain or natural ground water, if the basement is below the water table level. Sump pumps are used where basement flooding happens regularly and to solve dampness where the water table is above the foundation of a home. Sump pumps send water away from a house to any place where it is no longer problematic, such as the stormwater treatment system of the present invention. There are generally two types of sump pumps—pedestal and submersible. In the case of the pedestal pump, the motor is mounted above the sump—where it is more easily serviced, but is also more conspicuous. The pump impeller is driven by a long, vertical extension shaft and the impeller is in a scroll housing in the base of the pump. The submersible pump, on the other hand, is entirely mounted inside the sump, and is specially sealed to prevent electrical short circuits. There is debate about which variety of sump pump is better. Pedestal sump pumps usually last longer (25 to 30 years) if they are installed properly and kept free of debris. They are less expensive and easier to remove. Submersible pumps will only last 5 to 15 years. They are more expensive to purchase but can take up debris without clogging. Sump pump systems are also utilized in industrial and commercial applications to control water table-related problems in surface soil. An artesian aquifer or periodic high water table situation can cause the ground to become unstable due to water saturation. As long as the pump functions, the surface soil will remain stable. These sumps are typically ten feet in depth or more; lined with corrugated metal pipe that contains perforations or drain holes throughout. They may include electronic control systems with visual and audible alarms and are usually covered to prevent debris and animals from falling in. The foregoing descriptions and drawings should be assumed as illustrative only of the principles of the invention. The invention may be configured in a variety of shapes and sizes and is not limited by the aforementioned dimensions, construction and operation of the identified parts, materials or embodiments. It is understood that numerous modifications, changes, and substitutions of the invention will readily occur to those skilled in the art and may be resorted to falling within the scope and spirit the invention. While the previous description contains many specifics, these should not be construed as limitations on the scope of the invention, but as exemplifications of the presently preferred embodiments thereof. Thus the scope of the invention should be determined by the appended claims and their legal equivalents. It is not desired to be limited to the exact details of construction shown and described for obvious modifications will occur to a person skilled in the art, without departing from the spirit and scope of the appended claims. | <SOH> BACKGROUND OF THE INVENTION <EOH>Stormwater runoff transports varying quantities of pollutants such as oil/grease, phosphorous, nitrogen, bacteria, heavy metals, pesticides, sediments, and other inorganic and organic constituents with the potential to impair surficial water bodies, infiltrate groundwater and impact aquifer systems. The systemic sources of these pollutants are referred to as either ‘point’ or ‘nonpoint’ (sources). Point source pollution is typically associated with a release such as a spill, or “end of pipe” release from a chemical plant. These are considered releases that can be tracked to a single location. Nonpoint source pollution is not readily discernible with respect to a single location, but is associated with combined pollutant loading and deposition from many sources spread out over a large area including a variety of human activities on land (e.g., excess fertilizer runoff), vehicle emissions (e.g., oil, grease, antifreeze), vehicle material wear (e.g., brake pads, metal on metal rubbing, corrosion), as well as natural characteristics of the soil and erosion, climate, and topography. Sediment transport is the most common form of nonpoint source pollution as it can contain a myriad of soluble and insoluble pollutants, comingled and concentrated and easily transported over impervious and pervious surfaces. Nonpoint source pollution via stormwater runoff is considered to be the primary contributing factor in water degradation. Over the past three decades, many studies have been performed to identify the major pollutant constituents typically found in stormwater, and their relative concentrations found in both urban and suburban runoff. Studies have consistently concluded that pollutant levels, particularly in urban runoff, contain concentrations of nutrients and other pollutants, with the potential to significantly impact receiving waters such as streams, lakes, rivers, as well as our underground groundwater aquifer system. Pollutants in both soluble and insoluble forms such as nitrogen, phosphorous, zinc, copper, petroleum hydrocarbons, and pesticides at various concentrations are commonly found in the stormwater profile. These constituents maintain varying degrees of solubility and transport with some being more mobile than others. Some constituents have a chemical affinity to “sorb” (adsorb/absorb) and collect, or, “hitch a ride,” onto sand particles, sediment, or other non-aqueous matter entrained in the stormwater during transport, thereby increasing the mass of concentration. Sediment laden pollution can also impair waterways due to increased levels of turbidity thereby decreasing sunlight penetration within water bodies, and impairing aquatic life. Historically, stormwater management systems have relied on collection and conveyance via a network of catchments and underground piping that typically transfer and discharge stormwater to a downgradient water body. Additionally, the practice of stormwater detention and/or retention which relies on the collection or transfer of stormwater to surficial ponds or holding areas whereby infiltration takes place, has been a preferred management technique. Both of these management techniques are commonly referred to as “centralized” techniques which were designed primarily to move stormwater from paved areas, without consideration of the pollutant loading effect. Beginning in the early 1980's, academia, municipalities, state and federal environmental regulatory agencies began looking at ways to best mitigate problems associated with nonpoint source pollution and stormwater runoff. Instead of relying solely on centralized stormwater collection and conveyance, a more “decentralized” approach to stormwater management began to evolve. Such traditional physical factors in determining stormwater control practices as site topography soil percolation rates, and degree of impervious cover were integrated with strategic land planning in an attempt to best replicate pre-development conditions and preserve the natural process of direct subsurface infiltration of precipitation. The focus turned to ways in which innovative engineering, and systems design and construction practices in new development and redevelopment could best be employed to reduce the impact from increasing the impervious “footprint” thereby minimizing site impact. The term “best management practices” (BMPs) was used to collectively identify various stormwater control practices and methodologies to achieve decentralized versus centralized management by treating water at its source, instead of at the end of the pipe. Low impact development (LID) is a term used to described a land planning, engineering, and building design approach to managing stormwater runoff. LID emphasizes conservation and use of on-site natural features to protect water quality. This approach implements engineered small-scale hydrologic controls to replicate or mimic the pre-development hydrologic regime of watersheds through infiltrating, filtering, storing, evaporating and detaining runoff close to its source. The LID concept began in Prince George's County, Md. around 1990 by municipal officials as an alternative to traditional centralized control measures. These officials found that traditional practices of detention and retention and associated maintenance were not cost-effective, and many cases, did not meet stormwater management goals, particularly with respect to water quality goals. Today, LID stormwater management practices have shown in many cases to reduce development costs through the reduction or elimination of conventional storm water conveyance and collection systems and infrastructure. Furthermore, LID systems may reduce need for paving, curb and gutter fixtures, piping, inlet structures, and stormwater ponds by treating water at its source instead of at the end of the pipe. Although up-front costs for LID practices can be higher than traditional controls, developers often recoup these expenditures in the form of enhanced community marketability, and higher lot yields. Developers are not the only parties to benefit from the use of LID atom water management techniques, municipalities also benefit in the long term through reduced maintenance costs. Of particular interest in regard to the present invention is a BMP practice based on the principals of “bioretention.” Bioretention is typically defined as the filtering of stormwater runoff through a plant/soil complex to capture, remove, and cycle pollutants by a variety of physical, chemical, and biological processes. Bioretention is a practice that relies on gravity to allow stormwater to infiltrate through natural soil or engineered filter “media” complexes while providing some degree of sediment collection/separation, and encouraging microbial degradation of entrained pollutants. Such bioretention practices as “rain gardens” and “sand filters” which rely on infiltration and natural pollutant attenuation began to be incorporated as part of LID practices beginning in the 1990's. In these systems, the ability and rate of water movement is not based upon structural controls, but more a function of the composition of the media and/or soils and the infiltration capacity. Although sand filters provide some degree of bioretention efficacy, more importantly, rain gardens rely on plant systems to further enhance microbial activity, and assimilate and uptake pollutant constituents such as phosphorous, nitrogen, and various metals in their soluble form. Accumulated test data of pollutant removal rates for bioretention practices have consistency shown high levels of control and attenuation. Federal and state environmental protection agencies recognize infiltration practices as the preferred means for returning rainwater runoff to the natural aquifer system, as opposed to piping and discharging collected stormwater to a downgradient water body location such as a river, lake, or the ocean. Within the past decade, another BMP practice/system which relies on infiltration and bioretention to achieve pollutant removal goals has emerged. This system typically integrates a landscape tree or other plant material with stormwater collection and remediation through an engineered filter media. The system is commonly referred to as a “tree box filter” system. The University of Hampshire Stormwater Center (UNHSC) was one of the earliest institutions to construct and test a tree box filter system. In 2007, UNHSC installed a tree box filter system at their campus test center. The system as designed was an approximately six-foot diameter, three-foot deep, round concrete vault resembling a large inverted concrete pipe. It was filled with a bioretention soil mix composed of approximately 80 percent sand and 20 percent compost. It was underlain horizontally by a perforated “underdrain” pipe at the base of the vault that was connected to, and discharged infiltrated stormwater to an existing stormwater drainage system. The system also contained an open-topped, vertical bypass pipe near the surface to accommodate heavy stormwater events which would otherwise overwhelm the concrete vault. The vault was open-bottomed to provide some direct infiltration to the underlying soils. The filter media was approximately three feet deep and was designed to maximize permeability while providing organic content by the incorporation of compost and native soils to sustain the tree. The vault was designed to be integrated with a street curb opening to collect surface runoff. During a rain event, stormwater migrating along a street curb would enter the curb cut opening and the vault system. The water then infiltrated through the media and was primarily conveyed through the sub drain pipe to the existing (separate) stormwater drainage system. Although the device had the capability of infiltrating stormwater to the surrounding environment through the open bottom, it principally relied on the sub drain pipe to convey stormwater to the existing drainage system. Most recently several proprietary tree box filter systems, and other structural bioretention systems, have been introduced for commercial use and are currently marketed as stormwater treatment devices, for the collection, filtration, and discharge of (treated) stormwater. As with the previously described UNHSC system, these systems are primarily vault systems with enclosed walls. They typically are constructed as a water impermeable precast concrete container with four side walls with a perforated horizontal underdrain pipe located at the base of the container. However, in contrast to the aforementioned UNHSC design system, these proprietary systems typically have a water impermeable bottom wall essentially forming a five-sided container, with a partially open top sidewall to allow for plant growth. They are designed to be integrated with street curbside collection with stormwater entering the system via an opening (throat) on one side of the container. The container typically contains a filter media of specific composition, with an overlying organic mulch media layer. The drain pipe collects and conveys filtered stormwater to an outlet point exterior of the container that is typically connected to a downgradient catch basin or other existing stormwater drainage system structure. The drain pipe is typically embedded in a layer of stone to facilitate collection and transport of all infiltrating water to the outlet point. The collection and treatment capacity of these close sided systems are defined by the horizontal and vertical interior dimensions of the container. Plant material is resident in the container with root growth confined within the container. These systems are designed to collect and infiltrate stormwater emanating from aboveground surfaces, underground storm drains, and building roof runoff. Based on third party evaluation and testing data, these systems have proven to provide effective stormwater quality treatment with the capacity to provide substantial pollutant removal rates. Although tree box filters and other closed box systems have proven to be an effective pollutant removal technology, several perceived deficiencies to their long term efficacy have been identified, which are inspiration and basis of the present invention. Since tree box filter systems inherently closed systems, both the filter media and plant root systems are contained within a five-sided box, therefore, their identifying name. Not unlike a “pot bound” potted plant, the roots of the plant (particularly trees) within a tree box filter are confined and restricted normally developing and freely migrating beyond the walls of the container. It is common knowledge that the majority of tree root growth is in a horizontal versus vertical direction. Roots primarily grow and spread laterally outward, and away from the tree trunk in search of nourishment to include water, nutrients and oxygen. Based on documented studies and an accepted understanding of tree root growth by the arboriculture and horticulture community, as well as an evaluation of tree root systems following disturbance or “wind throw”, as much as 80% of a mature tree's root system typically resides in the top 12 inches of soil. Therefore, a tree's root mass exists, and growth takes place, within a shallow horizontal matrix. It is also understood that a tree's roots normally grow to and beyond the distance of its canopy, or outer perimeter of leaf growth, typically by a factor of two or three times the distance between the trunk and outer edge of the canopy. Therefore, a healthy and thriving tree would require an extensive and unobstructed horizontal dimension to develop properly. A majority of commercial proprietary tree box system containers encompass less than 40 square feet in horizontal dimension. Due to the aforementioned discussion of root growth requirements, an actively growing containerized tree, as typified by a tree box system, would be expected to “outgrow” its horizontal dimension prior to attaining maturity. The negative consequences from the exhaustion of growing area, and the adverse effects of restricting a tree's root system from expanding normally could be the stunting of growth, decline in health, and potential susceptibility to disease and insect infestation. Furthermore, actively growing roots will be deflected in opposing directions following contact with an impenetrable obstacle such as the wall(s) of a tree box container. These roots have the potential to encircle the tree's trunk causing a condition called “girdling” whereby the encircling roots can strangle the tree's trunk as well as other developing roots, choking off nourishment. These debilitating factors could potentially lead to the premature death of the tree. If the tree in a tree box system requires removal and replacement due to decline or premature death, significant labor and material costs would be incurred. To facilitate tree removal, presumably most, if not all of the media within the container would also require removal. This associated cost and labor burden could further be exacerbated due to the potential need to remove existing stone surrounding the aforementioned underdrain piping at the base of the container of the typical tree filter system. Another perceived deficiency due to the effect of the “consumption” of media space by the ever increasing mass of root growth within the confined space of a tree box system would be the eventual reduction of stormwater movement and infiltration through the media filter. Most commercial tree box filter systems depend on rapid stormwater infiltration through the media to achieve treatment goals. The typical tree box filter media is purposely engineered to be of a highly porous open structure composition, primarily consisting of larger particle gravelly sands, thus providing rapid infiltration, as opposed to common landscape or garden soils that typically contain finer particles of sands, silts, and clay that inhibit rapid infiltration. A lesser percentage of the media mix is typically made up of these latter constituents as well as organic materials such as peat moss or compost that have the ability to absorb and retain water. These constituents are critical in providing irrigation for the tree and to sustain root growth, as well as promoting microbial growth for the degradation of some pollutants. However, it is apparent that the ever expanding network of roots of a maturing tree confined within a tree box would be expected (in time) to interfere with and slow down the infiltration of stormwater, thus reducing operational efficiency of the system. An additional perceived deficiency with a conventional commercial tree box filter is that since these systems are primarily closed bottomed, the only means to discharge infiltrated stormwater outside of the tree box is by way of the underdrain pipe. Since this pipe is typically connected a downgradient catch basin, or other closed stormwater management system, there is little opportunity to directly infiltrate quantities of this filtered water to surrounding soils and the groundwater system. If the surrounding soils are sufficiently permeable, as previously explained, direct infiltration is the preferred mode for returning rain water, in the form of treated stormwater, to the groundwater system. Therefore, an open bottomed tree filter system could allow quantities of filtered stormwater to be returned to surrounding subsurface soils and ultimately the groundwater system. Additionally, commercial tree box filter systems typically utilize a four or six-inch diameter drain pipe as the sole means to discharge filtered water from the system container. The quantity of water, and speed for which water could be evacuated from the container, are therefore severely limited due to the use of a small diameter outlet pipe as opposed to an open bottomed system such as the present invention. As previously discussed, tree box filter systems (and other enclosed bioretention based structures) rely on an engineered media of high porosity that allows for the rapid infiltration of stormwater that is entering the system. These medias are composed of inorganic materials to allow for rapid infiltration, and organic materials which retain water within the media to provide irrigation for the plant material. When both inorganic and organic constituents are blended in correct proportions, the resulting engineered media provides a proper balance of high infiltration capacity coupled with sufficient water holding capacity. Recent studies have determined that the incorporation of specific manufactured products or reconstituted rock-based materials formed by expanding specific minerals under intense heat, often referred to as “ceramics”, into an engineered media that has the capacity to adsorb and absorb (sorption) nutrients commonly found in stormwater runoff. Excessive concentrations of specific nutrients such as nitrogen, phosphorus, and soluble metals are known to pollute soils and water bodies. Sorption occurs as a chemical or physical bonding process where nutrients become “attached” to a material as it passes in aqueous solution. Manufactured products such as activated aluminum and activated iron have shown a great affinity for the sorption of soluble phosphorus and other minerals in the aqueous stage. The incorporation of these materials in an engineered media have shown to provide a measurable reduction in soluble phosphorus in stormwater runoff influent. Ceramics such as expanded shale and expanded clay have also shown a propensity for adsorbing minerals such as phosphorus and nitrogen. The mechanism for this sorption reaction is due mainly in part to the presence of tiny holes and fissures within the lattice of the ceramic structure. These holes and fissures are the result of the artificially induced intense heating of the expanded rock during the manufacturing process that causes the material to “pop”, forming these openings. Water treatment plant processes employ manufactured products such as coagulants to remove inorganic and organic matter suspended in the untreated source water. Coagulants have the ability to bind small contaminant particles that are suspended in water which otherwise would avoid initial treatment. Water Treatment Residuals (WTRs) are the products produced following this coagulation process, and treatment process. This resulting product may be a thickened liquid or a dewatered solid, in the solid form, these coagulant residual materials may be either aluminum or iron base oxides and are known to have a strong capacity to retain soluble phosphorus. It has been determined that aluminum and iron based WTRs, when exposed to stormwater influent can continue to capture and retain over 90% of soluble phosphorus, even after several years of continued contact. Incorporating any of these manufactured products including, reconstituted rock, and/or WTRs at no greater than 20% (±5%) by volume with a high infiltrating engineered media achieving an infiltration capacity of greater than 50 (±5 inches per hours would be expected to provide a pollutant removal benefit in systems such as the present invention. Manufactured tree box filter systems and other enclosed bioretention based structures are currently being used in many parts of the country in both commercial and residential applications where a stormwater management system is essential to mitigate non-point source pollution. These systems are typically manufactured of precast concrete by concrete manufacturers or their affiliates. They are customarily delivered pre-filled with filter media and arrive at a site ready for installation and the incorporation of the final plant product. The primary intent of a closed box system design prefilled with media is to be one of a “packaged” and “drop in place” product, uniform in construction, thereby expediting installation and reducing handling time and associated costs. Essentially closed-bottomed and closed-sided pre-cast concrete water impermeable treatment containers are described in U.S. Pat. Nos. 8,333,885, 6,277,274, 6,569,321, and 8,771,515. Several advantages to the present invention as to be detailed in the following description are designed to rectify the perceived deficiencies in current tree box filter systems, as well as provide additional benefit. Some of these advantages include, an open sided and open bottomed design to allow for direct infiltration; incorporating an engineered media amended with a manufactured product(s) or reconstituted rock-based materials to provide greater nutrient pollutant removal efficacy; the ability to service street, and building roof runoff; allow for multiple subsurface pipe openings; and, the ability to use a flexible, impermeable or substantially permeable subsurface liner to provide an enclosed treatment area. These, and other advantages will become apparent from a consideration of the following description and accompanying drawings. | <SOH> BRIEF SUMMARY OF THE INVENTION <EOH>The present invention is intended to be a stormwater treatment system with bioretention functionality and is designed to treat stormwater runoff emanating from either previous or impervious surfaces (e.g., streets, parking lots, grassed areas, roof tops). An embodiment consists of a primarily open-bottomed container with a top sidewall at least partially open to the atmosphere, and side walls of varying vertical dimension. The container contains a filter media consisting of a mixture of organic and non-organic materials. Portions of the filter media on one or more sides of the container may maintain contact or otherwise communicate with the surrounding native or existing soil. Plant material will be located within the container with vegetative growth emanating through a central opening(s) in the top sidewall portion of the container, with at least partial, or free expression of the attended root system beyond the exterior “footprint” of the container. This and other embodiments and features of the present invention will become apparent from the following detailed description, accompanying illustrative drawings, and appended claims. | E03F50404 | 20171212 | 20180628 | 98010.0 | E03F504 | 2 | UPTON, CHRISTOPHER | STORMWATER BIOFILTRATION SYSTEM AND METHOD | MICRO | 0 | ACCEPTED | E03F | 2,017 |
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15,736,339 | PENDING | Pharmaceutical Combinations of Organo-Arsenoxide Compounds and mTOR Inhibitors | The present invention relates to synergistic pharmaceutical combinations comprising organic arsenoxide compounds and mTOR inhibitors. Further, the present invention relates to the use of these pharmaceutical combinations in therapy, in particular, treatment of proliferative diseases. | 1. A synergistic pharmaceutical combination comprising an organo-arsenoxide compound, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, and an mTOR inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof. 2. The synergistic pharmaceutical combination of claim 1, wherein the organo-arsenoxide compound is a compound of formula (I): wherein the As(OH)2 group is para- to the N-atom on the phenyl ring; R1 is selected from hydrogen and C1-3 alkyl; R2 and R3 may be the same or different and are independently selected from hydrogen and optionally substituted C1-3 alkyl; R4 and R5 may be the same or different and are independently selected from hydrogen and optionally substituted C1-3 alkyl; m is 1; n is 1; * indicates a chiral carbon atom; and wherein each optional substituent is independently C1-3 alkyl, C1-3 alkoxy, halo, hydroxyl, or hydroxy(C1-3)alkyl; salts, enantiomers and racemates thereof. 3. The synergistic pharmaceutical combination of claim 2, wherein R1 is selected from hydrogen, methyl and ethyl. 4. The synergistic pharmaceutical combination of claim 2 or 3, wherein R2 and R3 are independently selected from hydrogen, methyl, ethyl, hydroxymethyl and CF3. 5. The synergistic pharmaceutical combination of any one of claims 2 to 4, wherein R4 and R5 are independently selected from hydrogen, C1-3 alkyl, hydroxy-(C1-3)alkyl and halo(C1-3)alkyl. 6. The synergistic pharmaceutical combination of claim 2, wherein the As(OH)2 group is para- to the N-atom on the phenyl ring; R1 is hydrogen or methyl; R2 and R3 are independently selected from hydrogen, C1-3 alkyl, hydroxy(C1-3)alkyl and halo(C1-3)alkyl; R4 and R5 are independently selected from hydrogen, C1-3 alkyl, hydroxy(C1-3)alkyl and halo(C1-3)alkyl; in is 1; and n is 1. 7. The synergistic pharmaceutical combination of any one of claims 2 to 6 wherein the organo-arsenoxide has the following structural formula: or a salt, or an enantiomer or racemate thereof. 8. The synergistic pharmaceutical combination of claim 7, wherein the stereochemistry at the chiral carbon denoted * is (S), and salts thereof 9. The synergistic pharmaceutical combination of any one of claims 1 to 8, wherein the mTOR inhibitor is a rapalog. 10. The synergistic pharmaceutical combination of claim 9, wherein the rapalog is selected from the group consisting of everolimus, temsirolimus, deforolimus and zotarolimus. 11. The synergistic pharmaceutical combination of claim 9, wherein the rapalog is everolimus or temsirolimus. 12. The synergistic pharmaceutical combination of claim 1, wherein the organo-arsenoxide compound is 4-(N—(S-penicllaminylacetyl)amino)phenylarsinous acid (PENAO), or a pharmaceutically acceptable salt thereof, and the mTOR inhibitor is a rapalog. 13. The synergistic pharmaceutical combination of claim 1, wherein the organo-arsenoxide compound is PENAO, or a pharmaceutically acceptable salt thereof, and the mTOR inhibitor is selected from the group consisting of everolimus, temsirolimus and deforolimus. 14. The synergistic pharmaceutical combination of any one of claims 1 to 13, wherein the organo-arsenoxide compound or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof and the mTOR inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, are present in a single dosage form. 15. The synergistic pharmaceutical combination of any one of claims 1 to 13, wherein the organo-arsenoxide compound or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof and the mTOR inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, are present in separate dosage forms. 16. The synergistic pharmaceutical combination of any one of claims 1 to 15, wherein the pharmaceutical combination has a combination index (CI) of less than 1. 17. The synergistic pharmaceutical combination of any one claims 1 to 16, wherein the pharmaceutical combination has a CI of less than 0.8. 18. A pharmaceutical composition comprising an organo-arsenoxide compound, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, and an mTOR inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof. 19. The pharmaceutical composition of claim 18, wherein the organo-arsenoxide compound is PENAO, or a pharmaceutically acceptable salt thereof, and the mTOR inhibitor is a rapalog selected from the group consisting of everolimus, temsirolimus, deforolimus and zotarolimus. 20. A method of treating a cellular proliferative disease in a vertebrate, the method comprising administering to the vertebrate a therapeutically effective amount of the synergistic pharmaceutical combination of any one of claims 1 to 17, or the pharmaceutical composition of claim 18 or 19. 21. The method according to claim 20, wherein the proliferative disease is a solid tumour. 22. A method of inhibiting angiogenesis in a vertebrate, comprising administering to the vertebrate an effective amount of a compound of the synergistic pharmaceutical combination of any one of claims 1 to 17, or the pharmaceutical composition of claim 18 or 19. 23. A method of selectively inducing the Mitochondrial Permeability Transition (MPT) in proliferating cells in a vertebrate comprising administering to the vertebrate a therapeutically effective amount a compound of the synergistic pharmaceutical combination of any one of claims 1 to 17, or the pharmaceutical composition of claim 18 or 19. 24. A method of inducing apoptosis in proliferating mammalian cells, comprising administering to the mammal an apoptosis-inducing amount of a compound of the synergistic pharmaceutical combination of any one of claims 1 to 17, or the pharmaceutical composition of claim 18 or 19. 25. A method of treating a cellular proliferative disease in a vertebrate, the method comprising administering to the vertebrate a therapeutically effective amount of an organo-arsenoxide compound or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof and an mTOR inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof. 26. The method according to claim 25, wherein the organo-arsenoxide compound, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, and the mTOR inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, are administered simultaneously, separately or sequentially. 27. The method according to claim 25, wherein the organo-arsenoxide compound, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, and the mTOR inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, are administered simultaneously. 28. The method according to claim 25, wherein the organo-arsenoxide compound, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, is administered first, followed by the mTOR inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof. 29. Use of an organo-arsenoxide compound, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, and an mTOR inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, for the manufacture of a medicament for the treatment of a cellular proliferative disease. 30. The method of any one of claims 20 to 28, or the use of claim 29, wherein the organo-arsenoxide compound is PENAO, or a pharmaceutically acceptable salt thereof. 31. The method of any one of claim 20 to 28 or 30, or the use of claim 29 wherein the mTOR inhibitor is a rapalog, or a pharmaceutically acceptable salt thereof. 32. The method or use of claim 31, wherein the rapalog is selected from the group consisting of everolimus, temsirolimus, deforolimus and zotarolimus. 33. The method or use of claim 32, wherein the rapalog is everolimus or temsirolimus. 34. The method of any one of claims 25 to 28 or 30 to 33, or the use of claim 29, wherein the proliferative disease is a solid tumour. 35. The method or use of claim 35, wherein the solid tumour is selected from the group consisting of lung cancer; breast cancer; colorectal cancer; anal cancer; pancreatic cancer; prostate cancer; ovarian carcinoma; liver and bile duct carcinoma; esophageal carcinoma; non-Hodgkin's lymphoma; bladder carcinoma; carcinoma of the uterus; glioma, diffuse intrinsic pontine glioma, glioblastoma, medullablastoma, and other tumours of the brain; kidney cancer; cancer of the head and neck; cancer of the stomach; testicular cancer; germ cell tumour; neuroendocrine tumour; cervical cancer; oral cancer, carcinoids of the gastrointestinal tract, breast, and other organs; signet ring cell carcinoma; mesenchymal tumours including sarcomas, fibrosarcomas, haemangioma, angiomatosis, haemangiopericytoma, pseudoangiomatous stromal hyperplasia, myofibroblastoma, fibromatosis, inflammatory myofibroblastic tumour, lipoma, angiolipoma, granular cell tumour, neurofibroma, schwannoma, angiosarcoma, liposarcoma, rhabdomyosarcoma, osteosarcoma, leiomyoma or a leiomysarcoma. | TECHNICAL FIELD The present invention relates to synergistic pharmaceutical combinations comprising organic arsenoxide compounds and mTOR inhibitors. Further, the present invention relates to the use of these pharmaceutical combinations in therapy, in particular, treatment of proliferative diseases. BACKGROUND Arsenical compounds have been used in the past as therapeutic agents for the treatment of disease. However, the inherent toxicities of arsenical compounds and their generally unfavourable therapeutic index have largely precluded their use as pharmaceutical agents. Organic arsenoxide compounds are disclosed in WO 01/21628. Such compounds are described as having antiproliferative properties useful in the therapy of proliferative diseases. WO 04/042079 discloses the use of organic arsenoxide compounds for inducing the mitochondrial permeability transmission (MPT) and also the use of such compounds for inducing apoptosis and necrosis, particularly in endothelial cells. Further organic arsenoxide compounds are disclosed in WO2008/052279. In particular, the compound 4-(N—(S-penicllaminylacetyl)amino)phenylarsinous acid (PENAO) is disclosed in WO2008/052279. PENAO is a mitochondrial metabolism inhibitor in the final stages of Phase I clinical testing in patients with solid tumours refractory to standard therapy at three hospitals in Australia. PENAO is a cysteine mimetic trivalent arsenical that enters cells via an organic ion transporter and accumulates in the mitochondrial matrix where the arsenical moiety cross-links Cys160 and Cys257 on the matrix face of adenine nucleotide translocase (ANT), which inactivates the transporter (Dilda et al., 2009; Park et al., 2012). Its inactivation leads to partial uncoupling of oxidative phosphorylation, increase in superoxide production, proliferation arrest and ultimately apoptosis of the cell. PENAO only reacts with ANT when cells are proliferating as Cys160 and Cys257 appear to be disulphide bonded in growth quiescent cells, and so unreactive towards PENAO. Mammalian (mechanistic) target of rapamycin (mTOR) is a serine/threonine kinase that forms two distinct complexes called mTORC1 and mTORC2. Rapamycin (sirolimus) and rapamycin analogs (rapalogs) form a complex with the small protein FKBP12, that irreversibly binds to the FKBP12-rapamycin domain of mTORC1 and inhibits its kinase activity (Zaytseva et al., 2012). Rapamycin and rapalogs are small molecule inhibitors of mTOR and a number of clinical trials evaluating the anti-cancer efficacy of rapalogs as a monotherapy or as a part of combination therapy across a wide range of cancers types are currently in progress. The rapalogs are generally well tolerated in cancer patients (Zaytseva et al., 2012). ATP-competitive inhibitors of mTOR are also being developed (Schenone et al., 2011). These inhibitors compete with ATP for binding to the active site of the kinase. There is a need for improved therapies for treating proliferative diseases, such as cancer (including treatment of solid tumours), and related conditions. It has now surprisingly been found that the combination of an organo-arsenoxide compound, such as PENAO, with an mTOR inhibitor dramatically enhances the efficacy of the organo-arsenoxide compound in the treatment of proliferative diseases. The combination of the organo-arsenoxide compound and the rapamycin mTOR inhibitor has been found to act synergistically to mediate tumour cell death. SUMMARY In a first aspect the present invention relates to a synergistic pharmaceutical combination comprising an organo-arsenoxide compound, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, and an mTOR inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof. In one embodiment the organo-arsenoxide compound is PENAO. In one embodiment the mTOR inhibitor is a rapalog selected from the group consisting of everolimus, temsirolimus, deforolimus and zotarolimus. In a second aspect the present invention relates to a pharmaceutical composition comprising an organo-arsenoxide compound, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, and an mTOR inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof. In a third aspect the present invention relates to a method of treating a cellular proliferative disease in a vertebrate, the method comprising administering to the vertebrate a therapeutically effective amount of the synergistic pharmaceutical combination of the first aspect of the invention, or the pharmaceutical composition of the second aspect of the invention. In a fourth aspect the invention relates to a method of inhibiting angiogenesis in a vertebrate, comprising administering to the vertebrate a therapeutically effective amount of the synergistic pharmaceutical combination of the first aspect of the invention, or the pharmaceutical composition of the second aspect of the invention. In a fifth aspect the invention relates to a method of selectively inducing the Mitochondrial Permeability Transition (MPT) in proliferating cells in a vertebrate comprising administering to the vertebrate a therapeutically effective amount of the synergistic pharmaceutical combination of the first aspect of the invention, or the pharmaceutical composition of the second aspect of the invention. In a sixth aspect the invention relates to a method of inducing apoptosis in proliferating mammalian cells, comprising administering to the vertebrate a therapeutically effective amount of the synergistic pharmaceutical combination of the first aspect of the invention, or the pharmaceutical composition of the second aspect of the invention. In a seventh aspect the present invention relates to a method of treating a cellular proliferative disease in a vertebrate, the method comprising administering to the vertebrate a therapeutically effective amount of an organo-arsenoxide compound or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof and an mTOR inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof. In one embodiment the organo-arsenoxide compound and the mTOR inhibitor are administered simultaneously. In another embodiment the organo-arsenoxide compound is administered first, followed by the mTOR inhibitor. In yet another aspect the present invention relates to the use of an organo-arsenoxide compound, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, and an mTOR inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, for the manufacture of a medicament for the treatment of a cellular proliferative disease. In one embodiment of the aspects of the invention the organo-arsenoxide compound is PENAO. In one embodiment of the aspects of the invention the mTOR inhibitor is a rapalog selected from the group consisting of everolimus, temsirolimus, deforolimus and zotarolimus. In one embodiment of the aspects of the invention the cellular proliferative disease is a solid tumour. Definitions The following are some definitions that may be helpful in understanding the description of the present invention. These are intended as general definitions and should in no way limit the scope of the present invention to those terms alone, but are put forth for a better understanding of the following description. Unless the context requires otherwise or specifically stated to the contrary, integers, steps, or elements of the invention recited herein as singular integers, steps or elements clearly encompass both singular and plural forms of the recited integers, steps or elements. Throughout this specification, unless the context requires otherwise, the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated step or element or integer or group of steps or elements or integers, but not the exclusion of any other step or element or integer or group of elements or integers. Thus, in the context of this specification, the term “comprising” means “including principally, but not necessarily solely”. The terms “synergy”, “synergistic”, “synergistic effect” and “synergistic combination” as used herein refers to a mixture of two or more discrete agents which, when combined, display a degree of anticancer activity, such as anti-proliferative activity or cytotoxicity etc., which is greater than the expected additive effect of said agents. The terms also refer to the combined effect of administering an amount of one therapeutic agent that, when administered alone, produces no significant response but, when administered in combination with another therapeutic compound, produces an overall response that is significantly greater than that produced by the second compound alone. CompuSyn software was utilised to calculate combination index (CI) values for drug combinations. A CI of less than 1 is indicative of a synergistic effect in drug combinations, a CI of 1 is indicative of an additive effect in drug combinations and a CI of greater than 1 is indicative of an antagonism in drug combinations (Chou, 2010). Throughout this specification, unless the context requires otherwise, the term “combination” refers to either a fixed combination in one unit dosage form, or a non-fixed combination (or kit of parts) for the combined administration where the compound and a combination partner (e.g. another drug or therapeutic agent) are administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a co-operative, e.g. synergistic effect. The term “combined administration” as used herein is meant to encompass administration of the selected combination partners to a single subject in need thereof and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features. As used herein, the term “C1-3 alkyl group” includes within its meaning monovalent (“alkyl”) and divalent (“alkylene”) straight chain or branched chain saturated aliphatic groups having from 1 to 3 carbon atoms. Thus, for example, the term C1-3 alkyl includes methyl, ethyl, 1-propyl, and isopropyl. The term “alkoxy” as used herein refers to straight chain or branched alkyloxy (i.e., O-alkyl) groups, wherein alkyl is as defined above. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, and isopropoxy. The term “amino” as used herein refers to groups of the form —NRaRb wherein Ra and Rb are individually selected from hydrogen, optionally substituted (C1-4)alkyl, optionally substituted (C2-4)alkenyl, optionally substituted (C2-4)alkynyl, optionally substituted (C6-10)aryl and optionally substituted aralkyl groups, such as benzyl. The amino group may be a primary, secondary or tertiary amino group. The term “amino acid” as used herein includes naturally and non-naturally occurring amino acids, as well as substituted variants thereof. The term “amino acid” therefore encompasses, for example, α, β, and γ-amino acids. α-Amino acids are particularly preferred. The (L) and (D) forms of amino acids are also included in the scope of the term “amino acid”. (L)-amino acids are a preferred form. For example, the term “amino acid” includes within its scope glycine, alanine, valine, leucine, isoleucine, methionine, proline, phenylalanine, tryptophan, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, α-amino-β-hydroxy-isovaleric acid and penicillamine. The backbone of the amino acid residue may be substituted with one or more groups independently selected from (C1-6)alkyl, halogen, hydroxy, hydroxy(C1-6)alkyl, aryl, e.g., phenyl, aryl(C1-3)alkyl, e.g., benzyl, and (C3-6)cycloalkyl. In the context of this specification the term “arsenoxide” is synonymous with “arsinous acid” and refers to the moiety As(OH)2, which may also be represented as As=O. The term “halogen” or variants such as “halide” or “halo” as used herein refers to fluorine, chlorine, bromine and iodine. The term “optionally substituted” as used herein means the group to which this term refers may be unsubstituted, or may be substituted with one or more groups independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, halo, haloalkyl, haloalkynyl, hydroxyl, hydroxyalkyl, alkoxy, thioalkoxy, alkenyloxy, haloalkoxy, haloalkenyloxy, NO2, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroheterocyclyl, alkylamino, dialkylamino, alkenylamine, alkynylamino, acyl, alkenoyl, alkynoyl, acylamino, diacylamino, acyloxy, alkylsulfonyloxy, heterocycloxy, heterocycloamino, haloheterocycloalkyl, alkylsulfenyl, alkylcarbonyloxy, alkylthio, acylthio, phosphorus-containing groups such as phosphono and phosphinyl, aryl, heteroaryl, alkylaryl, aralkyl, alkylheteroaryl, cyano, cyanate, isocyanate, CO2H, C(O)NH2, —C(O)NH(alkyl), and —C(O)N(alkyl)2. In one embodiment substituents include C1-3 alkyl, C1-3 alkoxy, —CH2—(C1-3) alkoxy, C6-10 aryl, —CH2-phenyl, halo, hydroxyl, hydroxy(C1-3)alkyl (e.g., CH2OH), and halo(C1-3)alkyl (e.g., CF3, CH2CF3). Particularly preferred substituents include C1-3 alkyl, C1-3 alkoxy, halo, hydroxyl, hydroxy(C1-3)alkyl (e.g., CH2OH), and halo(C1-3)alkyl (e.g., CF3, CH2CF3). In one embodiment the optional substituent is C1-3 alkyl, C1-3 alkoxy, halo, hydroxyl or hydroxy(C1-3)alkyl (e.g., CH2OH). In the context of this specification the term “administering” and variations of that term including “administer” and “administration”, includes contacting, applying, delivering or providing a compound or composition of the invention to an organism, or a surface by any appropriate means. In the context of this specification, the term “vertebrate” includes humans and individuals of any species of social, economic or research importance including but not limited to members of the genus ovine, bovine, equine, porcine, feline, canine, primates (including human and non-human primates), rodents, murine, caprine, leporine, and avian. The vertebrate may be a human. In the context of this specification, the term “treatment”, refers to any and all uses which remedy a disease state or symptoms, prevent the establishment of disease, or otherwise prevent, hinder, retard, or reverse the progression of disease or other undesirable symptoms in any way whatsoever. In the context of this specification the term “effective amount” includes within its meaning a sufficient but non-toxic amount of a compound or composition of the invention to provide a desired effect. Thus, the term “therapeutically effective amount” includes within its meaning a sufficient but non-toxic amount of a compound or composition of the invention to provide the desired therapeutic effect. The exact amount required will vary from subject to subject depending on factors such as the species being treated, the sex, age and general condition of the subject, the severity of the condition being treated, the particular agent being administered, the mode of administration, and so forth. Thus, it is not possible to specify an exact “effective amount”. However, for any given case, an appropriate “effective amount” may be determined by one of ordinary skill in the art using only routine experimentation. BRIEF DESCRIPTION OF THE FIGURES FIG. 1. Treatment of tumour cells with PENAO and mTORC1 rapalog inhibitors results in strong synergistic effects on cell proliferation. A. G89 cells were seeded in 96-well plates, allowed to adhere for 24 h then treated with PENAO or temsirolimus for 72 h. Viable cells were determined using the vital dye, MTT, and the results expressed as % of viable cells relative to untreated controls. Data points and errors are the mean and range of duplicate determinations. The result is representative of two experiments. B. Drug concentrations employed are multiples of IC50 values for proliferation arrest in a 72 h assay (see Table 1). The combination index for G89 cells is 0.52±0.13, which is indicative of strong synergistic effect (see Table 2). Data points and errors are the mean and range of duplicate determinations. The result is representative of two experiments. FIG. 2. The order of treatment of tumour cells with PENAO and rapalog influences the synergistic effects on proliferation. 24 h after seeding, MiaPaca2 cells were treated concurrently or sequentially (at 24 and 48 h time points) with PENAO (P, 0.75 μM) and everolimus (E, 22 μM). Cell growth was recorded every 5 h using the xCELLigence System. Data points and errors are the mean and SD of triplicate determinations. The results are representative of two experiments. FIG. 3. Treatment with PENAO and rapalog depletes tumour cells of mTOR and induces autophagy and apoptosis. A. DIPG cells were treated with PENAO (2 μM) and/or temsirolimus (5 μM) for 48 h and lysate blotted for mTOR, Akt and 4EBP1 protein levels. Combination treatment ablates mTOR protein in the cells, but not AKT and 4EBP1. Loading control is GAPDH. The blots presented are representative of several separate experiments. B. Ovarian SKOV3 cancer cells were treated with PENAO (5 μM) and/or temsirolimus (10 μM) for 24 h and lysate blotted for autophagy (LC3BI/II) and apoptosis (cPARP-1). Loading control is β-actin. The blots presented are representative of 2 separate experiments. C. SKOV-3 cells were either untreated (i), treated with PENAO (5 μM, ii), temsirolimus (10 μM, iii) or with the combination (iv) for 24 h. An accumulation of acidic vesicles (red fluorescence) is indicative of autophagy. Images are representative fields from two separate experiments. Magnification is 400×. FIG. 4. Treatment with PENAO and rapalog results in synergistic inhibition of tumour growth. Subcutaneous human pancreatic MiaPaca2 tumours were established in the proximal midline of BALB/c nude mice. Mice bearing ˜100 mm3 tumours were randomized into four groups (n=8 per group) and implanted with subcutaneous (SC) micro-osmotic pumps in the flank that delivered vehicle or 0.25 mg/kg/day PENAO. Four days after pump implantation, mice were treated with 5 mg/kg/day everolimus per os (PO) for 5 days a week as indicated. Tumour volumes are expressed as relative tumour volumes, where the tumour volume at any given time is divided by the starting tumour volume. The data points and errors are the mean and SE of the tumour volumes. The tumour growth curves were compared using repeated measures two-way analysis of variance. *: p<0.05, **: p<0.01. FIG. 5. Treatment with PENAO and rapalog results in tumour necrosis. A. Subcutaneous human pancreatic MiaPaca2 tumours were established in the proximal midline of BALB/c nude mice. After 50 days, 5 mice bearing large ˜600 mm3 tumours were implanted with subcutaneous (SC) micro-osmotic pumps in the flank that delivered 3 mg/kg/day of PENAO. At day 54, mice were treated with 7.5 mg/kg/day everolimus per os (PO) for 7 days. The data points and errors are the mean and SE of the tumour volumes. B. At day 61, tumours were excised, fixed then analysed for necrosis. Two representative tumour sections of each group are presented. Necrosis regions (blue) were quantified and compared with viable tumour regions (red) using Genie Aperio Technologies LTD pattern-recognition software. C. Quantification of tumour necrosis in control versus combination PENAO+everolimus treated tumours. The bars and errors are the mean and SD of the analysis of 2 sections per control (n=8) and treated (n=5) tumour. **: p<0.01. DETAILED DESCRIPTION The present invention relates to synergistic pharmaceutical combinations of organic arsenoxide compounds, including PENAO, and mammalian (mechanistic) target of rapamycin (mTOR) inhibitors. It has surprisingly been found that the rapalog inhibitors of mTORC1 combine very effectively with PENAO to trigger tumour cell death in mice. The combination effectively ablates mTOR protein in tumour cells. Importantly, combination therapy at near maximal tolerated doses of the drugs is well tolerated in mice with no signs or symptoms of toxicity. Organo-Arsenoxide Compounds In one embodiment of the synergistic pharmaceutical combinations of the present invention the organo-arsenoxide compound comprises an optionally substituted amino acid moiety linked via a linker group to a phenylarsenoxide group. Organo-arsenoxide compounds in accordance with the present invention have a substituted or unsubstituted amino acid moiety. Examples of amino acid moieties include cysteinyl, substituted cysteinyl, for example penicillaminyl (also known as β,β-dimethylcysteinyl or 3-mercaptovalinyl), optionally substituted alaninyl, optionally substituted mercaptoalaninyl, optionally substituted valinyl, optionally substituted 4-mercaptovalinyl, optionally substituted leucinyl, optionally substituted 3- or 4-, or 5-mercaptoleucinyl, optionally substituted isoleucinyl, or optionally substituted 3-, 4- or 5-isoleucinyl. In a preferred embodiment of the invention the amino acid moiety is β,β-dimethylcysteinyl (“penicillaminyl”). In another embodiment of the invention the amino acid moiety is (S)-penicillaminyl. In another embodiment of the invention the amino acid moiety is cysteinyl. The amino acid moiety may have (L), (D), (R) or (S) configuration. Optional substituents include C1-3 alkyl, cyclopropyl, C1-3 alkoxy, —CH2—(C1-3)alkoxy, C6-10 aryl, —CH2-phenyl, halo, hydroxyl, hydroxy(C1-3)alkyl, and halo-(C1-3)alkyl, e.g., CF3, CH2CF3. In preferred embodiments the optional substituents are independently selected from hydroxyl, methoxy, halo, methyl, ethyl, propyl, cyclopropyl, CH2OH and CF3. The linker group of the organo-arsenoxide compounds in accordance with the present invention is a substituted or unsubstituted acetamido group. In one embodiment the linker group is an unsubstituted acetamido group. In one embodiment of the synergistic pharmaceutical combinations of the present invention the organo-arsenoxide compound is of formula (I): wherein the As(OH)2 group is para- to the N-atom on the phenyl ring; R1 is selected from hydrogen and C1-3 alkyl; R2 and R3 may be the same or different and are independently selected from hydrogen and optionally substituted C1-3 alkyl; R4 and R5 may be the same or different and are independently selected from hydrogen and optionally substituted C1-3 alkyl; m is 1; n is 1; * indicates a chiral carbon atom; and wherein each optional substituent is independently C1-3 alkyl, C1-3 alkoxy, halo, hydroxyl, or hydroxy(C1-3)alkyl; salts, enantiomers and racemates thereof. The stereochemistry at the chiral atom indicated by * in formula (1) may be (R) or (S). The present invention includes enantiomerically pure forms of compounds of formula (I), mixtures of enantiomers in any ratio, as well as racemates. In one embodiment of the invention the stereochemistry at the chiral atom indicated by * in formula (I) is (R). In another embodiment the invention the stereochemistry at the chiral atom indicated by * in formula (I) is (S). Preferred embodiments of the compounds of general formula (I) are described below. It should be understood that any one or more of the embodiment(s) disclosed herein may be combined with any other embodiment(s), including preferred embodiment(s). In one embodiment R1 is selected from hydrogen and C1-3alkyl. R1 may be hydrogen, methyl or ethyl. In one embodiment R1 is hydrogen. In one embodiment R2 and R3 may be the same or different. R2 and R3 may be independently selected from hydrogen, and optionally substituted C1-3 alkyl. In one embodiment R2 and R3 are independently selected from hydrogen, methyl, ethyl, hydroxymethyl and CF3. In a further embodiment R2 and R3 are independently selected from hydrogen, C1-3 alkyl, hydroxy(C1-3)alkyl and halo(C1-3)alkyl. In another embodiment R2 and R3 may be independently selected from hydrogen, methyl and ethyl. In another embodiment R2 is methyl and R3 is hydrogen. In another embodiment R2 and R3 are both hydrogen. In one embodiment R4 and R5 may be the same or different and are independently selected from hydrogen and optionally substituted C1-3 alkyl. In one embodiment R4 and R5 are independently selected from hydrogen, C1-3 alkyl, hydroxy-(C1-3)alkyl and halo(C1-3)alkyl. In another embodiment R4 and R5 may be independently selected from hydrogen, methyl, ethyl and CH2OH. In another embodiment R4 is methyl or ethyl and R5 is hydrogen or methyl. In another embodiment R4 is methyl and R5 is hydrogen. In another embodiment R4 and R5 are both hydrogen. In another embodiment R4 and R5 are both methyl. In one embodiment the optional substituent is independently C1-3 alkyl, C1-3 alkoxy, halo, hydroxyl, or hydroxy(C1-3)alkyl In one embodiment the optional substituents are independently selected from hydroxyl, methoxy, halo, methyl, ethyl, propyl, cyclopropyl, and CH2OH. In one embodiment there are no optional substituents. In one embodiment of the organo-arsenoxide compounds of Formula (I) the As(OH)2 group is para- to the N-atom on the phenyl ring; R−1 is hydrogen or methyl; R2 and R3 are independently selected from hydrogen, C1-3 alkyl, hydroxy(C1-3)alkyl and halo(C1-3)alkyl, R4 and R5 are independently selected from hydrogen, C1-3 alkyl, hydroxy(C1-3)alkyl and halo(C1-3)alkyl; m is 1; and n is 1. In another embodiment of the organo-arsenoxide compounds of Formula (I) the As(OH)2 group is para- to the N-atom on the phenyl ring; R1 is hydrogen; R2 is hydrogen or methyl; R3 is hydrogen; R4 is hydrogen or methyl; R5 is hydrogen or methyl; in is 1; and n is 1. In one embodiment the organo-arsenoxide compound has the following structural formula or a salt, an enantiomer or racemate thereof. This compound is referred to herein as “Penicillamine-arsenoxide” or “PENAO”. In one embodiment the stereochemistry at the chiral carbon denoted * is (S). In one embodiment of the synergistic pharmaceutical combinations of the invention the organo-arsenoxide compound of formula (I) is (S)-Penicillamine-arsenoxide. In another embodiment the compound of formula (I) is (R)-Penicillamine-arsenoxide. In another embodiment the compound of formula (I) comprises a mixture of (R) and (S) enantiomers of Penicillamine-arsenoxide. In another embodiment, the mixture of (R) and (S) enantiomers of Penicillamine-arsenoxide is a racemic mixture. mTOR Inhibitors Mammalian (mechanistic) target of rapamycin (mTOR) inhibitors of the present invention include rapamycin (sirolimus) and rapamycin analogs (rapalogs). Non-limiting examples of rapalogs include everolimus, temsirolimus, deforolimus and zotarolimus. mTOR inhibitors also include non-rapamycin inhibitors such as AXD8055, a selective ATP-competitive mTOR kinase inhibitor, and BEZ235, a dual PI3K and mTOR inhibitor. In a preferred embodiment of the synergistic pharmaceutical combinations of the present invention the mTOR inhibitor is a rapalog. In one embodiment of the synergistic pharmaceutical combinations of the present invention the mTOR inhibitor is selected from the group consisting of everolimius, temsirolimus, deforolimus and zotarolimus. In another embodiment of the synergistic pharmaceutical combinations of the present invention the mTOR inhibitor is selected from the group consisting of everolimius, temsirolimus and deforolimus. In a further embodiment of the synergistic pharmaceutical combinations of the present invention the mTOR inhibitor is everolimus or temsirolimus. In another embodiment of the synergistic pharmaceutical combinations of the present invention the mTOR inhibitor is everolimus. In a further embodiment of the synergistic pharmaceutical combinations of the present invention the mTOR inhibitor is temsirolimus. Synergistic Pharmaceutical Combinations In one aspect the present invention relates to a synergistic pharmaceutical combination comprising an organo-arsenoxide compound, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, and an mTOR inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof. Such a combination may be for simultaneous, separate or sequential administration. Such a combination may be useful in the treatment of proliferative diseases, including solid tumours. In one embodiment of the synergistic pharmaceutical combination of the present invention the organo-arsenoxide compound and the mTOR inhibitor are present in a single dosage form. In another embodiment of the synergistic pharmaceutical combination of the present invention the organo-arsenoxide compound and the mTOR inhibitor are present in separate dosage forms. In one embodiment the synergistic pharmaceutical combination comprises an organo-arsenoxide compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof and an mTOR inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof. In another embodiment the synergistic pharmaceutical combination comprises the organo-arsenoxide compound PENAO, or a pharmaceutically acceptable salt thereof and an mTOR inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof. In a further embodiment of the synergistic pharmaceutical combinations of the present invention the organo-arsenoxide compound is 4-(N—(S-penicllaminylacetyl)amino)phenylarsinous acid (PENAO), or a pharmaceutically acceptable salt thereof, and the mTOR inhibitor is a rapalog. In a further embodiment the synergistic pharmaceutical combination comprises the organo-arsenoxide compound PENAO, or a pharmaceutically acceptable salt thereof and a rapalog mTOR inhibitor. In another embodiment the synergistic pharmaceutical combination comprises PENAO, or a pharmaceutically acceptable salt thereof, and a rapalog selected from the group consisting of everolimus, temsirolimus, deforolimus and zotarolimus. In a further embodiment the synergistic pharmaceutical combination comprises PENAO, or a pharmaceutically acceptable salt thereof, and a rapalog selected from the group consisting of everolimus and temsirolimus. In another embodiment the synergistic pharmaceutical combination comprises PENAO, or a pharmaceutically acceptable salt thereof, and everolimus. In a further embodiment the synergistic pharmaceutical combination comprises PENAO, or a pharmaceutically acceptable salt thereof, and temsirolimus. The combination therapy provide herein may be useful for improving the efficacy and/or reducing the side effects of currently available cancer therapies for individuals who do not respond to such therapies. In one embodiment the combination of an organo-arsenoxide compound, such as PENAO, with an mTOR inhibitor, such as a rapalog dramatically enhances the efficacy of the organo-arsenoxide compound in the treatment of proliferative diseases. In one embodiment the therapeutic efficacy of the organo-arsenoxide compound may be enhanced by about 10% to about 2000%. In one embodiment the therapeutic effect may be enhanced by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 550%, 600%, 650%, 700%, 750%, 800%, 850%, 900%, 950%, 1000%, 1050%, 1100%, 1150%, 1200%, 1250%, 1300%, 1350%, 1400%, 1450%, 1500%, 1550%, 1600%, 1650%, 1700%, 1750%, 1800%, 1850%, 1900%, 1950% or about 2000%. In one embodiment of the pharmaceutical combinations of the present invention the organo-arsenoxide compound and the mTOR inhibitor have a combination index (CI) of less than 1. A CI of less than 1 is indicative of synergistic effect in drug combinations. In another embodiment of the pharmaceutical combinations of the present invention the organo-arsenoxide compound and the mTOR inhibitor have a CI of less than 0.8. In a further embodiment of the pharmaceutical combinations of the present invention the organo-arsenoxide compound and the mTOR inhibitor have a CI of less than 0.7. In another embodiment of the pharmaceutical combinations of the present invention the organo-arsenoxide compound and the mTOR inhibitor have a CI between 0.5 and 0.7. In a further embodiment of the pharmaceutical combinations of the present invention the organo-arsenoxide compound and the mTOR inhibitor have a CI between about 0.5 and about 0.8. A further aspect of the invention provides for a pharmaceutical composition comprising an organo-arsenoxide compound, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, and an mTOR inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof. In one embodiment of the pharmaceutical composition of the present invention the organo-arsenoxide compound is PENAO, or a pharmaceutically acceptable salt thereof, and the mTOR inhibitor is a rapalog selected from the group consisting of everolimus, temsirolimus, deforolimus and zotarolimus. Therapeutic Application(s) Compounds of formula (I) as disclosed herein, such as PENAO, and pharmaceutically acceptable salts and hydrates thereof, are capable of binding to cysteine residues of mitochondrial Adenine Nucleotide Translocator (ANT) in proliferating endothelial cells thereby inducing the Mitochondrial Permeability Transition (MPT). Accordingly, compounds of formula (I) according to the present invention may lead to proliferation arrest and cell death. Advantageously, compounds of formula (I) may be selective inhibitors of endothelial cell proliferation. For example, compounds of formula (I) may be selective inhibitors of endothelial cell proliferation compared to tumour cells. Compounds of formula (I) therefore may be useful in the treatment of proliferative diseases. Therefore, in other aspects of the invention the synergistic pharmaceutical combination of an organo-arsenoxide compound and an mTOR inhibitor may be useful in the treatment of proliferative diseases. Accordingly, another embodiment of the invention relates to a method of treating a cellular proliferative disease in a vertebrate, the method comprising administering to the vertebrate a therapeutically effective amount of a synergistic pharmaceutical combination of the present invention. The cells may be endothelial cells. The vertebrate may be a mammal, such as a human. In accordance with the present invention the organo-arsenoxide compound and mTOR inhibitor may be administered as a single pharmaceutical composition, as separate compositions or sequentially. In another embodiment the present invention relates to a method of inhibiting angiogenesis in a vertebrate, comprising administering to the vertebrate an effective amount of a synergistic pharmaceutical combination of the present invention. A further embodiment of the invention relates to a method of inducing the MPT in a vertebrate comprising administering to the vertebrate a therapeutically effective amount of a synergistic pharmaceutical combination of the present invention. Compounds of formula (I) as disclosed herein may induce the MPT by binding to cysteine residues on mitochondrial Adenine Nucleotide Translocator (ANT). Another embodiment of the invention relates to a method of inducing apoptosis in proliferating mammalian cells, comprising administering to the mammal an apoptosis-inducing amount of a synergistic pharmaceutical combination of the present invention. Another embodiment of the present invention relates to a method of treating a cellular proliferative disease in a vertebrate, the method comprising administering to the vertebrate a therapeutically effective amount of an organo-arsenoxide compound or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof and an mTOR inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof. In one embodiment the organo-arsenoxide compound and the mTOR inhibitor are administered simultaneously or concurrently. In a further embodiment the organo-arsenoxide compound is administered first, followed by the mTOR inhibitor. In another embodiment of the methods of the present invention PENAO and a rapalog selected from the group consisting of everolimus, temsirolimus and deforolimus are administered concurrently or simultaneously. In one embodiment PENAO and a rapalog selected from the group consisting of everolimus, temsirolimus and deforolimus act synergistically when administered concurrently. In a further embodiment of the methods of the present invention PENAO is administered first, followed by administration of a rapalog selected from the group consisting of everolimus, temsirolimus and deforolimus, to achieve a synergistic effect. In one embodiment the present invention relates to a method of treating a cellular proliferative disease in a vertebrate, the method comprising administering to the vertebrate a therapeutically effective amount of PENAO, or a pharmaceutically acceptable salt thereof and a rapalog selected from the group consisting of everolimus, temsirolimus and deforolimus. The present invention further relates to the use of an organo-arsenoxide compound, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, and an mTOR inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, for the manufacture of a medicament for the treatment of a cellular proliferative disease. In one embodiment the invention relates to the use of PENAO, or a pharmaceutically acceptable salt thereof, and a rapalog selected from the group consisting of everolimus, temsirolimus and deforolimus for the manufacture of a medicament for the treatment of a cellular proliferative disease. The present invention further relates to a kit comprising the pharmaceutical combination of an organo-arsenoxide compound, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, and an mTOR inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof. In one embodiment the cellular proliferative disease is a solid tumour. In one embodiment the solid tumour is selected from the group consisting of lung cancer; breast cancer; colorectal cancer; anal cancer; pancreatic cancer; prostate cancer; ovarian carcinoma; liver and bile duct carcinoma; esophageal carcinoma; non-Hodgkin's lymphoma; bladder carcinoma; carcinoma of the uterus; glioma, diffuse intrinsic pontine glioma, glioblastoma, medullablastoma, and other tumours of the brain; kidney cancer; cancer of the head and neck; cancer of the stomach; testicular cancer; germ cell tumour; neuroendocrine tumour; cervical cancer; oral cancer, carcinoids of the gastrointestinal tract, breast, and other organs; signet ring cell carcinoma; mesenchymal tumours including sarcomas, fibrosarcomas, haemangioma, angiomatosis, haemangiopericytoma, pseudoangiomatous stromal hyperplasia, myofibroblastoma, fibromatosis, inflammatory myofibroblastic tumour, lipoma, angiolipoma, granular cell tumour, neurofibroma, schwannoma, angiosarcoma, liposarcoma, rhabdomyosarcoma, osteosarcoma, leiomyoma or a leiomysarcoma. In one embodiment the solid tumour is selected from the group consisting of pancreatic cancer, ovarian carcinoma and glioblastoma. Therapeutic advantages may be realised through further combination regimens, with the addition of a third active agent. In combination therapy the respective agents may be administered simultaneously, or sequentially in any order. Accordingly, methods of treatment according to the present invention may be applied in conjunction with conventional therapy, such as radiotherapy, chemotherapy, surgery, or other forms of medical intervention. Examples of additional chemotherapeutic agents include adriamycin, taxol, fluorouricil, melphalan, cisplatin, oxaliplatin, alpha interferon, vincristine, vinblastine, angioinhibins, TNP-470, pentosan polysulfate, platelet factor 4, angiostatin, LM-609, SU-101, CM-101, Techgalan, thalidomide, SP-PG and the like. Other chemotherapeutic agents include alkylating agents such as nitrogen mustards including mechloethamine, melphan, chlorambucil, cyclophosphamide and ifosfamide, nitrosoureas including carmustine, lomustine, semustine and streptozocin; alkyl sulfonates including busulfan; triazines including dicarbazine; ethyenimines including thiotepa and hexamethylmelamine; folic acid analogues including methotrexate; pyrimidine analogues including 5-fluorouracil, cytosine arabinoside; purine analogues including 6-mercaptopurine and 6-thioguanine; antitumour antibiotics including actinomycin D; the anthracyclines including doxorubicin, bleomycin, mitomycin C and methramycin; hormones and hormone antagonists including tamoxifen and cortiosteroids and miscellaneous agents including cisplatin and brequinar, and regimens such as COMP (cyclophosphamide, vincristine, methotrexate and prednisone), etoposide, mBACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine and dexamethasone), and PROMACE/MOPP (prednisone, methotrexate (w/leucovin rescue), doxorubicin, cyclophosphamide, taxol, etoposide/mechlorethamine, vincristine, prednisone and procarbazine). Pharmaceutical and/or Therapeutic Formulations Typically, for medical use, salts of the compounds of the present invention will be pharmaceutically acceptable salts; although other salts may be used in the preparation of the inventive compounds or of the pharmaceutically acceptable salt thereof. By pharmaceutically acceptable salt it is meant those salts which, within the scope of sound medical judgement, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable salts of compounds of formula I may be prepared by methods known to those skilled in the art, including for example, (i) by reacting a compound of formula (I) with the desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of formula (I) or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or (iii) by converting one salt of the compound of formula (I) to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column. All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised. Thus, for instance, suitable pharmaceutically acceptable salts of compounds according to the present invention may be prepared by mixing a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, methanesulfonic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, phosphoric acid, acetic acid, oxalic acid, carbonic acid, tartaric acid, or citric acid with the compounds of the invention. Suitable pharmaceutically acceptable salts of the compounds of the present invention therefore include acid addition salts. S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1-19. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, triethanolamine and the like. Convenient modes of administration include injection (subcutaneous, intravenous, etc.), oral administration, inhalation, transdermal application, topical creams or gels or powders, or rectal administration. In one embodiment, the mode of administration is parenteral. In another embodiment, the mode of administration is oral. Depending on the route of administration, the formulation and/or compound may be coated with a material to protect the compound from the action of enzymes, acids and other natural conditions which may inactivate the therapeutic activity of the compound. The compound also may be administered parenterally or intraperitoneally. The organo-arsenoxide and the mTOR inhibitors of the present invention may be administered by different modes of administration. In one embodiment the organo-arsenoxide is administered subcutaneously and the mTOR inhibitor is administered orally. Dispersions of compounds according to the invention may also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, pharmaceutical preparations may contain a preservative to prevent the growth of microorganisms. Pharmaceutical compositions suitable for injection include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. Ideally, the composition is stable under the conditions of manufacture and storage and may include a preservative to stabilise the composition against the contaminating action of microorganisms such as bacteria and fungi. The compound(s) of the invention may be administered orally, for example, with an inert diluent or an assimilable edible carrier. The compound(s) and other ingredients may also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into an individual's diet. For oral therapeutic administration, the compound(s) may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Suitably, such compositions and preparations may contain at least 1% by weight of active compound. The percentage of the compound(s) of formula (I) in pharmaceutical compositions and preparations may, of course, be varied and, for example, may conveniently range from about 2% to about 90%, about 5% to about 80%, about 10% to about 75%, about 15% to about 65%; about 20% to about 60%, about 25% to about 50%, about 30% to about 45%, or about 35% to about 45%, of the weight of the dosage unit. The amount of compound in therapeutically useful compositions is such that a suitable dosage will be obtained. The language “pharmaceutically acceptable carrier” is intended to include solvents, dispersion media, coatings, anti-bacterial and anti-fungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the compound, use thereof in the therapeutic compositions and methods of treatment and prophylaxis is contemplated. Supplementary active compounds may also be incorporated into the compositions according to the present invention. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. “Dosage unit form” as used herein refers to physically discrete units suited as unitary dosages for the individual to be treated; each unit containing a predetermined quantity of compound(s) is calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The compound(s) may be formulated for convenient and effective administration in effective amounts with a suitable pharmaceutically acceptable carrier in an acceptable dosage unit. In the case of compositions containing supplementary active ingredients, the dosages are determined by reference to the usual dose and manner of administration of the said ingredients. In one embodiment, the carrier is an orally administrable carrier. Another form of a pharmaceutical composition is a dosage form formulated as enterically coated granules, tablets or capsules suitable for oral administration. Also included in the scope of this invention are delayed release formulations. Compounds of formula (I) according to the invention also may be administered in the form of a “prodrug”. Suitable prodrugs include esters, phosphonate esters etc., of the compound. In one embodiment, the compound of formula (I) may be administered by injection. In the case of injectable solutions, the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by including various anti-bacterial and/or anti-fungal agents. Suitable agents are well known to those skilled in the art and include, for example, parabens, chlorobutanol, phenol, benzyl alcohol, ascorbic acid, thimerosal, and the like. In many cases, it may be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminium monostearate and gelatin. Sterile injectable solutions can be prepared by incorporating the analogue in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilisation. Generally, dispersions are prepared by incorporating the analogue into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. Tablets, troches, pills, capsules and the like can also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin or a flavouring agent such as peppermint, oil of wintergreen, or cherry flavouring. When the dosage unit form is a capsule, it can contain, in addition to materials of the above type, a liquid carrier. Various other materials can be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules can be coated with shellac, sugar or both. A syrup or elixir can contain the analogue, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavouring such as cherry or orange flavour. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the analogue can be incorporated into sustained-release preparations and formulations. The pharmaceutical composition may further include a suitable buffer to minimise acid hydrolysis. Suitable buffer agents are well known to those skilled in the art and include, but are not limited to, phosphates, citrates, carbonates and mixtures thereof. Single or multiple administrations of the compounds and/or pharmaceutical compositions according to the invention may be carried out. One skilled in the art would be able, by routine experimentation, to determine effective, non-toxic dosage levels of the compound and/or composition of the invention and an administration pattern which would be suitable for treating the diseases and/or infections to which the compounds and compositions are applicable. Further, it will be apparent to one of ordinary skill in the art that the optimal course of treatment, such as the number of doses of the compound or composition of the invention given per day for a defined number of days, can be ascertained using convention course of treatment determination tests. Generally, an effective dosage per 24 hours may be in the range of about 0.0001 mg to about 1000 mg per kg body weight; for example, about 0.001 mg to about 750 mg per kg body weight; about 0.01 mg to about 500 mg per kg body weight; about 0.1 mg to about 500 mg per kg body weight; about 0.1 mg to about 250 mg per kg body weight; or about 1.0 mg to about 250 mg per kg body weight. More suitably, an effective dosage per 24 hours may be in the range of about 1.0 mg to about 200 mg per kg body weight; about 1.0 mg to about 100 mg per kg body weight; about 1.0 mg to about 50 mg per kg body weight; about 1.0 mg to about 25 mg per kg body weight; about 5.0 mg to about 50 mg per kg body weight; about 5.0 mg to about 20 mg per kg body weight; or about 5.0 mg to about 15 mg per kg body weight. Alternatively, an effective dosage may be up to about 500 mg/m2. For example, generally, an effective dosage is expected to be in the range of about 25 to about 500 mg/m2, about 25 to about 350 mg/m2, about 25 to about 300 mg/m2, about 25 to about 250 mg/m2, about 50 to about 250 mg/m2, and about 75 to about 150 mg/m2. In another embodiment, a compound of Formula (I) may be administered in an amount in the range from about 100 to about 1000 mg per day, for example, about 200 mg to about 750 mg per day, about 250 to about 500 mg per day, about 250 to about 300 mg per day, or about 270 mg to about 280 mg per day. Compounds in accordance with the present invention may be administered as part of a therapeutic regimen with other drugs. It may be desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition. Accordingly, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound of formula (I) according to the present invention, and at least one of which includes an mTOR inhibitor, may be combined in the form of a kit suitable for simultaneous or sequential administration of the compositions. The invention will now be described in more detail, by way of illustration only, with respect to the following examples. The examples are intended to serve to illustrate this invention and should not be construed as limiting the generality of the disclosure of the description throughout this specification. EXAMPLES Example 1—Treatment of Tumour Cells with PENAO and mTORC1 Rapalog Inhibitors Results in Strong Synergistic Effects on Cell Proliferation Except otherwise mentioned, all the reagents and chemicals were from Sigma (St Louis, Mo.). PENAO was prepared as described previously (WO2008/052279). Except otherwise mentioned, cells were from ATCC (Bethesda, Va.) and all culture media, serum, antibiotics and supplements were from Invitrogen (Mulgrave, VIC, Australia). All cultures contained 20 units/mL penicillin and 20 units/mL streptomycin. AsPC1 cells (human pancreatic adenocarcinoma, derived from metastatic site, Kras mutated G12D), SKOV3 (human endometrioid ovarian cancer) and U251MG (human glioblastoma astrocytoma) cells were cultured in RPMI 1640 medium containing 10% v/v foetal bovine serum and 2 mM glutamine. Panc1 (human pancreatic adenocarcinoma, Kras mutated G12D) cells were cultured in DMEM containing 2 mM glutamine. Capan1 (human pancreatic adenocarcinoma, derived from metastatic site, Kras mutated G12V) cells were cultured in IMDM containing 20% v/v foetal bovine serum and 2 mM glutamine. MiaPaca2 cells (human pancreatic adenocarcinoma, Kras mutated G12C) were cultured in DMEM containing 10% v/v foetal bovine serum, 2.5% v/v horse serum and 2 mM glutamine. G89 (primary glioblastoma patient-derived cells, unmethylated MGMT promoter) cells were cultured using serum free media (RHB-A, Cellartis, Takara Bio Inc) with 20 ng/mL EGF and FGF on freshly pre-coated Matrigel (1:100 in phosphate-buffered saline, Falcon, Corning). Subsequent passages upon confluency is performed with twice phosphate-buffered saline (5 mL) washes, followed by 5 min with accutase (2 mL per T75 flask) that is then inactivated with trypsin inhibitor (half the volume of accutase). G89 cells were obtained from A/Prof Kerrie McDonald. All cell lines were tested negative for contamination with Mycoplasma spp. and maintained in a controlled environment of 5% CO, and 95% relative humidity at 37° C. MiaPaca2, AsPC1, Panc1, Capan1, SKOV3 and U251MG cells were seeded at a density of 4×103 cells/well, and G89 cells at 1×104 cells/well, in 96-well plates. Cells were allowed to adhere for 24 h at 37° C. in a 5% CO2, 95% air atmosphere and then treated with compounds (see Table 1 and FIG. 1 for details) for 72 h. Viable cells were determined using the vital dye, MTT, according to the manufacturer's instructions. MiaPaca2 cells were seeded at a density of 4×103 cells per well in a E-Plate 96 PET to monitor real-time proliferation using the xCELLigence System RTCA MP instrument (Roche) according to the manufacturer's instructions. Cells were allowed to adhere for 24 h at 37° C. in a 5% CO2, 95% air atmosphere and then treated either concurrently or sequentially with PENAO and everolimus (see FIG. 2 for details) for up to 100 h. Results: PENAO and the rapalog inhibitors of mTORC1 (temsirolimus, everolimus and deforolimus) act synergistically to inhibit the proliferation of different human pancreatic, ovarian and brain tumour cells in culture (Tables 1 and 2, FIG. 1). Combination indices in the range 0.52 (G89) to 0.89 (AsPC1) were observed. An index of less than 1 is indicative of synergistic effect. The ATP-competitive mTOR inhibitors, AZD8055 and BEZ235, did not exhibit any synergistic effect with PENAO, only the rapalog inhibitors. PENAO and rapalog inhibitors of mTORC1 act synergistically to block the proliferation and induce autophagy and death of human tumour cells in culture. The ATP-competitive mTOR inhibitors do not exhibit any synergistic effect with PENAO, only the rapalog inhibitors. TABLE 1 PENAO and mTORC1 inhibitors induce proliferation arrest in cell lines established from pancreatic, ovarian and brain tumours. Tumour cell lines were seeded in 96-well plates, allowed to adhere for 24 h then treated with the compounds for 72 h. Viable cells were determined using the vital dye, MTT. IC50 values for proliferation arrest are mean ± SD from at least two experiments performed in triplicates. See FIG. 1A for an example of a cell proliferation result for brain G89 cells. Pancreas MiaPaca2 AsPC1 Panc1 Capan1 IC50 ± SD, IC50 ± SD, IC50 ± SD, IC50 ± SD, Compound μM μM μM μM PENAO 2.05 ± 0.54 8.98 ± 1.09 4.73 ± 0.96 9.19 ± 2.69 Temsirolimus 24.6 ± 3.1 19.0 ± 3.1 31.7 ± 0.9 29.2 ± 2.0 Everolimus 44.0 ± 4.0 23.9 ± 3.4 43.1 ± 0.6 34.3 ± 4.0 Deforolimus 56.4 ± 6.9 30.0 ± 5.8 59.3 ± 3.4 48.4 ± 3.5 AZD8055 0.14 ± 0.03 0.01 ± 0.00 >3 >1 BEZ235 0.12 ± 0.06 0.02 ± 0.01 n.d. n.d. Ovary Brain Skov3 U251MG G89 Compound IC50 ± SD, μM IC50 ± SD, μM IC50 ± SD, μM PENAO 7.78 ± 1.30 3.03 ± 0.01 4.74 ± 0.51 Temsirolimus 20.4 ± 0.5 13.6 ± 0.8 20.4 ± 2.7 Everolimus n.d. n.d. n.d. Deforolimus n.d. n.d. n.d. AZD8055 n.d. n.d. n.d. BEZ235 n.d. n.d. n.d. n.d. is not determined. TABLE 2 PENAO and mTORC1 rapalog inhibitors synergise to block the proliferation of cell lines established from pancreatic, ovarian and brain tumours. Tumour cell lines were seeded in 96-well plates, allowed to adhere for 24 h then treated with the compounds for 72 h, either as single agent or in a fixed ratio combination. Viable cells were determined using the vital dye, MTT. Combination index (CI) values at 50% of effective dose (ED50) were determined using CompuSyn software. CI values are mean ± SD from at least two experiments. See FIG. 1B for an example of a synergy cell proliferation result for brain G89 cells. Pancreas Combination MiaPaca2 AsPC1 Panc1 Capan1 with PENAO CI at ED50 CI at ED50 CI at ED50 CI at ED50 Temsirolimus 0.70 ± 0.05 0.77 ± 0.04 0.68 ± 0.04 0.74 ± 0.07 Everolimus 0.75 ± 0.05 0.78 ± 0.01 0.59 ± 0.11 0.82 ± 0.06 Deforolimus 0.80 ± 0.10 0.89 ± 0.04 0.73 ± 0.01 0.64 ± 0.12 AZD8055 1.26 ± 0.26 1.06 ± 0.17 n.d. n.d. BEZ235 1.41 ± 0.18 1.19 ± 0.08 n.d. n.d. Ovary Brain Combination Skov3 U251MG G89 with PENAO CI at ED50 CI at ED50 CI at ED50 Temsirolimus 0.74 ± 0.07 0.81 ± 0.06 0.52 ± 0.13 Everolimus n.d. n.d. n.d. Deforolimus n.d. n.d. n.d. AZD8055 n.d. n.d. n.d. BEZ235 n.d. n.d. n.d. n.d. is not determined. Example 2—the Order of Treatment of Tumour Cells with PENAO and Rapalog Influences the Synergistic Effects on Proliferation Addition of PENAO first followed by the rapalog (everolimus) results in synergistic inhibition of human pancreatic MiaPaca2 cell proliferation at levels comparable to when the compounds are added at the same time (FIG. 2). In contrast, the synergy is not apparent when everolimus is added before PENAO. The order of treatment of tumour cells influences the effects on proliferation, with addition of PENAO followed by a rapalog achieving comparable synergy as when the compounds are administered concurrently. The synergy of the two compounds is not apparent when a rapalog is administered first, followed by PENAO. Example 3—Treatment with PENAO and Rapalog Depletes Tumour Cells of mTOR and Induces Autophagy and Apoptosis Proteins from SKOV3 cell lysates were resolved by SDS-PAGE and immunoblotted with antibodies that recognise LC3B (Cell Signaling), cPARP-1 (Cell Signaling), mTOR, Akt, 3EBP1, β actin or GAPDH (Abcam). Images were acquired using an ImageQuant LAS 4000 system (GE Healthcare Life Sciences). Detection of autolysosomes was performed 24 h after compound exposure by staining for 15 min with Acridine Orange (0.25 μg/mL, Life Technologies). Images were acquired in the green (BP530-585 nm) and red (BP450-490 nm) fluorescence channels using a Zen2012 Carl-Zeiss-AxioVert.A.1 fluorescence microscope (Klionsky et al., 2012; Lena et al., 2009). Results: Combination PENAO and rapalog treatment ablates mTOR protein in human diffuse intrinsic pontine glioma (DIPG) cells, but not other proteins in the pathway (AKT and 4EBP1) (FIG. 3A). Combination treatment of human ovarian tumour cells results in autophagy and apoptosis in the cells (FIG. 3B and FIG. 3C). Example 4—Treatment with PENAO and Rapalog Results in Synergistic Inhibition of Tumour Growth and Tumour Necrosis in Mice Female 6-8 week old BALB/c nude mice were injected subcutaneously in the proximal midline with 4×106 pancreatic carcinoma MiaPaca2 cells. Mice bearing ˜100 mm3 tumours were randomized into four groups (n=8 per group) and implanted with subcutaneous Alzet micro-osmotic model 1004 pumps in the flank that delivered vehicle or 0.25 mg/kg/day PENAO. Four days after pump implantation, mice were treated with everolimus at 5 mg/kg/day per os 5 days a week. On another occasion, 5 mice bearing large ˜600 mm3 MiaPaca2 tumours were implanted with subcutaneous Alzet micro-osmotic model 2002 pumps in the flank that delivered 3 mg/kg/day of PENAO. Four days later, mice were treated with 7.5 mg/kg/day PO of mTORC1 inhibitor, everolimus, for 7 days. Tumour volumes were calculated using the relationship length×height×width×0.523 and are expressed as relative tumour volumes, where the tumour volume at any given time is divided by the starting tumour volume. The mean of these values was used to calculate the ratio between control and treatment tumours as an indicator of drug efficacy. Tumour growth curves were compared using repeated measures two-way analysis of variance (ANOVA) using GraphPad Prism 6 (Tseng et al., 2010). Control and treated tumours were fixed in formalin, embedded in paraffin and sections cut and stained with haematoxylin and eosin for the assessment of tumour necrosis. The percentage of tumour necrosis was measured using Genie Aperio Technologies LTD pattern-recognition software (Aperio Scanscope, Aperio Technologies LTD, Vista, Calif., USA) for the automated quantitative assessment of viable tumour tissue and necrosis (Beloueche-Babari et al., 2013). Changes in percentage of tumour necrosis were assessed with the Mann-Whitney test. All analyses were performed using GraphPad Prism (GraphPad, San Diego, Calif.). All tests of statistical significance were two-sided and p values <0.05 were considered statistically significant. Results: Treatment of human pancreatic tumours in immunocompromised mice with either PENAO or everolimus alone inhibited the rate of tumour growth (FIG. 4). There was a more profound inhibition of tumour growth when the compounds were administered at the same time. There was no sign or symptoms of toxicity in the treated mice. Treatment of large human pancreatic tumours in immunocompromised mice with PENAO and everolimus at near maximal tolerated dose levels resulted in tumour necrosis (FIG. 5). There was no sign or symptoms of toxicity in the treated mice. Treatment with PENAO and a rapalog results in synergistic inhibition of the rate of human tumour growth in mice and triggers tumour necrosis. The combination therapy is well tolerated, with no signs or symptoms of toxicity. REFERENCES Beloueche-Babari, M., Jamin, Y., Arunan, V., Walker-Samuel, S. Revill, M., Smith, P. D., Halliday, J., Waterton, J. C., Barjat, H., Workman, P., et al. (2013). Acute tumour response to the MEK1/2 inhibitor selumetinib (AZD6244, ARRY-142886) evaluated by non-invasive diffusion-weighted MRI. Br J Cancer 109, 1562-1569. Chou, T (2010) Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 70(2) 440-446. Dilda, P. J., Decollogne, S., Weerakoon, L., Norris, M. D., Haber, M., Allen, J. D., and Hogg, P. J. (2009). Optimization of the antitumor efficacy of a synthetic mitochondrial toxin by increasing the residence time in the cytosol. J Med Chem 52, 6209-6216. Klionsky, D. J., Abdalla, F. C., Abeliovich, H., Abraham, R. T., Acevedo-Arozena, A., Adeli, K., Agholme, L., Agnello, M., Agostinis, P., Aguirre-Ghiso, J. A., et al. (2012). Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 8, 445-544. Lena, A., Rechichi, M., Salvetti, A., Bartoli, B Vecchio, D., Scarcelli, V., Amoroso, R., Benvenuti, L., Gagliardi, R., Gremigni, V., et al. (2009). Drugs targeting the mitochondrial pore act as cytotoxic and cytostatic agents in temozolomide-resistant glioma cells. Journal of translational medicine 7, 13. Park, D., Chiu, J., Perrone, G. G., Dilda, P. J., and Hogg, P. J. (2012). The tumour metabolism inhibitors GSAO and PENAO react with cysteines 57 and 257 of mitochondrial adenine nucleotide translocase. Cancer cell international 12, 11. Ramsay, E. E., Hogg, P. J., and Dilda, P. J. (2011). Mitochondrial metabolism inhibitors for cancer therapy. Pharm Res 28, 2731-2744. Roberts, D. J., and Miyamoto, S. (2015). Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy. Cell Death Differ 22, 248-257. Roberts, D. J., Tan-Sah, V. P., Ding, E. Y., Smith, J. M., and Miyamoto, S. (2014). Hexokinase-II positively regulates glucose starvation-induced autophagy through TORC1 inhibition. Mol Cell 53, 521-533. Schenone, S., Brullo, C., Musumeci, F., Radi, M., and Botta, M. (2011). ATP-competitive inhibitors of mTOR: an update. Curr Med Chem 18, 2995-3014. Tseng, J. C., Granot, T., DiGiacomo, V., Levin, B., and Meruelo, D. (2010). Enhanced specific delivery and targeting of oncolytic Sindbis viral vectors by modulating vascular leakiness in tumor. Cancer Gene Ther 17, 244-255. Zaytseva, Y. Y., Valentino, J. D., Gulhati, P., and Evers, B. M. (2012). mTOR inhibitors in cancer therapy. Cancer Lett 319, 1-7. | <SOH> BACKGROUND <EOH>Arsenical compounds have been used in the past as therapeutic agents for the treatment of disease. However, the inherent toxicities of arsenical compounds and their generally unfavourable therapeutic index have largely precluded their use as pharmaceutical agents. Organic arsenoxide compounds are disclosed in WO 01/21628. Such compounds are described as having antiproliferative properties useful in the therapy of proliferative diseases. WO 04/042079 discloses the use of organic arsenoxide compounds for inducing the mitochondrial permeability transmission (MPT) and also the use of such compounds for inducing apoptosis and necrosis, particularly in endothelial cells. Further organic arsenoxide compounds are disclosed in WO2008/052279. In particular, the compound 4-(N—(S-penicllaminylacetyl)amino)phenylarsinous acid (PENAO) is disclosed in WO2008/052279. PENAO is a mitochondrial metabolism inhibitor in the final stages of Phase I clinical testing in patients with solid tumours refractory to standard therapy at three hospitals in Australia. PENAO is a cysteine mimetic trivalent arsenical that enters cells via an organic ion transporter and accumulates in the mitochondrial matrix where the arsenical moiety cross-links Cys160 and Cys257 on the matrix face of adenine nucleotide translocase (ANT), which inactivates the transporter (Dilda et al., 2009; Park et al., 2012). Its inactivation leads to partial uncoupling of oxidative phosphorylation, increase in superoxide production, proliferation arrest and ultimately apoptosis of the cell. PENAO only reacts with ANT when cells are proliferating as Cys160 and Cys257 appear to be disulphide bonded in growth quiescent cells, and so unreactive towards PENAO. Mammalian (mechanistic) target of rapamycin (mTOR) is a serine/threonine kinase that forms two distinct complexes called mTORC1 and mTORC2. Rapamycin (sirolimus) and rapamycin analogs (rapalogs) form a complex with the small protein FKBP12, that irreversibly binds to the FKBP12-rapamycin domain of mTORC1 and inhibits its kinase activity (Zaytseva et al., 2012). Rapamycin and rapalogs are small molecule inhibitors of mTOR and a number of clinical trials evaluating the anti-cancer efficacy of rapalogs as a monotherapy or as a part of combination therapy across a wide range of cancers types are currently in progress. The rapalogs are generally well tolerated in cancer patients (Zaytseva et al., 2012). ATP-competitive inhibitors of mTOR are also being developed (Schenone et al., 2011). These inhibitors compete with ATP for binding to the active site of the kinase. There is a need for improved therapies for treating proliferative diseases, such as cancer (including treatment of solid tumours), and related conditions. It has now surprisingly been found that the combination of an organo-arsenoxide compound, such as PENAO, with an mTOR inhibitor dramatically enhances the efficacy of the organo-arsenoxide compound in the treatment of proliferative diseases. The combination of the organo-arsenoxide compound and the rapamycin mTOR inhibitor has been found to act synergistically to mediate tumour cell death. | <SOH> SUMMARY <EOH>In a first aspect the present invention relates to a synergistic pharmaceutical combination comprising an organo-arsenoxide compound, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, and an mTOR inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof. In one embodiment the organo-arsenoxide compound is PENAO. In one embodiment the mTOR inhibitor is a rapalog selected from the group consisting of everolimus, temsirolimus, deforolimus and zotarolimus. In a second aspect the present invention relates to a pharmaceutical composition comprising an organo-arsenoxide compound, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, and an mTOR inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof. In a third aspect the present invention relates to a method of treating a cellular proliferative disease in a vertebrate, the method comprising administering to the vertebrate a therapeutically effective amount of the synergistic pharmaceutical combination of the first aspect of the invention, or the pharmaceutical composition of the second aspect of the invention. In a fourth aspect the invention relates to a method of inhibiting angiogenesis in a vertebrate, comprising administering to the vertebrate a therapeutically effective amount of the synergistic pharmaceutical combination of the first aspect of the invention, or the pharmaceutical composition of the second aspect of the invention. In a fifth aspect the invention relates to a method of selectively inducing the Mitochondrial Permeability Transition (MPT) in proliferating cells in a vertebrate comprising administering to the vertebrate a therapeutically effective amount of the synergistic pharmaceutical combination of the first aspect of the invention, or the pharmaceutical composition of the second aspect of the invention. In a sixth aspect the invention relates to a method of inducing apoptosis in proliferating mammalian cells, comprising administering to the vertebrate a therapeutically effective amount of the synergistic pharmaceutical combination of the first aspect of the invention, or the pharmaceutical composition of the second aspect of the invention. In a seventh aspect the present invention relates to a method of treating a cellular proliferative disease in a vertebrate, the method comprising administering to the vertebrate a therapeutically effective amount of an organo-arsenoxide compound or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof and an mTOR inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof. In one embodiment the organo-arsenoxide compound and the mTOR inhibitor are administered simultaneously. In another embodiment the organo-arsenoxide compound is administered first, followed by the mTOR inhibitor. In yet another aspect the present invention relates to the use of an organo-arsenoxide compound, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, and an mTOR inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, for the manufacture of a medicament for the treatment of a cellular proliferative disease. In one embodiment of the aspects of the invention the organo-arsenoxide compound is PENAO. In one embodiment of the aspects of the invention the mTOR inhibitor is a rapalog selected from the group consisting of everolimus, temsirolimus, deforolimus and zotarolimus. In one embodiment of the aspects of the invention the cellular proliferative disease is a solid tumour. | A61K31655 | 20180307 | 20180524 | 61731.0 | A61K31655 | 0 | HOWELL, THEODORE R | Pharmaceutical Combinations of Organo-Arsenoxide Compounds and mTOR Inhibitors | SMALL | 0 | REJECTED | A61K | 2,018 |
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15,738,233 | PENDING | RANDOM ACCESS METHOD, DEVICE AND SYSTEM | A random access method comprises: transmitting, by a firstuser equipment (UE) in a UE group, and according to a time-frequency resource, a preamble to an evolved node B (eNB); and monitoring, by a second UE in the UE group and/or the first UE, for a random access response (RAR) corresponding to the preamble transmitted by the eNB, wherein the first UE is at least one UE in the UE group, and the second UE is all or a part of the UEs in the UE group. | 1. A random access method, comprising: sending, by a first User Equipment (UE) in a UE group, a preamble to an evolved Node B (eNB) over a time-frequency resource, the time-frequency resource comprising a time domain resource and a frequency domain resource; and monitoring, by the first UE and/or a second UE in the UE group, a Random Access Response (RAR) corresponding to the preamble and sent by the eNB, wherein the first UE is at least one UE in the UE group, and the second UE is all or some UEs in the UE group. 2. The method according to claim 1, wherein the first UE is at least one of the following: at least one fixed UE; or, at least one UE determined according to a pre-set rule; or, at least one UE notified by the eNB. 3. The method according to claim 1, wherein the preamble and/or the time domain resource and/or the frequency domain resource are/is pre-set, or determined by a group Identifier (ID) of the UE group, or notified by the eNB. 4. The method according to claim 1, wherein monitoring, by the first UE and/or the second UE, the RAR corresponding to the preamble and sent by the eNB comprises: descrambling, by the first UE and/or the second UE, a Cyclic Redundancy Check (CRC) of Downlink Control Information (DCI) for scheduling the RAR according to a pre-set Random Access Radio Network Temporary Identity (RA-RNTI) or an RA-RNTI corresponding to the preamble, and receiving the RAR, the RAR comprising at least one Temporary Cell Radio Network Temporary Identity (TC-RNTI) and/or at least one Uplink (UL) grant; and determining, by the first UE and/or the second UE, a TC-RNTI and/or UL grant allocated thereto according to at least one TC-RNTI and/or at least one UL grant contained in the RAR; or monitoring, by the first UE and/or the second UE, the RAR corresponding to the preamble and sent by the eNB comprises: determining, by the first UE and/or the second UE, corresponding RA-RNTIs according to respective IDs and/or preambles, descrambling a CRC of DCI for scheduling the RAR according to the corresponding RA-RNTIs, and receiving corresponding RARs, the RAR comprising a TC-RNTI and/or a UL grant allocated to the first UE or second UE. 5. The method according to claim 4, wherein determining, by the first UE and/or the second UE, the TC-RNTI and/or the UL grant allocated thereto according to at least one TC-RNTI and/or at least one UL grant contained in the RAR comprises: determining, by the first UE and/or the second UE, a TC-RNTI and/or a UL grant allocated thereto according to an ID of the first UE and/or the second UE in accordance with a pre-set rule. 6. (canceled) 7. The method according to claim 4, further comprising: after monitoring, by the first UE and/or the second UE, the RAR corresponding to the preamble and sent by the eNB, sending, by the first UE and/or the second UE, a message 3 according to the UL grant allocated thereto. 8. The method according to claim 7, further comprising: after sending, by the first UE and/or the second UE, a message 3 according to the UL grant allocated thereto, receiving, by the first UE and/or the second UE, a message 4 sent by the eNB. 9. The method according to claim 8, wherein receiving, by the first UE and/or the second UE, the message 4 sent by the eNB comprises: scrambling a CRC of DCI for scheduling the message 4 by using the TC-RNTI allocated to the first UE and/or the second UE. 10. The method according to claim 9, wherein the message 4 comprises at least one set of radio resources, radio resources allocated to the first UE and/or the second UE determined by the first UE and/or the second UE according to at least one set of radio resources in the message 4; or the message 4 comprises a set of radio resources allocated to the first UE or second UE. 11. The method according to claim 10, wherein the radio resources allocated to the first UE and/or the second UE are further determined by the first UE and/or the second UE according to an ID of the first UE and/or the second UE in accordance with a pre-set rule. 12. (canceled) 13. The method according to claim 8, further comprising: after receiving, by the first UE and/or the second UE, the message 4 sent by the eNB, sending, by the first UE and/or the second UE, an indicating signal for notifying the eNB of a successful access of the first UE and/or the second UE to the eNB, wherein the indicating signal is a Scheduling Request (SR) or an Acknowledgement (ACK) signal. 14. (canceled) 15. The method according to claim 8, further comprising: after receiving, by the first UE and/or the second UE, a message 4 sent by the eNB, receiving, by the first UE and/or the second UE, indicating information, sent by the eNB, for indicating re-initiation of a random access of the first UE and/or the second UE. 16. The method according to claim 1, further comprising: before sending, by the first UE in the UE group, the preamble over the time-frequency resource, receiving, by the first UE and/or the second UE, DCI or a paging message or a Radio Resource Control (RRC) message sent by the eNB; or, receiving, by the first UE, random access request information sent by the second UE. 17. The method according to claim 16, wherein receiving, by the first UE and/or the second UE, DCI or a paging message or an RRC message sent by the eNB comprises at least one of the following: the DCI or a CRC of DCI for scheduling the paging message or the RRC message is scrambled by using a group ID of the UE group; the DCI or the paging message or the RRC message comprises a group ID of the UE group; the DCI or the paging message or the RRC message comprises an ID of the first UE and/or the second UE; and the DCI or the paging message or the RRC message comprises an ID of a preamble and/or a time domain resource of a preamble and/or a frequency domain resource of a preamble. 18. The method according to claim 16, further comprising: after receiving, by the first UE, random access request information sent by the second UE, counting, by the first UE, received random access requests of the second UE in the group; and when a count reaches a pre-set threshold, sending, by the first UE, a preamble over a time-frequency resource. 19. The method according to claim 1, wherein sending, by the first UE in the UE group, the preamble over the time-frequency resource comprises: periodically sending, by the first UE, the preamble over a frequency domain resource. 20. The method according to claim 8, wherein the message 3 and the message 4 comprise the group ID of the UE group or a pre-set field. 21. The method according to claim 7, wherein the message 3 comprises a number of UEs having random access requests in the UE group or a number of UEs contained in the UE group or a pre-set UE number. 22. The method according to claim 3, wherein the preamble and/or the time domain resource and/or the frequency domain resource correspond(s) to the number of UEs having random access requests in the UE group or the number of UEs contained in the UE group or the pre-set UE number. 23.-37. (canceled) 38. A User Equipment (UE), comprising: a sending unit and a monitoring unit, wherein the sending unit is configured to: send a preamble to an evolved Node B (eNB) over a time-frequency resource, the time-frequency resource comprising a time domain resource and a frequency domain resource; and the monitoring unit is configured to: monitor a Random Access Response (RAR) corresponding to the preamble and sent by the eNB. 39.-71. (canceled) | TECHNICAL FIELD The present disclosure relates to, but not limited to the field of communications, and in particular to a random access method, device and system. BACKGROUND A Machine Type Communication (MTC) User Equipment (UE or terminal) is also referred to as a Machine to Machine (M2M) user communication device, which is a main application form of a current internet of things. Recently, due to high spectral efficiency of a Long-Term Evolution (LTE)/Long-Term Evolution Advance (LTE-Advance or LTE-A) system, more and more mobile operators select the LTE/LTE-A as an evolution direction of a broadband wireless communication system. LTE/LTE-A based MTC multi-type data services will be more attractive. In the LTE system, a random access is a basic function, and a UE can be scheduled by the system to perform uplink transmission only after uplink synchronization with the system via a random access process. The random access in the LTE is divided into two forms namely a contention-based random access and a contention-free random access. An initial random access process is a contention-based access process, which can be divided into four steps. (1) A UE sends a preamble, and the UE randomly selects an available preamble to be sent. (2) An evolved Node B (eNB, also referred to as an evolved base station) sends a Random Access Response (RAR). When the eNB detects a preamble sequence sent by the UE, a response will be sent over a Downlink-Synchronization Channel (DL-SCH), the response including: an index number of the detected preamble, time adjustment information for uplink synchronization, initial uplink resource allocation (used for sending a subsequent message 3), and a Temporary Cell Radio Network Temporary Identity (TC-RNTI). It will be decided whether the TC-RNTI is converted into a permanent C-RNTI in Step (4) (contention resolution). The UE needs to monitor an RAR message over a Physical Downlink Control Channel (PDCCH) by using a Random Access RNTI (RA-RNTI). RA-RNTI=1+t_id+10*f_id, where t_id refers to an index number of a first subframe of a Physical Random Access Channel (PRACH) for sending a preamble (0<=t_id<10), f_id is a PRACH index in this subframe, i.e., a frequency domain position index (0=<f_id<=6), but there is only one frequency domain position for a Frequency Division Duplexing (FDD) system, and therefore f_id is always zero. (3) The UE sends the message 3. After receiving the RAR message, the UE obtains uplink time synchronization and uplink resources. However, at this time, it cannot be determined that the RAR message is sent to the UE itself instead of other UEs. The preamble sequence of the UE is randomly selected from common resources, thereby making it possible for different UEs to send the same access preamble sequence over the same time-frequency resource. Thus, they will receive the same RAR via the same RA-RNTI. Moreover, the UE is unable to know whether other UEs make a random access by using the same resource. For this purpose, the UE needs to resolve such a random access contention via the subsequent message 3 and message 4. (4) The eNB sends the message 4, namely a contention resolution message. If the UE receives the message 4 returned by the eNB and a UE Identifier (ID) carried therein conforms to an ID reported to the eNB in the message 3 within the time of a mac-Contention Resolution Timer, the UE considers that it wins this random access contention and the random access is successful, and sets the TC-RNTI obtained in the RAR message as an own C-RNTI. Otherwise, the UE considers that the random access is unsuccessful, and executes a random access retransmission process in accordance with the above-mentioned rule. As for the contention-free random access, the preamble sent by the UE is notified by the eNB, uplink synchronization is completed via the first two steps, and a contention resolution process is not executed. Future communication requirements for a huge number of machine devices are as follows. A random access concurrent transmission blocking rate is smaller than 0.1%, and the access density within 1 s to 10 s is not smaller than 10 UEs per square meter. So, at least tens of thousands of UEs are accessed to a micro cell within 1 s to 10 s. In order to meet this demand, even if UEs are uniformly accessed and each subframe can initiate a random access, at least hundreds of times of PRACH resources are needed in accordance with a random access mode in the related art. However, actually, the UEs are not uniformly accessed. Therefore, more resources may be needed. In a conventional LTE system, if one time-frequency resource receives 64 cyclic shifts of one preamble root sequence, resources are insufficient for a system having a bandwidth of 20 Mbps even though all bandwidths are used to send the PRACH. SUMMARY The following is a brief introduction for a subject described herein in detail. The brief introduction is not intended to restrict the scope of protection of claims. The disclosure provides a random access method, device and system, intended to save PRACH resources and meet requirements for a huge number of machine communications. The embodiments of the disclosure provide a random access method. The method includes the steps as follows. A first UE in a UE group sends a preamble to an eNB over a time-frequency resource, the time-frequency resource including a time domain resource and a frequency domain resource. The first UE and/or a second UE in the UE group monitor(s) an RAR corresponding to the preamble and sent by the eNB, herein the first UE is at least one UE in the UE group, and the second UE is all or some UEs in the UE group. In an embodiment, the first UE is at least one of the following: at least one fixed UE; or, at least one UE determined according to a pre-set rule; or, at least one UE notified by the eNB. In an embodiment, the preamble and/or the time domain resource and/or the frequency domain resource are/is pre-set, or determined by a group ID of the UE group, or notified by the eNB. In an embodiment, the operation that the first UE and/or the second UE monitor(s) an RAR corresponding to the preamble and sent by the eNB includes the following operations. The first UE and/or the second UE descramble(s) a Cyclic Redundancy Check (CRC) of Downlink Control Information (DCI) for scheduling the RAR according to a pre-set RA-RNTI or an RA-RNTI corresponding to the preamble, and receive(s) the RAR, the RAR including at least one TC-RNTI and/or at least one Uplink (UL) grant. The first UE and/or the second UE determine(s) a TC-RNTI and/or UL grant allocated thereto according to at least one TC-RNTI and/or at least one UL grant included in the RAR. In an embodiment, the operation that the first UE and/or the second UE determine(s) a TC-RNTI and/or a UL grant allocated thereto according to at least one TC-RNTI and/or at least one UL grant included in the RAR includes the following operation. The first UE and/or the second UE determine(s) a TC-RNTI and/or a UL grant allocated thereto according to an ID of the first UE and/or the second UE in accordance with a pre-set rule. In an embodiment, the operation that the first UE and/or the second UE monitor(s) an RAR corresponding to the preamble and sent by the eNB includes the following operation. The first UE and/or the second UE determine(s) corresponding RA-RNTIs according to respective IDs and/or preambles, descramble(s) a CRC of DCI for scheduling the RAR according to the corresponding RA-RNTIs, and receive(s) corresponding RARs, the RAR including a TC-RNTI and/or a UL grant allocated to the first UE or second UE. In an embodiment, after the first UE and/or the second UE monitor(s) an RAR corresponding to the preamble and sent by the eNB, the method further includes the step as follows. The first UE and/or the second UE send(s) a message 3 according to the UL grant allocated thereto. In an embodiment, after the first UE and/or the second UE send(s) a message 3 according to the UL grant allocated thereto, the method further includes the step as follows. The first UE and/or the second UE receive(s) a message 4 sent by the eNB. In an embodiment, the operation that the first UE and/or the second UE receive(s) a message 4 sent by the eNB includes the following operation. A CRC of DCI for scheduling the message 4 is scrambled by using the TC-RNTI allocated to the first UE and/or the second UE. In an embodiment, the message 4 includes at least one set of radio resources, radio resources allocated to the first UE and/or the second UE determined by the first UE and/or the second UE according to at least one set of radio resources in the message 4. In an embodiment, the radio resources allocated to the first UE and/or the second UE are further determined by the UE according to an ID of the first UE and/or the second UE in accordance with a pre-set rule. In an embodiment, the message 4 includes: a set of radio resources allocated to the first UE or second UE. In an embodiment, after the first UE and/or the second UE receive(s) a message 4 sent by the eNB, the method further includes the step as follows. The first UE and/or the second UE send(s), to the eNB, an indicating signal for notifying the eNB of a successful access of the first UE and/or the second UE. In an embodiment, the indicating signal is a Scheduling Request (SR) or an Acknowledgement (ACK) signal. In an embodiment, after the first UE and/or the second UE receive(s) a message 4 sent by the eNB, the method further includes the step as follows. The first UE and/or the second UE receive(s) indicating information, sent by the eNB, for indicating re-initiation of a random access of the first UE and/or the second UE. In an embodiment, before the first UE in the UE group sends a preamble over a time-frequency resource, the method further includes the steps as follows. The first UE and/or the second UE receive(s) DCI or a paging message or a Radio Resource Control (RRC) message sent by the eNB. Or, the first UE receives random access request information sent by the second UE. In an embodiment, the operation that the first UE and/or the second UE receive(s) DCI or a paging message or an RRC message sent by the eNB includes at least one of the following operations. The DCI or a CRC of DCI for scheduling the paging message or the RRC message is scrambled by using a group ID of the UE group. The DCI or the paging message or the RRC message includes a group ID of the UE group. The DCI or the paging message or the RRC message includes an ID of the first UE and/or the second UE. The DCI or the paging message or the RRC message includes an ID of a preamble and/or a time domain resource of a preamble and/or a frequency domain resource of a preamble. In an embodiment, after the first UE receives random access request information sent by the second UE, the method further includes the steps as follows. The first UE counts received random access requests of the second UE in the group. When a count reaches a pre-set threshold, the first UE sends a preamble over a time-frequency resource. In an embodiment, the operation that the first UE in the UE group sends a preamble over a time-frequency resource includes the following operation. The first UE sends a preamble over a frequency domain resource periodically. In an embodiment, the message 3 and the message 4 include the group ID of the UE group or a pre-set field. In an embodiment, the message 3 includes a number of UEs having random access requests in the UE group or a number of UEs contained in the UE group or a pre-set UE number. In an embodiment, the preamble and/or the time domain resource and/or the frequency domain resource correspond(s) to the number of UEs having random access requests in the UE group or the number of UEs contained in the UE group or the pre-set UE number. The embodiments of the disclosure also provide a random access method. The method includes the steps as follows. An eNB receives a preamble sent by a first UE in a UE group over a time-frequency resource, herein the time-frequency resource includes a time domain resource and a frequency domain resource, and the first UE is at least one UE in the UE group. The eNB sends an RAR corresponding to the preamble. In an embodiment, the RAR includes at least one TC-RNTI and/or at least one UL grant, the RAR is used for the first UE and/or the second UE to determine a TC-RNTI and/or UL grant allocated thereto from at least one TC-RNTI and/or UL grant according to an ID of the first UE and/or the second UE in accordance with a pre-set allocation rule, and the second UE is all or some UEs in the UE group. In an embodiment, the RAR includes a TC-RNTI and/or a UL grant allocated to the first UE or second UE, and the second UE is all or some UEs in the UE group. In an embodiment, after the eNB sends an RAR corresponding to the preamble, the method further includes the step as follows. The eNB receives a message 3 sent by the first UE and/or the second UE according to the UL grant allocated thereto. In an embodiment, after the eNB receives a message 3 sent by the first UE and/or the second UE according to the UL grant allocated thereto, the method further includes the step as follows. The eNB sends a message 4 to the first UE and/or the second UE. In an embodiment, the operation that the eNB sends a message 4 to the first UE and/or the second UE includes the following operation: a CRC of DCI for scheduling the message 4 is scrambled by using the TC-RNTI allocated to the first UE and/or the second UE. In an embodiment, the message 4 includes at least one set of radio resources, radio resources allocated to the first UE and/or the second UE determined by the first UE and/or the second UE according to at least one set of radio resources included in the message 4. In an embodiment, the message 4 includes: a set of radio resources allocated to the first UE or second UE. In an embodiment, after the eNB sends a message 4 to the first UE and/or the second UE, the method further includes the step as follows. The eNB receives an indicating signal, sent by the first UE and/or the second UE, for notifying the eNB of a successful access of the first UE and/or the second UE, the indicating signal being an SR or an ACK signal. In an embodiment, after the eNB sends a message 4 to the first UE and/or the second UE, the method further includes the step as follows. The eNB sends, to the first UE and/or the second UE, indicating information for indicating re-initiation of a random access of the first UE and/or the second UE. In an embodiment, before the eNB receives a preamble sent by a first UE in a UE group over a time-frequency resource, the method further includes the step as follows. The eNB sends DCI or a paging message or an RRC message to the first UE and/or the second UE. In an embodiment, the operation that the eNB sends DCI or a paging message or an RRC message to the first UE and/or the second UE includes at least one of the following operations. The DCI or a CRC of DCI for scheduling the paging message or the RRC message is scrambled by using a group ID of the UE group. The DCI or the paging message or the RRC message includes a group ID of the UE group. The DCI or the paging message or the RRC message includes an ID of the first UE and/or the second UE. The DCI or the paging message or the RRC message includes an ID of a preamble and/or a time domain resource of a preamble and/or a frequency domain resource of a preamble. In an embodiment, the operation that the eNB receives a preamble sent by the first UE in the UE group over a time-frequency resource includes the following operation. The eNB receives a preamble sent by the first UE over a frequency domain resource periodically. In an embodiment, the message 3 and the message 4 include the group ID of the UE group or a pre-set field. In an embodiment, the message 3 includes a number of UEs having random access requests in the UE group or a number of UEs contained in the UE group. The embodiments of the disclosure also provide a computer-readable storage medium, which stores a computer-executable instruction, herein when the computer-executable instruction is executed, the above-mentioned random access method is implemented. The embodiments of the disclosure also provide a UE. The UE includes: a sending unit and a monitoring unit, herein the sending unit is configured to: send a preamble to an eNB over a time-frequency resource, the time-frequency resource including a time domain resource and a frequency domain resource; and the monitoring unit is configured to: monitor an RAR corresponding to the preamble and sent by the eNB. In an embodiment, the monitoring unit includes: a first descrambling subunit, a first receiving subunit and an allocation subunit, herein the first descrambling subunit is configured to: descramble a CRC of DCI for scheduling the RAR according to a pre-set RA-RNTI or an RA-RNTI corresponding to the preamble; the first receiving subunit is configured to: receive the RAR, the RAR including at least one TC-RNTI and/or at least one UL grant; and the allocation subunit is configured to: determine a TC-RNTI and/or UL grant allocated to the UE according to at least one TC-RNTI and/or at least one UL grant included in the RAR. In an embodiment, the allocation subunit is configured to: determine a TC-RNTI and/or a UL grant allocated to the UE according to an ID of the UE in accordance with a pre-set rule. In an embodiment, the monitoring unit includes: a determination subunit, a second descrambling subunit and a second receiving subunit, herein the determination subunit is configured to: determine corresponding RA-RNTIs of the UE according to respective IDs and/or preambles of the UE; the second descrambling subunit is configured to: descramble a CRC of DCI for scheduling the RAR according to the corresponding RA-RNTIs of the UE; and the second receiving subunit is configured to: receive corresponding RARs of the UE, the RAR including a corresponding TC-RNTI and/or UL grant allocated to the UE. In an embodiment, the sending unit is further configured to: send a message 3 according to the UL grant allocated to the UE. In an embodiment, the UE further includes a receiving unit, configured to: receive a message 4 sent by the eNB. In an embodiment, receiving a message 4 sent by the eNB includes: scrambling a CRC of DCI for scheduling the message 4 by using the TC-RNTI allocated to a first UE and/or a second UE. In an embodiment, the message 4 includes at least one set of radio resources for the UE to determine radio resources allocated to the UE. In an embodiment, the message 4 includes: a set of radio resources allocated to the corresponding UE. In an embodiment, the sending unit is further configured to: send, to the eNB, an indicating signal for notifying the eNB of a successful access of the UE. In an embodiment, the indicating signal is an SR or an ACK signal. In an embodiment, the receiving unit is further configured to: receive indicating information, sent by the eNB, for indicating re-initiation of a random access of the UE. In an embodiment, the receiving unit is further configured to: receive DCI or a paging message or an RRC message sent by the eNB; or, receive random access request information sent by the second UE. In an embodiment, receiving DCI or a paging message or an RRC message sent by the eNB includes at least one of the following: the DCI or a CRC of DCI for scheduling the paging message or the RRC message is scrambled by using a group ID of a UE group; the DCI or the paging message or the RRC message includes the group ID of the UE group; the DCI or the paging message or the RRC message includes an ID of the first UE and/or the second UE; and the DCI or the paging message or the RRC message includes an ID of a preamble and/or a time domain resource of a preamble and/or a frequency domain resource of a preamble. In an embodiment, the sending unit is configured to: send a preamble over a frequency domain resource periodically. In an embodiment, the message 3 and the message 4 include the group ID of the UE group or a pre-set field. In an embodiment, the message 3 includes a number of UEs having random access requests in the UE group or a number of UEs contained in the UE group or a pre-set UE number. In an embodiment, the preamble and/or the time domain resource and/or the frequency domain resource correspond(s) to the number of UEs having random access requests in the UE group or the number of UEs contained in the UE group or the pre-set UE number. The embodiments of the disclosure also provide an eNB. The eNB includes: a receiving unit and a sending unit, herein the receiving unit is configured to: receive a preamble sent by a first UE in a UE group over a time-frequency resource, herein the time-frequency resource includes a time domain resource and a frequency domain resource, and the first UE is at least one UE in the UE group; and the sending unit is configured to: send an RAR corresponding to the preamble. In an embodiment, the RAR includes at least one TC-RNTI and/or at least one UL grant, the RAR is used for the first UE and/or the second UE to determine a TC-RNTI and/or UL grant allocated thereto from at least one TC-RNTI and/or UL grant according to an ID of the first UE and/or the second UE in accordance with a pre-set allocation rule, and the second UE is all or some UEs in the UE group. In an embodiment, the RAR includes a TC-RNTI and/or a UL grant allocated to the first UE or second UE, and the second UE is all or some UEs in the UE group. In an embodiment, the receiving unit is further configured to: receive a message 3 sent by the first UE and/or the second UE according to the UL grant allocated thereto. In an embodiment, the sending unit is further configured to: send a message 4 to the first UE and/or the second UE. In an embodiment, sending a message 4 to the first UE and/or the second UE includes: scrambling a CRC of DCI for scheduling the message 4 by using the TC-RNTI allocated to the first UE and/or the second UE. In an embodiment, the message 4 includes at least one set of radio resources for the first UE and/or the second UE to determine radio resources allocated thereto. In an embodiment, the message 4 includes: a set of radio resources allocated to the first UE or second UE. In an embodiment, the receiving unit is further configured to: receive an indicating signal, sent by the first UE and/or the second UE, for notifying the eNB of a successful access of the first UE and/or the second UE, the indicating signal being an SR or an ACK signal. In an embodiment, the sending unit is further configured to: send, to the first UE and/or the second UE, indicating information for indicating re-initiation of a random access of the first UE and/or the second UE. In an embodiment, the sending unit is further configured to: send DCI or a paging message or an RRC message to the first UE and/or the second UE. In an embodiment, sending DCI or a paging message or an RRC message to the first UE and/or the second UE includes at least one of the following: the DCI or a CRC of DCI for scheduling the paging message or the RRC message is scrambled by using a group ID of the UE group; the DCI or the paging message or the RRC message includes a group ID of the UE group; the DCI or the paging message or the RRC message includes an ID of the first UE and/or the second UE; and the DCI or the paging message or the RRC message includes an ID of a preamble and/or a time domain resource of a preamble and/or a frequency domain resource of a preamble. In an embodiment, the receiving unit is configured to: receive a preamble sent by the first UE over a frequency domain resource periodically. In an embodiment, the message 3 and the message 4 include the group ID of the UE group or a pre-set field. In an embodiment, the message 3 includes a number of UEs having random access requests in the UE group or a number of UEs contained in the UE group. The embodiments of the disclosure also provide a random access system. The system includes a UE and an eNB, herein a first UE in a UE group is configured to: send a preamble to the eNB over a time-frequency resource, the time-frequency resource including a time domain resource and a frequency domain resource; the first UE and/or a second UE in the UE group are/is configured to: monitor an RAR corresponding to the preamble and sent by the eNB, herein the first UE is at least one UE in the UE group, and the second UE is all or some UEs in the UE group; and the eNB is configured to: receive the preamble sent by the first UE in the UE group over the time-frequency resource, and send the RAR corresponding to the preamble. The embodiments of the disclosure provide a random access method, device and system. One or more UEs in a UE group send a preamble to an eNB over a time-frequency resource, so as to instruct the eNB to execute random accesses of some or all UEs in the UE group. Thus, a group of UEs only needs to occupy a PRACH resource (including a time domain resource, a frequency domain resource and a preamble) in a random access, so that PRACH resources can be greatly saved, thereby meeting requirements for a huge number of machine communications. After the drawings and the detailed descriptions are read and understood, other aspects may be understood. BRIEF DESCRIPTION OF DRAWINGS FIG. 1 shows a flowchart of a random access method according to an embodiment of the disclosure. FIG. 2 shows a flowchart of another random access method according to an embodiment of the disclosure. FIG. 3 shows a chart of a contention-free random access method according to an embodiment of the disclosure. FIG. 4 shows a chart of a method for triggering access of a UE group in a manner that an eNB sends a paging message according to an embodiment of the disclosure. FIG. 5 illustrates a structure diagram of a UE according to an embodiment of the disclosure. FIG. 6 illustrates a structure diagram of another UE according to an embodiment of the disclosure. FIG. 7 illustrates a structure diagram of a further UE according to an embodiment of the disclosure. FIG. 8 illustrates a structure diagram of an eNB according to an embodiment of the disclosure. DETAILED DESCRIPTION The detailed description will be made hereinbelow in conjunction with the drawings. It is important to note that the embodiments in the present disclosure and various modes in the embodiments can be combined without conflicts. First Embodiment FIG. 1 shows a flow of a random access method according to an embodiment of the disclosure. The method may be applied to a UE side and may include the steps as follows. In S101, a first UE in a UE group sends a preamble to an eNB over a time-frequency resource, the time-frequency resource including a time domain resource and a frequency domain resource. In S102: the first UE and/or a second UE in the UE group monitor(s) an RAR corresponding to the preamble and sent by the eNB. Herein, the first UE may be at least one UE in the UE group, and the first UE can be representative of the UE group. The second UE may be all or some UEs in the UE group, i.e., UEs having random access requests. Therefore, the second UE may include the first UE. It is important to note that the first UE may be at least one of the following: at least one fixed UE; or, at least one UE determined according to a pre-set rule; or, at least one UE notified by the eNB. Moreover, the preamble and/or the time domain resource and/or the frequency domain resource may be pre-set, or may be determined by a group ID of the UE group, or may be notified by the eNB. In an embodiment, the operation that the first UE and/or the second UE monitor(s) an RAR corresponding to the preamble and sent by the eNB may include the following operations. The first UE and/or the second UE descramble(s) a CRC of DCI for scheduling the RAR according to a pre-set RA-RNTI or an RA-RNTI corresponding to the preamble, and receive(s) the RAR, the RAR including at least one TC-RNTI and/or at least one UL grant. The first UE and/or the second UE determine(s) a TC-RNTI and/or UL grant allocated thereto according to at least one TC-RNTI and/or at least one UL grant included in the RAR. In an embodiment, the first UE and/or the second UE may determine a TC-RNTI and/or a UL grant allocated thereto according to an ID of the first UE and/or the second UE in accordance with a pre-set rule. In an embodiment, the operation that the first UE and/or the second UE monitor(s) an RAR corresponding to the preamble and sent by the eNB may include the following operation. The first UE and/or the second UE determine(s) corresponding RA-RNTIs according to respective IDs and/or preambles, descramble(s) a CRC of DCI for scheduling the RAR according to the corresponding RA-RNTIs, and receive(s) corresponding RARs, the RAR including a TC-RNTI and/or a UL grant allocated to the first UE or second UE. Exemplarily, after the first UE and/or the second UE monitor(s) an RAR corresponding to the preamble and sent by the eNB, the method may further include the step as follows. The first UE and/or the second UE send(s) a message 3 according to the UL grant allocated thereto. In an embodiment, after the first UE and/or the second UE send(s) a message 3 according to the UL grant allocated thereto, the method may further include the step as follows. The first UE and/or the second UE receive(s) a message 4 sent by the eNB. It is important to note that the operation that the first UE and/or the second UE receive(s) a message 4 sent by the eNB may include the following operation: a CRC of DCI for scheduling the message 4 is scrambled by using the TC-RNTI allocated to the first UE and/or the second UE. In an embodiment, the message 4 may include at least one set of radio resources, and the first UE and/or the second UE may determine radio resources allocated thereto according to at least one set of radio resources included in the message 4. In an embodiment, the UE may also determine the radio resources allocated thereto according to an ID of the UE in accordance with a pre-set rule. In an embodiment, the message 4 may also include a set of radio resources allocated to the first UE or second UE. In an embodiment, after the first UE and/or the second UE receive(s) a message 4 sent by the eNB, the method may further include the step as follows. The first UE and/or the second UE send(s), to the eNB, an indicating signal for notifying the eNB of a successful access of the first UE and/or the second UE, herein the indicating signal may be an SR or an ACK signal. In an embodiment, after the first UE and/or the second UE receive(s) a message 4 sent by the eNB, the method may further include the step as follows. The first UE and/or the second UE receive(s) indicating information, sent by the eNB, for indicating re-initiation of a random access of the first UE and/or the second UE. Exemplarily, before the first UE in the UE group sends a preamble over a time-frequency resource, the method may further include the steps as follows. The first UE and/or the second UE receive(s) DCI or a paging message or an RRC message sent by the eNB. Or, the first UE receives random access request information sent by the second UE. In an embodiment, the operation that the first UE and/or the second UE receive(s) DCI or a paging message or an RRC message sent by the eNB may include at least one of the following operations. The DCI or a CRC of DCI for scheduling the paging message or the RRC message is scrambled by using a group ID of the UE group. The DCI or the paging message or the RRC message includes a group ID of the UE group. The DCI or the paging message or the RRC message includes an ID of the first UE and/or the second UE. The DCI or the paging message or the RRC message includes an ID of a preamble and/or a time domain resource of a preamble and/or a frequency domain resource of a preamble. In an embodiment, after the first UE receives random access request information sent by the second UE, the method may further include the steps as follows. The first UE counts received random access requests of the second UE in the group. When a count reaches a pre-set threshold, the first UE sends a preamble over a time-frequency resource. Exemplarily, the operation that the first UE in the UE group sends a preamble over a time-frequency resource may include the following operation. The first UE sends a preamble over a frequency domain resource periodically. It is important to note that the message 3 and the message 4 may include the group ID of the UE group or a pre-set field. Moreover, the message 3 may include a number of UEs having random access requests in the UE group or a number of UEs contained in the UE group or a pre-set UE number. In an embodiment, the preamble and/or the time domain resource and/or the frequency domain resource may correspond to the number of UEs having random access requests in the UE group or the number of UEs contained in the UE group or the pre-set UE number. The present embodiment provides a random access method. A first UE in a UE group sends a preamble to an eNB over a time-frequency resource, and then the first UE and/or a second UE in the UE group monitor(s) an RAR corresponding to the preamble and sent by the eNB, and UL grant and resource allocation are completed. Thus, a group of UEs only needs to occupy a PRACH resource (including a time domain resource, a frequency domain resource and a preamble) in a random access, so that PRACH resources can be greatly saved, thereby meeting requirements for a huge number of machine communications. Second Embodiment FIG. 2 shows a flow of another random access method according to an embodiment of the disclosure. The method may be applied to an eNB side and may include the steps as follows. In S201, an eNB receives a preamble sent by a first UE in a UE group over a time-frequency resource, herein the time-frequency resource includes a time domain resource and a frequency domain resource. In S202, the eNB sends an RAR corresponding to the preamble. In an embodiment, the RAR may include at least one TC-RNTI and/or at least one UL grant, and the RAR may be used for the first UE and/or the second UE to determine a TC-RNTI and/or UL grant allocated thereto from at least one TC-RNTI and/or UL grant according to an ID of the first UE and/or the second UE in accordance with a pre-set allocation rule. In an embodiment, the RAR may include a TC-RNTI and/or a UL grant allocated to the first UE or second UE. It is important to note that the first UE in S201 to S202 may be at least one UE in the UE group, and the first UE can be representative of the UE group. The second UE may be all or some UEs in the UE group, i.e., UEs having random access requests. Therefore, the second UE may include the first UE. In an embodiment, after the eNB sends an RAR corresponding to the preamble, the method may further include the step as follows. The eNB receives a message 3 sent by the first UE and/or the second UE according to the UL grant allocated thereto. Moreover, after the eNB receives a message 3 sent by the first UE and/or the second UE according to the UL grant allocated thereto, the method may further include the step as follows. The eNB sends a message 4 to the first UE and/or the second UE. It is important to note that the operation that the eNB sends a message 4 to the first UE and/or the second UE may include the following operation: a CRC of DCI for scheduling the message 4 is scrambled by using the TC-RNTI allocated to the first UE and/or the second UE. In an embodiment, the message 4 may include at least one set of radio resources, and the first UE and/or the second UE may determine radio resources allocated thereto according to at least one set of radio resources included in the message 4. And/or, the message 4 may also include a set of radio resources allocated to the first UE or second UE. In an embodiment, after the eNB sends a message 4 to the first UE and/or the second UE, the method may further include the step as follows. The eNB receives an indicating signal, sent by the first UE and/or the second UE, for notifying the eNB of a successful access of the first UE and/or the second UE, the indicating signal being an SR or an ACK signal. Or, after the eNB sends a message 4 to the first UE and/or the second UE, the method may further include the step as follows. The eNB sends, to the first UE and/or the second UE, indicating information for indicating re-initiation of a random access of the first UE and/or the second UE. Exemplarily, before the eNB receives a preamble sent by a first UE in a UE group over a time-frequency resource, the method may further include the step as follows. The eNB sends DCI or a paging message or an RRC message to the first UE and/or the second UE. In an embodiment, the operation that the eNB sends DCI or a paging message or an RRC message to the first UE and/or the second UE may include at least one of the following operations. The DCI or a CRC of DCI for scheduling the paging message or the RRC message is scrambled by using a group ID of the UE group. The DCI or the paging message or the RRC message includes a group ID of the UE group. The DCI or the paging message or the RRC message includes an ID of the first UE and/or the second UE. The DCI or the paging message or the RRC message includes an ID of a preamble and/or a time domain resource of a preamble and/or a frequency domain resource of a preamble. In an embodiment, the operation that the eNB receives a preamble sent by the first UE in the UE group over a time-frequency resource may include the following operation. The eNB receives a preamble sent by the first UE over a frequency domain resource periodically. It is important to note that the message 3 and the message 4 may include the group ID of the UE group or a pre-set field. Moreover, the message 3 may include a number of UEs having random access requests in the UE group or a number of UEs contained in the UE group. The present embodiment provides a random access method. After receiving a preamble sent by a first UE in a UE group over a time-frequency resource, an eNB sends an RAR corresponding to the preamble, such that the UE completes UL grant and resource allocation. Thus, a group of UEs only needs to occupy a PRACH resource (including a time domain resource, a frequency domain resource and a preamble) in a random access, so that PRACH resources can be greatly saved, thereby meeting requirements for a huge number of machine communications. Third Embodiment On the basis of the same technical thought of the above-mentioned two embodiments, the present embodiment introduces the technical solutions of the above-mentioned two embodiments via the following four specific examples in detail. It is important to note that the following four examples are only used to illustrate the technical solutions of the embodiments of the disclosure, a person skilled in the art can combine the technical solutions of the four specific examples as required without creative work, and there is no elaboration in the embodiments of the disclosure. In the following examples, multiple (two or more) UEs form a UE group, a group of UEs has a group ID serving as a group identifier, and each UE has an own intra-group ID number namely own identification information. A forming manner of the group may be one of the following manners: (1) An operator configures fixed UEs installed by the operator or fixed UEs (such as vehicle-mounted UEs, or UEs in the same carriage of a train or a subway) with the same service at close relative positions as a group on an Operation Administration and Maintenance (OAM) background. (2) A network side detects Time Advance (TA) values of all terminals in a connected state, and if the TA values of some terminals always keep the same within a period of time, these terminals are configured as a group. (3) Some UEs within a shorter positioning distance are configured as a group by using a positioning system. (4) Under the condition that UEs may communicate with one another, for example, UEs spontaneously form a group by utilizing a Device to Device (D2D) discovery technology. The spontaneously forming of a group of UEs is similar to “discovery” in a D2D technology in the related art. (Only applied to a situation that intra-group UEs may communicate) EXAMPLE 1 Example 1 gives a contention-free random access method. Referring to FIG. 3, the example includes the steps as follows. In step 301, when a UE is in a connected state, an eNB allocates a group identifier or a group ID to a UE group, namely a group RNTI. In step 302, the eNB notifies the UE group of completion of uplink synchronization. The eNB notifies this group of UEs of random access to complete the uplink synchronization. Notification signaling may be physical layer signaling or may be high-layer signaling. The physical layer signaling may be DCI, a CRC of the DCI being scrambled or masked by using the group RNTI. The scrambling or masking manner may be a manner of performing exclusive-or operation according to bits. For example, a group RNTI is 16-bit, a CRC is also 16-bit, and exclusive-or operation is performed between bits of corresponding positions therebetween. For another example, a group RNTI is “0000110100001111”, and a CRC is “1111001111110011”, so the CRC is scrambled by using the group RNTI to obtain “1111111011111100”. Correspondingly, a UE receiving the scrambled CRC performs exclusive-or operation on the scrambled CRC and the group RNTI, so that a CRC not scrambled can be obtained. The high-layer signaling may also be an RRC message. The high-layer signaling may be common information sent to the UE group or may be an RRC message sent to a UE, the RRC message being used to notify the UE group of access. For example, the UE group may be notified of access via a bit indicator in the RRC message. In an embodiment, the notification signaling (DCI or RRC message) may only contain preamble-related information. For example, the notification signaling may contain index information of a preamble. Thus, after the notification signaling is received, a preamble to be sent may be determined according to the preamble-related information, and a time-frequency resource for sending the preamble may be pre-set, such as a fixed time-frequency resource pre-set by the UE group, or a time-frequency resource pre-appointed between the UE group and the eNB. Or, the notification signaling may also contain time domain resource information namely sending subframe information, used for instructing a UE in the UE group to send the preamble over the subframe. Thus, after the notification signaling is received, frequency domain information for sending the preamble may be pre-set, such as a fixed frequency domain resource pre-set by the UE group, or a frequency domain resource pre-appointed between the UE group and the eNB. Or, the notification signaling may contain preamble-related information and frequency domain resource information. Thus, after the notification signaling is received, subframe information for sending the preamble may be pre-set, such as a fixed time domain resource pre-set by the UE group, or a time domain resource pre-appointed between the UE group and the eNB. Or, the notification signaling may contain preamble-related information and time-frequency resource information (including time domain resource information and frequency domain resource information, the time domain resource information being subframe information). Or, the notification signaling may not include preamble-related information, time domain resource information and frequency domain resource information, and one or more UEs in the UE group, receiving the notification signaling, may directly send a preamble appointed with the eNB to the eNB via a pre-appointed time-frequency resource. In step 303, one or more UEs in the UE group, representative of intra-group UEs, send a preamble to the eNB. After receiving the notification signaling, a UE in the UE group sends a corresponding preamble (notified by the eNB, or pre-set or appointed) over a corresponding time-frequency resource (notified by the eNB, or pre-set or appointed). In an embodiment, the UE for sending the preamble is a first UE, which may be one of the following: (1) one or more fixed UEs, herein for example, a UE numbered as 0 is pre-specified to send a preamble, or a UE in the UE group, numbered as an even number, is pre-specified to send a preamble, or all UEs may be specified to send a preamble; (2) a certain or some UEs determined in accordance with a pre-set rule, herein for example, a UE for sending a preamble is determined according to the number of a UE for sending a preamble and a subframe number of a subframe receiving physical layer signaling or high-layer signaling; for example, if an odd subframe receives the physical layer signaling or the high-layer signaling, a UE numbered as an odd number sends a preamble, and if an even subframe receives the physical layer signaling or the high-layer signaling, a UE numbered as an even number sends a preamble; and (3) one or more UEs specified in the notification signaling sent by the eNB, herein in this case, the physical layer signaling or the high-layer signaling also needs to contain number information of a UE initiating a random access. After the UE sends a preamble, all UEs monitor an RAR, and a CRC of a PDCCH for scheduling the RAR is scrambled or masked by using an RA-RNTI, where the RA-RNTI may be pre-set, and is, for example, bound with the sending time of the preamble and the sent frequency domain resource (in FDD, only the sending time): RA-RNTI=1+t_id+10*f_id When a time-frequency resource is fixed, an RA-RNTI is also fixed. In this case, all UEs may monitor a PDCCH scrambled by the RA-RNTI to obtain an RAR. Or, the time-frequency resource may not be fixed. For example, a frequency domain resource is fixed, but a time domain resource may not be fixed. This situation may occur in case of specifying one UE to send a preamble. At this time, the UE sending the preamble may monitor the sent time-frequency resource to calculate a PDCCH scrambled by the RA-RNTI, and other UEs may need to monitor all possible time-frequency resources so as to calculate a plurality of PDCCHs scrambled by the RA-RNTI. After monitoring the PDCCH scrambled by the RA-RNTI, the UE may receive a Physical Downlink Shared Channel (PDSCH) scheduled by the UE, so as to obtain TA information. A random access in the related art is independently completed by each UE. However, in the present example, a group of UEs only occupies a PRACH resource (including a time domain resource, a frequency domain resource and a preamble) in a random access, so that PRACH resources can be greatly saved. EXAMPLE 2 Example 2 provides a method for triggering access of a UE group in a manner that an eNB sends a paging message. Referring to FIG. 4, the example includes the steps as follows. In step 401, an eNB sends a paging message to a UE group. In an embodiment, the paging message may be used to awaken all or some idle UEs in the UE group to initiate a random access. The paging message may include at least one of the following: (1) a group ID, where the group ID may be contained in the paging message, or the group ID may be adopted to scramble a CRC of a PDCCH for scheduling the paging message; (2) the number of a UE initiating a random access, namely, UE-ID; (3) a preamble ID, or where, the preamble ID may not be notified, namely, pre-set; (4) a time domain and/or frequency domain resource, or where, the time domain and/or frequency domain resource may not be notified and pre-set, or the time domain resource may be pre-set and the frequency domain resource may be notified, or the frequency domain resource may be pre-set and the time domain resource may be notified; and (5) the numbers (UE-ID) of some intra-group UEs, where this information may be contained only when some UEs therein are awakened to initiate a random access. When the above-mentioned paging message does not include the number of a UE initiating a random access, namely, UE-ID, the UE initiating the random access may be determined in the following manners: a. specifying one or more UEs in the UE group to initiate a random access, herein for example, a UE numbered as 0 is pre-defined to send a preamble, or a UE numbered as an even number is pre-defined to send a preamble, or all UEs send a preamble; and b. determining one or more UEs to initiate a random access in accordance with a certain rule, herein for example, one or more UEs initiating a random access may be determined according to a correspondence between the number of a UE sending a preamble and a subframe receiving physical signal signaling or high-layer signaling; for example, if an odd subframe receives the signaling, a UE numbered as an odd number sends a preamble, and if an even subframe receives the signaling, a UE numbered as an even number sends a preamble. It is important to note that one or more UEs initiating a random access, determined in the above-mentioned manners, may be identical to or different from a UE required to be awakened by the eNB. This difference may include: partial difference or total difference. In step 402, after a UE in the UE group receives the paging message, a random access is executed. Specifically, the random access may be implemented in the following three manners. Manner 1: In step 1, the one or more UEs initiating a random access send a preamble over the time-frequency resource. In step 2, after receiving the preamble, the eNB sends an RAR, the RAR carrying a TA and at least one of the following information: (1) TC-RNTI information, herein in an embodiment, the TC-RNTI information may include M TC-RNTIs, where M is the number of intra-group UEs, or the number of UE needing to be awakened, or a pre-set value; the M TC-RNTIs may be in a form of absolute value namely a 16 bit C-RNTI, or may be an absolute value of a C-RNTI and relative values of M−1 C-RNTIs relative to the absolute value, and all or some intra-group UEs needing to be awakened may correspond to different TC-RNTIs in accordance with a pre-set rule respectively, e.g., correspond in an ascending order of UE-ID or correspond randomly; or, the TC-RNTI information may be a TC-RNTI, and all or some intra-group UEs may correspond to TC-RNTI, TC-RNTI+1, TC-RNTI+2, . . . , TC-RNTI+M−1 in accordance with a pre-set rule respectively, e.g., correspond in an ascending order of UE-ID or correspond randomly; (2) UL grant information, herein for example, the UL grant information may be M pieces of independent UL grant information or may be UL grant information containing M pieces of scheduling information; all or some intra-group UEs may correspond to different pieces of UL grant information in accordance with a pre-set rule respectively, e.g., correspond in an ascending order of UE-ID or correspond randomly; or, the UL grant information may be a UL grant, and all or some intra-group UEs needing to be awakened may correspond to UL grants allocated thereto in accordance with a pre-set rule respectively; for example, if resource allocation in the UL grant is Physical Resource Bearer (PRB) #0-3, each UE may determine resources allocated to the UE according to the own number; for example, UE#1 corresponds to PRB#4-7 or corresponds randomly, and the remaining UE information such as a Modulation and Coding Scheme (MCS) may be identical to the UL grant. Or, in step 2, the eNB may also send M RARs. Herein, each RAR may be scrambled by using different RA-RNTIs. A UE may determine an RA-RNTI according to an own UE-ID and a pre-set rule to descramble a CRC of DCI, and receive a corresponding RAR. For example, an RA-RNTI of a UE of which a UE-ID is UE#0 may be determined according to a time-frequency resource for sending a preamble, and UE#1, UE#2, UE#n sequentially correspond to RA-RNTI+1, RA-RNTI+2, . . . , RA-RNTI+n; or, UEs with different numbers may also correspond to any one of RA-RNTI+1, RA-RNTI+2, . . . , RA-RNTI+n. In step 3, all or some intra-group UEs (all or some of the UEs refer to all or some UEs required to be awakened by the eNB) send a message (Msg) 3 over resources corresponding to own UL grants respectively. In step 4, the eNB sends an Msg 4 as for the Msg 3 sent in step 3. It is important to note that receiving of an RAR in this manner is relatively important, and in order to avoid missing detection of the RAR by the UE, the RAR may be re-sent within a window. Under the condition that some UEs do not receive RARs successfully, the eNB may re-send a call message to notify these UEs of access. Manner 2: In step 1, the one or more UEs initiating a random access send a preamble over the time-frequency resource. In step 2, after receiving the preamble, the eNB sends an RAR, the RAR carrying TA information, a TC-RNTI and a UL grant. In step 3, all or some intra-group UEs (all or some of the UEs refer to all or some UEs required to be awakened by the eNB) monitor the RAR, so as to obtain the TA and the TC-RNTI. In step 4, one or more UEs send an Msg 3. One or more UEs here may be the one or more UEs sending the preamble in step 1 or a pre-set UE (such as a UE having the smallest UE ID) in the UEs, the sent Msg 3 carries a group ID or a pre-set value, and the pre-set value may be shared by intra-group UEs. In step 5, the eNB sends an Msg 4 carrying a group ID, the Msg 4 is scrambled by using the TC-RNTI, and the Msg 4 may further include or may not include M−1 C-RNTIs. Under the condition that the Msg 4 includes M−1 C-RNTIs, all or some intra-group UEs (all or some of the UEs refer to all or some UEs required to be awakened by the eNB) may select a TC-RNTI as an own C-RNTI according to an own intra-group number. For example, a UE numbered as UE#5 corresponds to a fifth TC-RNTI; or, the UE may also randomly select a TC-RNTI as an own C-RNTI. Under the condition that the Msg 4 does not contain a TC-RNTI, all or some intra-group UEs may calculate a C-RNTI as an own C-RNTI according to an own intra-group number in accordance with a pre-set formula. For example, a UE numbered as UE#5 may add 5 to a TC-RNTI for scrambling a CRC of DCI for scheduling the Msg 4, so as to obtain an own C-RNTI; or, the UE may also randomly select a TC-RNTI from TC-RNTI1, . . . , TC-RNTI+M−1 to serve as an own C-RNTI. In an embodiment, the Msg 4 may further include one or M pieces of radio resource configuration information such as a Channel Quality Indicator (CQI) feedback resource and an SR resource. Under the condition that the Msg 4 includes M pieces of radio resource configuration information, all or some intra-group UEs may select a set of radio resource configuration information as own radio resource configurations according to own intra-group numbers. The selection manner here may be similar to the above-mentioned TC-RNTI selection manner. Under the condition that the Msg 4 includes one piece of radio resource configuration information, all or some intra-group UEs may obtain own radio resource configurations according to own intra-group numbers in accordance with a pre-set formula. For example, the radio resource configurations include an SR configuration, so the UE numbered as UE#5 may consider that the own SR configuration is SR configuration+5 included in the radio resource configuration; or, SR configurations corresponding to different UEs may also be determined by using a random selection manner. Receiving of an RAR and an Msg 4 in this manner is relatively important, and in order to avoid missing detection of the RAR and the Msg by the UE, the RAR and the Msg 4 may be repeatedly sent within a window respectively. Manner 3 In step 1, the one or more UEs send a preamble over the time-frequency resource. In step 2, the eNB sends an RAR, the RAR carrying TA information, M TC-RNTIs and a UL grant. All or some intra-group UEs (when some UEs therein are awakened to initiate a random access) may monitor the RAR, so as to obtain the TA and the TC-RNTI. The one or more UEs sending the preamble in step 1 or a pre-set UE (such as a UE having the smallest UE ID) in the UEs may send an Msg 3, carrying a group ID or a pre-set value. In step 3, the eNB sends an Msg 4, the Msg 4 carries a group ID or the pre-set value, and the UE monitors the Msg 4. In an embodiment, the eNB may send an Msg 4, the Msg 4 may be scrambled by using a TC-RNTI in the Msg 3, and contains one or M sets of radio resources (or may continuously carry multiple TC-RNTIs). The UE may determine a C-RNTI and radio resources allocated thereto in accordance with a manner similar to Manner 2; or, the eNB may send multiple messages 4 (Msg 4) which are scrambled by using M TC-RNTIs respectively, and the UE may randomly select a TC-RNTI according to an own number and receive an Msg 4 scheduled by DCI that is scrambled by the TC-RNTI. Under the condition that some UEs do not receive the RAR successfully, the eNB may re-page these UEs to perform access. EXAMPLE 3 Example 3 shows a method for access contention of a group of UEs. The example includes the steps as follows. In step 501, one or more UEs in a UE group send a preamble to an eNB over a time frequency domain resource periodically, so as to initiate a random access to the eNB, herein the UE sending the preamble may be one of the following: (1) one or more fixed UEs, herein for example, a UE numbered as 0 may be pre-specified to send a preamble, or a UE in the UE group, numbered as an even number, may be pre-specified to send a preamble, or all UEs may be specified to send a preamble; and (2) a certain or some UEs determined in accordance with a pre-set rule, herein for example, a UE for sending a preamble is determined according to the number of a UE for sending a preamble and a subframe number of a subframe receiving physical layer signaling or high-layer signaling; for example, if an odd subframe receives the signaling, a UE numbered as an odd number sends a preamble, and if an even subframe receives the signaling, a UE numbered as an even number sends a preamble. A sending period and an offset of a subframe sending a preamble may be pre-set according to practical requirements, and the set sending period and the set offset of the subframe sending the preamble may be shared by all intra-group UEs. There may be two situations during initiation of a random access. The first situation is that intra-group UE services are identical, and each access is access of the whole group. The second situation is that only some intra-group UEs need to be accessed during each access. The number of UEs accessed under the second situation may be random. In an embodiment, the random access may be implemented via the following three manners. Manner 1: In step 1, the one or more UEs initiating a random access send a pre-set preamble over a pre-set time-frequency resource, the preamble resource corresponding to a group ID. In step 2, after the eNB receives the preamble, the eNB learns of that the UE is representative of a group of UEs to be accessed via a PRACH resource (time-frequency resource information or preamble information) sent by the UE, and then the eNB sends an RAR, the RAR carrying a TA and at least one of the following information: (1) TC-RNTI information, herein in an embodiment, the TC-RNTI information may include M TC-RNTIs, where M is the number of intra-group UEs, or the number of UE needing to initiate a random access, or a pre-set value; before this step, the preamble sent by the UE and the time-frequency resource for sending the preamble are in one-to-one correspondence to the UE group, and the eNB knows information about the UE group in advance, such as the number of UEs in the UE group, so the eNB may determine the UE group initiating a random access via the received preamble and time-frequency resource information, so as to determine the information about the UE group, thereby obtaining the number M of UEs in the UE group; or M may be a pre-set value; besides, the UE may also carry the number M of UEs in this group or the number M of UEs needing to initiate a random access in the UE group or a pre-set value M when sending the preamble; the M TC-RNTIs may be in a form of absolute value namely a 16 bit C-RNTI, or may be an absolute value of a C-RNTI and relative values of M−1 C-RNTIs relative to the absolute value, and therefore when receiving the TC-RNTI information, all or some UEs needing to initiate a random access in the UE group may determine own TC-RNTIs in accordance with a pre-set rule respectively, e.g., sequentially correspond to different TC-RNTIs in an ascending order of UE-ID or correspond to TC-RNTIs randomly; or, the TC-RNTI information may be a TC-RNTI, and all or some intra-group UEs may correspond to TC-RNTI, TC-RNTI+1, TC-RNTI+2, . . . , TC-RNTI+M−1 in accordance with a pre-set rule respectively, e.g., correspond in an ascending order of UE-ID or correspond randomly; (2) UL grant information, herein for example, the UL grant information may be M pieces of independent UL grant information or may be UL grant information containing M pieces of scheduling information; all or some intra-group UEs may correspond to different pieces of UL grant information in accordance with a pre-set rule respectively, e.g., correspond in an ascending order of UE-ID or correspond randomly; or, the UL grant information may be a UL grant, and all or some intra-group UEs needing to perform a random access may correspond to UL grants allocated thereto in accordance with a pre-set rule respectively; for example, if resource allocation in the UL grant is PRB#0-3, each UE may determine resources allocated to the UE according to the own number; for example, UE#1 may correspond to PRB#4-7 or may correspond randomly, and the remaining UE information such as an MCS may be identical to the UL grant. Or, in step 2, the eNB may also send M RARs. Herein, each RAR may be scrambled by using different RA-RNTIs. A UE may determine an RA-RNTI according to an own UE-ID and a pre-set rule to descramble a CRC of DCI, and may receive a corresponding RAR. For example, an RA-RNTI of a UE of which a UE-ID is UE#0 is determined according to a time-frequency resource for sending a preamble, and UE#1, UE#2, UE#n sequentially correspond to RA-RNTI+1, RA-RNTI+2, . . . , RA-RNTI+n; or, UEs with different numbers may also correspond to any one of RA-RNTI+1, RA-RNTI+2, . . . , RA-RNTI+n. In step 3, all or some intra-group UEs (all or some UEs needing to perform a random access) send an Msg 3 over resources corresponding to own UL grants respectively. In step 4, the eNB sends an Msg 4 according to the received Msg 3, herein the number of the Msg 4 may be identical to the number of the Msg 3 received by the eNB. Receiving of an RAR in this manner is relatively important, and in order to avoid missing detection of the RAR by the UE, it may be considered that the RAR is repeatedly sent within a window. In case of an access failure, this group of UEs may re-initiate an access, or may be accessed in accordance with a manner in the related art, i.e., a single UE initiates a random access. Manner 2: In step 1, the one or more UEs initiating a random access send a pre-set preamble over a pre-set time-frequency resource, the preamble resource corresponding to a group ID. In step 2, after the eNB receives the preamble, the eNB learns of that the UE is representative of a group of UEs to be accessed via a PRACH resource (time-frequency resource information or preamble information) sent by the UE, and then the eNB sends an RAR, the RAR carrying information such as a TA and a TC-RNTI. In step 3, all or some UEs (UEs needing to perform a random access) in the UE group monitor the RAR, so as to obtain the TA and the TC-RNTI. In step 4, one or more UEs send an Msg 3. One or more UEs here may be the one or more UEs sending the preamble in step 1 or a pre-set UE (such as a UE having the smallest UE ID) in the UEs, and the sent Msg 3 may carry a group ID. In step 5, the eNB sends an Msg 4 carrying a group ID, the Msg 4 is scrambled by using the TC-RNTI, and the Msg 4 may further include or may not include M−1 C-RNTIs. In an embodiment, the Msg 4 may further include one or M pieces of radio resource configuration information such as a CQI feedback resource and an SR resource. A UE may determine a C-RNTI and radio resource allocation information allocated thereto according to a manner similar to Manner 2 in the Second Embodiment. Receiving of an RAR and an Msg 4 in this manner is relatively important, and in order to avoid missing detection of the RAR and the Msg by the UE, it may be considered that the RAR and the Msg 4 are repeatedly sent within a window respectively. Manner 3 In step 1, the one or more UEs send a pre-set preamble over a pre-set time-frequency resource, the preamble resource corresponding to a group ID. In step 2, the eNB learns of that the UE is representative of a group of UEs to be accessed via a PRACH resource (time-frequency resource information or preamble information) sent by the UE, and then the eNB sends an RAR, the RAR carrying information such as TAs and M TC-RNTIs. In step 3, all or some intra-group UEs (all or some of the UEs refer to UEs needing to perform a random access) monitor the RAR, so as to obtain TAs and TC-RNTIs. In step 4, the one or more UEs sending the preamble in step 1 or a pre-set UE (such as a UE having the smallest UE ID) in the UEs send an Msg 3, the Msg 3 carries a group ID, the Msg 3 is scrambled by using a TC-RNTI, and the TC-RNTI may be the first TC-RNTI in the TC-RNTIs obtained in step 3. In step 5, the eNB sends an Msg 4, and all or some intra-group UEs (all or some of the UEs refer to UEs needing to perform a random access) monitor the Msg 4. The Msg 4 may be one of the following: a. an Msg 4 scrambled by using a TC-RNTI in the Msg 3, herein the Msg 4 may carry a group ID, may further contain one or M sets of radio resources, and may continuously carry more of the M TC-RNTIs in step 2; in an embodiment, the Msg 4 may further include one or M pieces of radio resource configuration information such as a CQI feedback resource and an SR resource; the UE receiving the Msg 4 may determine a C-RNTI and radio resource allocation information allocated thereto according to a manner similar to Manner 2 in the Second Embodiment; b. the monitored Msg 4 may be multiple messages 4 (Msg 4) which may be scrambled by using M TC-RNTIs, may carry group IDs and may support a Hybrid Automatic Repeat reQuest (HARQ), so that in this case, each UE may perform feedback for the corresponding Msg 4 and send an ACK message, and therefore resource waste can be avoided; in this case, if the eNB does not receive an ACK message sent by a UE, it may be regarded that this set of resources is not used by any UE. In the above-mentioned three manners, in case of an access failure of a UE, this group of UEs may re-initiate a random access, or access of a corresponding UE may be implemented in accordance with a manner in the related art, i.e., a single UE initiates a random access independently. Further, if two UEs select the same radio resource (including C-RNTIs, radio air interface resources and the like), uplink data sent by the UEs may always collide, thereby causing a sending failure. If finding that these UEs always fail in transmission, the eNB may send indication signaling to instruct them to re-initiate an access. If the number of UEs correctly receiving an Msg 4 is smaller than the number of radio resources allocated by the eNB, waste will be caused. A UE may send information to indicate that it occupies a certain set of resources, and if the eNB does not receive the information about the certain set of resources, the eNB will consider that this set of resources is not occupied by any UE. For example, a time window may be defined, a UE sends indication information within the time window to indicate that it occupies this set of resources (TC-RNTIs and radio resources), the indication information may be an SR, an ACK or the like, and if the eNB does not receive the indication information, the eNB considers that this set of resources is wasted and can be shared by other UEs. EXAMPLE 4 Example 4 shows a method for access contention of a group of UEs. In this example, UEs in a UE group may communicate with one another. In an embodiment, the intra-group UEs may interact mutually by using a short-distance communication manner such as Wireless Fidelity (WIFI) and D2D. In this example, when intra-group members need to initiate a random access, the group members report it to a first UE (hereinafter referred to as a group leader), the group leader may be accessed in accordance with a certain period such as 100 ms, and if all the UEs do not have a random access request within 100 ms, an access may not be initiated. If one or more UEs have a random access request, the group leader may initiate a random access. Or, the group leader may initiate a random access when random access requests are accumulated to reach a certain number. The group leader may be pre-set, or may be a fixed UE with a certain ID number such as a fixed UE with an ID number 0, or may be determined as a UE in the UE group in accordance with a certain rule. Or, UEs with the same service type are probably gathered in a group. In this case, these UEs will initiate a random access at a fixed time, so that a group leader may be representative of the whole group of UEs to initiate a random access at a fixed time. A process of allowing a group leader to be representative of the whole group of UEs or some UEs to perform a random access is provided hereinbelow in Manner 1 to Manner 3. Manner 1: In step 1, a group leader sends a preamble over a specified time-frequency resource. In step 2, by means of a PRACH resource (time-frequency resource information or preamble information) sent by a UE, an eNB learns of that the UE is the group leader, and sends an RAR, the RAR carrying information such as a TA and a TC-RNTI. In step 3, the group leader sends an Msg 3, the Msg 3 carrying the number M of intra-group UEs needing to perform a random access. In step 4, the eNB sends an Msg 4, the Msg 4 is scrambled by using the TC-RNTI, and the Msg 4 may include or may not include M−1 C-RNTI values or M−1 difference values with the TC-RNTI. In an embodiment, the Msg 4 may further include one or M sets of radio resource configuration information such as a CQI feedback resource and an SR resource. In step 5, the group leader notifies UEs having a random access requirement of these pieces of information, herein notification may adopt a broadcast manner or a unicast manner and will not be limited here. Manner 2: In step 1, a group leader sends a preamble over a certain time-frequency resource, a PRACH resource corresponding to the number M of UEs needing to perform a random access, or, the number of random access requests known to an eNB. In step 2, by means of the PRACH resource (time-frequency resource information or preamble information) sent by the UE sending the preamble, the eNB learns of that the UE is the group leader, and sends an RAR, the RAR carrying information such as a TA and a TC-RNTI. In step 3, the group leader sends an Msg 3. In step 4, the eNB sends an Msg 4, the Msg 4 is scrambled by using the TC-RNTI, and the Msg 4 may include or may not include M−1 C-RNTI values or M−1 difference values with the TC-RNTI. The other allocated TC-RNTIs may be obtained in accordance with a pre-set rule. For example, the TC-RNTIs may be TC-RNTI, TC-RNTI+1, . . . , TC-RNTI+M+1. In an embodiment, the Msg 4 may further include one or M sets of radio resource configuration information such as a CQI feedback resource and an SR resource. If there is a set of radio resource configuration information, the other allocated radio resources may be obtained in accordance with a pre-set rule. The group leader may notify UEs having an SR of these pieces of information in a broadcast manner or a unicast manner, which will not be limited here. Manner 3: In step 1, a group leader sends a preamble over a certain time-frequency resource, a PRACH resource corresponding to the number M of UEs needing to perform a random access, or, the number of random access requests known to an eNB. In step 2, by means of the PRACH resource (time-frequency resource information or preamble information) sent by the UE, the eNB learns of that the UE is the group leader, and sends an RAR, the RAR carrying information such as a TA and M TC-RNTIs. In step 3, the UE sends an Msg 3, the Msg 3 being scrambled by using one of the M TC-RNTIs. In step 4, the eNB sends an Msg 4, the Msg 4 is scrambled by using the TC-RNTI in step 3, and the Msg 4 may include one or more sets of radio resources (or may continuously carry M TC-RNTIs). Manner 4: In this manner, group members know a PRACH resource (including a time-frequency resource and a preamble) sent by a group leader via short-distance communications, so as to obtain an RA-RNTI. A random access implementing process includes the steps as follows. In step 1, the group leader sends a preamble over a certain time-frequency resource, a PRACH resource corresponding to the number M of UEs needing to perform a random access. In step 2, by means of the PRACH resource (time-frequency resource information or preamble information) sent by the UE, the eNB learns of that the UE is the group leader, and sends an RAR, the RAR carrying TA information, TC-RNTI information and UL grant information, similar to Manner 1 in the Second Embodiment here. In step 3, intra-group UEs having an access request send messages (Msg 3) over resources corresponding to own UL grants respectively. In step 4, the eNB sends an Msg 4 according to the received Msg 3, the number of the Msg 4 being identical to the number of the Msg 3 received by the eNB. In this example, in order to avoid missing detection of an RAR by the UE, the eNB may repeatedly send the RAR within a window. Manner 5 In this manner, group members know a PRACH resource (including a time-frequency resource and a preamble) sent by a group leader via short-distance communications, so as to obtain an RA-RNTI. A random access process includes the steps as follows. In step 1, the group leader sends a preamble over a certain time-frequency resource. In step 2, by means of the received PRACH resource (time-frequency resource information or preamble information), the eNB learns of that the UE sending the PRACH resource is the group leader, and sends an RAR, the RAR carrying information such as a TA and a TC-RNTI. In step 3, all UEs or intra-group UEs having an access request monitor the RAR, so as to obtain the TA and the TC-RNTI. In step 4, after monitoring the RAR, the group leader UE sends an Msg 3, carrying a group ID or a pre-set value and the number M of intra-group UEs needing to perform a random access. The group ID or the pre-set value may be notified by the group leader, or may be notified by a network side, or may be pre-set. In step 5, the eNB sends an Msg 4, the Msg 4 carries the group ID or the pre-set value in the previous step, the Msg 4 is scrambled by using the TC-RNTI, and the Msg 4 may further include M−1 C-RNTI values and one or more sets of radio resource configuration information. All UEs or UEs having an access request in the UE group may monitor the Msg 4 scrambled by using the TC-RNTI, and obtain own C-RNTIs and radio resource configuration information in accordance with a pre-set rule. Before this manner is implemented, group member UEs may know the PRACH resource (time frequency and preamble) sent by the group leader UE, so as to obtain an RA-RNTI. Receiving of an RAR and an Msg 4 in this manner is relatively important, and in order to avoid missing detection of the RAR and the Msg by the UE, it may be considered that the RAR and the Msg 4 are repeatedly sent within a window respectively. Manner 6: Group member UEs know a PRACH resource (including a time-frequency resource and a preamble) sent by a group leader UE, so as to obtain an RA-RNTI. A random access process in this example includes the steps as follows. In step 1, a UE sends a preamble over a certain time-frequency resource, a PRACH resource corresponding to the number M of UEs needing to perform a random access or the number of random access requests known to an eNB. In step 2, by means of the received PRACH resource (time-frequency resource information or preamble information), the eNB learns of that the UE is a group leader, and sends an RAR, the RAR carrying information such as a TA and a TC-RNTI. In step 3, intra-group UEs having an access request monitor the RAR, so as to obtain the TA and the TC-RNTI. In step 4, the group leader sends an Msg 3, carrying an ID known to all intra-group UEs. In step 5, after receiving the Msg 3, the eNB sends an Msg 4, the Msg 4 is scrambled by using the TC-RNTI, and the Msg 4 contains M−1 C-RNTI values or M−1 difference values with the TC-RNTI, and includes one or M sets of radio resources. In step 6, all UEs in the UE group or intra-group UEs having an access request monitor the Msg 4 scrambled by using the TC-RNTI, and obtain own C-RNTIs and radio resource configuration information in accordance with a pre-set rule or a random manner. Manner 7: Group member UEs know a PRACH resource (including a time-frequency resource and a preamble) sent by a group leader UE, so as to obtain an RA-RNTI. A random access process in this manner includes the steps as follows. In step 1, a UE sends a preamble over a certain time-frequency resource, a PRACH resource corresponding to the number M of UEs needing to perform a random access or the number of random access requests known to an eNB. In step 2, by means of the received PRACH resource (time-frequency resource information or preamble information), the eNB learns of that the UE sending the PRACH resource is a group leader, and sends an RAR, the RAR carrying information such as a TA and multiple TC-RNTIs. In step 3, the group leader sends an Msg 3 by using a TC-RNTI, carrying a group ID or a pre-set value. In step 4, after receiving the Msg 3, the eNB sends an Msg 4, the Msg 4 may be a message scrambled by using the TC-RNTI in the Msg 3, and the Msg 4 may contain one or M sets of radio resources (or may continuously carry multiple TC-RNTIs). All UEs or intra-group UEs having an access request may monitor the Msg 4 scrambled by using the TC-RNTI, and obtain own C-RNTIs and radio resource configuration information in accordance with a pre-set rule. Or, the eNB may also send multiple messages (Msg 4) which are scrambled by using multiple TC-RNTIs respectively. All UEs or intra-group UEs having an access request may determine own C-RNTIs in accordance with a pre-set rule or a random manner, and receive the Msg 4 corresponding to the C-RNTIs. If two UEs select the same radio resource (including C-RNTIs, radio air interface resources and the like), uplink data sent by the UEs may always collide, thereby causing a sending failure. If finding that these UEs always fail in transmission, the eNB may send indication signaling to instruct them to re-initiate an access. If the number of UEs correctly receiving an Msg 4 is smaller than the number of radio resources allocated by the eNB, waste will be caused. A UE may send information to indicate that it occupies a certain set of resources, and if the eNB does not receive the information about the certain set of resources, the eNB will consider that this set of resources is not occupied by any UE. For example, a time window may be defined, a UE sends indication information within the time window to indicate that it occupies this set of resources (TC-RNTIs and radio resources), the indication information may be an SR, an ACK or the like, and if the eNB does not receive the indication information, the eNB considers that this set of resources is wasted and can be shared by other UEs. Fourth Embodiment On the basis of the same technical thought of the above-mentioned embodiments, FIG. 5 shows a UE 50 according to an embodiment of the disclosure. The UE may include: a sending unit 501 and a monitoring unit 502, herein the sending unit 501 is configured to: send a preamble to an eNB over a time-frequency resource, the time-frequency resource including a time domain resource and a frequency domain resource; and the monitoring unit 502 is configured to: monitor an RAR corresponding to the preamble and sent by the eNB. Exemplarily, referring to FIG. 6, the monitoring unit 502 may include: a first descrambling subunit 5021A, a first receiving subunit 5022A and an allocation subunit 5023A, herein, the first descrambling subunit 5021A is configured to: descramble a CRC of DCI for scheduling the RAR according to a pre-set RA-RNTI or an RA-RNTI corresponding to the preamble; the first receiving subunit 5022A is configured to: receive the RAR, the RAR including at least one TC-RNTI and/or at least one UL grant; and the allocation subunit 5023A is configured to: determine a TC-RNTI and/or UL grant allocated to the UE according to at least one TC-RNTI and/or at least one UL grant included in the RAR. In an embodiment, the allocation subunit 5023A is configured to: determine a TC-RNTI and/or a UL grant allocated to the UE according to an own ID of the UE in accordance with a pre-set rule. Exemplarily, referring to FIG. 7, the monitoring unit 502 may include: a determination subunit 5021B, a second descrambling subunit 5022B and a second receiving subunit 5023B, herein, the determination subunit 5021B is configured to: determine corresponding RA-RNTIs of the UE according to respective IDs and/or preambles of the UE; the second descrambling subunit 5022B is configured to: descramble a CRC of DCI for scheduling the RAR according to the corresponding RA-RNTIs of the UE; and the second receiving subunit 5023B is configured to: receive corresponding RARs of the UE, the RAR including a corresponding TC-RNTI and/or UL grant allocated to the UE. In an embodiment, the sending unit 501 may be further configured to: send a message 3 according to the UL grant allocated to the UE. In an embodiment, referring to FIG. 6 and FIG. 7, the UE 50 may further include a receiving unit 503, configured to: receive a message 4 sent by the eNB. In an embodiment, receiving a message 4 sent by the eNB may include: scrambling a CRC of DCI for scheduling the message 4 by using the TC-RNTI allocated to a first UE and/or a second UE. In an embodiment, the message 4 may include at least one set of radio resources for the UE to determine radio resources allocated to the UE. In an embodiment, the message 4 may include: a set of radio resources allocated to the corresponding UE. Exemplarily, the sending unit 501 may be further configured to: send, to the eNB, an indicating signal for notifying the eNB of a successful access of the UE. In an embodiment, the indicating signal may be an SR or an ACK signal. In an embodiment, the receiving unit 503 may be further configured to: receive indicating information, sent by the eNB, for indicating re-initiation of a random access of the UE. Exemplarily, the receiving unit 503 may be further configured to: receive DCI or a paging message or an RRC message sent by the eNB; or, receive random access request information sent by the second UE. In an embodiment, receiving DCI or a paging message or an RRC message sent by the eNB may include at least one of the following: the DCI or a CRC of DCI for scheduling the paging message or the RRC message is scrambled by using a group ID of a UE group; the DCI or the paging message or the RRC message includes the group ID of the UE group; the DCI or the paging message or the RRC message includes an ID of the first UE and/or the second UE; and the DCI or the paging message or the RRC message includes an ID of a preamble and/or a time domain resource of a preamble and/or a frequency domain resource of a preamble. Exemplarily, in an embodiment, the sending unit 501 is configured to: send a preamble over a frequency domain resource periodically. In an embodiment, the message 3 and the message 4 may include the group ID of the UE group or a pre-set field. In an embodiment, the message 3 may include a number of UEs having random access requests in the UE group or a number of UEs contained in the UE group or a pre-set UE number. In an embodiment, the preamble and/or the time domain resource and/or the frequency domain resource correspond(s) to the number of UEs having random access requests in the UE group or the number of UEs contained in the UE group or the pre-set UE number. Fifth Embodiment On the basis of the same technical thought of the above-mentioned embodiments, FIG. 8 shows an eNB 80 according to an embodiment of the disclosure. The eNB may include: a receiving unit 801 and a sending unit 802, herein the receiving unit 801 is configured to: receive a preamble sent by a first UE in a UE group over a time-frequency resource, herein the time-frequency resource includes a time domain resource and a frequency domain resource, and the first UE is at least one UE in the UE group; and the sending unit 802 is configured to: send an RAR corresponding to the preamble. Exemplarily, the RAR may include at least one TC-RNTI and/or at least one UL grant, the RAR may be used for the first UE and/or the second UE to determine a TC-RNTI and/or UL grant allocated thereto from at least one TC-RNTI and/or UL grant according to an ID of the first UE and/or the second UE in accordance with a pre-set allocation rule, and the second UE may be all or some UEs in the UE group. Exemplarily, the RAR may include a TC-RNTI and/or a UL grant allocated to the first UE or second UE, and the second UE may be all or some UEs in the UE group. In an embodiment, the receiving unit 801 may be further configured to: receive a message 3 sent by the first UE and/or the second UE according to the UL grant allocated thereto. In an embodiment, the sending unit 802 may be further configured to: send a message 4 to the first UE and/or the second UE. In an embodiment, sending a message 4 to the first UE and/or the second UE may include: scrambling a CRC of DCI for scheduling the message 4 by using the TC-RNTI allocated to the first UE and/or the second UE. In an embodiment, the message 4 may include at least one set of radio resources for the first UE and/or the second UE to determine radio resources allocated thereto. In an embodiment, the message 4 may include: a set of radio resources allocated to the first UE or second UE. Exemplarily, the receiving unit 801 may be further configured to: receive an indicating signal, sent by the first UE and/or the second UE, for notifying the eNB of a successful access of the first UE and/or the second UE, the indicating signal being an SR or an ACK signal. Exemplarily, the sending unit 802 may be further configured to: send, to the first UE and/or the second UE, indicating information for indicating re-initiation of a random access of the first UE and/or the second UE. Exemplarily, the sending unit 802 may be further configured to: send DCI or a paging message or an RRC message to the first UE and/or the second UE. In an embodiment, sending DCI or a paging message or an RRC message to the first UE and/or the second UE may include at least one of the following: the DCI or a CRC of DCI for scheduling the paging message or the RRC message is scrambled by using a group ID of the UE group; the DCI or the paging message or the RRC message includes a group ID of the UE group; the DCI or the paging message or the RRC message includes an ID of the first UE and/or the second UE; and the DCI or the paging message or the RRC message includes an ID of a preamble and/or a time domain resource of a preamble and/or a frequency domain resource of a preamble. Exemplarily, in an embodiment, the receiving unit 801 is configured to: receive a preamble sent by the first UE over a frequency domain resource periodically. In an embodiment, the message 3 and the message 4 may include the group ID of the UE group or a pre-set field. In an embodiment, the message 3 may include a number of UEs having random access requests in the UE group or a number of UEs contained in the UE group. Besides, on the basis of the same technical thought of the above-mentioned embodiments, the embodiment of the disclosure also provides a random access system. The system includes a UE and an eNB, herein a first UE in a UE group is configured to: send a preamble to the eNB over a time-frequency resource, the time-frequency resource including a time domain resource and a frequency domain resource; the first UE and/or a second UE in the UE group are/is configured to: monitor an RAR corresponding to the preamble and sent by the eNB, herein the first UE is at least one UE in the UE group, and the second UE is all or some UEs in the UE group; and the eNB is configured to: receive the preamble sent by the first UE in the UE group over the time-frequency resource, and send the RAR corresponding to the preamble. Sixth Embodiment The embodiment of the disclosure also provides a computer-readable storage medium, which stores a computer-executable instruction, herein when the computer-executable instruction is executed, the above-mentioned random access method is implemented. A person skilled in the art shall understand that the embodiments of the disclosure may be provided as a method, a system or a computer program product. Thus, forms of hardware embodiments, software embodiments or embodiments integrating software and hardware may be adopted in the disclosure. Moreover, a form of the computer program product implemented on one or more computer available storage media (including, but are not limited to, a disk memory, an optical memory and the like) containing computer available program codes may be adopted in the disclosure. The embodiments of the disclosure are described with reference to flowcharts and/or block diagrams of the method, the device (system) and the computer program product according to the embodiments of the disclosure. It will be appreciated that each flow and/or block in the flowcharts and/or the block diagrams and a combination of the flows and/or the blocks in the flowcharts and/or the block diagrams may be implemented by computer program instructions. These computer program instructions may be provided for a general computer, a dedicated computer, an embedded processor or processors of other programmable data processing devices to generate a machine, such that an apparatus for implementing functions designated in one or more flows of the flowcharts and/or one or more blocks of the block diagrams is generated via instructions executed by the computers or the processors of the other programmable data processing devices. These computer program instructions may also be stored in a computer readable memory capable of guiding the computers or the other programmable data processing devices to work in a specific mode, such that a manufactured product including an instruction apparatus is generated via the instructions stored in the computer readable memory, and the instruction apparatus implements the functions designated in one or more flows of the flowcharts and/or one or more blocks of the block diagrams. These computer program instructions may also be loaded to the computers or the other programmable data processing devices, such that processing implemented by the computers is generated by executing a series of operation steps on the computers or the other programmable devices, and therefore the instructions executed on the computers or the other programmable devices provide a step of implementing the functions designated in one or more flows of the flowcharts and/or one or more blocks of the block diagrams. A person of ordinary skill in the art may understand that all or some of the steps of the above-mentioned embodiments may be implemented by using a computer program flow. The computer program may be stored in a computer-readable storage medium. The computer program is executed on a corresponding hardware platform (such as system, device, apparatus, instrument, and processor). During execution, the computer program includes one of the steps of the method embodiment or a combination thereof. In an embodiment, all or some of the steps of the above-mentioned embodiments may also be implemented by using an integrated circuit. These steps may be manufactured into integrated circuit modules respectively, or a plurality of modules or steps therein are manufactured into a single integrated circuit module. Each apparatus/function module/function unit in the above-mentioned embodiments may be implemented by using a general computation apparatus. They may be centralized on a single computation apparatus or may be distributed on a network composed of a plurality of computation apparatuses. When being implemented in a form of software function module and sold or used as an independent product, each apparatus/function module/function unit in the above-mentioned embodiments may be stored in a computer-readable storage medium. The above-mentioned computer-readable storage medium may be a read-only memory, a magnetic disk or an optical disk. A person of ordinary skill in the art may understand that the technical solutions of the present disclosure may be modified or equivalently replaced without departing from the spirit and scope of the technical solutions of the present disclosure. The scope of protection of the present disclosure refers to the scope defined by the claims. INDUSTRIAL APPLICABILITY The embodiments of the disclosure provide a random access method, device and system. One or more UEs in a UE group send a preamble to an eNB over a time-frequency resource, so as to instruct the eNB to execute random accesses of some or all UEs in the UE group. Thus, a group of UEs only needs to occupy a PRACH resource (including a time domain resource, a frequency domain resource and a preamble) in a random access, so that PRACH resources can be greatly saved, thereby meeting requirements for a huge number of machine communications. Page 2 | <SOH> BACKGROUND <EOH>A Machine Type Communication (MTC) User Equipment (UE or terminal) is also referred to as a Machine to Machine (M2M) user communication device, which is a main application form of a current internet of things. Recently, due to high spectral efficiency of a Long-Term Evolution (LTE)/Long-Term Evolution Advance (LTE-Advance or LTE-A) system, more and more mobile operators select the LTE/LTE-A as an evolution direction of a broadband wireless communication system. LTE/LTE-A based MTC multi-type data services will be more attractive. In the LTE system, a random access is a basic function, and a UE can be scheduled by the system to perform uplink transmission only after uplink synchronization with the system via a random access process. The random access in the LTE is divided into two forms namely a contention-based random access and a contention-free random access. An initial random access process is a contention-based access process, which can be divided into four steps. (1) A UE sends a preamble, and the UE randomly selects an available preamble to be sent. (2) An evolved Node B (eNB, also referred to as an evolved base station) sends a Random Access Response (RAR). When the eNB detects a preamble sequence sent by the UE, a response will be sent over a Downlink-Synchronization Channel (DL-SCH), the response including: an index number of the detected preamble, time adjustment information for uplink synchronization, initial uplink resource allocation (used for sending a subsequent message 3 ), and a Temporary Cell Radio Network Temporary Identity (TC-RNTI). It will be decided whether the TC-RNTI is converted into a permanent C-RNTI in Step (4) (contention resolution). The UE needs to monitor an RAR message over a Physical Downlink Control Channel (PDCCH) by using a Random Access RNTI (RA-RNTI). in-line-formulae description="In-line Formulae" end="lead"? RA-RNTI=1 +t _id+10* f _id, in-line-formulae description="In-line Formulae" end="tail"? where t_id refers to an index number of a first subframe of a Physical Random Access Channel (PRACH) for sending a preamble (0<=t_id<10), f_id is a PRACH index in this subframe, i.e., a frequency domain position index (0=<f_id<=6), but there is only one frequency domain position for a Frequency Division Duplexing (FDD) system, and therefore f_id is always zero. (3) The UE sends the message 3 . After receiving the RAR message, the UE obtains uplink time synchronization and uplink resources. However, at this time, it cannot be determined that the RAR message is sent to the UE itself instead of other UEs. The preamble sequence of the UE is randomly selected from common resources, thereby making it possible for different UEs to send the same access preamble sequence over the same time-frequency resource. Thus, they will receive the same RAR via the same RA-RNTI. Moreover, the UE is unable to know whether other UEs make a random access by using the same resource. For this purpose, the UE needs to resolve such a random access contention via the subsequent message 3 and message 4 . (4) The eNB sends the message 4 , namely a contention resolution message. If the UE receives the message 4 returned by the eNB and a UE Identifier (ID) carried therein conforms to an ID reported to the eNB in the message 3 within the time of a mac-Contention Resolution Timer, the UE considers that it wins this random access contention and the random access is successful, and sets the TC-RNTI obtained in the RAR message as an own C-RNTI. Otherwise, the UE considers that the random access is unsuccessful, and executes a random access retransmission process in accordance with the above-mentioned rule. As for the contention-free random access, the preamble sent by the UE is notified by the eNB, uplink synchronization is completed via the first two steps, and a contention resolution process is not executed. Future communication requirements for a huge number of machine devices are as follows. A random access concurrent transmission blocking rate is smaller than 0.1%, and the access density within 1 s to 10 s is not smaller than 10 UEs per square meter. So, at least tens of thousands of UEs are accessed to a micro cell within 1 s to 10 s. In order to meet this demand, even if UEs are uniformly accessed and each subframe can initiate a random access, at least hundreds of times of PRACH resources are needed in accordance with a random access mode in the related art. However, actually, the UEs are not uniformly accessed. Therefore, more resources may be needed. In a conventional LTE system, if one time-frequency resource receives 64 cyclic shifts of one preamble root sequence, resources are insufficient for a system having a bandwidth of 20 Mbps even though all bandwidths are used to send the PRACH. | <SOH> SUMMARY <EOH>The following is a brief introduction for a subject described herein in detail. The brief introduction is not intended to restrict the scope of protection of claims. The disclosure provides a random access method, device and system, intended to save PRACH resources and meet requirements for a huge number of machine communications. The embodiments of the disclosure provide a random access method. The method includes the steps as follows. A first UE in a UE group sends a preamble to an eNB over a time-frequency resource, the time-frequency resource including a time domain resource and a frequency domain resource. The first UE and/or a second UE in the UE group monitor(s) an RAR corresponding to the preamble and sent by the eNB, herein the first UE is at least one UE in the UE group, and the second UE is all or some UEs in the UE group. In an embodiment, the first UE is at least one of the following: at least one fixed UE; or, at least one UE determined according to a pre-set rule; or, at least one UE notified by the eNB. In an embodiment, the preamble and/or the time domain resource and/or the frequency domain resource are/is pre-set, or determined by a group ID of the UE group, or notified by the eNB. In an embodiment, the operation that the first UE and/or the second UE monitor(s) an RAR corresponding to the preamble and sent by the eNB includes the following operations. The first UE and/or the second UE descramble(s) a Cyclic Redundancy Check (CRC) of Downlink Control Information (DCI) for scheduling the RAR according to a pre-set RA-RNTI or an RA-RNTI corresponding to the preamble, and receive(s) the RAR, the RAR including at least one TC-RNTI and/or at least one Uplink (UL) grant. The first UE and/or the second UE determine(s) a TC-RNTI and/or UL grant allocated thereto according to at least one TC-RNTI and/or at least one UL grant included in the RAR. In an embodiment, the operation that the first UE and/or the second UE determine(s) a TC-RNTI and/or a UL grant allocated thereto according to at least one TC-RNTI and/or at least one UL grant included in the RAR includes the following operation. The first UE and/or the second UE determine(s) a TC-RNTI and/or a UL grant allocated thereto according to an ID of the first UE and/or the second UE in accordance with a pre-set rule. In an embodiment, the operation that the first UE and/or the second UE monitor(s) an RAR corresponding to the preamble and sent by the eNB includes the following operation. The first UE and/or the second UE determine(s) corresponding RA-RNTIs according to respective IDs and/or preambles, descramble(s) a CRC of DCI for scheduling the RAR according to the corresponding RA-RNTIs, and receive(s) corresponding RARs, the RAR including a TC-RNTI and/or a UL grant allocated to the first UE or second UE. In an embodiment, after the first UE and/or the second UE monitor(s) an RAR corresponding to the preamble and sent by the eNB, the method further includes the step as follows. The first UE and/or the second UE send(s) a message 3 according to the UL grant allocated thereto. In an embodiment, after the first UE and/or the second UE send(s) a message 3 according to the UL grant allocated thereto, the method further includes the step as follows. The first UE and/or the second UE receive(s) a message 4 sent by the eNB. In an embodiment, the operation that the first UE and/or the second UE receive(s) a message 4 sent by the eNB includes the following operation. A CRC of DCI for scheduling the message 4 is scrambled by using the TC-RNTI allocated to the first UE and/or the second UE. In an embodiment, the message 4 includes at least one set of radio resources, radio resources allocated to the first UE and/or the second UE determined by the first UE and/or the second UE according to at least one set of radio resources in the message 4 . In an embodiment, the radio resources allocated to the first UE and/or the second UE are further determined by the UE according to an ID of the first UE and/or the second UE in accordance with a pre-set rule. In an embodiment, the message 4 includes: a set of radio resources allocated to the first UE or second UE. In an embodiment, after the first UE and/or the second UE receive(s) a message 4 sent by the eNB, the method further includes the step as follows. The first UE and/or the second UE send(s), to the eNB, an indicating signal for notifying the eNB of a successful access of the first UE and/or the second UE. In an embodiment, the indicating signal is a Scheduling Request (SR) or an Acknowledgement (ACK) signal. In an embodiment, after the first UE and/or the second UE receive(s) a message 4 sent by the eNB, the method further includes the step as follows. The first UE and/or the second UE receive(s) indicating information, sent by the eNB, for indicating re-initiation of a random access of the first UE and/or the second UE. In an embodiment, before the first UE in the UE group sends a preamble over a time-frequency resource, the method further includes the steps as follows. The first UE and/or the second UE receive(s) DCI or a paging message or a Radio Resource Control (RRC) message sent by the eNB. Or, the first UE receives random access request information sent by the second UE. In an embodiment, the operation that the first UE and/or the second UE receive(s) DCI or a paging message or an RRC message sent by the eNB includes at least one of the following operations. The DCI or a CRC of DCI for scheduling the paging message or the RRC message is scrambled by using a group ID of the UE group. The DCI or the paging message or the RRC message includes a group ID of the UE group. The DCI or the paging message or the RRC message includes an ID of the first UE and/or the second UE. The DCI or the paging message or the RRC message includes an ID of a preamble and/or a time domain resource of a preamble and/or a frequency domain resource of a preamble. In an embodiment, after the first UE receives random access request information sent by the second UE, the method further includes the steps as follows. The first UE counts received random access requests of the second UE in the group. When a count reaches a pre-set threshold, the first UE sends a preamble over a time-frequency resource. In an embodiment, the operation that the first UE in the UE group sends a preamble over a time-frequency resource includes the following operation. The first UE sends a preamble over a frequency domain resource periodically. In an embodiment, the message 3 and the message 4 include the group ID of the UE group or a pre-set field. In an embodiment, the message 3 includes a number of UEs having random access requests in the UE group or a number of UEs contained in the UE group or a pre-set UE number. In an embodiment, the preamble and/or the time domain resource and/or the frequency domain resource correspond(s) to the number of UEs having random access requests in the UE group or the number of UEs contained in the UE group or the pre-set UE number. The embodiments of the disclosure also provide a random access method. The method includes the steps as follows. An eNB receives a preamble sent by a first UE in a UE group over a time-frequency resource, herein the time-frequency resource includes a time domain resource and a frequency domain resource, and the first UE is at least one UE in the UE group. The eNB sends an RAR corresponding to the preamble. In an embodiment, the RAR includes at least one TC-RNTI and/or at least one UL grant, the RAR is used for the first UE and/or the second UE to determine a TC-RNTI and/or UL grant allocated thereto from at least one TC-RNTI and/or UL grant according to an ID of the first UE and/or the second UE in accordance with a pre-set allocation rule, and the second UE is all or some UEs in the UE group. In an embodiment, the RAR includes a TC-RNTI and/or a UL grant allocated to the first UE or second UE, and the second UE is all or some UEs in the UE group. In an embodiment, after the eNB sends an RAR corresponding to the preamble, the method further includes the step as follows. The eNB receives a message 3 sent by the first UE and/or the second UE according to the UL grant allocated thereto. In an embodiment, after the eNB receives a message 3 sent by the first UE and/or the second UE according to the UL grant allocated thereto, the method further includes the step as follows. The eNB sends a message 4 to the first UE and/or the second UE. In an embodiment, the operation that the eNB sends a message 4 to the first UE and/or the second UE includes the following operation: a CRC of DCI for scheduling the message 4 is scrambled by using the TC-RNTI allocated to the first UE and/or the second UE. In an embodiment, the message 4 includes at least one set of radio resources, radio resources allocated to the first UE and/or the second UE determined by the first UE and/or the second UE according to at least one set of radio resources included in the message 4 . In an embodiment, the message 4 includes: a set of radio resources allocated to the first UE or second UE. In an embodiment, after the eNB sends a message 4 to the first UE and/or the second UE, the method further includes the step as follows. The eNB receives an indicating signal, sent by the first UE and/or the second UE, for notifying the eNB of a successful access of the first UE and/or the second UE, the indicating signal being an SR or an ACK signal. In an embodiment, after the eNB sends a message 4 to the first UE and/or the second UE, the method further includes the step as follows. The eNB sends, to the first UE and/or the second UE, indicating information for indicating re-initiation of a random access of the first UE and/or the second UE. In an embodiment, before the eNB receives a preamble sent by a first UE in a UE group over a time-frequency resource, the method further includes the step as follows. The eNB sends DCI or a paging message or an RRC message to the first UE and/or the second UE. In an embodiment, the operation that the eNB sends DCI or a paging message or an RRC message to the first UE and/or the second UE includes at least one of the following operations. The DCI or a CRC of DCI for scheduling the paging message or the RRC message is scrambled by using a group ID of the UE group. The DCI or the paging message or the RRC message includes a group ID of the UE group. The DCI or the paging message or the RRC message includes an ID of the first UE and/or the second UE. The DCI or the paging message or the RRC message includes an ID of a preamble and/or a time domain resource of a preamble and/or a frequency domain resource of a preamble. In an embodiment, the operation that the eNB receives a preamble sent by the first UE in the UE group over a time-frequency resource includes the following operation. The eNB receives a preamble sent by the first UE over a frequency domain resource periodically. In an embodiment, the message 3 and the message 4 include the group ID of the UE group or a pre-set field. In an embodiment, the message 3 includes a number of UEs having random access requests in the UE group or a number of UEs contained in the UE group. The embodiments of the disclosure also provide a computer-readable storage medium, which stores a computer-executable instruction, herein when the computer-executable instruction is executed, the above-mentioned random access method is implemented. The embodiments of the disclosure also provide a UE. The UE includes: a sending unit and a monitoring unit, herein the sending unit is configured to: send a preamble to an eNB over a time-frequency resource, the time-frequency resource including a time domain resource and a frequency domain resource; and the monitoring unit is configured to: monitor an RAR corresponding to the preamble and sent by the eNB. In an embodiment, the monitoring unit includes: a first descrambling subunit, a first receiving subunit and an allocation subunit, herein the first descrambling subunit is configured to: descramble a CRC of DCI for scheduling the RAR according to a pre-set RA-RNTI or an RA-RNTI corresponding to the preamble; the first receiving subunit is configured to: receive the RAR, the RAR including at least one TC-RNTI and/or at least one UL grant; and the allocation subunit is configured to: determine a TC-RNTI and/or UL grant allocated to the UE according to at least one TC-RNTI and/or at least one UL grant included in the RAR. In an embodiment, the allocation subunit is configured to: determine a TC-RNTI and/or a UL grant allocated to the UE according to an ID of the UE in accordance with a pre-set rule. In an embodiment, the monitoring unit includes: a determination subunit, a second descrambling subunit and a second receiving subunit, herein the determination subunit is configured to: determine corresponding RA-RNTIs of the UE according to respective IDs and/or preambles of the UE; the second descrambling subunit is configured to: descramble a CRC of DCI for scheduling the RAR according to the corresponding RA-RNTIs of the UE; and the second receiving subunit is configured to: receive corresponding RARs of the UE, the RAR including a corresponding TC-RNTI and/or UL grant allocated to the UE. In an embodiment, the sending unit is further configured to: send a message 3 according to the UL grant allocated to the UE. In an embodiment, the UE further includes a receiving unit, configured to: receive a message 4 sent by the eNB. In an embodiment, receiving a message 4 sent by the eNB includes: scrambling a CRC of DCI for scheduling the message 4 by using the TC-RNTI allocated to a first UE and/or a second UE. In an embodiment, the message 4 includes at least one set of radio resources for the UE to determine radio resources allocated to the UE. In an embodiment, the message 4 includes: a set of radio resources allocated to the corresponding UE. In an embodiment, the sending unit is further configured to: send, to the eNB, an indicating signal for notifying the eNB of a successful access of the UE. In an embodiment, the indicating signal is an SR or an ACK signal. In an embodiment, the receiving unit is further configured to: receive indicating information, sent by the eNB, for indicating re-initiation of a random access of the UE. In an embodiment, the receiving unit is further configured to: receive DCI or a paging message or an RRC message sent by the eNB; or, receive random access request information sent by the second UE. In an embodiment, receiving DCI or a paging message or an RRC message sent by the eNB includes at least one of the following: the DCI or a CRC of DCI for scheduling the paging message or the RRC message is scrambled by using a group ID of a UE group; the DCI or the paging message or the RRC message includes the group ID of the UE group; the DCI or the paging message or the RRC message includes an ID of the first UE and/or the second UE; and the DCI or the paging message or the RRC message includes an ID of a preamble and/or a time domain resource of a preamble and/or a frequency domain resource of a preamble. In an embodiment, the sending unit is configured to: send a preamble over a frequency domain resource periodically. In an embodiment, the message 3 and the message 4 include the group ID of the UE group or a pre-set field. In an embodiment, the message 3 includes a number of UEs having random access requests in the UE group or a number of UEs contained in the UE group or a pre-set UE number. In an embodiment, the preamble and/or the time domain resource and/or the frequency domain resource correspond(s) to the number of UEs having random access requests in the UE group or the number of UEs contained in the UE group or the pre-set UE number. The embodiments of the disclosure also provide an eNB. The eNB includes: a receiving unit and a sending unit, herein the receiving unit is configured to: receive a preamble sent by a first UE in a UE group over a time-frequency resource, herein the time-frequency resource includes a time domain resource and a frequency domain resource, and the first UE is at least one UE in the UE group; and the sending unit is configured to: send an RAR corresponding to the preamble. In an embodiment, the RAR includes at least one TC-RNTI and/or at least one UL grant, the RAR is used for the first UE and/or the second UE to determine a TC-RNTI and/or UL grant allocated thereto from at least one TC-RNTI and/or UL grant according to an ID of the first UE and/or the second UE in accordance with a pre-set allocation rule, and the second UE is all or some UEs in the UE group. In an embodiment, the RAR includes a TC-RNTI and/or a UL grant allocated to the first UE or second UE, and the second UE is all or some UEs in the UE group. In an embodiment, the receiving unit is further configured to: receive a message 3 sent by the first UE and/or the second UE according to the UL grant allocated thereto. In an embodiment, the sending unit is further configured to: send a message 4 to the first UE and/or the second UE. In an embodiment, sending a message 4 to the first UE and/or the second UE includes: scrambling a CRC of DCI for scheduling the message 4 by using the TC-RNTI allocated to the first UE and/or the second UE. In an embodiment, the message 4 includes at least one set of radio resources for the first UE and/or the second UE to determine radio resources allocated thereto. In an embodiment, the message 4 includes: a set of radio resources allocated to the first UE or second UE. In an embodiment, the receiving unit is further configured to: receive an indicating signal, sent by the first UE and/or the second UE, for notifying the eNB of a successful access of the first UE and/or the second UE, the indicating signal being an SR or an ACK signal. In an embodiment, the sending unit is further configured to: send, to the first UE and/or the second UE, indicating information for indicating re-initiation of a random access of the first UE and/or the second UE. In an embodiment, the sending unit is further configured to: send DCI or a paging message or an RRC message to the first UE and/or the second UE. In an embodiment, sending DCI or a paging message or an RRC message to the first UE and/or the second UE includes at least one of the following: the DCI or a CRC of DCI for scheduling the paging message or the RRC message is scrambled by using a group ID of the UE group; the DCI or the paging message or the RRC message includes a group ID of the UE group; the DCI or the paging message or the RRC message includes an ID of the first UE and/or the second UE; and the DCI or the paging message or the RRC message includes an ID of a preamble and/or a time domain resource of a preamble and/or a frequency domain resource of a preamble. In an embodiment, the receiving unit is configured to: receive a preamble sent by the first UE over a frequency domain resource periodically. In an embodiment, the message 3 and the message 4 include the group ID of the UE group or a pre-set field. In an embodiment, the message 3 includes a number of UEs having random access requests in the UE group or a number of UEs contained in the UE group. The embodiments of the disclosure also provide a random access system. The system includes a UE and an eNB, herein a first UE in a UE group is configured to: send a preamble to the eNB over a time-frequency resource, the time-frequency resource including a time domain resource and a frequency domain resource; the first UE and/or a second UE in the UE group are/is configured to: monitor an RAR corresponding to the preamble and sent by the eNB, herein the first UE is at least one UE in the UE group, and the second UE is all or some UEs in the UE group; and the eNB is configured to: receive the preamble sent by the first UE in the UE group over the time-frequency resource, and send the RAR corresponding to the preamble. The embodiments of the disclosure provide a random access method, device and system. One or more UEs in a UE group send a preamble to an eNB over a time-frequency resource, so as to instruct the eNB to execute random accesses of some or all UEs in the UE group. Thus, a group of UEs only needs to occupy a PRACH resource (including a time domain resource, a frequency domain resource and a preamble) in a random access, so that PRACH resources can be greatly saved, thereby meeting requirements for a huge number of machine communications. After the drawings and the detailed descriptions are read and understood, other aspects may be understood. | H04W740833 | 20171220 | 20180628 | 62307.0 | H04W7408 | 1 | SMARTH, GERALD A | GROUP BASED RANDOM ACCESS METHOD DEVICE AND SYSTEM | UNDISCOUNTED | 0 | ACCEPTED | H04W | 2,017 |
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15,738,271 | PENDING | METHOD AND A LIQUID DISTRIBUTION SYSTEM FOR SAVING LIQUID AND THERMAL ENERGY | A method and a system for saving liquid and thermal energy, where a centrally located source of liquid is connected via separate feeding conduits to a plurality of liquid tap units. Each feeding conduit (FC1) is connected to a dampening chamber (D1) via a passage (OP1) containing an inlet (INi) to a liquid valve (VI) adapted to open when liquid reaches the inlet, so that liquid will flow from the feeding conduit to the associated liquid tap unit (LT1). Each feeding conduit is also connected to an evacuation pump (EP) via an evacuation valve (EV), which pump empties the feeding conduit after supply of the respective tap unit. | 1. A method to save liquid and thermal energy in a liquid distribution system, where a centrally located source of liquid is connected via separate feeding conduits to a plurality of liquid tap units, comprising the steps of: evacuating the liquid from the associated feeding conduit, after completion of a tapping operation at the associated liquid tap unit, by generating a backward pressure gradient in said associated feeding conduit by means of a liquid evacuation pump, so that the liquid flows backwards towards said liquid source and said associated feeding conduit thereafter contains only gas being retained therein, and refilling, upon activating said liquid tap unit, said associated feeding conduit with liquid by generating a forward pressure gradient in said associated feeding conduit and permitting liquid to flow from said liquid source to said associated liquid tap unit, while pushing the remaining gas in the feeding conduit towards said associated liquid tap unit at an operating pressure exceeding an ambient air pressure level, wherein keeping each of said feeding conduits, during the entire operation of the liquid distribution system, in communication with an associated dampening chamber via an associated passage, said associated passage accommodating an inlet to a liquid valve which is connected to said associated liquid tap unit, and said feeding conduit, said associated passage and said associated dampening chamber forming, in use, a closed system being separated, in respect of the remaining gas therein, from the ambient air, evacuating, during the evacuation step, all liquid from the particular feeding conduit and said associated pas passage by means of said liquid evacuation pump, while reducing the pressure of the remaining gas down to a lowermost pressure level, which is substantially lower than the pressure level of the ambient air at said associated liquid tap unit, bringing the refilling liquid, during the refilling step, to flow through said feeding conduit and beyond said associated pas passage, while pushing said remaining gas, by means of said operating pressure which is substantially higher than said ambient air pressure level at any one of said liquid tap units, into said associated dampening chamber, and keeping said liquid valve closed during the refilling step, until the refilling liquid has reached said inlet and passed beyond said associated pas passage, whereupon the liquid valve is caused to open so as to let the refilling liquid, but no gas or air, flow via said liquid valve into said associated liquid tap unit. 2. The method defined in claim 1, wherein said liquid valve is caused to open when the pressure of the refilling liquid in said passage reaches a threshold pressure level which is substantially higher than said ambient air pressure level, or a sensor or a mechanical element has detected the presence of liquid at said inlet of the liquid valve. 3. The method defined in claim 1, or 2, wherein a rising pressure in the particular feeding conduit during the refilling step is achieved by opening a control valve located in said particular feeding conduit adjacent to said liquid source, so that the particular feeding conduit will communicate directly with said liquid source, the liquid pressure in said liquid source being maintained at said operating pressure. 4. The method defined in claim 1, wherein, during said evacuation step, liquid is recirculated from said particular feeding conduit into said liquid source by means of said liquid evacuation pump. 5. The method defined in claim 1, wherein the evacuation of liquid from said feeding conduit, during said evacuation step, is initiated by opening a separate evacuation valve being connected between said feeding conduit and said separate liquid pump. 6. The method defined in claim 1, wherein said lowermost pressure level is 20to 80% of the ambient air pressure, and wherein said operating pressure is at least 300% of the ambient air pressure. 7. A liquid distribution system, for saving liquid and thermal energy, comprising a centrally located liquid source, a number of feeding conduits being separately connected to said centrally located liquid source, each separate feeding conduit being connected to an associated liquid tap unit via an associated liquid valve, a liquid evacuation pump for evacuation of liquid in each feeding conduit when an associated tap unit is closed, each feeding conduit being refilled with liquid when the tap unit is opened, each of said liquid valves being adapted, during a refilling operation, to keep the associated feeding conduit separated from the associated liquid tap unit by keeping said liquid valve closed, while pushing remaining gas into an associated gas passage until the refilling liquid has reached said gas passage, and said liquid valve is adapted to open after the entrance of liquid into said passage and compression of the remaining gas in said dampening chamber during a refilling operation, wherein: a dampening chamber is associated with each feeding conduit, each of said feeding conduits communicates with said dampening chamber via said gas passage which accommodates an inlet to said liquid valve, each feeding conduit, the associated gas passage and the associated dampening chamber together for a closed part of the system being separated, in respect of any remaining gas therein, from the ambient air, said liquid valve is adapted to open after the entrance of liquid into said gas passage and compression of the remaining gas in said dampening chamber during a refilling operation, and a liquid evacuation pump adapted, during each evacuation operation, to evacuate the liquid in the associated feeding conduit until lowermost pressure has been reached which is substantially lower than the ambient air pressure at each associated liquid tap unit. 8. The liquid distribution system defined in claim 7, wherein said liquid evacuation pump is connectable to each feeding conduit via a separate evacuation valve. 9. The liquid distribution system defined in claim 7, wherein said liquid valve is adapted to open: when the pressure of the refilling liquid in said passage reaches a threshold pressure level which is substantially higher than said ambient air pressure level, or a sensor or a mechanical element has sensed the presence of liquid at said inlet of the liquid valve. 10. The liquid distribution system defined in claim 7, wherein a control valve is arranged in each feeding conduit adjacent to said liquid source. 11. The liquid distribution system defined in claim 7, wherein a pressure sensor is arranged to sense the liquid pressure level at the outlet side of said liquid valve, for initiating said evacuation operation when an increased liquid pressure is sensed upon closing the associated liquid tap. 12. The liquid distribution system defined in claim 7, wherein an electronic control unit is connected to at least one of a pressure sensor located at the outlet side of said liquid valve, a control valve, located in each feeding conduit adjacent to said liquid source, a level sensor, located in each feeding conduit adjacent to said liquid sourced, said liquid evacuation pump, and a separate evacuation valve. 13. The liquid distribution system defined in claim 7, wherein said associated gas passage comprises a gas inlet valve adapted to permit the flow of gas from said feeding conduit to said dampening chamber during refilling of the system with liquid, and a gas outlet valve adapted to permit the flow of gas from the dampening chamber during evacuation of liquid from the system. 14. The liquid distribution system defined in claim 7, where said liquid valve comprises at least one non-return valve and pressure responsive part. 15. The liquid distribution system defined in claim 14, wherein said pressure responsive part comprises a non-linear spring device causing a valve body to move a long way from a closed position to an open position, so as permit a high flow of said liquid immediately after a threshold pressure level has been reached. | FIELD OF THE INVENTION The present invention relates to a method and a liquid distribution system for saving liquid and thermal energy, where a centrally located source of liquid is connected via separate feeding conduits to a plurality of liquid tap units, comprising the steps of evacuating the liquid from the associated feeding conduit after completion of a tapping operation at an associated liquid tap unit, by generating a backward pressure gradient in said associated feeding conduit, so that the liquid flows backwards towards said liquid source and said associated feeding conduit thereafter contains only gas being retained therein, and refilling, upon activating said liquid tap unit, said associated feeding conduit with liquid by generating a forward pressure gradient in said associated feeding conduit and to permit liquid to flow from said liquid source to said associated liquid tap unit, while pushing the remaining gas in the feeding conduit towards said associated liquid tap unit at an operating pressure exceeding an ambient air pressure level. Primarily, the method has been developed for hot water distribution systems in buildings, but the principles applied in the invention may very well be implemented also for other liquids, and also for distributing cold liquids. In both cases, there is an inherent problem that thermal energy will be lost when the hot or cold liquid is retained stationary in the feeding conduits, when the associated liquid tap units are not being used. Apart from the thermal loss, there will also be an inevitable loss of liquid if the volume of liquid remaining in a feeding conduit, after many hours, will be tapped, since the consumer will let the liquid flow until the desired temperature of the flowing liquid will be attained. A normal system will entail a hot water system in a large building, with a plurality of water tap units. Each such tap unit may comprise a number of taps, e.g. in a rest room, a kitchen, or some other room where there are one or more taps for hot water, normally also being serviced by cold water feeding conduits, including mixing taps where the water temperature may be controlled by the consumer. Such a system can be used for example in a relatively large building, with many apartments or offices, possibly at many stories, or in a small building, e.g. for a single family. The liquid source, i.e. the point of liquid supply to the various feeding conduits, may be connected to a public water supply line or a local water supply or heating vessel. Normally, it has a capacity which will enable a supply of cold and hot water at a substantially constant pressure, which is typically much higher than the ambient air pressure, such as 2 to 5 bars over-pressure (above the pressure of the ambient air at the liquid source). BACKGROUND OF THE INVENTION AND PRIOR ART Such a method is disclosed in Applicant's international (PCT) patent application WO2012/148351. A similar method is also previously known from the German published specification DE 4406150 A1 (Pumpe et al). In both these prior art cases, the liquid in the feeding conduits is sucked back to the liquid source after completion of a tapping operation. Also, in both cases, there is a gas valve unit located in proximity to a liquid valve unit for feeding gas or air into the system so as to replace the liquid with gas, after completion of a tapping operation. This gas or air will thus flow into the feeding conduit through a gas passage in a gas valve unit. In this way, the pressure in the feeding conduits will remain very close to the ambient air pressure. Moreover, this gas passage is separate from a liquid passage, where liquid flows from the feeding conduit to the associated liquid tap unit. The gas valve unit will serve both as a gas inlet valve and as a gas outlet valve. Therefore, the gas pressure in the evacuated feeding conduits will be almost the same as the ambient air pressure. OBJECT OF THE INVENTION Against this background, a main object of the present invention is to provide a similar method and a system where the refilling of liquid will proceed faster than in the prior art systems, while securing an effective dampening of the liquid when it reaches the vicinity of the liquid tap unit during each refilling operation. This should also be achieved with simple means which are easy to manufacture and install in a building or the like. There should be no need for an elevated (higher than normal) pressure or capacity at the liquid source. SUMMARY OF THE INVENTION In order to achieve these objects, the present invention provides an improved method, wherein the liquid distribution system operates at a relatively low pressure, when the liquid is being evacuated after a tapping operation, and at a relatively high, but typically still fairly normal, pressure during a tapping operation, as indicated in the appended claims. During the entire operation of the liquid distribution system, each of the feeding conduits is kept in communication with an associated dampening chamber via an associated passage accommodating an inlet to a liquid valve which is connected to or integrated with an associated liquid tap unit. In use, the feeding conduit, the associated passage and the associated dampening chamber form a closed system being separated in respect of the remaining gas therein, from the ambient air. During the refilling step, the refilling liquid is brought to flow through the feeding conduit into the associated passage while pushing the remaining gas into the associated dampening chamber, which will thus collect the remaining gas. During the refilling step, the liquid valve is kept closed until the refilling liquid has reached and passed beyond the inlet. Thereafter, the liquid valve is caused to open, so as to let liquid, but no gas or air other than possibly during a start-up phase of the liquid distribution system, to flow via the liquid valve into the associated liquid tap unit. Preferably, a low enough pressure of the refilling liquid is achieved by reducing the pressure, at the end of the evacuating step, until the associated feeding conduit is free of liquid, or a lowermost pressure level has been reached which is substantially lower than the pressure level of the ambient air at the associated liquid tap unit. Importantly, no ambient air is let into the closed system formed by the particular feeding conduit, the associated passage and the associated dampening chamber, during the evacuation step. The liquid valve may be caused to open when the pressure of the liquid at said inlet of the liquid valve reaches a threshold pressure level being substantially higher than the ambient air pressure level, e.g. 25% to 75% of the pressure at the liquid source, or a sensor has sensed the presence of refilling liquid at said inlet of said liquid valve. In normal operation, at stationary conditions, there will be no discharge of gas to or from the particular feeding conduit through the liquid tap unit. Possibly, some gas or air will escape through the liquid valve into liquid tap unit during a start-up phase of the system. It may occur that the system (each feeding conduit) is totally filled with air when the system is being filled with liquid for the first time. Then, it will take a number of evacuation and refilling cycles until a certain volume (or rather weight or mass of air) has escaped via the liquid valve, so that the liquid valve will then be closed until the inflowing or refilling liquid has passed the inlet of the valve during a refilling operation. At this point, a steady state has been reached and the same kind of cycles will be repeated every time a liquid tap unit is activated. A liquid distribution system according to the invention is characterized in that each of the feeding conduits communicates with a dampening chamber via an associated passage accommodating an inlet of a liquid valve which is connected to said associated liquid tap unit, each liquid valve being adapted, during a refilling operation, to keep the associated feeding conduit separated from the associated liquid tap unit by keeping the liquid valve closed, while pushing remaining gas into the associated chamber, until the refilling liquid has reached and passed beyond the inlet, said liquid valve being adapted to open after the entrance of liquid into said passage and compression of remaining gas in said closed dampening chamber during a refilling operation, each feeding conduit, the associated passage and the associated dampening chamber together forming a closed part of the system being separated in respect of any remaining gas therein, from the ambient air, at least after a possible start-up phase of the system, and a separate liquid evacuation pump is connectable to the feeding conduits and is adapted, upon being connected during an evacuation operation, to evacuate that feeding conduit until it is free of liquid. Then, due to the fact that no ambient air is let into the feeding conduit, the remaining air or gas in the feeding conduit has reached a lowermost pressure which is substantially lower than the ambient air pressure at each associated liquid tap unit and which will secure a low enough pressure during a subsequent refilling operation. The method and the system according to the invention will entail the following advantages: The refilling operation will proceed at a high speed, because the inflowing liquid will propagate with virtually no resistance initially, thanks to the low pressure of the gas remaining in the evacuated feeding conduit and the relatively high pressure at the liquid source. Only when a large portion of the total volume (of the feeding conduit and an associated dampening chamber) has been refilled with liquid will the pressure build up to a relatively high level therein. Provided that there is only a small amount of gas in the system, in particular in the respective feeding conduits, the pressure will be relatively high only at the very last stage of the refilling process, then causing an effective dampening of the fast flowing liquid. There is no need for a large dampening volume, because of the relatively high threshold pressure level of the liquid valve, so the apparatus, containing a dampening chamber, can be made in small dimensions and at relatively low cost, thus ensuring also moderate installation costs and no voluminous apparatus. Since there is no need for a separate air valve communicating with the ambient air, there is no risk for problems originating from the malfunctioning of such an air valve, such as leakage of liquid and, of course, lower installation costs. Even if the pressure of the liquid source is temporarily reduced somewhat, the system will continue to operate as long as the pressure in the liquid source is retained at a level exceeding any threshold level of the liquid valve being connected to the inlet of the particular tapping unit. During the evacuation step, a separate evacuation pump will pump out the liquid in the particular feeding conduit, until a lowermost liquid level is reached. In this way, the operation will be reliable, and there is no risk of leaving any liquid in the feeding conduit after a tapping operation. By using a separate evacuation pump, and possibly a separate evacuation valve, it will be possible to feed liquid into at least one of the feeding conduits while at the same time evacuating liquid from at least one other feeding conduit. The various components to be used in the liquid distribution system according to the present invention may be modified in many ways, for example as disclosed in the parallel patent applications filed by the same applicant on the same day, relating to a “a liquid distribution unit”, “a dampening valve unit” and “a fluid stop valve unit”. Further features and advantages will appear from the detailed description below, where a preferred embodiment of the invention, and some modifications, are disclosed. BRIEF DESCRIPTION OF THE DRAWINGS The invention will now be explained further below, with reference to the appended drawings which illustrate preferred embodiments of a valve device according to the invention. FIG. 1 illustrates schematically a prior art liquid distribution system as disclosed in the above mentioned international patent application; FIG. 2 shows, likewise schematically, a liquid distribution system according to the present invention, in a preferred embodiment; FIGS. 3, 3A, 3B show, in sectional views, a dampening valve unit being used in the system of FIG. 2, and FIGS. 4, 5, 6, 7A, 7B, and 8, 8A, 8B show a number of modified embodiments of the dampening valve unit of FIG. 3. DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT OF THE INVENTION In the description below, the liquid distribution system is intended for hot water, e.g. in a building. However, those skilled in the art will realize that the system may alternatively be used for any other liquid. Furthermore, the system may alternatively be used for the distribution of cold water or some other cold liquid. In the prior art system shown in FIG. 1, water is supplied from a source S of fresh water, e.g. a public water supply line SL or a local water supply, via a non-return valve 1 to a hot water tank 2, where the water is heated to a relatively high temperature, typically in the interval 60-90° C. There is a re-circulating loop 22 of hot water passing through the water heater 2 and a hydro-pressure vessel 3 serving to accommodate a variable volume of air or gas at an operating pressure. The hot water is circulated by means of a circulation pump (not shown) adjacent to the heater 2, and two further non-return valves 4a,4b will ensure that the circulation is maintained in one direction only. Moreover, there is a hot water feed line 6 bridging the loop 22 at two points 24 and 23. In the hot water feed line 6, there is a pump 5 for circulating hot water along the feed line 6. The pump 5 will operate even in case all hot water feeding conduits 7,8, leading to various hot water tap units 9,10 in a building, are passive or closed, so that the liquid remaining in the feeding conduits may be evacuated. Thus, the pump 5 has a dual purpose. In each hot water feeding conduit 7,8, adjacent to the connection to the hot water source S, there is a control valve 11 and 12, respectively, which can be opened or closed, a level sensor 13 and 14, respectively, and a pressure sensor 15 and 16, respectively. All these components are located centrally, near the hot water source, together with the hot water tank 2 and the circulating loop 22 with its bridging line 6. In the hot water bridging line 6, there is also a non-return valve 25 and a control valve 26. The hot water tank 2, the re-circulating loop 22 and the bridging hot water line 6 may be regarded as a heat source or hot water source 5, since the circulating water is always kept at an elevated temperature and will continuously supply hot water to the hot water feeding conduits 7, 8. If necessary, the hot water source may be contained in an insulated enclosure, or the components may be individually covered with by an insulating material. As described in the above-mentioned PCT application WO2012/148351, hot water will only be present in the liquid feeding conduits 7, 8 when hot water is being tapped from the respective tap unit 9 and 10. When the tap unit 9, 10 is being closed, possibly after a short delay (e.g. a few minutes) which does not significantly affect the temperature of the hot water in the conduit, the hot water remaining in the respective feeding conduit will be pumped out in the backward direction by means of the pump 5, back to the hot water source 2, 22. In this process, the hot water will be replaced by ambient air or gas in the liquid conduit 7, 8. However, when the hot water has been evacuated, the respective valve 11, 12 will be closed, and a gas or air pressure, slightly below the ambient atmospheric air pressure, will remain in the feeding conduit 7, 8. When hot water is going to be tapped again from the tap 8 or 10, a refilling operation will be initiated. The present invention provides for an improved method and system, as illustrated schematically in FIG. 2. A central liquid source LS, possibly corresponding to the hot water source 2, 22 in FIG. 1, is connected to a number of hot water feeding conduits FC1, FC2, etc. via a feed line FL, separate connections C1, C2, etc. and individual control valves CV1, CV2, etc. When the control valve CV1 is opened, hot water will flow rapidly into the associated feeding conduit FC1 which has been evacuated in a previous evacuation step. There will be a high pressure gradient in the feeding conduit FC1, since the control valve CV1 is open and thus conveys a driving pressure from below, corresponding to the pressure prevailing in the liquid source LS (typically about 2 to 5 bars over-pressure or, in absolute terms, more than 300% of the ambient air pressure), and an upper very low pressure, such as 0.2 to 0.8 bar under-pressure or, in absolute terms, about 20 to 80% of the ambient air pressure. Accordingly, the hot water will flow at a high velocity towards the water tapping unit LT1. Normally the feeding conduits are at least 5 to 30 m long, from the liquid source LS to the respective hot water tap unit LT1, etc. within a building. When the hot water approaches the liquid tap unit, there is a risk for a hard striking impulse, a so called “water hammer”, of the hot water. However, as is known per se, from the above-mentioned PCT application WO 2012/1408351, a dampening chamber D1 is arranged in the vicinity of a liquid valve V1, so that an air or gas cushion will dampen the impact of the rapidly moving hot water. According to the present invention, each dampening chamber D1, D2, etc. is connected to the end of the associated feeding conduit FC1, FC2, etc. via a passage OP1, OP2, etc. In this passage, there is an inlet to a liquid valve unit V1, V2, etc., e.g. a stop valve, a non-return valve or a check valve. See also FIGS. 3,4,5,6 and 7A, 7B, 8, 8A, 8B. The structure of the dampening valve unit DV1, DV2, etc. (see FIGS. 3, 3A, 3B) is disclosed in detail in two separate patent applications being filed at the same day as the present application, denoted “a dampening valve” and “a fluid stop valve”, respectively. Thus, the liquid valve unit V1, V2 may comprise two check-valves VA1, VA2 connected in series, being biased towards a closing position by a pressure responsive part, e.g. a non-linear spring device S1, comprising two mirrored diaphragm springs, so that the valve will shift from a closing position (FIG. 3B) to an open position (FIG. 3A) when a threshold pressure level (typically 25% to 75% of the pressure at the liquid source LS) has been reached at the inlet IN1, IN2, etc. of the valve. The non-linear spring device S1, etc. is such that, when the threshold pressure is reached, the valve body will move suddenly a relatively long way into its opening position (to the right in FIG. 3). So, the valve will open distinctly and permit a high flow of hot water immediately after the threshold pressure level has been reached. The spring device S1 is coupled to the two check-valves VA1, VA2 by means of an axial rod R, so that the end positions of the spring device will be transferred to the check valves which will thus be open (FIG. 3A) or closed (FIG. 3B). The dampening chamber D1, D2, etc. can be housed in a separate casing (as shown in FIGS. 3, 4, 5, 6, 7A, 7B), or it can be formed by a housing where the liquid valve V1 is located centrally (FIG. 8). In either case, the upper end of the feeding conduit FC1, FC2, etc. (FIG. 2) adjoins the above-mentioned passage OP1, OP2, etc., which also accommodates the inlet IN1, IN2, etc. of the valve V1, V2, etc. The prevailing pressures and the volumes of the feeding conduits FC1, FC2, etc. are such that the pressure of the refilling water is still relatively low when it reaches the passage OP1, OP2, etc., below the set threshold pressure of the valve. Therefore, the water will move further upwards, beyond the passage OP1, OP2, etc. before the air or gas, being trapped in the adjoining dampening chamber D1, D2, etc., is compressed to such a degree that the air or gas pressure, causing a corresponding pressure in the water adjacent thereto, rises to a level corresponding to the threshold level of the valve V1, V2, etc. Then, the valve suddenly opens, and the hot water will flow through the valve into the adjoining liquid tap unit LT1, LT2, etc. Since there is now only water in the passage OP1, OP2, etc., only water, an no gas or air, will flow through the valve and into the liquid tap LT1, LT2, etc. The pressure in the liquid source LS, being much higher than the ambient air pressure (even at the liquid tap unit LT1, LT2, etc.) and the threshold pressure of the liquid valve V1, V2, etc., will ensure that the air or gas compressed in the dampening chamber D1, D2, etc. will stay compressed and not expand into the passage OP1, OP2, etc. during normal operation of the liquid distribution system. As an alternative to opening the liquid valve upon reaching a threshold pressure, it is possible to provide a sensor that senses the presence of liquid in the passage OP1, OP2, etc. at the inlet IN1, IN2, etc. of the liquid valve V1, V2, etc. The sensor can be a level sensor, an optical sensor or a float sensor, in combination with a corresponding actuator, e.g. an electromagnetic device or a mechanical actuator, which will open the liquid valve V1, V2, etc. upon sensing the presence of liquid. A further alternative is to provide a valve V1, V2, etc. which is held in a closed position also by a locking or latching member (not shown) which is released when a water detecting element has detected the presence of liquid at the inlet IN1, IN2, etc. of the valve. A resetting mechanism may then be provided for returning the valve to its closed position during the subsequent evacuation step. Only when the tap handle, or a corresponding device or sensor, is activated for closing the particular liquid tap unit LT1, LT2, etc. will there be a change. Then, a pressure sensor PS1, PS2, etc. (see FIG. 2), inserted between the valve V1, V2, etc. and the associated liquid tap unit LT1, LT2 (or at some other location adjacent to the liquid valve or the liquid tap unit), will sense an increased pressure (the flow is stopped but the feeding pressure is still present) and send an electric signal to a control unit CU which will in turn close the control valve CV1, CV2, etc. adjacent to the liquid source LS. The control unit CU will also send a signal to a separate evacuation valve EV1, EV2, etc. so as to open the latter. This evacuation valve is arranged in a branch connection located downstream (as seen when the feeding conduit is refilled) but adjacent to the control valve CV1, CV2, etc. The evacuation valves EV1, EV2, etc. are jointly connected to an evacuation pump EP which will recirculate the hot water to the liquid source LS. The pressure sensors PS1 and PS2 are schematically shown to be connected to the (short) conduit between the liquid valve V1, V2, etc. and the liquid tap unit LT1, LT2. However, alternatively, they may be arranged inside the casing of the liquid valve, at the outlet side thereof, or at or adjacent to the liquid tap unit itself. Of course, instead of sending an electric signal via a control unit, it is possible, as disclosed in the above-mentioned PCT application WO 2012/148351, to let a pressure pulse or other physical variable propagate along the feeding conduit to the liquid source, where the pulse or other physical variable is sensed and used to trigger the closing of the control valve CV1, CV2, etc. and the opening of the evacuation valve EV1, EV2, etc. When the particular feeding conduit FC1, FC2, etc. is connected to the liquid source via the evacuation valve EV1, EV2, etc., the liquid (hot water) will be sucked back by the evacuation pump EP into the liquid source LS. There is also a level sensor LS1, LS2, arranged to sense the liquid level at (or adjacent to) the branch connection. When this sensor senses that the liquid surface has reached a lowermost level, this indicates that all the liquid has been evacuated (removed) from the associated feeding conduit FC1, FC2, etc. An alternative is just to sense the low pressure adjacent to the control valve or the evacuation valve, the low pressure indicating that virtually all liquid has been evacuated from the feeding conduit. Thus, at this time there will be a very low pressure, such as 0.5 bar under-pressure (50% of the ambient air pressure), or a pressure in the interval 0.2-0.8 bar under-pressure in the particular feeding conduit FC1, FC2, etc. Then, a signal is sent to the control unit CU, which will close the evacuation valve EV1, EV2, etc., so that the associated feeding conduit is retained in an evacuated state, and there will be no thermal loss due to heat being dissipated from the feeding conduit. In the feeding conduit FC1, FC2, etc. there is only gas or air left at a very low pressure (almost vacuum). A new refilling cycle can begin, being triggered or initiated by the opening of one of the liquid tap units. The arrangement of the control valves CV1, CV2, etc. and the evacuation valves EV1, EV2, etc., being located separately in the branch connections, has the advantage that any one or a number of feeding conduits FC1, FC1, etc. can be evacuated independently of each other. Therefore, one or more of the feeding conduits FC1, FC2 may be evacuated while one or more of the other feeding conduits FC2, FC1, etc. are being refilled or are operative for tapping hot water at the associated liquid tap unit LT2, LT1, etc. In the prior art system as shown in FIG. 1, on the other hand, this was not possible. Rather, it was necessary to wait until all the feeding conduits were non-operative before it was possible to connect them to a jointly operating pump. The special liquid distribution unit, comprising the feed line FL, the control valves CV1, CV2, etc., the separate evacuation valves EV1, EV2, etc. and the jointly connected evacuation pump EP, is disclosed in more detail in a separate patent application, entitled “a liquid distribution unit” being filed on the same date by the same applicant. The modified embodiments in FIGS. 4, 5, 6, 7A, 7B and 8, 8A, 8B will now be described briefly. In FIG. 4, the liquid valve unit V1 is exactly like the liquid valve in FIG. 3. However, the associated dampening chamber D1 is connected to the feeding conduit FC1 via a passage OP′1 accommodating two parallel valve devices, a gas inlet valve GIV1, in the form of a non-return valve, for letting gas into the dampening chamber during the refilling of the feeding conduit FC1 when the pressure is higher than the ambient air pressure, e.g. exceeding 0.1 bar over-pressure, and a gas outlet valve GOV1, which will permit gas to flow back into the feeding conduit FC1 during evacuation of the latter. The gas outlet valve GOV1 will open when there a pressure difference exceeding a set value, e.g. 2 to 3 bars, is reached. The gas outlet valve is structured like the liquid valve unit V1 but has only one check valve (non-return valve) VA′1. Even when the pressure difference is reduced during evacuation, the gas outlet valve will stay open as long as there is a small pressure difference, and it may even stay open when the pressure difference has been reversed. Then, during the subsequent refilling with water, the entering water will cause the gas outlet valve to shift to its closed position. When a pressure of about 0.2 bar overpressure has been reached, the gas inlet valve GIV1 will open and let gas, and possibly some water, flow into the dampening chamber. The gas outlet valve GOV1 will stay closed during the tapping of hot water through the liquid valve V1. The valve arrangement with the parallel outlet and inlet valves GOV1, GIV1 will ensure that the gas in the dampening chamber D1 will stay there when the liquid valve V1 opens, with an accompanying pressure reduction in the feeding conduit FC1, until a steady state is reached for the water flowing out through the valve Vito the associated hot water tap unit (LT1 in FIG. 2). In this way, it is avoided that air or gas will flow through the liquid valve V1. The dampening chamber may have a free inner space, as shown in FIGS. 3 and 4, or it may have a displaceable piston P as shown in FIG. 5 for the dampening chamber D′1 or a flexible diaphragm D1 as shown in FIG. 6 for the dampening chamber D″1. The piston P or the diaphragm will define an innermost compartment having a preset initial gas pressure which will vary but the gas in this compartment will not mix with the water during the refilling step. The liquid valve may be structured differently, e.g. as shown in FIGS. 7A and 7B, where an elastomeric body V′1 is disposed in the passage OP″1 between the feeding conduit FC1 and the dampening chamber D1 and is displaceable between a position (FIG. 7A) where the passage OP″1 is open (and the liquid valve part to the right is closed) and a position (FIG. 7B) where the passage OP″1 is closed (and the liquid valve part to the right is open). The latter position is taken when hot water is flowing to the hot water tap unit LT1, whereas the other position is taken during the other phases of the cycle. FIGS. 8, 8A, and 8B show an embodiment of the dampening valve DV′1 which is especially compact. Here the liquid valve V1 is disposed centrally within a housing H defining an internal dampening chamber D1. The inlet IN1 is located in an open passage OP1 between the feeding conduit FC1 and the dampening chamber D1. The inlet IN1, in the form of a small orifice, communicates with the liquid valve unit V1 via a conduit CO. The inner diameter of the conduit and the orifice inlet IN1 are such that even during evacuation of the feeding conduit FC1, water will remain in the conduit CO and prevent that gas enters into the liquid valve V1. Of course, in this case as well, the threshold level of the valve V1 is high enough to ensure that liquid (hot water) will reach the inlet IN1 before the valve V1 opens and permits the water to flow into the water tap unit LT1. Those skilled in the art can modify the method and the liquid distribution system within the scope defined by the appended claims. For example, as indicated above, it would be possible to use the system for cold liquids rather than hot ones. The feeding conduits may consist of metal tubing, or plastic hoses. Of course, the threshold pressure level of the liquid valve V1, V2, etc. may be variable, so as to be set at a suitable value in each case, and it is also possible to vary these threshold pressure levels so as to optimize the system and the dampening characteristics at each dampening valve unit DV1, DV2, etc. Possibly, the volumes of the dampening chambers may also be variable. As indicated above, it is a great advantage that there is no discharge of air or other gas during normal operation of the system. The dampening chamber is closed in relation to the ambient air, and the other fittings and connections should be air tight, even at very low or rather high pressures. There is no need for letting in ambient air through an inlet air valve, as was the case in the prior art systems. Therefore, the system will operate swiftly with a high refilling velocity and with great reliability and, therefore, at rather low service costs after a proper installation in a building. The system may also be used in other units than buildings, e.g. in large vessels (water or air-borne) or moving vehicles, or in other units where there is a need for distributing hot or cold liquid to various tapping units. | <SOH> BACKGROUND OF THE INVENTION AND PRIOR ART <EOH>Such a method is disclosed in Applicant's international (PCT) patent application WO2012/148351. A similar method is also previously known from the German published specification DE 4406150 A1 (Pumpe et al). In both these prior art cases, the liquid in the feeding conduits is sucked back to the liquid source after completion of a tapping operation. Also, in both cases, there is a gas valve unit located in proximity to a liquid valve unit for feeding gas or air into the system so as to replace the liquid with gas, after completion of a tapping operation. This gas or air will thus flow into the feeding conduit through a gas passage in a gas valve unit. In this way, the pressure in the feeding conduits will remain very close to the ambient air pressure. Moreover, this gas passage is separate from a liquid passage, where liquid flows from the feeding conduit to the associated liquid tap unit. The gas valve unit will serve both as a gas inlet valve and as a gas outlet valve. Therefore, the gas pressure in the evacuated feeding conduits will be almost the same as the ambient air pressure. | <SOH> SUMMARY OF THE INVENTION <EOH>In order to achieve these objects, the present invention provides an improved method, wherein the liquid distribution system operates at a relatively low pressure, when the liquid is being evacuated after a tapping operation, and at a relatively high, but typically still fairly normal, pressure during a tapping operation, as indicated in the appended claims. During the entire operation of the liquid distribution system, each of the feeding conduits is kept in communication with an associated dampening chamber via an associated passage accommodating an inlet to a liquid valve which is connected to or integrated with an associated liquid tap unit. In use, the feeding conduit, the associated passage and the associated dampening chamber form a closed system being separated in respect of the remaining gas therein, from the ambient air. During the refilling step, the refilling liquid is brought to flow through the feeding conduit into the associated passage while pushing the remaining gas into the associated dampening chamber, which will thus collect the remaining gas. During the refilling step, the liquid valve is kept closed until the refilling liquid has reached and passed beyond the inlet. Thereafter, the liquid valve is caused to open, so as to let liquid, but no gas or air other than possibly during a start-up phase of the liquid distribution system, to flow via the liquid valve into the associated liquid tap unit. Preferably, a low enough pressure of the refilling liquid is achieved by reducing the pressure, at the end of the evacuating step, until the associated feeding conduit is free of liquid, or a lowermost pressure level has been reached which is substantially lower than the pressure level of the ambient air at the associated liquid tap unit. Importantly, no ambient air is let into the closed system formed by the particular feeding conduit, the associated passage and the associated dampening chamber, during the evacuation step. The liquid valve may be caused to open when the pressure of the liquid at said inlet of the liquid valve reaches a threshold pressure level being substantially higher than the ambient air pressure level, e.g. 25% to 75% of the pressure at the liquid source, or a sensor has sensed the presence of refilling liquid at said inlet of said liquid valve. In normal operation, at stationary conditions, there will be no discharge of gas to or from the particular feeding conduit through the liquid tap unit. Possibly, some gas or air will escape through the liquid valve into liquid tap unit during a start-up phase of the system. It may occur that the system (each feeding conduit) is totally filled with air when the system is being filled with liquid for the first time. Then, it will take a number of evacuation and refilling cycles until a certain volume (or rather weight or mass of air) has escaped via the liquid valve, so that the liquid valve will then be closed until the inflowing or refilling liquid has passed the inlet of the valve during a refilling operation. At this point, a steady state has been reached and the same kind of cycles will be repeated every time a liquid tap unit is activated. A liquid distribution system according to the invention is characterized in that each of the feeding conduits communicates with a dampening chamber via an associated passage accommodating an inlet of a liquid valve which is connected to said associated liquid tap unit, each liquid valve being adapted, during a refilling operation, to keep the associated feeding conduit separated from the associated liquid tap unit by keeping the liquid valve closed, while pushing remaining gas into the associated chamber, until the refilling liquid has reached and passed beyond the inlet, said liquid valve being adapted to open after the entrance of liquid into said passage and compression of remaining gas in said closed dampening chamber during a refilling operation, each feeding conduit, the associated passage and the associated dampening chamber together forming a closed part of the system being separated in respect of any remaining gas therein, from the ambient air, at least after a possible start-up phase of the system, and a separate liquid evacuation pump is connectable to the feeding conduits and is adapted, upon being connected during an evacuation operation, to evacuate that feeding conduit until it is free of liquid. Then, due to the fact that no ambient air is let into the feeding conduit, the remaining air or gas in the feeding conduit has reached a lowermost pressure which is substantially lower than the ambient air pressure at each associated liquid tap unit and which will secure a low enough pressure during a subsequent refilling operation. The method and the system according to the invention will entail the following advantages: The refilling operation will proceed at a high speed, because the inflowing liquid will propagate with virtually no resistance initially, thanks to the low pressure of the gas remaining in the evacuated feeding conduit and the relatively high pressure at the liquid source. Only when a large portion of the total volume (of the feeding conduit and an associated dampening chamber) has been refilled with liquid will the pressure build up to a relatively high level therein. Provided that there is only a small amount of gas in the system, in particular in the respective feeding conduits, the pressure will be relatively high only at the very last stage of the refilling process, then causing an effective dampening of the fast flowing liquid. There is no need for a large dampening volume, because of the relatively high threshold pressure level of the liquid valve, so the apparatus, containing a dampening chamber, can be made in small dimensions and at relatively low cost, thus ensuring also moderate installation costs and no voluminous apparatus. Since there is no need for a separate air valve communicating with the ambient air, there is no risk for problems originating from the malfunctioning of such an air valve, such as leakage of liquid and, of course, lower installation costs. Even if the pressure of the liquid source is temporarily reduced somewhat, the system will continue to operate as long as the pressure in the liquid source is retained at a level exceeding any threshold level of the liquid valve being connected to the inlet of the particular tapping unit. During the evacuation step, a separate evacuation pump will pump out the liquid in the particular feeding conduit, until a lowermost liquid level is reached. In this way, the operation will be reliable, and there is no risk of leaving any liquid in the feeding conduit after a tapping operation. By using a separate evacuation pump, and possibly a separate evacuation valve, it will be possible to feed liquid into at least one of the feeding conduits while at the same time evacuating liquid from at least one other feeding conduit. The various components to be used in the liquid distribution system according to the present invention may be modified in many ways, for example as disclosed in the parallel patent applications filed by the same applicant on the same day, relating to a “a liquid distribution unit”, “a dampening valve unit” and “a fluid stop valve unit”. Further features and advantages will appear from the detailed description below, where a preferred embodiment of the invention, and some modifications, are disclosed. | F24D17001 | 20171220 | 20180621 | 78651.0 | F24D1700 | 0 | ANDERSON II, STEVEN S | METHOD AND A LIQUID DISTRIBUTION SYSTEM FOR SAVING LIQUID AND THERMAL ENERGY | SMALL | 0 | ACCEPTED | F24D | 2,017 |
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15,739,024 | PENDING | ELECTRONIC AEROSOL PROVISION SYSTEMS | An inductive heating assembly for generating an aerosol from an aerosol precursor material in an aerosol provision system, the inductive heating assembly including: a susceptor; and a drive coil arranged to induce current flow in the susceptor to heat the susceptor and vaporize aerosol precursor material in proximity with a surface of the susceptor, and wherein the susceptor includes regions of different susceptibility to induced current flow from the drive coil, such that when in use the surface of the susceptor in the regions of different susceptibility are heated to different temperatures by the current flow induced by the drive coil. | 1. An inductive heating assembly for generating an aerosol from an aerosol precursor material in an aerosol provision system, the inductive heating assembly comprising: a susceptor; and a drive coil arranged to induce current flow in the susceptor to heat the susceptor and vaporize aerosol precursor material in proximity with a surface of the susceptor, wherein the susceptor comprises regions of different susceptibility to induced current flow from the drive coil, such that when in use the surface of the susceptor in the regions of different susceptibility to induced current flow from the drive coil is heated to different temperatures by the current flow induced by the drive coil. 2. The inductive heating assembly of claim 1, wherein the regions of different susceptibility to induced current flow from the drive coil are provided by regions of the susceptor comprising different materials. 3. The inductive heating assembly of claim 1, wherein the materials are selected from the group consisting of: copper, aluminum, zinc, brass, iron, tin, and steel. 4. The inductive heating assembly of claim 1, wherein the susceptor has a generally planar form, and wherein the regions of different susceptibility to induced current flow from the drive coil are provided by regions in which the generally planar form of the susceptor is oriented at different angles to a magnetic field created by the drive coil when in use. 5. (canceled) 6. The inductive heating assembly of claim 1, wherein the regions of different susceptibility to induced current flow from the drive coil are defined by a wall of the susceptor which is not parallel to a direction of induced current flow, thereby disrupting the induced current flow in the susceptor to create regions of different current density. 7. The inductive heating assembly of claim 6, wherein the wall is an outer wall of the susceptor. 8. The inductive heating assembly of claim 6, wherein the wall is an inner wall of the susceptor associated with an opening in the susceptor. 9. The inductive heating assembly of claim 1, wherein the drive coil extends along a coil axis about which a magnetic field generated by the drive coil when in use is generally circularly symmetric, and wherein the susceptor is not circularly symmetric about the coil axis. 10. The inductive heating assembly of claim 1, wherein the regions of different susceptibility to induced current flow from the drive coil are provided by regions of the susceptor having different electrical resistivity. 11. The inductive heating assembly of claim 1, wherein the regions of different susceptibility to induced current flow from the drive coil are provided by regions of the susceptor having different thicknesses along a direction parallel to a magnetic field generated at the susceptor when the drive coil is in use. 12. The inductive heating assembly of claim 1, wherein the regions of different susceptibility to induced current flow from the drive coil are provided by regions in which a [[the]] magnetic field generated at the susceptor when the drive coil is in use has a different strength. 13. The inductive heating assembly of claim 1, wherein the susceptor has a generally planar form. 14. The inductive heating assembly of claim 13, wherein the regions of different susceptibility to induced current flow from the drive coil are concentrically arranged in the plane of the susceptor. 15. The inductive heating assembly of claim 1, wherein the aerosol precursor material comprises a liquid formulation. 16. The inductive heating assembly of claim 15, wherein the susceptor comprises a porous material arranged to wick liquid formulation from a source of liquid formulation by capillary action to replace liquid formulation vaporized by the susceptor when in use. 17. The inductive heating assembly of claim 15, further comprises a wicking element adjacent the susceptor, wherein the wicking element is arranged to wick liquid formulation from a source of liquid formulation by capillary action to replace liquid formulation vaporized by the susceptor when in use. 18. An aerosol provision system comprising: an inductive heating assembly according to claim 1. 19. The aerosol provision system of claim 18, wherein the aerosol provision system comprises a host device and a cartridge, and wherein the host device comprises the drive coil of the inductive heating assembly and the cartridge comprises the susceptor of the inductive heating assembly. 20. A cartridge for use in an aerosol provision system comprising an inductive heating assembly, wherein the cartridge comprises: a susceptor that comprises regions of different susceptibility to induced current flow from an external drive coil, such that when in use a surface of the susceptor in the regions of different susceptibility to induced current flow from an external drive coil are heated to different temperatures by current flows induced by the external drive coil. 21. An inductive heating assembly means for generating an aerosol from an aerosol precursor material in an aerosol provision system, the inductive heating assembly means comprising: susceptor means; and induction means for inducing current flow in the susceptor means to heat the susceptor means and vaporize aerosol precursor material in proximity with a surface of the susceptor means, wherein the susceptor means comprises regions of different susceptibility to induced current flow from the induction means such that in use the surface of the susceptor means in the regions of different susceptibility is heated to different temperatures by the current flow induced by the induction means. 22. A method of generating an aerosol from an aerosol precursor material, the method comprising: providing an inductive heating assembly comprising a susceptor and a drive coil arranged to induce current flow in the susceptor, wherein the susceptor comprises regions of different susceptibility to induced current flow from the drive coil so a surface of the susceptor in the regions of different susceptibility is heated to different temperatures by current flows induced by the drive coil, and using the drive coil to induce currents in the susceptor to heat the susceptor and vaporize aerosol precursor material in proximity with the surface of the susceptor to generate the aerosol. 23. (canceled) 24. (canceled) | CROSS REFERENCE TO RELATED APPLICATION The present application is a National Phase entry of PCT Application No. PCT/GB2016/051731, filed Jun. 10, 2016, which claims priority from GB Patent Application No. 1511358.2, filed Jun. 29, 2015, each of which is hereby fully incorporated herein by reference. FIELD The present disclosure relates to electronic aerosol provision systems such as electronic nicotine delivery systems (e.g. e-cigarettes). BACKGROUND FIG. 1 is a schematic diagram of one example of a conventional e-cigarette 10. The e-cigarette has a generally cylindrical shape, extending along a longitudinal axis indicated by dashed line LA, and comprises two main components, namely a control unit 20 and a cartomizer 30. The cartomizer 30 includes an internal chamber containing a reservoir of liquid formulation including nicotine, a vaporizer (such as a heater), and a mouthpiece 35. The cartomizer 30 may further include a wick or similar facility to transport a small amount of liquid from the reservoir to the heater. The control unit 20 includes a re-chargeable battery to provide power to the e-cigarette 10 and a circuit board for generally controlling the e-cigarette 10. When the heater receives power from the battery, as controlled by the circuit board, the heater vaporizes the nicotine and this vapor (aerosol) is then inhaled by a user through the mouthpiece 35. The control unit 20 and cartomizer 30 are detachable from one another by separating in a direction parallel to the longitudinal axis LA, as shown in FIG. 1, but are joined together when the device 10 is in use by a connection, indicated schematically in FIG. 1 as 25A and 25B, to provide mechanical and electrical connectivity between the control unit 20 and the cartomizer 30. The electrical connector on the control unit 20 that is used to connect to the cartomizer also serves as a socket for connecting a charging device (not shown) when the control unit 20 is detached from the cartomizer 30. The cartomizer 30 may be detached from the control unit 20 and disposed of when the supply of nicotine is exhausted (and replaced with another cartomizer if so desired). FIGS. 2 and 3 provide schematic diagrams of the control unit 20 and cartomizer 30, respectively, of the e-cigarette 10 of FIG. 1. Note that various components and details, e.g. such as wiring and more complex shaping, have been omitted from FIGS. 2 and 3 for reasons of clarity. As shown in FIG. 2, the control unit 20 includes a battery or cell 210 for powering the e-cigarette 10, as well as a chip, such as a (micro) controller for controlling the e-cigarette 10. The controller is attached to a small printed circuit board (PCB) 215 that also includes a sensor unit. If a user inhales on the mouthpiece 35, air is drawn into the e-cigarette 10 through one or more air inlet holes (not shown in FIGS. 1 and 2). The sensor unit detects this airflow, and in response to such a detection, the controller provides power from the battery 210 to the heater in the cartomizer 30. As shown in FIG. 3, the cartomizer 30 includes an air passage 161 extending along the central (longitudinal) axis of the cartomizer 30 from the mouthpiece 35 to the connector 25A for joining the cartomizer 30 to the control unit 20. A reservoir of nicotine-containing liquid 170 is provided around the air passage 161. This reservoir 170 may be implemented, for example, by providing cotton or foam soaked in the liquid. The cartomizer 30 also includes a heater 155 in the form of a coil for heating liquid from reservoir 170 to generate vapor to flow through air passage 161 and out through mouthpiece 35. The heater is powered through lines 166 and 167, which are in turn connected to opposing polarities (positive and negative, or vice versa) of the battery 210 via connector 25A. One end of the control unit 20 provides a connector 25B for joining the control unit 20 to the connector 25A of the cartomizer 30. The connectors 25A and 25B provide mechanical and electrical connectivity between the control unit 20 and the cartomizer 30. The connector 25B includes two electrical terminals, an outer contact 240 and an inner contact 250, which are separated by insulator 260. The connector 25A likewise includes an inner electrode 175 and an outer electrode 171, separated by insulator 172. When the cartomizer 30 is connected to the control unit 20, the inner electrode 175 and the outer electrode 171 of the cartomizer 30 engage the inner contact 250 and the outer contact 240, respectively, of the control unit 20. The inner contact 250 is mounted on a coil spring 255 so that the inner electrode 175 pushes against the inner contact 250 to compress the coil spring 255, thereby helping to ensure good electrical contact when the cartomizer 30 is connected to the control unit 20. The cartomizer connector 25A is provided with two lugs or tabs 180A, 180B, which extend in opposite directions away from the longitudinal axis of the e-cigarette 10. These tabs are used to provide a bayonet fitting for connecting the cartomizer 30 to the control unit 20. It will be appreciated that other embodiments may use a different form of connection between the control unit 20 and the cartomizer 30, such as a snap fit or a screw connection. As mentioned above, the cartomizer 30 is generally disposed of once the liquid reservoir 170 has been depleted, and a new cartomizer 30 is purchased and installed. In contrast, the control unit 20 is re-usable with a succession of cartomizers 30. Accordingly, it is particularly desirable to keep the cost of the cartomizer 30 relatively low. One approach to doing this has been to construct a three-part device, based on (i) a control unit, (ii) a vaporizer component, and (iii) a liquid reservoir. In this three-part device, only the final part, the liquid reservoir, is disposable, whereas the control unit and the vaporizer are both re-usable. However, having a three-part device can increase the complexity, both in terms of manufacture and user operation. Moreover, it can be difficult in such a three-part device to provide a wicking arrangement of the type shown in FIG. 3 to transport liquid from the reservoir to the heater. Another approach is to make the cartomizer 30 re-fillable, so that it is no longer disposable. However, making a cartomizer 30 re-fillable brings potential problems, for example, a user may try to re-fill the cartomizer 30 with an inappropriate liquid (one not provided by the supplier of the e-cigarette 10). There is a risk that this inappropriate liquid may result in a low quality consumer experience, and/or may be potentially hazardous, whether by causing damage to the e-cigarette itself, or possibly by creating toxic vapors. Accordingly, existing approaches for reducing the cost of a disposable component (or for avoiding the need for such a disposable component) have met with only limited success. SUMMARY The invention is defined in the appended claims. According to a first aspect of certain embodiments there is provided an inductive heating assembly for generating an aerosol from an aerosol precursor material in an aerosol provision system, the inductive heating assembly comprising: a susceptor; and a drive coil arranged to induce current flow in the susceptor to heat the susceptor and vaporize aerosol precursor material in proximity with a surface of the susceptor, and wherein the susceptor comprises regions of different susceptibility to induced current flow from the drive coil, such that when in use the surface of the susceptor in the regions of different susceptibility are heated to different temperatures by the current flow induced by the drive coil. According to a second aspect of certain embodiments there is provided an aerosol provision system comprising an inductive heating assembly for generating an aerosol from an aerosol precursor material in an aerosol provision system, the inductive heating assembly comprising: a susceptor; and a drive coil arranged to induce current flow in the susceptor to heat the susceptor and vaporize aerosol precursor material in proximity with a surface of the susceptor, and wherein the susceptor comprises regions of different susceptibility to induced current flow from the drive coil, such that when in use the surface of the susceptor in the regions of different susceptibility are heated to different temperatures by the current flow induced by the drive coil. According to a third aspect of certain embodiments there is provided a cartridge for use in an aerosol provision system comprising an inductive heating assembly, wherein the cartridge comprises a susceptor that comprises regions of different susceptibility to induced current flow from an external drive coil, such that when in use the surface of the susceptor in the regions of different susceptibility are heated to different temperatures by current flows induced by the external drive coil. According to a fourth aspect of certain embodiments there is provided an inductive heating assembly means for generating an aerosol from an aerosol precursor material in an aerosol provision system, the inductive heating assembly means comprising: susceptor means; and induction means for inducing current flow in the susceptor means to heat the susceptor means and vaporize aerosol precursor material in proximity with a surface of the susceptor means, wherein the susceptor means comprises regions of different susceptibility to induced current flow from the induction means such that in use the surface of the susceptor means in the regions of different susceptibility are heated to different temperatures by the current flow induced by the induction means. According to a fifth aspect of certain embodiments there is provided a method of generating an aerosol from an aerosol precursor material, the method comprising: providing an inductive heating assembly comprising a susceptor and a drive coil arranged to induce current flow in the susceptor, wherein the susceptor comprises regions of different susceptibility to induced current flow from the drive coil so the surface of the susceptor in the regions of different susceptibility are heated to different temperatures by current flows induced by the drive coil, and using the drive coil to induce currents in the susceptor to heat the susceptor and vaporize aerosol precursor material in proximity with a surface of the susceptor to generate the aerosol. It will be appreciated that features and aspects of the invention described above in relation to the first and other aspects of the invention are equally applicable to, and may be combined with, embodiments of the invention according to other aspects of the invention as appropriate, and not just in the specific combinations described above. BRIEF DESCRIPTION OF THE DRAWINGS Embodiments of the disclosure will now be described, by way of example only, with reference to the accompanying drawings, in which: FIG. 1 is a schematic (exploded) diagram illustrating an example of a known e-cigarette. FIG. 2 is a schematic diagram of the control unit of the e-cigarette of FIG. 1. FIG. 3 is a schematic diagram of the cartomizer of the e-cigarette of FIG. 1. FIG. 4 is a schematic diagram illustrating an e-cigarette in accordance with some embodiments of the disclosure, showing the control unit assembled with the cartridge (top), the control unit by itself (middle), and the cartridge by itself (bottom). FIGS. 5 and 6 are schematic diagrams illustrating an e-cigarette in accordance with some other embodiments of the disclosure. FIG. 7 is a schematic diagram of the control electronics for an e-cigarette such as shown in FIGS. 4, 5 and 6 in accordance with some embodiments of the disclosure. FIGS. 7A, 7B and 7C are schematic diagrams of part of the control electronics for an e-cigarette such as shown in FIG. 6 in accordance with some embodiments of the disclosure. FIG. 8 schematically represents an aerosol provision system comprising an inductive heating assembly in accordance with certain example embodiments of the present disclosure. FIGS. 9 to 12 schematically represent heating elements for use in the aerosol provision system of FIG. 8 in accordance with different example embodiments of the present disclosure. FIGS. 13 to 20 schematically represent different arrangements of source liquid reservoir and vaporizer in accordance with different example embodiments of the present disclosure. DETAILED DESCRIPTION Aspects and features of certain examples and embodiments are discussed/described herein. Some aspects and features of certain examples and embodiments may be implemented conventionally and these are not discussed/described in detail in the interests of brevity. It will thus be appreciated that aspects and features of apparatus and methods discussed herein which are not described in detail may be implemented in accordance with any conventional techniques for implementing such aspects and features. As described above, the present disclosure relates to an aerosol provision system, such as an e-cigarette. Throughout the following description the term “e-cigarette” is sometimes used but this term may be used interchangeably with aerosol (vapor) provision system. FIG. 4 is a schematic diagram illustrating an e-cigarette 410 in accordance with some embodiments of the disclosure (please note that the term e-cigarette is used herein interchangeably with other similar terms, such as electronic vapor provision system, electronic aerosol provision system, etc.). The e-cigarette 410 includes a control unit 420 and a cartridge 430. FIG. 4 shows the control unit 420 assembled with the cartridge 430 (top), the control unit 420 by itself (middle), and the cartridge 430 by itself (bottom). Note that for clarity, various implementation details (e.g. such as internal wiring, etc.) are omitted. As shown in FIG. 4, the e-cigarette 410 has a generally cylindrical shape with a central, longitudinal axis (denoted as LA, shown in dashed line). Note that the cross-section through the cylinder, i.e. in a plane perpendicular to the line LA, may be circular, elliptical, square, rectangular, hexagonal, or some other regular or irregular shape as desired. The mouthpiece 435 is located at one end of the cartridge 430, while the opposite end of the e-cigarette 410 (with respect to the longitudinal axis) is denoted as the tip end 424. The end of the cartridge 430 which is longitudinally opposite to the mouthpiece 435 is denoted by reference numeral 431, while the end of the control unit 420 which is longitudinally opposite to the tip end 424 is denoted by reference numeral 421. The cartridge 430 is able to engage with and disengage from the control unit 420 by movement along the longitudinal axis LA. More particularly, the end 431 of the cartridge 430 is able to engage with, and disengage from, the end of the control unit 421. Accordingly, ends 421 and 431 will be referred to as the control unit engagement end and the cartridge engagement end, respectively. The control unit 420 includes a battery 411 and a circuit board 415 to provide control functionality for the e-cigarette 410, e.g. by provision of a controller, processor, ASIC or similar form of control chip. The battery 411 is typically cylindrical in shape, and has a central axis that lies along, or at least close to, the longitudinal axis LA of the e-cigarette 410. In FIG. 4, the circuit board 415 is shown longitudinally spaced from the battery 411, in the opposite direction to the cartridge 430. However, the skilled person will be aware of various other locations for the circuit board 415, for example, it may be at the opposite end of the battery 411. A further possibility is that the circuit board 415 lies along the side of the battery 411—for example, with the e-cigarette 410 having a rectangular cross-section, the circuit board 415 located adjacent one outer wall of the e-cigarette 410, and the battery 411 then slightly offset towards the opposite outer wall of the e-cigarette 410. Note also that the functionality provided by the circuit board 415 (as described in more detail below) may be split across multiple circuit boards and/or across devices which are not mounted to a PCB, and these additional devices and/or PCBs can be located as appropriate within the e-cigarette 410. The battery or cell 411 is generally re-chargeable, and one or more re-charging mechanisms may be supported. For example, a charging connection (not shown in FIG. 4) may be provided at the tip end 424, and/or the engagement end 421, and/or along the side of the e-cigarette 410. Moreover, the e-cigarette 410 may support induction re-charging of battery 411, in addition to (or instead of) re-charging via one or more re-charging connections or sockets. The control unit 420 includes a tube portion 440, which extends along the longitudinal axis LA away from the engagement end 421 of the control unit 420. The tube portion 440 is defined on the outside by outer wall 442, which may generally be part of the overall outer wall or housing of the control unit 420, and on the inside by inner wall 424. A cavity 426 is formed by inner wall 424 of the tube portion 440 and the engagement end 421 of the control unit 420. This cavity 426 is able to receive and accommodate at least part of a cartridge 430 as it engages with the control unit 420 (as shown in the top drawing of FIG. 4). The inner wall 424 and the outer wall 442 of the tube portion 440 define an annular space which is formed around the longitudinal axis LA. A (drive or work) coil 450 is located within this annular space, with the central axis of the coil 450 being substantially aligned with the longitudinal axis LA of the e-cigarette 410. The coil 450 is electrically connected to the battery 411 and circuit board 415, which provide power and control to the coil 450, so that in operation, the coil 450 is able to provide induction heating to the cartridge 430. The cartridge 430 includes a reservoir 470 containing liquid formulation (typically including nicotine). The reservoir 470 comprises a substantially annular region of the cartridge 430, formed between an outer wall 476 of the cartridge 430, and an inner tube or wall 472 of the cartridge 430, both of which are substantially aligned with the longitudinal axis LA of the e-cigarette 410. The liquid formulation may be held free within the reservoir 470, or alternatively the reservoir 470 may incorporated in some structure or material, e.g. sponge, to help retain the liquid within the reservoir 470. The outer wall 476 has a portion 476A of reduced cross-section. This allows this portion 476A of the cartridge 430 to be received into the cavity 426 in the control unit 420 in order to engage the cartridge 430 with the control unit 420. The remainder of the outer wall 476 has a greater cross-section in order to provide increased space within the reservoir 470, and also to provide a continuous outer surface for the e-cigarette 410—i.e. cartridge wall 476 is substantially flush with the outer wall 442 of the tube portion 440 of the control unit 420. However, it will be appreciated that other implementations of the e-cigarette 410 may have a more complex/structured outer surface (compared with the smooth outer surface shown in FIG. 4). The inside of the inner tube 472 defines a passageway 461 which extends, in a direction of airflow, from air inlet 461A (located at the end 431 of the cartridge 430 that engages the control unit 420) through to air outlet 461B, which is provided by the mouthpiece 435. Located within the central passageway 461, and hence within the airflow through the cartridge 430, are heater 455 and wick 454. As can be seen in FIG. 4, the heater 455 is located approximately in the center of the drive coil 450. In particular, the location of the heater 455 along the longitudinal axis LA can be controlled by having the step at the start of the portion 476A of reduced cross-section for the cartridge 430 abut against the end (nearest the mouthpiece 435) of the tube portion 440 of the control unit 420 (as shown in the top diagram of FIG. 4). The heater 455 is made of a metallic material so as to permit use as a susceptor (or workpiece) in an induction heating assembly. More particularly, the induction heating assembly comprises the drive (work) coil 450, which produces a magnetic field having high frequency variations (when suitably powered and controlled by the battery 411 and controller on PCB 415). This magnetic field is strongest in the center of the coil 450, i.e. within cavity 426, where the heater 455 is located. The changing magnetic field induces eddy currents in the conductive heater 455, thereby causing resistive heating within the heater element 455. Note that the high frequency of the variations in magnetic field causes the eddy currents to be confined to the surface of the heater element 455 (via the skin effect), thereby increasing the effective resistance of the heater element 455, and hence the resulting heating effect. Furthermore, the heater element 455 is generally selected to be a magnetic material having a high permeability, such as (ferrous) steel (rather than just a conductive material). In this case, the resistive losses due to eddy currents are supplemented by magnetic hysteresis losses (caused by repeated flipping of magnetic domains) to provide more efficient transfer of power from the drive coil 450 to the heater element 455. The heater 455 is at least partly surrounded by wick 454. Wick 454 serves to transport liquid from the reservoir 470 onto the heater 455 for vaporization. The wick 454 may be made of any suitable material, for example, a heat-resistant, fibrous material and typically extends from the passageway 461 through holes in the inner tube 472 to gain access into the reservoir 470. The wick 454 is arranged to supply liquid to the heater 455 in a controlled manner, in that the wick 454 prevents the liquid leaking freely from the reservoir 470 into passageway 461 (this liquid retention may also be assisted by having a suitable material within the reservoir 470 itself). Instead, the wick 454 retains the liquid within the reservoir 470, and on the wick 454 itself, until the heater 455 is activated, whereupon the liquid held by the wick 454 is vaporized into the airflow, and hence travels along passageway 461 for exit via mouthpiece 435. The wick 454 then draws further liquid into itself from the reservoir 470, and the process repeats with subsequent vaporizations (and inhalations) until the cartridge 430 is depleted. Although the wick 454 is shown in FIG. 4 as separate from (albeit encompassing) the heater element 455, in some implementations, the heater element 455 and wick 454 may be combined together into a single component, such as a heating element 455 made of a porous, fibrous steel material which can also act as a wick 454 (as well as a heater). In addition, although the wick 454 is shown in FIG. 4 as supporting the heater element 455, in other embodiments, the heater element 455 may be provided with separate supports, for example, by being mounted to the inside of tube 472 (instead of or in addition to being supported by the heater element 455). The heater 455 may be substantially planar, and perpendicular to the central axis of the coil 450 and the longitudinal axis LA of the e-cigarette, since induction primarily occurs in this plane. Although FIG. 4 shows the heater 455 and wick 454 extending across the full diameter of the inner tube 472, typically the heater 455 and wick 454 will not cover the whole cross-section of the air passage-way 461. Instead, space is typically provided to allow air to flow through the inner tube 472 from inlet 461A and around heater 455 and wick 454 to pick up the vapor produced by the heater 455. For example, when viewed along the longitudinal axis LA, the heater 455 and wick 454 may have an “O” configuration with a central hole (not shown in FIG. 4) to allow for airflow along the passageway 461. Many other configurations are possible, such as the heater 455 having a “Y” or “X” configuration. (Note that in such implementations, the arms of the “Y” or “X” would be relatively broad to provide better induction). Although FIG. 4 shows the engagement end 431 of the cartridge 430 as covering the air inlet 461A, this end of the cartomizer 30 may be provided with one or more holes (not shown in FIG. 4) to allow the desired air intake to be drawn into passageway 461. Note also that in the configuration shown in FIG. 4, there is a slight gap 422 between the engagement end 431 of the cartridge 430 and the corresponding engagement end 421 of the control unit 420. Air can be drawn from this gap 422 through air inlet 461A. The e-cigarette 410 may provide one or more routes to allow air to initially enter the gap 422. For example, there may be sufficient spacing between the outer wall 476A of the cartridge 430 and the inner wall 444 of tube portion 440 to allow air to travel into gap 422. Such spacing may arise naturally if the cartridge 430 is not a tight fit into the cavity 426. Alternatively one or more air channels may be provided as slight grooves along one or both of these walls 476A, 444 to support this airflow. Another possibility is for the housing of the control unit 420 to be provided with one or more holes, firstly to allow air to be drawn into the control unit 420, and then to pass from the control unit 420 into gap 422. For example, the holes for air intake into the control unit 420 might be positioned as indicated in FIG. 4 by arrows 428A and 428B, and engagement end 421 might be provided with one or more holes (not shown in FIG. 4) for the air to pass out from the control unit 420 into gap 422 (and from there into the cartridge 430). In other implementations, gap 422 may be omitted, and the airflow may, for example, pass directly from the control unit 420 through the air inlet 461A into the cartridge 430. The e-cigarette 410 may be provided with one or more activation mechanisms for the induction heater assembly, i.e. to trigger operation of the drive coil 450 to heat the heating element 455. One possible activation mechanism is to provide a button 429 on the control unit 420, which a user may press to active the heater 455. This button 429 may be a mechanical device, a touch sensitive pad, a sliding control, etc. The heater 455 may stay activated for as long as the user continues to press or otherwise positively actuate the button 429, subject to a maximum activation time appropriate to a single puff of the e-cigarette 410 (typically a few seconds). If this maximum activation time is reached, the controller may automatically de-activate the induction heater 455 to prevent over-heating. The controller may also enforce a minimum interval (again, typically for a few seconds) between successive activations. The induction heater assembly may also be activated by airflow caused by a user inhalation. In particular, the control unit 420 may be provided with an airflow sensor for detecting an airflow (or pressure drop) caused by an inhalation. The airflow sensor is then able to notify the controller of this detection, and the induction heater 455 is activated accordingly. The induction heater 455 may remain activated for as long as the airflow continues to be detected, subject again to a maximum activation time as above (and typically also a minimum interval between puffs). Airflow actuation of the heater 455 may be used instead of providing button 429 (which could therefore be omitted), or alternatively the e-cigarette 410 may require dual activation in order to operate—i.e. both the detection of airflow and the pressing of button 429. This requirement for dual activation can help to provide a safeguard against unintended activation of the e-cigarette 410. It will be appreciated that the use of an airflow sensor generally involves an airflow passing through the control unit 420 upon inhalation, which is amenable to detection (even if this airflow only provides part of the airflow that the user ultimately inhales). If no such airflow passes through the control unit 420 upon inhalation, then button 429 may be used for activation, although it might also be possible to provide an airflow sensor to detect an airflow passing across a surface of (rather than through) the control unit 420. There are various ways in which the cartridge 430 may be retained within the control unit 420. For example, the inner wall 444 of the tube portion 440 of the control unit 420 and the outer wall of reduced cross-section 476A may each be provided with a screw thread (not shown in FIG. 4) for mutual engagement. Other forms of mechanical engagement, such as a snap fit or a latching mechanism (perhaps with a release button or similar) may also be used. Furthermore, the control unit 420 may be provided with additional components to provide a fastening mechanism, such as described below. In general terms, the attachment of the cartridge 430 to the control unit 420 for the e-cigarette 410 of FIG. 4 is simpler than in the case of the e-cigarette 10 shown in FIGS. 1-3. In particular, the use of induction heating for e-cigarette 410 allows the connection between the cartridge 430 and the control unit 420 to be mechanical only, rather than also having to provide an electrical connection with wiring to a resistive heater. Consequently, the mechanical connection may be implemented, if so desired, by using an appropriate plastic molding for the housing of the cartridge 430 and the control unit 420; in contrast, in the e-cigarette 10 of FIGS. 1-3, the housings of the cartomizer 30 and the control unit 20 have to be somehow bonded to a metal connector. Furthermore, the connector of the e-cigarette 10 of FIGS. 1-3 has to be made in a relatively precise manner to ensure a reliable, low contact resistance, electrical connection between the control unit 20 and the cartomizer 30. In contrast, the manufacturing tolerances for the purely mechanical connection between the cartridge 430 and the control unit 420 of e-cigarette 410 are generally greater. These factors all help to simplify the production of the cartridge 430 and thereby to reduce the cost of this disposable (consumable) component. Furthermore, conventional resistive heating often utilizes a metallic heating coil surrounding a fibrous wick, however, it is relatively difficult to automate the manufacture of such a structure. In contrast, an inductive heating element 455 is typically based on some form of metallic disk (or other substantially planar component), which is an easier structure to integrate into an automated manufacturing process. This again helps to reduce the cost of production for the disposable cartridge 430. Another benefit of inductive heating is that conventional e-cigarettes may use solder to bond power supply wires to a resistive heater coil. However, there is some concern that heat from the coil during operation of such an e-cigarette might volatize undesirable components from the solder, which would then be inhaled by a user. In contrast, there are no wires to bond to the inductive heater element 455, and hence the use of solder can be avoided within the cartridge 430. Also, a resistive heater coil as in a conventional e-cigarette generally comprises a wire of relatively small diameter (to increase the resistance and hence the heating effect). However, such a thin wire is relatively delicate and so may be susceptible to damage, whether through some mechanical mistreatment and/or potentially by local overheating and then melting. In contrast, a disk-shaped heater element 455 as used for induction heating is generally more robust against such damage. FIGS. 5 and 6 are schematic diagrams illustrating an e-cigarette 510 in accordance with some other embodiments of the invention. To avoid repetition, aspects of FIGS. 5 and 6 that are generally the same as shown in FIG. 4 will not be described again, except where relevant to explain the particular features of FIGS. 5 and 6. Note also that reference numbers having the same last two digits typically denote the same or similar (or otherwise corresponding) components across FIGS. 4 to 6 (with the first digit in the reference number corresponding to the Figure containing that reference number). In the e-cigarette 510 shown in FIG. 5, the control unit 520 is broadly similar to the control unit 420 shown in FIG. 4, however, the internal structure of the cartridge 530 is somewhat different from the internal structure of the cartridge 430 shown in FIG. 4. Thus rather than having a central airflow passage, as for e-cigarette 410 of FIG. 4, in which the liquid reservoir 470 surrounds the central airflow passage 461, in the e-cigarette 510 of FIG. 5, the air passageway 561 is offset from the central, longitudinal axis (LA) of the cartridge. In particular, the cartridge 530 contains an internal wall 572 that separates the internal space of the cartridge 530 into two portions. A first portion, defined by internal wall 572 and one part of external wall 576, provides a chamber for holding the reservoir 570 of liquid formulation. A second portion, defined by internal wall 572 and an opposing part of external wall 576, defines the air passage way 561 through the e-cigarette 510. In addition, the e-cigarette 510 does not have a wick, but rather relies upon a porous heater element 555 to act both as the heating element (susceptor) and the wick to control the flow of liquid out of the reservoir 570. The porous heater element may be made, for example, of a material formed from sintering or otherwise bonding together steel fibers. The heater element 555 is located at the end of the reservoir 570 opposite to the mouthpiece 535 of the cartridge 530, and may form some or all of the wall of the reservoir 570 chamber at this end. One face of the heater element 555 is in contact with the liquid in the reservoir 570, while the opposite face of the heater element 555 is exposed to an airflow region 538 which can be considered as part of air passageway 561. In particular, this airflow region 538 is located between the heater element 555 and the engagement end 531 of the cartridge 530. When a user inhales on mouthpiece 435, air is drawn into the region 538 through the engagement end 531 of the cartridge 530 from gap 522 (in a similar manner to that described for the e-cigarette 410 of FIG. 4). In response to the airflow (and/or in response to the user pressing button 529), the coil 550 is activated to supply power to heater 555, which therefore produces a vapor from the liquid in reservoir 570. This vapor is then drawn into the airflow caused by the inhalation, and travels along the passageway 561 (as indicated by the arrows) and out through mouthpiece 535. In the e-cigarette 610 shown in FIG. 6, the control unit 620 is broadly similar to the control unit 420 shown in FIG. 4, but now accommodates two (smaller) cartridges 630A and 630B. Each of these cartridges 630A and 630B is analogous in structure to the reduced cross-section portion 476A of the cartridge 420 in FIG. 4. However, the longitudinal extent of each of the cartridges 630A and 630B is only half that of the reduced cross-section portion 476A of the cartridge 420 in FIG. 4, thereby allowing two cartridges to be contained within the region in e-cigarette 610 corresponding to cavity 426 in e-cigarette 410, as shown in FIG. 4. In addition, the engagement end 621 of the control unit 620 may be provided, for example, with one or more struts or tabs (not shown in FIG. 6) that maintain cartridges 630A, 630B in the position shown in FIG. 6 (rather than closing the gap region 622). In the e-cigarette 610, the mouthpiece 635 may be regarded as part of the control unit 620. In particular, the mouthpiece 635 may be provided as a removable cap or lid, which can screw or clip onto and off the remainder of the control unit 620 (or any other appropriate fastening mechanism can be used). The mouthpiece cap 635 is removed from the rest of the control unit 635 to insert a new cartridge or to remove an old cartridge, and then fixed back onto the control unit for use of the e-cigarette 610. The operation of the individual cartridges 630A, 630B in e-cigarette 610 is similar to the operation of cartridge 430 in e-cigarette 410, in that each cartridge 630A, 630B includes a wick 654A, 654B extending into the respective reservoir 670A, 670B. In addition, each cartridge 630A, 630B includes a heating element 655A, 655B, accommodated in a respective wick 654A, 654B, and may be energized by a respective coil 650A, 650B provided in the control unit 620. The heaters 655A, 655B vaporize liquid into a common passageway 661 that passes through both cartridges 630A, 630B and out through mouthpiece 635. The different cartridges 630A, 630B may be used, for example, to provide different flavors for the e-cigarette 610. In addition, although the e-cigarette 610 is shown as accommodating two cartridges 630A, 630B, it will be appreciated that some devices may accommodate a larger number of cartridges. Furthermore, although cartridges 630A and 630B are the same size as one another, some devices may accommodate cartridges of differing size. For example, an e-cigarette may accommodate one larger cartridge having a nicotine-based liquid, and one or more small cartridges to provide flavor or other additives as desired. In some cases, the e-cigarette 610 may be able to accommodate (and operate with) a variable number of cartridges. For example, there may be a spring or other resilient device mounted on control unit engagement end 621, which tries to extend along the longitudinal axis towards the mouthpiece 635. If one of the cartridges shown in FIG. 6 is removed, this spring would therefore help to ensure that the remaining cartridge(s) would be held firmly against the mouthpiece for reliable operation. If an e-cigarette has multiple cartridges, one option is that these are all activated by a single coil that spans the longitudinal extent of all the cartridges. Alternatively, there may an individual coil 650A, 650B for each respective cartridge 630A, 630B, as illustrated in FIG. 6. A further possibility is that different portions of a single coil may be selectively energized to mimic (emulate) the presence of multiple coils. If an e-cigarette does have multiple coils for respective cartridges (whether really separate coils, or emulated by different sections of a single larger coil), then activation of the e-cigarette (such as by detecting airflow from an inhalation and/or by a user pressing a button) may energize all coils. The e-cigarettes 410, 510, 610 however support selective activation of the multiple coils, whereby a user can choose or specify which coil(s) to activate. For example, e-cigarette 610 may have a mode or user setting in which in response to an activation, only coil 650A is energized, but not coil 650B. This would then produce a vapor based on the liquid formulation in coil 650A, but not coil 650B. This would allow a user greater flexibility in the operation of e-cigarette 610, in terms of the vapor provided for any given inhalation (but without a user having to physically remove or insert different cartridges just for that particular inhalation). It will be appreciated that the various implementations of e-cigarette 410, 510 and 610 shown in FIGS. 4-6 are provided as examples only, and are not intended to be exhaustive. For example, the cartridge design shown in FIG. 5 might be incorporated into a multiple cartridge device such as shown in FIG. 6. The skilled person will be aware of many other variations that can be achieved, for example, by mixing and matching different features from different implementations, and more generally by adding, replacing and/or removing features as appropriate. FIG. 7 is a schematic diagram of the main electronic components of the e-cigarettes 410, 510, 610 of FIGS. 4-6 in accordance with some embodiments of the invention. With the exception of the heater element 455, which is located in the cartridge 430, the remaining elements are located in the control unit 420. It will be appreciated that since the control unit 420 is a re-usable device (in contrast to the cartridge 430 which is a disposable or consumable), it is acceptable to incur one-off costs in relation to production of the control unit which would not be acceptable as repeat costs in relation to the production of the cartridge. The components of the control unit 420 may be mounted on circuit board 415, or may be separately accommodated in the control unit 420 to operate in conjunction with the circuit board 415 (if provided), but without being physically mounted on the circuit board 415 itself. As shown in FIG. 7, the control unit 420 includes a re-chargeable battery 411, which is linked to a re-charge connector or socket 725, such as a micro-USB interface. This connector 725 supports re-charging of battery 411. Alternatively, or additionally, the control unit 420 may also support re-charging of battery 411 by a wireless connection (such as by induction charging). The control unit 420 further includes a controller 715 (such as a processor or application specific integrated circuit, ASIC), which is linked to a pressure or airflow sensor 716. The controller 715 may activate the induction heating, as discussed in more detail below, in response to the sensor 716 detecting an airflow. In addition, the control unit 420 further includes a button 429, which may also be used to activate the induction heating, as described above. FIG. 7 also shows a comms/user interface 718 for the e-cigarette. This may comprise one or more facilities according to the particular implementation. For example, the user interface 718 may include one or more lights and/or a speaker to provide output to the user, for example to indicate a malfunction, battery charge status, etc. The interface 718 may also support wireless communications, such as Bluetooth or near field communications (NFC), with an external device, such as a smartphone, laptop, computer, notebook, tablet, etc. The e-cigarette may utilize this comms interface 718 to output information such as device status, usage statistics, etc., to the external device, for ready access by a user. The comms interface 718 may also be utilized to allow the e-cigarette to receive instructions, such as configuration settings entered by the user into the external device. For example, the user interface 718 and controller 715 may be utilized to instruct the e-cigarette to selectively activate different coils 650A, 650B (or portions thereof), as described above. In some cases, the comms interface 718 may use the work coil 450 to act as an antenna for wireless communications. The controller 715 may be implemented using one or more chips as appropriate. The operations of the controller 715 are generally controlled at least in part by software programs running on the controller 715. Such software programs may be stored in non-volatile memory, such as ROM, which can be integrated into the controller 715 itself, or provided as a separate component (not shown). The controller 715 may access the ROM to load and execute individual software programs as and when required. The controller 715 controls the inductive heating of the e-cigarette by determining when the device is or is not properly activated—for example, whether an inhalation has been detected, and whether the maximum time period for an inhalation has not yet been exceeded. If the controller 715 determines that the e-cigarette is to be activated for vaping, the controller 715 arranges for the battery 411 to supply power to the inverter 712. The inverter 712 is configured to convert the DC output from the battery 411 into an alternating current signal, typically of relatively high frequency—e.g. 1 MHz (although other frequencies, such as 5 kHz, 20 kHz, 80 KHz, or 300 kHz, or any range defined by two such values, may be used instead). This AC signal is then passed from the inverter to the work coil 450, via suitable impedance matching (not shown in FIG. 7) if so required. The work coil 450 may be integrated into some form of resonant circuit, such as by combining in parallel with a capacitor (not shown in FIG. 7), with the output of the inverter 712 tuned to the resonant frequency of this resonant circuit. This resonance causes a relatively high current to be generated in work coil 450, which in turn produces a relatively high magnetic field in heater element 455, thereby causing rapid and effective heating of the heater element 455 to produce the desired vapor or aerosol output. FIG. 7A illustrates part of the control electronics for an e-cigarette 610 having multiple coils in accordance with some implementations (while omitting for clarity aspects of the control electronics not directly related to the multiple coils). FIG. 7A shows a power source 782A (typically corresponding to the battery 411 and inverter 712 of FIG. 7), a switch configuration 781A, and the two work coils 650A, 650B, each associated with a respective heater element 655A, 655B as shown in FIG. 6 (but not included in FIG. 7A). The switch configuration 781A has three outputs denoted A, B and C in FIG. 7A. It is also assumed that there is a current path between the two work coils 650A, 650B. In order to operate the induction heating assembly, two out of three of these outputs A, B, C are closed (to permit current flow), while the remaining output stays open (to prevent current flow). Closing outputs A and C activates both coils, and hence both heater elements 655A, 655B; closing A and B selectively activates just work coil 650A; and closing B and C activates just work coil 650B. Although it is possible to treat work coils 650A and 650B just as a single overall coil (which is either on or off together), the ability to selectively energize either or both of work coils 650A and 650B, such as provided by the implementation of FIG. 7, has a number of advantages, including: a) choosing the vapor components (e.g. flavorants) for a given puff. Thus activating just work coil 650A produces vapor just from reservoir 670A; activating just work coil 650B produces vapor just from reservoir 670B; and activating both work coils 650A, 650B produces a combination of vapors from both reservoirs 670A, 670B. b) controlling the amount of vapor for a given puff. For example, if reservoir 670A and reservoir 670B in fact contain the same liquid, then activating both work coils 650A, 650B can be used to produce a stronger (higher vapor level) puff compared to activating just one work coil by itself. c) prolonging battery (charge) lifetime. As already discussed, it may be possible to operate the e-cigarette 610 of FIG. 6 when it contains just a single cartridge, e.g. 630B (rather than also including cartridge 630A). In this case, it is more efficient just to energize the work coil 650B corresponding to cartridge 630B, which is then used to vaporize liquid from reservoir 670B. In contrast, if the work coil 650A corresponding to the (missing) cartridge 630A is not energized (because this cartridge and the associated heater element 650A are missing from e-cigarette 610), then this saves power consumption without reducing vapor output. Although the e-cigarette 610 of FIG. 6 has a separate heater element 655A, 655B for each respective work coil 650A, 650B, in some implementations, different work coils may energize different portions of a single (larger) workpiece or susceptor. Accordingly, in such an e-cigarette 610, the different heater elements 655A, 655B may represent different portions of the larger susceptor, which is shared across different work coils. Additionally (or alternatively), the multiple work coils 650A, 650B may represent different portions of a single overall drive coil, individual portions of which can be selectively energized, as discussed above in relation to FIG. 7A. FIG. 7B shows another implementation for supporting selectivity across multiple work coils 650A, 650B. Thus in FIG. 7B, it is assumed that the work coils 650A, 650B are not electrically connected to one another, but rather each work coil 650A, 650B is individually (separately) linked to the power source 782B via a pair of independent connections through switch configuration 781B. In particular, work coil 650A is linked to power source 782B via switch connections A1 and A2, and work coil 650B is linked to power source 782B via switch connections B1 and B2. This configuration of FIG. 7B offers similar advantages to those discussed above in relation to FIG. 7A. In addition, the architecture of FIG. 7B may also be readily scaled up to work with more than two work coils. FIG. 7C shows another implementation for supporting selectivity across multiple work coils, in this case three work coils denoted 650A, 650B and 650C. Each work coil 650A, 650B, 650C is directly connected to a respect power supply 782C1, 782C2 and 782C3. The configuration of FIG. 7 may support the selective energization of any single work coil, 650A, 650B, 650C, or of any pair of work coils at the same time, or of all three work coils 650A, 650B, 650C at the same time. In the configuration of FIG. 7C, at least some portions of the power supply 782 may be replicated for each of the different work coils 650. For example, each power supply 782C1, 782C2, 782C3 may include its own inverter, but they may share a single, ultimate power source, such as battery 411. In this case, the battery 411 may be connected to the inverters via a switch configuration analogous to that shown in FIG. 7B (but for DC rather than AC current). Alternatively, each respective power line from a power supply 782 to a work coil 650 may be provided with its own individual switch, which can be closed to activate the work coil (or opened to prevent such activation). In this arrangement, the collection of these individual switches across the different lines can be regarded as another form of switch configuration. There are various ways in which the switching of FIGS. 7A-7C may be managed or controlled. In some cases, the user may operate a mechanical or physical switch that directly sets the switch configuration. For example, e-cigarette 610 may include a switch (not shown in FIG. 6) on the outer housing, whereby cartridge 630A can be activated in one setting, and cartridge 630B can be activated in another setting. A further setting of the switch may allow activation of both cartridges 630A, 630B together. Alternatively, the control unit 610 may have a separate button associated with each cartridge 630A, 630B, and the user holds down the button for the desired cartridge (or potentially both buttons if both cartridges should be activated). Another possibility is that a button or other input device on the e-cigarette may be used to select a stronger puff (and result in switching on both or all work coils). Such a button may also be used to select the addition of a flavor, and the switching might operate a work coil associated with that flavor—typically in addition to a work coil for the base liquid containing nicotine. The skilled person will be aware of other possible implementations of such switching. In some e-cigarettes, rather than direct (e.g. mechanical or physical) control of the switch configuration, the user may set the switch configuration via the comms/user interface 718 shown in FIG. 7 (or any other similar facility). For example, this interface 718 may allow a user to specify the use of different flavors or cartridges (and/or different strength levels), and the controller 715 can then set the switch configuration 781 according to this user input. A further possibility is that the switch configuration may be set automatically. For example, e-cigarette 610 may prevent work coil 650A from being activated if a cartridge is not present in the illustrated location of cartridge 630A. In other words, if no such cartridge is present, then the work coil 650A may not be activated (thereby saving power, etc). There are various mechanisms available for detecting whether or not a cartridge is present. For example, the control unit 620 may be provided with a switch which is mechanically operated by inserting a cartridge into the relevant position. If there is no cartridge in position, then the switch is set so that the corresponding work coil is not powered. Another approach would be for the control unit to have some optical or electrical facility for detecting whether or not a cartridge is inserted into a given position. Note that in some devices, once a cartridge has been detected as in position, then the corresponding work coil is always available for activation—e.g. it is always activated in response to a puff (inhalation) detection. In other devices that support both automatic and user-controlled switch configuration, even if a cartridge has been detected as in position, a user setting (or such-like, as discussed above) may then determine whether or not the cartridge is available for activation on any given puff. Although the control electronics of FIGS. 7A-7C have been described in connection with the use of multiple cartridges, such as shown in FIG. 6, they may also be utilized in respect of a single cartridge that has multiple heater elements. In other words, the control electronics is able to selectively energize one or more of these multiple heater elements within the single cartridge. Such an approach may still offer the benefits discussed above. For example, if the cartridge contains multiple heater elements, but just a single, shared reservoir, or multiple heater elements, each with its own respective reservoir, but all reservoirs containing the same liquid, then energizing more or fewer heater elements provides a way for a user to increase or decrease the amount of vapor provided with a single puff. Similarly, if a single cartridge contains multiple heater elements, each with its own respective reservoir containing a particular liquid, then energizing different heater elements (or combinations thereof) provides a way for a user to selectively consume vapors for different liquids (or combinations thereof). In some e-cigarettes, the various work coils and their respective heater elements (whether implemented as separate work coils and/or heater elements, or as portions of a larger drive coil and/or susceptor) may all be substantially the same as one another, to provide a homogeneous configuration. Alternatively, a heterogeneous configuration may be utilized. For example, with reference to e-cigarette 610 as shown in FIG. 6, one cartridge 630A may be arranged to heat to a lower temperature than the other cartridge 630B, and/or to provide a lower output of vapor (by providing less heating power). Thus if one cartridge 630A contains the main liquid formulation containing nicotine, while the other cartridge 630B contains a flavorant, it may be desirable for cartridge 630A to output more vapor than cartridge 630B. Also, the operating temperature of each heater element 655 may be arranged according to the liquid(s) to be vaporized. For example, the operating temperature should be high enough to vaporize the relevant liquid(s) of a particular cartridge, but typically not so high as to chemically break down (disassociate) such liquids. There are various ways of providing different operating characteristics (such as temperature) for different combinations of work coils and heater elements, and thereby produce a heterogeneous configuration as discussed above. For example, the physical parameters of the work coils and/or heater elements may be varied as appropriate—e.g. different sizes, geometry, materials, number of coil turns, etc. Additionally (or alternatively), the operating parameters of the work coils and/or heater elements may be varied, such as by having different AC frequencies and/or different supply currents for the work coils. The example embodiments described above have primarily focused on examples in which the heating element (inductive susceptor) has a relatively uniform response to the magnetic fields generated by the inductive heater drive coil in terms of how currents are induced in the heating element. That is to say, the heating element is relatively homogenous, thereby giving rise to relatively uniform inductive heating in the heating element, and consequently a broadly uniform temperature across the surface of the heating element surface. However, in accordance with some example embodiments of the disclosure, the heating element may instead be configured so that different regions of the heating element respond differently to the inductive heating provided by the drive coil in terms of how much heat is generated in different regions of the heating element when the drive coil is active. FIG. 8 represents, in highly schematic cross-section, an example aerosol provision system (electronic cigarette) 300 which incorporates a vaporizer 305 that comprises a heating element (susceptor) 310 embedded in a surrounding wicking material/matrix. The heating element 310 of the aerosol provision system 300 represented in FIG. 8 comprises regions of different susceptibility to inductive heating, but apart from this many aspects of the configuration of FIG. 8 are similar to, and will be understood from, the description of the various other configurations described herein. When the system 300 is in use and generating an aerosol, the surface of the heating element 310 in the regions of different susceptibility are heated to different temperatures by the induced current flows. Heating different regions of the heating element 310 to different temperatures can be desired in some implementations because different components of a source liquid formulation may aerosolize/vaporize at different temperatures. This means that providing a heating element (susceptor) with a range of different temperatures can help simultaneously aerosolize a range of different components in the source liquid. That is to say, different regions of the heating element can be heated to temperatures that are better suited to vaporizing different components of the liquid formulation. Thus, the aerosol provision system 300 comprises a control unit 302 and a cartridge 304 and may be generally based on any of the implementations described herein apart from having a heating element 310 with a spatially non-uniform response to inductive heating. The control unit 302 comprises a drive coil 306 in addition to a power supply and control circuitry (not shown in FIG. 8) for driving the drive coil 306 to generate magnetic fields for inductive heating as discussed herein. The cartridge 304 is received in a recess of the control unit 302 and comprises the vaporizer 305 comprising the heating element 310, a reservoir 312 containing a liquid formulation (source liquid) 314 from which the aerosol is to be generated by vaporization at the heating element 310, and a mouthpiece 308 through which aerosol may be inhaled when the system 300 is in use. The cartridge 304 has a wall configuration (generally shown with hatching in FIG. 8) that defines the reservoir 312 for the liquid formulation 314, supports the heating element 310, and defines an airflow path through the cartridge 304. Liquid formulation may be wicked from the reservoir 312 to the vicinity of the heating element 310 (more particular to the vicinity of a vaporizing surface of the heating element 310) for vaporization in accordance with any of the approaches described herein. The airflow path is arranged so that when a user inhales on the mouthpiece 308, air is drawn through an air inlet 316 in the body of the control unit 302, into the cartridge 304 and past the heating element 310, and out through the mouthpiece 308. Thus a portion of liquid formulation 314 vaporized by the heating element 310 becomes entrained in the airflow passing the heating element 310 and the resulting aerosol exits the system 300 through the mouthpiece 308 for inhalation by the user. An example airflow path is schematically represented in FIG. 8 by a sequence of arrows 318. However, it will be appreciated the exact configuration of the control unit 302 and the cartridge 304, for example in terms of how the airflow path through the system 300 is configured, whether the system 300 comprises a re-useable control unit 302 and replaceable cartridge 304 assembly, and whether the drive coil 306 and heating element 310 are provided as components of the same or different elements of the system 300, is not significant to the principles underlying the operation of a heating element 310 having a non-uniform induced current response (i.e. a different susceptibility to induced current flow from the drive coil 306 in different regions) as described herein. Thus, the aerosol provision system 300 schematically represented in FIG. 8 comprises in this example an inductive heating assembly comprising the heating element 310 in the cartridge 304 part of the system 300 and the drive coil 306 in the control unit 302 part of the system 300. In use (i.e. when generating aerosol) the drive coil 306 induces current flows in the heating element 310 in accordance with the principles of inductive heating such as discussed elsewhere herein. This heats the heating element 310 to generate an aerosol by vaporization of an aerosol precursor material (e.g. liquid formation 314) in the vicinity of a vaporizing surface the heating element 310 (i.e. a surface of the heating element 310 which is heated to a temperature sufficient to vaporize adjacent aerosol precursor material). The heating element 310 comprises regions of different susceptibility to induced current flow from the drive coil 306 such that areas of the vaporizing surface of the heating element 310 in the regions of different susceptibility are heated to different temperatures by the current flow induced by the drive coil 306. As noted above, this can help with simultaneously aerosolizing components of the liquid formulation which vaporize/aerosolize at different temperatures. There are a number of different ways in which the heating element 310 can be configured to provide regions with different responses to the inductive heating from the drive coil 306 (i.e. regions which undergo different amounts of heating/achieve different temperatures during use). FIGS. 9A and 9B schematically represent respective plan and cross-section views of a heating element 330 comprising regions of different susceptibility to induced current flow in accordance with one example implementation of an embodiment of the disclosure. That is to say, in one example implementation of the system schematically represented in FIG. 8, the heating element 310 has a configuration corresponding to the heating element 330 represented in FIGS. 9A and 9B. The cross-section view of FIG. 9B corresponds with the cross-section view of the heating element 310 represented in FIG. 8 (although rotated 90 degrees in the plane of the figure) and the plan view of FIG. 9A corresponds with a view of the heating element 330 along a direction that is parallel to the magnetic field created by the drive coil 306 (i.e. parallel to the longitudinal axis of the aerosol provision system 300). The cross-section of FIG. 9B is taken along a horizontal line in the middle of the representation of FIG. 9A. The heating element 330 has a generally planar form, which in this example is flat. More particularly, the heating element 330 in the example of FIGS. 9A and 9B is generally in the form of a flat circularly disc. The heating element 330 in this example is symmetric about the plane of FIG. 9A in that it appears the same whether viewed from above or below the plane of FIG. 9A. The characteristic scale of the heating element 330 may be chosen according to the specific implementation at hand, for example having regard to the overall scale of the aerosol provision system 300 in which the heating element 330 is implemented and the desired rate of aerosol generation. For example, in one particular implementation the heating element 330 may have a diameter of around 10 mm and a thickness of around 1 mm. In other examples the heating element 330 may have a diameter in the range 3 mm to 20 mm and a thickness of around 0.1 mm to 5 mm. The heating element 330 comprises a first region 331 and a second region 332 comprising materials having different electromagnetic characteristics, thereby providing regions of different susceptibility to induced current flow. The first region 331 is generally in the form of a circular disc forming the center of the heating element 330 and the second region 332 is generally in the form of a circular annulus surrounding the first region 331. The first and second regions may be bonded together or may be maintained in a press-fit arrangement. Alternatively, the first and second regions may not be attached to one another, but may be independently maintained in position, for example by virtue of both regions being embedded in a surrounding wadding/wicking material. In the particular example represented in FIGS. 9A and 9B, it is assumed the first and second regions 331, 332 comprise different compositions of steel having different susceptibilities to induced current flows. For example, the different regions may comprise different material selected from the group of copper, aluminum, zinc, brass, iron, tin, and steel, for example ANSI 304 steel. The particular materials in any given implementation may be chosen having regard to the differences in susceptibility to induced current flow which are appropriate for providing the desired temperature variations across the heating element 330 when in use. The response of a particular heating element 330 configuration may be modeled or empirically tested during a design phase to help provide a heating element configuration having the desired operational characteristics, for example in terms of the different temperatures achieved during normal use and the arrangement of the regions over which the different temperatures occur (e.g., in terms of size and placement). In this regard, the desired operational characteristics, e.g. in terms the desired range of temperatures, may themselves be determined through modeling or empirical testing having regard to the characteristic and composition of the liquid formulation in use and the desired aerosol characteristics. It will be appreciated the heating element 330 represented in FIGS. 9A and 9B is merely one example configuration for a heating element comprising different materials for providing different regions of susceptibility to induced current flow. In other examples, the heating element may comprise more than two regions of different materials. Furthermore, the particular spatial arrangement of the regions comprising different materials may be different from the generally concentric arrangement represented in FIGS. 9A and 9B. For example, in another implementation the first and second regions may comprise two halves (or other proportions) of the heating element, for example each region may have a generally planar semi-circle form. FIGS. 10A and 10B schematically represents respective plan and cross-section views of a heating element 340 comprising regions of different susceptibility to induced current flow in accordance with another example implementation of an embodiment of the disclosure. The orientations of these views correspond with those of FIGS. 9A and 9B discussed above. The heating element 340 may comprise, for example, ANSI 304 steel, and/or another suitable material (i.e. a material having sufficient inductive properties and resistance to the liquid formulation), such as such as copper, aluminum, zinc, brass, iron, tin, and other steels. The heating element 340 again has a generally planar form, although unlike the example of FIGS. 9A and 9B, the generally planar form of the heating element 340 is not flat. That is to say, the heating element 340 comprises undulations (ridges/corrugations) when viewed in cross-section (i.e. when viewed perpendicular to the largest surfaces of the heating element 340). These one or more undulation(s) may be formed, for example, by bending or stamping a flat template former for the heating element. Thus, the heating element 340 in the example of FIGS. 10A and 10B is generally in the form of a wavy circular disc which, in this particular example, comprises a single “wave”. That is to say, a characteristic wavelength scale of the undulation broadly corresponds with the diameter of the disc. However, in other implementations there may be a greater number of undulations across the surface of the heating element 340. Furthermore, the undulations may be provided in different configurations. For example, rather than going from one side of the heating element 340 to the other, the undulation(s) may be arranged concentrically, for example comprising a series of circular corrugations/ridges. The orientation of the heating element 340 relative to magnetic fields generated by the drive coil when the heating element is in use in an aerosol provision system are such that the magnetic fields will be generally perpendicular to the plane of FIG. 10A and generally aligned vertically within the plane of FIG. 10B, as schematically represented by magnetic field lines B. The field lines B are schematically directed upwards in FIG. 10B, but it will be appreciated the magnetic field direction will alternate between up and down (or up and off) for the orientation of FIG. 10B in accordance with the time-varying signal applied to the drive coil 306. Thus, the heating element 340 comprises locations where the plane of the heating element 340 presents different angles to the magnetic field generated by the drive coil 306. For example, referring in particular to FIG. 10B, the heating element 340 comprises a first region 341 in which the plane of the heating element 340 is generally perpendicular to the local magnetic field B and a second region 342 in which the plane of the heating element 340 is inclined with respect to the local magnetic field B. The degree of inclination in the second region 342 will depend on the geometry of the undulations in the heating element 340. In the example of FIG. 10B, the maximum inclination is on the order of around 45 degrees or so. Of course it will be appreciated there are other regions of the heating element 340 outside the first region 341 and the second region 342 which present still other angles of inclination to the magnetic field. The different regions of the heating element 340 oriented at different angles to the magnetic field created by the drive coil 306 provide regions of different susceptibility to induced current flow, and therefore different degrees of heating. This follows from the underlying physics of inductive heating whereby the orientation of a planar heating element to the induction magnetic field affects the degree of inductive heating. More particularly, regions in which the magnetic field is generally perpendicular to the plane of the heating element 340 will have a greater degree of susceptibility to induced currents than regions in which the magnetic field is inclined relative to the plane of the heating element 340. Thus, in the first region 341 the magnetic field is broadly perpendicular to the plane of the heating element 340 and so this region (which appears generally as a vertical stripe in the plan view of FIG. 10A) will be heated to a higher temperature than the second region 342 (which again appears generally as a vertical stripe in the plan view of FIG. 10A) where the magnetic field is more inclined relative to the plane of the heating element 340. The other regions of the heating element 340 will be heated according to the angle of inclination between the plane of the heating element 340 in these locations and the local magnetic field direction. The characteristic scale of the heating element 340 may again be chosen according to the specific implementation at hand, for example having regard to the overall scale of the aerosol provision system in which the heating element 340 is implemented and the desired rate of aerosol generation. For example, in one particular implementation the heating element 340 may have a diameter of around 10 mm and a thickness of around 1 mm. The undulations in the heating element 340 may be chosen to provide the heating element 340 with angles of inclination to the magnetic field from the drive coil 306 ranging from 90° (i.e. perpendicular) to around 10 degrees or so. The particular range of angles of inclination for different regions of the heating element 340 to the magnetic field may be chosen having regard to the differences in susceptibility to induced current flow which are appropriate for providing the desired temperature variations (profile) across the heating element 340 when in use. The response of a particular heating element configuration (e.g., in terms of how the undulation geometry affects the heating element temperature profile) may be modeled or empirically tested during a design phase to help provide a heating element configuration having the desired operational characteristics, for example in terms of the different temperatures achieved during normal use and the spatial arrangement of the regions over which the different temperatures occur (e.g., in terms of size and placement). FIGS. 11A and 11B schematically represents respective plan and cross-section views of a heating element 350 comprising regions of different susceptibility to induced current flow in accordance with another example implementation of an embodiment of the disclosure. The orientations of these views correspond with those of FIGS. 9A and 9B discussed above. The heating element 350 may comprise, for example, ANSI 304 steel, and/or another suitable material such as discussed above. The heating element 350 again has a generally planar form, which in this example is flat. More particularly, the heating element 350 in the example of FIGS. 11A and 11B is generally in the form of a flat circular disc having a plurality of openings therein. In this example the plurality of openings 354 comprise four square holes passing through the heating element 350. The openings 354 may be formed, for example, by stamping a flat template former for the heating element 350 with an appropriately configured punch. The openings 354 are defined by walls which disrupts the flow of induced current within the heating element 350, thereby creating regions of different current density. In this example the walls may be referred to as internal walls of the heating element 350 in that they are associated with opening/holes in the body of the susceptor (heating element). However, as discussed further below in relation to FIGS. 12A and 12B, in some other examples, or in addition, similar functionality can be provided by outer walls defining the periphery of a heating element 350. The characteristic scale of the heating element 350 may be chosen according to the specific implementation at hand, for example having regard to the overall scale of the aerosol provision system in which the heating element is implemented and the desired rate of aerosol generation. For example, in one particular implementation the heating element 350 may have a diameter of around 10 mm and a thickness of around 1 mm with the openings 354 having a characteristic size of around 2 mm. In other examples the heating element 330 may have a diameter in the range 3 mm to 20 mm and a thickness of around 0.1 mm to 5 mm, and the one or more openings 354 may have a characteristic size of around 10% to 30% of the diameter, but in some case may be smaller or larger. The drive coil 306 in the configuration of FIG. 8 will generate a time-varying magnetic field which is broadly perpendicular to the plane of the heating element 350 and so will generate electric fields to drive induced current flow in the heating element 350 which are generally azimuthal. Thus, in a circularly symmetric heating element, such as represented in FIG. 9A, the induced current densities will be broadly uniform at different azimuths around the heating element 350. However, for a heating element which comprises walls that disrupt the circular symmetry, such as the walls associated with the holes 354 in the heating element 350 of FIG. 11A, the current densities will not be broadly uniform at different azimuths, but will be disrupted, thereby leading to different current densities, hence different amounts of heating, in different regions of the heating element. Thus, the heating element 350 comprises locations which are more susceptible to induced current flow because current is diverted by walls into these locations leading to higher current densities. For example, referring in particular to FIG. 11A, the heating element 350 comprises a first region 351 adjacent one of the openings 354 and a second region 352 which is not adjacent one of the openings 354. In general, the current density in the first region 351 will be different from the current density in the second region 352 because the current flows in the vicinity of the first region 351 are diverted/disrupted by the adjacent opening 354. Of course it will be appreciated these are just two example regions identified for the purposes of explanation. The particular arrangement of openings 354 that provide the walls for disrupting otherwise azimuthal current flow may be chosen having regard to the differences in susceptibility to induced current flow across the heating element 350 which are appropriate for providing the desired temperature variations (profile) when in use. The response of a particular heating element configuration (e.g., in terms of how the openings affect the heating element temperature profile) may be modeled or empirically tested during a design phase to help provide a heating element configuration having the desired operational characteristics, for example in terms of the different temperatures achieved during normal use and the spatial arrangement of the regions over which the different temperatures occur (e.g., in terms of size and placement). FIGS. 12A and 12B schematically represents respective plan and cross-section views of a heating element 360 comprising regions of different susceptibility to induced current flow in accordance with yet another example implementation of an embodiment of the disclosure. The heating element 360 may again comprise, for example, ANSI 304 steel, and/or another suitable material such as discussed above. The orientations of these views correspond with those of FIGS. 9A and 9B discussed above. The heating element 360 again has a generally planar form. More particularly, the heating element 360 in the example of FIGS. 12A and 12B is generally in the form of a flat star-shaped disc, in this example a five-pointed star. The respective points of the star are defined by outer (peripheral) walls of the heating element 360 which are not azimuthal (i.e. the heating element 360 comprises walls extending in a direction which has a radial component). Because the peripheral walls of the heating element 360 are not parallel to the direction of electric fields created by the time-varying magnetic field from the drive coil 306, they act to disrupt current flows in the heating element 360 in broadly the same manner as discussed above for the walls associated with the openings 354 of the heating element 350 shown in FIGS. 11A and 11B. The characteristic scale of the heating element 360 may be chosen according to the specific implementation at hand, for example having regard to the overall scale of the aerosol provision system in which the heating element 360 is implemented and the desired rate of aerosol generation. For example, in one particular implementation the heating element 360 may comprise five uniformly spaced points extending from 3 mm to 5 mm from a center of the heating element 360 (i.e. the respective points of the star may have a radial extent of around 2 mm). In other examples the protrusions (i.e. the points of the star in the example of FIG. 12A) could have different sizes, for example they may extend over a range from 1 mm to 20 mm. As discussed above, the drive coil 306 in the configuration of FIG. 8 will generate a time-varying magnetic field which is broadly perpendicular to the plane of a the heating element 360 and so will generate electric fields to drive induced current flows in the heating element 360 which are generally azimuthal. Thus, for a heating element 360 which comprises walls that disrupt the circular symmetry, such as the outer walls associated with the points of the star-shaped pattern for the heating element 360 of FIG. 12A, or a more simple shape, such as a square or rectangle, the current densities will not be uniform at different azimuths, but will be disrupted, thereby leading to different amounts of heating, and hence temperatures, in different regions of the heating element 360. Thus, the heating element 360 comprises locations which have different induced currents as current flows are disrupted by the walls. Thus, referring in particular to FIG. 12A, the heating element 360 comprises a first region 361 adjacent one of the outer walls and a second region 362 which is not adjacent one of the outer walls. Of course it will be appreciated these are just two example regions identified for the purposes of explanation. In general, the current density in the first region 361 will be different from the current density in the second region 362 because the current flows in the vicinity of the first region 361 are diverted/disrupted by the adjacent non-azimuthal wall of the heating element. In a manner similar to that described for the other example heating element configurations having locations with differing susceptibility to induced current flows (i.e. regions with different responses to the drive coil in terms of the amount of induced heating), the particular arrangement for the heating element's peripheral walls for disrupting the otherwise azimuthal current flow may be chosen having regard to the differences in susceptibility which are appropriate for providing the desired temperature variations (profile) when in use. The response of a particular heating element configuration (e.g., in terms of how the non-azimuthal walls affect the heating element temperature profile) may be modeled or empirically tested during a design phase to help provide a heating element configuration having the desired operational characteristics, for example in terms of the different temperatures achieved during normal use and the spatial arrangement of the regions over which the different temperatures occur (e.g., in terms of size and placement). It will be appreciated broadly the same principle underlies the operation of the heating element 350 represented in FIGS. 11A and 11B and the heating element 360 represented in FIGS. 12A and 12B in that the locations with different susceptibilities to induced currents are provided by non-azimuthal edges/walls to disrupt current flows. The difference between these two examples is in whether the walls are inner walls (i.e. associated with holes in the heating element) or outer walls (i.e. associated with a periphery of the heating element). It will further be appreciated the specific wall configurations represented in FIGS. 11A and 12A are provided by way of example only, and there are many other different configurations which provide walls that disrupt current flows. For example, rather than a star-shaped configuration such as represented in FIG. 12A, in another example the sector may comprise slot openings, e.g., extended inwardly from a periphery or as holes in the heating element. More generally, what is significant is that the heating element is provided with walls which are not parallel to the direction of electric fields created by the time-varying magnetic field. Thus, for a configuration in which the drive coil is configured to generate a broadly uniform and parallel magnetic field (e.g. for a solenoid-like drive coil), the drive coil extends along a coil axis about which the magnetic field generated by the drive coil is generally circularly symmetric, but the heating element has a shape which is not circularly symmetric about the coil axis (in the sense of not being symmetric under all rotations, although it may be symmetric under some rotations). Thus, there has been described above a number of different ways in which a heating element in an inductive heating assembly of an aerosol provision system can be provided with regions of different susceptibility to induced current flows, and hence different degrees of heating, to provide a range of different temperatures across the heating element. As noted above, this can be desired in some scenarios to facilitate simultaneous vaporization of different components of a liquid formulation to be vaporized having different vaporization temperatures/characteristics. It will be appreciated there are many variations to the approaches discussed above and many other ways of providing locations with different susceptibility to induced current flows. For example, in some implementations the heating element may comprise regions having different electrical resistivity in order to provide different degrees of heating in the different regions. This may be provided by a heating element comprising different materials having different electrical resistivities. In another implementation, the heating element may comprise a material having different physical characteristics in different regions. For example, there may be regions of the heating element having different thicknesses in a direction parallel to the magnetic fields generated by the drive coil and/or regions of the heating element having different porosity. In some examples, the heating element itself may be uniform, but the drive coil may be configured so the magnetic field generated when in use varies across the heating element such that different regions of the heating element in effect have different susceptibility to induced current flow because the magnetic field generated at the heating element when the drive coil is in use has different strengths in different locations. It will further be appreciated that in accordance with various embodiments of the disclosure, a heating element having characteristics arranged to provide regions of different susceptibility to induced currents can be provided in conjunction with other vaporizer characteristics described herein, for example the heating element having different regions of susceptibility to induced currents may comprise a porous material arranged to wick liquid formulation from a source of liquid formulation by capillary action to replace liquid formulation vaporized by the heating element when in use and/or may be provided adjacent to a wicking element arranged to wick liquid formulation from a source of liquid formulation by capillary action to replace liquid formulation vaporized by the heating element when in use. It will furthermore be appreciated that a heating element comprising regions having different susceptibility to induced currents is not restricted to use in aerosol provision systems of the kind described herein, but can be used more generally in an inductive heat assembly of any aerosol provision system. Accordingly, although various example embodiments described herein have focused on a two-part aerosol provision system comprising a re-useable control unit 302 and a replaceable cartridge 304, in other examples, a heating element having regions of different susceptibility may be used in an aerosol provision system that does not include a replaceable cartridge, but is a disposable system or a refillable system. Similarly, although the various example embodiments described herein have focused on an aerosol provision system in which the drive coil is provided in the reusable control unit 302 and the heating element is provided in the replaceable cartridge 304, in other implementations the drive coil may also be provided in the replaceable cartridge, with the control unit and cartridge having an appropriate electrical interface for coupling power to the drive coil. It will further be appreciated that in some example implementations a heating element may incorporate features from more than one of the heating elements represented in FIGS. 9 to 12. For example, a heating element may comprise different materials (e.g. as discussed above with reference to FIGS. 9A and 9B) as well as undulations (e.g. as discussed above with reference to FIGS. 10A and 10B), and so on for other combinations of features. It will further be appreciated that whilst some the above-described embodiments of a susceptor (heating element) having regions that respond differently to an inductive heater drive coil have focused on an aerosol precursor material comprising a liquid formulation, heating elements in accordance with the principles described herein may also be used in association with other forms of aerosol precursor material, for example solid materials and gel materials. Thus there has also been described an inductive heating assembly for generating an aerosol from an aerosol precursor material in an aerosol provision system, the inductive heating assembly comprising: a heating element; and a drive coil arranged to induce current flow in the heating element to heat the heating element and vaporize aerosol precursor material in proximity with a surface of the heating element, and wherein the heating element comprises regions of different susceptibility to induced current flow from the drive coil, such that when in use the surface of the heating element in the regions of different susceptibility are heated to different temperatures by the current flow induced by the drive coil. FIG. 13 schematically represents in cross-section a vaporizer assembly 500 for use in an aerosol provision system, for example of the type described above, in accordance with certain embodiments of the present disclosure. The vaporizer assembly 500 comprises a planar vaporizer 505 and a reservoir 502 of source liquid 504. The vaporizer 505 in this example comprises an inductive heating element 506 the form of a planar disk comprising ANSI 304 steel or other suitable material such as discussed above, surrounded by a wicking/wadding matrix 508 comprising a non-conducting fibrous material, for example a woven fiberglass material. The source liquid 504 may comprise an E-liquid formulation of the kind commonly used in electronic cigarettes, for example comprising 0-5% nicotine dissolved in a solvent comprising glycerol, water, and/or propylene glycol. The source liquid may also comprise flavorings. The reservoir 502 in this example comprises a chamber of free source liquid, but in other examples the reservoir 502 may comprise a porous matrix or any other structure for retaining the source liquid until such time that it is required to be delivered to the aerosol generator/vaporizer. The vaporizer assembly 500 of FIG. 13 may, for example, be part of a replaceable cartridge for an aerosol provision system of the kinds discussed herein. For example, the vaporizer assembly 500 represented in FIG. 13 may correspond with the vaporizer 305 and reservoir 312 of source liquid 314 represented in the example aerosol provision system 300 of FIG. 8. Thus, the vaporizer assembly 500 is arranged in a cartridge of an electronic cigarette so that when a user inhales on the cartridge/electronic cigarette, air is drawn through the cartridge and over a vaporizing surface of the vaporizer. The vaporizing surface of the vaporizer is the surface from which vaporized source liquid is released into the surrounding airflow, and so in the example of FIG. 13, is the left-most face of the vaporizer 505. (It will be appreciated that references to “left” and “right”, and similar terms indicating orientation, are used to refer to the orientations represented in the figures for ease of explanation and are not intended to indicate any particular orientation is required for use.) The vaporizer 505 is a planar vaporizer in the sense of having a generally planar/sheet-like form. Thus, the vaporizer 505 comprises first and second opposing faces connected by a peripheral edge wherein the dimensions of the vaporizer 505 in the plane of the first and second faces, for example a length or width of the vaporizer 505 faces, is greater than the thickness of the vaporizer 505 (i.e. the separation between the first and second faces), for example by more than a factor of two, more than a factor of three, more than a factor of four, more than a factor of five, or more than a factor of 10. It will be appreciated that although the vaporizer 505 has a generally planar form, the vaporizer 505 does not necessarily have a flat planar form, but could include bends or undulations, for example of the kind shown for the heating element 340 in FIG. 10B. The heating element 506 part of the vaporizer 505 is a planar heating element in the same way as the vaporizer 505 is a planar vaporizer. For the sake of providing a concrete example, the vaporizer assembly 500 schematically represented in FIG. 13 is taken to be generally circularly-symmetric about a horizontal axis through the center of, and in the plane of, the cross-section view represented in FIG. 13, and to have a characteristic diameter of around 12 mm and a length of around 30 mm, with the vaporizer 505 having a diameter of around 11 mm and a thickness of around 2 mm, and with the heating element 506 having a diameter of around 10 mm and a thickness of around 1 mm. However, it will be appreciated that other sizes and shapes of vaporizer assembly 500 can be adopted according to the implementation at hand, for example having regard to the overall size of the aerosol provision system. For example, some other implementations may adopt values in the range of 10% to 200% of these example values. The reservoir 502 for the source liquid (e-liquid) 504 is defined by a housing comprising a body portion (shown with hatching in FIG. 13) which may, for example, comprise one or more plastic molded pieces, which provides a sidewall and end wall of the reservoir 502 whilst the vaporizer 505 provides another end wall of the reservoir 502. The vaporizer 505 may be held in place within the reservoir housing body portion in a number of different ways. For example, the vaporizer 505 may be press-fitted and/or glued in the end of the reservoir housing body portion. Alternatively, or in addition, a separate fixing mechanism may be provided, for example a suitable clamping arrangement could be used. Thus, the vaporizer assembly 500 of FIG. 13 may form part of an aerosol provision system for generating an aerosol from a source liquid, the aerosol provision system comprising the reservoir 502 of source liquid 504 and the planar vaporizer 505 comprising the planar heating element 506. By having the vaporizer 505, and in particular in the example of FIG. 13, the wicking material 508 surrounding the heating element 506, in contact with source liquid 504 in the reservoir 502, the vaporizer 505 draws source liquid from the reservoir 502 to the vicinity of the vaporizing surface of the vaporizer 505 through capillary action. An induction heater coil of the aerosol provision system in which the vaporizer assembly 500 is provided is operable to induce current flow in the heating element 506 to inductively heat the heating element 506 and so vaporize a portion of the source liquid 504 in the vicinity of the vaporizing surface of the vaporizer 505, thereby releasing the vaporized source liquid 504 into air flowing around the vaporizing surface of the vaporizer 505. The configuration represented in FIG. 13 in which the vaporizer 505 comprises a generally planar form comprising an inductively-heated generally planar heating element 506 and configured to draw source liquid 504 to the vaporizer's vaporizing surface provides a simple yet efficient configuration for feeding source liquid to an inductively heated vaporizer of the types described herein. In particular, the use of a generally planar vaporizer provides a configuration that can have a relatively large vaporizing surface with a relatively small thermal mass. This can help provide a faster heat-up time when aerosol generation is initiated, and a faster cool-down time when aerosol generation ceases. Faster heat-up times can be desired in some scenarios to reduce user waiting, and faster cool-down times can be desired in some scenarios to help avoid residual heat in the vaporizer from causing ongoing aerosol generation after a user has stopped inhaling. Such ongoing aerosol generation in effect represents a waste of source liquid and power, and can lead to source liquid condensing within the aerosol vision system. In the example of FIG. 13, the vaporizer 505 includes the non-conductive porous material 508 to provide the function of drawing source liquid from the reservoir 502 to the vaporizing surface through capillary action. In this case the heating element 506 may, for example, comprise a nonporous conducting material, such as a solid disc. However, in other implementations the heating element 506 may also comprise a porous material so that it also contributes to the wicking of source liquid from the reservoir to the vaporizing surface. In the vaporizer 505 represented in FIG. 13, the porous material 508 fully surrounds the heating element 506. In this configuration the portions of porous material 508 to either side of the heating element 506 may be considered to provide different functionality. In particular, a portion of the porous material 508 between the heating element 506 and the source liquid 504 in the reservoir 502 may be primarily responsible for drawing the source liquid 504 from the reservoir 502 to the vicinity of the vaporizing surface of the vaporizer 505, whereas the portion of the porous material 508 on the opposite side of the heating element 506 (i.e. to the left in FIG. 13) may absorb source liquid 504 that has been drawn from the reservoir 502 to the vicinity of the vaporizing surface of the vaporizer 505 so as to store/retain the source liquid 504 in the vicinity of the vaporizing surface of the vaporizer 505 for subsequent vaporization. Thus, in the example of FIG. 13, the vaporizing surface of the vaporizer 505 comprises at least a portion of the left-most face of the vaporizer 505 and source liquid 504 is drawn from the reservoir 502 to the vicinity of the vaporizing surface through contact with the right-most face of the vaporizer 505. In examples where the heating element 506 comprises a solid material, the capillary flow of source liquid 504 to the vaporizing surface may pass through the porous material 508 at the peripheral edge of the heating element 506 to reach the vaporizing surface. In examples where the heating element 506 comprises a porous material, the capillary flow of source liquid 504 to the vaporizing surface may in addition pass through the heating element 506. FIG. 14 schematically represents in cross-section a vaporizer assembly 510 for use in an aerosol provision system, for example of the type described above, in accordance with certain other embodiments of the present disclosure. Various aspects of the vaporizer assembly 510 of FIG. 14 are similar to, and will be understood from, correspondingly numbered elements of the vaporizer assembly 500 represented in FIG. 13. However, the vaporizer assembly 510 differs from the vaporizer assembly 500 in having an additional vaporizer 515 provided at an opposing end of the reservoir 512 of source liquid 504 (i.e. the vaporizer 505 and the further vaporizer 515 are separated along a longitudinal axis of the aerosol provision system). Thus, the main body of the reservoir 512 (shown hatched in FIG. 14) comprises what is in effect a tube which is closed at both ends by walls provided by a first vaporizer 505, as discussed above in relation to FIG. 13, and a second vaporizer 515, which is in essence identical to the vaporizer 505 at the other end of the reservoir 512. Thus, the second vaporizer 515 comprises a heating element 516 surrounded by a porous material 518 in the same way as the vaporizer 505 comprises a heating element 506 surrounded by a porous material 508. The functionality of the second vaporizer 515 is as described above in connection with FIG. 13 for the vaporizer 505, the only difference being the end of the reservoir 504 to which the vaporizer 515 is coupled. The approach of FIG. 14 can be used to generate greater volumes of vapor since, with a suitably configured airflow path passing both vaporizers 505, 515, a larger area of vaporization surface is provided (in effect doubling the vaporization surface area provided by the single-vaporizer configuration of FIG. 13). In configurations in which an aerosol provision system comprises multiple vaporizers, for example as shown in FIG. 14, the respective vaporizers may be driven by the same or separate induction heater coils. That is to say, in some examples a single induction heater coil may be operable simultaneously to induce current flows in heating elements of multiple vaporizers, whereas in some other examples, respective ones of multiple vaporizers may be associated with separate and independently driveable induction heater coils, thereby allowing different ones of the multiple vaporizer to be driven independently of each other. In the example vaporizer assemblies 500, 510 represented in FIGS. 13 and 14, the respective vaporizers 505, 515 are fed with source liquid 504 in contact with a planar face of the vaporizer 505, 515. However, in other examples, a vaporizer may be fed with source liquid in contact with a peripheral edge portion of the vaporizer, for example in a generally annular configuration such as shown in FIG. 15. Thus, FIG. 15 schematically represents in cross-section a vaporizer assembly 520 for use in an aerosol provision system in accordance with certain other embodiments of the present disclosure. Aspects of the vaporizer assembly 520 shown in FIG. 15 which are similar to, and will be understood from, corresponding aspects of the example vaporizer assemblies represented in the other figures are not described again in the interest of brevity. The vaporizer assembly 520 represented in FIG. 15 again comprises a generally planar vaporizer 525 and a reservoir 522 of source liquid 524. In this example the reservoir 522 has a generally annular cross-section in the region of the vaporizer assembly 520, with the vaporizer 525 mounted within the central part of the reservoir 522, such that an outer periphery of the vaporizer 525 extends through a wall of the reservoir's housing (schematically shown hatched in FIG. 15) so as to contact liquid 524 in the reservoir 522. The vaporizer 525 in this example comprises an inductive heating element 526 the form of a planar annular disk comprising ANSI 304 steel, or other suitable material such as discussed above, surrounded by a wicking/wadding matrix 528 comprising a non-conducting fibrous material, for example a woven fiberglass material. Thus, the vaporizer 525 of FIG. 15 broadly corresponds with the vaporizer 505 of FIG. 13, except for having a passageway 527 passing through the center of the vaporizer 525 through which air can be drawn when the vaporizer 525 is in use. The vaporizer assembly 520 of FIG. 15 may, for example, again be part of a replaceable cartridge for an aerosol provision system of the kinds discussed herein. For example, the vaporizer assembly 520 represented in FIG. 15 may correspond with the wick 454, heating element 455 and reservoir 470 represented in the example aerosol provision system/e-cigarette 410 of FIG. 4. Thus, the vaporizer assembly 520 is a section of a cartridge of an electronic cigarette so that when a user inhales on the cartridge/electronic cigarette, air is drawn through the cartridge and through the passageway 527 in the vaporizer 525. The vaporizing surface of the vaporizer 525 is the surface from which vaporized source liquid 524 is released into the passing airflow, and so in the example of FIG. 15, corresponds with surfaces of the vaporizer 525 which are exposed to the air path through the center of the vaporizer assembly 520 For the sake of providing a concrete example, the vaporizer 525 schematically represented in FIG. 15 is taken to have a characteristic diameter of around 12 mm and a thickness of around 2 mm with the passageway 527 having a diameter of 2 mm. The heating element 526 is taken to have having a diameter of around 10 mm and a thickness of around 1 mm with a hole of diameter 4 mm around the passageway. However, it will be appreciated that other sizes and shapes of vaporizer can be adopted according to the implementation at hand. For example, some other implementations may adopt values in the range of 10% to 200% of these example values. The reservoir 522 for the source liquid (e-liquid) 524 is defined by a housing comprising a body portion (shown with hatching in FIG. 15) which may, for example, comprise one or more plastic molded pieces which provide a generally tubular inner reservoir wall in which the vaporizer 525 is mounted so the peripheral edge of the vaporizer 525 extends through the inner tubular wall of the reservoir housing to contact the source liquid 524. The vaporizer 525 may be held in place with the reservoir housing body portion in a number of different ways. For example, the vaporizer 525 may be press-fitted and/or glued in the corresponding opening in the reservoir housing body portion. Alternatively, or in addition, a separate fixing mechanism may be provided, for example a suitable clamping arrangement may be provided. The opening in the reservoir housing into which the vaporizer 525 is received may be slightly undersized as compared to the vaporizer 525 so the inherent compressibility of the porous material 528 helps in sealing the opening in the reservoir housing against fluid leakage. Thus, and as with the vaporizer assemblies of FIGS. 13 and 14, the vaporizer assembly 522 of FIG. 15 may form part of an aerosol provision system for generating an aerosol from a source liquid comprising the reservoir 522 of source liquid 524 and the planar vaporizer 525 comprising the planar heating element 526. By having the vaporizer 525, and in particular in the example of FIG. 15, the porous wicking material 528 surrounding the heating element 526, in contact with source liquid 524 in the reservoir 522 at the periphery of the vaporizer 525, the vaporizer 525 draws source liquid 524 from the reservoir 522 to the vicinity of the vaporizing surface of the vaporizer 525 through capillary action. An induction heater coil of the aerosol provision system in which the vaporizer assembly 520 is provided is operable to induce current flow in the planar annular heating element 526 to inductively heat the heating element 526 and so vaporize a portion of the source liquid 524 in the vicinity of the vaporizing surface of the vaporizer 525, thereby releasing the vaporized source liquid into air flowing through the central tube defined by the reservoir 522 and the passageway 527 through the vaporizer 525. The configuration represented in FIG. 15 in which the vaporizer 525 comprises a generally planar form comprising an inductively-heated generally planar heating element 526 and configured to draw source liquid 524 to the vaporizer vaporizing surface provides a simple yet efficient configuration for feeding source liquid to an inductively heated vaporizer of the types described herein having a generally annular liquid reservoir. In the example of FIG. 15, the vaporizer 525 includes the non-conductive porous material 528 to provide the function of drawing source liquid 524 from the reservoir 522 to the vaporizing surface through capillary action. In this case the heating element 526 may, for example, comprise a nonporous material, such as a solid disc. However, in other implementations the heating element 526 may also comprise a porous material so that it also contributes to the wicking of source liquid 524 from the reservoir 522 to the vaporizing surface. Thus, in the example of FIG. 15, the vaporizing surface of the vaporizer 525 comprises at least a portion of each of the left- and right-facing faces of the vaporizer 525, and wherein source liquid 524 is drawn from the reservoir 522 to the vicinity of the vaporizing surface through contact with at least a portion of the peripheral edge of the vaporizer 525. In examples, where the heating element 526 comprises a porous material, the capillary flow of source liquid 524 to the vaporizing surface may in addition pass through the heating element 526. FIG. 16 schematically represents in cross-section a vaporizer assembly 530 for use in an aerosol provision system, for example of the type described above, in accordance with certain other embodiments of the present disclosure. Various aspects of the vaporizer assembly 530 of FIG. 16 are similar to, and will be understood from, corresponding elements of the vaporizer assembly 520 represented in FIG. 15. However, the vaporizer assembly 530 differs from the vaporizer assembly 520 in having two vaporizers 535A, 535B provided at different longitudinal positions along a central passageway through a reservoir housing 532 containing source liquid 534. The respective vaporizers 535A, 535B each comprise a heating element 536A, 536B surrounded by a porous wicking material 538A, 538B. The respective vaporizers 535A, 535B and the manner in which they interact with the source liquid 534 in the reservoir 532 may correspond with the vaporizer 525 represented in FIG. 15 and the manner in which that vaporizer 525 interacts with the source liquid 524 in the reservoir 522. The functionality and purpose for providing multiple vaporizers 535A, 535B in the example represented in FIG. 16 may be broadly the same as discussed above in relation to the vaporizer assembly 510 comprising multiple vaporizers 505, 515 represented in FIG. 14. FIG. 17 schematically represents in cross-section a vaporizer assembly 540 for use in an aerosol provision system, for example of the type described above, in accordance with certain other embodiments of the present disclosure. Various aspects of the vaporizer 540 of FIG. 17 are similar to, and will be understood from, correspondingly numbered elements of the vaporizer assembly 500 represent in FIG. 13. However, the vaporizer assembly 540 differs from the vaporizer assembly 500 in having a modified vaporizer 545 as compared to the vaporizer 505 of FIG. 13. In particular, whereas in the vaporizer 505 of FIG. 13 the heating element 506 is surrounded by the porous material 508 on both faces, in the example of FIG. 17, the vaporizer 545 comprises a heating element 546 which is only surrounded by porous material 548 on one side, and in particular on the side facing the source liquid 504 in the reservoir 502. In this configuration the heating element 546 comprises a porous conducting material, such as a web of steel fibers, and the vaporizing surface of the vaporizer is the outward facing (i.e. shown left-most in FIG. 17) face of the heater element 546. Thus, the source liquid 504 may be drawn from the reservoir 502 to the vaporizing surface of the vaporizer by capillary action through the porous material 548 and the porous heater element 546. The operation of an electronic aerosol provision system incorporating the vaporizer of FIG. 17 may otherwise be generally as described herein in relation to the other induction heating based aerosol provision systems. FIG. 18 schematically represents in cross-section a vaporizer assembly 550 for use in an aerosol provision system, for example of the type described above, in accordance with certain other embodiments of the present disclosure. Various aspects of the vaporizer assembly 550 of FIG. 18 are similar to, and will be understood from, correspondingly numbered elements of the vaporizer assembly 500 represented in FIG. 13. However, the vaporizer assembly 550 differs from the vaporizer assembly 500 in having a modified vaporizer 555 as compared to the vaporizer 505 of FIG. 13. In particular, whereas in the vaporizer 505 of FIG. 13 the heating element 506 is surrounded by the porous material 508 on both faces, in the example of FIG. 18, the vaporizer 555 comprises a heating element 556 which is only surrounded by porous material 558 on one side, and in particular on the side facing away from the source liquid 504 in the reservoir 502. The heating element 556 again comprises a porous conducting material, such as a sintered/mesh steel material. The heating element 556 in this example is configured to extend across the full width of the opening in the housing of the reservoir 502 to provide what is in effect a porous seal and may be held in place by a press fit in the opening of the housing of the reservoir and/or glued in place and/or include a separate clamping mechanism. The porous material 558 in effect provides the vaporization surface for the vaporizer 555. Thus, the source liquid 504 may be drawn from the reservoir 502 to the vaporizing surface of the vaporizer by capillary action through the porous heater element 556. The operation of an electronic aerosol provision system incorporating the vaporizer of FIG. 18 may otherwise be generally as described herein in relation to the other induction heating based aerosol provision systems. FIG. 19 schematically represents in cross-section a vaporizer assembly 560 for use in an aerosol provision system, for example of the type described above, in accordance with certain other embodiments of the present disclosure. Various aspects of the vaporizer assembly 560 of FIG. 19 are similar to, and will be understood from, correspondingly numbered elements of the vaporizer assembly 500 represented in FIG. 13. However, the vaporizer assembly 560 differs from the vaporizer assembly 500 in having a modified vaporizer 565 as compared to the vaporizer 505 of FIG. 13. In particular, whereas in the vaporizer 505 of FIG. 13 the heating element 506 is surrounded by the porous material 508, in the example of FIG. 19, the vaporizer 565 consists of a heating element 566 without any surrounding porous material. In this configuration the heating element 566 again comprises a porous conducting material, such as a sintered/mesh steel material. The heating element 566 in this example is configured to extend across the full width of the opening in the housing of the reservoir 502 to provide what is in effect a porous seal and may be held in place by a press fit in the opening of the housing of the reservoir and/or glued in place and/or include a separate clamping mechanism. The heating element 546 in effect provides the vaporization surface for the vaporizer 565 and also provides the function of drawing source liquid 504 from the reservoir 502 to the vaporizing surface of the vaporizer by capillary action. The operation of an electronic aerosol provision system incorporating the vaporizer of FIG. 19 may otherwise be generally as described herein in relation to the other induction heating based aerosol provision systems. FIG. 20 schematically represents in cross-section a vaporizer assembly 570 for use in an aerosol provision system, for example of the type described above, in accordance with certain other embodiments of the present disclosure. Various aspects of the vaporizer assembly 570 of FIG. 20 are similar to, and will be understood from, correspondingly numbered elements of the vaporizer assembly 520 represented in FIG. 15. However, the vaporizer assembly 570 differs from the vaporizer assembly 520 in having a modified vaporizer 575 as compared to the vaporizer 525 of FIG. 15. In particular, whereas in the vaporizer 525 of FIG. 15 the heating element 526 is surrounded by the porous material 528, in the example of FIG. 20, the vaporizer 575 consists of a heating element 576 without any surrounding porous material. In this configuration the heating element 576 again comprises a porous conducting material, such as a sintered/mesh steel material. The periphery of the heating element 576 is configured to extend into a correspondingly sized opening in the housing of the reservoir 522 to provide contact with the liquid formulation and may be held in place by a press fit and/or glue and/or a clamping mechanism. The heating element 546 in effect provides the vaporization surface for the vaporizer 575 and also provides the function of drawing source liquid 524 from the reservoir 522 to the vaporizing surface of the vaporizer 575 by capillary action. The operation of an electronic aerosol provision system incorporating the vaporizer of FIG. 20 may otherwise be generally as described herein in relation to the other induction heating based aerosol provision systems. Thus, FIGS. 13 to 20 show a number of different example liquid feed mechanisms for use in an inductively heater vaporizer of an electronic aerosol provision system, such as an electronic cigarette. It will be appreciated these example set out principles that may be adopted in accordance with some embodiments of the present disclosure, and in other implementations different arrangements may be provided which include these and similar principles. For example, it will be appreciated the configurations need not be circularly symmetric, but could in general adopt other shapes and sizes according to the implementation hand. It will also be appreciated that various features from the different configurations may be combined. For example, whereas in FIG. 15 the vaporizer is mounted on an internal wall of the reservoir 522, in another example, a generally annular vaporizer may be mounted at one end of a annular reservoir. That is to say, what might be termed an “end cap” configuration of the kind shown in FIG. 13 could also be used for an annular reservoir whereby the end-cap comprises an annular ring, rather than a non-annular disc, such as in the Example of FIGS. 13, 14 and 17 to 19. Furthermore, it will be appreciated the example vaporizers of FIGS. 17, 18, 19 and 20 could equally be used in a vaporizer assembly comprising multiple vaporizers, for example shown in FIGS. 15 and 16. It will furthermore be appreciated that vaporizer assemblies of the kind shown in FIGS. 13 to 20 are not restricted to use in aerosol provision systems of the kind described herein, but can be used more generally in any inductive heating based aerosol provision system. Accordingly, although various example embodiments described herein have focused on a two-part aerosol provision system comprising a re-useable control unit and a replaceable cartridge, in other examples, a vaporizer of the kind described herein with reference to FIGS. 13 to 20 may be used in an aerosol provision system that does not include a replaceable cartridge, but is a one-piece disposable system or a refillable system. It will further be appreciated that in accordance with some example implementations, the heating element of the example vaporizer assemblies discussed above with reference to FIGS. 13 to 20 may correspond with any of the example heating elements discussed above, for example in relation to FIGS. 9 to 12. That is to say, the arrangements shown in FIGS. 13 to 20 may include a heating element having a non-uniform response to inductive heating, as discussed above. Thus, there has been described an aerosol provision system for generating an aerosol from a source liquid, the aerosol provision system comprising: a reservoir of source liquid; a planar vaporizer comprising a planar heating element, wherein the vaporizer is configured to draw source liquid from the reservoir to the vicinity of a vaporizing surface of the vaporizer through capillary action; and an induction heater coil operable to induce current flow in the heating element to inductively heat the heating element and so vaporize a portion of the source liquid in the vicinity of the vaporizing surface of the vaporizer. In some example the vaporizer further comprises a porous wadding/wicking material, e.g. an electrically non-conducting fibrous material at least partially surrounding the planar heating element (susceptor) and in contact with source liquid from the reservoir to provide, or at least contribute to, the function of drawing source liquid from the reservoir to the vicinity of the vaporizing surface of the vaporizer. In some examples the planar heating element (susceptor) may itself comprise a porous material so as to provide, or at least contribute to, the function of drawing source liquid from the reservoir to the vicinity of the vaporizing surface of the vaporizer. In order to address various issues and advance the art, this disclosure shows by way of illustration various embodiments in which the claimed invention(s) may be practiced. The advantages and features of the disclosure are of a representative sample of embodiments only, and are not exhaustive and/or exclusive. They are presented only to assist in understanding and to teach the claimed invention(s). It is to be understood that advantages, embodiments, examples, functions, features, structures, and/or other aspects of the disclosure are not to be considered limitations on the disclosure as defined by the claims or limitations on equivalents to the claims, and that other embodiments may be utilized and modifications may be made without departing from the scope of the claims. Various embodiments may suitably comprise, consist of, or consist essentially of, various combinations of the disclosed elements, components, features, parts, steps, means, etc. other than those specifically described herein, and it will thus be appreciated that features of the dependent claims may be combined with features of the independent claims in combinations other than those explicitly set out in the claims. The disclosure may include other inventions not presently claimed, but which may be claimed in future. | <SOH> BACKGROUND <EOH>FIG. 1 is a schematic diagram of one example of a conventional e-cigarette 10 . The e-cigarette has a generally cylindrical shape, extending along a longitudinal axis indicated by dashed line LA, and comprises two main components, namely a control unit 20 and a cartomizer 30 . The cartomizer 30 includes an internal chamber containing a reservoir of liquid formulation including nicotine, a vaporizer (such as a heater), and a mouthpiece 35 . The cartomizer 30 may further include a wick or similar facility to transport a small amount of liquid from the reservoir to the heater. The control unit 20 includes a re-chargeable battery to provide power to the e-cigarette 10 and a circuit board for generally controlling the e-cigarette 10 . When the heater receives power from the battery, as controlled by the circuit board, the heater vaporizes the nicotine and this vapor (aerosol) is then inhaled by a user through the mouthpiece 35 . The control unit 20 and cartomizer 30 are detachable from one another by separating in a direction parallel to the longitudinal axis LA, as shown in FIG. 1 , but are joined together when the device 10 is in use by a connection, indicated schematically in FIG. 1 as 25 A and 25 B, to provide mechanical and electrical connectivity between the control unit 20 and the cartomizer 30 . The electrical connector on the control unit 20 that is used to connect to the cartomizer also serves as a socket for connecting a charging device (not shown) when the control unit 20 is detached from the cartomizer 30 . The cartomizer 30 may be detached from the control unit 20 and disposed of when the supply of nicotine is exhausted (and replaced with another cartomizer if so desired). FIGS. 2 and 3 provide schematic diagrams of the control unit 20 and cartomizer 30 , respectively, of the e-cigarette 10 of FIG. 1 . Note that various components and details, e.g. such as wiring and more complex shaping, have been omitted from FIGS. 2 and 3 for reasons of clarity. As shown in FIG. 2 , the control unit 20 includes a battery or cell 210 for powering the e-cigarette 10 , as well as a chip, such as a (micro) controller for controlling the e-cigarette 10 . The controller is attached to a small printed circuit board (PCB) 215 that also includes a sensor unit. If a user inhales on the mouthpiece 35 , air is drawn into the e-cigarette 10 through one or more air inlet holes (not shown in FIGS. 1 and 2 ). The sensor unit detects this airflow, and in response to such a detection, the controller provides power from the battery 210 to the heater in the cartomizer 30 . As shown in FIG. 3 , the cartomizer 30 includes an air passage 161 extending along the central (longitudinal) axis of the cartomizer 30 from the mouthpiece 35 to the connector 25 A for joining the cartomizer 30 to the control unit 20 . A reservoir of nicotine-containing liquid 170 is provided around the air passage 161 . This reservoir 170 may be implemented, for example, by providing cotton or foam soaked in the liquid. The cartomizer 30 also includes a heater 155 in the form of a coil for heating liquid from reservoir 170 to generate vapor to flow through air passage 161 and out through mouthpiece 35 . The heater is powered through lines 166 and 167 , which are in turn connected to opposing polarities (positive and negative, or vice versa) of the battery 210 via connector 25 A. One end of the control unit 20 provides a connector 25 B for joining the control unit 20 to the connector 25 A of the cartomizer 30 . The connectors 25 A and 25 B provide mechanical and electrical connectivity between the control unit 20 and the cartomizer 30 . The connector 25 B includes two electrical terminals, an outer contact 240 and an inner contact 250 , which are separated by insulator 260 . The connector 25 A likewise includes an inner electrode 175 and an outer electrode 171 , separated by insulator 172 . When the cartomizer 30 is connected to the control unit 20 , the inner electrode 175 and the outer electrode 171 of the cartomizer 30 engage the inner contact 250 and the outer contact 240 , respectively, of the control unit 20 . The inner contact 250 is mounted on a coil spring 255 so that the inner electrode 175 pushes against the inner contact 250 to compress the coil spring 255 , thereby helping to ensure good electrical contact when the cartomizer 30 is connected to the control unit 20 . The cartomizer connector 25 A is provided with two lugs or tabs 180 A, 180 B, which extend in opposite directions away from the longitudinal axis of the e-cigarette 10 . These tabs are used to provide a bayonet fitting for connecting the cartomizer 30 to the control unit 20 . It will be appreciated that other embodiments may use a different form of connection between the control unit 20 and the cartomizer 30 , such as a snap fit or a screw connection. As mentioned above, the cartomizer 30 is generally disposed of once the liquid reservoir 170 has been depleted, and a new cartomizer 30 is purchased and installed. In contrast, the control unit 20 is re-usable with a succession of cartomizers 30 . Accordingly, it is particularly desirable to keep the cost of the cartomizer 30 relatively low. One approach to doing this has been to construct a three-part device, based on (i) a control unit, (ii) a vaporizer component, and (iii) a liquid reservoir. In this three-part device, only the final part, the liquid reservoir, is disposable, whereas the control unit and the vaporizer are both re-usable. However, having a three-part device can increase the complexity, both in terms of manufacture and user operation. Moreover, it can be difficult in such a three-part device to provide a wicking arrangement of the type shown in FIG. 3 to transport liquid from the reservoir to the heater. Another approach is to make the cartomizer 30 re-fillable, so that it is no longer disposable. However, making a cartomizer 30 re-fillable brings potential problems, for example, a user may try to re-fill the cartomizer 30 with an inappropriate liquid (one not provided by the supplier of the e-cigarette 10 ). There is a risk that this inappropriate liquid may result in a low quality consumer experience, and/or may be potentially hazardous, whether by causing damage to the e-cigarette itself, or possibly by creating toxic vapors. Accordingly, existing approaches for reducing the cost of a disposable component (or for avoiding the need for such a disposable component) have met with only limited success. | <SOH> SUMMARY <EOH>The invention is defined in the appended claims. According to a first aspect of certain embodiments there is provided an inductive heating assembly for generating an aerosol from an aerosol precursor material in an aerosol provision system, the inductive heating assembly comprising: a susceptor; and a drive coil arranged to induce current flow in the susceptor to heat the susceptor and vaporize aerosol precursor material in proximity with a surface of the susceptor, and wherein the susceptor comprises regions of different susceptibility to induced current flow from the drive coil, such that when in use the surface of the susceptor in the regions of different susceptibility are heated to different temperatures by the current flow induced by the drive coil. According to a second aspect of certain embodiments there is provided an aerosol provision system comprising an inductive heating assembly for generating an aerosol from an aerosol precursor material in an aerosol provision system, the inductive heating assembly comprising: a susceptor; and a drive coil arranged to induce current flow in the susceptor to heat the susceptor and vaporize aerosol precursor material in proximity with a surface of the susceptor, and wherein the susceptor comprises regions of different susceptibility to induced current flow from the drive coil, such that when in use the surface of the susceptor in the regions of different susceptibility are heated to different temperatures by the current flow induced by the drive coil. According to a third aspect of certain embodiments there is provided a cartridge for use in an aerosol provision system comprising an inductive heating assembly, wherein the cartridge comprises a susceptor that comprises regions of different susceptibility to induced current flow from an external drive coil, such that when in use the surface of the susceptor in the regions of different susceptibility are heated to different temperatures by current flows induced by the external drive coil. According to a fourth aspect of certain embodiments there is provided an inductive heating assembly means for generating an aerosol from an aerosol precursor material in an aerosol provision system, the inductive heating assembly means comprising: susceptor means; and induction means for inducing current flow in the susceptor means to heat the susceptor means and vaporize aerosol precursor material in proximity with a surface of the susceptor means, wherein the susceptor means comprises regions of different susceptibility to induced current flow from the induction means such that in use the surface of the susceptor means in the regions of different susceptibility are heated to different temperatures by the current flow induced by the induction means. According to a fifth aspect of certain embodiments there is provided a method of generating an aerosol from an aerosol precursor material, the method comprising: providing an inductive heating assembly comprising a susceptor and a drive coil arranged to induce current flow in the susceptor, wherein the susceptor comprises regions of different susceptibility to induced current flow from the drive coil so the surface of the susceptor in the regions of different susceptibility are heated to different temperatures by current flows induced by the drive coil, and using the drive coil to induce currents in the susceptor to heat the susceptor and vaporize aerosol precursor material in proximity with a surface of the susceptor to generate the aerosol. It will be appreciated that features and aspects of the invention described above in relation to the first and other aspects of the invention are equally applicable to, and may be combined with, embodiments of the invention according to other aspects of the invention as appropriate, and not just in the specific combinations described above. | A24F47008 | 20171221 | 20180712 | 60315.0 | A24F4700 | 0 | NGUYEN, THANG H | ELECTRONIC AEROSOL PROVISION SYSTEMS, INDUCTIVE HEATING ASSEMBLIES AND CARTRIDGES FOR USE THEREWITH, AND RELATED METHODS | UNDISCOUNTED | 0 | PENDING | A24F | 2,017 |
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15,739,229 | PENDING | PROTECTIVE COMPOSITION FOR GASTROINTESTINAL MUCOSA | An object of the present invention is to provide a protective composition for gastrointestinal mucosa, for example, for inhibiting occurrence of a gastrointestinal mucosa disorder when an oral drug that induces the gastrointestinal mucosa disorder is taken. The protective composition for gastrointestinal mucosa of the present invention as a resolution for achieving the object is characterized by comprising at least a macromolecular polysaccharide, sodium hydrogen carbonate and/or magnesium carbonate, and a polyhydric alcohol. According to the protective composition for gastrointestinal mucosa of the present invention, sodium hydrogen carbonate or magnesium carbonate foams through contact with a gastric juice in stomach to thereby generate diffusing power for the macromolecular polysaccharide. This power can allow the macromolecular polysaccharide to quickly dissolve or disperse in the gastric juice and allow the macromolecular polysaccharide to effectively exert a gastric mucosa protective action. In addition, the macromolecular polysaccharide dissolved or dispersed in the gastric juice moves into intestine without degradation in stomach, then dissolves in an intestinal juice having a neutral or alkaline pH, and exerts an intestinal mucosa protective action without degradation also in intestine. The polyhydric alcohol plays a role as a dispersion medium for the macromolecular polysaccharide and sodium hydrogen carbonate or magnesium carbonate which are powder, or enables formulation of the protective composition for gastrointestinal mucosa of the present invention into various dosage forms, according to the nature and use amount thereof. | 1: A protective composition for gastrointestinal mucosa, characterized by comprising at least a macromolecular polysaccharide, 0.1 to 50 a of sodium hydrogen carbonate and/or magnesium carbonate relative to 1 g of the macromolecular polysaccharide, and 18% to 90° C. of a polyhydric alcohol relative to the total weight of the composition, the polyhydric alcohol dissolves in a gastric juice in stomach, whereby the sodium hydrogen carbonate and/or magnesium carbonate foams through contact with the gastric juice to thereby generate diffusing power for the macromolecular polysaccharide, the power then allowing the macromolecular polysaccharide to dissolve or disperse in the gastric juice. 2: The protective composition for gastrointestinal mucosa according to claim 1, characterized in that the macromolecular polysaccharide is at least one selected from a mucopolysaccharide, xanthan gum, and fucoidan. 3: The protective composition for gastrointestinal mucosa according to claim 1, characterized in that the polyhydric alcohol is at least one selected from glycerine, diglycerine, polyglycerine, polyethylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, isopropylene glycol, and 1,3-butylene glycol. 4: The protective composition for gastrointestinal mucosa according to claim 1, characterized by further comprising a polyvalent carboxylic acid or a pharmaceutically acceptable salt thereof. 5: The protective composition for gastrointestinal mucosa according to claim 1, characterized by further comprising an oral drug. 6: An oral formulation, characterized in that the protective composition for gastrointestinal mucosa according to claim 1 is formulated. | TECHNICAL FIELD The present invention relates to a protective composition for gastrointestinal mucosa, for example, for inhibiting occurrence of a gastrointestinal mucosa disorder when an oral drug that induces the gastrointestinal mucosa disorder is taken. BACKGROUND ART Some of oral drugs induce a gastrointestinal mucosa disorder as an adverse effect on the other side of their excellent pharmacological function, and nonsteroidal anti-inflammatory drugs (NSAIDs) are a typical example thereof. Thus, a method is demanded for inhibiting occurrence of a gastrointestinal mucosa disorder due to an oral drug that induces the gastrointestinal mucosa disorder by protecting gastrointestinal mucosa when the drug is taken. As an ingredient having a protective action for gastrointestinal mucosa, various ingredients have been heretofore reported, and one example is a macromolecular polysaccharide such as a mucopolysaccharide typified by hyaluronic acid. For example, Patent Document 1 proposes a gastric mucosa protective agent containing chondroitin sulfate which is one of mucopolysaccharides. PRIOR ART DOCUMENTS Patent Document Patent Document 1: JP-A-5-320056 SUMMARY OF THE INVENTION Problems that the Invention is to Solve In the case of using a macromolecular polysaccharide as an ingredient for inhibiting occurrence of a gastrointestinal mucosa disorder when an oral drug that induces the gastrointestinal mucosa disorder is taken, the macromolecular polysaccharide may be taken before or at the same time as the taking of the drug. However, since the macromolecular polysaccharide which is powder has poor solubility in an acidic (pH 1-2) gastric juice, when the macromolecular polysaccharide is taken as it is in the powder form, the macromolecular polysaccharide can not quickly dissolve or disperse in stomach to exert the mucosa protection effect. Although there is not such a problem when the macromolecular polysaccharide is taken in an aqueous solution form, when the macromolecular polysaccharide is tried to be dissolved in water for preparing an aqueous solution of the macromolecular polysaccharide, an undissolved lump is generated and thus it is taken a long period of time to dissolve the lump. Even if the lump can be dissolved over a long period of time, the viscosity of the aqueous solution may increase or the macromolecular polysaccharide in water may degrade with time. Accordingly, it is impossible to prepare or formulate an aqueous solution of a macromolecular polysaccharide at time of use. Accordingly, the present invention has an object to provide a protective composition for gastrointestinal mucosa containing a macromolecular polysaccharide, for example, for inhibiting occurrence of a gastrointestinal mucosa disorder when an oral drug that induces the gastrointestinal mucosa disorder is taken. Means for Solving the Problems A protective composition for gastrointestinal mucosa of the present invention made in view of the above point is characterized, as set forth in claim 1, by comprising at least a macromolecular polysaccharide, sodium hydrogen carbonate and/or magnesium carbonate, and a polyhydric alcohol. The protective composition for gastrointestinal mucosa set forth in claim 2 is characterized, in the protective composition for gastrointestinal mucosa according to claim 1, in that the macromolecular polysaccharide is at least one selected from a mucopolysaccharide, xanthan gum, and fucoidan. The protective composition for gastrointestinal mucosa set forth in claim 3 is characterized, in the protective composition for gastrointestinal mucosa according to claim 1, in that the polyhydric alcohol is at least one selected from glycerine, diglycerine, polyglycerine, polyethylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, isopropylene glycol, and 1,3-butylene glycol. The protective composition for gastrointestinal mucosa set forth in claim 4 is characterized, in the protective composition for gastrointestinal mucosa according to claim 1, by further comprising a polyvalent carboxylic acid or a pharmaceutically acceptable salt thereof. The protective composition for gastrointestinal mucosa set forth in claim 5 is characterized, in the protective composition for gastrointestinal mucosa according to claim 1, by further comprising an oral drug. Furthermore, an oral formulation of the present invention is characterized, as set forth in claim 6, in that the protective composition for gastrointestinal mucosa according to claim 1 is formulated. Effect of the Invention According to the protective composition for gastrointestinal mucosa of the present invention, sodium hydrogen carbonate or magnesium carbonate foams through contact with a gastric juice in stomach to thereby generate diffusing power for the macromolecular polysaccharide. This power can allow the macromolecular polysaccharide to quickly dissolve or disperse in the gastric juice and allow the macromolecular polysaccharide to effectively exert a gastric mucosa protective action. In addition, the macromolecular polysaccharide dissolved or dispersed in the gastric juice moves into intestine without degradation in stomach, then dissolves in an intestinal juice having a neutral or alkaline pH (6-8), and exerts an intestinal mucosa protective action without degradation also in intestine. The polyhydric alcohol plays a role as a dispersion medium for the macromolecular polysaccharide and sodium hydrogen carbonate or magnesium carbonate which are powder, or enables formulation of the protective composition for gastrointestinal mucosa of the present invention into various dosage forms, according to the nature and the use amount thereof. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows appearances of the protective composition for gastrointestinal mucosa of the present invention. The left dish shows a composition of a gel form obtained in Example 1 (the lower is the composition itself and the upper is the composition filled in a hard capsule). The central dish shows a composition of a clay form obtained in Example 2. The right dish shows a composition of a solid form obtained in Example 3. MEANS FOR CARRYING OUT THE INVENTION A protective composition for gastrointestinal mucosa of the present invention is characterized by containing at least a macromolecular polysaccharide, sodium hydrogen carbonate and/or magnesium carbonate, and a polyhydric alcohol. The macromolecular polysaccharide contained in the protective composition for gastrointestinal mucosa of the present invention may be, for example, one that is known to have a protective action for gastrointestinal mucosa, and specific examples thereof include a mucopolysaccharide, xanthan gum, and fucoidan. Mucopolysaccharides are a macromolecular polysaccharide having an aminosugar or a derivative thereof as a constituent sugar, and the mucopolysaccharide may be an acidic mucopolysaccharide or a neutral mucopolysaccharide. As an acidic mucopolysaccharide, hyaluronic acid, chondroitin sulfate A, chondroitin sulfate C, dermatan sulfate (chondroitin sulfate B), heparin, keratan sulfate, etc. are exemplified. As a neutral mucopolysaccharide, chitin and chitosan are exemplified. Xanthan gum is a macromolecular polysaccharide obtained by microbial fermentation. Fucoidan is a macromolecular polysaccharide largely contained in mucilage such as kombu seaweed, wakame seaweed, and mozuku seaweed. As a macromolecular polysaccharide, for example, commercially available powder having a molecular weight of 100,000 to 5,000,000 may be used. When the molecular weight of the macromolecular polysaccharide is lower than 100,000, the protective action for gastrointestinal mucosa is deteriorated. On the other hand, when the molecular weight exceeds 5,000, 000, the macromolecular polysaccharide is difficult to dissolve or disperse in a gastric juice. The molecular weight of the macromolecular polysaccharide is desirably 500,000 to 3,000,000. Sodium hydrogen carbonate or magnesium carbonate contained in the protective composition for gastrointestinal mucosa of the present invention foams through contact with a gastric juice in stomach to generate diffusing power for the macromolecular polysaccharide, the power allowing the macromolecular polysaccharide to quickly dissolve or disperse in the gastric juice. Either one of sodium hydrogen carbonate and magnesium carbonate may be used or both may be used in mixture. Specific examples of the polyhydric alcohol contained in the protective composition for gastrointestinal mucosa of the present invention include glycerine, diglycerine, polyglycerine, polyethylene glycol (macrogol), propylene glycol, dipropylene glycol, polypropylene glycol, isopropylene glycol, and 1,3-butylene glycol. Average molecular weights of polyglycerine, polyethylene glycol, and polypropylene glycol each may be, for example, 200 to 35,000. The polyhydric alcohol may be used alone or in mixture of plural kinds, taking the nature and the use amount into account. In the protective composition for gastrointestinal mucosa of the present invention, in order to allow sodium hydrogen carbonate or magnesium carbonate to foam through contact with s gastric juice to generate diffusing power for the macromolecular polysaccharide and to allow the macromolecular polysaccharide to dissolve or disperse in the gastric juice by the power, the mixing ratio of sodium hydrogen carbonate or magnesium carbonate to the macromolecular polysaccharide is desirably 0.1 g to 50 g, more desirably 0.5 g to 30 g, and further desirably 1 g to 15 g relative to 1 g of the macromolecular polysaccharide. Incidentally, the dose of the macromolecular polysaccharide at one time by the protective composition for gastrointestinal mucosa of the present invention is desirably 10 mg to 500 mg for allowing the macromolecular polysaccharide to effectively exert the protective action for the gastrointestinal mucosa (the protective composition for gastrointestinal mucosa of the present invention may be formulated so that one formulation contains the above amount of the macromolecular polysaccharide). The protective composition for gastrointestinal mucosa of the present invention can be produced, for example, by mixing a macromolecular polysaccharide, sodium hydrogen carbonate or magnesium carbonate, and a polyhydric alcohol. The polyhydric alcohol may be mixed with the macromolecular polysaccharide and sodium hydrogen carbonate or magnesium carbonate, as it is if the polyhydric alcohol is in a liquid form at a normal temperature (for example, 25° C.), or after heating if the polyhydric alcohol is in a solid form at the above temperature. The content of the polyhydric alcohol in the protective composition for gastrointestinal mucosa of the present invention may be, for example, 5% to 90% relative to the total weight of the composition. Although depending on the kind of the polyhydric alcohol, when the content of the polyhydric alcohol is, for example, 10% or more relative to the total weight of the composition, the polyhydric alcohol plays a role as a dispersion medium for the macromolecular polysaccharide and sodium hydrogen carbonate or magnesium carbonate which are powder. Since the macromolecular polysaccharide and sodium hydrogen carbonate or magnesium carbonate can not dissolve in a polyhydric alcohol, these substances are stably present in the polyhydric alcohol as it is in a powder form. By using a polyhydric alcohol alone, taking the nature into account, or using plural polyhydric alcohols having different natures in mixture of a prescribed ratio, the protective composition for gastrointestinal mucosa of the present invention can be obtained in different forms such as a liquid form, a gel form, a semi-solid form, and a solid form in which the macromolecular polysaccharide and sodium hydrogen carbonate or magnesium carbonate are dispersed in the polyhydric alcohol, whereby the composition can be formulated into various dosage forms. In any dosage form, after taking, the polyhydric alcohol quickly dissolves in a gastric juice in stomach, whereby sodium hydrogen carbonate or magnesium carbonate foams through contact with the gastric juice to thereby generate diffusing power for the macromolecular polysaccharide, the power then allowing the macromolecular polysaccharide to quickly dissolve or disperse in the gastric juice and allowing the macromolecular polysaccharide to effectively exert a gastric mucosa protective action (when the volume of the gastric acid is increased by water taken at the taking of the composition, the effect increases). In addition, the macromolecular polysaccharide dissolved or dispersed in the gastric juice moves into intestine without degradation in stomach, then dissolves in an intestinal juice having a neutral or alkaline pH, and exerts an intestinal mucosa protective action without degradation also in intestine. In addition, although depending on the kind of the polyhydric alcohol, when the content of the polyhydric alcohol is, for example, 20% or less relative to the total weight of the composition, the polyhydric alcohol plays a role as a binder between the macromolecular polysaccharide and sodium hydrogen carbonate or magnesium carbonate, whereby the protective composition for gastrointestinal mucosa of the present invention can be formulated into a solid form. Also in this composition, sodium hydrogen carbonate or magnesium carbonate foams through contact with a gastric juice in stomach to generate diffusing power for the macromolecular polysaccharide, the power then allowing the macromolecular polysaccharide to quickly dissolve or disperse in the gastric juice and allowing the macromolecular polysaccharide to effectively exert a gastric mucosa protective action (when the volume of the gastric acid is increased by water taken at the taking of the composition, the effect increases). In addition, the macromolecular polysaccharide dissolved or dispersed in the gastric juice moves into intestine without degradation in stomach, then dissolves in an intestinal juice having a neutral or alkaline pH, and exerts an intestinal mucosa protective action without degradation also in intestine. The protective composition for gastrointestinal mucosa of the present invention may further contain a polyvalent carboxylic acid or a pharmaceutically acceptable salt thereof. When such a substance is contained, even if the pH in stomach does not have an enough acidity to allow sodium hydrogen carbonate or magnesium carbonate to foam (for example, when the pH exceeds 3), the pH can be lowered to induce the sodium hydrogen carbonate or magnesium carbonate to foam. Specific examples of the polyvalent carboxylic acid include citric acid, succinic acid, maleic acid, fumaric acid, malic acid, and tartaric acid. Examples of the pharmaceutically acceptable salt of a polyvalent carboxylic acid include a sodium salt, a potassium salt, a calcium salt, and an ammonium salt. When a free polyvalent carboxylic acid has or may have an adverse effect on stability of another component contained in the protective composition for gastrointestinal mucosa of the present invention, not a free polyvalent carboxylic acid but a pharmaceutically acceptable salt of the polyvalent carboxylic acid is desirably used. The content of a polyvalent carboxylic acid or a pharmaceutically acceptable salt thereof may be, for example, 1% to 30% relative to the total weight of the composition. Incidentally, the protective composition for gastrointestinal mucosa of the present invention may contain, as another component, a cellulose such as crystalline cellulose, carmellose sodium, and hydroxypropyl cellulose, glucose, sorbitol, mannitol, dextrin, potato starch, corn starch, calcium hydrogen phosphate, light anhydrous silicic acid, etc. as a binder or an excipient. However, it is desired that substantially no water is contained. The reason is that water, if present in the composition, has an adverse effect on stability of the macromolecular polysaccharide and sodium hydrogen carbonate or magnesium carbonate. The explanation above is made, for example, about the protective composition for gastrointestinal mucosa of the present invention in which a macromolecular polysaccharide exerts a protective action for gastrointestinal mucosa when the composition is taken before or at the same time as the taking of an oral drug that induces a gastrointestinal mucosa disorder, but the protective composition for gastrointestinal mucosa of the present invention may further contain, for example, an oral drug that induces a gastrointestinal mucosa disorder. The protective composition for gastrointestinal mucosa of the present invention containing an oral drug that induces a gastrointestinal mucosa disorder can be orally administered as a drug composition having a gastrointestinal mucosa protective action. As the oral drug that induces a gastrointestinal mucosa disorder here, exemplified are a nonsteroidal anti-inflammatory drug including diclofenac, indomethacin, ibuprofen, ketoprofen, naproxen, loxoprofen, piroxicam, lornoxicam, and meloxicam; an antipyretic analgesic, such as aspirin, salicylic acid, and acetaminophen; an immunosuppressive drug, such as mizoribine; a calcitonin-related formulation, such as disodium etidronate, ipriflavone, sodium alendronate hydrate, sodium risedronate hydrate, and sevelamer hydrochloride; an antibiotic, such as erythromycin, clindamycin, and ribavirin; a corticosteroid, such as prednisolone, dexamethasone, betamethasone, hydrocortisone, and methylprednisolone; and a lipid-lowering drug, such as probucol (these substances may be in a form of a pharmaceutically acceptable salt thereof). Such an oral drug is not deteriorated in the stability even when existing with a macromolecular polysaccharide, sodium hydrogen carbonate or magnesium carbonate, and a polyhydric alcohol, and thus stably exists in the composition. Incidentally, in the protective composition for gastrointestinal mucosa of the present invention containing an oral drug that induces a gastrointestinal mucosa disorder, the content of the oral drug can be appropriately determined so that the oral drug exerts a prescribed pharmacological action when a formulated composition is taken (the content of the oral drug in one formulation is, for example, 1 mg to 3 g). EXAMPLES Hereinunder, the present invention is explained in detail with reference to examples. The present invention should not be construed to be limited to the following description. Example 1 A protective composition for gastrointestinal mucosa of the present invention containing powdery ibuprofen sodium salt as an oral drug was obtained in the following manner: 3000 mg of macrogol 400 and 400 mg of macrogol 4000 were uniformly dissolved through heating to 70C, followed by lowering the liquid temperature to 60° C., then 2000 mg of ibuprofen sodium salt, 150 mg of hyaluronic acid (manufactured by Kewpie Corporation, molecular weight: about 1,200,000, the same applies hereinafter), and 500 mg of sodium hydrogen carbonate were sequentially added, and the mixture was cooled with mixing by thorough stirring. The resulting protective composition for gastrointestinal mucosa of the present invention was a white gel form having high viscosity in which ibuprofen sodium salt, hyaluronic acid, and sodium hydrogen carbonate were uniformly dispersed in a mixture of macrogol 400 and macrogol 4000. When put in a pharmacopeial artificial gastric juice, the composition immediately foamed vigorously and dispersed therein to form a uniform white opaque liquid, and then the components of the composition became dissolved or dispersed in the liquid without remaining on the liquid surface. The appearance of the resulting protective composition for gastrointestinal mucosa of the present invention is shown in FIG. 1 (left dish: the lower is the composition itself and the upper is the composition filled in a No. 1 hard capsule made of pullulan, the total content of macrogol 400 and macrogol 4000 was 56% relative to the total weight of the composition). Example 2 A protective composition for gastrointestinal mucosa of the present invention containing powdery ibuprofen sodium salt as an oral drug was obtained in the following manner: 1000 mg of macrogol 400 and 200 mg of macrogol 4000 were uniformly dissolved through heating to 70° C., followed by lowering the liquid temperature to 60° C., then 2000 mg of ibuprofen sodium salt, 150 mg of hyaluronic acid, and 1000 mg of sodium hydrogen carbonate were sequentially added, and the mixture was cooled with mixing by thorough stirring. The resulting protective composition for gastrointestinal mucosa of the present invention was a white semi-solid form (clay form) in which ibuprofen sodium salt, hyaluronic acid, and sodium hydrogen carbonate were uniformly dispersed by a mixture of macrogol 400 and macrogol 4000. When put in a pharmacopeial artificial gastric juice, the composition immediately foamed vigorously and dispersed therein to form a uniform white opaque liquid, and then the components of the composition became dissolved or dispersed in the liquid without remaining on the liquid surface. The appearance of the resulting protective composition for gastrointestinal mucosa of the present invention is shown in FIG. 1 (central dish: the composition formed into a pill form, the total content of macrogol 400 and macrogol 4000 was 28% relative to the total weight of the composition). Example 3 A protective composition for gastrointestinal mucosa of the present invention containing powdery naproxen sodium salt as an oral drug was obtained in the following manner: 800 mg of macrogol 400 and 100 mg of macrogol 4000 were uniformly dissolved through heating to 70° C., followed by lowering the liquid temperature to 60° C., then 2000 mg of naproxen sodium salt, 150 mg of hyaluronic acid, and 2000 mg of sodium hydrogen carbonate were sequentially added, and the mixture was cooled with mixing by thorough stirring. The resulting protective composition for gastrointestinal mucosa of the present invention was a white semi-solid form (clay form) in which naproxen sodium salt, hyaluronic acid, and sodium hydrogen carbonate were uniformly dispersed by a mixture of macrogol 400 and macrogol 4000. When allowed to stand in a room for one day, the composition was changed into a solid, and when put into a pharmacopeial artificial gastric juice, the composition immediately foamed vigorously and dispersed therein to form a uniform white opaque liquid, and then the components of the composition became dissolved or dispersed in the liquid without remaining on the liquid surface. The appearance of the resulting protective composition for gastrointestinal mucosa of the present invention (solid) is shown in FIG. 1 (right dish, the total content of macrogol 400 and macrogol 4000 is 18% relative to the total weight of the composition). Example 4 A protective composition for gastrointestinal mucosa of the present invention containing powdery diclofenac sodium salt as an oral drug was obtained in the following manner: 2000 mg of macrogol 400 and 320 mg of macrogol 4000 were uniformly dissolved through heating to 65° C., then 200 mg of diclofenac sodium salt, 120 mg of hyaluronic acid, and 400 mg of sodium hydrogen carbonate were sequentially added, and the mixture was cooled with mixing by thorough stirring. The resulting protective composition for gastrointestinal mucosa of the present invention was a white viscous opaque liquid form in which diclofenac sodium salt, hyaluronic acid, and sodium hydrogen carbonate were uniformly dispersed in a mixture of macrogol 400 and macrogol 4000. When put in a pharmacopeial artificial gastric juice, the composition immediately foamed vigorously and dispersed therein to form a uniform white opaque liquid, and then the components of the composition became dissolved or dispersed in the liquid without remaining on the liquid surface. Example 5 A protective composition for gastrointestinal mucosa of the present invention containing powdery diclofenac sodium salt as an oral drug was obtained in the following manner: 2500 mg of macrogol 400 and 400 mg of macrogol 4000 were uniformly dissolved through heating to 65° C., then 250 mg of diclofenac sodium salt, 150 mg of hyaluronic acid, and 500 mg of sodium hydrogen carbonate were sequentially added, and the mixture was cooled with mixing by thorough stirring. The resulting protective composition for gastrointestinal mucosa of the present invention was a white gel form having high viscosity in which diclofenac sodium salt, hyaluronic acid, and sodium hydrogen carbonate were uniformly dispersed in a mixture of macrogol 400 and macrogol 4000. When put in a pharmacopeial artificial gastric juice, the composition immediately foamed vigorously and dispersed therein to form a uniform white opaque liquid, and then the components of the composition became dissolved or dispersed in the liquid without remaining on the liquid surface. Example 6 A protective composition for gastrointestinal mucosa of the present invention containing powdery diclofenac sodium salt as an oral drug was obtained in the following manner: 2500 mg of macrogol 400 and 400 mg of macrogol 4000 were uniformly dissolved through heating to 65° C., then 250 mg of diclofenac sodium salt, 150 mg of sodium chondroitin sulfate (manufactured by Kishida Chemical Co., Ltd.), and 500 mg of sodium hydrogen carbonate were sequentially added, and the mixture was cooled with mixing by thorough stirring. The resulting protective composition for gastrointestinal mucosa of the present invention was a white semi-solid form (wax form) in which diclofenac sodium salt, sodium chondroitin sulfate, and sodium hydrogen carbonate were uniformly dispersed by a mixture of macrogol 400 and macrogol 4000. When put in a pharmacopeial artificial gastric juice, the composition immediately foamed vigorously and dispersed therein to form a uniform white opaque liquid, and then the components of the composition became dissolved or dispersed in the liquid without remaining on the liquid surface. Example 7 A protective composition for gastrointestinal mucosa of the present invention containing powdery diclofenac sodium salt as an oral drug was obtained in the following manner: 2500 mg of macrogol 400 and 400 mg of macrogol 4000 were uniformly dissolved through heating to 65° C., then 250 mg of diclofenac sodium salt, 150 mg of chitosan (manufactured by Yaizu Suisankagaku Industry Co., Ltd.), and 500 mg of sodium hydrogen carbonate were sequentially added, and the mixture was cooled with mixing by thorough stirring. The resulting protective composition for gastrointestinal mucosa of the present invention was a white gel form having high viscosity in which diclofenac sodium salt, chitosan, and sodium hydrogen carbonate were uniformly dispersed in a mixture of macrogol 400 and macrogol 4000. When put in a pharmacopeial artificial gastric juice, the composition immediately foamed vigorously and dispersed therein to form a uniform white opaque liquid, and then the components of the composition became dissolved or dispersed in the liquid without remaining on the liquid surface. Example 8 A protective composition for gastrointestinal mucosa of the present invention containing powdery diclofenac sodium salt as an oral drug was obtained in the following manner: 2500 mg of macrogol 400 and 400 mg of macrogol 4000 were uniformly dissolved through heating to 65° C., then 250 mg of diclofenac sodium salt, 150 mg of fucoidan (manufactured by Yaizu Suisankagaku Industry Co., Ltd., molecular weight: about 200,000), and 500 mg of sodium hydrogen carbonate were sequentially added, and the mixture was cooled with mixing by thorough stirring. The resulting protective composition for gastrointestinal mucosa of the present invention was a white gel form having high viscosity in which diclofenac sodium salt, fucoidan, and sodium hydrogen carbonate were uniformly dispersed in a mixture of macrogol 400 and macrogol 4000. When put in a pharmacopeial artificial gastric juice, the composition immediately foamed vigorously and dispersed therein to form a uniform white opaque liquid, and then the components of the composition became dissolved or dispersed in the liquid without remaining on the liquid surface. Example 9 A protective composition for gastrointestinal mucosa of the present invention containing powdery naproxen sodium salt as an oral drug was obtained in the following manner: 1500 mg of propylene glycol and 2150 mg of macrogol 4000 were uniformly dissolved through heating to 70° C., followed by lowering the liquid temperature to 60° C., then 2000 mg of naproxen sodium salt, 150 mg of hyaluronic acid, and 1500 mg of sodium hydrogen carbonate were sequentially added, and the mixture was cooled with mixing by thorough stirring. The resulting protective composition for gastrointestinal mucosa of the present invention was a white semi-solid form (wax form) in which naproxen sodium salt, hyaluronic acid, and sodium hydrogen carbonate were uniformly dispersed by a mixture of propylene glycol and macrogol 4000. When put in a pharmacopeial artificial gastric juice, the composition immediately foamed vigorously and dispersed therein to form a uniform white opaque liquid, and then the components of the composition became dissolved or dispersed in the liquid without remaining on the liquid surface. Example 10 A protective composition for gastrointestinal mucosa of the present invention containing powdery diclofenac sodium salt as an oral drug was obtained in the following manner: 500 mg of macrogol 400 and 500 mg of macrogol 4000 were uniformly dissolved through heating to 70° C., followed by lowering the liquid temperature to 60° C., then 250 mg of diclofenac sodium salt, 150 mg of hyaluronic acid, 1500 mg of sodium hydrogen carbonate, and 1500 mg of potato starch were sequentially added, and the mixture was cooled with mixing by thorough stirring. The resulting protective composition for gastrointestinal mucosa of the present invention was a white semi-solid form (clay form) in which diclofenac sodium salt, hyaluronic acid, sodium hydrogen carbonate, and potato starch were uniformly dispersed by a mixture of macrogol 400 and macrogol 4000. When put in a pharmacopeial artificial gastric juice, the composition immediately foamed vigorously and dispersed therein to form a uniform white opaque liquid, and then the components of the composition became dissolved or dispersed in the liquid without remaining on the liquid surface. Example 11 A protective composition for gastrointestinal mucosa of the present invention containing powdery prednisolone as an oral drug was obtained in the following manner: to 800 mg of macrogol 400 heated to 65° C. were sequentially added 5 mg of prednisolone, 25 mg of hyaluronic acid, and 50 mg of sodium hydrogen carbonate, and the mixture was cooled with mixing by thorough stirring. The resulting protective composition for gastrointestinal mucosa of the present invention was a white viscous opaque liquid form in which prednisolone, hyaluronic acid, and sodium hydrogen carbonate were uniformly dispersed in macrogol 400. When put in a pharmacopeial artificial gastric juice, the composition immediately foamed vigorously and dispersed therein to form a uniform white opaque liquid, and then the components of the composition became dissolved or dispersed in the liquid without remaining on the liquid surface. Example 12 A protective composition for gastrointestinal mucosa of the present invention containing no oral drug was obtained in the following manner: 1840 mg of macrogol 400 and 40 mg of macrogol 4000 were uniformly dissolved through heating to 70° C., then 120 mg of hyaluronic acid and 320 mg of sodium hydrogen carbonate were sequentially added, and the mixture was cooled with mixing by thorough stirring. The resulting protective composition for gastrointestinal mucosa of the present invention was a white viscous opaque liquid form in which hyaluronic acid and sodium hydrogen carbonate were uniformly dispersed in a mixture of macrogol 400 and macrogol 4000. When put in a pharmacopeial artificial gastric juice, the composition immediately foamed vigorously and dispersed therein to form a uniform white opaque liquid, and then the components of the composition became dissolved or dispersed in the liquid without remaining on the liquid surface. Comparative Example 1 After 1840 mg of macrogol 400 and 40 mg of macrogol 4000 were uniformly dissolved through heating to 70° C., 120 mg of hyaluronic acid was added thereto, and the mixture was cooled with mixing by thorough stirring, whereby a white viscous opaque liquid form in which hyaluronic acid was uniformly dispersed in a mixture of macrogol 400 and macrogol 4000 was obtained. When this liquid was put in a pharmacopeial artificial gastric juice, it only gradually dispersed on a liquid surface, and did not become to a state where hyaluronic acid dissolved or dispersed in the liquid. Example 13 A protective composition for gastrointestinal mucosa of the present invention containing no oral drug was obtained in the following manner: 1840 mg of macrogol 400 and 40 mg of macrogol 4000 were uniformly dissolved through heating to 70° C., then 120 mg of xanthan gum (manufactured by MP Biomedicals, molecular weight: 2,000,000 or higher) and 320 mg of sodium hydrogen carbonate were sequentially added, and the mixture was cooled with mixing by thorough stirring. The resulting protective composition for gastrointestinal mucosa of the present invention was a white viscous opaque liquid form in which xanthan gum and sodium hydrogen carbonate were uniformly dispersed in a mixture of macrogol 400 and macrogol 4000. When put in a pharmacopeial artificial gastric juice, the composition immediately foamed vigorously and dispersed therein to form a uniform white opaque liquid, and then the components of the composition became dissolved or dispersed in the liquid without remaining on the liquid surface. Example 14 A protective composition for gastrointestinal mucosa of the present invention containing no oral drug was obtained in the following manner: 1500 mg of polyglycerine 500 and 2150 mg of macrogol 4000 were uniformly dissolved through heating to 70° C., then 150 mg of hyaluronic acid and 1500 mg of magnesium carbonate were sequentially added, and the mixture was cooled with mixing by thorough stirring. The resulting protective composition for gastrointestinal mucosa of the present invention was a white semi-solid form (wax form) in which hyaluronic acid and magnesium carbonate were uniformly dispersed by a mixture of polyglycerine 500 and macrogol 4000. When put in a pharmacopeial artificial gastric juice, the composition immediately foamed vigorously and dispersed therein to form a uniform white opaque liquid, and then the components of the composition became dissolved or dispersed in the liquid without remaining on the liquid surface. Example 15 A protective composition for gastrointestinal mucosa of the present invention containing no oral drug was obtained in the following manner: 1500 mg of polyglycerine 500 and 2150 mg of macrogol 4000 were uniformly dissolved through heating to 70° C., then 150 mg of hyaluronic acid, 1500 mg of magnesium carbonate, and 1000 mg of fumaric acid sodium salt were sequentially added, and the mixture was cooled with mixing by thorough stirring. The resulting protective composition for gastrointestinal mucosa of the present invention was a white semi-solid form (wax form) in which hyaluronic acid, magnesium carbonate, and fumaric acid sodium salt were uniformly dispersed by a mixture of polyglycerine 500 and macrogol 4000. When put in a pharmacopeial artificial gastric juice, the composition immediately foamed vigorously and dispersed therein to form a uniform white opaque liquid, and then the components of the composition became dissolved or dispersed in the liquid without remaining on the liquid surface. INDUSTRIAL AVAILABILITY The present invention has an industrial availability in the capability of providing a protective composition for gastrointestinal mucosa, for example, for inhibiting occurrence of a gastrointestinal mucosa disorder when an oral drug that induces the gastrointestinal mucosa disorder is taken. | <SOH> BACKGROUND ART <EOH>Some of oral drugs induce a gastrointestinal mucosa disorder as an adverse effect on the other side of their excellent pharmacological function, and nonsteroidal anti-inflammatory drugs (NSAIDs) are a typical example thereof. Thus, a method is demanded for inhibiting occurrence of a gastrointestinal mucosa disorder due to an oral drug that induces the gastrointestinal mucosa disorder by protecting gastrointestinal mucosa when the drug is taken. As an ingredient having a protective action for gastrointestinal mucosa, various ingredients have been heretofore reported, and one example is a macromolecular polysaccharide such as a mucopolysaccharide typified by hyaluronic acid. For example, Patent Document 1 proposes a gastric mucosa protective agent containing chondroitin sulfate which is one of mucopolysaccharides. | <SOH> SUMMARY OF THE INVENTION <EOH> | A61K31728 | 20171222 | 20180628 | 82648.0 | A61K31728 | 0 | HENRY, MICHAEL C | PROTECTIVE COMPOSITION FOR GASTROINTESTINAL MUCOSA | SMALL | 0 | PENDING | A61K | 2,017 |
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15,741,488 | PENDING | MIXED-REALITY ARCHITECTURAL DESIGN ENVIRONMENT | A computer system for managing multiple distinct perspectives within a mixed-reality design environment loads a three-dimensional architectural model into memory. The three-dimensional architectural model is associated with a virtual coordinate system. The three-dimensional architectural model comprises at least one virtual object that is associated with an independently executable software object that comprises independent variables and functions that are specific to a particular architectural element that is represented by the at least one virtual object. The computer system associates the virtual coordinate system with a physical coordinate system within a real-world environment. The computer system transmits to each device of multiple different devices rendering information. The rendering information comprises three-dimensional image data for rendering the three-dimensional architectural model and coordinate information that maps the virtual coordinate system to the physical coordinate system. | 1. A computer system for managing multiple distinct perspectives within a mixed-reality design environment, comprising: one or more processors; and one or more computer-readable media having stored thereon executable instructions that when executed by the one or more processors configure the computer system to perform at least the following: load a three-dimensional architectural model into memory, wherein: the three-dimensional architectural model is associated with a virtual coordinate system, and the three-dimensional architectural model comprises at least one virtual object that is associated with an independently executable software object that comprises independent variables and functions that are specific to a particular architectural element that is represented by the at least one virtual object; associate the virtual coordinate system with a physical coordinate system within a real-world environment; and transmit to each device of multiple different devices rendering information, wherein the rendering information comprises: three-dimensional image data comprising rendering instructions for the at least one virtual object within least a portion of the three-dimensional architectural model, and coordinate information that maps the virtual coordinate system to the physical coordinate system. 2. The computer system as recited in claim 1, wherein the executable instructions include instructions that are executable to configure the computer system to: receive from a particular device of the multiple different devices a ray that extends from a particular portion of a user's perspective towards a rendered portion of the three-dimensional architectural model; determine that the ray intersects with a rendered representation of the at least one virtual object; identify one or more functions associated with the independently executable software object that is associated with the at least one virtual object; and generate a command interface within the three-dimensional architectural model that depicts one or more commands related to the one or more functions. 3. The computer system as recited in claim 2, wherein determining that the ray intersects with a rendered representation of the at least one virtual object, comprises: extending the ray within the three-dimensional architectural model until it intersects the at least one virtual object. 4. The computer system as recited in claim 2, wherein the command interface is only generated within the three-dimensional architectural model that is rendered by the particular device. 5. The computer system as recited in claim 2, wherein the ray comprises coordinates within the three-dimensional architectural model and a direction. 6. The computer system as recited in claim 5, wherein the coordinates within the three-dimensional architectural model comprises a set of coordinates associated with a center of a user's field-of-view. 7. The computer system as recited in claim 1 wherein the executable instructions include instructions that are executable to configure the computer system to: update at least a portion of the three-dimensional architectural model; generate an updated three-dimensional image data that incorporates the updated portion; and transmit to each device of the multiple different devices updated rendering information, wherein the updated rendering information comprises the updated three-dimensional image data. 8. The computer system as recited in claim 1, wherein the three-dimensional image data consists of geometry information and texture information describing objects within the three-dimensional architectural model. 9. The computer system as recited in claim 1, wherein additional rendering information is only transmitted when a change is made to the three-dimensional architectural model. 10. A computer-implemented method for managing multiple distinct perspectives within a mixed-reality design environment, the method comprising: loading a three-dimensional architectural model into memory, wherein: the three-dimensional architectural model is associated with a virtual coordinate system, and the three-dimensional architectural model comprises at least one virtual object that is associated with an independently executable software object that comprises independent variables and functions that are specific to a particular architectural element that is represented by the at least one virtual object; associating the virtual coordinate system with a physical coordinate system within a real-world environment; and transmitting to each device of multiple different devices rendering information, wherein the rendering information comprises: three-dimensional image data comprising rendering instructions for the at least one virtual object within least a portion of the three-dimensional architectural model, and coordinate information that maps the virtual coordinate system to the physical coordinate system. 11. The computer-implemented method as recited in claim 10, furthering comprising: receiving from a particular device of the multiple different devices a ray that extends from a particular portion of a user's perspective towards a rendered portion of the three-dimensional architectural model; determining that the ray intersects with a rendered representation of the at least one virtual object; identifying one or more functions associated with the independently executable software object that is associated with the at least one virtual object; and generating a visual object within the three-dimensional architectural model that depicts one or more commands related to the one or more functions. 12. The computer-implemented method as recited in claim 11, further comprising: extending the ray within the three-dimensional architectural model until it intersects the at least one virtual object. 13. The computer-implemented method as recited in claim 11, wherein the visual object is only generated within the three-dimensional architectural model that is rendered by the particular device. 14. The computer-implemented method as recited in claim 11, wherein the ray comprises coordinates within the three-dimensional architectural model and a direction. 15. The computer-implemented method as recited in claim 14, wherein the coordinates within the three-dimensional architectural model comprises a set of coordinates associated with a center of a user's field-of-view. 16. The computer-implemented method as recited in claim 10 further comprising: updating at least a portion of the three-dimensional architectural model; generating an updated three-dimensional image data that incorporates the updated portion; and transmitting to each device of the multiple different devices updated rendering information, wherein the updated rendering information comprises the updated three-dimensional image data. 17. The computer-implemented method as recited in claim 10, wherein the three-dimensional image data consists of geometry information and texture information describing objects within the three-dimensional architectural model. 18. The computer-implemented method as recited in claim 10, wherein additional rendering information is only transmitted when a change is made to the three-dimensional architectural model. 19. A system for managing multiple distinct perspectives within a mixed-reality design environment, comprising: a mixed-reality server comprising executable instructions that when executed configure the mixed-reality server to perform at least the following: load a three-dimensional architectural model into memory, wherein: the three-dimensional architectural model is associated with a virtual coordinate system, and the three-dimensional architectural model comprises at least one virtual object that is associated with an independently executable software object that comprises independent variables and functions that are specific to a particular architectural element that is represented by the at least one virtual object; associate the virtual coordinate system with a physical coordinate system within a real-world environment; and transmit rendering information to a first mixed-reality device and a second mixed reality device, wherein the rendering information comprises: three-dimensional image data comprising rendering instructions for the at least one virtual object within least a portion of the three-dimensional architectural model, and coordinate information that maps the virtual coordinate system to the physical coordinate system; the first mixed-reality device comprising executable instructions that when execute configure the first mixed-reality device to perform at least the following: based upon the three-dimensional image data, render a first mixed-reality environment from a first perspective that is unique to the first mixed-reality device; and in response to a user input, communicate a first ray to the mixed-reality server; and the second mixed-reality device comprising executable instructions that when execute configure the second mixed-reality device to perform at least the following: based upon the three-dimensional image data, render a second mixed-reality environment from a second perspective that is unique to the second mixed-reality device; and in response to a user input, communicate a second ray to the mixed-reality server. 20. The system as recited in claim 19, wherein: the first ray comprises a first set of coordinates associated with a center of a user's field-of-view associated with the first mixed-reality device; and the second ray comprises a second set of coordinates associated with a center of a user's field-of-view associated with the second mixed-reality device. | BACKGROUND As computerized systems have increased in popularity, so have the range of applications that incorporate computational technology. Computational technology now extends across a broad range of applications, including a wide range of productivity and entertainment software. Indeed, computational technology and related software can now be found in a wide range of generic applications that are suited for many environments, as well as fairly industry-specific software. One such industry that has employed specific types of software and other computational technology increasingly over the past few years is that related to building and/or architectural design. In particular, architects and interior designers (“or designers”) use a wide range of computer-aided design (CAD) software or building information (BIM) software (i.e., “architectural design software applications”) for designing the aesthetic as well as functional aspects of a given residential or commercial space. For example, a designer might use a CAD or BIM program to design a building or part of a building, and then utilize drawings or other information from that program to order or manufacture building components. One particular benefit that is offered by modern CAD and BIM software is the ability to see a three-dimensional rendering of an architectural design. This can provide tremendous value to designers and/or clients who wish to visualize a design before starting the actual building process. For example, in at least one conventional system, a user may be able to view on a computer screen a completely rendered office building. The user may be able to navigate within the three-dimensional renderings such that the user can view different perspectives and locations throughout the design. While three-dimensional renderings can provide a user with a general idea regarding a final product, conventional three-dimensional renderings suffer from several shortcomings. For example, navigation of conventional three-dimensional renderings can be cumbersome as a user tries to achieve particular views of various features. Additionally, conventional systems may not be able to portray a true scale of a finished product. For example, a user's view of a conventional three-dimensional rendering on a computer screen may fall short of conveying a full appreciation for the scale of a particular feature or design. Accordingly, there are a number of problems in the art that can be addressed. BRIEF SUMMARY Embodiments of the present invention comprise systems, methods, and apparatus configured to allow one or more users to navigate and interact with a three-dimensional rendering of an architectural design. In particular, implementations of the present invention comprise mixed-reality components that create a mixed-reality environment that immerses a user. For example, the mixed-reality components may comprise a headset that at least partially covers a user's eyes and tracks the viewing angle of the user's eyes and/or head movement, a mobile phone that displays, to a user, mixed-reality elements, or any other device capable of providing a user a view of a real-world environment and accompanying mixed-reality elements. As such, the mixed-reality components can be used to generate a mixed-reality environment that allows a user to interact with an architectural design within a real-world space. Embodiments disclosed here include a computer system for managing multiple distinct perspectives within a mixed-reality design environment. The computer system loads a three-dimensional architectural model into memory. The three-dimensional architectural model is associated with a virtual coordinate system. The three-dimensional architectural model comprises at least one virtual object that is associated with an independently executable software object that comprises independent variables and functions that are specific to a particular architectural element that is represented by the at least one virtual object. The computer system associates the virtual coordinate system with a physical coordinate system within a real-world environment. The computer system transmits to each device of multiple different devices rendering information. The rendering information comprises three-dimensional image data for rendering the three-dimensional architectural model and coordinate information that maps the virtual coordinate system to the physical coordinate system. Disclosed embodiments also comprise a system for managing multiple distinct perspectives within a mixed-reality design environment. The system includes a mixed-reality server that loads a three-dimensional architectural model into memory. The three-dimensional architectural model is associated with a virtual coordinate system. The three-dimensional architectural model also comprises at least one virtual object that is associated with an independently executable software object that comprises independent variables and functions that are specific to a particular architectural element that is represented by the at least one virtual object. The mixed-reality server associates the virtual coordinate system with a physical coordinate system within a real-world environment. The mixed-reality server then transmits rendering information to a first mixed-reality device and a second mixed reality device. The rendering information comprises three-dimensional image data comprising rendering instructions for the at least one virtual object within least a portion of the three-dimensional architectural model, and coordinate information that maps the virtual coordinate system to the physical coordinate system. The first mixed-reality device renders a first mixed-reality environment from a first perspective that is unique to the first mixed-reality device. In response to a user input, the first mixed-reality device communicates a first ray to the mixed-reality server. Similarly, the second mixed-reality device renders a second mixed-reality environment from a second perspective that is unique to the second mixed-reality device. In response to a user input, the second mixed-reality device communicates a second ray to the mixed-reality server. This Summary is provided to introduce a selection of concepts in a simplified form that are further described below in the Detailed Description. This Summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject matter. Additional features and advantages will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by the practice of the teachings herein. Features and advantages of the invention may be realized and obtained by means of the instruments and combinations particularly pointed out in the appended claims. Features of the present invention will become more fully apparent from the following description and appended claims, or may be learned by the practice of the invention as set forth hereinafter. BRIEF DESCRIPTION OF THE DRAWINGS In order to describe the manner in which the above-recited and other advantages and features can be obtained, a more particular description of the subject matter briefly described above will be rendered by reference to specific embodiments which are illustrated in the appended drawings. Understanding that these drawings depict only typical embodiments and are not therefore to be considered to be limiting in scope, embodiments will be described and explained with additional specificity and detail through the use of the accompanying drawings in which: FIG. 1 illustrates a schematic diagram of an embodiment of an architectural design software application. FIG. 2 illustrates a user's view of a room within an embodiment of a mixed-reality environment. FIG. 3 illustrates a user interacting with the mixed-reality environment depicted in FIG. 2. FIG. 4 illustrates an embodiment of a user interfacing with a mixed-reality environment. FIG. 5 illustrates a schematic of a user interaction with the mixed-reality environment depicted in FIG. 2. FIG. 6 illustrates a flowchart of a series of acts in an embodiment of a method for managing multiple distinct perspectives within a mixed-reality design environment. DETAILED DESCRIPTION Disclosed embodiments extend to systems, methods, and apparatus configured to allow one or more users to navigate and interact with a three-dimensional rendering of an architectural design. In particular, implementations of the present invention comprise mixed-reality components that create a mixed-reality environment that immerses a user. For example, the mixed-reality components may comprise a headset that at least partially covers a user's eyes and tracks the viewing angle of the user's eyes and/or head movement, a mobile phone that displays, to a user, mixed-reality elements, or any other device capable of providing a user a view of a real-world environment and accompanying mixed-reality elements. As such, the mixed-reality components can be used to generate a mixed-reality environment that allows a user to interact with an architectural design within a real-world space. Disclosed embodiments include a mixed-reality architectural design system that injects mixed-reality elements into a real-world space. For example, a user may be interested in building out office space on an empty floor of a high-rise building. In various disclosed embodiments, the mixed-reality architectural design system injects mixed-reality elements into the floor space through the user's viewing device. The viewing device may comprise a mixed-reality headset, a virtual reality headset, a mobile phone display, or any other device capable of capturing the real-world space and rendering three-dimensional objects. Disclosed embodiments allow a user to view virtual renderings of architectural designs within the real world. For instance, the mixed-reality architectural design system is capable of displaying to the user mixed-reality elements that include walls, furniture, lights, textures, and various other design elements that have been designed for the user's office. Additionally, the mixed-reality architectural design system is capable of receiving commands and presenting options to the user that manipulate and change the architectural design within the mixed-reality world. For example, while wearing a mixed-reality headset, the user may determine that a particular wall needs to be extended. Using appropriate input, which may include hand motions, eye motions, head movement, input through a keyboard, input through a touch interface, or other similar input, the user directs the mixed-reality architectural design system to extend the wall. In at least one embodiment, the mixed-reality architectural design system extends the wall in real-time such that the user sees the wall being extended within the mixed-reality environment. Turning now to the figures, FIG. 1 illustrates a schematic diagram of an embodiment of an architectural design software application 100 (also referred to herein as a mixed-reality architectural design system). The depicted architectural design software application 100 comprises various modules and components including a processing unit 110, an architectural design module 120, a data storage 130, and an input/output interface 140. One will understand, however, that the depicted modules and components are merely exemplary and are provided for the sake of explanation. In various additional or alternative embodiments, an architectural design software application 100 may comprise different configurations and descriptions of modules and components that are equivalent to those described herein. As depicted, the architectural design software application 100 is in communication with various mixed-reality devices, including, a virtual-reality device 150a, an augmented-reality device 150b, and a smart phone 150c. As used herein, mixed-reality comprises any usage of computer generated elements that incorporate a virtual object within a user's real-world space. For example, mixed reality includes virtual reality where a user is completely immersed within a virtual world, augmented reality where a user is immersed within both a real-world space and a virtual space, and any other combination thereof of real-world and virtual elements. The architectural design software application 100 allows a user to incorporate virtual elements within a real-world space. For example, the user can design an architectural model or schematic using conventional CAD systems and then interfacing with architectural design software application 100 through a mixed-reality environment. For example, the user can create an architectural design within a two-dimensional CAD interface. The two-dimensional design can be transformed into a three-dimensional model that can be incorporated into a mixed-reality environment. Similarly, the user may be able to view the two-dimensional design within the mixed-reality environment. Additionally, a user can also create a two- or three-dimensional architectural design within the mixed-reality environment by placing virtual architectural elements within the mixed-reality environment in real-time. For example, the user can cause a wall to be generated within the mixed-reality environment. An associated CAD file can then be updated to reflect the new wall. Accordingly, an entire architectural design can be created entirely within a mixed-reality environment. In at least one embodiment, a processing unit 110 manages communication and interfacing between an input/output interface 140 and architectural design module 120. The architectural design module 120 may comprise a special-purpose CAD program or a conventional CAD program that is capable of exporting architectural design schematics. In various embodiments, the architectural design module 120 accesses architectural designs files that are stored within the data storage 130. As such, the architectural design module 120 can load a conventional architectural design file that is within design storage 120 and provide the file to processing unit 110. The processing unit 110 then loads the three-dimensional architectural model into memory. In at least one embodiment, the three-dimensional architectural model comprises one or more architectural design elements that have been designed to fit within a real-world space. For example, the three-dimensional architectural model may comprise an entire building that has been designed to fit on a plot of land. In contrast, the three-dimensional architectural model may also comprise a design for the lobby of a business. The three-dimensional architectural model may include architectural design elements such as wiring, plumbing, wall position, furniture, lighting, and other related design features. Additionally, in at least one embodiment, one or more of the architectural design elements are associated with independently executable software objects. The independently executable software objects are functional within the architectural design software application 100 to provide context and functionality specific to the individual architecture design elements with which each independently executable software object is associated. By way of explanation, an independently executable software object comprises a set of computer-executable instructions used in object-oriented program code, and which relate to a particular physical component or feature. In addition, software objects can be interrelated via parent/child dependency relationships where changes in a parent object flow through to a child object and vice versa. For example, a software object created for a table may have several child objects for each leg. In other cases, the software objects can be related to other software objects that represent physically proximate components (e.g., a wall object that is positioned next to the table object). For example, the above-mentioned table software object and leg software objects can independently execute in a correlated fashion to ensure each corresponding physical component (i.e., the table top, or the table legs) is positioned appropriately, or otherwise colored and designed consistent with the user's specifications. For instance, a leg software object can identify that its location next to a wall renders a physical leg unnecessary, and accordingly can automatically incorporate a bracket to attach directly to the wall in place of a physical leg. As such, each independently executable software object comprises independent variables and functions that are specific to the particular architectural element that is represented by the at least one virtual object. For example, the exemplary table from above may be associated with a selection of possible woods. The independently executable software object associated with the table, may comprise variables that are associated with the different possible woods and also the functions necessary to switch between the different possible woods. Additionally, in at least one embodiment, the processing unit 110 generates a coordinate system that associates a virtual coordinate system within the architectural design schematic with a physical coordinate system with a real-world environment. For example, the processing unit 110 may generate a coordinate system that associates the architectural schematic for a user's planned office space with a physical coordinates system that is associated with the physical office space itself. As such, when rendering the mixed-reality elements that are associated with the architectural design schematic, the elements appear within the correct position within the real-world environment due to the common coordinate system generated by the processing unit 110. The processing unit 110 then transmits to the input/out interface (and on to the mixed-reality devices 150(a-c)) rendering information. The rendering information comprises three-dimensional model data describing at least a portion of the three-dimensional architectural model and coordinate information that maps the virtual coordinate system to the physical coordinate system. In at least one embodiment, the three-dimensional model data consists of geometry information and texture information describing objects within the three-dimensional architectural model. As such, in at least one embodiment, the mixed-reality devices 150(a-c) are only rendering received geometries and textures without any metadata or knowledge about the independently executable software objects or other attributes associated with the architectural elements. In contrast to providing the entire data available within the CAD file, providing only geometries and textures provides several significant technical benefits, such as requiring significantly less processing power at the mixed-reality devices 150(a-c) and requiring less bandwidth to communicate the information. FIG. 2 illustrates a user's view of a room within a mixed-reality environment 200. In particular, FIG. 2 depicts an empty room that comprises various virtual elements 220, 230, 240. As used herein, a virtual element, also referred to as a virtual object, comprises a rendered object within the mixed-reality environment 200. In contrast, a real-world element comprises a physical object within the mixed-reality environment 200. The depicted room comprises a triangle shaped cubicle 220 with an associated desk surface 230 and a light fixture 240. In addition to the virtual elements 220, 230, 240 within the room. The room also comprises a real-world element in the form of real-world target 210. In at least one embodiment, before a virtual element is displayed to a user, the user must point their mixed-reality device 150 (a-c) at the target 210 within the physical world. The location of the target 210 within the physical world is known to the processing unit 110. As such, the processing unit 110 can generate the shared coordinate system between the three-dimensional model (i.e., the mixed-reality elements) and the real-world room. In various additional or alternative embodiments, the target 210 may comprise a set of lights, a particular symbol, or known objects within the real-world environment. For example, in at least one embodiment, a user may utilize the mixed-reality device outdoors to view a proposed building that is to be built. The mixed-reality device may utilize a real-world building, or some other physical landmark, as a target. The processing unit 110 may also be aware of the location of the currently built building and thus can generate a common coordinate system. In at least one embodiment, however, a target 210 is not necessary to generate a common coordinate system. For example, in at least one embodiment, a one or more of an electronic compass, an altimeter, a GPS, a Wi-Fi receiver, a BLUETOOTH receiver, or some other location aware device may be sufficient to generate a common coordinate system. In addition to allowing a user to view virtual elements within the real-world environment in which the virtual elements are designed to fit, disclosed embodiments also provide tools for a user to interact with and change the virtual elements. For example, area 250 depicts a particular portion of the mixed-reality environment that a user desires to interact with. Various different methods can be utilized by the user to select the area. For example, the user may point at the area, the user may make a pinching motion over the area, the user may select the area with an interface device integrated within the mixed-reality device 150(a-c) or through any other method suitable for interacting with a mixed-reality element. As depicted in FIG. 3, in at least one embodiment, the user interacts with the mixed-reality light fixture 240 by making a pinching motion with their hand 310 that intersects at the lighting fixture 140 within the user's view. Upon making the pinching motion, the user's mixed-reality device 150(a-c) calculates a ray that extends from a particular portion 300 of the user's perspective towards the direction in which the user pinched, or in this case, towards areas 250. FIG. 4 illustrates a different perspective of a user 400 interfacing with the mixed-reality environment 200 of FIG. 3. As depicted, the user 400 is wearing a head-mounted display 410 through which virtual elements are rendered. The user's makes a pinching motion with his hand 310. Upon identifying the pinching motion, the processing unit 110 calculates an angle 420 that indicates the direction of the ray 430 relative to center of the user's field-of-view (e.g., particular portion 300). One will appreciate that similar functionality can be accomplished with a video camera and display on a smart phone, where an angle 420 is calculated from the center point of the user's view within the display. Once the angle 420 is identified, the ray 430 can be fully described using only the angle 420 and the coordinates of the center of the user's field-of-view. One will appreciate that the coordinates could also be associated with a location other than the center of the user's field-of-view. In at least one embodiment, the coordinates comprises coordinates within either the virtual coordinate system or the physical coordinate system, which the processing unit 110 is able to interchange between. Additionally, in at least one embodiment, the angle 420 comprises an angle within three-dimensional space. For example, the angle 420 may be associated with multiple individual values that properly place the angle within the physical coordinate system or the virtual coordinate system. In at least one embodiment, once the ray 430 is identified, the user's mixed-reality device (i.e., head-mounted display 410) communicates the ray 430 to the processing unit 110. The processing unit 110 then extends the ray within the three-dimensional architectural model until it intersects the at least one virtual object. For example, the processing unit 110 is aware of the entire mixed-reality environment. Using this awareness, the processing unit 110 is capable determining whether the ray intersects with a virtual object, such as the light fixture 240. As such, in at least one embodiment, upon receiving a user input (e.g., the pinching motion), the mixed-reality device communicates only a ray 430 generated from the user input to the processing unit 110. The processing unit 110 then determines what virtual object the user is interacting with by extending the ray until it intersects with the target virtual object. Upon identifying the intersected object (in this example the light fixture 240), the processing unit 110 identifies one or more functions associated with the independently executable software object that is associated with the at least one virtual object. For example, the independently executable software object associated with light fixture 240 comprises functions for selecting the color of the light shade, the color of the light, the intensity of the light, whether the light is on or off, and various other similar attributes. The processing unit 110 then generates the necessary rendering information for the user's mixed-reality device to generate a command interface within the three-dimensional architectural model that depicts one or more commands related to the one or more functions. For example, FIG. 3 depicts a command interface 320 that indicates various functions that can be performed on the light fixture 240. In at least one embodiment, the same methods and systems described above are used by the user to select a particular option in the command interface 320. For example, the user can simply make a pinching motion over the command of choice. One will appreciate, in view of the above, that disclosed embodiments provide a highly efficient system for communicating a three-dimensional architectural model to one or more users and allowing them to interact with the model. For example, in at least one embodiment, several dozen or even hundreds of users may be viewing an architectural model of a building using their own mobile phones. One will appreciate the tremendous amount of bandwidth it would require to communicate the entire model to each device. Instead of communicating the entire model to each device, disclosed embodiments communicate only textures, geometries, and coordinates systems to the mixed-reality. Further, in some embodiments, the architectural design software application 100 only communicates the portions of the textures and geometries need to each individual device. As such, each device may comprise different textures and geometries, but each device can receive additional textures and geometries as needed. Further, in at least one embodiment, each user is capable of interacting with the three-dimensional architectural model by simply communicating rays to the architectural design software application 100. The processing unit 110 then determines what virtual objects the respective rays intersect with, and communicates back to the respective mixed-reality devices the textures and geometries necessary to render the respective command interfaces. In at least one embodiment, each respective command interface is only rendered by the mixed-reality device with which it is associated. Accordingly, disclosure embodiments utilize a highly efficient method of communicate data that removes heavy processing loads from the individual mixed-reality devices. In at least one embodiment, executing the command comprises changing the three-dimensional architectural model in some way. Once the model is changed, the architectural design module 120 communicates the updated model to the processing unit 110. The processing unit 110 then communicates an updated rendering information 200 to the user, and any other users also within the same mixed-reality environment. In at least one embodiment, to conserve bandwidth, the processing unit 110 only communicates the updated portions of the mixed-reality environment and only communicates it to users who are likely to view the updated portions. As such, in various embodiments, a user can manipulate an architectural design from within a mixed-reality environment. The respective changes can be made within an architectural design module 120, which updates a corresponding CAD file. Additionally, the changes can be propagated simultaneously to multiple mixed-reality devices 150(a-c) for viewing in real time. Further, bandwidth and processing power can be conserved by communicating only textures and geometries to the mixed-reality devices 150(a-c), and, in turn, primarily communicating rays back to the architectural design software application 100 for interpretation into specific commands and requests. As mentioned above, in various embodiments, multiple mixed-reality devices 150(a-c) can be within the same mixed-reality environment 200 simultaneously. For example, in at least one embodiment, a first user may be utilizing an augmented reality headset 150b within mixed-reality environment 200, while a large group of other users are experiencing the mixed-reality environment 200 through their mobile phones 150c. For example, the other group of users may hold their phones before their faces and see the mixed-reality elements displayed within the viewing screen of their phone in the mixed-reality environment 200. Additionally, various motion tracking sensors within the phones may allow the users to move around and change perspective with respect to the mixed-reality environment. Similarly, as described above, in at least one embodiment, one or more of the users with phones may be able to simultaneously manipulate and change the mixed-reality environment by issuing commands from their phones. For example, a user's phone can communicate rays to the architectural design software application 100, which processes the ray as described above. Additionally, in at least one embodiment, fixed-cameras can be utilized within the mixed-reality environment. For example, the location and height of a camera can be entered into the architectural design software application 100. The architectural design software application 100 can then communicate the fixed camera's view to a display screen for individuals to view the mixed-reality environment. Additionally, in at least one embodiment, data received from the fixed camera can be used to control objects within the real-world environment. For example, an automated vacuum cleaner may receive a command to stop before running into a virtual wall that is not apparent to the vacuum cleaner, but is apparent within the mixed-reality environment from the perspective of the fixed camera. Accordingly, FIGS. 1-5 and the corresponding text illustrate or otherwise describe one or more components, modules, and/or mechanisms for rendering a specular effect within a three-dimensional model. One will appreciate that disclosed embodiments can allow multiple users to view a mixed-reality environment while processing and receiving a minimal amount of information. The following discussion now refers to a number of methods and method acts that may be performed. Although the method acts may be discussed in a certain order or illustrated in a flow chart as occurring in a particular order, no particular ordering is required unless specifically stated, or required because an act is dependent on another act being completed prior to the act being performed. For example, FIG. 6 illustrates that a method 600 for managing multiple distinct perspectives within a mixed-reality design environment includes an act 610 of loading a three-dimensional architectural model into memory. Act 610 comprises loading a three-dimensional architectural model into memory. The three-dimensional architectural model is associated with a virtual coordinate system. The three-dimensional architectural model comprises at least one virtual object that is associated with an independently executable software object that comprises independent variables and functions that are specific to a particular architectural element that is represented by the at least one virtual object. For example, as depicted and described with respect to FIGS. 1 and 2, the processing unit 110 loads into memory a three-dimensional architectural model that is associated with the room depicted in FIG. 2. An exemplary virtual object, the light fixture 240, is associated with independently executable software objects that include functions and variables describing the light fixture 200. Additionally, method 600 includes an act 620 of associating a virtual coordinate system with a physical coordinate system. Act 620 comprises associating the virtual coordinate system with a physical coordinate system within a real-world environment. For example, as depicted and described with respect to FIGS. 1 and 2, a target 210 within the room is used to map a virtual coordinate system to a real-world coordinate system. Method 600 also includes an act 630 of transmitting rendering information. Act 630 comprises transmitting to each device of multiple different devices rendering information. The rendering information comprises three-dimensional image data comprising rendering instructions for the at least one virtual object within least a portion of the three-dimensional architectural model, and coordinate information that maps the virtual coordinate system to the physical coordinate system. For example, as depicted and described with respect to FIGS. 1-3, the processing unit communicates rendering information in the form of textures and geometries. The textures and geometries describe virtual objects such as lighting fixture 240. Accordingly, embodiments disclosed herein include systems and methods for displaying and interacting with three-dimensional architectural designs within a mixed-reality environment. In particular, disclosed embodiments overcome several different technical challenges relating to processor limitations and bandwidth limitations when communicating with large numbers of devices and or underpowered devices. For example, as described above, disclosed embodiments allow mixed-reality devices 150(a-c) to generate mixed-reality environments using only a common coordinate system and textures and geometries. As such, a user is able to intuitively and personally interact with an architectural design in real-time within an actual physical design space without requiring large amounts of processing power and bandwidth. Further, the methods may be practiced by a computer system including one or more processors and computer-readable media such as computer memory. In particular, the computer memory may store computer-executable instructions that when executed by one or more processors cause various functions to be performed, such as the acts recited in the embodiments. Embodiments of the present invention may comprise or utilize a special purpose or general-purpose computer including computer hardware, as discussed in greater detail below. Embodiments within the scope of the present invention also include physical and other computer-readable media for carrying or storing computer-executable instructions and/or data structures. Such computer-readable media can be any available media that can be accessed by a general purpose or special purpose computer system. Computer-readable media that store computer-executable instructions are physical storage media. Computer-readable media that carry computer-executable instructions are transmission media. Thus, by way of example, and not limitation, embodiments of the invention can comprise at least two distinctly different kinds of computer-readable media: physical computer-readable storage media and transmission computer-readable media. Physical computer-readable storage media includes RAM, ROM, EEPROM, CD-ROM or other optical disk storage (such as CDs, DVDs, etc.), magnetic disk storage or other magnetic storage devices, or any other medium which can be used to store desired program code means in the form of computer-executable instructions or data structures and which can be accessed by a general purpose or special purpose computer. A “network” is defined as one or more data links that enable the transport of electronic data between computer systems and/or modules and/or other electronic devices. When information is transferred or provided over a network or another communications connection (either hardwired, wireless, or a combination of hardwired or wireless) to a computer, the computer properly views the connection as a transmission medium. Transmissions media can include a network and/or data links which can be used to carry or desired program code means in the form of computer-executable instructions or data structures and which can be accessed by a general purpose or special purpose computer. Combinations of the above are also included within the scope of computer-readable media. Further, upon reaching various computer system components, program code means in the form of computer-executable instructions or data structures can be transferred automatically from transmission computer-readable media to physical computer-readable storage media (or vice versa). For example, computer-executable instructions or data structures received over a network or data link can be buffered in RAM within a network interface module (e.g., a “NIC”), and then eventually transferred to computer system RAM and/or to less volatile computer-readable physical storage media at a computer system. Thus, computer-readable physical storage media can be included in computer system components that also (or even primarily) utilize transmission media. Computer-executable instructions comprise, for example, instructions and data which cause a general purpose computer, special purpose computer, or special purpose processing device to perform a certain function or group of functions. The computer-executable instructions may be, for example, binaries, intermediate format instructions such as assembly language, or even source code. Although the subject matter has been described in language specific to structural features and/or methodological acts, it is to be understood that the subject matter defined in the appended claims is not necessarily limited to the described features or acts described above. Rather, the described features and acts are disclosed as example forms of implementing the claims. Those skilled in the art will appreciate that the invention may be practiced in network computing environments with many types of computer system configurations, including, personal computers, desktop computers, laptop computers, message processors, hand-held devices, multi-processor systems, microprocessor-based or programmable consumer electronics, network PCs, minicomputers, mainframe computers, mobile telephones, PDAs, pagers, routers, switches, and the like. The invention may also be practiced in distributed system environments where local and remote computer systems, which are linked (either by hardwired data links, wireless data links, or by a combination of hardwired and wireless data links) through a network, both perform tasks. In a distributed system environment, program modules may be located in both local and remote memory storage devices. Alternatively, or in addition, the functionality described herein can be performed, at least in part, by one or more hardware logic components. For example, and without limitation, illustrative types of hardware logic components that can be used include Field-programmable Gate Arrays (FPGAs), Program-specific Integrated Circuits (ASICs), Program-specific Standard Products (ASSPs), System-on-a-chip systems (SOCs), Complex Programmable Logic Devices (CPLDs), etc. The present invention may be embodied in other specific forms without departing from its spirit or characteristics. The described embodiments are to be considered in all respects only as illustrative and not restrictive. The scope of the invention is, therefore, indicated by the appended claims rather than by the foregoing description. All changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope. | <SOH> BACKGROUND <EOH>As computerized systems have increased in popularity, so have the range of applications that incorporate computational technology. Computational technology now extends across a broad range of applications, including a wide range of productivity and entertainment software. Indeed, computational technology and related software can now be found in a wide range of generic applications that are suited for many environments, as well as fairly industry-specific software. One such industry that has employed specific types of software and other computational technology increasingly over the past few years is that related to building and/or architectural design. In particular, architects and interior designers (“or designers”) use a wide range of computer-aided design (CAD) software or building information (BIM) software (i.e., “architectural design software applications”) for designing the aesthetic as well as functional aspects of a given residential or commercial space. For example, a designer might use a CAD or BIM program to design a building or part of a building, and then utilize drawings or other information from that program to order or manufacture building components. One particular benefit that is offered by modern CAD and BIM software is the ability to see a three-dimensional rendering of an architectural design. This can provide tremendous value to designers and/or clients who wish to visualize a design before starting the actual building process. For example, in at least one conventional system, a user may be able to view on a computer screen a completely rendered office building. The user may be able to navigate within the three-dimensional renderings such that the user can view different perspectives and locations throughout the design. While three-dimensional renderings can provide a user with a general idea regarding a final product, conventional three-dimensional renderings suffer from several shortcomings. For example, navigation of conventional three-dimensional renderings can be cumbersome as a user tries to achieve particular views of various features. Additionally, conventional systems may not be able to portray a true scale of a finished product. For example, a user's view of a conventional three-dimensional rendering on a computer screen may fall short of conveying a full appreciation for the scale of a particular feature or design. Accordingly, there are a number of problems in the art that can be addressed. | <SOH> BRIEF SUMMARY <EOH>Embodiments of the present invention comprise systems, methods, and apparatus configured to allow one or more users to navigate and interact with a three-dimensional rendering of an architectural design. In particular, implementations of the present invention comprise mixed-reality components that create a mixed-reality environment that immerses a user. For example, the mixed-reality components may comprise a headset that at least partially covers a user's eyes and tracks the viewing angle of the user's eyes and/or head movement, a mobile phone that displays, to a user, mixed-reality elements, or any other device capable of providing a user a view of a real-world environment and accompanying mixed-reality elements. As such, the mixed-reality components can be used to generate a mixed-reality environment that allows a user to interact with an architectural design within a real-world space. Embodiments disclosed here include a computer system for managing multiple distinct perspectives within a mixed-reality design environment. The computer system loads a three-dimensional architectural model into memory. The three-dimensional architectural model is associated with a virtual coordinate system. The three-dimensional architectural model comprises at least one virtual object that is associated with an independently executable software object that comprises independent variables and functions that are specific to a particular architectural element that is represented by the at least one virtual object. The computer system associates the virtual coordinate system with a physical coordinate system within a real-world environment. The computer system transmits to each device of multiple different devices rendering information. The rendering information comprises three-dimensional image data for rendering the three-dimensional architectural model and coordinate information that maps the virtual coordinate system to the physical coordinate system. Disclosed embodiments also comprise a system for managing multiple distinct perspectives within a mixed-reality design environment. The system includes a mixed-reality server that loads a three-dimensional architectural model into memory. The three-dimensional architectural model is associated with a virtual coordinate system. The three-dimensional architectural model also comprises at least one virtual object that is associated with an independently executable software object that comprises independent variables and functions that are specific to a particular architectural element that is represented by the at least one virtual object. The mixed-reality server associates the virtual coordinate system with a physical coordinate system within a real-world environment. The mixed-reality server then transmits rendering information to a first mixed-reality device and a second mixed reality device. The rendering information comprises three-dimensional image data comprising rendering instructions for the at least one virtual object within least a portion of the three-dimensional architectural model, and coordinate information that maps the virtual coordinate system to the physical coordinate system. The first mixed-reality device renders a first mixed-reality environment from a first perspective that is unique to the first mixed-reality device. In response to a user input, the first mixed-reality device communicates a first ray to the mixed-reality server. Similarly, the second mixed-reality device renders a second mixed-reality environment from a second perspective that is unique to the second mixed-reality device. In response to a user input, the second mixed-reality device communicates a second ray to the mixed-reality server. This Summary is provided to introduce a selection of concepts in a simplified form that are further described below in the Detailed Description. This Summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject matter. Additional features and advantages will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by the practice of the teachings herein. Features and advantages of the invention may be realized and obtained by means of the instruments and combinations particularly pointed out in the appended claims. Features of the present invention will become more fully apparent from the following description and appended claims, or may be learned by the practice of the invention as set forth hereinafter. | G06T19006 | 20180102 | 20180712 | 74251.0 | G06T1900 | 1 | TSWEI, YU-JANG | MIXED-REALITY ARCHITECTURAL DESIGN ENVIRONMENT | UNDISCOUNTED | 0 | ACCEPTED | G06T | 2,018 |
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15,743,737 | PENDING | METHOD AND DEVICE FOR GENERATING A DEVICE-SPECIFIC IDENTIFIER, AND DEVICES COMPRISING A PERSONALIZED PROGRAMMABLE CIRCUIT COMPONENT | Provided is a method for generating a device-specific identifier in a device which contains at least one programmable circuit component and the circuit of which consists of individual components that are configured by loading a bitstream, having the following method steps: displaying the reference identifier as a bit sequence and assigning each bit of the reference identifier to a respective different component of the circuit component; generating a reference bitstream for a reference circuit of the circuit component, the bitstream containing at least the specified component of the reference identifier, and entering the device specific identifier as a binary sequence by overwriting the bits of the corresponding components of the reference identifier directly in the reference bitstream. | 1. A method for generating a device-specific identifier in a device, which contains at least one programmable circuit element and whose circuit comprises individual components which are configured by loading a bitstream, the method comprising: representing a reference identifier as a bit sequence, and the assignment of each bit of the reference identifier to a different component of the at least one programmable circuit element in each case; generating a reference bitstream for a reference circuit of the at least one programmable circuit element, in which at least the predetermined components of the reference identifier are contained; and entering the device-specific identifier as a binary sequence by overwriting the bits of the corresponding components of the reference identifier directly in the reference bitstream. 2. The method as claimed in claim 1, wherein each component of the reference identifier is configured in a fixed manner to output either a value zero or a value one. 3. The method as claimed in claim 1, wherein an existing checksum across the reference bitstream is replaced by a newly calculated checksum over the device-specific bitstream. 4. The method as claimed in claim 1, wherein the bits through which a component of the reference identifier is encoded in the bitstream are determined by the method: (a) generating a reference bitstream of the reference circuit, (b) generating a further bitstream for a further circuit changed by at least one bit of the predetermined reference identifier, and (c) determining at least one position of a bit which is changed in the generated further bitstream in comparison with the reference bitstream. 5. The method as claimed in claim 1, wherein the predetermined reference identifier consists of a plurality of partial reference identifiers distributed arbitrarily in the reference circuit. 6. The method as claimed in claim 4, wherein the further bitstream is only generated for a partial region of the reference circuit which comprises the reference identifier. 7. The method as claimed in claim 4, wherein the circuit, which is changed by one bit, is used as a new reference circuit for the determination of the position of a next bit of the reference identifier. 8. The method as claimed in claim 4, wherein, in a multiply changed circuit, more than one bit of the reference identifier is changed, and/or through the combination of a plurality of further bitstreams generated from multiply changed circuits, the positions of the bits in the bitstream of the changed bit in the changed circuit are determined. 9. The method as claimed in claim 4, wherein a table is generated in which the at least one position of a bit that is changed in comparison with the reference bitstream in the further bitstream generated therefrom is assigned to each changed bit of the reference circuit. 10. The method as claimed in claim 1, wherein the device-specific identifier is a cryptographic key or a serial number. 11. An apparatus for the generation of a device-specific identifier in a programmable circuit element whose circuit comprises individual components, which is configured by loading a bitstream, comprising: an assignment unit which is configured to represent a reference identifier as a bit sequence and to assign a different component of the at least one programmable circuit element to each bit of the reference identifier; a generation unit which is designed to generate a reference bitstream for a reference circuit of the at least one programmable circuit element in which at least the predetermined components of the reference identifier are contained; and an insertion unit which is designed to insert the device-specific identifier as a binary sequence by overwriting the bits of the corresponding components of the reference identifier directly into the reference bitstream. 12. The apparatus as claimed in claim 11, additionally containing a determination unit which is designed to: generate a reference bitstream of the reference circuit, generate a further bitstream for a further circuit that is changed by at least one bit of the predetermined reference identifier, and determine at least one position of a bit which is changed in the generated further bitstream in comparison with the reference bitstream. 13. The apparatus as claimed in claim 11, additionally comprising a memory unit which is designed to store a table in which the at least one position of a bit which is changed in the generated further bitstream in comparison with the reference bitstream is assigned to each changed bit of the reference circuit. 14. A first device comprising a programmable circuit element, wherein a device-specific identifier according to the method of claims 1 is introduced into the programmable circuit element. 15. A second device comprising: a programmable circuit element; a memory unit which contains a device-specific identifier, a reference bitstream of a reference circuit of the circuit element along with a table, wherein the at least one position (PFi) of a bit which is changed in the further bitstream in comparison with the reference bitstream is assigned to each changed bit of the reference circuit; and an encoding unit which generates a device-specific bitstream from the reference bitstream and the device-specific identifier making use of the table. 16. A device comprising a programmable circuit element; a memory unit that contains a reference bitstream of a reference circuit of the circuit element as well as a table, wherein the at least one position of a bit that is changed in comparison with the reference bitstream in the further bitstream generated therefrom is assigned in the table to each changed bit of the reference circuit; and a random number generator that generates a device-specific identifier; and an encoding unit that generates a device-specific bitstream from the reference bitstream and the device-specific identifier making use of the table. 17. The device as claimed in claim 16, wherein the memory unit is designed to delete the table after the generation of the device-specific bitstream. 18. A computer program product, comprising a computer readable hardware storage device having computer readable program code stored therein, said program code executable by a processor of a computer system to implement a method that can be loaded directly into a memory of a digital computer, comprising program code segments that are suitable for carrying out the steps of the method as claimed in claim 1. 19. A data carrier that stores the computer program product as claimed in claim 18. | CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to PCT Application No. PCT/EP2016/064823, having a filing date of Jun. 27, 2016, based on German Application No. 10 2015 213 300.1, having a filing date of Jul. 15, 2015, the entire contents both of which are hereby incorporated by reference. FIELD OF TECHNOLOGY The following relates to a method and an apparatus for generating a device-specific identifier through bitstream-personalization of a programmable circuit element, a device comprising a programmable circuit element, and a computer program product (non-transitory computer readable storage medium having instructions, which when executed by a processor, perform actions) that carries out the steps of the method, as well as a data carrier that stores the computer program product. BACKGROUND Programmable circuit elements, also known as field programmable gate arrays (FPGA) are integrated circuits of digital technology, into which logical circuits can be programmed. FPGAs therefore differ from computer processors (CPU) and programmable logic controllers (PLC) in which the functional structure must be specified before fabrication, and only the temporal flow has to be programmed, in that in the case of an FPGA, even the functional structure is still to be programmed after production, or can even be changed again. This is even possible on-site at the time of installation and during use. During the programming of an FPGA, functional structures, and thereby different integrated components, i.e. the desired circuit of the FPGA, are specified. This circuit can be created graphically in the form of a circuit diagram or by means of a hardware description language, also known as HDL. A bitstream of the integrated components, e.g. of lookup tables or flip-flops and associated connecting structures is then generated with a synthesis tool, taking particular account of the hardware resources of the target FPGA. At run time, i.e. when the operating voltage at the FPGA is switched on, this bitstream is then loaded from an additionally necessary, non-volatile memory into the volatile FPGA. With this, the components are implemented in the FPGA as specified in the circuit diagram. The FPGA retains this circuit structure until the operating voltage is switched off, or until a different bitstream is loaded. In the circuit diagram, also referred to below simply as the circuit, data such as constants can also be hard-coded. These can be used internally by the FPGA, or may also be output. Cryptographic keys can also be placed in the FPGA in this way. Hard-coded data within a circuit can very easily be changed, for example using the HDL hardware description language. A new bitstream, however, must be created with the synthesis tool from every circuit, and this typically takes many minutes. The bitstream contains the configuration data, i.e. the circuit, in a proprietary, unknown format, which is often manufacturer-specific or also FPGA-specific. If it is desired to operate devices using FPGAs with individual data bitstreams which contain, for example, individual device serial numbers and/or individual cryptographic device keys, a unique bitstream must be generated afresh for each device with the aid of the synthesis tool. Even with a small number of devices, this entails a high requirement for computation and time to generate the different bitstream files, and can, in particular, hardly be carried out when the devices are produced at a high frequency. FPGAs are known from the Internet publication by Dirk Koch and Christian Beckhoff: Hierarchical Reconfiguration of FPGAs, FPL 2004, https://www.fp12014.tum.de/fileadmin/w00bpo/www/gallery/W2a 01 FPL2014 Hierarchical Reconfiguration of FPGAs Koch-Beckhoff.pdf, which support decomposition of the FPGA programming into individual modules which are generated separately and stored as partial bitstreams, and which can be loaded independently of one another and exchanged at run time. Cryptographic keys can also be made available as modules. However, this dynamic loading of modules has so far only been supported by a small number of newer FPGAs. In addition, the part that is to be exchanged must already be identified when the circuit diagram is designed, placed into its own module, and provided with an interface. In addition, a cryptographic key introduced in this way is present in a separate file on the device, and can therefore be easily identified and read out. SUMMARY An aspect relates to being able to insert device-specific data into an FPGA with little computing effort, and thus to be able to quickly and easily personalize large numbers of devices. The method according to embodiments of the invention for the generation of a device-specific identifier in a device (200) which contains at least one programmable circuit element (210) and whose circuit consists of individual components that are configured by loading a bitstream, comprises the steps of: representation (11) of the reference identifier (R-Id) as a bit sequence and the assignment of each bit of the reference identifier (R-Id) to a different component of the circuit element in each case, generation (12) of a reference bitstream (B0) for a reference circuit (F0) of the circuit element (210), in which at least the predetermined components of the reference identifier (R-Id) are contained, entering (13) the device-specific identifier (G-Id) as a binary sequence by overwriting the bits of the corresponding components of the reference identifier (R-Id) directly into the reference bitstream (B0). Personalized information can thus be placed in a bitstream for a programmable circuit element, without the bitstream having to be regenerated each time from the circuit by a synthesis tool. Through the assignment, and thus with the binding, of each bit of the reference identifier to a specific component of the programmable circuit element, e.g. a flip-flop, a lookup table or a Block RAM, a clear and in particular linear relationship between the bits of the reference identifier in the circuit and the bits of the bitstream generated from this by a synthesis tool is achieved. Each bit of the reference identifier is thus represented by a specific number of bits in the bitstream which are specific for this bit of the data bitstream. If the corresponding positions in the bitstream of all the bits of the reference identifier that are to be encoded for a particular device-specific identifier are known, a device-specific identifier can be introduced directly by modifying the bits in the bitstream. A translation of a circuit with device-specific identifier to a bitstream is no longer necessary. The time for the generation of a personalized bitstream is thus greatly shortened. In an advantageous embodiment, each component of the reference identifier is configured to add either a value of zero or a value of one. In this way any arbitrary identifier can be represented by a number of components that output the corresponding bit sequence. In an advantageous embodiment, the bits through which a component of the reference identifier is encoded in the bitstream, are determined through the method steps of: (a) generating a reference bitstream of the reference circuit, (b) generating a further bitstream for a further circuit changed by at least one bit of the predetermined reference identifier, and (c) determining at least one position of a bit that is changed in the generated further bitstream with respect to the reference bitstream. If the bitstream contains the circuit in an unknown proprietary format, a kind of translation rule for each component of the reference identifier in the corresponding bits in the bitstream can be generated by the method steps. If the translation rule is known, for example, for each single component of the reference identifier, then any arbitrary device-specific identifier with a length of the reference identifier can be entered directly into the bitstream. In an advantageous embodiment, the predetermined reference identifier consists of a plurality of partial reference identifiers distributed arbitrarily in the reference circuit. This allows a device-specific identifier to be placed in a veiled or obfuscated manner in the bitstream. This makes it more difficult for an attacker to localize the device-specific identifier in the bitstream and to determine the identifier. In an advantageous exemplary embodiment, the further bitstream is only generated for a partial region of the reference circuit which comprises the reference identifier. In this way it is not necessary in each case to analyze, for example, the entire reference bitstream. The computing time for determination of the bits in the bitstream that correspond to a component of the reference identifier can in this way he reduced further. In an advantageous embodiment, the circuit, changed by at least one bit, is used as a new reference circuit for the determination of the position of the next bit of the reference identifier. This permits an efficient determination of the bitstream bit belonging to one bit of the reference circuit. A renewed loading of the reference circuit to determine the bitstream bit of a further component of the reference identifier is thus avoided. The circuit used in the previous determination step can be used as a new reference circuit. The difference between the bitstreams of sequential reference circuits is now determined. In an advantageous embodiment, more than one bit of the reference identifier is changed in a multiply changed circuit. Frequently occurring bit combinations in the device-specific identifier can thus be determined and used through the correspondingly changed bitstream as a whole. In an advantageous embodiment, the position of the bits in the bitstream for a plurality of the changed bits in the changed circuit are determined through combining a plurality of further bitstreams generated from multiply changed circuits. Care should be taken here to ensure that the combinations of multiply changed circuits extend over the full range of the data bits of the desired reference identifier, so that arbitrary device-specific identifiers can be encoded in the bitstream. In an advantageous embodiment, a table is generated in which each changed bit of the reference circuit is assigned to at least one position of a bit that is changed in the further bitstream generated therefrom in comparison with the reference bitstream. The table thus contains the information as to which bits in the bitstream have to be changed in comparison with the reference bitstream in order to change bits of the reference identifier with respect to the reference circuit. With this table each device can be given a unique, individual bitstream, and thus provided with a unique device-specific identifier in a simple manner, without in each case having to generate the individual bitstream by means of a synthesis tool starting from an individual circuit. In an advantageous embodiment, the device-specific identifier is a cryptographic key or a serial number. When a bitstream is generated by a synthesis tool, a checksum is usually prepared over the bitstream, and added to the bitstream. In this way the resulting bitstream is protected against unintended changes such as, for example, transmission errors. In an advantageous embodiment, this checksum over the device-specific bitstream is appropriately adjusted after changing the device-specific bitstream with respect to the reference bitstream. An apparatus according to embodiments of the invention for the generation of a device-specific identifier in a programmable circuit element, whose circuit consists of individual components and which is configured by loading a bitstream, comprises an assignment unit that is designed to represent a reference identifier as a bit sequence, and to assign a different component of the circuit element respectively to each bit of the reference identifier, a generation unit that is designed to generate a reference bitstream for a reference circuit of the circuit element, in which at least the predetermined components of the reference identifier are contained, and an insertion unit that is designed to insert the device-specific identifier as a binary sequence by overwriting the bits of the corresponding components of the reference identifier directly in the reference bitstream. The apparatus can thus carry out a bitstream personalization of a programmable circuit element without having to recreate the corresponding bitstream from an individual circuit using a synthesis tool. In an advantageous embodiment, the apparatus additionally comprises a determination unit that is designed to generate a reference bitstream of the reference circuit, a further bitstream for a further circuit changed by at least one bit of the predetermined reference identifier, and to determine at least one position of a bit that is changed in the further generated bitstream with respect to the reference bitstream. The apparatus can thus determine this encoding even for non-disclosed encoding of the components of a circuit. In an advantageous embodiment, the apparatus additionally comprises a memory unit that is designed to save a table in which the at least one position of a bit that is changed in the further bitstream generated therefrom in comparison with the reference bitstream is assigned to each changed bit of the reference circuit. Any arbitrary device-specific identifier can thus be encoded directly in the bitstream without having to create a corresponding bitstream from a circuit that contains the device-specific identifier using a synthesis tool. This leads to a significant reduction in the time required to generate the bitstream. A first device according to embodiments of the invention comprises a programmable circuit element, wherein a device-specific identifier is inserted into the programmable circuit element in accordance with the method according to embodiments of the invention. Such first devices are easy and economical to manufacture with device-specific identifiers in FPGAs. A second device according to embodiments of the invention comprises a programmable circuit element, a memory device that contains a device-specific identifier, a reference bitstream of a reference circuit of the circuit element, and a table, wherein the at least one position of a bit that is changed in the further bitstream generated therefrom in comparison with the reference bitstream is assigned to each changed bit of the reference circuit in the table. It comprises moreover a random number generator that generates a device-specific identifier, and an encoding unit that generates a device-specific bitstream making use of the table from the reference bitstream and the device-specific identifier. A second device can, for example, itself generate serial numbers in the FPGA and provide them to other functions as an input value. A third device according to embodiments of the invention comprises a programmable circuit element, a memory device that contains a reference bitstream of a reference circuit of the circuit element, and a table, wherein the at least one position of a bit that is changed in the further bitstream generated therefrom in comparison with the reference bitstream is assigned to each changed bit of the reference circuit in the table, a random number generator that generates a device-specific identifier, and an encoding unit that generates a device-specific bitstream making use of the table from the reference bitstream and the device-specific identifier. In such a device a secret key, for example, that represents a device-specific identifier is never known outside the device, and is thus particularly secure against manipulation and unauthorized access. In an advantageous embodiment, the memory device is designed to delete the table after generating the device-specific bitstream. In this way, reading out the table during later operation is also prevented. The device-specific identifier generated could, in turn, be deduced from the table. A computer program product according to embodiments of the invention that can be loaded directly into a memory of a digital computer comprises program code segments that are suitable for carrying out the steps of the method according to one of claims 1 to 10. A data carrier according to embodiments of the invention stores the computer program product according to embodiments of the invention. BRIEF DESCRIPTION Some of the embodiments will be described in detail, with references to the following figures, wherein like designations denote like members, wherein: FIG. 1 shows a flow diagram of an exemplary embodiment of a method; FIG. 2 shows schematically an exemplary embodiment of a component of a programmable circuit element which can output a value of 0 or 1; FIG. 3 shows schematically an exemplary embodiment of the determination of the position of bits in the bitstream for each one bit in a reference circuit; FIG. 4 shows schematically an example of a device-specific circuit and of a resulting device-specific bitstream; FIG. 5 shows schematically a method according to embodiments of the invention; FIG. 6 shows a block diagram of an apparatus according to embodiments of the invention; and FIG. 7 shows a block diagram of an exemplary embodiment of a device according to embodiments of the invention. Parts that correspond to one another are given the same reference signs in all the figures. DETAILED DESCRIPTION In order to be able to insert a device-specific identifier into a device comprising programmable circuit elements, this can be done through bitstream-personalization of a programmable circuit element. For this purpose, a device-specific circuit which comprises the device-specific identifier as well as further components of the programmable circuit element is generated and, for example by means of a synthesis tool, a device-specific bitstream is generated from that and is loaded into the programmable circuit element. Since the generation of the device-specific bitstream BK by a synthesis tool is very time-consuming, the method according to embodiments of the invention is now explained with reference to a flow diagram, see FIG. 2. Starting from an initial state 10, a reference identifier is represented as a bit sequence in a first method step 11, and a different component of the circuit element is assigned to each bit of the reference identifier. The circuit is structured here such that each bit of the reference identifier, also referred to below as a data bit, is permanently bound to a specific component of the programmable circuit element. Each data bit is represented here by a component of the circuit. The component is configured here such that it either outputs the value zero or the value one. Such a component 30, 31, see FIG. 1, can, for example, be configured as a lookup table. The component 30 is configured such that, independently of an applied input signal 32, no signal 33 is output at the output, and the value zero is thus represented. The component 31, in contrast, is configured such that independently of the applied input signal 32 a signal is always output at the output 34, which is interpreted as the value one. Any constant data value can thus be encoded by a number of such components such as, for example, 30, 31 of a circuit element, and output. In method step 12 a reference bitstream is generated for a reference circuit of the circuit element in which at least the predetermined components of the reference identifier are contained. The reference circuit can, in addition to the components of the reference identifier, also comprise further components if the circuit element is to carry out further functions. In particular here, the same predetermined components are always to be used to represent the bits of the reference identifier. In method step 13, the device-specific identifier is entered as a binary sequence by overwriting the bits of the corresponding components of the reference identifier directly in the reference bitstream. By loading the bitstream into the circuit element, the device-specific identifier is active in the circuit element, and can be read from there into the device that contains the circuit element. This is, in particular, easily possible if the encoding of the corresponding components in the bitstream is known. If the encoding of the individual components in the bitstream is not known, then through the additional method steps 21, 22, 23, which are shown dotted in FIG. 2, as an optional method step. For this purpose a reference bitstream B0 of the reference circuit F0 is generated in method step 21. A further bitstream is then generated for a changed further circuit differing by at least one bit from the predetermined reference identifier, see method step 22. Through a comparison 23 of the further bitstream with the reference bitstream B0 at least one position of a bit that is changed in the further bitstream that has been generated in comparison with the reference bitstream B0 is determined. This is repeated until the positions and values of all the bits of the reference identifier in the bitstream are known. It is also possible for only the positions and values of a subset of the bits of the reference identifier to be determined, in particular if device-specific identifiers to be encoded require fewer bits for their representation. The insertion of the bits of the desired device-specific identifier into the reference bitstream B0 can either be carried out immediately after the determination of the position of a single bit or a plurality of data bits in the bitstream. It is also however possible for the encoding in the bitstream to be determined only for that portion of the bits that are required for the device-specific identifier, or for all the bits of the reference identifier R-Id. A device-specific bitstream, with all the bits of the device-specific identifier is then encoded into the reference bitstream B0. FIG. 3 shows an exemplary embodiment for the execution of steps 21 to 23. The reference circuit F0 comprises a large number of components, wherein the components S1, . . . , SN each have a fixed assignment to a data bit of an N-bit-long reference identifier R-Id. The further components, which carry out other functions S of the reference circuit F0, are illustrated by way of example through two partial regions of components in FIG. 3. The functions S can also be encoded as a contiguous block or, however, in a plurality of partial regions of the reference circuit F0. The reference identifier R-Id can also be assigned in one block or, however, as a plurality of non-continuous blocks, not illustrated here, in the reference circuit F0. A reference bitstream B0 is now generated from this reference circuit F0 for example by means of a synthesis tool. The reference identifier R-Id consists entirely of zeroes in the example illustrated. A further circuit F1 is now prepared in which one component S1, which represents a first, for example low-value, bit of the reference identifier R-Id is changed in comparison with the reference circuit F0, here encoded as a one instead of a zero. The further circuit F1 is converted by means of the synthesis tool into a corresponding further bitstream B1, see method step 12. Through comparison of the further bitstream B1 with the reference bitstream B0, the positions PF1 of the bits changed in the bitstream B1, and thereby the bits of the component S1 in the bitstream, are determined. Correspondingly, a second further circuit F2 is generated, in which the second bit, or the second component S2 of the reference identifier R-Id, is set to one, and then an associated second bitstream B2 is generated from it. Through a comparison of the second further bitstream B2 with the reference bitstream B0 the changed bits PF2 of the second bitstream, and thus the encoding of the changed second bit S2 of the reference identifier, are in turn determined. An assignment of the changed bits PF1, PF2 to the corresponding components S1, S2, or to bits of the reference identifier R-Id is, for example, saved in a table. This is repeated for every bit of the reference identifier R-Id. The data bitstream FN changed in the last bit of the reference identifier, in this case Nth bit, and the bitstream BN generated from it with the changed bits PFN, are also illustrated here. The changed bits PF1, . . . , PFN do not necessarily appear in the bitstream B1, . . . , BN in the same sequence as the changed bits S1, . . . , SN in the reference identifier R-Id in the circuit F1 to FN. Regions with changed bits PFi in the generated further bitstream Bi for different changed bits S1, . . . , Sn in the circuit F1, . . . , FN can also overlap. In particular, a plurality of bits PFi in the bitstream can be changed for one changed bit Si in the circuit. The predetermined reference identifier R-Id does not have to consist exclusively of zeroes, as illustrated, but can be any arbitrary binary sequence. It is also possible for determination of the bits PFi in the bitstream for the changed second bit Si of the reference identifier R-Id to compare the bitstream Bi with the bitstream Bi-1 instead of with the reference bitstream B0. Any bitstream for which the associated reference identifier is known can serve as the reference bitstream. It is not necessary to respectively convert the entire further circuit Fi into a further bitstream Bi. It is possible—if the circuit element or the associated synthesis tool supports this—also to work with a partial region of the further circuit Fi which must, however, contain the reference identifier. In this way the computing time for the generation of the bitstream Bi and thus for the determination of the encoding, i.e. the bits PFi of the data bits Si in the bitstream, Bi can be further reduced. The positions determined in this way for the individual changed bits Si of the reference identifier R-Id are, for example, entered into a table. The encoding of a data bit, or of a component, can then be determined from the table and directly entered into the reference bitstream B0. It is also possible to change a plurality of bits Si of the reference identifier R-Id and then to convert a data bitstream referred to as multiply changed by means of the synthesis tool into a further bitstream. The bits changed with respect to the reference bitstream B0 can then be determined through combinations of different multiply changed data bitstreams. It is also however possible for the changed bits in the bitstream resulting from a combination of changed bits in the circuit to be entered into the table and then used for the encoding of a device-specific identifier G-Id in the reference bitstream B0. Care should be taken here to ensure that the combination of the multiply changed data bitstreams are spread over the full range of the desired reference identifier R-Id, since otherwise not all arbitrary, device-specific identifiers can be generated in the bitstream. A circuit F(G-Id) with a device-specific identifier G-Id is illustrated in FIG. 4. The device-specific identifier G-Id is here distributed over the circuit in components in two partial blocks SB1, SB2. In order to protect a device-specific bitstream B(G-Id) generated in this way against unintended changes, such as transmission errors for example, or to be able to detect these, a checksum CRC is formed over the bitstream B(G-Id). This checksum CRC is usually appended to the device-specific bitstream. In FIG. 5, the generation of personalized bitstreams, i.e. a bitstream that contains a device-specific identifier such as, for example, a cryptographic key, is illustrated. Through such a personalized bitstream, devices of the same construction receive a device-specific identifier. Starting from a circuit S, which forms the other functions of a programmable circuit element, a reference data stream F0 is generated in preparation for the personalization, in that a reference identifier R-Id, with a length of, for example, N bits, is inserted in predetermined components. From this reference circuit F0, N+1 bitstreams B0, . . . , BN are now generated. B1, . . . , BN are here generated, for example, from circuits F1 to FN, differing in each case by one bit from the reference identifier. From a comparison of each of the bitstreams Bi with the reference bitstream B0, the encoding of the changed bit Si of the circuit Fi is determined. These determined bits in the bitstream are assigned in a table T to the correspondingly changed bit Si in the circuit Fi. The resulting table T thus for example contains an entry with the corresponding encoding in the bitstream for every bit of the reference identifier R-Id that is set to the value one. A device-specific bitstream can thus be prepared directly in the bitstream from a reference bitstream B0 and the desired device-specific identifier G-Id making use of the table T. To generate bitstreams with sequential serial numbers, it is favorable to start with a reference circuit F0 or with the associated reference bitstream B0. The lowest-value bit S1 in the reference data bitstream is then changed, and the corresponding further bitstream B1 is generated. From this, a first serial number 0 and the serial number 1 can be generated from this as device-specific bitstream. Only after this is a further circuit F2 generated with a changed bit S2, and the corresponding bitstream B2 is determined. All the device-specific bitstreams that can be formed with the bits of the reference identifier that have so far been changed are now generated from this. These are the serial numbers 0 to 3. A changed circuit F3 with a subsequent bit S3 set to the value 1 is only generated, and the associated further bitstream B3 formed, to generate the device-specific bitstream for serial number 4. All the device-specific bitstreams that can be formed with the bits 1 to 3 of the reference identifier, i.e. serial numbers 4 to 7, can now be generated. The number of determinations of the encoding of the reference bit is minimized in this way. The apparatus 100 illustrated in FIG. 6 for the generation of a device-specific programming of a device with a programmable circuit element 210 comprises a generation unit 110, an insertion unit 120 and an assignment unit 150. The assignment unit 150 is designed to represent a reference identifier R-Id as a bit sequence, and to assign a different component of the circuit element to each bit of the reference identifier R-Id. The generation unit 110 is designed to generate a reference bitstream B0 for a reference circuit F0 of the circuit element 210, in which at least the predetermined components of the reference identifier R-Id are contained. The insertion unit 120 makes it possible to insert the device-specific identifier G-Id as a binary sequence by overwriting the bits of the corresponding components of the reference identifier R-Id directly in the reference bitstream B0, and to adjust a checksum if one is present. The apparatus 100 additionally comprises a memory unit 140 that to store a table T with an assignment of each single bit of the reference identifier in a circuit to its encoding in the bitstream. The table T can already be available in the apparatus, or can be determined by a determination unit 130. The determination unit 130 is designed to generate a reference bitstream B0 of the reference circuit F0, a further bitstream Bi for a further circuit Fi changed by at least one bit of the predetermined reference identifier R-Id, and to determine at least one bit PFi which is changed in the generated further bitstream Bi with respect to the reference bitstream B0. The bits PFi determined are assigned in the table to the changed bit of the reference identifier R-Id, and stored. The insertion unit 120 comprises an interface 160, through which an appropriately formed device-specific bitstream can be loaded into the programmable circuit element 210. FIG. 7 shows a device 200 that comprises a programmable circuit element 210. The device 200 can be formed as a first device. A first device only necessarily comprises the circuit element 210 into which a device-specific identifier is inserted according to the method described, or making use of the apparatus 100. The device 200 can also be formed as a second device. In that case it comprises a programmable circuit element 210 and, in addition, a memory device 220 and an encoding unit 240. The memory device 220 contains a device-specific identifier G-Id, a reference bitstream B0 of a reference circuit B0 of the circuit element 210, along with a table. In the table, the at least one position PFi of a bit that is changed in comparison with the reference bitstream B0 in the further bitstream Bi generated from this is assigned to each changed bit Si of the reference circuit F0. The encoding unit 240 generates a device-specific bitstream B(G-Id) from the reference bitstream B0 and the device-specific identifier R-Id making use of the table. The device 200 can also be formed as a third device. The third device 200 comprises, in addition to the components of the second device, a random number generator 230 which, for example, generates true random numbers for a randomly formed key. The device furthermore comprises an encoding unit 240 which generates a device-specific bitstream B(G-Id) from the reference circuit and the device-specific identifier G-Id using the table T, and transfers it into the programmable circuit element 210. The method, the apparatus and the device can also save the device-specific identifier G-Id in a masked or obfuscated form on the device 200. The bits of the device-specific identifier G-Id are then, for example, differently distributed or contained in the circuit in a permutated sequence, or are processed at run-time by a function before they can be used as a key. With the method described it is, in particular, possible to supply devices with a programmable circuit element in production with an individual bitstream. The method functions with all available programmable circuit elements, including those which do not support reloading modules. With this, devices can easily be supplied with device-specific keys, or with individual serial numbers. If a device does not contain a random number generator 230, then an individual entropy file can be inserted in the same way into the programmable circuit element. The entropy file can then be used as a basis for the formation of cryptographic keys. Attackers who successfully compromise a device only obtain access to the individual key of a single circuit element, and not to a system-wide key. If an encoding has to be determined for each bit, depending on the length of the key, the method is particularly suitable for the insertion of symmetric keys or of elliptical curve keys. Longer keys such as, for example, RSA keys can also be implemented with the method of the invention, but do, however, require significantly more effort to prepare the assignment table T. If the assignment of the encoding to the reference bits is known, the method is suitable for any type of cryptographic keys and for other data such as serial numbers and so forth. Although the invention has been illustrated and described in greater detail with reference to the preferred exemplary embodiment, the invention is not limited to the examples disclosed, and further variations can be inferred by a person skilled in the art, without departing from the scope of protection of the invention. For the sake of clarity, it is to be understood that the use of “a” or “an” throughout this application does not exclude a plurality, and “comprising” does not exclude other steps or elements. | <SOH> BACKGROUND <EOH>Programmable circuit elements, also known as field programmable gate arrays (FPGA) are integrated circuits of digital technology, into which logical circuits can be programmed. FPGAs therefore differ from computer processors (CPU) and programmable logic controllers (PLC) in which the functional structure must be specified before fabrication, and only the temporal flow has to be programmed, in that in the case of an FPGA, even the functional structure is still to be programmed after production, or can even be changed again. This is even possible on-site at the time of installation and during use. During the programming of an FPGA, functional structures, and thereby different integrated components, i.e. the desired circuit of the FPGA, are specified. This circuit can be created graphically in the form of a circuit diagram or by means of a hardware description language, also known as HDL. A bitstream of the integrated components, e.g. of lookup tables or flip-flops and associated connecting structures is then generated with a synthesis tool, taking particular account of the hardware resources of the target FPGA. At run time, i.e. when the operating voltage at the FPGA is switched on, this bitstream is then loaded from an additionally necessary, non-volatile memory into the volatile FPGA. With this, the components are implemented in the FPGA as specified in the circuit diagram. The FPGA retains this circuit structure until the operating voltage is switched off, or until a different bitstream is loaded. In the circuit diagram, also referred to below simply as the circuit, data such as constants can also be hard-coded. These can be used internally by the FPGA, or may also be output. Cryptographic keys can also be placed in the FPGA in this way. Hard-coded data within a circuit can very easily be changed, for example using the HDL hardware description language. A new bitstream, however, must be created with the synthesis tool from every circuit, and this typically takes many minutes. The bitstream contains the configuration data, i.e. the circuit, in a proprietary, unknown format, which is often manufacturer-specific or also FPGA-specific. If it is desired to operate devices using FPGAs with individual data bitstreams which contain, for example, individual device serial numbers and/or individual cryptographic device keys, a unique bitstream must be generated afresh for each device with the aid of the synthesis tool. Even with a small number of devices, this entails a high requirement for computation and time to generate the different bitstream files, and can, in particular, hardly be carried out when the devices are produced at a high frequency. FPGAs are known from the Internet publication by Dirk Koch and Christian Beckhoff: Hierarchical Reconfiguration of FPGAs, FPL 2004, https://www.fp12014.tum.de/fileadmin/w00bpo/www/gallery/W2a 01 FPL2014 Hierarchical Reconfiguration of FPGAs Koch-Beckhoff.pdf, which support decomposition of the FPGA programming into individual modules which are generated separately and stored as partial bitstreams, and which can be loaded independently of one another and exchanged at run time. Cryptographic keys can also be made available as modules. However, this dynamic loading of modules has so far only been supported by a small number of newer FPGAs. In addition, the part that is to be exchanged must already be identified when the circuit diagram is designed, placed into its own module, and provided with an interface. In addition, a cryptographic key introduced in this way is present in a separate file on the device, and can therefore be easily identified and read out. | <SOH> SUMMARY <EOH>An aspect relates to being able to insert device-specific data into an FPGA with little computing effort, and thus to be able to quickly and easily personalize large numbers of devices. The method according to embodiments of the invention for the generation of a device-specific identifier in a device ( 200 ) which contains at least one programmable circuit element ( 210 ) and whose circuit consists of individual components that are configured by loading a bitstream, comprises the steps of: representation ( 11 ) of the reference identifier (R-Id) as a bit sequence and the assignment of each bit of the reference identifier (R-Id) to a different component of the circuit element in each case, generation ( 12 ) of a reference bitstream (B 0 ) for a reference circuit (F 0 ) of the circuit element ( 210 ), in which at least the predetermined components of the reference identifier (R-Id) are contained, entering ( 13 ) the device-specific identifier (G-Id) as a binary sequence by overwriting the bits of the corresponding components of the reference identifier (R-Id) directly into the reference bitstream (B 0 ). Personalized information can thus be placed in a bitstream for a programmable circuit element, without the bitstream having to be regenerated each time from the circuit by a synthesis tool. Through the assignment, and thus with the binding, of each bit of the reference identifier to a specific component of the programmable circuit element, e.g. a flip-flop, a lookup table or a Block RAM, a clear and in particular linear relationship between the bits of the reference identifier in the circuit and the bits of the bitstream generated from this by a synthesis tool is achieved. Each bit of the reference identifier is thus represented by a specific number of bits in the bitstream which are specific for this bit of the data bitstream. If the corresponding positions in the bitstream of all the bits of the reference identifier that are to be encoded for a particular device-specific identifier are known, a device-specific identifier can be introduced directly by modifying the bits in the bitstream. A translation of a circuit with device-specific identifier to a bitstream is no longer necessary. The time for the generation of a personalized bitstream is thus greatly shortened. In an advantageous embodiment, each component of the reference identifier is configured to add either a value of zero or a value of one. In this way any arbitrary identifier can be represented by a number of components that output the corresponding bit sequence. In an advantageous embodiment, the bits through which a component of the reference identifier is encoded in the bitstream, are determined through the method steps of: (a) generating a reference bitstream of the reference circuit, (b) generating a further bitstream for a further circuit changed by at least one bit of the predetermined reference identifier, and (c) determining at least one position of a bit that is changed in the generated further bitstream with respect to the reference bitstream. If the bitstream contains the circuit in an unknown proprietary format, a kind of translation rule for each component of the reference identifier in the corresponding bits in the bitstream can be generated by the method steps. If the translation rule is known, for example, for each single component of the reference identifier, then any arbitrary device-specific identifier with a length of the reference identifier can be entered directly into the bitstream. In an advantageous embodiment, the predetermined reference identifier consists of a plurality of partial reference identifiers distributed arbitrarily in the reference circuit. This allows a device-specific identifier to be placed in a veiled or obfuscated manner in the bitstream. This makes it more difficult for an attacker to localize the device-specific identifier in the bitstream and to determine the identifier. In an advantageous exemplary embodiment, the further bitstream is only generated for a partial region of the reference circuit which comprises the reference identifier. In this way it is not necessary in each case to analyze, for example, the entire reference bitstream. The computing time for determination of the bits in the bitstream that correspond to a component of the reference identifier can in this way he reduced further. In an advantageous embodiment, the circuit, changed by at least one bit, is used as a new reference circuit for the determination of the position of the next bit of the reference identifier. This permits an efficient determination of the bitstream bit belonging to one bit of the reference circuit. A renewed loading of the reference circuit to determine the bitstream bit of a further component of the reference identifier is thus avoided. The circuit used in the previous determination step can be used as a new reference circuit. The difference between the bitstreams of sequential reference circuits is now determined. In an advantageous embodiment, more than one bit of the reference identifier is changed in a multiply changed circuit. Frequently occurring bit combinations in the device-specific identifier can thus be determined and used through the correspondingly changed bitstream as a whole. In an advantageous embodiment, the position of the bits in the bitstream for a plurality of the changed bits in the changed circuit are determined through combining a plurality of further bitstreams generated from multiply changed circuits. Care should be taken here to ensure that the combinations of multiply changed circuits extend over the full range of the data bits of the desired reference identifier, so that arbitrary device-specific identifiers can be encoded in the bitstream. In an advantageous embodiment, a table is generated in which each changed bit of the reference circuit is assigned to at least one position of a bit that is changed in the further bitstream generated therefrom in comparison with the reference bitstream. The table thus contains the information as to which bits in the bitstream have to be changed in comparison with the reference bitstream in order to change bits of the reference identifier with respect to the reference circuit. With this table each device can be given a unique, individual bitstream, and thus provided with a unique device-specific identifier in a simple manner, without in each case having to generate the individual bitstream by means of a synthesis tool starting from an individual circuit. In an advantageous embodiment, the device-specific identifier is a cryptographic key or a serial number. When a bitstream is generated by a synthesis tool, a checksum is usually prepared over the bitstream, and added to the bitstream. In this way the resulting bitstream is protected against unintended changes such as, for example, transmission errors. In an advantageous embodiment, this checksum over the device-specific bitstream is appropriately adjusted after changing the device-specific bitstream with respect to the reference bitstream. An apparatus according to embodiments of the invention for the generation of a device-specific identifier in a programmable circuit element, whose circuit consists of individual components and which is configured by loading a bitstream, comprises an assignment unit that is designed to represent a reference identifier as a bit sequence, and to assign a different component of the circuit element respectively to each bit of the reference identifier, a generation unit that is designed to generate a reference bitstream for a reference circuit of the circuit element, in which at least the predetermined components of the reference identifier are contained, and an insertion unit that is designed to insert the device-specific identifier as a binary sequence by overwriting the bits of the corresponding components of the reference identifier directly in the reference bitstream. The apparatus can thus carry out a bitstream personalization of a programmable circuit element without having to recreate the corresponding bitstream from an individual circuit using a synthesis tool. In an advantageous embodiment, the apparatus additionally comprises a determination unit that is designed to generate a reference bitstream of the reference circuit, a further bitstream for a further circuit changed by at least one bit of the predetermined reference identifier, and to determine at least one position of a bit that is changed in the further generated bitstream with respect to the reference bitstream. The apparatus can thus determine this encoding even for non-disclosed encoding of the components of a circuit. In an advantageous embodiment, the apparatus additionally comprises a memory unit that is designed to save a table in which the at least one position of a bit that is changed in the further bitstream generated therefrom in comparison with the reference bitstream is assigned to each changed bit of the reference circuit. Any arbitrary device-specific identifier can thus be encoded directly in the bitstream without having to create a corresponding bitstream from a circuit that contains the device-specific identifier using a synthesis tool. This leads to a significant reduction in the time required to generate the bitstream. A first device according to embodiments of the invention comprises a programmable circuit element, wherein a device-specific identifier is inserted into the programmable circuit element in accordance with the method according to embodiments of the invention. Such first devices are easy and economical to manufacture with device-specific identifiers in FPGAs. A second device according to embodiments of the invention comprises a programmable circuit element, a memory device that contains a device-specific identifier, a reference bitstream of a reference circuit of the circuit element, and a table, wherein the at least one position of a bit that is changed in the further bitstream generated therefrom in comparison with the reference bitstream is assigned to each changed bit of the reference circuit in the table. It comprises moreover a random number generator that generates a device-specific identifier, and an encoding unit that generates a device-specific bitstream making use of the table from the reference bitstream and the device-specific identifier. A second device can, for example, itself generate serial numbers in the FPGA and provide them to other functions as an input value. A third device according to embodiments of the invention comprises a programmable circuit element, a memory device that contains a reference bitstream of a reference circuit of the circuit element, and a table, wherein the at least one position of a bit that is changed in the further bitstream generated therefrom in comparison with the reference bitstream is assigned to each changed bit of the reference circuit in the table, a random number generator that generates a device-specific identifier, and an encoding unit that generates a device-specific bitstream making use of the table from the reference bitstream and the device-specific identifier. In such a device a secret key, for example, that represents a device-specific identifier is never known outside the device, and is thus particularly secure against manipulation and unauthorized access. In an advantageous embodiment, the memory device is designed to delete the table after generating the device-specific bitstream. In this way, reading out the table during later operation is also prevented. The device-specific identifier generated could, in turn, be deduced from the table. A computer program product according to embodiments of the invention that can be loaded directly into a memory of a digital computer comprises program code segments that are suitable for carrying out the steps of the method according to one of claims 1 to 10 . A data carrier according to embodiments of the invention stores the computer program product according to embodiments of the invention. | G06F944505 | 20180111 | 20180719 | 86853.0 | G06F9445 | 0 | CHOUDHURY, ZAHID | METHOD AND DEVICE FOR GENERATING A DEVICE-SPECIFIC IDENTIFIER, AND DEVICES COMPRISING A PERSONALIZED PROGRAMMABLE CIRCUIT COMPONENT | UNDISCOUNTED | 0 | ACCEPTED | G06F | 2,018 |
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15,743,803 | PENDING | SYSTEM FOR REMOTELY STARTING AND STOPPING A TIME CLOCK IN AN ENVIRONMENT HAVING A PLURALITY OF DISTINCT ACTIVATION SIGNALS | A sports event time clock control system utilizing remotely activated game clock controls in which the sonic fingerprints including multiple harmonic frequencies of each official's whistle blow is compared with prerecorded sonic fingerprints of the officials for activation of the game clock upon a match in sonic fingerprints and to identify and record the official who blew the whistle along with the strength if the whistle blow. Sonic fingerprints include the strongest harmonic plus selected strong overtone and undertone frequencies. | 1. A sports event time clock remote control system comprising: a game clock; a plurality of sonic generators each adapted to be carried by a plurality of officials; each of said sonic generators providing a sonic signal when activated by the official carrying said sonic generators; a means to analyze each of said sonic signals to determine which of said officials activated a sonic generator; said means to analyze determining the dominant harmonic frequency of each sonic signal plus at least one overtone harmonic above and one undertone harmonic below said dominant harmonic frequency to generate sonic fingerprints; means to compare the sonic fingerprints generated during said sporting event with the prerecorded sonic fingerprint of each official; and means to generate a game clock actuating signal in response to those sonic fingerprints generated during a game which match a prerecorded sonic fingerprint. 2. The sports event control system of claim 1, wherein said means to analyze provides at least two harmonic frequencies above and at least two harmonic frequencies below, said dominant harmonic frequency, each of which are the next highest amplitude to said dominant harmonic frequency. 3. The sports event control system of claim 2 wherein those sonic fingerprints, which match a prerecorded sonic fingerprint are utilized to identify the official generating said sonic fingerprint, and to record the identity and the time thereof as shown by said game clock. 4. The sports event control system of claim 3 wherein said means to analyze includes a band pass filter, said sonic generators are whistles, and said band pass filter passes the frequencies of said whistles. 5. The sports event control system of claim 4 wherein a signal comparator is provided to exclude those signals which are below a predetermined signal level. 6. The sports event control system of claim 4 wherein an analog to digital converter and fast fourier transform network working within the frequency bypass of said band pass filter are provided to convert time based signals to frequency based signals. 7. The sports event control system of claim 6 wherein said harmonics above and said harmonics below said dominant frequency are averaged, and those averages within a preset tolerance parameter provide a control signal indicating that a whistle has been detected is provided to a base station for identification. 8. The sports event control system of claim 7 wherein means in said base station is provided to store said sonic fingerprint signals for comparison with sonic fingerprint signals generated during said sports event to establish a match used for actuation of said game clock. 9. The sports event control system of claim 8 wherein said stored sonic signals are provided by each official blowing their game whistle shortly prior to the commencement of the sports event in the environment of said sports event. 10. The sports control system of claim 8 including a remotely accessible sonic fingerprint file to provide a sonic fingerprint signal of one or more of the officials officiating a particular sports event. 11. A remote game clock control, and identification system for officials in a sporting event comprising: a game clock for the sporting event; a whistle adapted to be blown by each of the officials to generate a sonic signal to control the starting and stopping of play in said sporting event; a pack adapted to be carried by each of said officials which transmits said sonic signal to a base unit; said base unit converting said sonic signal to a sonic fingerprint signal including multiple harmonics of said sonic signal; said base unit including means for containing a sonic fingerprint file with the sonic fingerprints of each of said officials; said base unit including means to compare said sonic fingerprint signals with those in said fingerprint file; and means to generate a time clock actuating control signal upon a match in said sonic fingerprint signals. 12. The remote time clock control and identification system of claim 11 wherein each of said sonic fingerprint signals include a plurality of the strongest harmonics in each said sonic signal. 13. The remote time control and identification system of claim 12 wherein said plurality of the strongest harmonics include the strongest harmonic and at least one of the next strongest harmonics above and one of the next strongest harmonic below said strongest harmonic. 14. The remote time clock control and identification system of claim 13 wherein said plurality of strongest harmonics includes at least two of the next strongest harmonics above and two of the next strongest harmonics below the frequency of said strongest harmonic to provide said sonic fingerprint. 15. The remote time clock control and identification system of claim 14 wherein said match in said sonic fingerprint signals is utilized to identify the official who blew the whistle generating said match and means are provided to record said identity and the time as indicated by said game clock. 16. The sports event control system of claim 15 wherein the strength of each said match is recorded to enable the identification of those officials who may have low whistle strength for the purpose of subsequent improvement in said whistle strength. 17. The remote time clock control identification system of claim 11 in which said sonic signal is passed through a band pass filter and subsequently through a fast fourier transform in advance of said comparing of said sonic fingerprint signals. 18. The remote control system of claim 16 wherein means are provided to average the harmonic signals on either side of said strongest harmonic prior to said comparing of said signals. 19. The remote time clock control identification system of claim 11 including a repository of sonic fingerprints of officials who may officiate said sports event and said repository is remotely accessible prior to said sports event for storage in said base unit for said comparison with said sonic fingerprint signals produced during said sports event. | This invention relates to a remote time clock activation and identification system for a game clock such as those used in basketball games. In many sports, such as basketball, a contest is divided into specific time periods or durations of play which require accurate timing. The play periods are frequently interrupted for time outs including those for official or television commercial reasons, time outs allocated to each team, fouls called by the officials, and for time clock violations. Such fouls or actions requiring penalties must be assessed to the player committing the foul, and play is stopped to allow, for example, any applicable free throws resulting from the foul. In addition, officials may stop play for a wet floor or an injured player. As a result, the official time clock is frequently started and stopped upon such actions of any of the officials or the timekeeper. Officials typically signal the stop and start of play by whistles and the corresponding starting and stopping of the official time clock is effectuated by the timekeeper pressing a button. Alternatively, the official time clock may be started and stopped remotely and automatically by the officials' whistles using equipment such as shown in U.S. Pat. No. 5,293,354, issued Mar. 8, 1994 to Michael J. Costabile and U.S. Pat. No. 7,920,052 issued Apr. 5, 2011 to Michael J. Costabile, both of which are hereby incorporated in their entirety. Existing technology has limitations. For example, existing technology requires that the officials use a specific whistle that is recognized by the system. Moreover, existing technology recognizes only that a whistle has been blown, but can't identify the specific whistle. This is less than ideal because it is often desirable in a multi-whistle environment to know the specific whistle, and therefore the specific official, that actuated the time clock. Identifying the specific whistle that actuates the time clock is important in a variety of situations. For example, problems may be encountered when there is an inadvertent blowing of the whistle by an official who may be reluctant to own up to the error, or even by a spectator, or inadvertent pressing of the start/stop button by the timekeeper. Being able to identify which official blew his whistle is also important when multiple whistles are blown, and when calls by officials are in question. Also, sports operations staff for sports associations such as the National Basketball Association (“NBA”) and college conference offices routinely review videotapes of all games in their quality and accuracy review of the calls by the officials, and to insure and preserve the integrity of the game. Officials do make mistakes which can affect which team wins a particular game. Moreover, the overall environment is often loud with shouting by spectators and bands playing. When officials are later determined to have made a serious error, particularly one affecting the outcome of a game, they may be punished such as by suspension for a specified period. The potential of after-game detection and punishment of officiating error encourages diligence and correct performance by officials. Moreover, because of potential bias or other improprieties, it is important that official calls be scrutinized, even after a game is completed. Since officials frequently signal a game stopping event such as a foul by three or four quick whistle blasts, the blasts of two officials may be simultaneous or overlapping. An analysis for quality control review of the event is helped by the precise and reliable recording of the whistle blasts and identification of the officials involved. Television replays are not designed to present an accurate review of the actions of officials and do not identify who blew a whistle first in the case of multiple whistles. Moreover, if television playback is slowed down to closely examine a play, the whistle blasts frequently become inaudible. As a result, it is highly desirous to have a reliable record of each starting and stopping of play along with the identity of the initiator of such actions. SUMMARY OF THE INVENTION In accordance with one form of the invention, a record of the sonic fingerprint of the whistle blowing by the individuals officiating a sports event is digitally stored prior to commencement of the event, for subsequent comparison with whistles blown during the event in order to identify which individual blew the whistle during the event and to initiate actions, be it stopping play or starting play. The sonic signal sensed by a microphone located close to the whistle worn by officials is passed through a band pass filter and then digitized for comparison with the stored signals to identify which official blew the whistle. The band of frequencies obtained by a Fast Fourier Transform are processed to identify and store the highest amplitude resonant or center frequency signal. Also stored are the signals representing the next strongest resonant frequencies above and below the center frequency signal to provide a multiplicity of frequencies for comparison of the stored fingerprints with whistle blows during the sporting event. To minimize false acceptance and increase reliability while detecting a valid whistle, multiple parameters are measured and compared to the stored standard. Those whistle signals for which there is a match are displayed and stored with identification of which official initiated the action and at what time the action was used to activate the official time clock, be it stopping play or starting play. They are also as indicated by the time clock response. Many variables can affect how a whistle sounds each time it is blown, such as the way an individual blows air into it, or the way he/she holds it, or even the environment that it's in, whether inside a small room or a large gym or a crowded coliseum. Because of these variables, a certain level of tolerance must be accepted as to whether one whistle blow compares to another. But too much tolerance will cause false acceptances. IDENTIFICATION OF DRAWINGS FIG. 1 is an overview of the activation system; FIG. 2 depicts an official wearing an activation module, with a block diagram of associated hardware shown in an exploded view; FIG. 3 depicts a base station, with a block diagram of associated hardware shown in an exploded view; FIG. 4 depicts hardware and signals associated with stopping a game clock; FIG. 5 depicts three block diagrams of hardware associated with three activation modules; FIG. 6 is a block diagram of method of using the system; and FIG. 7 is a whistle fingerprint. DESCRIPTION OF THE INVENTION As used herein, the following terms shall apply: The following structure numbers refer to the following structures among the various figures: 10—Activation system; 20—Activation module; 22—Microphone; 23—Sonic signal; 25—Filter amplifier; 27—Voltage comparator; 28—Audio frequency signal; 29—Radio transmitters; 30—Base station; 31—Radio receiver; 32—Analog to digital converter; 33—Digital signal 34—Fast fourier transform; 35—Frequency selection; 36—Fingerprint; 37—Comparator storage; 38—Comparator level control; 39—Central fingerprint file; 50—Whistle; 55—Whistle signal; 60—Game clock; 62—Clock actuation signal; 64—Game clock actuator; 66—Timekeeper control button; 70—Remote location; 100—First official; 101—Second official; 102—Third official; and 200—Timekeeper. An overview of activation system 10 for a basketball game is depicted in FIG. 1. More specifically, officials 100, 101 and 102 are each outfitted with their own activation modules 20a, 20b and 20c respectively. As shown, officials 100 and 102 (but not 101) have blown their respective whistles, thereby activating their respective activation modules 20a and 20c, thereby sending audio frequency signals 28a and 28c from activation modules 20a and 20c to base station 30, thereby sending clock activation signal 62 from base station 30 to game clock 60, which signals the game clock to stop. Referring to FIG. 2, activation module 20 is adapted to be worn by an official, and is activated when that official's specific whistle 50 produces whistle signal 55. Whistle 50 may be “Fox Classic 40” whistles manufactured by Fox 40 International, Inc. of Canada, which are standard in the NBA, and many college and high school basketball leagues. These whistles include no moving parts and emit an audible sonic signal around 3150 hertz. The system of the present invention may be made particularly responsive to that whistle by being tuned to 3150 hertz, although the system may be readily tuned to accommodate other whistle types or audible signaling devices operating at other frequencies including blow horns, alarms, musical instruments, and digital noisemakers. Each official, 100, 101 and 102 carries one microphone 22 in close proximity to their whistle 50, preferably attached to the official's whistle cord, or on their short in the vicinity of the neck portion. Microphones 22 produce sonic signals 23 which pass through filter amplifiers 25 which include a multi-feedback band-pass filter which has somewhat sharp rejection drop-offs at the outer band frequencies, for example the following parameters: Multiple Feedback Band Pass @ 3 KHz Damping Ratio=1.01 Q=0.493 Gain x20 Amplifier Lower Freqcutoff @ −3 db=˜1.25 KHz Upper Freqcutoff @ −3 db=7.5 KHz HPF Slope 2 KHZ to 200 HZ=−12 db/decade LPF Slope 6 KHZ to 600 KHZ=−24 db/decade LPF Slope 600 KHz to 6 MHz=−48 db/decade The sharp rejection of the outer bands helps eliminate unwanted harmonics and other frequencies with large amplitudes such that they are not further processed. The signal within the band pass is amplified to a usable level without clipping, since clipping would cause harmonics that could result in a false detection. Amplified sonic signals 23 are sampled by voltage comparator 27 to determine if they are of a large enough amplitude or strength for further processing. The signal sensitivity level determines which signals pass through voltage comparator 27. The selected audio frequency signals 28 are then transmitted by radio transmitters 29 to base station 30 shown in FIG. 3. Referring for a moment to FIG. 5, each official wears one activation module 20 (20a; 20b or 20c) which is specifically calibrated for use with one whistle 50 (50a; 50b; or 50c, respectively). Referring next to FIG. 3, the selected audio signals 28 are received by radio receiver 31 and provided to analog to digital converter 32 for conversion to digital signal 33 representing whistle signals 55. Digital signal 33 is then processed by fast fourier transform 34 which is configured within the frequency band pass of filter-amplifier 25 to convert the time based signal data into a frequency based signal. This allows processing the frequency based data by frequency selection 35 to determine the center frequency of whistles 50 by selecting the frequency with the highest amplitude. This center frequency is then passed as part of sonic fingerprint 36 for storage in comparator storage 37 as the center frequency. Referring to FIG. 7, since many whistle types have similar center frequencies, additional frequencies in audio whistle signal 55 are collected to form a reliable sonic fingerprint containing multiple frequencies including both overtone and undertone frequencies in addition to the center frequency. The next highest amplitude signal within the band of frequencies above the center frequency is taken and stored as the first upper harmonic frequency, after which the next highest amplitude within the band of frequencies above the first upper harmonic frequency is taken and stored as the second upper harmonic frequency which together form the overtone frequencies. The selection from the frequencies below the center frequency or undertone frequencies include those two frequencies with the next highest amplitude below the center frequency to obtain a sonic fingerprint 36 of the whistle blow including a center frequency and two overtone frequencies above and two undertone frequencies below the center frequency. These five frequencies shown on FIG. 7 form a sonic fingerprint 36 of the official who blew whistle 50. A sample sonic fingerprint 36 of each official taken before the beginning of the sports event is stored in comparator storage 37 as the standard sample sonic fingerprint of the particular whistle blow of an official after which all subsequent sonic fingerprints 36 are compared. This step is set forth on as the 5th step on FIG. 6, “Calibrate Whistles.” Subsequent sonic signals 23 pass through the filter of amplifier filter 25 which then pass through the level setting of voltage comparator 27 (see FIG. 2) and are sent to base station 30 where they are processed by fast fourier transform 34, just as the standard sample, to find its center frequency and if there is a match as determined by frequency selection 35 the remaining four harmonics are averaged and compared to the average of the four similar frequencies of the standard sample's harmonics in the comparator storage 37. Referring back to FIG. 3, if the averages are determined by comparator storage 37 to be within the tolerance as set by the operator by comparator level control 38, this is considered a match and a clock actuation signal 62 is sent to game clock actuator 64 to activate game clock 60. If either comparison of the center frequency or the harmonics average of the sonic signal and those of the stored sample do not match then the signal is rejected. As shown in FIG. 4, timekeeper control button 66 is provided to enable the timekeeper to manually activate game clock 60 through game clock actuator 64. Once the desired signal match level or strength is set by the timekeeper the system not only passes and identifies all whistle signals which meet or exceed the match level but also records in percent (%) the actual level. This enables the identification of those officials with a weak or barely passable whistle blowing level to enable instructing those officials to blow their whistle more strongly to avoid any possibility of very weak whistle blows for which the subject time clock activation and identification system would be unresponsive. It is preferable that the standard samples of the officials' sonic fingerprints are obtained and stored shortly before commencement of play by having each official blow his or her whistle 50 for that purpose. (Step 5 of FIG. 6). This is preferably done in the environment in which the sporting event will be played. However it circumstances where it is difficult or impossible to calibrate under ideal conditions, a central sonic fingerprint file 39 can be established which may be remotely accessed and used. Such a file may be maintained at the conference level in college basketball since persons from the same group of officials are generally selected to officiate at games within the conference, or it could be maintained for a geographic area for the same reasons. Alternatively it could be maintained by the manufacturer of the subject equipment or at a central headquarters location if available, such as at the NBA. Sonic fingerprints stored in central sonic fingerprint file 39 at a remote location 70 can be provided to the comparator storage 37 as needed, usually by the official timekeeper, prior to the sporting event. A method of using system 10 is set forth in FIG. 6. In step 1 the base station is set up by performing steps such as connecting the power supply, connecting game clock and data cables, connecting an Ethernet cable, raising the antenna, and powering on. In step 2 the game is configured by entering information such as names of officials. This is typically performed at remotely and the data is automatically imported upon booting the system, but can be accomplished on site as well. Step 3 is setting the whistle settings including match threshold, preferably approximately 90%, and sensitivity level (Amplified Signal Peak Voltage Level), preferably approximately 23 for a lanyard style microphone setup having 1 microphone, or approximately 20 for a lapel style microphone setup having 2 microphones. In step 5 each individual whistle is calibrated by blowing the whistle several times with the microphone in the proper location until system prompts user that a reliable reading was taken. In step 6 the game is started as usual, with whistle blows (step 7) stopping the game clock (step 8). Data related to game clock stops, for example when clock stopped in real time, and identity of official who blew their whistle, is sent to remote location for further analysis and back-up. In step 10 the game is resumed until a whistle is blown again (step 7), or the game is ended (step 11). Data is downloaded at conclusion of game (step 12). It should be understood, of course, that the foregoing relates to exemplary embodiments of the invention and that modifications may be made without departing from the spirit and scope of the invention as set forth in the following claims. By way of example, the system could be used in connection with other time-sensitive games and sports such as soccer, football, team handball, water polo, volleyball, wrestling and lacrosse. Also, a variety of different noisemakers, including bullhorns, musical instruments, alarms and/or and digital noisemakers could be used. Also, instead of stopping a time clock, the present invention could be modified to initiate a camera upon an auditory signal such as opening a door, squeaking a floor board, or breaking a window, which has security applications. Also, the system could be modified to identify which gun has been shot in an environment having multiple weapons. This could have security, gaming, hunting, and/or law enforcement applications. The system could also be modified to recognize certain sounds such as emergency vehicles, specific crying babies, specific animals, machine failure, and so forth, and activate the desired apparatus such as camera, lights, medical equipment, signal notification device, and so forth. As used herein, “approximately” and the like shall mean +/−10%, unless such a range would be nonsensical, such as a negative length. All ranges set forth shall include the endpoints themselves, as well as all increments there between. | <SOH> SUMMARY OF THE INVENTION <EOH>In accordance with one form of the invention, a record of the sonic fingerprint of the whistle blowing by the individuals officiating a sports event is digitally stored prior to commencement of the event, for subsequent comparison with whistles blown during the event in order to identify which individual blew the whistle during the event and to initiate actions, be it stopping play or starting play. The sonic signal sensed by a microphone located close to the whistle worn by officials is passed through a band pass filter and then digitized for comparison with the stored signals to identify which official blew the whistle. The band of frequencies obtained by a Fast Fourier Transform are processed to identify and store the highest amplitude resonant or center frequency signal. Also stored are the signals representing the next strongest resonant frequencies above and below the center frequency signal to provide a multiplicity of frequencies for comparison of the stored fingerprints with whistle blows during the sporting event. To minimize false acceptance and increase reliability while detecting a valid whistle, multiple parameters are measured and compared to the stored standard. Those whistle signals for which there is a match are displayed and stored with identification of which official initiated the action and at what time the action was used to activate the official time clock, be it stopping play or starting play. They are also as indicated by the time clock response. Many variables can affect how a whistle sounds each time it is blown, such as the way an individual blows air into it, or the way he/she holds it, or even the environment that it's in, whether inside a small room or a large gym or a crowded coliseum. Because of these variables, a certain level of tolerance must be accepted as to whether one whistle blow compares to another. But too much tolerance will cause false acceptances. | G07C128 | 20180111 | 20180719 | 65883.0 | G07C128 | 2 | CARTER, KEVIN M | SYSTEM FOR REMOTELY STARTING AND STOPPING A TIME CLOCK IN AN ENVIRONMENT HAVING A PLURALITY OF DISTINCT ACTIVATION SIGNALS | SMALL | 0 | ACCEPTED | G07C | 2,018 |
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15,744,259 | PENDING | AUTOMATIC INJECTION DEVICE | There is provided an injection device for delivering a medicament from a container. The device includes, a housing for housing a container, a plunger substantially housed within the housing and which is movable within the housing, a force applicator for applying a force to the plunger, a trigger coupled to the force applicator for releasing the force applicator to fire the device, a boot, a dose selector for allowing a user to select a dose of medicament, and a first mechanical interlock arranged such that the force applicator cannot be released until the dose selector has been operated to select the dose of medicament, and a second mechanical interlock arranged such that the dose selector cannot be operated to select the dose of medicament prior to removal of the boot. | 1-44. (canceled) 45. An injection device for delivering a medicament from a container, the device comprising: a housing for housing a container; a plunger substantially housed within the housing and which is movable within the housing; a force applicator for applying a force to the plunger; a trigger coupled to the force applicator for releasing the force applicator to fire the device; a boot; a dose selector for allowing a user to select a dose of medicament; and a first mechanical interlock arranged such that the device cannot be fired until the dose selector has been operated to select the dose of medicament; and a second mechanical interlock arranged such that the dose selector cannot be operated to select the dose of medicament prior to removal of the boot. 46. An injection device according to claim 45, wherein the first mechanical interlock is provided by a first coupling between the housing and the plunger. 47. An injection device according to claim 46, wherein the first coupling comprises an abutment between a first abutment element on, or mechanically coupled to, one of the housing and the plunger and a second abutment element on, or mechanically coupled to, the other of the housing and the plunger. 48. An injection device according to claim 47, wherein the first mechanical interlock is arranged such that the abutment of the first abutment element and the second abutment element prevents the plunger from being displaced axially. 49. An injection device according to claim 45, wherein the second mechanical interlock is provided by a second coupling between the dose selector and the boot. 50. An injection device according to claim 49, wherein the second coupling comprises an abutment between a third abutment element on, or coupled to, the dose selector and a fourth abutment element on, or coupled to, the boot. 51. An injection device according to claim 45, wherein the dose selector is rotatable relative to the housing, said rotation allowing a user to select the dose of medicament. 52. An injection device according to claim 51, wherein the dose selector and plunger are rotationally coupled such that rotation of the dose selector rotates the plunger and removes the abutment of the first abutment element and the second abutment element. 53. An injection device according to claim 47, wherein the first abutment element is either a peg or shoulder on the plunger and the second abutment element is the other of a peg or shoulder on the housing. 54. An injection device according to claim 52, wherein the second mechanical interlock is arranged such that the abutment of the third abutment element and the fourth abutment element prevents the dose selector from being rotated relative to the housing. 55. An injection device according to claim 54, wherein removal of the boot removes the second coupling between the third abutment element and the fourth abutment element. 56. An injection device according to claim 50, wherein the third abutment element is a first surface on the plunger and the fourth abutment element is a second surface mechanically coupled to the boot. 57. An injection device according to claim 56, further comprising a sleeve housed in the housing and which is rotationally fixed and axially moveable with respect to the housing. 58. An injection device according to claim 57, wherein the sleeve comprises the second surface and wherein the sleeve is axially coupled to the boot such that axially movement of the sleeve is restricted while the boot is attached to the device. 59. An injection device according to claim 57, further comprising a boot remover for removing the boot, and wherein the boot remover abuts the sleeve while the boot remover is attached to the device, preventing axial movement of the sleeve. 60. An injection device according to claim 47, wherein the second coupling comprises an abutment between a third abutment element on, or coupled to, the dose selector and a fourth abutment element on, or coupled to, the boot, and wherein the first abutment element and the third abutment element are the same abutment element. 61. An injection device according to claim 57, wherein, when the device is fired, the plunger is arranged to abut the sleeve so as to axially displace the sleeve, and wherein the abutment between the plunger and the sleeve is via the first and/or third abutment element abutting a distal surface of the sleeve. 62. An injection device according to claim 57, wherein the housing comprises a viewing window, and wherein the sleeve is arranged such that a portion of the sleeve is visible through the viewing window after the device has been fired. 63. An injection device according to claim 57, wherein the sleeve comprises a step like profile along its distal end, where at least one step corresponds with a particular dose. 64. An injection device according to claim 63, wherein the steps provide the distal surface that the first and/or third abutment element abut, and wherein the sleeve comprises a resiliently flexible arm having a wedge portion, and is arranged such that, prior to firing the device, the resiliently flexible arm is bent radially inward due to an abutment between the wedge portion and an inner surface of the housing, placing the resiliently flexible lock arm under tension, and is further arranged such that after firing the injection device, the wedge portion is proximally displaced so as to line up with the viewing window such that the wedge portion no longer abuts the inner surface of the housing, allowing the tension in the resiliently flexible lock arm to be released, driving the wedge portion into the viewing window. | FIELD OF THE INVENTION The present invention relates to injection devices for delivering a medicament from a container. BACKGROUND OF THE INVENTION Injection devices, such as automatic injection devices, are routinely used in the medical field to deliver a measured dose of medicine to a user. Typically, injection devices have a user friendly design, allowing them to be safely used by patients for self-administration, although in some circumstances they may be used by trained personnel. They may be designed to be carried by the user for use at any time, in which case they should be as small and inconspicuous as possible to improve user compliance. Automatic injection devices for the self-administration of parenteral drugs include single dose and multi dose reusable and disposable auto-injectors and pen injectors (e.g. insulin pens), which are suitable for a wide range of primary containers, including pre-filled glass and plastic syringes and pre-filled cartridges. A typical automatic injection device comprises several parts which may include; a syringe containing medicine, a needle fixed to the end of the syringe, a firing mechanism including a spring (or possibly other drive means such as an electric motor or gas drive means), a trigger, and a dose selector which allows a user to select a dose of medicine that they require. The firing mechanism is activated by the trigger and forces the medicine through the needle and into the user. The firing mechanism may also be arranged to perform an initial step of inserting the needle through the skin using the force provided by the injection spring (or possible a secondary spring). A mechanical lock may be provided to prevent the trigger from being accidentally pressed. This could be, for example, a catch that must be moved out of the way in order to access the trigger. Automatic injection devices are delivered to end users in an assembled state, with a medicine syringe contained within the device housing and a needle fixed to the end of the syringe. In order to ensure sterility of the needle, the projecting end of the needle is contained within a rubber, elastomer “boot”, which may have a rigid polymer cover. Typically, the boot forms an interference fit around the narrowed end portion of the syringe housing. The tip of the needle may penetrate the end of the boot. The injection device may also comprise a boot remover to allow the end user to easily and safely remove the boot and thereby expose the needle. Typically, the boot remover is fitted around or inside a proximal end (end closest to injection site) of the device prior to insertion of the syringe into the housing. A needle shield may be further provided around the needle, such that the needle remains protected even after the boot has been removed. This is relevant to automatic injection devices which, in addition to driving the medicine through the needle (medicine delivery phase), perform the initial step of inserting the needle through the skin (needle insertion phase). When an automatic injection device is to be used, typically a user removes the boot using the boot remover to expose the needle, and then selects a dose of medicine to be delivered. The user will then release the mechanical lock, such that the trigger can be pressed, place the automatic injection device against the surface of the skin and press the trigger to push the needle through the skin and force the medicine through the needle. A carriage and carriage-return spring may cause the needle to be returned to a position within the needle shield to prevent accidental injury after the device has been used. A problem with injection devices occurs when a user forgets to first remove the boot, and, instead, operates the trigger with the boot still in place. If the boot is not removed before firing, no drug is delivered to the user. Furthermore, since the medicine will now be under pressure, there is a risk that the user may inadvertently empty the syringe contents into the air if, when realising their error, they subsequently remove the boot. A user may not have an abundance of medicine and so waste may be a serious issue. Waste may also be undesirable due to cost implications: some medicines can be extremely expensive. Therefore, there exists a need to provide an improved automatic injection device. SUMMARY In a first aspect of the invention, there is provided an injection device for delivering a medicament from a container. The device comprises, a housing for housing a container, a plunger substantially housed within the housing and which is movable within the housing, a force applicator for applying a force to the plunger, a trigger coupled to the force applicator for releasing the force applicator to fire the device, a boot, a dose selector for allowing a user to select a dose of medicament, and a first mechanical interlock arranged such that the force applicator cannot be released until the dose selector has been operated to select the dose of medicament, and a second mechanical interlock arranged such that the dose selector cannot be operated to select the dose of medicament prior to removal of the boot. The two mechanical interlocks force the user to perform a sequential order of steps before the injection device will fire. Advantageously, this prevents a user from accidentally firing the device while the boot is still attached, or while no dose is set. The force applicator may be a helical spring which, in an initial, unfired, condition is held in a compressed state. The trigger may not physically contact the force applicator, but just be linked to the force applicator such that on activating the trigger (such as by pressing it), the helical spring is no longer held in the compressed state, and is able to expand so as to deliver medicament. The term, fire, may refer to any action involved with delivering the medicament. For example, when the device is fired, the needle may be driven into a user's skin (needle insertion phase) followed by the medicament being forced through the needle and into the user (medicament delivery phase). The first mechanical interlock may be provided by a first coupling between the housing and the plunger. The first coupling may comprise an abutment between a first abutment element on, or coupled to, one of the housing and the plunger and a second abutment element on, or coupled to, the other of the housing and the plunger. The term “coupled” is used to denote that the components are mechanically linked, such that a force applied to one component ultimately causes a force to be applied to the other component. For example, the abutment need not be between features on the plunger and housing, but may, for example, be between features of components coupled to the plunger and housing, such as intermediate components between the plunger and housing. The first mechanical interlock may be arranged such that the abutment of the first abutment element and the second abutment element prevents the plunger from being displaced axially. For example, the first coupling may comprise an abutment between a shoulder on the housing and a peg on the plunger, preventing proximal axial movement of the plunger. In order to fire the device, the peg may need to be moved such that it does not abut the shoulder. The second mechanical interlock may be provided by a second coupling between the dose selector and the boot. The second coupling may comprise an abutment between a third abutment element on, or coupled to, the dose selector and a fourth abutment element on, or coupled to, the boot. For example, the third abutment element and fourth abutment element need not be features on the dose selector and boot, but may, for example, be features on components coupled to the dose selector and boot, such as intermediate components between the dose selector and boot. The dose selector may be rotatable relative to the housing, said rotation allowing a user to select the dose of medicament. The dose selector and plunger may be rotationally coupled such that rotation of the dose selector rotates the plunger and removes the abutment of the first abutment element and the second abutment element. Optionally, the first abutment element may be either a peg or shoulder on the plunger and the second abutment element may be the other of a peg or shoulder on the housing. For example, the first coupling may comprise an abutment between a shoulder on the housing and a peg on the plunger, preventing axial movement of the plunger. Upon rotation of the dose selector, the plunger is rotated, which displaces the peg relative to the shoulder such that the peg no longer abuts the shoulder, allowing the plunger to be proximally axially displaced. The second mechanical interlock may be arranged such that the abutment of the third abutment element and the fourth abutment element prevents the dose selector from being rotated relative to the housing. For example, the abutment of the third abutment element and the fourth abutment element may prevent a user from setting a dose using the dose selector. Optionally, removal of the boot may remove the second coupling between the third abutment element and the fourth abutment element, allowing rotation of the dose selector with respect to the housing. The third abutment element may be a first surface on the plunger and the fourth abutment element may be a second surface coupled to the boot. If the plunger is coupled to the dose selector, such that they rotate together, then preventing the plunger from rotation will prevent the dose selector from rotation. The first surface may be a protrusion, such as a peg, on the plunger, and the second surface coupled to the boot may be a part of a boot remover, or may be a part of an internal sleeve rotationally fixed and axially moveable with respect to the housing, boot and/or boot remover. The injection device may further comprise a sleeve housed in the housing and which may be rotationally fixed and axially moveable with respect to the housing. The sleeve may take the form of a tube, or partial tube, that fits within the housing. The sleeve may comprise the second surface and the sleeve may be axially coupled to the boot such that axially movement of the sleeve is restricted while the boot is attached to the device. The second surface may axially extend past the first surface such that the second surface presents a barrier to rotation of the first surface. The injection device may further comprise a boot remover for removing the boot. The axial coupling between the sleeve and boot may act between a boot remover, where the boot remover may abut the sleeve while the boot remover is attached to the device, preventing axial movement of the sleeve. The first abutment element and the third abutment element may be the same abutment element. For example, the first abutment element and the third abutment element may be the same peg on the plunger. When the device is fired, the plunger may be arranged to abut the sleeve so as to axially displace the sleeve. For example, as the plunger is axially displaced in a proximal direction (towards the user's skin), the plunger may also proximally axially displace the sleeve. The abutment between the plunger and the sleeve may be via the first and/or third abutment element abutting a distal surface of the sleeve. For example, a peg of the plunger may abut a distal end of the sleeve during displacement. The housing may comprise a viewing window, and the sleeve may be arranged such that a portion of the sleeve is visible through the viewing window after the device has been fired. Advantageously, this provides a visual cue to the user that the device has been fired. Alternatively, a portion of the sleeve may be visible prior to firing the device, and during a firing process the sleeve is displaced such that a portion of the sleeve is not visible through the viewing window after firing the device. The sleeve may comprise a step like profile along its distal end, where at least one step corresponds with a particular dose. The steps may provide the distal surface that the first and/or third abutment element abut on the sleeve. For example, if the first and third abutment element is a peg on the plunger, the peg abuts a step corresponding to the selected dose during firing of the device, so as to axially displace the sleeve. The sleeve may further comprise a resiliently flexible arm having a wedge portion, and may be arranged such that, prior to firing the device, the resiliently flexible arm is bent radially inward due to an abutment between the wedge portion and an inner surface of the housing, placing the resiliently flexible lock arm under tension. The resiliently flexible arm may further be arranged such that after firing the injection device, the wedge portion is proximally displaced so as to line up with the viewing window such that the wedge portion no longer abuts the inner surface of the housing, allowing the tension in the resiliently flexible lock arm to be released, driving the wedge portion into the viewing window. In a second aspect of the invention there is provided an injection device for delivering a medicament from a container. The device comprises a housing for a container, a plunger movable within the housing to expel a dose of medicament, a force applicator for applying a force to the plunger, a trigger coupled to the force applicator for releasing the force applicator, a dose selector for allowing a user to select a dose of medicament from a plurality of doses, and an indicator element for indicating to a user that a selected dose has been delivered, the indicator element being arranged to be axially moveable by the plunger from a first position when a selected dose of medicament has not been expelled, to a second position when a selected dose of medicament has been expelled, and wherein the plunger and the indicator element are arranged such that the axial distance traveled by the indicator element between the first and second position is substantially the same for each of the plurality of doses. Advantageously, the second aspect provides an injection device that can be set to deliver a large range of doses of medicament, while reliably providing an indication that the selected dose has been delivered. This is due, in part, to the fact that the indicator element is driven proximally forward by the plunger for the same distance, regardless of what dose is set, and therefore what distance the plunger travels. The indicator element may be substantially housed in the housing and may comprise a sleeve portion. The sleeve portion may take the form of a tube, or partial tube, that fits within the housing. The sleeve portion may comprise a step like profile along a part of its distal end, wherein each step corresponds with a specific dose of medicament, and defines an axial distance which the plunger must travel before a peg of the plunger makes contact with the step and axially displaces the indicator element from the first position to the second position. The housing may comprise a plurality of tracks, where each track corresponds to a specific dose and has a corresponding length associated with a specific dose. For example, longer tracks correspond with larger doses, and shorter tracks with smaller doses. The tracks may be arranged to receive the peg of the plunger. In this way, the tracks define how far the plunger may travel, and therefore define the amount of medicament expelled. The specific steps of the step like profile may be arranged to correspond with specific track lengths such that the axial distance traveled by the indicator element between the first and second position is substantially the same for each of the plurality of doses. The relative change in height of each step may directly correspond with the relative change in the length of each track. For example, longer tracks may correspond with steps that define a shorter length of the sleeve portion, and shorter tracks may correspond with steps that define a longer length of the sleeve portion. The housing may further comprise a viewing window. The indicator element may comprise a visual indicator which is arranged to line up with the viewing window when in the second position, so as to indicate to a user that a selected dose has been delivered. The visual indicator may comprise a wedge portion coupled to a resiliently flexible arm, and may be arranged such that, prior to firing the device, the resiliently flexible arm is bent radially inward due to an abutment between the wedge portion and an inner surface of the housing, placing the resiliently flexible lock arm under tension. The resiliently flexible arm may further be arranged such that after firing the injection device, the wedge portion is proximally displaced so as to line up with the viewing window such that the wedge portion no longer abuts the inner surface of the housing, allowing the tension in the resiliently flexible lock arm to be released, driving the wedge portion into the viewing window. In a third aspect of the invention, there is provided a plunger for use in an injection device. The plunger comprises a first portion and a second portion, the first and second portions being formed as separate components, and wherein the first portion is arranged to receive and accommodate the second portion in one of a plurality of positions, wherein each position defines a specific length of the plunger. The first portion may be a distal portion of the plunger, and the second portion may be a proximal portion of the plunger. Advantageously, the third aspect provides a plunger that's length can easily be adjusted during assembly by altering the position at which the two portions of the plunger are assembled. This allows fixed size components to be manufactured, which can then be combined to achieve a plunger having a range of possible lengths. The lengths may relate to the specific doses that the injection device, in which the plunger is to be used, delivers. The first portion may comprise an opening arranged to receive the second portion. The opening may comprise a recessed region along an edge of the first potion. The recessed region may comprise a series of saw tooth features which may be arranged to interlock with corresponding saw tooth features on the second portion. Alternatively, the opening may comprise an opening on a proximal end of the first portion, and may be arranged such that a distal portion of the second portion may be loaded into the opening. The first portion may comprise a plurality of apertures along an axial length of the first portion, each aperture defining a particular length of the plunger, and the second plunger potion may comprises an extendable arm which is arranged to enter one of the apertures in the first plunger portion so as to hold the second plunger portion in place relative to the first plunger portion. In a fourth aspect of the invention, there is provided a method of manufacturing a plunger. The method comprises, forming a first portion having means to receive and accommodate a second portion in one of a plurality of positions, wherein each position defines a specific length of the plunger, forming a second portion, and accommodating the second portion in a position of the plurality of positions. In a fifth aspect of the invention, there is provided an injection device for delivering a medicament from a syringe. The device comprises, a housing for housing a syringe, a plunger substantially housed within the housing and which is movable within the housing, a force applicator for applying a force to the plunger, a trigger coupled to the force applicator for releasing the force applicator, and a high friction surface coupled between the plunger and the housing, and arranged to reduce the initial acceleration of the plunger while the force is applied to the plunger during a needle insertion phase. The high friction surface is a surface having a relatively high coefficient of friction compared with other materials typically used in an injection device. For example, the high friction surface may be provided by a rubber material. The high friction surface may be applied to the housing, and the plunger may be arranged to slide against the rubber material. The high friction surface may be applied to any component of the injection device that the plunger axially moves relative to during a needle insertion phase. Typically, a force applicator, such as a helical spring, performs the job of inserting a needle and displacing a bung in a syringe so as to deliver medicament. This can lead to peak impacts which are absorbed by components of the syringe such as a flange of the syringe. Such peak impacts can damage components of the syringe and/or injection device. By providing a high friction surface, the initial acceleration of the plunger is reduced, thereby reducing the magnitude of the peak impacts. The plunger or housing may comprise the high friction surface and the other of the plunger or housing may comprise a surface which is arranged to slide against the high friction surface so as to reduce the initial acceleration of the plunger. The high friction surface may have an axial length that corresponds to a length traveled by the plunger during the needle insertion phase of the injection device, such that the high friction surface reduces the acceleration of the plunger during the needle insertion phase. Once the needle has been inserted, the plunger clears the high friction surface, allowing the medicament to be delivered with the force applicator being undamped. The housing may further comprise tracks of differing lengths, each track corresponding to a specific dose, the tracks being arranged to receive and accommodate a peg coupled to the plunger, and wherein the tracks comprise the high friction surface or a further high friction surface. The peg of the plunger may then be arranged to slide against the high friction surface applied to the track, reducing the initial acceleration of the plunger. The plunger may comprise a bore which is arranged to accommodate a rod which is axially fixed with respect to the housing, and the rod may comprise the high friction surface or a further high friction surface. In an unfired position, the rod will be located within the bore, and an interference fit is achieved between the high friction surface on the rod and the inner surface of the bore. As the injection device is fired, the plunger moves axially with respect to the rod, meaning that the inner surface of the bore slides against the high friction surface on the rod, reducing the initial acceleration of the plunger. The injection device may further comprises a syringe carrier arranged to accommodate a syringe, wherein the syringe carrier may be axially displaced during the needle insertion phase, a resiliently deformable material arranged between the syringe carrier and a syringe, wherein the resiliently deformable material may be arranged such that when the syringe carrier reaches the end of its travel, axial movement between the syringe carrier and a syringe is damped by the resiliently deformable material. The resiliently deformable material may be arranged to act between a flange of the syringe carrier and a flange of a syringe. The resiliently deformable material may be in the form of a lip around a distal end of the syringe carrier. As the distance between the syringe flange and the syringe carrier flange reduces, the resiliently deformable material is compressed between the two flanges, absorbing energy and reducing the impact between the flanges. The high friction surface and/or the resiliently deformable material may comprise a thermoplastic elastomer. BRIEF DESCRIPTION OF DRAWINGS FIG. 1 is a perspective view of an injector device; FIG. 2a is a cross-section of the injector device; FIG. 2b is a cross-section of the injector device along a plane perpendicular to the cross section of FIG. 2a; FIG. 3 is a perspective view of a dose selector of the injector device; FIG. 4 is a perspective view of a distal end of a housing; FIG. 5 is a perspective view of a lock shuttle and trigger catch of a plunger in isolation; FIG. 6 is a further perspective view of the lock shuttle and trigger catch; FIG. 7 is a perspective partial view through the dose selector and showing a distal part of the lock shuttle; FIG. 8 is a perspective partial view of the proximal end of the dose selector; FIG. 9 is a side on view of a shuttle carrier in isolation; FIG. 10 is a perspective cross-section view of a distal end of the housing, showing the trigger catch within the housing; FIG. 11 is a perspective view of the lock shuttle and boot remover in isolation; FIG. 12a is a partial see-through view of the injection device showing the trigger catch in a mid-delivery position; FIG. 12b is a close up external view of the housing showing a viewing window of the injection device shown in FIG. 12a; FIG. 13a is a partial see through view of the injection device showing the trigger catch following delivery of a dose of medicament (fired position); FIG. 13b is a close up external view of the housing showing a viewing window of the injection device shown in FIG. 13a; FIG. 14 is a cross section of a perspective view of the injection device, showing the relative position of steps on the lock shuttle with respect to tracks within the housing; FIG. 15 is a close up side on view of a peg of the plunger; FIG. 16 shows two perspective views of a plunger in an assembled, and unassembled state. FIG. 17 shows two perspective views of an alternative plunger in an assembled, and unassembled state. FIG. 18 is a close up cross sectional view of a distal end of a syringe; FIG. 19 is a close up cross sectional view of the trigger lock prior to firing the injection device; FIG. 20 is a close up cross sectional view of the trigger lock during firing of the injection device; FIG. 21 is a perspective, cross sectional view showing the plunger and inner surface of the housing; FIG. 22 is a cross sectional view of a distal end of the injection device having a modified plunger; and FIG. 23 is a perspective, cross sectional view of the injection device shown in FIG. 22. DETAILED DESCRIPTION With reference to FIGS. 1 to 15, there will now be described an injection device 1 according to the invention. The embodiment shown is a specific embodiment and is not intend to limit the manner in which the invention is implemented. For example, where some parts are shown as separate but would function mechanically if they were integral then the skilled person will recognise that both implementations are disclosed herein; similarly where certain parts are shown as integral but could be provided as two or more parts then such an implementation is also envisaged as falling within the present invention. FIG. 1 shows a perspective view of an automatic injection device 1, henceforth referred to as an auto-injector 1, showing, amongst other components, a boot remover 2, a housing 3, a dose selector 4, a trigger button 5 and a viewing window 6. FIGS. 2a and 2b show cross sections through the auto-injector 1, (where the plane of the cross section of FIG. 2a is at 90 degrees of the plane of the cross section of FIG. 2b) showing, amongst other components, a boot 2b, a plunger 7, a lock shuttle 8, a drive spring 9, a syringe carrier 10 and a syringe 11. The terms distal and proximal are sometimes used interchangeably. In the following description, the distal direction refers to a direction away from an injection site and the proximal direction refers to the direction towards the injection site. Therefore, the trigger button 5 is located at a distal end of the auto-injector 1 and the boot remover 2 is located at a proximal end of the auto-injector 1. The syringe 11 comprises a generally cylindrical container portion 12 for accommodating a fluid 13 such as a medicament, syringe flange 14, and a needle 15. The needle 15 is in communication with the interior of container portion 12 so that the fluid 13 may be expelled through needle 15. A bung 16 is inserted in the container portion 12 at the distal end of the container portion 12. The bung 16 seals the fluid 13 within the container portion 12 and is arranged such that proximal displacement of the bung 16, relative to the container portion 12, expels the fluid 13 through the needle 15. The syringe carrier 10 houses the syringe 11 (or other container for a substance). The syringe carrier 10 comprises a distal barrel portion 10a, a proximal barrel portion 10b and a compressive connector portion 10c (see FIG. 9). In the embodiment shown in the figures, the compressive connector portion 10c comprises an integral spring like structure which is arranged between the distal barrel portion 10a and the proximal barrel portion 10b. When the compressive connector portion 10c is in an uncompressed state, the proximal barrel portion 10b of the syringe carrier 10 extends beyond the needle 15 so as to provide a shield for the needle 15. When the compressive connector portion 10c is in a compressed state, the proximal barrel portion 10b of the syringe carrier 10 does not extend beyond the needle 15, exposing the needle 15. The syringe 11 is substantially axially held relative to the syringe carrier 10 by an interference fit between the syringe 11 and the distal barrel portion 10a of the syringe carrier 10. A rubber sleeve 17 is positioned between the syringe 11 and syringe carrier 10 to help provide the interference fit (see FIG. 18 and further description below). However, during an injection process, the forces involved may overcome the interference fit, causing the syringe 11 to move proximally relative to the syringe carrier 10 (described in detail below). A resiliently deformable flange damper 18 is located between the syringe flange 14 and a flange 19 on the distal barrel portion 10a of the syringe carrier 10 (see FIG. 18) in order to help reduce the load on the syringe flange 14 during an injection process. In the embodiment shown in the FIG. 18, the rubber sleeve 17 and resiliently deformable flange damper 18 are integral. However, the skilled person will realise that these components may be separate. The auto-injector 1 is arranged such that a user may select discrete doses to be expelled from the syringe 11 by rotating the dose selector 4, in this case, anticlockwise relative to the housing 3. The dose selector 4 is prevented from initially rotating clockwise via an abutment of features between the dose selector 4 and the housing 3 (described below). The dose selector 4 and housing 3 have complementary markings 20, 21, which provide a visual indication of what discrete dose is set when a user rotates the dose selector 4. The dose selector 4 has a selector peg 22 (shown in FIG. 3) located in line with the visual marking 20, which is arranged to fit between saw-tooth like grooves defined by raised features 23 on an inner surface of the housing 3 (shown in FIG. 4—not all raised features are highlighted), where the bight of each groove is in line with a corresponding visual marking 21 on the housing 3. The selector peg 22 is resiliently deformable, such that as the dose selector 4 is rotated, the selector peg 22 is deformed radially inward each time it travels over a raised feature 23. This arrangement provides some resistance to rotation between the discrete dose settings, and allows the dose setter 4 to “click” into place for each dose. The drive spring 9 is preloaded, and acts to urge the plunger 7 in the proximal direction when the trigger button 5 is pressed. The plunger 7 has a trigger catch 7a (the trigger catch is shown in more detail in FIGS. 5 and 6) at its distal end, which is arranged to co-operate with the trigger button 5. In an initial condition (i.e. before use), the trigger catch 7a is axially held in place relative to the dose selector 4 by four shoulders 25 (see FIGS. 7 and 8) carried by the internal wall of the dose selector 4, which co-operate with four co-operating portions in the form of outwardly projecting teeth 26 on resiliently flexible fingers 27 of the trigger catch 7a. The trigger catch 7a is also rotationally fixed relative to the dose selector, before use, via extended portions 28 which abut the sides of the shoulders 25 (see FIG. 7, where the dose selector 4 has been drawn using dashed lines to help differentiate it from the trigger catch 7a). This ensures that as the dose selector 4 is rotated relative to the housing 3 to set a dose, the trigger catch 7a is also rotated. It will be appreciated by the skilled person that any suitable number of shoulders and co-operating portions may be used, such as three shoulders and three corresponding co-operating potions. The trigger button 5 has four flexible arms 29 with cam surfaces 30 that co-operate with cam surfaces 31 on the flexible fingers 27 of the trigger catch 7a, such that proximal movement of the trigger button 5 relative to the trigger catch 7a will flex the fingers 27 of the trigger catch 7a radially inward, releasing the outwardly projecting teeth 26 from the shoulders 25. Once the outwardly projecting teeth 26 of the trigger catch 7a have been released from the shoulders 25, the plunger 7 is no longer axially or rotationally coupled to the dose selector 4, and is urged forcefully by the drive spring 9 in the proximal direction. Once the trigger catch 7a has been released during the above process, the trigger button 5 is prevented from further, significant, proximal movement relative to the dose selector 4 by the ends of the flexible arms of the trigger button 5 abutting the shoulders 25. Alternatively, further co-operating elements can be supplied on the trigger button 5 or housing dose selector 4, or both in order to prevent further movement of the trigger button on release of the trigger catch 7a. Once the plunger 7 is released, a proximal end 7f of the plunger 7 acts on the bung 16 of the syringe 11. Due to fluid resistance from the liquid 13 in the syringe 11, the load is transferred from the bung 16 to the syringe 11, which transfers the load to the distal barrel portion 10a of the syringe carrier 10. The distal barrel portion 10a of the syringe carrier 10 is then driven forward in the proximal direction. The proximal end of the proximal barrel portion 10b is arranged to be pressed against the user's skin during use (see FIG. 9, which shows the syringe carrier 10 in isolation, distal barrel portion 10a and proximal barrel portion 10b are indicated by two rectangles placed over the syringe carrier). This abutment between the skin and the proximal barrel portion 10b holds the proximal barrel portion 10b in place relative to skin. As the distal barrel portion 10a of the syringe carrier 10 is driven forward in the proximal direction, the compressive connector portion 10c compresses, allowing the needle to extend beyond the syringe carrier 10 and penetrate the user's skin. After the needle 15 has traveled a predetermined distance, preferably between about 6-10 mm, the flange 19 of the distal barrel portion 10a of the syringe carrier 10 abuts a stop face 32 on the inner surface of the housing 3 (see FIG. 11), which prevents further proximal movement of distal barrel portion 10a of the syringe carrier 10. The load from the drive spring 9 is now transferred to the bung 16. The load from the drive spring 9 overcomes the fluid resistance of the fluid 13 in the syringe 11, allowing the bung 16 to move proximally through the syringe delivering the fluid to the user through the needle 15 (the medicament delivery phase). Once the dose has been delivered the user pulls the auto-injector 1 away from the skin. This action withdraws the needle 15 and allows the compressive connector portion 10c to expand, allowing the proximal barrel portion 10b of the syringe carrier 10 to cover the exposed needle 15. In the initial condition, the above process is prevented from occurring by a mechanical interaction between the boot remover 2, lock shuttle 8 and trigger catch 7a. In order for the auto-injector 1 to fire when the trigger button 5 is pressed, the user must first have removed the boot remover 2 and then dialed a dose, in that order. Once these two sequential steps have been completed, the device will fire when the trigger button 5 is pressed. This sequential ordering of steps, described in more detail below, makes it more difficult for the user to accidentally fire the auto-injector 1. In order to better describe the interaction between the trigger catch 7a and the lock shuttle 8, these components are shown in isolation in FIGS. 5 and 6. The lock shuttle 8 cannot be rotated relative to the housing 3, due to an engagement between an axial track 33 (shown in FIG. 6) running along the outer surface of the lock shuttle 8 and raised guide portion 34 (shown in FIG. 10) running along the inner surface of the housing 3. When unobstructed, the lock shuttle 8 can move axially with respect to the housing 3. In the initial condition, legs 8a of the lock shuttle 8 abut legs 2a of the boot remover 2 (see FIG. 11 which shows the boot remover 2 and lock shuttle 8 in isolation). This abutment prevents the lock shuttle 8 moving in the proximal direction while the boot remover 2 is still attached to the auto-injector 1. This restriction in proximal movement of the lock shuttle 8 also prevents rotation of the dose selector 4, meaning a dose cannot be set (described in more detail below). When the user removes the boot remover 2, the legs 2a no longer abut the legs 8a, and the lock shuttle 8 is free to move in the proximal direction. The boot remover 2 may be attached to the housing 3 via any suitable means, such as, for example, interlocking features on the housing and boot remover 2. The trigger catch 7a has a pair of pegs 35 located on either side of its external surface. These pegs are arranged to fit within tracks 36 located on an inner surface of the housing 3 (see FIG. 4—not all tracks have been referenced for clarity). Each track 36 corresponds with a specific dose setting and has a length which corresponds with the distance the plunger 7 needs to travel in order to deliver the correct dose (i.e. a smaller dose corresponds with a shorter track and a larger dose corresponds with a longer track). For each specific dose, there are two corresponding tracks having the same length located on either side of the housing 3. This is to accommodate the two pegs 35 on either side of the trigger catch 7a. Therefore, the dose selector 4 may be rotated through less than 180 degrees between no dose being set, and a maximum dose being set. However, the skilled person will realise that only one peg 35 and one track may be used. As the auto-injector 1 is fired, the pegs 35 travel along a specific track 36 corresponding with a specific dose. When the pegs 35 reach the end of the tracks 36, they abut raised surfaces 36a within the tracks which prevent further proximal movement of the plunger 7. By rotating the dose selector 4 to a specific dose, the pegs 35 can be made to line up with the corresponding specific track (i.e. lined up when looked at end on). The tracks 36 are separated by internally raised portions 37. In the initial condition, each peg 35 is not lined up with a track 36, but instead lined up with a pair of shoulders 37a on the inner surface of the housing 3 that correspond with no dose being set. Therefore, the auto-injector 1 will not fire prior to a dosage being selected, due to abutment of the pegs 35 with the shoulders 37a on the inner surface of the housing 3. In the initial condition the dose selector cannot be rotated anti-clockwise to set a dose due to abutment of the pegs 35 with a pair of dial locks 38 located on the distal end of the lock shuttle 8 (see FIG. 5 which shows one of the dial locks 38, the other being located on the opposite side of the lock shuttle 8). The dial locks 38 extend past the pegs 35 so as to prevent anti-clockwise rotation. The dose selector 4 is also initially prevented from rotating clockwise due to abutment between a rib 53 on the inner surface of the housing 3 and the peg 35 (see FIG. 15, which shows a close up view of the peg 35 with the housing 3 partially transparent so as to show the rib 53). FIG. 15 also shows a ridge 54 on the inner surface of the housing 3, which provides an initial resistance to rotating the dose selector 4 in the anti-clockwise direction. This helps to prevent accidentally setting a dose during handling once the boot remover 2 has been removed. FIG. 15 also shows the peg 35 having a tapered like profile 35a. This arrangement assists the peg 35 in travelling past the ridge 54 when a user rotates the dose selector 4 to set a dose. In order to select a dose using the dose selector 4 the dial locks 38 must be proximally displaced such that they are no longer in the rotational path of the pegs 35. However, in the initial condition, the boot remover 2 prevents axial displacement of the lock shuttle 8 and hence the dial locks 38. Therefore, the boot remover 2 must be removed in order to allow proximal movement of the lock shuttle 8. The dial locks 38 feature a chamfered edge 38a, such that when the boot remover 2 has been removed and the dose selector 4 is rotated, the pegs 35 interact with the chamfered edge 38a to help proximally displace the dial lock 38 out of the rotational path of the pegs 35. This then allows the user to continue to rotate the dose selector 4 to a specific dose. Therefore, the dose selector 4 cannot be rotated prior to removal of the boot remover 2. This sequential ordering of steps prevents a user from accidentally firing the device, forcing the user to first remove the boot, and then set a dose. The lock shuttle 8 is arranged to travel the same distance in the proximal direction during firing of the auto-injector 1, regardless of what dose has been set. This is facilitated by the lock shuttle 8 having a series of steps 39 (see FIGS. 5, 6, and 7 which show some of the steps 39—for clarity, not all steps are referenced) along its distal end defining different lengths of the lock shuttle 8, where each step 39 corresponds with a specific track 36 (and therefore dose) (see FIGS. 12a and 13a which show a transparent view of the housing 3, along with the trigger catch 7a and the lock shuttle 8). As described above, in the embodiment shown, there are two pegs 35 on opposite sides of the trigger catch 7a. Therefore, there are two corresponding steps 39 for each dose, one located on either side of the lock shuttle 8. Once the user has rotated the dose selector 4 to a desired dose, the pegs 35 line up with the corresponding steps 39 on either side of the lock shuttle 8 and the corresponding tracks 36 on either side of the housing 3 for that dose. As the auto-injector 1 is fired, the plunger 7 is axially displaced in the proximal direction under the force of the drive spring 9. The lock shuttle 8 is not substantially proximally displaced until the pegs 35 make contact with the corresponding steps 39 relating to the dose that has been selected. Once the pegs 35 abut the steps 39, the lock shuttle 8 is also axially displaced in the proximal direction under the force of the drive spring 9, until the pegs 35 reach the end of the tracks 36 and abut the raised surfaces 36a within the tracks 36. The differing height of the steps 39 therefore provide different offsets which the pegs 35 must travel before coming into contact with, and displacing, the lock shuttle 8, i.e. the length of the lock shuttle 8 as seen from the pegs 35 is differs depending on what step 39 is selected. The arrangement of the relative lengths of the tracks 36 and the offset provided by the corresponding step 39 is such that the lock shuttle 8 is driven by the drive spring 9 for substantially the same distance no matter what dose has been set prior to firing. For example, if the user rotates the dose selector 4 to the first dose setting (0.80 ml) shown in FIG. 1, the pegs 35 line up with relatively short tracks 36 and also line up with steps 39 which define a relatively short offset, and hence longer length of the lock shuttle 8. In some embodiments, the smallest dose may have a step 39 that immediately contacts the peg 35 after the dose has been set, i.e. there is no gap between the peg 35 and the first step 39, and so the offset is effectively zero. This is shown in FIG. 12a which shows a close up of the housing 3 mid-delivery (where the housing 3 is shown as partially transparent), and where the smallest dose has been set. As the auto-injector 1 is fired, the pegs 35 of the plunger 7 begin to travel down the tracks 36, and due to the abutment of the pegs 35 with the steps 39, the lock shuttle 8 is also driven proximally forward with the plunger 7. The plunger 7 reaches the end of its travel when the pegs 35 abut the raised surfaces 36a within the tracks 36 (shown in FIG. 13a). If a larger dose is set, the pegs 35 will line up with relatively long tracks and also line up with steps which define a relatively long offset, and hence shorter length of the lock shuttle 8. When the auto-injector 1 is fired, the pegs 35 begin to travel down the longer tracks 36, and due to the relatively short length of the lock shuttle 8 as defined by the offset of the steps 39, the pegs 35 will travel a further distance before coming into contact with the steps 39. The relative change in height (offset) of each step 36 corresponds with the relative change in the length of each track 36. This is shown in FIG. 14 which shows an isolated section of the inside of the housing 3 with the lock shuttle 8 fully driven proximally forwards. As can be seen, the end 36a of each track 36 is at substantially at the same axially point as its corresponding step 39. Note that FIG. 14 does not show the syringe for clarity. The lock shuttle 8 features a mechanism for providing an indication to a user that the full dose has been delivered. The lock shuttle 8 features a pair of lock arms 40 located on either side of the lock shuttle 8. Each lock arm 40 has a wedge portion 41 (see FIGS. 5 and 6), which, in the initial condition, press against an inner surface of the housing 3. This arrangement bends each lock arm 40 radially inward, creating tension in the lock arms 40. Once the lock shuttle 8 has traveled its full length after firing, the wedge portions 41 line up with the viewing windows 6 on either side of the housing 3. The viewing windows are in the form of cut outs in the housing 3. When the wedge portions 41 reach the viewing windows 6, the wedge portions 41 no longer press against the inner surface of the housing 3 (due to the presence of the cut out), and so the tension stored in the lock arms 40 is released, snapping the wedge portions 41 into the cut outs of the viewing windows 6. Abutment of the wedge portions 41 with a distal surface 42 of the cut out prevents the lock shuttle from moving distally once the device has been fired. This provides both a visual indication to the user that the device 1 has been fired, and an audio indication as the wedge portions 41 “click” into place. The wedge portions 41 may have a symbol or coloured portion to help easily identify the wedge potions 41 when they are located in the viewing windows 6. FIG. 12b shows a close up of one of the viewing windows 6 before the auto-injector 1 has been fired, and FIG. 13b shows the viewing window 6 after the auto-injector 1 has been fired, with the wedge portion 41 showing through the viewing window 6. In other words, regardless of the specific dose delivered, the lock shuttle 8 ends up in the same final position such that the wedge portions 41 line up with the viewing windows 6. This then gives the user an indication that the full does has been delivered. In order to prevent the wedge portion 41 from prematurely entering the cut-out prior to firing (for example, if the user orientates the auto-injector 1 such that the proximal end faces the ground after the boot remover 2 has been removed), a pair of flexible positioning arms 43 are provided on either side of the proximal end of the lock shuttle 8, and which are arranged to abut a lip 44 around the inner surface of the housing 3. The flexible positioning arms 43 extend from the lock shuttle 8 at an angle offset from the axis of the auto-injector 1. As the lock shuttle 8 moves proximally forward, abutment between the flexible positioning arms 43 and the lip 44 occurs before the wedge portions 41 reach the viewing windows 6. The flexible positioning arms 43 have sufficient rigidity so as to not significantly deform when they abut the lip 44, unless the lock shuttle is being driven by the drive spring 9. When the lock shuttle 8 is proximally driven by the drive spring 9 during firing, the flexible positioning arms 41 are deformed against the lip 44 under the force of the drive spring 9, which then allows the wedge portions 41 to reach the viewing windows 6 and snap into place. FIG. 12a shows one positioning arm 43 prior to firing (un-deformed) and FIG. 13a shows the positioning arm 43 in a deformed state after firing. This arrangement negates the need for positioning springs and complex geometry on the inner surface of the housing 3 in order to prevent the lock shuttle 8 from sliding proximally forward prior to firing. The plunger 7 will now be described in more detail with reference to FIGS. 16 and 17. FIG. 16 show two perspective views of the plunger 7 in an assembled state and unassembled state. The plunger 7 comprises the trigger catch 7a, a plunger stem 7b, and an extended plunger portion 7c. The trigger catch 7a and the plunger stem 7b are integrally formed. The extended plunger portion 7c is formed separately from the trigger catch 7a and the plunger 7b. The stem 7b features a recessed region 45 along a part of its length. The recessed region 45 is arranged to receive and accommodate the extended plunger portion 7c. The recessed region 45 couples with the extended plunger portion 7c via a series of interlocking saw tooth features 7d located on the inner surface of the recessed region 45 and saw tooth features 7e located on the outer surface of the extended plunger portion 7c. During manufacture of the plunger 7, the extended plunger portion 7c is placed at a predetermined position within the stem 7b such that the total length of the plunger 7 is the desired length for the purpose of the plunger 7. The extended plunger portion 7c may be fixed in position, using, for example, an adhesive. Alternatively, there may be sufficient friction between the saw tooth features 7d, 7e such that adhesive is not required. A proximal end 7f of the extended plunger portion 7c is arranged to contact a bung of a cartridge. Advantageously, by providing a plunger that is formed from two separate component parts, the length of the plunger 7 may be easily adjusted during manufacture of the plunger 7. During production of the plunger 7, two moulds are required; one for the trigger catch 7a and stem 7b, and one for the extended plunger portion 7c. However, the dimensions of these two separate component parts do not need to be changed to produce plungers of different lengths. Therefore, moulds used to produce the trigger catch 7a and stem 7b, and extended plunger portion 7c do not need to be reconfigured each time the length of the plunger needs to be adjusted. Instead, a desired length of the plunger 7 can be achieved by inserting the extended plunger portion 7c in the stem 7b at a desired location, such that the total length of the plunger 7 corresponds with the desired length. Furthermore, the saw-tooth nature of the coupling between the stem 7b and the extended plunger portion 7c allows discrete lengths to be easily chosen. FIG. 17 show a modified plunger 46 according to an alternative embodiment. The modified plunger 46 comprises a trigger catch 7a, a stem 47 featuring four pairs of apertures 48 arranged on either side of the length of the stem 47, and an extended plunger portion 49. The extended plunger portion 49 features a pair of wedges 50 which are located on either side of the extended plunger portion 49 and which are arranged, when in a relaxed position, to extend radially outwardly into a pair of apertures 48 on the stem 47. The extended plunger portion 49 also features a hollowed out portion 51 located between the wedges 50, which is arranged to allow the extended plunger portion 49 to be radially compressed, i.e. forcing the wedges 50 together causes the extended plunger potion to compress into the hollowed out portion 51. The material of the extended plunger portion 49 is such that, on removal of the force, the extended plunger potion 49 returns to its relaxed state. In order to set the length of the plunger 46, the extended plunger portion 49 is loaded into a proximally facing opening 47a on the stem 47. Prior to insertion, the wedges 50 are compressed radially inward such that the wedges 50 do not prevent the extended plunger portion 49 from entering the opening 47a. Once the extended plunger portion is located in the desired position, the wedges 50 are released, allowing the hollowed out portion 51 to return to their relaxed position such that they enter a pair of apertures 48, locking the extended plunger portion 49 in place relative to the stem 47. It will be appreciated that any number of apertures 48 may be used, and that it is not necessary for there to be a pair on either side, i.e. there may be one aperture per length setting. The embodiments shown in FIGS. 16 and 17 allow a syringe plunger length to be adjusted during assembly by altering the position at which two components of the plunger are assembled. This allows plunger components of fixed lengths to be manufactured that can then be used in a variety of different devices, such as the auto-injector 1, which can accept a wide range of syringe fill volumes, for example, from 0.02 ml to 1.0 ml. Since the plunger 7 can be tailored to a particular device having a particular syringe fill volume, a further advantage of the plunger described herein is that a gap between the bung 16 and the plunger end 7f, prior to firing the device, can be reduced. This reduces the velocity at which the plunger 7 strikes the bung reducing resultant glass stresses on the syringe at the moment of impact. In an embodiment, the length of the plunger 7 may variable such as to be usable with syringe volumes that vary in 0.01 ml increments. With reference to FIGS. 18 to 23, there will now be described a damping arrangement which helps to reduce the magnitude of the peak impacts during a firing operation of the auto-injector 1. As described above, once the trigger catch 7a is released, the first 10 mm or so of travel drives the needle 15 into the skin (the needle insertion phase). There are typically two main impacts during this phase. The first peak impact occurs when the plunger end 7f makes contact with the bung 16 of the syringe 11. The load from the plunger 7 is applied to the bung 16, but resistance to compression from the fluid 13 in the syringe 11 means no fluid is expelled and instead the syringe 11 and syringe carrier 10 are driven proximally forward (as described above). The second peak impact occurs when the syringe carrier 10 reaches the end of its travel by abutting the stop face 32. The stop face 32 may be in the form of a lip around, or protrusion from, the inner surface of the housing 3. These peak impacts can damage the syringe 11, which is usually made from a brittle material such as glass or plastic material. The following embodiments help to reduce the magnitude of these peak impacts. A rubber insert 52 is arranged on an inner surface of the dose selector 4 below the shoulder 25 (see FIGS. 19 and 20). The rubber insert 52 provides a relatively high frictional surface compared with the typical plastic like material used to construct an auto-injector (such as POM Acetal). The rubber insert 52 may comprise TPE rubber. FIG. 19 shows a close up cross sectional view of the auto-injector 1 in the initial condition, where the trigger catch 7a is axially fixed due to the abutment of the outwardly projecting teeth 26 with the shoulders 25. FIG. 20 shows a close up cross sectional view of the auto-injector 1 just after the trigger button 5 has been pressed, releasing the outwardly projecting teeth 26 from the shoulders 25 and allowing the plunger 7 to be displaced proximally under the force of the drive spring 9. Once the outwardly projecting teeth 26 on the flexible fingers 27 have cleared the shoulders 25, the outwardly projecting teeth 26 slide against the rubber insert 52 (see FIG. 20). The friction between the outwardly projecting teeth 26 and the rubber insert 52 helps to reduce the acceleration of the plunger 7 during the needle insertion phase. The inner diameter of the rubber insert 52 is smaller than the outer diameter of the outwardly projecting teeth 26 when the resiliently flexible fingers 27 are in a relaxed (un-flexed) position. This arrangement means that as the outwardly projecting teeth 26 pass through the rubber insert 52, the resiliently flexible fingers 27 are held radially inward. This provides a radially outward biasing force on the outwardly projecting teeth 26, increasing the friction between the teeth 26 and the rubber insert 52. FIG. 20 shows the rubber insert 52 undergoing deformation as the teeth 26 slide past it due to the outward biasing force. The axial length of the rubber insert 52 is arranged such that the outwardly projecting teeth 26 reach a proximal end 52a of the rubber insert 52 just after the syringe carrier 10 has reached the end of its travel. This leads to the needle insertion phase being damped, and the medicament delivery phase being substantially un-damped by the rubber insert 52. This arrangement reduces the load delivered to the bung 16, and hence the magnitude of the first peak impact, during the needle insertion phase by reducing the plunger's 7 acceleration under the force of the drive spring 9. This arrangement also reduces the magnitude of the second peak impact as the syringe carrier 10 will not be travelling as fast it would otherwise have been when the flange 19 of the syringe carrier 10 abuts the stop face 32. Once the needle insertion phase has been complete (when the flange 19 of the syringe carrier 10 abuts the stop face 32), the outwardly projected teeth 26, which continue to be displaced proximally under the force of the drive spring 9, clear the proximal end of the rubber insert 52a allowing the fluid delivery phase to commence un-damped. The skilled person will recognise that any material may be used for the rubber insert 52 that provides a relatively high friction surface to help slow the acceleration of the plunger. In alternative embodiments, the high friction surface may be applied instead, or in addition, to the teeth 26. Any suitable surface may be used to apply the relatively high friction surface. In an embodiment, each track 36 features a separate rubber insert 36b (see FIG. 21). The rubber inserts 36b in the tracks 36 are arranged to provide a relatively high frictional surface for the pegs 35. The axial length of the rubber inserts 36b are such that the pegs 35 reach the a proximal end of the rubber inserts 36b just after the syringe carrier 10 has reached the end of its travel, meaning that the fluid delivery phase is substantially un-damped by the rubber inserts 36b. The separate rubber inserts 36b in the tracks 36 may be used separately, or in combination with the rubber insert 52. FIGS. 22 and 23 show the auto-injector 1 having a modified plunger 55 according to another embodiment. FIG. 22 shows a cross sectional of the distal end of the auto injector 1, and FIG. 23 shows a cross section perspective view of the distal part of the auto injector 1 without the housing 3. The modified plunger 55 operates in the same way as the plunger 7, but is modified to include a central bore 56 which is arranged to receive a rod 57. The rod 57 extends through the drive spring 9 and is axially fixed with respect to the dose selector 4. The rod 57 comprises a high friction surface 58, the dimensions of which are arranged so as to achieve an interference fit between the bore 56 and rod 57. In the initial, unfired, condition, the rod 57 is located within the bore 56. As the auto-injector 1 is fired, the plunger 55 moves axially with respect to the rod 57. As the rod 57 does not move axially relative to the dose selector 4 (and housing 3), the inner surface of the bore 56 slides against the high friction surface 58 of the rod 57, which slows the acceleration of the plunger 55. The axial distance at which the rod 57 penetrates the bore 56 is arranged such that the rod 57 exits the bore 56 just after the syringe carrier 10 has reached the end of its travel. This arrangement allows the rod 57 to exit the bore 56 once the needle insertion phase has ended, which removes the damping effect and allows the medicament delivery phase to begin, undamped. The high friction surface 58 may comprise a rubber material. The skilled person will appreciate that the bore 56 may carry the high friction surface instead of, or as well as, the rod 57. In an embodiment, the high friction surface 58 comprises four arms which extend radially outward (not shown) in a cross like manner when viewed end on. The distance between the end of each arm is arranged such that the distance is larger than the diameter of bore 56 of the plunger 55. This arrangement leads to the arms deforming when the rod 57 is inserted into the bore 56, which helps create the interference fit between the rod 57 and bore 56. The skilled person will realise that any suitable shape of high friction material may be used to achieve an interference fit. The second peak impact is generated when the syringe carrier 10 hits the stop face 32 and transfers load from the syringe carrier 10 to the syringe 11. While the syringe carrier 10 comes to an abrupt halt, the plunger 7, under the force of the drive spring 9, continues to apply pressure to the bung 16. Fluid resistance initially prevents the bung 16 from forward movement, which leads to a slight compression of the bung 16 and which transfers load through a wall of the syringe 11 as the bung 16 tries to expand. This transfer of load can temporarily overcome the interference fit between the syringe 11 and the syringe carrier 10, driving the syringe 11 proximally forward within the syringe carrier 10 by a small distance (typically around 0.5 mm-1 mm), until the fluid 13 beings to flow from the needle 15. As the syringe 11 moves proximally relative to the syringe carrier 10, the distance between the flange 19 of the syringe carrier 10 and the flange 14 of the syringe 11 is reduced and the resiliently deformable flange damper 18, which is arranged between the flanges 19, 14, is compressed (see FIG. 18 which shows the resiliently deformable flange damper 18 in an uncompressed state). Compression of the resiliently deformable flange damper 18 helps to dissipate this load, thereby reducing stress on the syringe flanges 14. The resiliently deformable flange damper 18 may comprise rubber, or any other resiliently deformable material, and may comprise any shape suitable for reducing load of the syringe flanges 14. For example, FIG. 18 shows the resiliently deformable flange damper 18 having a raised lip 18a to aid with dissipating the load. Embodiments of the invention have been described. Variations and modifications will suggest themselves to those skilled in the art without departing from the scope of the inventions as defined by the appended claims. Furthermore, separate embodiments that have been described may be combined with other embodiments described, or used separately. While various parts have been referred to as shoulders, lips, pegs, protrusions, tracks, it will be appreciated that these features may be replaced by features which achieve the same effect, i.e. a single lip around an inner surface may be replaced by one or more shoulders of other protrusions. Furthermore, where cooperating features between the housing and the plunger or lock shuttle have been described, such as the positioning arms and lip, it will be understood that these may be swapped around where appropriate. For example, the positioning arms 43 may be fixed to the housing 3 and the lip 44 arranged around an outer surface of the lock shuttle 8. The boot 2b has been described as being separate from the boot remover 2, however the boot remover 2 may be integral with the boot 2b, and the leg 2a of the boot remover 2 may be replaced by an extended portion of the boot 2b. | <SOH> BACKGROUND OF THE INVENTION <EOH>Injection devices, such as automatic injection devices, are routinely used in the medical field to deliver a measured dose of medicine to a user. Typically, injection devices have a user friendly design, allowing them to be safely used by patients for self-administration, although in some circumstances they may be used by trained personnel. They may be designed to be carried by the user for use at any time, in which case they should be as small and inconspicuous as possible to improve user compliance. Automatic injection devices for the self-administration of parenteral drugs include single dose and multi dose reusable and disposable auto-injectors and pen injectors (e.g. insulin pens), which are suitable for a wide range of primary containers, including pre-filled glass and plastic syringes and pre-filled cartridges. A typical automatic injection device comprises several parts which may include; a syringe containing medicine, a needle fixed to the end of the syringe, a firing mechanism including a spring (or possibly other drive means such as an electric motor or gas drive means), a trigger, and a dose selector which allows a user to select a dose of medicine that they require. The firing mechanism is activated by the trigger and forces the medicine through the needle and into the user. The firing mechanism may also be arranged to perform an initial step of inserting the needle through the skin using the force provided by the injection spring (or possible a secondary spring). A mechanical lock may be provided to prevent the trigger from being accidentally pressed. This could be, for example, a catch that must be moved out of the way in order to access the trigger. Automatic injection devices are delivered to end users in an assembled state, with a medicine syringe contained within the device housing and a needle fixed to the end of the syringe. In order to ensure sterility of the needle, the projecting end of the needle is contained within a rubber, elastomer “boot”, which may have a rigid polymer cover. Typically, the boot forms an interference fit around the narrowed end portion of the syringe housing. The tip of the needle may penetrate the end of the boot. The injection device may also comprise a boot remover to allow the end user to easily and safely remove the boot and thereby expose the needle. Typically, the boot remover is fitted around or inside a proximal end (end closest to injection site) of the device prior to insertion of the syringe into the housing. A needle shield may be further provided around the needle, such that the needle remains protected even after the boot has been removed. This is relevant to automatic injection devices which, in addition to driving the medicine through the needle (medicine delivery phase), perform the initial step of inserting the needle through the skin (needle insertion phase). When an automatic injection device is to be used, typically a user removes the boot using the boot remover to expose the needle, and then selects a dose of medicine to be delivered. The user will then release the mechanical lock, such that the trigger can be pressed, place the automatic injection device against the surface of the skin and press the trigger to push the needle through the skin and force the medicine through the needle. A carriage and carriage-return spring may cause the needle to be returned to a position within the needle shield to prevent accidental injury after the device has been used. A problem with injection devices occurs when a user forgets to first remove the boot, and, instead, operates the trigger with the boot still in place. If the boot is not removed before firing, no drug is delivered to the user. Furthermore, since the medicine will now be under pressure, there is a risk that the user may inadvertently empty the syringe contents into the air if, when realising their error, they subsequently remove the boot. A user may not have an abundance of medicine and so waste may be a serious issue. Waste may also be undesirable due to cost implications: some medicines can be extremely expensive. Therefore, there exists a need to provide an improved automatic injection device. | <SOH> SUMMARY <EOH>In a first aspect of the invention, there is provided an injection device for delivering a medicament from a container. The device comprises, a housing for housing a container, a plunger substantially housed within the housing and which is movable within the housing, a force applicator for applying a force to the plunger, a trigger coupled to the force applicator for releasing the force applicator to fire the device, a boot, a dose selector for allowing a user to select a dose of medicament, and a first mechanical interlock arranged such that the force applicator cannot be released until the dose selector has been operated to select the dose of medicament, and a second mechanical interlock arranged such that the dose selector cannot be operated to select the dose of medicament prior to removal of the boot. The two mechanical interlocks force the user to perform a sequential order of steps before the injection device will fire. Advantageously, this prevents a user from accidentally firing the device while the boot is still attached, or while no dose is set. The force applicator may be a helical spring which, in an initial, unfired, condition is held in a compressed state. The trigger may not physically contact the force applicator, but just be linked to the force applicator such that on activating the trigger (such as by pressing it), the helical spring is no longer held in the compressed state, and is able to expand so as to deliver medicament. The term, fire, may refer to any action involved with delivering the medicament. For example, when the device is fired, the needle may be driven into a user's skin (needle insertion phase) followed by the medicament being forced through the needle and into the user (medicament delivery phase). The first mechanical interlock may be provided by a first coupling between the housing and the plunger. The first coupling may comprise an abutment between a first abutment element on, or coupled to, one of the housing and the plunger and a second abutment element on, or coupled to, the other of the housing and the plunger. The term “coupled” is used to denote that the components are mechanically linked, such that a force applied to one component ultimately causes a force to be applied to the other component. For example, the abutment need not be between features on the plunger and housing, but may, for example, be between features of components coupled to the plunger and housing, such as intermediate components between the plunger and housing. The first mechanical interlock may be arranged such that the abutment of the first abutment element and the second abutment element prevents the plunger from being displaced axially. For example, the first coupling may comprise an abutment between a shoulder on the housing and a peg on the plunger, preventing proximal axial movement of the plunger. In order to fire the device, the peg may need to be moved such that it does not abut the shoulder. The second mechanical interlock may be provided by a second coupling between the dose selector and the boot. The second coupling may comprise an abutment between a third abutment element on, or coupled to, the dose selector and a fourth abutment element on, or coupled to, the boot. For example, the third abutment element and fourth abutment element need not be features on the dose selector and boot, but may, for example, be features on components coupled to the dose selector and boot, such as intermediate components between the dose selector and boot. The dose selector may be rotatable relative to the housing, said rotation allowing a user to select the dose of medicament. The dose selector and plunger may be rotationally coupled such that rotation of the dose selector rotates the plunger and removes the abutment of the first abutment element and the second abutment element. Optionally, the first abutment element may be either a peg or shoulder on the plunger and the second abutment element may be the other of a peg or shoulder on the housing. For example, the first coupling may comprise an abutment between a shoulder on the housing and a peg on the plunger, preventing axial movement of the plunger. Upon rotation of the dose selector, the plunger is rotated, which displaces the peg relative to the shoulder such that the peg no longer abuts the shoulder, allowing the plunger to be proximally axially displaced. The second mechanical interlock may be arranged such that the abutment of the third abutment element and the fourth abutment element prevents the dose selector from being rotated relative to the housing. For example, the abutment of the third abutment element and the fourth abutment element may prevent a user from setting a dose using the dose selector. Optionally, removal of the boot may remove the second coupling between the third abutment element and the fourth abutment element, allowing rotation of the dose selector with respect to the housing. The third abutment element may be a first surface on the plunger and the fourth abutment element may be a second surface coupled to the boot. If the plunger is coupled to the dose selector, such that they rotate together, then preventing the plunger from rotation will prevent the dose selector from rotation. The first surface may be a protrusion, such as a peg, on the plunger, and the second surface coupled to the boot may be a part of a boot remover, or may be a part of an internal sleeve rotationally fixed and axially moveable with respect to the housing, boot and/or boot remover. The injection device may further comprise a sleeve housed in the housing and which may be rotationally fixed and axially moveable with respect to the housing. The sleeve may take the form of a tube, or partial tube, that fits within the housing. The sleeve may comprise the second surface and the sleeve may be axially coupled to the boot such that axially movement of the sleeve is restricted while the boot is attached to the device. The second surface may axially extend past the first surface such that the second surface presents a barrier to rotation of the first surface. The injection device may further comprise a boot remover for removing the boot. The axial coupling between the sleeve and boot may act between a boot remover, where the boot remover may abut the sleeve while the boot remover is attached to the device, preventing axial movement of the sleeve. The first abutment element and the third abutment element may be the same abutment element. For example, the first abutment element and the third abutment element may be the same peg on the plunger. When the device is fired, the plunger may be arranged to abut the sleeve so as to axially displace the sleeve. For example, as the plunger is axially displaced in a proximal direction (towards the user's skin), the plunger may also proximally axially displace the sleeve. The abutment between the plunger and the sleeve may be via the first and/or third abutment element abutting a distal surface of the sleeve. For example, a peg of the plunger may abut a distal end of the sleeve during displacement. The housing may comprise a viewing window, and the sleeve may be arranged such that a portion of the sleeve is visible through the viewing window after the device has been fired. Advantageously, this provides a visual cue to the user that the device has been fired. Alternatively, a portion of the sleeve may be visible prior to firing the device, and during a firing process the sleeve is displaced such that a portion of the sleeve is not visible through the viewing window after firing the device. The sleeve may comprise a step like profile along its distal end, where at least one step corresponds with a particular dose. The steps may provide the distal surface that the first and/or third abutment element abut on the sleeve. For example, if the first and third abutment element is a peg on the plunger, the peg abuts a step corresponding to the selected dose during firing of the device, so as to axially displace the sleeve. The sleeve may further comprise a resiliently flexible arm having a wedge portion, and may be arranged such that, prior to firing the device, the resiliently flexible arm is bent radially inward due to an abutment between the wedge portion and an inner surface of the housing, placing the resiliently flexible lock arm under tension. The resiliently flexible arm may further be arranged such that after firing the injection device, the wedge portion is proximally displaced so as to line up with the viewing window such that the wedge portion no longer abuts the inner surface of the housing, allowing the tension in the resiliently flexible lock arm to be released, driving the wedge portion into the viewing window. In a second aspect of the invention there is provided an injection device for delivering a medicament from a container. The device comprises a housing for a container, a plunger movable within the housing to expel a dose of medicament, a force applicator for applying a force to the plunger, a trigger coupled to the force applicator for releasing the force applicator, a dose selector for allowing a user to select a dose of medicament from a plurality of doses, and an indicator element for indicating to a user that a selected dose has been delivered, the indicator element being arranged to be axially moveable by the plunger from a first position when a selected dose of medicament has not been expelled, to a second position when a selected dose of medicament has been expelled, and wherein the plunger and the indicator element are arranged such that the axial distance traveled by the indicator element between the first and second position is substantially the same for each of the plurality of doses. Advantageously, the second aspect provides an injection device that can be set to deliver a large range of doses of medicament, while reliably providing an indication that the selected dose has been delivered. This is due, in part, to the fact that the indicator element is driven proximally forward by the plunger for the same distance, regardless of what dose is set, and therefore what distance the plunger travels. The indicator element may be substantially housed in the housing and may comprise a sleeve portion. The sleeve portion may take the form of a tube, or partial tube, that fits within the housing. The sleeve portion may comprise a step like profile along a part of its distal end, wherein each step corresponds with a specific dose of medicament, and defines an axial distance which the plunger must travel before a peg of the plunger makes contact with the step and axially displaces the indicator element from the first position to the second position. The housing may comprise a plurality of tracks, where each track corresponds to a specific dose and has a corresponding length associated with a specific dose. For example, longer tracks correspond with larger doses, and shorter tracks with smaller doses. The tracks may be arranged to receive the peg of the plunger. In this way, the tracks define how far the plunger may travel, and therefore define the amount of medicament expelled. The specific steps of the step like profile may be arranged to correspond with specific track lengths such that the axial distance traveled by the indicator element between the first and second position is substantially the same for each of the plurality of doses. The relative change in height of each step may directly correspond with the relative change in the length of each track. For example, longer tracks may correspond with steps that define a shorter length of the sleeve portion, and shorter tracks may correspond with steps that define a longer length of the sleeve portion. The housing may further comprise a viewing window. The indicator element may comprise a visual indicator which is arranged to line up with the viewing window when in the second position, so as to indicate to a user that a selected dose has been delivered. The visual indicator may comprise a wedge portion coupled to a resiliently flexible arm, and may be arranged such that, prior to firing the device, the resiliently flexible arm is bent radially inward due to an abutment between the wedge portion and an inner surface of the housing, placing the resiliently flexible lock arm under tension. The resiliently flexible arm may further be arranged such that after firing the injection device, the wedge portion is proximally displaced so as to line up with the viewing window such that the wedge portion no longer abuts the inner surface of the housing, allowing the tension in the resiliently flexible lock arm to be released, driving the wedge portion into the viewing window. In a third aspect of the invention, there is provided a plunger for use in an injection device. The plunger comprises a first portion and a second portion, the first and second portions being formed as separate components, and wherein the first portion is arranged to receive and accommodate the second portion in one of a plurality of positions, wherein each position defines a specific length of the plunger. The first portion may be a distal portion of the plunger, and the second portion may be a proximal portion of the plunger. Advantageously, the third aspect provides a plunger that's length can easily be adjusted during assembly by altering the position at which the two portions of the plunger are assembled. This allows fixed size components to be manufactured, which can then be combined to achieve a plunger having a range of possible lengths. The lengths may relate to the specific doses that the injection device, in which the plunger is to be used, delivers. The first portion may comprise an opening arranged to receive the second portion. The opening may comprise a recessed region along an edge of the first potion. The recessed region may comprise a series of saw tooth features which may be arranged to interlock with corresponding saw tooth features on the second portion. Alternatively, the opening may comprise an opening on a proximal end of the first portion, and may be arranged such that a distal portion of the second portion may be loaded into the opening. The first portion may comprise a plurality of apertures along an axial length of the first portion, each aperture defining a particular length of the plunger, and the second plunger potion may comprises an extendable arm which is arranged to enter one of the apertures in the first plunger portion so as to hold the second plunger portion in place relative to the first plunger portion. In a fourth aspect of the invention, there is provided a method of manufacturing a plunger. The method comprises, forming a first portion having means to receive and accommodate a second portion in one of a plurality of positions, wherein each position defines a specific length of the plunger, forming a second portion, and accommodating the second portion in a position of the plurality of positions. In a fifth aspect of the invention, there is provided an injection device for delivering a medicament from a syringe. The device comprises, a housing for housing a syringe, a plunger substantially housed within the housing and which is movable within the housing, a force applicator for applying a force to the plunger, a trigger coupled to the force applicator for releasing the force applicator, and a high friction surface coupled between the plunger and the housing, and arranged to reduce the initial acceleration of the plunger while the force is applied to the plunger during a needle insertion phase. The high friction surface is a surface having a relatively high coefficient of friction compared with other materials typically used in an injection device. For example, the high friction surface may be provided by a rubber material. The high friction surface may be applied to the housing, and the plunger may be arranged to slide against the rubber material. The high friction surface may be applied to any component of the injection device that the plunger axially moves relative to during a needle insertion phase. Typically, a force applicator, such as a helical spring, performs the job of inserting a needle and displacing a bung in a syringe so as to deliver medicament. This can lead to peak impacts which are absorbed by components of the syringe such as a flange of the syringe. Such peak impacts can damage components of the syringe and/or injection device. By providing a high friction surface, the initial acceleration of the plunger is reduced, thereby reducing the magnitude of the peak impacts. The plunger or housing may comprise the high friction surface and the other of the plunger or housing may comprise a surface which is arranged to slide against the high friction surface so as to reduce the initial acceleration of the plunger. The high friction surface may have an axial length that corresponds to a length traveled by the plunger during the needle insertion phase of the injection device, such that the high friction surface reduces the acceleration of the plunger during the needle insertion phase. Once the needle has been inserted, the plunger clears the high friction surface, allowing the medicament to be delivered with the force applicator being undamped. The housing may further comprise tracks of differing lengths, each track corresponding to a specific dose, the tracks being arranged to receive and accommodate a peg coupled to the plunger, and wherein the tracks comprise the high friction surface or a further high friction surface. The peg of the plunger may then be arranged to slide against the high friction surface applied to the track, reducing the initial acceleration of the plunger. The plunger may comprise a bore which is arranged to accommodate a rod which is axially fixed with respect to the housing, and the rod may comprise the high friction surface or a further high friction surface. In an unfired position, the rod will be located within the bore, and an interference fit is achieved between the high friction surface on the rod and the inner surface of the bore. As the injection device is fired, the plunger moves axially with respect to the rod, meaning that the inner surface of the bore slides against the high friction surface on the rod, reducing the initial acceleration of the plunger. The injection device may further comprises a syringe carrier arranged to accommodate a syringe, wherein the syringe carrier may be axially displaced during the needle insertion phase, a resiliently deformable material arranged between the syringe carrier and a syringe, wherein the resiliently deformable material may be arranged such that when the syringe carrier reaches the end of its travel, axial movement between the syringe carrier and a syringe is damped by the resiliently deformable material. The resiliently deformable material may be arranged to act between a flange of the syringe carrier and a flange of a syringe. The resiliently deformable material may be in the form of a lip around a distal end of the syringe carrier. As the distance between the syringe flange and the syringe carrier flange reduces, the resiliently deformable material is compressed between the two flanges, absorbing energy and reducing the impact between the flanges. The high friction surface and/or the resiliently deformable material may comprise a thermoplastic elastomer. | A61M531501 | 20180112 | 20180719 | A61M5315 | 0 | BUI, ANH T | AUTOMATIC INJECTION DEVICE | UNDISCOUNTED | 0 | REJECTED | A61M | 2,018 |
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15,744,747 | PENDING | SYSTEMS AND METHODS FOR PRODUCING A FOAMABLE AND/OR FLOWABLE MATERIAL FOR CONSUMPTION | The present disclosure describes devices, systems, and methods for the production and/or delivery of a foamable and/or flowable material for consumption, such as by direct application to a consumer, such as directly to the mouth of the consumer. A device and/or system for converting a material from a first, unfoamed state to a second, foamed state is provided, and a device and/or system for converting a material from a first, non or semi-flowable state to a second, flowable state is provided. | 1. A product comprising: a container having a first cavity that is sized to hold an ingestible substance; a delivery nozzle forming a pathway from the container, the delivery nozzle comprising a proximal portion and a distal portion, the proximal portion being sized and adapted to be received in a mouth of a consumer, the proximal portion further having an exit aperture from the pathway that is adapted to deliver the ingestible substance to the mouth of the consumer; a valve mechanism associated with the delivery nozzle, and having a feeding mechanism associated with the first cavity of the container to access the ingestible substance therein, the valve mechanism having a valve configured to regulate a flow of the ingestible material from an inlet aperture of the feeding mechanism in the first cavity through the pathway formed by the delivery nozzle and to the exit aperture of the delivery nozzle; a consumer-operable flow controller to control the valve to vary the flow between no flow and a maximal flow based on a physical force applied by the consumer to the consumer-operable flow controller; and a propelling mechanism configured to generate a positive pressure within the first cavity sufficient to propel the ingestible substance through the feeding mechanism and out of the distal portion of the delivery nozzle for delivery of the ingestible substance to the mouth of the consumer when the valve is controlled by the consumer-operable flow controller; such that while the ingestible substance is delivered, the inlet aperture is proximate a portion of the container that is closest toward the center of the earth, and an angle between a vector from the inlet aperture of the feeding mechanism to the exit aperture of the delivery nozzle and a vector from the inlet aperture of the feeding mechanism to the center of the earth is greater than 90 degrees. 2. The product in accordance with claim 1, wherein the valve mechanism is associated with the distal portion of the delivery nozzle. 3. The product in accordance with claim 1, wherein the pathway through the proximal portion of the delivery nozzle is angled from the pathway through the distal portion. 4. The product in accordance with claim 1, further comprising a foaming mechanism coupled with the first cavity of the container, the foaming mechanism being adapted to convert, using a foaming agent, the ingestible substance from a non-foamed state to a foamed state for exiting the exit aperture of the delivery nozzle. 5. The product in accordance with claim 4, wherein the foaming mechanism is controlled based on the operation of the consumer-operable flow controller. 6. The product in accordance with claim 1, wherein the ingestible substance comprises a beverage. 7. The product in accordance with claim 1, wherein the ingestible substance comprises a flowable food material. 8. The product in accordance with claim 1, wherein the proximal portion of the delivery nozzle at least partially includes a flexible member at the exit aperture. 9. The product in accordance with claim 1, wherein the pathway between the valve and the exit aperture of the delivery nozzle is flexible. 10. The product in accordance with claim 1, wherein the propelling mechanism includes a propellant that is introduced to the first cavity upon the operation of a consumer-operable conduit to the first cavity. 11. The product in accordance with claim 1, wherein the container includes a second cavity coupled with the first cavity by the consumer-operable conduit, the second cavity containing a propellant to create the positive pressure within the first cavity. 12. The product in accordance with claim 10, wherein the propellant is a gas. 13. The product in accordance with claim 4, wherein the propelling mechanism includes a gas propellant that is introduced from the first cavity to a mixing chamber upon the operation of the consumer-operable flow controller of the valve, and wherein the gas propellant is the foaming agent to convert the ingestible substance from a non-foamed state to a foamed state for exiting the exit aperture of the delivery nozzle. 14. The product in accordance with claim 13, wherein an amount of the gas proportion to convert the ingestible substance to the foamed state is controllable by the consumer-operable flow controller. 15. A product comprising: a container having a first cavity to hold an ingestible substance in a non-foamed state; a delivery nozzle forming a pathway from the first cavity of the container, the delivery nozzle comprising a distal portion extending from the container, and a proximal portion that is sized and adapted to be received in a mouth of a consumer, the proximal portion having an exit aperture from the pathway that is adapted to deliver the ingestible substance directly to the mouth of the consumer; a valve to control a passage of the ingestible substance through the pathway of the delivery nozzle, the valve having a proximal portion coupled with the delivery nozzle, and a distal portion associated with the first cavity of the container; a consumer-operable flow controller connected with the valve to control and regulate a flow of the ingestible substance from the first cavity and through the pathway of the delivery nozzle and out the exit aperture; a feeding mechanism having a proximal end coupled with the distal portion of the valve, and a distal end positioned in the first cavity, the distal end having an inlet aperture; and a propelling mechanism connected with the first cavity, the propelling mechanism, based on operation of the consumer-operable flow controller of the valve, propelling the ingestible substance into the inlet aperture, through the feeding mechanism and out of the exit aperture of the distal portion of the delivery nozzle for delivery of the ingestible substance directly to the mouth of the consumer; such that while the ingestible substance is delivered, the inlet aperture is proximate a portion of the container that is closest toward the center of the earth, and an angle between a vector from the inlet aperture of the feeding mechanism to the exit aperture of the delivery nozzle and a vector from the inlet aperture of the feeding mechanism to the center of the earth is greater than 90 degrees. 16. A product comprising: a container having a first cavity to hold an ingestible substance in a non-foamed state; a delivery nozzle forming a pathway from the first cavity of the container, the delivery nozzle comprising a distal portion extending from the container, and a proximal portion that is sized and adapted to be received in a mouth of a consumer, the proximal portion having an exit aperture from the pathway that is adapted to deliver the ingestible substance directly to the mouth of the consumer; a valve to control a flow of the ingestible substance through the pathway of the delivery nozzle, the valve having a proximal portion coupled with the delivery nozzle, and a distal portion associated with a feeding mechanism in the first cavity of the container, the feeding mechanism having an inlet aperture; a consumer-operable flow controller connected with the valve to control the valve and regulate the flow of the ingestible substance from the first cavity and through the pathway of the delivery nozzle and out the exit aperture; a propelling mechanism associated with the first cavity, the propelling mechanism propelling the ingestible substance through the feeding mechanism based on operation of the consumer-operable flow controller of the valve for delivery of the ingestible substance to the exit aperture of the delivery nozzle; and a foaming mechanism having a foaming agent to convert the ingestible substance from the non-foamed state to a foamed state for exiting the exit aperture of the delivery nozzle in the foamed state; such that while the ingestible substance is delivered, the inlet aperture is proximate a portion of the container that is closest toward the center of the earth, and an angle between a vector from the inlet aperture of the feeding mechanism to the exit aperture of the delivery nozzle and a vector from the inlet aperture of the feeding mechanism to the center of the earth is greater than 90 degrees. 17. A delivery cap for a container that contains an ingestible substance, the delivery cap comprising: a cap that seals over a portion of the container, the portion of the container having an opening into an inner cavity of the container; a delivery nozzle having a proximal portion that is sized and adapted to be received in a mouth of a consumer and a distal portion coupled with the cap, the proximal portion having an exit aperture from a pathway that is adapted to deliver the ingestible substance directly to the mouth of the consumer; a valve to control a passage of the ingestible substance through the pathway of the delivery nozzle, the valve having a proximal portion coupled with the delivery nozzle, and a distal portion associated with the inner cavity of the container through the opening of the portion of the container, the distal portion having an inlet aperture; and a consumer-operable flow controller connected with the valve to control and regulate a flow of the ingestible substance from the inner cavity and through the pathway of the delivery nozzle and out the exit aperture; such that while the ingestible substance is delivered, the inlet aperture is proximate a portion of the container that is closest toward the center of the earth, and an angle between a vector from the inlet aperture of the feeding mechanism to the exit aperture of the delivery nozzle and a vector from the inlet aperture of the feeding mechanism to the center of the earth is greater than 90 degrees. 18. An apparatus for a container having a cavity that is sized to hold an ingestible substance, the apparatus comprising: a delivery nozzle forming a pathway from the container, the delivery nozzle having a proximal portion that is sized and adapted to be received in a mouth of a consumer and a distal portion coupled with a cap, the proximal portion having an exit aperture from a pathway that is adapted to deliver the ingestible substance directly to the mouth of the consumer; a valve mechanism coupled with the delivery nozzle, and having a feeding mechanism configured to interface with the cavity of the container to access the ingestible substance therein, the valve mechanism having a valve configured to regulate a flow of the ingestible material from the first cavity through the pathway formed by the delivery nozzle; a cap associated with the feeding mechanism, the cap having a retaining mechanism to retain the cap with the container, and a sealing mechanism to seal an interface between the cap and the container to seal the cavity of the container; and a consumer-operable flow controller to control the valve to vary the flow between no flow and a maximal flow based on a physical force applied by the consumer to the consumer-operable flow controller, such that while the ingestible substance is delivered, the inlet aperture is proximate a portion of the container that is closest toward the center of the earth, and an angle between a vector from the inlet aperture of the feeding mechanism to the exit aperture of the delivery nozzle and a vector from the inlet aperture of the feeding mechanism to the center of the earth is greater than 90 degrees. 19. An apparatus in accordance with claim 18, further comprising a propelling mechanism configured to generate a pressure within the first cavity sufficient to propel the ingestible substance through the feeding mechanism and out of the distal portion of the delivery nozzle for delivery of the ingestible substance to the mouth of the consumer when the valve is controlled by the consumer-operable flow controller. 20. An apparatus for serving an ingestible substance, the apparatus comprising: a container having a first cavity to hold an ingestible substance, the first cavity having a movable portion; a delivery nozzle forming a pathway from the container, the delivery nozzle comprising a distal portion extending from the container, and a proximal portion having an exit aperture from the pathway that is adapted to deliver the ingestible substance to an external food item; a valve mechanism coupled with the delivery nozzle, and having a feeding mechanism associated with the first cavity of the container to access the ingestible substance therein, the valve mechanism having a valve configured to regulate a flow of the ingestible substance from the first cavity through the pathway formed by the delivery nozzle; a consumer-operable flow controller mechanically coupled with the valve to control the valve to vary the flow between no flow and a maximal flow proportional to a degree of a physical force applied by the consumer to the consumer-operable flow controller; and a propelling mechanism coupled with the first cavity to generate a pressure against the movable portion of the first cavity sufficient to propel the ingestible substance from the first cavity, through the feeding mechanism and out of the distal portion of the delivery nozzle for delivery of the ingestible substance to the external item when the valve is controlled by the consumer-operable flow controller. 21. The apparatus in accordance with claim 20, wherein the movable portion of the first cavity includes a deformable bladder. 22. The apparatus in accordance with claim 20, wherein the propelling mechanism comprises a second cavity enveloping at least the moveable portion of the first cavity. 23. The apparatus in accordance with claim 22, wherein the second cavity exerts a pneumatic pressure against the movable portion of the first cavity. 24. The apparatus in accordance with claim 21, wherein the second cavity is associated with a piston that moves to exert pressure against the first cavity. 25. The apparatus in accordance with claim 20, wherein the movable portion includes a piston. 26. The apparatus in accordance with claim 20, wherein the propelling mechanism includes an elastic member that exerts pressure against the movable portion of the first cavity. 27. The apparatus in accordance with claim 20, wherein the propelling mechanism includes a spring member that exerts pressure against the movable portion of the first cavity. 28. The apparatus in accordance with claim 20, further comprising a consumer-operated air pump rigidly attached to the container for exerting pressure against the movable portion of the first cavity upon a force exerted on the consumer-operated air pump. 29. The apparatus in accordance with claim 20, wherein the propelling mechanism comprises a second cavity that holds a gas. 30. The apparatus in accordance with claim 20, further comprising: a plurality of first cavities, each of the plurality of first cavities adapted to hold a different ingestible substance, and each of the plurality of first cavities having a movable portion; and wherein the propelling mechanism is coupled with each of the plurality of first cavities to generate a pressure against the movable portion of one or more of the plurality of first cavities sufficient to propel the ingestible substance from each of the one or more of the plurality of first cavities, through the feeding mechanism and out of the distal portion of the delivery nozzle for delivery of the ingestible substance to the external food item when the valve is controlled by the consumer-operable flow controller. 31. The apparatus in accordance with claim 30, wherein the consumer-operable flow controller is adapted to vary a proportion of delivery of each ingestible substance from each of the one or more of the plurality of first cavities. 32. The apparatus in accordance with claim 30, further comprising a mixing chamber coupled with the delivery nozzle for mixing each ingestible substance from each of the one or more of the plurality of first cavities. 33. The apparatus in accordance with claim 30, wherein the nozzle rotates from one of the plurality of first cavities to another of the plurality of first cavities. 34. The apparatus in accordance with claim 30, wherein the pressure generated by the propelling mechanism is selectively applied to the one or more of the plurality of first cavities. 35. The apparatus in accordance with claim 20, further comprising a foaming mechanism having a foaming chamber for mixing a pressurized gas with the ingestible substance to convert the ingestible substance from a non-foamed state to a foamed state for exiting the exit aperture of the delivery nozzle in the foamed state. 36. The apparatus in accordance with claim 35, wherein the propelling mechanism includes a second cavity containing the pressurized gas, and wherein the foaming mechanism includes a conduit from the second cavity to the foaming chamber to deliver the pressurized gas to the foaming chamber, the foaming mechanism further comprising a second valve to regulate a flow of the pressurized gas to the foaming chamber. 37. The apparatus in accordance with claim 36, wherein the conduit passes through the movable portion of the first cavity. 38. The apparatus in accordance with claim 36, wherein the second cavity is associated with a piston that moves to exert pressure against the first cavity, and wherein the conduit passes through an aperture of the piston. 39. The apparatus in accordance with claim 22, wherein the second cavity is bounded by a container body that is rigid under pressure. 40. An apparatus for serving an ingestible substance, the apparatus comprising: a container having a first cavity to hold an ingestible substance, the first cavity having a movable portion; a delivery nozzle forming a pathway from the container, the delivery nozzle comprising a distal portion extending from the container, and a proximal portion having an exit aperture from the pathway that is adapted to deliver the ingestible substance directly to a mouth of a consumer; a valve mechanism coupled with the delivery nozzle, and having a feeding mechanism associated with the first cavity of the container to access the ingestible substance therein, the valve mechanism having a valve configured to regulate a flow of the ingestible substance from the first cavity through the pathway formed by the delivery nozzle; a consumer-operable flow controller mechanically coupled with the valve to control the valve to vary the flow between no flow and a maximal flow proportional to a degree of a physical force applied by the consumer to the consumer-operable flow controller; and a propelling mechanism coupled with the first cavity to generate a pressure against the movable portion of the first cavity sufficient to propel the ingestible substance from the first cavity, through the feeding mechanism and out of the distal portion of the delivery nozzle for delivery of the ingestible substance to the external item when the valve is controlled by the consumer-operable flow controller. 41. The apparatus in accordance with claim 40, wherein the movable portion of the first cavity includes a deformable bladder. 42. The apparatus in accordance with claim 40, wherein the propelling mechanism comprises a second cavity enveloping at least the moveable portion of the first cavity. 43. The apparatus in accordance with claim 42, wherein the second cavity exerts a pneumatic pressure against the movable portion of the first cavity. 44. The apparatus in accordance with claim 41, wherein the second cavity is associated with a piston that moves to exert pressure against the first cavity. 45. The apparatus in accordance with claim 40, wherein the movable portion includes a piston. 46. The apparatus in accordance with claim 40, wherein the propelling mechanism includes an elastic member that exerts pressure against the movable portion of the first cavity. 47. The apparatus in accordance with claim 40, wherein the propelling mechanism includes a spring member that exerts pressure against the movable portion of the first cavity. 48. The apparatus in accordance with claim 40, further comprising a consumer-operated air pump rigidly attached to the container for exerting pressure against the movable portion of the first cavity upon a force exerted on the consumer-operated air pump. 49. The apparatus in accordance with claim 40, wherein the propelling mechanism comprises a second cavity that holds a gas. 50. The apparatus in accordance with claim 40, further comprising: a plurality of first cavities, each of the plurality of first cavities adapted to hold a different ingestible substance, and each of the plurality of first cavities having a movable portion; and wherein the propelling mechanism is coupled with each of the plurality of first cavities to generate a pressure against the movable portion of one or more of the plurality of first cavities sufficient to propel the ingestible substance from each of the one or more of the plurality of first cavities, through the feeding mechanism and out of the distal portion of the delivery nozzle for delivery of the ingestible substance to the external food item when the valve is controlled by the consumer-operable flow controller. 51. The apparatus in accordance with claim 50, wherein the consumer-operable flow controller is adapted to vary a proportion of delivery of each ingestible substance from each of the one or more of the plurality of first cavities. 52. The apparatus in accordance with claim 50, further comprising a mixing chamber coupled with the delivery nozzle for mixing each ingestible substance from each of the one or more of the plurality of first cavities. 53. The apparatus in accordance with claim 50, wherein the nozzle rotates from one of the plurality of first cavities to another of the plurality of first cavities. 54. The apparatus in accordance with claim 50, wherein the pressure generated by the propelling mechanism is selectively applied to the one or more of the plurality of first cavities. 55. The apparatus in accordance with claim 40, further comprising a foaming mechanism having a foaming chamber for mixing a pressurized gas with the ingestible substance to convert the ingestible substance from a non-foamed state to a foamed state for exiting the exit aperture of the delivery nozzle in the foamed state. 56. The apparatus in accordance with claim 55, wherein the propelling mechanism includes a second cavity containing the pressurized gas, and wherein the foaming mechanism includes a conduit from the second cavity to the foaming chamber to deliver the pressurized gas to the foaming chamber, the foaming mechanism further comprising a second valve to regulate a flow of the pressurized gas to the foaming chamber. 57. The apparatus in accordance with claim 56, wherein the conduit passes through the movable portion of the first cavity. 58. The apparatus in accordance with claim 56, wherein the second cavity is associated with a piston that moves to exert pressure against the first cavity, and wherein the conduit passes through an aperture of the piston. 59. The apparatus in accordance with claim 42, wherein the second cavity is bounded by a container body that is rigid under pressure. | REFERENCE TO PRIORITY DOCUMENT This application claims priority to co-pending U.S. Provisional Patent Application Ser. No. 62/192,991, filed Jul. 15, 2015. Priority to the aforementioned filing date is claimed and the provisional patent application is incorporated herein by reference in its entirety. FIELD OF THE DISCLOSURE The following disclosure relates to the production and delivery of a foamable and/or flowable material for consumption as well as the methods for producing and the vessels for storing and/or dispensing the same. BACKGROUND Foamable materials are known in the art. For instance, whipped cream is known to be stored in a canister under pressure such that when shaken and released, the whipped cream is expulsed from the canister, such as when being applied to a food item, such as a dessert. The addition of this whipped cream to the food item is experienced by some as enhancing the flavor of the underlying food item to which it is applied, thereby making the overall consumption experience more pleasurable. As such, whipped cream has been employed in the art as a food additive and is not formulated for direct consumption, that is, whipped cream is not meant to be consumed by itself directly from the canister. Although whipped cream can be prepared by hand and be stored in any suitable manner, such as in a flexible confectioner's decorating pastry bag, often times, such as when produced for convenient mass consumption, for instance, in a ready-to-use formulation, whipped cream may be stored under pressure in a rigid canister that is capable of maintaining its contents under such pressure. For example, prior to its placement in the dispensing container, the cream is whipped in such a manner that gas bubbles are mixed within a matrix of the cream so as to produce a colloid material that in some instances may be double or triple its volume prior to being whipped and/or dispensed. Typically, in order to form a material having such a colloid consistency, the material must be capable of forming a matrix wherein bubbles may be trapped as the material is whipped, such as prior to storage within or dispensing from the canister. Traditionally, therefore, in order to be considered a foamable material, the material was assumed to need to be comprised of fat, such as at least 30% fat, such as butterfat, having a network of fat droplets wherein bubbles may be captured so as to form the colloid, such as prior to dispensing. Additionally, foamable materials, such as whipped cream, had to be stored under pressure in combination with a propellant, such as an aerosol, in a canister adapted for being able to maintain its contents under such pressures, and having a minimally configured release valve, such that in order to be dispensed the material within the canister must be inverted prior to operating the release valve. Accordingly, when properly used the canister would be inverted, the valve depressed, and the pressurized contents would then be released. Such minimally configured release valves are problematic because they allow for incorrect operation such that if operated without inversion the propellant is rapidly depleted rendering the contents inaccessible and unusable. These propellants are stored under pressure in the canister and serve two functions. First it keeps the gas suspended within the colloidal cream formulation. Secondly, it served as a propellant forcing the whipped cream out of the canister when the release valve was triggered. Typically, there is a gas-tight seal between the canister and the release valve that assists in maintaining the stored whipped cream under pressure. However, with use and/or if the seal of the canister is compromised in any way, which often happens with use and/or time, the compressed gas may leave the cream formulation, and along with the propellant, e.g., nitrous oxide, will leak out or otherwise be released from the canister resulting in the foamed material becoming defoamed making it unpleasant and unsuitable for its intended use as a food additive, if it can be released from the container at all. Propellants have also been used in conjunction with the delivery of non-foamable materials, so as to make them flowable. For instance, Cheese Whiz is a secondary food item that has been configured to be stored under pressure and delivered in a flowable manner as a topping for a secondary food item. For example, Cheese Whiz includes a cheese flavored material that is formulated in such a manner that in a suitably configured delivery canister, the cheese-like material may be delivered in a flowable form to a secondary food substrate such as a cracker, a vegetable, bread, and the like. In such an instance, the canister may include a cavity having two compartments. A first compartment containing the cheese material, and a second compartment containing a gas, where the two compartments are separated from one another by a moveable platform, so as to form a piston-like configuration. In this instance, the gas exerts a positive pressure on the platform such that when a delivery nozzle is tilted, a passageway is opened allowing the piston to move and push the cheese-like material out of the nozzle and on to the food substrate. In most of these instances, the cream, cheese, and other such flowable and dispensable materials have been formulated for delivery of the food topping to a secondary food item, such as prior to consumption of that secondary food item by the consumer. Hence, the dispensing mechanisms presently known are adapted for delivery to a secondary food item, and not configured for direct delivery to the mouth of the user. There are, however, those who have tried to employ such existing dispensing mechanisms for delivery of the food topping directly to the mouth, but with less than satisfactory results. Particularly, there are, for instance, a multiplicity of resultant problems given the configuration and mechanics of the delivery mechanisms and their intended use. For example, the attendant nozzles are not shaped nor angled for delivery to the mouth, the canister's themselves have not been ergonomically designed for such delivery, and functional operation has not be adapted to account for such usage. More particularly, users who insist on direct delivery of such secondary food toppings directly to their mouth, are required to hold the canister in an inverted position above the head so that the bottom of the container and its contents are above the nozzle; otherwise, the propellant will escape and/or delivery cannot be commenced. However, this requires the arm be raised and the neck to be tilted back and/or crimped prior to usage. Such bodily contortions are uncomfortable, cannot be engaged while mobile, such as when exercising, block one's field of vision, and are all around unpleasant. Further, in such instances, the canisters themselves become unwieldy, lack grip, and are hard to operate. Moreover, if the angle of operation is not appropriately aligned within the design dimensions of the canister, spluttering and/or resultant gas leakage can cause frustration, embarrassment, and/or lead to consequential physical damage. These results, therefore, make such usage dangerous, socially unacceptable, and open to ridicule. Specifically, fast food consumption often takes place while driving. However, to consume such flowable materials of the prior art while driving requires a tilted head position that is difficult to achieve, if possible at all, and further requires one to take his or her eyes off the road, e.g., looking upwards and not forwards, and is generally incompatible with such usage. Additionally, the canister itself, as well as the user's hand, blocks the user's field of vision. Further, the operation of the existing dispensing mechanisms requires dexterous manipulations of the actuator that interferes with concentration required for driving, and in the inverted dispensing position, the canister can collide with the headliner and/or other structures of the vehicle making driving dangerous. Similar problems can be experienced while walking, running, cycling, or participating in other forms of exercise, as well as when watching TV and/or engaging in conversation. For instance, head tilting is often times incompatible with participating in sporting events, following high-paced action, such as on a TV screen, interrupts eye contact often required for effective communication, and is a distracting gesture that may adversely affect others such as by impeding their field of view in a manner that may be considered rude and/or socially unacceptable. As seen above, whipped cream, cheese-whiz and other such flowable food topping mechanisms have focused on the application of the material to secondary food items. Presently, there are no systems that have been specifically developed and well adapted for direct delivery to the mouth of consumer of food products and beverages that have been precisely formulated for optimal taste and texture as an imbibable food substance. Accordingly, as foamed and flowable liquid, beverage, and other food materials are experienced by some to be pleasant to the taste, there is a need in the art for the storage, production, and delivery of a wider range of such materials, which can be formulated for direct delivery to and consumption by the mouth of the consumer. It has now been determined that a wide variety of directly consumable materials may be foamed by a wide variety of foaming agents, which are safe for consumption, without being overly limited by the fat content of the material to be foamed. Additionally, it has been determined that a wide array of liquids, beverages, and other food materials may be prepared so as to be flowably contained within a specially designed container for automatic delivery to a user. There is a need, therefore, for an apparatus, system, and/or delivery method that allows all such foamable and/or flowable materials to be stored in greater density, such as in a prefoamed state, and delivered direct to the consumer, such as in a manner that ensures that the foamed composition is optimally foamed substantially at the same time as delivery. This will not only allow for a greater quantity of material to be stored in a given delivery apparatus, but also ensure that the right amount of foaming agent is mixed with the right amount of foamable material so as to evoke the optimal taste experience upon delivery and consequent consumption by the consumer. Further, there is a need for an apparatus, system, and/or delivery method that allows ingestible materials to be stored in a manner that will allow them to automatically be delivered directly to the consumer, such as in a manner that ensures that the flowable composition is optimally delivered. The devices, methods, and systems of this present disclosure aim at meeting one or more of these and other related needs, while maximizing the individual's choice and enjoyment in consumable products. SUMMARY OF THE DISCLOSURE The present disclosure, in its many aspects, describes devices, systems, and methods for the production and/or delivery of a foamable and/or flowable material for consumption, such as by direct application to a consumer, such as directly to the mouth of the consumer. Accordingly, in one aspect, a device and/or system for converting a material from a first, unfoamed state to a second, foamed state is provided. In another aspect, a device and/or system for converting a material from a first, non or semi-flowable state to a second, flowable state is provided. In some instances, the device and/or system may be configured for assisting delivery of a foamable and/or flowable material to a user. In another aspect, a method is provided wherein the method is directed to converting a foamable and/or flowable material from a first, non-foamed and/or semi- or non-flowable state, to a second foamed and/or flowable state, and/or for delivering the foamable and flowable material from within the container directly to the mouth of the user. In a further aspect, a foamed and/or flowable consumable product is provided, wherein the foamed and/or flowable material is derived from a material and/or produced by a process that was not heretofore known to be foamable and/or flowable in the manner presented herein. Accordingly, in additional aspects, novel devices and methods for producing them and/or using them to produce foamed and/or flowable materials, such as for consumption, are provided. Systems including such materials, devices, and methods are also provided. For instance, in a first aspect, a device for foaming, flowing, and/or containing a foamed and/or flowable material is provided. In various instances, the device includes a container. Any suitable container may be used so long as it is capable of retaining a material, such as a consumable or otherwise ingestible material, which material may be retained under pressure, such as where the pressure is added to the material, or a container retaining the material, so as to convert it from one state into another, such as from a non-foamed to a foamed state, and/or from a non- or semi-flowable to a flowable state. The container can be any suitable shape and of any suitable size, such as circular, triangular, square, rectangular, round, spherical, cylindrical, cubical, tubular, and/or a mixture of the above, and the like. For example, in one particular instance, the container may have a body, such as an extended and/or tubular body having a proximal portion and a distal portion that are separated from one another by an elongated body portion, which extended and tubular body may enclose or otherwise bound one or more cavities, such as a cavity configured for containing the foamed and/or flowable or to be foamed and flowable material and/or one or more foaming and/or propelling agents. Accordingly, in certain instances, the extended and/or tubular body is configured such that it at least partially bounds a cavity, such as a cavity that is adapted for retaining the material in one or more of its non-foamed and/or non-flowable to a foamed and/or flowable state. In such an instance, the cavity may also be bounded by one or more of a proximal and/or distal end portion. In particular, in some instances, the container is box-like and includes an elongated body formed from a plurality of opposed surfaces, such as opposed front and back surfaces, as well as left and right side surfaces, such as where the front and back surfaces are separated one from the other by the opposed side surfaces. Likewise, the box-like container may additionally include opposed top and bottom surfaces. Accordingly, in such an instance, the elongated body may include one or both of a top member and/or a bottom member, e.g., transverse to the opposed bounding surfaces, for closing a top and/or bottom portion of the elongated body, and thereby enclosing the cavity. In various other instances, the extended body may include one or more walls that are configured in a tubular shape, such as where the extended body includes a single wall that is curved so as to bound a cavity, such as where the wall includes a plurality of surfaces, such as an interior surface facing the cavity, and an outer surface opposite the interior surface. In such an instance, the wall forms a bounding member for the cavity, and in various embodiments may include one or both of a top member and/or a bottom member, e.g., transverse to the bounding wall, for closing a top and/or bottom portion of the elongated body, and thereby enclosing the cavity. In some instances, the top and/or bottom members may be removable and/or replaceable. In various instances, the bounding surfaces and/or walls may include one or more angles or curves so as to give the extended body an angled or curved configuration, thereby increasing or decreasing the interior surface area so as to better modulate the foaming and/or flowing action of the container. Regardless of the configuration, the extended body member may be configured for bounding a cavity, such as a cavity including one or more interior portions, e.g., lumens or compartments, wherein the interior surface of the extended body forms a bounding member for the lumen(s) and/or compartment(s), which lumen(s) or compartment(s) may be configured for retaining one or more of a material to be foamed, e.g., in a prefoamed state, a semi-foamed or foamed material, and/or a flowable material, e.g., in a pre-flowable, a semi-flowable or flowable state, a foaming agent, and/or a propellant. Accordingly, in various instances, a container is provided wherein the container includes a cavity having a foamable and/or flowable material retained therein, and the cavity may additionally include one or more of a foaming agent and/or a propellant and/or be connected to another cavity containing the same. In other instances, the cavity can be subdivided, e.g., by one or more partitions or dividers, into compartments or sub-compartments, such as where each sub-compartment has its own lumen. For instance, the container may have a cavity that is further divided into first, second, third, fourth, fifth, sixth, etc., lumens. For example, in some embodiments, a container is provided wherein the container includes at least a cavity with at least a first lumen and a second lumen, such as where the first lumen is configured for retaining the foamable and/or flowable material, and the second lumen is configured for retaining a foaming agent and/or propellant, such as where the first and second lumen are separate from one another. In other embodiments, a third and/or fourth lumen may be provided, such as where the third and/or fourth lumen includes a propellant and/or a mixing chamber. In various instances, the one or more lumens may include one or more materials to be mixed and/or delivered when leaving the container, and may further include one or more of a foaming agent and a propellant. Particularly, in various embodiments, the container includes a plurality of container portions, such as where the container includes a first container portion, such as for retaining the foamable material, and a second container portion, such as for retaining a foaming and/or propelling agent, where the first and second container portions are separated one from the other by one or more divider portions. In various of such instances, the first container portion may not be in communication with the second container portion, such as where the container includes an elastic member, such as a non-movable wall, a stretchable bladder, or a moveable and/or flexible diaphragm, that divides the lumen into two sections, for instance, a section containing the material to be expelled from the container, and a section containing a foaming agent and/or propellant, such as a gas. For example, the second container portion may include a wall, elastic member, or diaphragm that is substantially impermeable to the foaming agent and/or propellant, and thus may be under a positive pressure caused by the forces the gas, e.g., of the foaming and/or propelling agent exerts against the bladder and/or diaphragm. In such an instance, when the container or a passageway there through is opened a volume of the contained material under pressure may escape through the opening. Correspondingly, as the gas expands against a bladder it causes the lumen containing the material to be compressed, or where a diaphragm is included, it causes the diaphragm to be retracted, thereby reducing the volume of the lumen and allowing the contents within the cavity to be expelled. However, in various other instances, the plurality of container portions may be in communication with one another, such as by permeable interfaces, walls, and/or one or more conduits. For instance, one or more passageways and/or valves may be provided in a bounding member of the container portions, such as a wall or divider, so as to allow communication between various of the different compartments and/or the materials stored therein. Additionally, in various embodiments, one or more conduits may be present whereby the plurality of compartments or the materials within the compartments are fed into an additional compartment, such as a mixing chamber, which may or may not be part of the container, wherein in the additional compartment the two or more materials are allowed to intermix, such as to form a foamed and/or flowable material therein. For example, in one embodiment, a container is provided wherein the container includes at least a first compartment, having a lumen containing a material to be delivered, such as a foamable and/or flowable material, and a second compartment, having a lumen containing a foaming agent and/or propellant, such as where the first compartment is separated from the second compartment by a divider, wherein the divider includes a conduit or passageway that is configured for allowing and/or controlling the flow of the contents from one compartment into another compartment. In such an instance, the conduit can be an opening, such as an opening fitted with a valve, e.g., a controllable valve, whereby the opening connects the first and second compartments thereby allowing flow between the two, and the valve may further be configured for controlling the rate of that flow. The valve may have an orifice of variable dimensions, from fully open to fully closed, and variations in between, which opening and closing may be controlled by an actuator. More particularly, the actuator may be configured to control the opening and closing of the orifice of a portion of the conduit and thereby control the flow through that passageway. For instance, controlling the flow of the foaming agent to the foamable material, such as from one compartment to the other, so as to convert the foamable material from a nonfoamed state to a foamed state and/or to expel the flowable material from the lumen of the container, and/or controlling the flow of the propelling agent to the flowable material, such as from one compartment to the other, so as to convert a non or semi-flowable material from a first state to a flowable state and/or to expel the flowable material from the lumen of the container. In other embodiments, the conduit may be a plurality of conduits, such as a first conduit that is interconnected with a first chamber, and a second conduit that is interconnected with a second chamber, wherein the two conduits may themselves be interconnected with a third chamber, which third chamber may be present within the container and/or a dispensing mechanism associated therewith, whereby the first and second conduits may feed into the third chamber, e.g., a mixing chamber, thereby allowing the contents of the first and second chambers to intermix, for instance, in the third chamber, such as prior to dispensing, such as through a third conduit or other passageway. In certain of these instances, one or more of these chambers may be configured for receiving a removable storage chamber unit, such as a cartridge, for instance, a cartridge containing one or more of a foamable and/or flowable material and/or a foaming agent and/or propellant. For example, in various instances, the container may be configured to include an auxiliary chamber unit or cartridge having a foaming and/or propelling agent therein, and thus may be configured as a foaming and/or propelling member, such as where the foaming and/or propelling agent is a gas, such as nitrous oxide, nitrogen, oxygen, carbon dioxide, a noble gas, e.g., argon, butane, methane, and the like. Accordingly, once the foaming and/or propelling member is coupled with, e.g., inserted into the container, and a valve associated with one or more of the auxiliary chamber and the container is opened, the foaming agent, which may be configured as a propellant, may be released into the chamber containing the foamable material so as to intermix therewith and thereby convert the material from a non-foamed to a pre-foamed or foamed state and/or from a non or semi-flowable to a flowable state. Accordingly, in some instances, the container may include at least a first chamber for retaining a material to be foamed and/or flowably delivered, and may further include a separate compartment containing a foaming agent and/or propellant, where the separate compartment includes an actuator mechanism that is configured for releasing the foaming agent and/or propellant into the first chamber for effectuating foaming and/or release of the material within and/or from the container. The material to be delivered may be any material, such as a flowable and/or a foamable, pre-foamed, and/or foamed material. In some instances, the material may be a material capable of being foamed, such as being converted from a first, non-foamed state, into a second foamed state, and in some instances, may further be converted into one or more additional foamed states. In other instances, the material may be a material capable of being flowed, such as being converted from a first, non or semi-flowable state, into a second flowable state. For instance, in various embodiments, the material may be an ingestible material, such as a drink or food item, condiment, topping, additive, and the like, that is configured to be controllably delivered to a user of the container, such as by the operation of an actuator, for instance, by use with one or more hands of the consumer. In various instances, the deliverable material may be a flowable material, such as a medicine, a medicament, and the like. A suitable foaming agent may be any agent that is capable of converting the non-foamed material into a pre-foamed or foamed material or super-foamed material, such as when applied to or otherwise mixed with the non-foamed material. For example, a foaming agent may be a gas, liquid, solid, powder, suspension, and/or catalyst that when introduced to and/or mixed with the foamable material converts it from being substantially non-foamed into being pre-foamed or foamed and/or may convert it into a super foamed state, such as where the solution includes an increased number, density, or area of bubbles, and/or bubbles that last for a relatively longer time period within the matrix before popping or leaving the solution. A suitable propelling agent may be any one or more agents that is capable of causing the flow of a material, such as from within to outside of the container and/or a compartment thereof, and may be capable of converting a non or semi-flowable material into a flowable material, such as when applied to or otherwise mixed with the material. For example, a propellant may be any agent capable of being added to the material, e.g., the foamable and/or foamed material, and thereby facilitating the expulsion of the material from a lumen of the container. In certain instances, a plurality of agents may be employed that when mixed together form a propelling and/or foaming agent. In various instances, a foaming and/or propelling member may be included, such as where the foaming and/or propelling member may be configured as a mechanical mechanism and/or may be a chemical catalyst, such as a gas, a liquid, a suspension, a pill, a powder, and/or the like, and may further be configured for causing the movement and/or foaming and/or delivery of the ingestible material to the consumer, such as in a controlled manner. For instance, the propelling member may be configured for effectuating the movement of a foaming and/or propelling agent so as to contact and/or be at least partially subsumed within the consumable material, and/or the propelling member may be configured for effectuating the movement of the foamed and/or flowable material out of one or more compartments of the container and/or out of the container itself. Particularly, the foaming and/or propelling member may be configured for effectuating the movement of a foaming and/or propelling agent into the chamber containing the ingestible material and/or into another container portion, e.g., a mixing chamber, into which the foaming and/or flowable material may be added, such as in combination with the foaming and/or propelling agent. In more particular instances, the propelling member may be an additional material added to one or more of the chambers, such as in addition to one or more of the foaming and/or flowable material and/or foaming agent and/or propellant. For example, the foaming and/or propelling member may be any agent that is capable of creating one or more pressure and/or temperature gradients within and/or between one or more chambers or cavities of the container, which pressure gradient(s) can be employed in a manner sufficient to foam the foamable material and/or eject the foamable and/or flowable material out of the container, such as when the dispensing member, e.g., actuator, is actuated. Hence, in various embodiments, the one or more chambers of the container, e.g., the two or three chambers, along with the one or more control valves controlling communication between the chambers, may be configured for allowing and/or regulating the extent and/or rate of intermixing of the foamable and/or flowable material with the foaming agent and/or propelling agent, such as within a mixing region of the container, so as to ensure the production of a flowable and consumable end product having the optimal proportion of foamable and/or flowable material to foaming agent/propellant such that the resulting foamed and/or flowable material has the desired amount of foaminess and/or flowability. This intermixing may be performed prior to insertion of the foamed and/or flowable material into the container, after insertion within the container, such as within a single, e.g., main, chamber within the container, and/or within an auxiliary chamber, such as a mixing chamber, within or associated with the container, external to the container, and/or within a dispensing member of the container. As indicated above, where the foaming and/or flowing process takes place within the container, the foamable and/or flowable material may be within the same chamber or may be separated, such as by a partition, from the foaming agent and/or propellant, but in such a manner that the materials are capable of being intermixed, such as in a controlled fashion, upon an activation event, so as to produce the foamed and/or flowable material, and/or are capable of being expulsed out of the container. Accordingly, a conduit may be provided for allowing one or more of the materials within the container to be transported there through. Hence, in various instances, the conduit may include a control mechanism, such as a control valve, for regulating flow through the conduit, and thus, the conduit may be a control release conduit. Particularly, in various instances, a controlled release conduit may be included in one or more bounding members or partitions of the container so as to regulate the rate and extent of flow and/or intermixing of the various materials within the container. In such instances, the controlled release conduit and the container itself may be configured in such a manner so as to accommodate the physical characteristics of the foaming and/or propelling agent being employed as well as to accommodate the foaming and/or propelling action. In various instances, dependent on the identity of the foaming and/or propelling agent and/or the configuration of the container and its portions, the conduit, such as a controlled release conduit, may have any configuration suitable to creating a pressure and/or temperature differential between the inside of the container and the outside of the container and/or between various different chambers within or otherwise associated with the container, such as between the chamber containing the foamable and/or flowable material and the chamber(s) containing the foaming and/or propelling agent(s). For instance, in various embodiments, a controlled release conduit may be included where the controlled release conduit may have a mechanical configuration so as to operate mechanically. For example, the controlled release conduit may be configured as and/or otherwise be associated with a slow or quick release valve, a hand or screw pump, a screw and plate, a spring release plate, an elastic member, a diaphragm, a tear-able or puncture-able membrane, a lever, one or more of the same including a motor, a compressor, a pyrotechnic composition, piezo-electric component, or other mechanical and/or electrical element capable of increasing the pressure in at least one conduit or chamber, such as by exerting a force against the contents of that chamber, and the like. In such an instance, in certain embodiments, the foaming and/or propelling mechanism and controlled release conduit may be one in the same. In various other embodiments, the controlled release conduit may have or otherwise be associated with an electrical and/or electro-mechanical configuration so as to operate at least in part electronically. For instance, the controlled release conduit may be configured as or otherwise include an electronic slow or quick release valve, an electronic pump, electronic screw plate, an electronically activated spring release plate, an electronic lever or fan or propeller or compressor, an electronic solenoid, an electronic MEMS device, piezo-electric device, and the like. In various instances, where the conduit is controlled mechanically and/or electronically, the conduit may have control circuitry, such as a microprocessor that controls a mechanism that in turn controls the opening of the conduit and/or the size, e.g., volume, of one or more of the chambers, and thereby controls the extent and rate of expulsion and/or communication between the chambers. In such an instance, the microprocessor may include one or more of a CPU, a memory, a transmitter, a receiver, other communications module, and/or one or more sensors or gauges, such as for determining flow rate, one or more flow characteristics, and/or the amount of air, gas, or other foaming and/or propelling agent being captured within the generated foam matrix or colloid of the foamable material. In further embodiments, the foaming agent and/or propellant may be a chemical composition, and the conduit, such as a control release conduit, may be configured for facilitating the mixing of the chemical foaming and/or propelling agent with the foamable and/or flowable material, such as where the foaming and/or propelling agent is in a gaseous, liquid, gel, powder, suspension, and/or semi or solid form, and the like. For instance, the foaming and/or propelling agent may be one or more components that when intermixed with each other and/or the foamable material and/or material to be expelled from the container, cause an increase in pressure within one or more of the conduits and/or chambers of the container, which increase in pressure may be employed, via the conduit, e.g., control release conduit, or other valve, so as to pre-foam or foam the foamable material and/or facilitate in the expulsion of the material from the container, such as in response to activation of an actuator or other dispensing member. For example, the foaming and/or propelling agent may include one or more elements that when admixed causes an exothermic or endothermic or other reaction that transfers energy from one material to another in such a manner as to create a pressure differential, such as an increase or decrease in pressure, such as within a conduit and/or chamber of the container. For instance, any consumable chemical agent that undergoes a physical change, such as from a solid to a semi-solid, to a liquid and/or to a gas, with a resultant pressure change, such as an increase or decrease in pressure, for instance, due to occupying more or less space within the chamber after the change in form, may be employed in this manner. Additionally, in various instances, the foaming and/or propelling agent may include one or more elements that when admixed causes an exothermic or endothermic or other reaction that transfers energy within the system in such a manner so as to create a temperature differential, such as between the temperature prior to admixture and/or subsequent thereto, such as an increase or a decrease in temperature, such as within a chamber of the container. In various embodiments, where there is a pressure change, the resultant change in pressure may be accompanied with a change in the temperature, either higher or lower, such as of the foamable and/or propelling material, which change in temperature may be produced for the purpose of heating or cooling the foamable and/or propelling material, such as prior to dispensing. In certain instances, the addition of the foaming agent and/or propelling agent to the foamable and/or propelling material may be accompanied by a change in pressure and/or temperature such as within the container. In particular instances, the foaming and/or propelling agent may be in a gaseous form, such as carbon dioxide, nitrous oxide, hydrogen, helium, argon, other noble gas, compressed air, and the like, wherein the gas is contained within a chamber, such as an insertable and/or removable chamber, within the container, and the control release conduit controls the flow of the gas into the chamber containing the foamable and/or propelling material, whereby upon mixing of the gas with the foamable and/or propelling material a foamed and/or flowable material is produced. Accordingly, in one aspect, the disclosure is directed to the conversion of a foamable material from a first, non-foamed state to a second, foamed state, such as by the introduction of a foaming agent into the foamable material, for instance, for the production of a consumable foamed material end product having a desired amount of foaminess. For example, the foamable material and the foaming agent are selected such that when admixed the foamable material is converted from a non-foamed state to a foamed state wherein in the foamed state, the foamable material has a colloidal structure that is characterized by the amount of foaming agent that is trapped within the colloid. In such an instance, the foamable material is changed by the foaming agent, such as being converted from a liquid state to a state wherein the composition includes the foaming agent, such as in a foamed or partially foamed state. For instance, in various instances, the foamable material is a material capable of absorbing and/or otherwise retaining within its formulation at least a portion of the foaming and/or propelling agent or a reactant of the foaming and/or propelling agent. For example, in certain embodiments, the foamable material is a liquid and the foaming agent is one or more of a gas, such as a soluble gas, a dissolvable powder, a suspension, a solute, a liquid, and the like. In other embodiments, the foamable material may be one or more of a gas, such as a soluble gas, a dissolvable powder, a suspension, a solute, a liquid, and the like, and the foaming and/or propelling agent may be a liquid. Accordingly, in various embodiments, a composition is provided wherein the composition includes a formulation produced by introducing a foaming agent to a foamable material, such as to produce a foamed composition, such as where the foamable material goes from a first, non-foamed state, to a second foamed state, such as by intermixing with the foaming agent. More particularly, in certain embodiments, the composition provided is a consumable product, such as a beverage, such as a foamed beverage, or other food item to be delivered to a user of the container. In certain instances, the foaming agent and/or propellant and/or a reactant thereof may already be present within the foamable and/or flowable material, such as in a latent form that is activatable, where in such an instance, prior to activation the foaming agent and/or propellant, is quiescent within the foamable material, which may be in a non or only partially foamed or flowable state, but upon activation of the foaming agent and/or propellant, it is converted from a latent form to an active form whereby it then causes the foamable material to change from a non or partially foamed state to a foamed or super foamed and/or flowable state. In certain instances, the activatable foaming agent and/or propellant is capable of several different levels of activation and can thus convert the foamable material into a foamed and/or flowable material a multiplicity of times and/or to a multiplicity of extents, such as from partially foamed, foamed, superfoamed, and/or flowable states, and the like. Particularly, in certain instances, the foaming agent may already be present within the foamable material, such as in a latent form that is activatable, where in such an instance, prior to activation the foaming agent is quiescent within the foamable material, which may be in a non or only partially foamed state, but upon activation the foaming agent is converted from its latent form to its active form whereby it then causes the foamable material to change from a non or partially foamed state to a foamed or super foamed state. In instances, the activatable foaming agent is capable of several different levels of activation and can thus convert the foamable material into a foamed material a multiplicity of times and/or to a multiplicity of extents, such as from partially foamed, foamed, superfoamed, and the like. More particularly, in certain instances, the propellant is present within the foamable material in a latent form that is quiescent within the foamable and/or flowable material but capable of being activated, where upon activation of the propellant, it is converted from its latent form to its active form whereby it then causes the foamable material to be foamed and/or ejected or otherwise propelled out of the container or from one portion of the container to another portion of the container, such as in flowable form. In certain instances, the activatable propellant is capable of several different levels of activation and can thus act to propel the foamed material a multiplicity of times and/or to a multiplicity of different compartments, and the like. Accordingly, in various embodiments, a container is provided, wherein the container includes a foamable and/or flowable material, such as a liquid capable of being foamed and/or flowed, and further includes a foaming and/or propelling agent, such as at least a partially soluble, e.g., a liquid soluble, foaming and/or flowable agent, wherein the container is configured for allowing the foamable and/or flowable material to intermix with the foaming and/or propelling agent in such a manner that a solution of the two results. In various instances, the intermixing of the foamable and/or flowable material and the foaming and/or propelling agent results in a change in pressure and/or temperature, such as an increase or decease of pressure and/or temperature, as described herein. Hence, the container and/or its component parts may be configured so as to withstand any resultant pressure or temperature change without substantially being deformed and/or without allowing the increased or decreased pressure and/or temperature from substantially escaping its bounds prior to activated release. For example, in certain embodiments, the beverage is provided within a container, such as a container described above. In such an instance, the container may include a foamable material, or other material, to be retained within a first container portion of the container, such as in a non-foamed state, prior to expulsion therefrom and delivery to a user. In various instance, a foaming agent or other propellant may also be included, such as a foaming agent or propellant retained in a second container portion of the container. In such an instance, the second container portion may be connected to the first container portion, such as by a secondary compartment, conduit, or other dispensing mechanism that is operable, for instance, by an actuator. For instance, in such an instance, when the actuator is actuated, the foaming agent and/or propellant may be added to the contained material to be mixed therewith, thereby converting the foamable material from a non-foamed state to a foamed state and/or propelling the material out of the container, such as through a release valve. Accordingly, in various instances, the container may include an outlet, such as an outlet that is coupled with the first and/or second container portions, such that once intermixed the foamed, flowable, and/or other material may be translated from within a lumen of the container to the outside of the container, such as through a translating member, for instance, and out through the outlet for delivery to a user, e.g., for consumption. Where an additive or sweetener is included, such as a flavor, the flavor may be delivered with the material, such as in a foamed, flavored beverage form. Accordingly, in various aspects, a container is provided, where in various instances, the container is configured in such a way that an auxiliary reservoir may be coupled therewith, such as a reservoir that may include a foaming agent and/or propellant, which reservoir may be included in a separate compartment within the container, e.g., within a lumen thereof, or may otherwise be coupled with the container, or a portion thereof, e.g., such as by being inserted therein, or be associated with the outside of the bounds of the container, in such a manner that the auxiliary reservoir is in communication with a retaining lumen of the container. For instance, in certain instances, a foaming member, containing a foaming agent, or propellant, may be included, such as within an insertable and/or ejectable reservoir that is configured for being coupled to the container, such as a container having a foaming and/or propelling member receptacle therein. Hence, in these various embodiments, the container may be configured to facilitate the intermixing of the foamable and/or flowable material, such as in liquid form, with the foaming agent and/or propellant, or other material, such as where the foaming agent, or propellant, is at least partially dissolvable within the foamable and/or flowable material, and functions at least in part to assist the conversion of the foamable material from a non or partially foamed state to a foamed or super foamed state and/or functions to expel the material, foamed or otherwise, out of the container. Accordingly, in various instances, the foamable and/or flowable material may be a liquid, such as a beverage, or a gel, or other solid or fluid matrix, and the foaming agent converts the foamable material from its present state into a foamed state, such as within the canister. In other instances, the foamable material may be a foamed or a partially foamed material, e.g., within the container, and the addition of the foaming agent thereto results in the production of a super foamed material. In other instances, the material is a material that is meant to be flowed, and the addition of a propelling material assists in that flowing. As indicated above, the foaming and/or propelling process may take place within or through the container, such as within one or more compartments or passageways within the container, and/or within a chamber or passageway that is associated with the container, such as within a chamber that is part of a translating element and/or within a release valve and/or within an outlet mechanism associated with the container, such as a conduit and/or control valve. In one aspect, therefore, a system is provided, wherein the system may include one or more of: a container, as exemplified above, such as a canister that contains a material, e.g., a foamable material; one or more conduits, which conduits may include one or more valves, such as controllable release valves; one or more translating members, for translating the material, e.g., a non-foamed, partially foamed, or foamed material from the inside of the canister to the outside of the canister, e.g., through a release valve and/or nozzle; and may further include a foaming agent or propellant, which foaming agent or propellant may be contained within a separate portion of the container and/or within a foaming and/or propelling member associated therewith. In some instances, there may be a conduit, e.g., including a control valve that regulates the transmission of the foaming agent and/or propellant to the flowable and/or foamable material, or vice versa. In various instances, the foamable material may be positioned within the container after it has at least been partially or fully foamed, and in such an instance, the container may be configured for retaining the foamed material in the foamed state, and a foaming agent may be employed to make the foam super foamed or a foaming agent need not be provided. Hence, in such instances, foaming may have already occurred and/or may occur through providing a shock and/or a shake to the container, so as to assist with or further promote foaming. A shock and/or shake can also be employed to break a seal that separates the material, e.g., foamable material, from the foaming agent and/or propellant. Accordingly, the container may be configured for facilitating the intermixing of the foamable and/or flowable material, such as in liquid form, with the foaming agent and/or propellant, such as where the foaming and/or propelling agent, or an other agent associated therewith, is at least partially dissolvable within the foamable material, and functions at least in part to assist the conversion of the foamable material from a non or partially foamed state to a foamed or super foamed state. Hence, in various instances, the foamable material may be a liquid, such as a beverage, or a gel, or a semi-solid or solid, or a gas or other fluid matrix, and the foaming agent converts the foamable material from its present state into a foamed state, such as within the container. In other instances, the foamable material may be a foamed or a partially foamed material, e.g., within the container, and the addition of the foaming agent thereto results in the production of a super foamed material. As indicated above, the foaming process may take place within the container, within one or more compartments within the container, and/or within a chamber that is associated with the container, such as within a chamber that is part of a translating element and/or within a release valve and/or within an outlet mechanism associated with the container, such as control valve. In various embodiments, the propellant converts the flowable material from its then present state at rest into a flowable state, such as within the container. In various of these embodiments, the container not only facilitates the intermixing of the foamable material with the foaming agent, but may also, or alternatively, facilitate the intermixing of the foamable material with a propellant, such as when the foamable and/or propelling material is in its pre-flowable, prefoamed and/or foamed state, e.g., precedent or subsequent to the intermixing of the foamable and/or flowable material with the foaming and/or propelling agent. Accordingly, in various instances, the propellant, or an agent associated therewith, is at least partially dissolvable within the flowable, foamable, and/or foamed material, and functions in one or more of assisting the conversion of the foamable material from a non or partially foamed state to a foamed or super foamed state, and/or propelling the material from the container, such as through one or more translating elements and/or dispensing mechanisms. Hence, in various instances, the foamable and/or flowable material may be a liquid, such as a beverage, or a gel, or a semi-solid or solid, or gas or fluid matrix, the foaming agent (and/or propellant) converts the foamable material from its present state into a foamed state, such as within the container, and/or the propellant functions to expel the flowable material, e.g., the at least partially foamed material, out from the interior of the container. In other instances, the foamable material may be a foamed or a partially foamed material, e.g., within the container or canister, and the addition of the foaming agent and/or propellant thereto results in the production of a super foamed material. As indicated above, the foaming process may take place within the container, within one or more compartments within the container, and/or within a chamber that is associated with the container, such as within a chamber that is part of a translating element and/or within a release valve and/or within an outlet mechanism associated with the container, such as a control valve, and the movement of the flowable, foamable and/or foamed material through the container is facilitated by the addition of the propellant or a proponent thereof to the flowable and/or foamable material. As indicated, in one aspect, a translating element, e.g., for coupling to and/or for use with a container, such as a canister described herein, may be provided. In such an instance, the translating element may be configured as an extended member, for instance, as an extended member having an elongated, hollow and/or tubular body. The hollow extended member includes a proximal portion and a distal portion separated by a medial portion. The distal portion of the elongated body may be configured for interfacing with and/or receiving within its bounds the foamable, flowable, and/or other material, and the proximal portion may be configured for interfacing with an outlet of the canister, such as a release valve member and/or passageway associated therewith. Further, the elongated body may be configured for allowing the transmission or movement of the material, e.g., the partially or fully foamed and/or flowable material, from within the bounds of the cavity to the exterior of the cavity, such as by translating the material from the distal portion to the proximal portion of the extender tubular member. Accordingly, in various instances, a translating element or member is provided, such as where the translating member is configured as a feeder element, for example, a feeder tube that is adapted for moving or otherwise transferring the material, e.g., a foamed and/or flowable beverage, from within a cavity of the container to the outlet. In such an instance, the outlet of the container may be configured as, or otherwise be associated with, a valve, such as an actuatable release valve. For instance, a release valve that is configured for allowing and/or effectuating the movement of the foamable material from within the container to outside of the container, such as through the feeder tube, such as when the actuateable release valve is actuated, such as for consumption or ingestion of the foamable and/or flowable material directly or indirectly by a user. In various instances, the foaming agent, where included, may also function as a propellant, so as to also facilitate the expulsion of the foamable and/or flowable material out of the container, such as out through the feeder tube and/or outlet, such as a nozzle associated there with. In other instances, a propellant may be employed wherein the propellant does not substantially intermix with the foamable and/or flowable material, such as where the propellant is substantially immiscible with and/or non-soluble in the foamable and/or flowable material. Where a propellant is included, a feeder element, such as a translating element, may or may not be included within the container and it's systems. For instance, where included the propellant may be employed to facilitate the movement of the material, e.g., foamable and/or flowable material, such as in a non-foamed, partially foamed, or foamed state, through the translating element and out through the outlet, e.g., either directly or through a controllable release valve and/or associated nozzle. However, in other instances, the propellant may be employed to facilitate the movement of the flowable and/or foamable material, in a foamed, partially foamed, or non foamed state, directly out through the outlet, e.g., not via a translating tube, such as through an opening and/or a controllable release valve coupled to the opening of the container itself. Various different types of propellants and/or propelling members having various different types of configurations may be employed. In certain instances, the propellant may be the same as, or different from, the foaming agent and/or other foaming member. Any suitable propellant may be used, so long as it is capable of facilitating the movement and/or translation of the foamable material form within the container to outside of the container, and where the foamable material is provided for consumption, the foamable material and/or propellant should also be at least inert with respect to consumption, e.g., it should be consumable, such as GRAS. Further, as indicated, the foaming agent and/or propellant may already be present within the foamable material, such as in a latent form that is activateable, where in such an instance, prior to activation the foaming agent and/or propellant, is quiescent within the foamable material, which may be in a non or only partially foamed state, but upon activation of the foaming agent and/or propellant, it is converted from its latent form to an active form whereby it then causes the foamable material to change from a non or partially foamed state to a foamed or super foamed state and/or from a non-flowable to a flowable state. In certain instances, the activatable foaming agent and/or propellant is capable of several different levels of activation and can thus convert the foamable and/or flowable material into a foamed and/or flowable material a multiplicity of times and/or to a multiplicity of extents, such as from partially foamed, foamed, superfoamed, and the like. Accordingly, in various embodiments, a container or canister is provided, wherein the canister includes a foamable material, such as a liquid capable of being foamed, and/or includes a propellant, such as a soluble, e.g., a liquid soluble, gas propellant, wherein the canister is configured for allowing the foamable material to intermix with the foaming agent and/or propellant in such a manner that a solution of the two results. In various instances, the intermixing of the foamable material and the foaming agent and/or propellant results in a change in pressure and/or temperature, such as an increase or decease of pressure and/or temperature, as described above. Hence, the canister may be configured so as to withstand any resultant pressure and/or temperature change without substantially being deformed and/or without allowing the increased or decreased pressure and/or temperature from substantially escaping its bounds prior to activated release. For example, in various instances, the material of the container or canister may be one or more of a non-conductive, insulated, thermal retaining material that is adapted to retain the foamable material, e.g., once foamed, under pressure and/or within a warmed or cooled state. For instance, in certain instances, the foamable material is a liquid and one or more of the foaming agent and/or propellant is a liquid soluble gas or solute that at least to some extent intermixes with and/or is otherwise at least partially dissolvable within the liquid, so as to form a solution and/or suspension; and in various instances, the formation of the solution may result in the generation of an increased pressure gradient, such as within the canister, such as a pressure gradient that is increased as compared to outside of the canister, or as between different portions within the canister. In such an instance, the foaming agent and/or propellant going into solution may cause a pressure increase within a portion of the canister and may further thereby cause the foamable material to foam. In other instances, the foaming agent and/or propellant may already be in solution and the foaming occurs by the creation of a pressure and/or temperature gradient or other mechanism that draws the foaming agent and/or propellant out of solution, so as to equalize the pressure and/or temperature in the local environment, thereby causing the foamable material to foam, such as by the foaming agent exiting the solution, e.g., by bubbling out of solution such as where the bubbling generates the foaming action and/or causes the material to become flowable. In certain instances, the foamable and/or flowable material, e.g., a liquid portion, and the foaming and/or propelling agent, e.g., a gas portion, are contained in separate portions of the canister, and are not intermixed until exiting the canister, such that just prior to egress the foaming agent is intermixed with the foamable material, which intermixing causes the foaming material to foam, such as by the foaming agent, e.g., liquid soluble gas, forming gas bubbles within the foamable material, e.g., liquid beverage, such as by at least partially dissolving therein, prior to exiting the outlet of the canister. For instance, the container or canister may include a release valve portion that is configured for allowing the foamable material and the foaming agent to intermix, such as just prior to egress from the canister. More particularly, the canister may include at least two distinct portions, one containing the foamable material and the other containing the foaming agent. In such an instance, the canister may further include two distinct translation element portions, such as one interfacing with the foamable material and the other interfacing with the foaming agent, such as where the translating element are two separate translating elements or where the translating element is forked, such as where the translating element is configured for translating the foamable material and the foaming agent into a common receptacle, such as for intermixing, prior to release from the canister. In various instances, the outlet of the canister may be configured to feed into a valve, such as a control release valve, where the valve includes a chamber into which one or both of the foamable material and/or the foaming agent are delivered thereto, such as for intermixing and/or foaming, e.g., prior to release through the valve, for instance, upon actuation of the valve, and/or the valve may further feed into a delivery nozzle. Accordingly, in one aspect, a valve is provided, wherein the valve is configured for interfacing with a portion of a container, canister, and/or a translation member associated therewith so as to facilitate, e.g., control, the release of a flowable and/or foamable material from within the canister to outside of the canister, such as for delivery to a user, e.g., a consumer of the translated flowable material. Accordingly, the valve may have a distal portion, such as for interfacing with a portion of the canister, e.g., a portion of the canister bounding an opening therein, or a translating element associated therewith; and it may have a proximal portion, such as for interfacing with a user of the canister of the system, such as for dispensing the fluid therein, such as to a user. Typically, the valve will have an orifice or passageway extending the length of the valve, such as an orifice for translating the flowable and/or foamable material through the valve, such as for dispensing the flow of the flowable and/or foamable material out from the cavity of the canister. In various instances, the orifice may be of increasing or decreasing radius and may have one or more internal configurations, such as for creating shear with respect to the flowable and/or foamable material. In various instances, the valve may be a control valve, such as a control release valve that upon activation allows and/or facilitates the flow of the flowable and/or foamable material, e.g., in the foamed state, out of the canister, such as by interacting with the outlet of the canister and/or one or more translation members associated therewith. The valve may have any suitable configuration so long as it is capable of facilitating and/or controlling the movement and/or release of the contents of the canister out of the container, such as in a controllable manner, e.g., with respect to one or more of flow rate, density, pressure, temperature, aeration, foaminess, and/or contour of the flowable material. For instance, in one particular instance, the valve is adapted to allow the flowable and/or foamable material, such as in a beverage form, to mix with one or more of the foaming agent and/or propellant, e.g., in gas form, such as in the presence of a pressure gradient, for example, in a pressure gradient created by the valve itself, which mixing of the liquid beverage and the gas, such as in the presence of a pressure gradient, causes gas bubbles to form within the liquid, or exit therefrom, thereby creating a foam. In various instances, the amount of the foaming agent/propellant that is intermixed with and/or absorbed by the flowable and/or foamable material is controlled so as to control the nature of the flowable and/or a foamable material. It is to be noted that the above has been described with respect to a valve associated with the container or canister, however, it is understood that the valve may be part of the canister or be part of a dispensing mechanism, such as a nozzle, and/or one or more of these functions may be performed by either the valve, the nozzle, or other dispensing element. Accordingly, as indicated, the dispensing mechanism, e.g., translating passageway, valve and/or nozzle, may be adapted for increasing or decreasing the pressure of the flow, e.g., of the flowabale and/or foamed material, such as by having a passageway there through that changes dimensions, such as from larger to smaller or smaller to larger, and in some instances, the dimensions of the passageway are capable of being changed, such as where the valve is articulable thereby being able to change the dimensions and/or openings of one or more portions of the orifice thereby increasing or decreasing the pressure driving the flow of the flowable material through that portion(s) of the orifice. Additionally, the valve may be configured for increasing or decreasing foamability of the foamable material, for instance, the passageway, valve, and/or nozzle may be configured so as to include one or more additional openings such as to aerate the foamable material as it passes through the passageway, valve, and/or nozzle, such as in a controllable fashion, so as to make the foamable material more or less foamy and/or flowable. More particularly, the passageway, valve, and/or nozzle may be configured for allowing air, or another gas, such as the foaming agent and/or the propellant to intermix with the flowable material so as to modulate the foaminess and/or flowability of the material, such as when it passes through the passageway, valve, and/or nozzle. Hence, the flow of the material may be regulated so as to be a relatively fast, medium, or slow flow rate, such as by thickening, thinning, aerating, foaming, defoaming, and/or otherwise changing the characteristics of the flowable material and/or the container or its components itself. Accordingly, in certain instances, the passageway, valve, and/or nozzle are configured for changing a characteristic of the flowable and/or foamable material, such as with respect to flowability, e.g., thickness, viscosity, thixotropic effect, and the like, the taste, flavor, shape, look, and/or feel, such as in the delivery of the flowable material. For instance, the passageway, valve, and/or nozzle may be configured for contouring the shape of the flowable and/or foamed material, so as to enhance the flow, taste, flavor, shape, look, and/or feel of the flowable material, such as to make it easier to use and/or more pleasant to the user, e.g., upon delivery directly to the user such as for direct consumption by the user. For example, in various particular instances, various different types of passageways, release valves, and/or nozzles, and/or translating elements, alone or in combination, may be employed for one or more of translating and/or extracting the foamable and/or flowable material from a portion of the container; translating and/or extracting the foaming agent and/or propellant from one or more other portions of the container; and/or introducing the foaming agent and/or propellant into a common reservoir where these components can intermix, which intermixing can be fashioned in such a way as to change the flow, taste, flavor, shape, contour, look, and/or feel of the flowable material, for instance, the taste may be changed such as by adding a flavoring agent upon the mixing and/or contouring the foamed material upon release. The rate of release may also be important either for enhancing taste and/or for ensuring optimal mixing of propellant and/or foaming agent with the translatable material to ensure appropriate amount of foaming and/or flowability. Hence, in some particular instances, a system is provided wherein a material, such as an ingestible, foamable and/or flowable material is stored in one physical state within a container or canister and undergoes a physical change, such as prior to delivery, e.g., direct delivery to a user, whereby due to the physical change the foamable and/or flowable material is converted at least partially to another physical state, such as from a non-foamed and/or non-flowable state to at least a partially foamed and/or flowable state. For instance, in various instances, the foamable material may be a beverage, in a liquid form, and upon the addition or intermixing of the foamable material, the liquid is changed, e.g., converted, from a liquid to at least a partial colloid or matrix, such as to form a foamable material. More particularly, the foamable material may be such that it is capable of forming a matrix with one or more components of the foaming agent and/or propellant and may further form a colloid such as upon the foaming agent and/or propellant being introduced with and/or mixed with the foamable material, wherein the foaming agent and/or propellant may at least be partially dissolvable within the foamable material so as to be captured within the matrix and may thereby form a foamable colloid therewith. For example, a container having at least a first cavity and a passageway, conduit and/or valve may be provided where in a portion within the cavity a foamable material, such as a liquid, e.g., a beverage, is stored; and within a second portion of the cavity a foaming agent and/or propellant, such as a gas, e.g., a liquid soluble gas or a mixture of gasses, is stored, and at some point prior to dispensing the liquid beverage is intermixed with the liquid soluble gas in a manner sufficient to form a foam and/or a flowable material that may then be delivered directly to the mouth of a user for consumption, such as for drinking. Hence, in various instances, the container may be a beverage container that contains a liquid beverage as well as a foaming agent and/or propellant, such as a gas or mixture of gases, such that prior to or upon actuation of the valve, e.g., a control valve, a solution of the liquid and gas, e.g., in a foamed or semi-foamed state, is released or otherwise dispensed, such as directly to the mouth of the consumer, e.g., by single-handed activation of a delivery actuator, such as via a nozzle, in a manner that allows for the direct drinking, imbibing, or otherwise ingesting of the beverage by the user. For instance, in a particular embodiment, the container or canister along with the foamable and/or flowable material, e.g., liquid beverage and/or food, in combination with the foaming agent and/or propelling agent, e.g., in gaseous form, forms a pressure and/or temperature gradient, such as between the contents within the container and the ambient pressure outside of the container, such that as the valve is actuated the foamable liquid and/or food material and the gaseous foaming agent and/or propellant exit the container, e.g., through the valve, in a manner such that the pressure and/or temperature gradient causes the gas to go into solution and/or gas already in solution to leave the solution, which entering and/or exiting of the gas into and/or out of solution causes bubbling, which bubbling is at such an amount and rate so as to cause the liquid beverage or food item to flow and/or foam, e.g., by gas bubbles being created and/or captured within a matrix of the material, e.g., so as to form a colloid or by gas bubbles already present within the matrix to leave the solution, which foamed beverage and/or food material may be delivered to the user, such as via a nozzle, for direct consumption by the mouth of the user, such as for drinking and/or eating or otherwise imbibing the flowable and/or foamed solution. Accordingly, as detailed herein, a container for containing a beverage or food product, and/or a beverage or food product so contained, may be provided where the container includes one or more of a top, a bottom and a side wall, such as a side wall between the top and the bottom. The container may include a first cavity, such as within or otherwise defined by the top, bottom, and sidewall, where the first cavity is sized or otherwise configured to hold an ingestible material, e.g., beverage, such as a foamable liquid in a pre-, mid-, or post-foamed state. The container may include a valve mechanism having a proximal portion and a distal portion, such as where the proximal portion of the valve mechanism extends outward from the top of the container, and the distal portion of the valve mechanism extends inwards toward the first cavity of the container. In such an instance, the valve mechanism may include a valve, such as a valve configured to regulate the flow of the ingestible material from within the interior of the container to outside of the container, such as through an inlet aperture of a feeding mechanism that may be associated with the valve mechanism. Hence, the valve may be a control valve that is controllable by a consumer, such as via a consumer-operable flow controller, so as to control the valve in a manner sufficient to vary the flow, such as between no flow and a maximal flow, e.g., based on a physical force applied by the consumer to the consumer-operable flow controller. In a manner such as this, the flow of the ingestible beverage into the distal portion and out through the proximal portion of the valve may be regulated, e.g., in response to the operation of a suitably configured control mechanism. Further, in various instances, the valve mechanism may be coupled with a nozzle, such as a delivery nozzle having a distal portion configured for being coupled with the proximal portion of the valve, and a proximal portion configured for delivering the ingestible substance directly to the user, e.g., to the mouth of the user, such as for direct ingestion, e.g., drinking and/or eating, by the user. For instance, the delivery nozzle may be configured to form a pathway that extends from the container, e.g., associated with the first cavity, through the nozzle to an exit aperture that is adapted to deliver the ingestible substance to the mouth of the consumer. In such an instance, the pathway between the valve and the exit aperture of the delivery nozzle may be flexible. In particular instances, the proximal portion of the nozzle may be sized and adapted to be received in a mouth of the consumer. Accordingly, in operation, the ingestible substance may be translated from the interior of the cavity, through the pathway formed by the delivery nozzle and to the exit aperture of the delivery nozzle. In various instances, the pathway through a proximal, medial, and/or distal portion of the delivery nozzle may be angled from the pathway through one or more of the other, e.g., distal, portion of the nozzle and/or outlet thereof. The container may include a feeding mechanism, for instance, a translating member, e.g., a feeder tube, having a proximal end that is coupled with the distal portion of the valve, and a distal end positioned in the first cavity, such as proximate the bottom of the container. Hence, the feeding mechanism may be associated with the first cavity of the container so as to access the ingestible substance therein. Particularly, the feeder element may include an elongated body having a proximal interface and a distal interface, such as where the proximal interface is configured for communicating with the proximal or top portion of the container, such as via the distal portion of the valve; and where the distal interface is configured for communicating with the ingestible beverage, e.g., foamable and/or flowable material, within the first cavity. In various embodiments, the feeder and/or translating element may be configured or otherwise adapted for transferring the ingestible substance, e.g., foamable and/or flowable beverage, from the lumen of the first cavity to the valve of the container, such as for delivery of the ingestible beverage to the user, for example prior to or post foaming of the beverage. The container may include one or both of a foaming and/or propelling mechanism that may be connected with one or more of the first cavity or a secondary and/or third cavity, such as a secondary or tertiary cavity within a valve, e.g., a dispensing valve, of the container. In various instances, the foaming and/or propelling mechanism is adapted to or otherwise configured for converting an ingestible beverage and/or food item and/or medicine from a non-foamed and/or non-flowable state to a foamed and/or flowable state. Hence, the foaming and/or propelling mechanism may be configured for flowing, e.g., upon consumer control of a controllable dispensing valve, the ingestible beverage and/or food item and/or medicine, e.g., in the foamed and/or flowable state, through the feeding mechanism to the controllable dispensing valve and out the proximal portion of the valve, e.g., out through the nozzle, if included. In certain embodiments, the foaming and propelling mechanism includes a foaming agent, e.g., the foaming and propelling mechanism may be the same as the foaming agent, and in other embodiments, they are distinct elements that may act in concert to foam and/or propel the ingestible substance, e.g., beverage or other food item, such as within and/or out of the container. In some embodiments, a foaming mechanism is included wherein the foaming mechanism is coupled with the first cavity of the container and adapted to convert, e.g., using a foaming agent, the ingestible substance from a non-foamed state to a foamed state for exiting the exit aperture, e.g., of the delivery nozzle, such as in response to the operation of a controller, e.g., a consumer-operable flow controller. Accordingly, in particular embodiments, the container may include a propelling mechanism, such as a mechanism that is configured for generating a positive pressure within the first cavity, which propelling mechanism is sufficient to propel the ingestible substance through the container, e.g., a feeding mechanism where included, and out of the proximal portion of the delivery nozzle, such as for delivery of the ingestible substance to the mouth of the consumer, for example, when the valve is controlled by the consumer-operable flow controller. In certain instances, the proximal portion of the delivery nozzle at least partially includes a flexible member, such as at the exit aperture In various embodiments, the container may include a second cavity that may be operationally or otherwise connected with the first cavity, such as by a secondary valve, e.g., a controllable feeding valve, or by a feeder element. In such an instance, the first cavity may be configured for retaining and storing the flowable and/or foamable beverage or food item, and the second cavity may be configured for retaining and/or storing the foaming and/or propelling mechanism, e.g., foaming and/or propelling agent, such as until the consumer activates one or both of the dispensing and/or feeder control valves. For instance, in certain embodiments, the foaming and/or propelling mechanism may include a foaming agent and/or propellant that may be introduced into the first cavity, such as upon the operation of a consumer-operable conduit, e.g., a feeder valve, to the first cavity. In such instances, the feeder valve may be configured so as to control the feeding of the foaming and/or propelling agent into contact with the foamable and/or flowable material, such as within the first or second or even third cavity, so as to create a positive pressure therein. For example, the foaming and/or propelling mechanism may include a gas, such as a foaming agent and/or propellant, that is introduced from the second cavity to the first cavity, and/or a third cavity, such as a mixing chamber. Such introduction may take place as a result of the operation of an operable, e.g., consumer-operable, flow controller for controlling a passageway and/or a valve thereof. In various instances, the gas propellant may also be the foaming agent and may therefore function to convert the ingestible substance from a non-foamed state to a foamed state and/or a flowable state for exiting the exit aperture of the delivery nozzle. As indicated, the valve controller may operate to control the flow of an amount of the gas proportion of a mixture with the ingestible substance sufficient to convert the ingestible substance to the foamed and/or flowable state. Accordingly, in certain embodiments, a third cavity, e.g., a mixing cavity, may also be present such as where the third cavity is operationally or otherwise coupled with one or both of the first and/or second cavities, such as where the first and/or second cavities feed directly into the third cavity, e.g., via a tertiary operational flow control valve, such as a mixing valve. In such an instance, the first and/or second cavities may feed into the third cavity, such as for the purpose of mixing the foamable material with the foaming agent, by the operation of the feeder control element. Additionally, in various embodiments, a foaming mechanism may be included, where the foaming mechanism includes a foaming agent that is configured for converting the ingestible substance from a non-foamed state to a foamed state, e.g., within the first, second, and/or third cavities, prior to exiting the exit aperture of the delivery nozzle in the foamed state. As indicated above, in various instances, such a third cavity may be part of, e.g., within the bounds of the container, and/or may be a part of a control, e.g., a dispensing, valve; and/or part of a dispensing nozzle. It is to be understood that any of the passageways, valves and/or nozzles disclosed herein may be configured for regulating the flow, mixing, and/or foaminess of the flowable and/or mixable materials disclosed herein, such as with respect to controlling or otherwise regulating the rate, amount, quality, and/or other characteristics of the flow, mixing, taste, texture, and/or foaminess of the flowable and/or mixable materials. The valves may be positioned anywhere within the bounds of the container or a component thereof such as between the boundaries of the various compartments or within one or more of the translating elements and/or nozzles. In view of the different configurations of the container and/or the cavities therein, a feeding mechanism, such as a translating element, e.g., feeder tube, may be configured so as to act as a conduit directing the flow of the various flowable materials held within one or more components of the system. For instance, the translating element may be composed of one or more elements that are configurable for or otherwise adapted for directing a flow of one or more of the flowable materials, e.g., the one or more foamable materials and/or one more foaming agents and/or propellants, that are held or otherwise stored within the one or more cavities of the container. One or more control valves may be included as part of the feeder element so as to further control and direct the flow of the flowable materials through the feeder element. Hence, the translating element may include a portion that contacts the flowable and/or foamable material and/or may include a portion that contacts the flowable foaming agent and/or propellant, and may include another portion that contacts a top portion of the container, such as via a dispensing valve and/or dispensing nozzle, so as to facilitate the flow and/or mixing of the flowable and/or foamable materials within and/or out of the container. For example, a feeding member may be provided, wherein the feeding member has a proximal end that may be coupled with the distal portion of a valve mechanism, and the feeding member has a distal end that may be positioned in the first cavity, such as where the distal end has an inlet aperture. Particularly, the container may include a valve mechanism that is coupled with a delivery nozzle and further includes a feeding mechanism, such as a feeder member that is associated with the first cavity of the container so as to access the ingestible substance therein, such as where the valve mechanism includes a valve configured to regulate the flow of the ingestible substance from the first cavity and through the pathway formed by the feeding mechanism and delivery nozzle. In various embodiments, the translating mechanism includes a member that translates the one or more flowable materials through its componentry via the action of a propellant, actuation of one or more of control mechanisms, such as a consumer-operable flow controller detailed herein, and/or the creation of a pressurized chamber or vacuum, such as that created by a user sucking or blowing into one or more of a user contactable portion of a dispensing nozzle, dispensing valve, and/or proximal portion of the translating member directly. For instance, a propelling mechanism connected with a first cavity of the container may be included, wherein operation of the propelling mechanism is based on operation of a consumer-operable flow controller for controlling a valve regulating the flow through the feeding and/or dispensing mechanism of the container, which functions to propel the ingestible substance into an inlet aperture, e.g., of a delivery nozzle, through the feeding mechanism, and out of an exit aperture of a distal portion of the nozzle, such as for delivery of the ingestible substance, e.g., directly to the mouth of the consumer. In certain instances, the propelling mechanism may be capable of mechanical motion and the operable flow controller may be mechanically coupled with the valve so as to control the valve in a manner sufficient to vary the flow, e.g., between no flow and a maximal flow, proportional to a degree of a physical force applied by the user to the user-operable flow controller. In such an instance, the propelling mechanism, which may be a deformable bladder and/or an elastic member, may be coupled with the first cavity in such a manner so as to generate a pressure against the movable portion of the first cavity sufficient to propel the ingestible substance from the first cavity, through the feeding mechanism and out of the distal portion of the delivery nozzle for delivery of the ingestible substance to the user and/or to an external item when the valve is controlled by the consumer-operable flow controller. Accordingly, a translating member, e.g., a feeder tube, of the disclosure may have any suitable configuration that may be useful in translating the flowable ingestible materials through the system such as for one or both of mixing and/or direct dispensing to the user, e.g., directly to the mouth of the user for ingestion, such as for drinking. In various instances, the translating member is configured for functioning regardless of the orientation of the canister, such as regardless of how the device is manipulated and/or used by the consumer in ingesting, e.g., drinking and/or eating, the foamable material stored therein. Hence, the feeder tube(s), as disclosed herein, may be configured to assist in directing the flow of the mixable elements, assisting in mixing the elements, and for delivering the mixture to a user, such as in a flowable, foamed state, e.g. via a control valve, such as a syphon valve, or nozzle. In various instances, the container may be configured for simple activation, such as via single left or right hand of the user. Additionally, in particularly instances, the delivery mechanism, e.g., nozzle, passageway, and/or valves, may be configured with respect to the feeder mechanism and/or container and/or a cavity therein such that while the ingestible substance is delivered, the inlet aperture is proximate a portion of the container that is closest toward the center of the earth, and an angle between a vector from the inlet aperture of the feeding mechanism to the exit aperture of the delivery nozzle and a vector from the inlet aperture of the feeding mechanism to the center of the earth is greater than about 45, greater than about 60, or greater than about 90 degrees. In a particular embodiment, an apparatus such as for serving an ingestible substance is provided, wherein in the apparatus includes a container, such as a container having a at least a first cavity such as to hold an ingestible substance therein. In various instance, the first cavity may have a movable portion. In certain instances, the container may include a delivery nozzle, which nozzle may be configured so as to form a pathway through or from the container. The delivery nozzle includes a distal portion that may extend away from the container, and a proximal portion having an exit aperture extending from the pathway that is adapted to deliver the ingestible substance directly to a mouth of a user, e.g., a consumer of the ingestible sub stance. In certain embodiments, the container may additionally include a valve mechanism that may be coupled with the delivery nozzle. The container may also have a feeding mechanism that may be associated with the first cavity so as to access the ingestible substance therein, such as where the valve mechanism includes a valve that is configured to regulate the flow of the ingestible substance from the first cavity through the pathway formed by the delivery nozzle. Additionally, the container may include a consumer-operable flow controller that is mechanically coupled with the valve and configured to control the valve so as to vary the flow, e.g., between no flow and a maximal flow proportional to a degree of a physical force that is applied by the consumer to the consumer-operable flow controller. In certain instances, a propelling mechanism may be included and be coupled with the first cavity so as to generate a pressure against the movable portion of the first cavity, such as a pressure that is sufficient to propel the ingestible substance from the first cavity, such as through the feeding mechanism and out of the distal portion of the delivery nozzle for delivery of the ingestible substance to the user and/or an external item when the valve is controlled by the consumer-operable flow controller. In particular instances, the container may include a plurality of first cavities, such as where each of the plurality of first cavities is adapted to hold a different ingestible substance. As indicated above, one or more or all of the plurality of first cavities may have a movable portion therein. In such an instance, one or more propelling mechanisms may be included, where the propelling mechanism(s) may be coupled with one or more, e.g., each, of the plurality of first cavities so as to generate a pressure against the movable portion(s) of one or more of the plurality of first cavities, such as a pressure sufficient to propel the ingestible substance from one or more of the plurality of first cavities. In such an instance, the force is sufficient to push the ingestible substance through the feeding mechanism and out of the distal portion of the delivery nozzle for delivery of the ingestible substance such as when the consumer-operable flow controller is operated so as to control the valve to effectuate the release. In various instances, the propelling mechanism may include a second cavity that envelopes at least the moveable portion of the first cavity, such as where the second cavity exerts a pneumatic pressure against the movable portion of the first cavity. For instance, the second cavity may be associated with a piston that moves to exert pressure against the first cavity, such as where the moveable portion is the piston. In particular instances, a spring member may be include such as where the spring member exerts the pressure against the movable portion of the first cavity. In some instances, a consumer-operated air pump may be included and rigidly attached to the container, such as for exerting pressure against the movable portion of the first cavity upon a force exerted on the consumer-operated air pump. In such an instance, a consumer-operable flow controller is included and adapted to vary the proportion of delivery of each ingestible substance from each of the one or more of the plurality of first cavities. In certain instances, a moveable nozzle may be included such as where the nozzle rotates or pivots from one of the plurality of first cavities to another of the plurality of first cavities, such as where the pressure generated by the propelling mechanism may be selectively applied to the one or more of the plurality of first cavities. Additionally, in various embodiments, the container may include a foaming mechanism, such as where the foaming mechanism includes a foaming agent that is configured for converting the ingestible substance from a non-foamed state to a foamed state, such as prior to exiting the exit aperture of the container or a delivery nozzle associated therewith in the foamed state. For instance, a foaming mechanism having a foaming member associated therewith may be included such as where the foaming member has a foaming chamber associated with it, such as for mixing a pressurized gas with the ingestible substance so as to convert the ingestible substance from a non-foamed state to a foamed state for exiting the exit aperture of the delivery nozzle in the foamed state. A propelling mechanism may also be included where the propelling mechanism may be included in or may include a second cavity, such as a second cavity containing a pressurized propellant gas. In some instances, the foaming mechanism may include a conduit from the second cavity to the foaming chamber so as to deliver the pressurized gas to the foaming chamber. In particular instances, the foaming mechanism further includes a second valve so as to regulate the flow of the pressurized gas to the foaming chamber, such as where the conduit passes through a movable portion of the first cavity and/or where the second cavity is associated with a piston that moves to exert pressure against the first cavity. In such an instance, the conduit may be configured to pass through an aperture of the piston. In particular instances, the first and/or second cavity may be bounded by a container body that is rigid under pressure, where as the first cavity may be bounded by a more flexible and/or stretchable body. Hence, in various embodiments, the container may include a liquid or a mixture of liquids, e.g., in a drinkable and/or foamable beverage form, and/or may include a liquid soluble gas or a mixture of gasses that may be configured as one or both of a foaming and/or a propelling agent, wherein upon contact, under increased or decreased pressure and/or temperature, the liquid(s) in admixture with the soluble gas(es) may form a solution, such as a foamable and/or flowable solution, that may be delivered to a user, such as for drinking, e.g. directly from the container, such as through a suitably formed delivery nozzle. As indicated, the liquid(s) and/or liquid soluble gas(es) may be retained within the container in the same or different compartments, can be intermixed in the same or different compartments, and/or can be translated throughout the system and/or to a user, such as through one or more suitably formed translating elements, e.g., feeder tubes, and/or one or more control valves associated therewith. In some embodiments, the container includes a first compartment for retaining both a liquid and a gas, such as where the liquid and the gas are separated from one another in the container, such as via a pressure gradient between the two, e.g., under increased pressure; and in some embodiments, the container includes a first compartment for retaining the liquid, which first compartment may be flexible or semi-flexible, and a second compartment for retaining the gas, which may be rigid or semi rigid, such as where the liquid and the gas are separated from one another in the canister by a dividing wall, which may be moveable, but may be configured for communicating with one another, such as for the purpose of intermixing, such as via one or more valves, e.g., a feeding, mixing, and/or dispensing valve, and/or one or more translating elements, and/or one or more passageways and/or nozzle elements. In such an instance, the liquid may be an ingestible beverage or food item, the gas may be at least a partially liquid soluble gas, and the feeder element(s) and/or release valve(s) may be configured for intermixing the liquid and the liquid soluble gas, such as to produce a foamed and/or flowable material, such as on release, e.g., actuation of a release mechanism, e.g., an operable control mechanism, of the container. For instance, the gas may be a dissolved gas in solution of the ingestible substance. Particularly, the dissolved gas may create a propelling mechanism so as to generate a pressure within the first cavity sufficient to propel the ingestible substance through the container, e.g., a feeding mechanism associated therewith, and out of a proximal portion of a delivery nozzle. As indicated, in various embodiments, the container may include a plurality of compartments, such as a first compartment for retaining the ingestible substance, and a second compartment for retaining the foaming agent and/or propellant. In various instances, the second compartment may be configured for receiving an interchangeable gas reservoir, such as a cartridge containing a foaming and/or propelling member therein, e.g., a gas cartridge, which cartridge may be inserted into the container for discharging, and may be replaceable once the cartridge has been discharged, such as through activation of a release mechanism of the container or a component associated with the container. In various embodiments, a cap that seals over a portion of the container having an opening into an inner cavity of the container, e.g., a proximal portion of the nozzle, a feeder mechanism, and/or the container, may be included. In such instances, a retaining mechanism for retaining the cap in relation to the nozzle, feeder mechanism, and/or container may be included. A sealing mechanism such as to seal an interface between the cap and the container to seal the cavity of the nozzle, feeder mechanism, and/or container may be provided. In a further aspect, methods for producing a foamable and/or flowable material are provided, such as where the foamable and/or flowable material is comprised of a liquid, such as a beverage, or other food item or topping or medicine that may be consumed, for instance, in imbibeable and/or ingestible form, or where the foamable material is at least partially prefoamed but subjected to conditions that function to increase or decrease the foaminess of the material, such as prior to delivery from a storage and/or delivery canister. The methods may include one or more steps, such as a step that includes actuating a delivery mechanism of the container, which actuation functions to eject the foamable and/or foamed material in conjunction with one another and/or out of the container. For example, the actuation of the delivery mechanism, e.g., via a consumer operable controller, may involve the actuation of one or more of a nozzle, a valve, and/or a translation element associated with a container configured for retaining the foamable material, such as where the actuation may involve activating a control element, such as depressing or pulling a button, turning a nozzle or screw or knob, pulling a trigger, squeezing a depressible element, flipping a switch, biting a valve, pulling a tab, removing a pin or stop, operating a pressure differential valve, activating an electronically controlled valve by an electrical input sensor or signal, and the like. In some instances, one or more of the components contained within the container may be under pressure, and such actuation may function to mix the contained components and/or release one or more of the contained components, such as after they have been mixed together, such as to produce a non-foamed or at least a partially foamed material. In various instances, the container or a portion thereof may include a cap or seal that must be removed or unsealed, e.g., burst or punctured or the like, prior to delivery of the ingestible material. In particular, the recited actuation may involve one or more of releasing one flowable component into another flowable component contained within the container, such as by the operating of one or more valves that function to open one or more conduits and/or translating element(s); and/or the translating of one or more of the components such that they come into contact with one another, such as within one or more chambers within the container, passageways, valves, and/or nozzles associated therewith, such as prior to or in conjunction with actuation of the delivery mechanism and/or release from the container. In some instances, the actuation may involve an electronic control mechanism, for instance involving a control circuit that may be in a wired or wireless configuration, such as part of a processor on a microchip, such that by electronic activation of the control circuit the delivery mechanism may be activated and the components of the container may be mixed and/or released, such as for delivery of the foamable and/or flowable material to a user. Such control may be operated in a wired configuration such as by employing an integrated circuit, or may be performed wirelessly, such as through Bluetooth or Low Energy Bluetooth. BRIEF DESCRIPTION OF THE DRAWINGS The above-mentioned features and objects of the present disclosure will become more apparent with reference to the following description taken in conjunction with the accompanying drawings wherein like reference numerals denote like elements and in which: FIG. 1A is a schematic representation of a container, e.g., a soda bottle, as known in the prior art; FIG. 1B is a schematic representation of another container, e.g., a soda can, as known in the prior art; FIG. 1C is a schematic representation of an exemplary delivery mechanism configured as a conversion for a container, such as the bottle of FIG. 1A; FIG. 1D is a schematic representation of another exemplary delivery mechanism configured as a conversion for a container, such as the can of FIG. 1B; FIG. 1E is a schematic representation of an exemplary embodiment of a container, e.g., configured as a soda bottle, of the present disclosure; FIG. 1F is a schematic representation of a further exemplary embodiment of a container, e.g., configured as a soda can, of the present disclosure; FIG. 2A is a schematic representation of an additional exemplary embodiment of a container of the present disclosure, where the container includes a propelling mechanism configured as a stretchable membrane; FIG. 2B is a schematic representation of a further exemplary embodiment of the container of FIG. 2A, where the container includes a secondary propelling mechanism configured as an auxiliary propelling canister; FIG. 2C is a schematic representation of another exemplary embodiment of a container of the present disclosure, where the container includes a propelling mechanism configured as a moveable platform; FIG. 3 is another schematic representation of a further exemplary embodiment of a container of the present disclosure, the container including an auxiliary foaming and/or propelling member chamber; FIG. 4A is a schematic representation of an additional exemplary embodiment of a container of the present disclosure, the container having a delivery mechanism including an auxiliary foaming and/or propelling chamber; FIG. 4B is a schematic representation of another embodiment of an exemplary container of the present disclosure, the container including an auxiliary pumping mechanism for increasing pressure within the cavity; FIG. 5A is a schematic representation of an additional exemplary embodiment of a container of the present disclosure, the container including a plurality of sub-compartments containing ingestible substances; FIG. 5B is a schematic representation of a further embodiment of FIG. 5A in accordance with the present disclosure. FIG. 5C is a schematic representation of a further embodiment of FIG. 5A in accordance with the present disclosure. DETAILED DESCRIPTION In the following paragraphs, the present apparatuses, systems, and methods of using the same will be described in detail by way of example, sometimes with reference to the appended drawings. Throughout this description, the various aspects, embodiments, instances, and/or examples shown should be considered as exemplary, rather than as limitations on the present implementations. Additionally, as used herein, the use of the words “embodiment” and “instance” refer to any one of the embodiments and/or instances of the disclosure described herein, and any equivalents thereof. Furthermore, reference to various feature(s) of the present disclosure throughout this document does not mean that all claimed embodiments and/or instances must include the referenced feature(s) and/or elements as these features may be mixed or matched in any logical manifestation dependent upon the particular embodiment being employed. The present disclosure, in its many aspects, describes devices, systems, and methods of using the same for the production of a consumable material, such as a foamable and/or flowable material, for instance, for ingestion, such as by direct delivery to a consumer, such as by drinking, eating and/or otherwise imbibing and/or consumption. In one aspect, a device and/or a system using the device is provided, such as, a device for foaming and/or delivering an ingestible material, such as to a user. In another aspect, a method is provided wherein the method is directed to converting a foamable material from a first, semi or non-foamed state, to a second foamed state and/or from a semi or non-flowable state to a flowable state. Additionally, in some embodiments, a method is provided for manufacturing a delivery apparatus of the disclosure and/or using the device for delivering a material, such as a foamable and/or a flowable material, from within a chamber of the device containing the material. In a further aspect, a foamed and/or flowable consumable product is provided, wherein the foamed and/or flowable material is derived from a material and/or produced by a process that was not heretofore known to be foamable and/or flowable in the manner presented herein. Accordingly, in further aspects, novel methods and devices for foaming and/or delivering materials, such as fluid and flowable materials are provided, and in other aspects methods for producing foamed and/or flowable materials, such as for ingestion, are provided. Systems including such materials, devices, and methods are also provided. Hence, in various aspects, a material is provided, such as a material capable of being foamed, for instance, by being converted from a first, e.g., non-foamed state, to a second, foamed state, or from a foamed state to a super foamed state. In certain instances, the foamable material may be any material capable of forming a matrix, such as by at least partially absorbing a gas, such as a dissolvable gas therein, such as by forming a colloid there with. More particularly, the material may be converted to a foam such as by the partial absorption and/or desorption of gas bubbles within a matrix of the material. For instance, in various instances, the material is a foamable material that is foamed such as by the contacting of the material with a foaming agent, such as where the foaming agent is a gas, or where the foaming agent is a mechanism that is capable of forming a gas that is contactable with the foamable material, such that upon contact gas bubbles may be formed and/or trapped within the foamable material and/or a matrix therein such as to form a colloid with the foamable material. In other instances, the material may be converted to a foam such as by gas bubbles leaving the solution of the material and/or by other purely mechanical mechanisms. For example, the foamable and/or flowable may be formulated such that it forms a matrix into which a foaming agent, such as a gas, may be retained so as to form a solution therewith. In such an instance, as the container or a passageway or a valve thereof is opened, the gas is allowed to expand, leaving the solution, and thereby causing the material to foam, such as prior to exiting the nozzle. In various aspects, a flowable material may be produced, such as a material capable of being flowed, for instance, by being converted from a first, e.g., non- or semi-flowable state, to a second, flowable state, or from a flowable state to a super flowable state. In certain instances, the flowable material may be any material capable of being converted into a flowing form and/or capable of being modulated with respect to one or more of its flowable properties, such as to increase or decrease flowability. More particularly, the material may be converted to a more or less flowable state, such as by becoming more or less viscous, thixotropic, and/or the like. In certain instances, the flowable material may be a foamable material. Accordingly, in various instances, the flowable and/or foamable material may be a liquid, a solution, a semi-liquid, an emulsion, a gel, a solid, a semi-solid, a powder, and the like, capable of being flowed and/or foamed. For instance, material may be foamed and then placed in the container, under pressure, so as to retain the foaminess. In such an instance, the foamed material may include a gas, such as a gas dissolved within the fluid, such as a liquid under pressure. Hence, when the pressure drops, the more volatile gas may leave solution thereby forming a foamed matrix. In some instances, the flowable material may be a prefoamed material, such as where the liquid and/or prefoamed material is retained within a container of the disclosure prior to being foamed and/or delivered. For example, the flowable liquid and/or foamed material may be a drink and/or food item and/or medicine adapted for being imbibed and/or consumed, such as directly from the container, such as by a user drinking or eating or otherwise ingesting the flowable material. In various instances, the flowable material may be one or more liquids, semi-liquids, gels, solids, semi-solids, suspensions, powders, and/or the like. In some instances, the material is foamable and thus is capable of being foamed such as by the contacting of the material with a foaming agent, such as where the foaming agent is a gas, a liquid, a semi-liquid, a gel, a solid, a semi-solid, a powder, or the like. For instance, in certain instances, the foaming agent may have one form that is convertible to another form, such as when contacted with the flowable material and thereby causing the foamable material to foam. For example, the foaming agent may have one form prior to contact with the foamable material, however, upon contact with the foamable material, the foaming agent may then be converted into another form, such as by forming a gas that may then be contactable with the foamable material, such that upon contact therewith gas bubbles may be formed and/or trapped within the foamable material and/or a matrix therein such as to form a colloid with the foamable material causing it to foam. In other instances, the foaming agent may be configured for being trapped, e.g., in gaseous form, within the matrix of the foamable material, such as in a latent form, which when exposed to the appropriate conditions the foaming agent leaves the matrix and thereby causes the material to foam. In various embodiments, the foaming agent may be a mechanism that is capable of generating a gas that is contactable with the foamable material, such that upon contact between the foamable material and generated gas, bubbles may be foamed and/or trapped within the foamable material, and/or a matrix therein, such as to form a colloid within the foamable material. In various instances, the foaming agent, therefore, may be a chemical agent, such as a chemical agent that is a liquid, a semi-liquid, a solution, a gel, a gas, a solid, a semi-solid, a powder, and the like. In other instances, the foaming agent may be a mechanical mechanism and in some instances, the mechanical mechanism may be configured for releasing a chemical agent. For instance, in some instances, the foaming agent may be a liquid or a semi-liquid and/or a solution. In some instances, the material is a material to be flowed, such as from an inside portion of the container to outside of the container, and thus is capable of being flowed such as by the contacting of the material with a propelling agent, such as where the propelling agent is a gas, a liquid, a semi-liquid, a gel, a solid, a semi-solid, a powder, or the like. For example, the propelling agent may have one form prior to contact with the material to be flowed, however, upon contact with the flowable material, the propelling agent may then be converted into another form. Hence, in various instances, the propelling agent may be a chemical agent, such as a chemical agent that is a liquid, a semi-liquid, a solution, a gel, a gas, a solid, a semi-solid, a powder, and the like. In other instances, the propelling agent may be a mechanical mechanism and in some instances, the mechanical mechanism may be configured for releasing a chemical agent. In a further aspect, a device for foaming and/or flowing a material, such as a material described herein, is provided. In various instances, the device may be part of a containing mechanism such as a container, vessel, receptacle, canister, or the like. Any suitable containing mechanism may be employed so long as it is capable of retaining a material, such as a consumable or otherwise ingestible material, in some instances under pressure. For instance, in various embodiments, the material may be a foamable material that is foamed prior to insertion into a canister; in other embodiments, the material is inserted into the canister in a non or prefoamed state, and then foamed. In such an instance, the prefoamed material may be inserted into the canister, e.g., via a suitably configured insertion valve, along with the foaming agent and/or propellant, for example, under pressure, such as where the foamable material is a liquid, and the foaming and/or propelling agent is a gaseous element, such as where the liquid and gas are phase separated within the canister and maintained therein, such as under pressure. Particularly, in certain instances, the foaming and/or propelling agent may be one or more gasses, such as a gas that is subsumed or otherwise dissolved, or at least partially dissolved within the foamable and/or flowable material, such as to from a solution therewith. And in such instances, foaming and/or flowing may occur because of an increase or decrease of pressure and/or a partial pressure within the canister. In an instance such as this, the foamable and/or flowable material and foaming and/or propelling agent may combine to form a foam and/or a flowable material such as upon release of the pressure from the canister, for instance, when the canister is opened, and air ingresses into the canister and/or mixing chamber associated therewith and/or when the foaming and/or propelling agent, e.g., gas(es), and/or foamable and/or flowable material egresses from the canister, such as where the ingestion of the foamable material is to be consumed, e.g., by a user wishing to imbibe the foamed and/or flowable material. Where the foamed material is prefoamed prior to being inserted into the canister, or foamed subsequent thereto but prior to release, the foamed material may be imbibed directly from the canister, such as upon opening the canister. In such an instance, the foamable material may be foamed by the foaming agent combining to form a foam such as upon an increase in pressure within the canister, for example, when the foaming agent mixes with the foamable material within a chamber within the canister. Accordingly, in certain embodiments, the foamable and/or flowable material is inserted into the canister and separated from the foaming and/or propelling agent, e.g., phase separated, such as where the foaming and/or propelling agent is a gas and the gas is maintained under pressure. In such an instance, contacting of the foaming and/or propelling agent with the foamable and/or flowable material under pressure converts the foamable and/or flowable material from a first state into a second state. The present devices, systems, and methods of using the same will now be described in greater detail by way of example with reference to the appended drawings. For instance, as can be seen with respect to FIGS. 1A and 1B, a container 1 is provided. The container can be any suitable vessel, such as a canister or bottle 1, for instance, a typical soda bottle or soda can, as known in the art. In various instances, such a vessel may be configured to retain its contents, such as under minimal pressure. The present container may be configured to contain its contents under greater pressure, such as much greater pressure than that of the prior art. The container or other canister of the disclosure can be of any suitable shape and of any suitable size, such as circular, triangular, square, rectangular, round, spherical, cylindrical, pyramidal, cubical, tubular, and the like. As exemplified in FIGS. 1A and 1B, in particular instances, the container 1 may have a body 10, such as an extended body having a proximal portion 12 and a distal portion 16 that are separated from one another by an extended, e.g., medial, portion 15. In particular instances, the extended body 10 may be tubular and therefore may have a curved configuration. In certain instances, the extended body 10 may be spherical or semi-spherical, e.g., the extended body may have a rounded body configuration. The extended body 10 may be configured such that it at least partially bounds a chamber 50, such as a chamber that is adapted for retaining a material 100 in one or more of its non-foamed, non-flowed, and/or foamed and/or flowable states. In such an instance, the chamber 50 may be bounded by a rounded and/or curved body 10, and may further be bounded by one or more of a distal end 17 and/or a proximal end 11 of the canister, such as a proximal end 11 having threading, or other coupling mechanism 13. In some embodiments, the bounding member 10 may be rigid, semi-rigid, semi-flexible, flexible, and/or the like. As can be seen with respect to FIGS. 1C and 1D, in various embodiments, a delivery mechanism 20 may be provided. The delivery mechanism 20 may be configured as a dispensing mechanism that may be adapted so as to be coupled to a device 1. The delivery mechanism 20 may have any suitable configuration so long as it is capable of effectuating the movement of the flowable and/or foamable material 100 from within the container 1 to outside of the container 1. To effectuate such movements, the delivery mechanism 20 may include an elongated hollow and/or tubular member 30, which tubular member may be configured as a feeder or straw element. The feeder element 30 will include a proximal portion 33, having a proximal end 32, which may be configured so as to be coupled to an outlet of the container 1, such as a nozzle 60, which nozzle 60 may include a passageway 61 that is configured increase velocity of the flowable material and/or pressure within the passageway. Additionally, the feeder element 30 will include a distal portion 36, having a distal end 37, such as where the distal end 37 is configured for contacting the material 100 within the container 1 and functions to receive and/or translate that material 100 out of the container 1. The feeder element 30 will also include a medial portion 35 that separates the proximal portion 32 from the distal portion 36. Additionally, the delivery mechanism 20 may include a container interface 13B, which may be configured for associating the delivery mechanism 20 with the container 1, such as by allowing it to be coupled to a proximal end 11 of the container 1. This coupling may be by any suitable means such as by screwing, snapping, stamping, clamping, crimping, welding, and/or adhering the coupling mechanism 13b on to the container 1, and as such the container interface may include suitable snaps, and/or threads, and/or adhesives, and/or deformable gaskets, and the like. Additionally, as can be seen with respect to FIGS. 1C and 1D, the device 1 may include a delivery or dispensing mechanism 20, as described above, and in some embodiments, the delivery mechanism 20 may be coupled to a nozzle 60, which nozzle may be constructed to be rigid, semi-rigid, semi-flexible, flexible, moveable, and/or articulable. The nozzle 60 will include a proximal portion 63, having a proximal end 62, and a distal portion 66, having a distal end 67. The nozzle will additionally include a medial portion 65 separating the proximal portion 63 from the distal portion 66. The nozzle 60 may have any suitable configuration so long as it is capable of participating in the translation of the flowable material out of the container, such as into the mouth of a user, and in this instance the nozzle 60 is configured so as to include a curve or bend, such as in its medial portion 65, so that as the fluid is drawn up into the nozzle 60, its flow path 61 transcribes an angular arc. The angle between the proximal 63 and distal 66 portions of the nozzle may be any suitable angle from 0 degrees to about 180 degrees, such as from about 45 degrees to about 160 degrees, for instance, from about 60 degrees to about 160 degrees, including about 90 degrees to about 120 degrees. In various instances, the nozzle 60 may have a plurality of bends or curves and/or contain a plurality of angles between its proximal 62 and distal ends 67. In various instances, the nozzle portion 60 may be configured to be movable with respect to the container body 10, such as to facilitate delivery, such as in a pumping towards and away action, and/or ease of use, such as in a rotational or pivotal motion. In further instances, the container 1 and/or the nozzle 60 may include one or more valve mechanisms 40, which valve may be operably connected to one or more of a control mechanism 45 and/or an actuator 27, such as a trigger, together which valve 40, control mechanism 45 and actuator 27 may be adapted to control the flow of the material 100 out of the container 1, such as through the feeder element 30 and/or nozzle 60. Accordingly, in various instances, a valve 40 is provided, such as where the valve 40 has a conduit 41 there through its length, and is configured for interfacing with a proximal portion 12 of the container 1, and/or a translation member 30 associated therewith, so as to facilitate, e.g., control, the release of the flowable material 100 from within a chamber 50 of the container 1 to outside of the container through an outlet 61 of the nozzle, such as for delivery to a user, e.g., a consumer of the translated flowable material 100. As can be seen with respect to FIGS. 1E and 1F, the valve 40 may have any suitable configuration, and may be any suitable size and shape, but in various embodiments, may have a proximal portion 42, such as for interfacing with a distal portion of a nozzle 66, and may have a distal portion 46, such as for interfacing with a portion of the container 1, e.g., a portion of the container bounding an opening or conduit therein, or a 33 proximal portion of the translating element 30 associated therewith. The valve 40 may also have medial portion 43, between the proximal 42 and distal 46 portions, such as where the medial portion 43 has a bend therein, for instance, a bend that corresponds to a bend in the nozzle 60. In various embodiments, the valve 40 itself may be configured for interfacing directly with a user of the container 1, and/or for interfacing with some other dispensing mechanism 20, associated therewith, such as for dispensing the fluid therein to a user. Typically, the valve 40 will have an orifice 41 extending the length of the valve 40, such as an orifice for translating the flowable and/or foamable material 100 through the valve, such as for controlling the dispensing of the flow of the foamable material out from a chamber 50 of the container 1. In such instances, the valve 40 may be a control valve, such as a control release valve 45 that upon activation allows and/or facilitates the flow of the flowable and/or foamable material 100, e.g., in the foamed state, out of the container 1, such as by interfacing with the outlet of the container 1 and/or one or more translation members 30 associated therewith. Such activation may be through operation of an actuator 27, as depicted in the cutout portion of FIG. 1E, which actuation may result from an upwards force (F) being applied to the actuator 27 causing the control valve 45 to lower relative to the nozzle portion 60, thereby opening the valve 40; or through actuation of the nozzle portion 60, such as by asserting a downwards force (F) by depressing the nozzle 60 relative to the container 1, as depicted in the cutout portion of FIG. 1F, which depression moves the nozzle portion 60 downwards towards the container 1, actuating the valve 40 so as to open up and thereby connect the passageways 41 and 61 thereby allowing for release of the contained material(s). It is to be understood that the configuration of the valves 40 as detailed herein are for exemplary descriptive purposes only, and can be configured to function in a number of different ways to effectuate delivery of the consumable material 100, such as by the application of forces from different directions of exertion with the corresponding adjustments being made to the delivery mechanism 20 and/or valve 40 componentry. Hence, the valve 40 may be operably connected with a control mechanism 45. Such a control mechanism 45 may have any suitable configuration so long as it is capable of facilitating and/or controlling the movement and/or release of the material 100 out of the container 1, such as in a controllable manner, e.g., with respect to one or more of flow rate, density, pressure, temperature, aeration, intermixing between gases and flowable material, foaminess, and/or contour of the flowable material. For instance, the control mechanism 45 of the valve 40 may be configured as a simple push or pull valve, or other control element that turns flow on or shuts it off, such as by opening or closing the passageway 41 or conduit there through. The action of opening and/or closing of the passageway 41 may be effectuated by any suitable mechanism, such as by articulating or otherwise rotating or pivoting about a hinge or pivot point, such as in a flap valve configuration. In some instances, the valve 40 may include an obstructing member 48, e.g., a flap member, plunger, or ball, that can controllably articulate within a passageway 41, such as by at least partially impinging or non-impinging the passage therein. In such instances, the control mechanism 45 of the valve may include a biasing, e.g., a spring, element that is operably connected to the obstructing and/or occluding member 48, such as a diaphragm, wherein based on the condition of the spring element, e.g., in its compressed or non-compressed (e.g., biased) form, the passageway may either be opened or closed or partially there between, such as by the positioning of the diaphragm in relation to the diameter of the passageway, which positioning may be governed by the spring element, such as via the control mechanism 45 and/or actuator 27. In various instances, the dimensionalities of the valve 40 and/or passageways 41 and/or 61 may be controlled by mechanics and/or electronically, and the valve 40 may be configured as a hydraulic, pneumatic, solenoid (piston), motorized, electronic, and/or manually operated valve. In certain instances, the valve may be a one-way (one-directional), two-way (bi-directional), or three or more way (multi-directional) valve, which may allow the fluid within the passageways to flow in one, two, three, or more directions through the system. For example, the valve may be a check valve that is at least partially opened by the flow of material from greater pressure or temperature to lower pressure or temperature, but closes in the absence of such a pressure and/or temperature gradient. Such a valve may be operated, e.g., opened, by flow in one direction, and closed by flow in the opposite direction, and/or in various instances, may be opened or closed manually, mechanically, electrically, and/or by the suction, vacuum, and/or blow forces exerted on the system by a user of the device 1. The control mechanism 45 of the valve 40 may be configured so as to be operated by a control element 45a. The control element 45a may be a mechanical element, such as a handle, lever, a twist valve, tilt valve, bite valve, crimp valve, depressible button, switch, turn knob or wheel, twist screw, vacuum or suction activated valve, diaphragm, and/or the like, and in some instances, the control element 45a may be an electronic actuator. In either instance, the control element 45a may be configured for effectuating the opening and closing and/or diameter of the valve 40 and/or the passageways 41, 61 associated therewith. For instance, the control element 45a may be configured for effectuating the opening and closing via mechanical operation, or the opening and closing may be effectuated through receipt of an electronic signal or impulse that then automatically controls the opening or closing of the valve, e.g., through an electronically controlled mechanical actuator, e.g., a motor. Particularly, in various embodiments, the valve mechanism 40 and/or control mechanism 45 and/or control element 45a (or 45b) may be controlled via a controller, such as valve actuator 27. More particularly, the valve actuator 27 may be configured for controlling a control mechanism 45 and/or control element 45a/45b that is adapted for controlling the opening and/or closing and/or diameter of the passageway 41 of the valve 40 through which the material 100 flows. Such a valve actuator 27 and/or controller 45 may include a control mechanism configured to control the condition of one or more of the valve elements 40 of the system, such as based on the various inputs it receives thereby allowing the one or more valves 40 of the system to be accurately positioned thereby allowing minute control of the flow through the system based on a wide variety of system conditions (e.g., pressure, temperature, foaminess, flow rate, etc.) and/or user selected and/or controlled configurations, e.g., by selecting which valves will be opened, to what diameter, how, when, and under what conditions. Hence, the valve 40 may be configured so as to control the flow through a passageway 41 and/or 61 of the container 1. Accordingly, in certain instances, the delivery mechanism 20 may be configured so as to be associated with a feeder element 30. For instance, the delivery mechanism 20 may be configured such that it associates the proximal portion 33, e.g., the proximal end 32, of the feeder element 30 with the distal end 67 of the nozzle 60. This association may further be mediated, such as by control valve 40 and/or control mechanism 45. In such instances, the distal portion 36 of the feeder tube 30 may be configured for contacting the flowable material 100 and facilitating translation of the flowable material into and through its body, such as through its distal end 37, for instance, in response to activation of the control actuator 27. Additionally, as can be seen with respect to FIGS. 1E and 1F, the shape and/or dimensions of the nozzle 60 and/or delivery mechanism 20, the passageways 41, 61 there through as well as the feeder element 30, may be configured with respect to one another such that there is an angle between these elements or parts thereof. For instance, the container may include a delivery nozzle 60 having a proximal portion 63 and a distal portion 66 together which form pathways 41, 61 from the container 1. In such an instance, the distal portion 66 of the nozzle 60 and/or delivery mechanism 20 may include an inlet aperture, e.g., 61, for receiving the flowable material 100. Furthermore, in some of these instances, the inlet aperture 41 may further be associated with a feeder element 30, such as via a proximal portion 33 thereof, where the feeder element 30 has a distal end 37, having a corresponding inlet aperture 41 passing there through, which inlet aperture may be in contact with the foamable and/or flowable material 100 to be delivered. Further still, pathway 41, 61 of the delivery mechanism 20 and/or nozzle 60 may pass through a proximal portion, e.g., 63, having an exit aperture 61, such as where the passageway 61 may be adapted to deliver the ingestible substance to the mouth of the consumer, and in various instances, the proximal portion 63 of the nozzle 60 may be sized and adapted to be received and/or conformed directly by a mouth of a consumer. In particular instances, the angle between the feeder tube 30 and/or the delivery mechanism 20 and/or the nozzle 60, and/or the various inlet/outlet apertures, and/or passageways thereof, may range from 0 degrees to 180 degrees in the positive or negative direction. For instance, the nozzle 60 and/or the delivery mechanism 20 may be configured and/or positioned in relation to one another and/or the feeder element 30 such that there is an angle between them, which angle may be between about 10 or 15 degrees and about 140 degrees or 160 degrees, such as between about 20 or 30 degrees and about 110 or 120 degrees, for example, between about 45 or 60 degrees and about 90 or about 100 degrees, including about 75 degrees. Further, in some instances, there may be a curve between these elements, which curve may have a radian equivalent to the angles detailed herein. Particularly, the configuration between the feeder element 30, delivery mechanism 20, and/or nozzle 60 may be such that while the ingestible substance 100 is delivered, the inlet aperture, e.g., of the feeder element 30 and/or delivery and/or control mechanism 20 and/or nozzle 60 or their component parts, is proximate a portion, e.g., 16 or 17, of the container 1 that is closest toward the center of the earth, and an angle between a vector (V1) from the inlet aperture, e.g., of the feeding mechanism 37, to the exit aperture 61, e.g., of the delivery nozzle 60, and a vector (V2) from the inlet aperture, e.g., of the feeding mechanism 37, to the center of the earth is greater than about 90 degrees but less than about 180 degrees, such as about 120 to about 160 degrees or there between. In various instances, a valve mechanism 40 may be included and be associated with one or more of the delivery nozzle 60, the delivery mechanism 20, and the feeding mechanism 30, which feeding mechanism 30 may be associated with the first cavity 50 of the container 1 so as to access the ingestible substance 100 therein. Hence, in particular instances, the valve mechanism 40 may have a controllable valve 45 that is configured to regulate a flow of the ingestible material 100 from an inlet aperture of the feeding mechanism 37 in a first cavity 52a of chamber 50, such as through a pathway 41 to delivery mechanism 20 formed by the delivery nozzle 60 and to the exit aperture 61 of the delivery nozzle. In various instances, the proximal portion 63 of the nozzle 60 and/or exit aperture 61 may be flexible and/or may have a shape and/or configuration adapted to be closely and comfortably associated with the mouth of a user. In such an instance, the inlet aperture 41 and/or 61 may be orientated with respect to the container 1, and the material 100 to be delivered, such that the inlet, e.g., 37, 46, 67, is closest to the center of the earth. In various instances, the reverse may be the case such as where the outlets 61, 42, and/or 32 are closest to the center of the earth when the container 1 is in use. This may be useful so as to assure that the maximal amount of contents 100 are capable of being expelled without the substantial loss of propellant 300, regardless of the orientation of the container 1 when employed for delivery. Particularly, in certain particular embodiments the container 1 may be configured with the specific gravities of the materials to be contained and employed in performing a delivery in mind, such that the specific gravity of the flowable and/or foamable material 100 is greater than that of the foaming agent 200 and/or propellant 300, such that the material to be delivered 100 will naturally center itself by the force of gravity within the container 1 so as to be positioned closest to the center of the earth during delivery. Specifically, where the material to be delivered 100 is a liquid or flowable material, and the propellant 300 and/or foaming agent 200 is a gas, or a liquid or fluid with a lesser specific gravity, the component with the lesser specific gravity will form one or more layers on top of the layer with the greater specific gravity, and thus, dependent on the particular specific gravities and orientation of the fluids relative to one another to be delivered, the container 1 can be configured to preferentially deliver one fluid over the other and/or in one orientation over the other, such as by being held with the nozzle 60 further away from the earth's center of gravity, where the flowable substance 100 with the greater specific gravity will rest at the bottom 17 of the container, and therefore be delivered in preference over the fluid with the lesser specific gravity, such as where the feeder tube 30 extends proximate the bottom portion 16 of the container; or by being held with the nozzle 60 closest to the earth's center of gravity, where the flowable substance 100 with the greater specific gravity will rest at the top 13 of the container 1, such as where the feeder tube 30 extends proximate the top portion 12 of the container 1. Accordingly, in such an instance, the inlet, e.g., of one or more of the feeder tube 30 or delivery mechanism 20 or the nozzle 60, may be designed so as to be proximate the material to be delivered 100, e.g., at the lower or lowest point of the material, when the container is positioned in its configured use orientation. This is particularly useful for preventing the loss of foaming agent and/or propellant as well as assuring that the maximal amount of the contents are capable of being expelled. For instance, the container may be configured so that in intended use the container may be orientated during dispensing such that the feeding point will be closest to the center of gravity at its intended use orientation, which will require a long feeding tube or short feeding tube or no feeding tube at all dependent on the specific gravities, desired use orientation, and resultant configuration of the container and its components. In various instances, the interior surface 8 of the cavity may be contoured so as to effectuate the desired flow characteristics, for example, the interior bounding walls may be configured to effectuate a funneling type flow of the fluids prior to delivery. As can be seen with respect to FIGS. 2A-2C, in particular instances, the container 1 includes an elongated body 10. The elongated body 10 is formed of an interior surface 8 and an exterior surface 9. As depicted, the elongated body 10 is rounded or curved so as to be cylindrical and tubular, such that the interior and/or exterior surfaces transcribes an arc, e.g., of 360 degrees, thereby forming a chamber 50 within its bounds, in such an instance the interior surface 8 is positioned so as to face the interior of the chamber 50. However, in various instances (not depicted), the body 10 of the container may be configured so as to include a plurality of walls, such as a plurality of opposed walls that together form edges in such a manner as to bound the chamber 50. For instance, the container may be formed as a cube having front and back surfaces that are separated one from the other by one or more side portions, such as by a pair of opposed side surfaces. However, as depicted in FIGS. 2A-2C, the extended body 10 of the container 1 is comprised of one or more surfaces that are configured in a tubular form such as where the extended body 10 is elongated and/or curved and includes a single bounding member that separates the inside of the cavity 50 from the outside of the canister, and is thus composed of interior and an exterior surface portions. In various instances, the container may also include a top surface and a bottom surface to further bound the top and bottom of the chamber 50. Regardless of the shape of the container, the extended body member 10 may be configured for bounding a chamber 50. The bounding member 10 may be rigid, semi-rigid, semi-flexible, flexible, or a combination thereof. In various embodiments, the chamber 50 may include a plurality of interior portions, e.g., sub-chambers or cavities 52, wherein the interior surface 8 of the extended body 10 forms a bounding member for the chamber 50, and may further bound one or more lumens, e.g., 52a, 52b, and/or 52c, within the chamber 50, such as where each lumen may be bounded at least partially by the bounding member 10. In such instances, one or more of the cavities and/or one or more lumens may be configured for retaining one or more of a flowable and/or material to be foamed 100, and/or a foaming agent 200, and/or a propellant 300. As indicated, the flowable and/or foamable material 100, which may be contained within the chamber 50, or a sub-chamber or lumen thereof 52a, of the container 1, may be any material capable of being foamed and/or flowed, such as by being converted from a first, non-foamed and/or non-flowable state, into a second foamed and/or flowable state. For example, a typical foamable and/or flowable material 100 may be a gas, liquid, semi-liquid, solution, gel, solid, powder, and/or catalyst that may be contained within the container, and in some instances may be such that when contacted and/or mixed with the foaming agent is converted from being non-foamed into being foamed. Further, as indicated, a suitable foaming agent 200, which may be contained within one or more lumens, e.g., 52b, of the container 1, may be any agent that is capable of converting a non-foamed material into a foamed material, such as when applied to, contacted with, or otherwise mixed amongst the non-foamed material. For instance, a foaming agent may be a gas, liquid, semi-liquid, solution, gel, solid, powder, and/or catalyst that when introduced to and/or mixed with the foamable material converts the foamable material from being substantially non-foamed into being foamed. In various instances, the foaming may be instantaneous upon mixing, or may be upon activation, such as pursuant to an activating event. In various instances, such as depicted in FIG. 2B, a suitable propellant 300, which may be contained within one or more lumens, e.g., 52b and/or 52c, of the container 1, may be any agent that is capable of associating with one or more of the flowable and/or foamable material 100 and/or foaming agent 200 and causing the one or more of the material 100 and/or foaming agent 200 to be moved from one position to another, such as within or out from the container, such as for causing the material 100 and/or foaming agent 200 to be expulsed from the chamber 50 of the container 1, such as when the container is opened. For example, a propellant 300 may be a gas, liquid, semi-liquid, solution, gel, solid, powder, mechanical element, and/or catalyst that when introduced to and/or mixed with the flowable and/or foamable material 100 and/or foaming agent 200 causes the one to move with respect to the other and/or causes both to move, such as from within the container 1 to outside of the container 1, e.g., through one or more nozzles 60 and/or valves 40 and/or translating elements 30, or passageways 41, 61 therein, as herein described. Accordingly, with respect to FIGS. 2A-2C, in various instances, a container 1 is provided wherein the container includes a chamber 50, which chamber can be subdivided, e.g., by one or more partitions or dividers 51, into sub compartments or sub-chambers, e.g., 2a, 2b, and/or 2c, etc., such as where each sub compartment has its own lumen or cavity, e.g., 52a, 52b, and/or 52c, etc. For instance, the container 1 may have a chamber 50 that is further divided into first, second, third, fourth, fifth, etc., lumens, such as by being separated by dividers, e.g., 51a, 51b, and/or 51c, etc. For example, as can be seen with respect to FIG. 2A, in some instances, a container 1 is provided wherein the container 1 includes at least a chamber 50 with at least a first lumen 52a and a second lumen 52b, such as where the first lumen 52a is configured for retaining the flowable and/or foamable material 100, and the second lumen 52b is configured for retaining the foaming agent 200 and/or propellant 300, such as where the first 52a and second lumen 52b are separated from one another, such as by a divider 51, which divider 51 may be an expandable, flexible, or otherwise stretchable membrane that is capable of expanding, such as to receive a foamable and/or flowable material 100 therein. Accordingly, in some embodiments, a container 1 is provided wherein the container is configured to include a first 2a and a second 2b container portion, so as to at least form a chamber 50 where the chamber 50 includes at least a first lumen 52a and a second lumen 52b where the two lumens are separated by a divider 51. However, as can be seen with respect to FIG. 2B, in various embodiments, the container 1 may be configured to include a third container portion 2c, and may, therefore, additionally include a third lumen 52c. For instance, the first container portion 2a may include lumen 52a, which lumen 52a includes the flowable and/or foamable material 100, and the second container portion 2b includes lumen 52b, which lumen 52b includes one or more of a foaming agent 200 and/or propellant 300, such as where the foamable material 100 and the foaming agent 200 and/or propellant 300 are separated from one another by a divider 51a. Additionally, the container 1 may include a third container portion 2c that includes a third lumen 52c, which third lumen 52c may include one or more of a foaming agent 200 and/or propellant 300, such as where the contents contained within lumen 52b are separated from the contents contained in lumen 52c by a divider 51b. In particular instances, the foaming agent 200 and/or propellant 300 may be retained within an auxiliary chamber unit 310. Further, as configured in FIGS. 2A and 2B, the flowable material 100 may be retained within a first lumen 52a within a first container portion 2a, and the foaming agent and/or propellant 200/300 may be retained in a second lumen 52b within a second container portion 2b, in such a manner that the two materials do not intermix, such as where the two lumens are separated by an expandable, resilient, non-permeable membrane that functions as a divider 51, which membrane may also serve as a mechanical propellant, e.g., which may be due to its expandability and/or elasticity. In various instances, the membrane 51 may be permeable or semi-permeable. Additionally, as depicted the material to be delivered 100 is retained within the compartment 2a, and the foaming agent 200 and/or propellant 300 is retained within the compartment 2b. As depicted in FIG. 2A, the lumen 52b contains a foaming agent 200, and as depicted in FIG. 2B, the lumen 52b contains a propellant 300. However, in various other instances, the material to be delivered 100 may be retained within the compartment 2b, while the foaming agent 200 and/or propellant 300 may be retained within the compartment 2a and/or the nozzle 60 positioned in relation to the elongated body 10 to accommodate such a change in configuration. Further, in these and other such embodiments, the elastic divider portion 51 and compartment 2a may be in a reverse orientation as depicted, so as to couple to the distal portion 16 of the container 1, such as in relation to an inlet positioned therein, which inlet may be employed so as to fill the chamber 2a with one or more of the material to be delivered, the foaming agent, and/or the propellant. In such an instance, the filling or the releasing of the contents within the chamber 2a may effectuate the delivery of the foamable and/or flowable material 100. In certain instances, as depicted in FIGS. 2B and 3, the container 1 may be configured such that it includes at least two chambers, such as where one or more of these chambers may be configured for receiving an insertable and/or removable chamber unit 310, such as a cartridge or cylinder, for instance, a cartridge 310 for containing one or more of a propellant 300, and in some instances may include a foaming agent 200 and/or a foamable material 100. For example, as depicted in FIG. 2B, the container 1 may be configured to include a first chamber 50 having a first 2a and a second 2b chamber portion, such as a first chamber portion 2a, for containing a flowable and/or foamable material to be delivered; and may include a second chamber portion 2b, for containing a foaming 200 and/or propelling 300 agent, which in this instance is a propelling agent. Further, the container 1 may include a second chamber 2c, such as for containing an additional auxiliary chamber unit 310, such as for containing an additional propellant 300. Specifically, as can be seen with respect to FIG. 2B, the chamber portion 2c may have a cavity 52c that may be adapted for receiving an insertable and/or removable chamber unit 310 containing the propellant 300. Additionally, as can be seen with respect to FIG. 3, the container 1 may have a first chamber 50 having a first chamber portion 2a for retaining both the material to be delivered 100 and a foaming agent 200 and/or propellant 300, such as where these components share the same cavity 52a. The container may also include a second chamber 2c that may have a cavity 52c that may be adapted for receiving an insertable and/or removable chamber unit 310 containing the foaming agent 200 and/or propellant 300. In such instances as depicted in FIGS. 2B and 3, the cartridge 310 may be configured as a foaming member 200, such as where the foaming agent is a gas, such as nitrous oxide, carbon dioxide, oxygen, an inert gas, and the like, that is retained under pressure in the cartridge 310, which cartridge 310 may be fitted within the chamber 52c of the container 1. And as indicated, in other instances, the cartridge 310 may be configured as a propellant 300, such as where the propellant is a gas that is retained under pressure in the cartridge 310. Further, in such instances, the container 1 may include one or more conduits, such as a conduit 48 forming a passageway by which two or more of the chambers and/or cavities may communicate one with the other. In certain instances, conduit 48 may be controlled by a flow control mechanism 49, which may be configured to regulate communication between the various chambers. Such a control mechanism 49 may have any configuration adapted to control the flow through the passageways, e.g., 48, such as upon an activation event. For instance, the control mechanism 49 may be configured for multiple uses, such as a controllable valve, or may be a single use seal that is sealed and thereby prevents communication but then allows such communication once opened. Such a seal may be opened by the application of a force, such as a shear force, by puncturing, bursting, piercing, tearing, fracturing, translating, bending, deforming, displacing, dissolving, burning (pyrotechnic meltable), a needle and seat valve, and the like. As indicated, in various instances, the passageway of the conduit 48 may further include a valve 49, such as a control valve, which is configured for controlling the flow of the foaming agent 200 and/or propellant 300 out of the cartridge 310, and/or out of chamber 2c, through the conduit 48, and into the cavity 52a or 52b, such as the cavity containing one or more of the flowable and/or foamable material 100 and/or foaming agent 200 and/or propellant 300, such as for intermixing therewith. Hence, once the cartridge 310 containing the foaming agent and/or propellant is coupled with, e.g., inserted into, the container 1, and the control valve 49 opened, the foaming agent and/or propellant may be released out of the cavity 52c, through the conduit 48, and into the cavity 52a or 52b, such as via actuation of an actuator 27 operably connected to the control valve 49, so as to intermix the foamable material 100 with the foaming agent 200 and/or to convert the material 100 from a non-foamed to a foamed state, and/or so as to intermix the flowable material 100 with the propellant 300, and/or so as to propel the material 100 out from the container. Accordingly, in various instances, the communication between the various chamber portions 2a and/or 2b and/or 2c and/or 2d (as set forth below) may be controlled by the actuator 27, or may be separably controlled, such as by individually or collectively controllable actuators. As noted above, in this and other instances described herein, the foaming agent and/or propellant may include one or more elements that when admixed causes an exothermic or endothermic or other reaction that transfers thermal energy in such a manner so as to create a temperature differential, such as between the temperature prior to admixture and subsequent thereto, such as an increase or a decrease in temperature, such as within a chamber of the canister. For instance, any consumable chemical agent that undergoes a physical change, such as from a solid to a liquid and/or gas, or vice-versa, with a resultant temperature change, such as an increase or decrease in temperature, for instance, due to occupying more or less space within the chamber after the change in form, may be employed in this manner. Accordingly, in various embodiments, the temperature change may accompany a change in pressure, such as where there is a pressure change, the resultant change in pressure may produce a change in the temperature, or vice-versa, either higher or lower, such as of the foamable and/or flowable material, which change in pressure may be produced for the purpose of causing the foamable material to foam, such as prior to dispensing. In certain instances, the change in temperature may be produced for the purpose of heating or cooling the foamable material, such as prior to dispensing Additionally, in various instances, the foaming agent and/or propellant may include one or more elements that when admixed, e.g., with one another or the foamable material, causes an exothermic or endothermic or other reaction that transfers energy within the system in such a manner so as to create a pressure differential, such as between the pressure prior to admixture and subsequent thereto, such as an increase or a decrease in pressure, such as within a chamber of the canister. In various embodiments, where there is a pressure change, the resultant change in pressure may be accompanied with a change in the temperature, either higher or lower, such as of the foamable material. For instance, any consumable chemical agent that undergoes a physical change, such as from a solid to a liquid and/or gas, or vice-versa, with a resultant pressure change, such as an increase or decrease in pressure, for instance, due to occupying more or less space within the chamber after the change in form, may be employed in this manner. In such an instance, the change in pressure and/or temperature may be for one or both of converting the foamable material from a non-foamed and/or flowable material to a foamed and/or flowable material and/or the change in temperature and/or pressure may be for the purpose of heating or cooling the temperature of the flowable and/or foamed material. Accordingly, as set forth above, the addition of the foaming agent and/or propellant to the foamable material may be accompanied by a change in pressure which may result in a temperature change within the canister. For example, a drop in pressure, such as caused by a gas leaving solution by moving into a larger space may result in a coincident lowering of temperature of the remaining solution. Particularly, as a gas expands over an increased volume the temperature within the chamber may drop. Likewise, an increase in pressure, such as caused by a gas being compressed into a smaller space may result in a coincident increase in temperature. Particularly, as increased gas moves into a confined space, such as by more gas entering into solution, the temperature of the chamber and/or resultant solution may be raised, such as due to an increase in thermal energy caused by the gas. More particularly, in various instances, the foaming and/or propelling agent may be in a gaseous form, such as carbon dioxide, nitrous oxide, hydrogen, helium, argon, other noble gas, compressed air, and the like, wherein the gas is contained within a canister, such as a removable canister, and the control release conduit controls the flow of the gas into the chamber containing the foamable and/or flowable material, whereby upon mixing of the gas with the foamable and/or flowable material one or more of a pressure gradient and/or a temperature gradient is formed and/or a foamed and/or flowable material is produced, such as by the mixing of the foaming agent and/or propellant with the foamable and/or flowable material, such as in the presence of a pressure and/or temperature gradient, which may or may not result in an increase or decrease in temperature of the resultant flowable and/or foamed material. In various instances, the foaming agent may also be a propellant or may include a propellant. Accordingly, in one aspect, the disclosure is directed to the conversion of a foamable material from a first, non-foamed state to a second, foamed state, such as by the introduction of a foaming agent and/or propellant into the foamable material, for instance, for the production of a consumable foamed material end product having a desired amount of foaminess. For example, the foamable material and the foaming agent and/or propellant are selected such that when admixed the foamable material is converted from a non-foamed state to a foamed state wherein in the foamed state, the foamable material has a colloidal structure that is characterized by the amount of foaming agent that is trapped within the colloid. In various instances, the foamed composition includes 98% of foamable material and 2% foaming agent, 95% of foamable material and 5% foaming agent, 93% of foamable material and 7% foaming agent, 90% of foamable material and 10% foaming agent, 87% of foamable material and 13% foaming agent, 85% of foamable material and 15% foaming agent, 83% of foamable material and 17% foaming agent, 80% of foamable material and 20% foaming agent, 77% of foamable material and 23% foaming agent, 75% of foamable material and 25% foaming agent, 73% of foamable material and 27% foaming agent, 70% of foamable material and 30% foaming agent, 67% of foamable material and 33% foaming agent, 65% of foamable material and 35% foaming agent, 63% of foamable material and 37% foaming agent, 60% of foamable material and 40% foaming agent, 57% of foamable material and 43% foaming agent, 55% of foamable material and 45% foaming agent, 53% of foamable material and 47% foaming agent, 50% of foamable material and 50% foaming agent, 45% of foamable material and 50% foaming agent or 40% of foamable material and 60% foaming agent. In such an instance, the foamable material is changed by the foaming agent, such as being converted from a liquid or semi-liquid or solution or gel or solid, or powder state to a state wherein the composition includes the foaming agent, such as in a foamed state. For instance, in various instances, the foamable material is a material capable of absorbing and/or otherwise retaining within its formulation at least a portion of the foaming agent and/or propellant. For example, in certain embodiments, the foamable material is a liquid or the like and the foaming agent and/or propellant is one or more of a gas, such as a soluble gas, a liquid, a semi liquid, a solution, a solute, a solid, a gel, a dissolvable powder, a suspension, and the like. In other embodiments, the foamable material may be one or more of a gas, such as a soluble gas, a liquid, a semi liquid, a solution a solute, a solid, a gel, a dissolvable powder, a suspension, and the like, and the foaming agent may be a liquid or the like. Accordingly, in various embodiments, a composition is provided wherein the composition includes a formulation produced by introducing the foaming agent and/or propellant to the foamable material, such as to produce a foamed composition, such as where the foamable material goes from a first, non-foamed state, to a second foamed state, such as by intermixing with the foaming agent and/or propellant. More particularly, in certain embodiments, the composition provided is a consumable product, such as a beverage, such as a foamed beverage. In further instances, the foamable material is a material capable of absorbing and/or otherwise retaining within its formulation at least a portion of a propellant. For example, in certain embodiments, a propellant may be included wherein the propellant is one or more of a gas, such as a soluble gas, a liquid, a semi liquid, a solution, a solute, a solid, a gel, a dissolvable powder, a suspension, and the like. Additionally, in one aspect, the disclosure is directed to the conversion of a material from a first, non- or partially flowable state to a second, more flowable state, such as by the introduction of a propellant into the material, for instance, for the production of a consumable flowable material end product having a desired amount of flowability. For instance, the material and the propellant may be selected such that when admixed the material is converted from a non- or semi-flowable state to a more flowable state wherein in the flowable state, the flowable material has a viscosity and/or thixotropic structure that is characterized by the amount of propelling agent and/or other additive that is trapped within the structure. In various instances, the flowable composition includes 98% of flowable material and 2% propelling agent, 95% of flowable material and 5% propelling agent, 93% of flowable material and 7% propelling agent, 90% of flowable material and 10% propelling agent, 87% of flowable material and 13% propelling agent, 85% of flowable material and 15% propelling agent, 83% of flowable material and 17% propelling agent, 80% of flowable material and 20% propelling agent, 77% of flowable material and 23% propelling agent, 75% of flowable material and 25% propelling agent, 73% of flowable material and 27% propelling agent, 70% of flowable material and 30% propelling agent, 67% of flowable material and 33% propelling agent, 65% of flowable material and 35% propelling agent, 63% of flowable material and 37% propelling agent, 60% of flowable material and 40% propelling agent, 57% of flowable material and 43% propelling agent, 55% of flowable material and 45% propelling agent, 53% of flowable material and 47% propelling agent, 50% of flowable material and 50% propelling agent, 45% of flowable material and 50% propelling agent or 40% of flowable material and 60% propelling agent. In such an instance, the flowable material is changed by the propelling agent and/or an additional additive, such as being converted from a liquid or semi-liquid or solution or gel or solid, or powder state to a state wherein the composition includes the propelling agent, such as in a flowable state. For instance, in various instances, the flowable material is a material capable of absorbing and/or otherwise retaining within its formulation at least a portion of the propellant. For example, in certain embodiments, the flowable material is a liquid or the like and the propelling agent and/or propellant is one or more of a gas, such as a soluble gas, a liquid, a semi liquid, a solution, a solute, a solid, a gel, a dissolvable powder, a suspension, and the like. In other embodiments, the flowable material may be one or more of a gas, such as a soluble gas, a liquid, a semi liquid, a solution a solute, a solid, a gel, a dissolvable powder, a suspension, and the like, and the propelling agent may be a liquid or the like. Accordingly, in various embodiments, a composition is provided wherein the composition includes a formulation produced by introducing the propellant and/or an additive to the material to be delivered, such as to produce a flowable composition with a determined flow characteristic, such as where the deliverable material goes from a first, non- or partially flowable state, to a second flowable state, such as by intermixing with the propellant and/or additive. More particularly, in certain embodiments, the composition provided is a consumable product, such as a beverage, such as a flowable beverage or other food item. In further instances, the deliverable material is a material capable of absorbing and/or otherwise retaining within its formulation at least a portion of a foaming agent, as described above, and/or an additive, such as listed above. For example, in certain embodiments, a foaming agent and/or an additive may be included or added to the foamable material such as wherein the foaming agent and/or additive is one or more of a gas, such as a soluble gas, a liquid, a semi liquid, a solution, a solute, a solid, a semi-solid, a gel, a dissolvable powder, a suspension, and the like. Accordingly, in various instances, as depicted in FIGS. 2A and 2C, the container 1 may include a chamber 2d configured as an intermixing duct, such as a duct that is configured to allow the contents of one cavity, e.g., 52a, to communicate with the contents of another cavity, e.g., 52b, such as for intermixing within a third cavity, e.g., 52d, such as for the intermixing of the various different substances within the container. For example, the intermixing duct 2d may be connected to a first cavity 52a by a first feeder element 30a, through a first passageway 41a having a first valve 40a associated therewith. Additionally, the intermixing duct 2d may also be connected to a second cavity 52b by a second feeder element 30b, through a second passageway 41b having a second valve 40b associated therewith. In various instances, the valves 40a and 40b, may include control elements 45a and 40b, respectively. Hence, the container 1 may be configured so as to connect a first cavity, e.g., 52a, containing a material to be foamed and/or flowed 100, and may further connect a second cavity, e.g., 52b, containing a foaming agent 200 and/or a propellant 300 with the intermixing duct 52d, such as where the intermixing chamber 2d may be configured so as to be part of the dispensing mechanism 20. In such an instance, the flowable and foamable material 100 is translated through a distal portion of the translating element 37a, e.g. through one or more valves 40a, into the mixing chamber 2d within the dispensing mechanism 20, and the foaming agent and/or propellant 200/300 is translated through a distal portion of the translating element 37b, e.g. through one or more valves 40b, into the mixing chamber 2d, wherein upon mixing of the foaming agent 200 and/or propellant 300 with the foamable material 100, the foamable material may be converted from a non-foamed to a foamed state, such as by intermixing with the foaming agent 200 and/or propellant 300, which intermixing may be initiated via the operation of a consumer operable control actuator 27. In such an instance, two or more control valves may be employed, as depicted, so as to prevent the foaming and/or propelling agents from escaping directly into the various chambers, such as mixing duct, and/or out of the passageways 41 and/or 61, such as in an attempt to equalize within the system. Such intermixing may take place prior to insertion of the foamed material into the container, after insertion within the container, such as within a single, e.g., the main, chamber within the container, and/or within one or more auxiliary chambers, such as a mixing chamber, within the container and/or within the dispensing mechanism associated with the container. As indicated above, where the foaming process takes place within the container, the foamable material may be separated, such as by a phase shift or by a physical partition, from the foaming agent and/or an additive or flavoring agent, but in such a manner that the two or more materials are capable of being intermixed, such as in a controlled fashion, so as to produce the foamed material having the desired foaminess and/or flow characteristics. Likewise, where the process of converting a non- or semi-flowable material into a flowable material takes place within the container, the material to be flowed may be separated, such as by a phase shift or by a physical partition, from the propelling agent and/or an additive and/or a flavoring agent, but in such a manner that the two or more materials are capable of being intermixed, such as in a controlled fashion, so as to produce a flowable material having a desirable flow characteristic. Accordingly, when physically separated, as depicted in FIGS. 2A-2C, such as by a partition or divider 51, a controlled release conduit 41 and/or 48 may be included in the partition and/or an intermixing duct 2d so as to regulate the rate and extent of intermixing between one or more of the flowable and foamable material 100, the foaming agent 200, and/or the propellant 300 and/or an additive or flavoring agent, where the controlled release conduit 41 and/or 48 may be configured in such a manner so as to accommodate the physical characteristics of the foamable material, the foaming agent, and/or the propellant, and/or additives, and/or flavoring agents being employed as well as any changes to the same due to such intermixing. In such an instance, dependent on the identity of the foaming agent 200 and/or propellant 300 and/or additive and/or flavoring agent, the controlled release conduit 41 and/or 48 may have any configuration suitable to creating a pressure and/or temperature differential between the inside of the container 1 and the outside of the container and/or between various different cavities 52 within the container 1, such as between the cavity 52a containing the foamable and/or flowable material 100 and the cavity 52b containing the foaming agent 200 and/or the cavity 52c containing the propellant 300 and/or one or more additional cavities having one or more additives and/or flavoring agents therein. For instance, in various embodiments, one or more control release conduits of the container for allowing communication between the various different chambers and/or cavities of the container, may have a mechanical configuration so as to operate mechanically. For example, a control release conduit may be configured as or to include a slow or quick release valve where the conduit or valve has various controllable diameter dimensions; a hand or screw pump; a screw and plate, a spring release plate, a lever, or other mechanical element capable of increasing the pressure and/or temperature in at least one chamber such as by decreasing the size of that chamber (such as prior to release of the foaming agent from that chamber) or receiving more of a gas therein, a fan, and the like. In various instances, the foaming agent and/or propellant and/or the control release conduit may be one in the same. In various embodiments, such a control release conduit may have a mechanical, an electrical, and/or electro-mechanical configuration so as to operate at least in part electronically. In such an instance, the control release conduit may be configured as or include an electronic slow or quick release valve; an electronic pump, electronic screw plate, an electronically activated spring release plate; an electronic lever or fan; an electronic MEMS device, and the like. In various instances, where the conduit is controlled electronically, the conduit may have control circuitry, such as a microprocessor that controls the conduit and thereby controls the extent and rate of communication between the chambers. In such an instance, the microprocessor may include one or more of a CPU, a memory, a transmitter, a receiver, a GPS locator, a pressure sensor, a temperature sensor, and/or one or more other sensors or gauges, such as for determining the amount of air or foaming agent or propellant or additive or flavoring agent captured within the generated matrix, colloid, and/or solution of the foamable and/or flowable material generally. In instances such as this, in certain embodiments, the foaming agent, propellant, additive, etc. and controlled release conduit may be one in the same, such as where the opening and closing as well as the diameter of the opening of the conduit is controlled such as either mechanically or electronically. In specific embodiments, the foaming and/or propelling agent may be a chemical composition and the control release conduit may be configured for facilitating the mixing of the chemical foaming and/or propelling agent and/or additive and/or flavoring agent with the foamable material, such as where the foaming agent and/or additive and/or flavoring agent is in a gaseous, liquid, semi-liquid, solution, gel, solid, and/or powder form, and the like. For instance, the foaming agent and/or propellant may be one or more components that when intermixed with each other and/or the foamable and/or flowable material and/or additive and/or flavoring agent cause an increase in pressure and/or temperature within one or more of the chambers of the container, which increase in pressure and/or temperature may be employed, via the control release conduit, so as to foam the foamable material and/or facilitate in its expulsion from the container, such as in response to activation of the dispensing member. Of course, as indicated, any of the flowable and/or foamable material 100, foaming agent 200, and/or propellant 300 may be one and the same, or in two or more, e.g., three different lumens, such as three or more separate lumens within three or more separate compartments 2a, 2b, 2c, and/or 2d, and/or the like, of the container 1, which one or more compartments can be configured to communicate with one another such as via one or more conduits 41 and/or 48 and/or valves 40, control mechanisms 45, and/or mixing ducts 2d, and/or mixing chambers 52d. Accordingly, as depicted in FIGS. 1E and 1F, the foaming material 100 may be in the same chamber 50 as the foaming agent 200. However, as depicted in FIGS. 2A and 2C, the foamable material 100 may be in a separate lumen 52a from the lumen 52b wherein the foaming agent 200 resides, such as where the two lumens 52a and 52b are separated by a divider 51, which divider may be configured as a stretchable membrane or as a moveable platform or diaphragm. And further, as depicted in FIG. 2B, an additional or alternative compartment 2c may be included, e.g., within chamber 50, such as where the compartment 2c forms a lumen 52c, such as for housing a propellant 300, which in this instance is housed within an auxiliary canister 310. Further, as depicted in FIGS. 2A and 2C, the container 1 may include one or more mixing ducts 2d, which ducts may be adapted for allowing the contents in one container portion, e.g., 2a, to flow to and intermix with the contents in a different container portion, e.g., 2b, such as within an intermixing chamber 52d of the dispensing mechanism 20. Additionally, as can be seen with respect to FIG. 2C, in various embodiments, a vessel such as a container 1 is provided, wherein the container 1 includes chamber 50, such as where the chamber 50 may include at least a first container portion 2a, such as for retaining the foamable material 100, and may further include a second container portion 2b, such as for retaining a foaming agent 200 and/or propellant 300, where the first and second container portions are separated one from the other by one or more divider portions 51, such as an articulable divider portion capable of moving within the chamber 50 of the container 1 in such a manner that the internal area of the chamber 50 can be of variable volume, so as to be increased or decreased. In a manner such as this, the foaming agent and/or propellant 200/300 within the second container portion 2b may be such that it exerts a pressure against the divider portion 51. In such an instance, the actuator 27 may be configured such that when depressed, valves 40a and 40b may be opened simultaneously or sequentially, e.g., by activation of control mechanisms 45a, 45b, respectively, thereby opening passageways 41a and 41b and allowing an egress route out of the cavities 52a and 52b and into mixing chamber 52d, such that as propellant 300 exerts pressure against the articulable divider portion 51, the divider portion moves upwards towards the proximal portion 12 away from distal portion 16 of the container 1 forcing the foamable and flowable material 100 to be translated through the translating element 30a and be delivered to chamber 52d. Also, valve 40b may be opened, e.g., by the initial depressing of actuator 27 or a subsequent depressing action, so as to allow the ingress of foaming agent 200/300 to be received within feeder element 30b via distal portion 37b so as to be delivered to mixing chamber 52d so as to allow the mixing of the flowable and/or foamable material 100 with the foaming agent and/or propelling agent 200/300, such as in mixing duct 2d. In such an instance, a further actuation of the actuator 27 may effectuate the opening of valve 40c via control mechanism 45c so as to open up access to passageway 61 of nozzle 60 for dispensing of the mixed and/or foamed material to the user. Further, as depicted in the cut away of FIG. 2C, in various instances, the divider 51 may be configured to articulate within the chamber 50 such as by being rotated around an axle unit 29, which rotations may be actuated by an actuator 28 that when twisted or turned moves the divider 51 upwards along the axle unit 29 thereby compressing the contents 100 within the cavity 50 and forcing them out of the nozzle 60. In such an instance, one or more of the interior of the chamber wall 8 and/or the axle unit 29 may include threading or the like to facilitate the movement, such as by converting the rotating motion into linear movement along the axis, e.g., upwards or downwards. The axle unit 29 may be positioned centrally, such as along a central axis within the chamber 50, or may be positioned off center. The divider 51 may have any suitable shape such as circular, donut shaped, square, etc. In various instances, the central axis unit 29 may have a passageway there through, e.g., it may be tubular, with an opening along its length through which one or more of the flowable material 100, the foaming agent 200, and/or propellant 300 may translate, hence, in various instances, the axis unit 29 may function as a feeder tube, as described herein. Furthermore, as depicted the container 1 may include a chamber 50 that in turn includes a plurality of sub-chambers, such as sub-chambers 2a and 2b that are formed by the divider 51 intersecting the chamber 50. As indicated, in various instances, the platform 51 may be torus such that the axle 29 may be inserted there through, which axle 29 may be covered by a membrane to separate it from the contents within the chamber 2a. In various instances, a further divider 51a may be present, which divider 51a may be a compressible member, such as a membrane, that is configured so as to be folded upon itself like an accordion so as to be compressed, such as by the articulations of the rotating member 28. Hence, in some embodiments, by rotating the screw-like member 28, the divider 51 moves axially upwards toward the proximal portion of the chamber 50, causing the membrane 51 to fold upon itself and compress the chamber 2a, thereby expelling the contents therein, such as through the delivery mechanism 20. In some embodiments, the divider 51 and membrane 51a may be configured as a bellows that is controllable by the movements of one or more of the axle 29 and control lever 28, and in such as instance, the compressing action may be carried out by twisting, pushing, and/or pulling. In some instances, one or more rollers or other compressive elements providing a compressive force to the membrane 51a may be included so as to effectuate the compressing of the chamber 2a and/or the expulsion of the material 100, such as by the collapsing of the chamber 2a. Such expulsion can also be through a ratcheting type configuration and/or mechanism. In certain instances, the divider 51 and/or the axle 29 and/or other interior bounding members of the chamber 50 may include one or more elastic members, a spring element, or other biasing element that is coupled thereto so as to facilitate the collapsing of the chamber 2a, such as where the platform 51 and axle 29 form a piston type and/or plunger mechanism. In such instances as these, a chemical based propellant may or may not be employed. Rather, the material to be delivered is inserted within the sub-chamber 2a, causing it to expand, creating potential energy that is then released when the chamber is opened, such as via valve 40 and through passageway 41. Additionally, in some embodiments, the central axle unit 29 may comprise an internal element adapted to create a positive pressure within the chamber 50, such as one or more spring or biasing elements that may be configured to couple a top or bottom portion of the container 1 to the divider 51 for assisting in the articulation of the divider 51 within the chamber. Hence, in various instances, the container 1 may include an element configured for creating a positive pressure within the chamber 50 for the expulsion of its contents 100, which element may include one or more of a spring, e.g., a spring loaded valve, a stretchable membrane or bladder, or other source for storing potential energy within the chamber 50 or one or more of its associated cavities 52. As depicted in FIGS. 2A, 2C, and 3, container 1 includes a mixing chamber 52d that is separated from main chamber 50, by one or more passageways 41, e.g., via one or more control valves 45, and further includes an intermixing cavity 2d associated therewith. Particularly, chamber 50 includes a first container portion 2a that retains a foamable material 100, and includes a second container portion 2b/2c that retains a foaming agent 200 and/or propellant 300. The first 2a and second 2b/2c container portions are separated one from the other by divider portion 51, and may feed into container portion 2d, such as through one or mover valves 40, which valves may include one or more control mechanisms 45. Hence, in various instances, the container 1, may include one or more metering valves 40/45 that are configured so as to meter the exact proportions of materials to be received within the mixing chamber 2d so as to be precisely intermixed therein. The metering valves may be configured to meter exact volumes, such as by controlling amount of materials flowed into chamber 2d, time of flowing, proportion of materials flowed therein, and the like. Particularly, the proportion of materials to be flowed into chamber 2d may be determined so as to ensure that the final deliverable composition is not too foamy, but not under foamed. More particularly, the metering valves can be configured so to ensure that the first portion delivered maintains the same consistency as the last portion to be delivered. In such instances, the system can be configured so as to not run out of foaming agent and/or propellant prior to delivering the last amount of substantial material. Furthermore, the valves and/or control mechanisms thereof may be configured for sequential activation and subsequently to sequential delivery into mixing chamber 2d and/or to the consumer. As indicated herein, such activation may be controlled mechanically, e.g., through switches, toggles, and/or motors, and/or electronically, such as through control of various settings of a microprocessor. In various instances, the container 1 may include one or more sensors, and/or the microprocessor may include a memory containing one or more flavoring and/or foaming and/or projecting profiles so as to allow the user to select the parameters and taste experience of the delivery. For example, the container portion 2a is connected to the container portion 2d via valve 40a through passageway 41a, and the container portion 2b is connected to the container portion 2d via valve 40b through passageway 41b. Flow through passageways 41a and 41b and into mixing duct 2d may be controlled via control mechanisms 45a and 45b, respectively, that control the operation of valves 40a and 40b, such as in response to one or more operations of actuator 27. Hence, upon the appropriate activations, the passageways 41a and 41b are opened, simultaneously or sequentially, thereby allowing the contents of container portions 2a and 2b to intermix within container portion 2d. In such an instance, the actuator 27 may be configured such that when depressed one valve 40a is opened thereby releasing the foamable material 100 to be released into mixing duct 2d. And when depressed a second time valve 40b is opened thereby opening passageway 41b and allowing the foaming agent 200 to also be released into mixing duct 2d, so as to allow the foamable material 100 to intermix with foaming agent 200 and to be foamed thereby, such as prior to release from the container 1. Additionally, a further actuation of the actuator 27 may effectuate the opening of valve 40c via control mechanism 45c so as to open up access to passageway 61 of nozzle 60 for dispensing of the mixed and/or foamed material to the user. Accordingly, the intermixing cavity 52d may be configured to be part of the dispensing mechanism 20 and adapted to allow the contents in chamber portion 2a and the contents of chamber portion 2b to communicate within chamber 2d, such as for the intermixing of the substances. For example, the intermixing cavity 52d is connected to chamber 2a, containing the flowable material 100, by translating element 30a, which forms passageway 41a and allows the flowable substance to flow into chamber 2d through valve 40a. Further, the intermixing cavity 52d is additionally connected to chamber 2b, containing the foaming agent 200, by translating element 30b, which forms passageway 41b and allows the foaming agent to flow into chamber 2d through valve 40b. In such an instance, the chamber portion 2d may be configured as a foaming chamber so as to allow a foaming agent, such as a gaseous element, to intermix with a food or beverage item, such as for foaming thereof, such as when the actuator 27 is depressed thereby opening up valve mechanisms 45a and 45b. Where the propellant 300 is also a foaming agent 200, when it intermixes with the flowable material 100, such as in chamber 2d, it foams the material 100, such as prior to release through the nozzle 60 and/or directly to the mouth of the consumer. Hence, when actuated, the flowable and foamable material 100 may be translated through the translating element 30a through the valve 45a into the mixing chamber 2d within the dispensing mechanism 20 for mixing with the foaming agent 200/300, upon which mixing the foamable material 100 is converted from the non-foamed to the foamed state, such as by the intermixing with the foaming agent 200 and/or propellant 300. As can be seen with respect to FIG. 3, in various embodiments, a vessel such as a container 1 is provided, wherein the container 1 includes at least a first container portion 2a having a main chamber 50, including a first cavity 52a, such as for retaining the foamable material 100, and may further include a second container portion 2c having a sub-chamber 52c, such as for retaining a foaming agent 200 and/or propellant 300, where the first and second container portions are separated one from the other by one or more divider portions 51, such as divider portion(s) 51 having a conduit 48 there through so as to allow communication between the first container portion 2a with the second container portion 2c. In various embodiments, a foaming agent 200 may also be included, such as within the first container portion 2a and may further be included in the second container portion 2b, in some embodiments. The foaming agent 200 and/or propellant 300 may be in various forms, from liquids to solids to powders, and the like, and as indicated, may further be included in the same or in one or more separate compartments from the compartment containing the foamable material. Accordingly, as can be seen with respect to FIG. 3, the container 1 includes the main chamber 50 having sub-chamber 2a including the flowable and/or foamable material 100. The main chamber 50 additionally includes the sub-chamber 2c including the propellant 300. Hence, in this particular instance, the foaming agent 200 is included and retained within the same chamber 50 as the flowable and foamable material 100, such as in compartment 2a, and the propellant 300 is retained within a separate compartment 2c. The foamable material 100 may be facilitated with respect to flowing and/or foaming and/or inter-mixing with the propellant 300 by conduit 48, which conduit 48 may comprise a control release valve 49. In this instance, the propellant 300 is contained within a propellant/foaming member 310, e.g., a canister containing the propellant 300, which canister is insertable within or otherwise coupled with the container 1. However, in other instances, the canister 310 may be configured so as to be associated with the outside of the bounds of the container 1, such as by a threaded or cammed interface. For example, in certain instances, a foaming and/or propellant member 310, containing a foaming agent 200 and/or a propellant 300, may be included, such as within an insertable and/or ejectable canister or container 310 that is configured for being coupled to the container 1, such as a container 1 having a sub-chamber 2c configured so as to have a foaming member receptacle 52c therein. As can be seen with respect to FIG. 3, the container 1 may include one or more lumens or cavities, 52a and 52c, where the one or more cavities of the container, e.g., the one, two, or three cavities, may be in communication with one another, such as through one or more conduits 48, which conduits may be controlled such as via a control mechanism 49. Additionally, in various embodiments, the container 1 may include a dispensing mechanism 20 that may be coupled to a nozzle 60. The nozzle 60 may be capable of participating in the translation of the flowable material out of the container 1, and in various instances, the nozzle 60 may be operably connected to a series of valve mechanisms 40a, 40b, and 40c and/or 49, which valve mechanisms 40 may be adapted to function in concert or independently to control the flow of the materials 100, 200, and/or 300 throughout the container 1, such as through the various feeder elements 30 and 30b and out of the container 1 through the nozzle 60. In some embodiments, the dispensing mechanism 20 may include a mixing chamber 2d having a lumen 52d for allowing one or more of the flowable and/or foamable material 100 and/or foaming agent 200 and/or propellant 300 and/or an additive, etc. to intermix. In some instance, a valve 40 may be included where the valve 40 may be comprised of a plurality of valve elements 40a, 40b, and 40c, and/or 49. For instance, a first valve element 40a may include a first conduit 41a that is configured for interfacing with a primary translation member 30a so as to facilitate and/or control the release of the flowable material 100 from within the chamber 50, such as for delivery to mixing chamber 2d and/or to a user and/or a consumer of the translated material 100. For example, the container 1 may include a valve controller and/or other control mechanism, such as actuator 27, for controlling the various valve mechanisms 40, 45, 48, 49, and/or communication between the chambers and/or for allowing and/or regulating the extent and/or rate of intermixing of the foamable material 100 with the foaming agent 200, such as within a mixing cavity region 52d of the container or a dispensing mechanism associated therewith 20, so as to ensure the production of a consumable and/or otherwise ingestible end product having the optimal proportion of foamable material to foaming agent and/or propellant and/or additive, flavoring agent, etc. such that the resulting foamed and/or flowable material has the desired amount of foaminess and/or rate of flow, such as rate of egress from the container and/or canister. Additionally, in certain instances, the delivery mechanism 20, may include or otherwise be associated with a secondary conduit 41b, which secondary conduit 41b may be connected to a secondary translation member 30b, as well as with mixing chamber 2d, such as through additional valve element 40b. In such an instance, the main translation member 30a may be relatively long, extending so as to be proximate the distal portion 16 of the chamber 50, and configured for delivering the flowable material 100 to the dispensing mechanism 20, such as through mixing cavity 52d, such as when the container 1 is positioned in a first orientation, for instance, when held with the proximal portion 12 upwards, positioned above the distal portion 16, towards the mouth of the user. In addition, the secondary translation member 30b may be shorter, extending interiorly within the chamber 50, but proximate the proximal portion 12, and configured for delivering the flowable material 100 to the dispensing mechanism 20, when the container 1 is positioned in a second orientation, for instance, when held with the distal portion 16 upwards, positioned above the proximal portion 12, towards the mouth of the user. The valve controller 40 may additionally include a valve element 40c, which valve element 40c may be configured for controlling release of the mixed substances out of the nozzle 60 and to the user, such as through passageway 61. As can be seen with respect to FIG. 4A, a container 1 containing an ingestible composition 100 is provided, wherein the ingestible composition, in certain embodiments, is a beverage. In such an instance, the ingestible beverage 100 may be a foamable material, such as a flowable material capable of being foamed and therefore may be a foamable material that is retained with in a cavity 52a of chamber 50 in a first container portion 2a, such as in a non-foamed state. In various instances, the material may be a material to be flowed, and as such a foaming agent 200 and/or propellant 300 may be included. In certain instances, the propellant and/or foaming agent 200/300 may be retained within the same container portion 2a as the foamable material 100. Further, in various instances, as depicted in FIG. 4A, a (additional) foaming agent 200 and/or propellant may also be included and may be retained in a second container portion 2e having a second cavity 52e. For instance, in various instances, the container 1 may include an auxiliary container portion 2e, which container portion may be part of or otherwise associated with a dispensing mechanism 20 that is positioned at a proximal portion 12 of the container 1. In such an instance, the auxilary cavity 52e may be connected to the first cavity 52a, such as by a conduit 41e that is capable of being opened, for instance, by an actuator 27, which actuator may also be configured for effectuating the release of the foamable material 100, such as through the translating element 30, through the demand valve 45, into conduit 41a and out through the distal opening 61 of the nozzle 60. In such instances, a foaming agent 200 and/or propellant 300 may also be included, such as a propellant that may be retained in the first container portion 2a, or in some instances a propellant may not be included. In various embodiments, where a propellant is included, the propellant 300 may be retained within a second or even a third container portion of the container 1, such as depicted in FIGS. 2B and 3. Where a third or fourth container portion is present, the third and/or fourth container portion may be connected to the first and/or second container portions, such as by one or more conduits that are openable, for instance, by the actuator 27. In various embodiments, where the foaming agent 200 and/or propellant 300 is retained within an auxiliary cavity portion 52e that is connected to a first cavity portion 52a, such as through conduit 41e, the foaming agent 200 and/or propellant 300 may be composed of a material that when contacted and/or admixed with the foamable material 100 converts the foamable and/or flowable material from a first, non-foamed state to a second, foamed and/or flowable state. In such an instance, the foaming agent 200 may be any material that is capable of producing a foam when contacted with the foamable material, such as an effervescence material configured as a tablet. In certain instances, one or more of the foamable material and/or the foaming agent may include an additive and/or a flavoring agent. In other instances, the cavity 52e may retain a propellant 300 and/or additive, flavoring agent, and/or the like within and be releaseable from the cavity 52e, such as upon activation of an actuator 27, and the like. Accordingly, such a cavity 52e of the container 1, may include a flavoring agent, thickening agent, and/or other food or beverage topping. For instance, one or more powders having various radii of preselected sizes so as to achieve a various preselected flow characteristic. For example, a powder may be present wherein each component of the powder may be of uniform volume and/or size, which may be employed so as to increase or decrease the density of the overall composition, such as where the powder may be distributed according to particle size and selectively employed to trap air within the composition so as to enhance its flow characteristics, e.g., make the composition more flowable. In some instances, air may be added directly to the composition, such as through an aeration process, so as to enhance its flowability or taste. Particularly, where no extra air is contained in the composition, it may be more compressive, and may be more dense and flow more slowly. However, where air is added, the composition may become less dense and flow more swiftly and/or smoothly. Hence, in certain instances, the dispensing mechanism 20 may be configured such that the foaming, propelling, and/or flavoring agent is released for contact with the foamable and/or flowable material when the actuator 27 is actuated thereby at least partially opening the conduit 41e, such that when the actuator 27 is actuated, e.g., by being depressed, the foaming agent and/or propellant and/or additive and/or flavoring agent may be released, may traverse through a suitably configured conduit 41e, and enter into the main cavity 52a so as to be mixed with the foamable material 100, thereby converting the foamable material from the non-foamed and/or non-flowable state to a foamed and/or flowable state. In various instances, the container 1 may include an additional container portion housing a propellant, which propellant may be released into the main container portion 2a for intermixing therewith, such as through an additional conduit that may be controlled by actuating actuator 27 of dispensing mechanism 20, or some other controlling mechanism. As indicated above, the container may include an outlet 41a, such as an outlet that is coupled with the first (and/or second) container portion(s), such that once produced the foamed and/or flowable material may be translated, e.g., via the translating member 30, from within the first container portion 2a to the outside of the container 1, such as through the control valve 45, for instance, and out through the outlet of the nozzle 61 for delivery to a consumer, e.g., for consumption and/or adding to another food or drink item. In various instances, such as depicted in FIG. 4A, the translation of the flowable and/or foamed material 100 may be facilitated by the inclusion of a propellant 300, as described above, which propellant may be within the main chamber 50 (and/or in a tertiary container portion) in a state of partial admixture with the foamable material 100, such as where the propellant 300 is at least partially soluble within the foamable material. In such an instance, when the foaming agent 200 is contacted with the foamable material 100, such as via activation of the actuator 27 and/or the conduit 41a is opened, thereby allowing pressure, e.g., gas pressure, within the container 1 to begin to equalize with the air pressure outside of the container, the foamable material 100 may be converted to a foamed state and may be propelled out of the container 1, such as through the translating element 30 and/or valve 40 and/or nozzle 60. For instance, when the foamable material is mixed with one or more of the foaming agent 200 and/or propellant 300, these agents may act to expel the resultant composition out from the interior 50 of the container 1, such as through the translating element 30. Where an additive is included, such as a flavor, the flavor may be delivered with the foamed material, such as in a foamed, flavored beverage form. As can be seen with respect to FIG. 4B, in various instances, a container 1 is provided. The container includes a chamber 50 having a first cavity 52a and/or a second cavity 52b, such as where the first cavity includes a foamable and/or flowable material 100 and the second cavity includes a propellant 300. In this instance, the first cavity 52a is divided from the second cavity 52b by a divider 51, such as a flexible and/or stretchable membrane that may expand or otherwise change its volumetric capacity when filled with the foamable and/or flowable material 100. In such an instance, when actuator 27 is depressed, valve 40, such as control release valve 45, may be articulated and thereby open passageway 41a, thereby allowing the contents of the first cavity 52a to be expelled out of the container 1, such as by flowing through the nozzle 60 and out from the outlet 61. In various instances, as indicated, the interior container portion 50 may include a propellant 300 to facilitate such expulsion. In particular instances, the divider 51 is not included and the propellant 300 acts directly on the contents 100. Additionally, as can be seen with respect to FIG. 4B, in particular embodiments, a pumping mechanism 28 may be included, such as proximate the dispensing mechanism 20, which pumping mechanism may include a plunger or other pumping element 29 that is adapted to move within a conduit 41f and further configured so as to thereby increase the pressure and/or temperature within the chamber 50, and consequently further the expulsion of the material 100 from the chamber, such as when the actuator 27 is depressed and the valve 45 is opened. In such an instance, the plunger 29 would be in an airtight sealing with the proximal end 13 of the container 1, such as via a gasket, e.g., an o-ring, positioned around the plunger 29 and within the conduit 41f so as to seal the conduit 41f. In various instances, the chamber 50, or one or more of its subparts may be self-pressurizing. Hence, by activating the pumping mechanism 28 pressure and/or temperature within the chamber 50 would be increased by pushing and pulling the plunger 29 up and down, so as to increase pressure within the chamber 50 and/or facilitate the expulsion of the contents 100, such as through passageway 61, which may be a food or drink item or an additive or flavoring thereto, such as a topping or condiment. For instance, in various embodiments, as seen in FIGS. 5A, 5B, and 5C, a container 1 of the disclosure is provided wherein the container may have a cavity 50. The cavity 50 may be configured as or otherwise include or be associated with a plurality of chambers, 52a and 52b, such as one or more sub-chambers each adapted for containing a flowable and/or foamable material, such as a food and/or drink item and/or food supplement, condiment, or topping therefore. For example, a container 1 of the disclosure may be configured to retain and dispense a combination of materials that are commonly or uncommonly paired together. For example, one chamber, e.g., 52a, may include, a drinkable liquid, such as milk or soy milk or almond milk or formula, a first juice component, a first soda, an alcohol, or the like, and the other chamber, e.g., 52b, may include a mixer, such as a flowable chocolate, a second juice component, a second soda, another alcohol or tonic or soda water or water, or other mixer, e.g., fruit juice, and the like. Likewise, in various instances, one or more of the chambers may include flowable food supplements, or condiments, such as ketchup, mustard, mayonnaise, relish or a vegetable item, such as an onion, pepper, a dressing or spread, such as ranch or blue cheese or thousand islands, or honey mustard, or Italian dressing, an oil, a vinegar, butter, a vegetable spread, a pate, and the like, such as for delivery in combination and/or sequentially to a food or drink item. In other instances, the one or more chambers may include one or more flowable food items, such as a peanut or almond or other nut based spread, e.g., nutella, jelly or jam, a fruit, and the like. In various instances, the contained materials may be those not commonly thought of as miscible, e.g., oil and water, an acetone (e.g., wine) and oxygen, and/or may be retained and delivered in such a manner so as to prevent contamination or rancidity, such as is caused when oil is mixed with air. In some instances, the contained material may be a flowable material, such as a medicine, a medicament, and the like. Accordingly, to effectuate such sequential and/or conjunctive delivery, the container 1 may include a cavity 50 having two or more separate reservoirs 52a and 52b therein, such as where one reservoir, e.g., 52a, contains one flowable material 100a that is meant to be mixed with the contents of a second reservoir, e.g., 52b, containing a second material 100b, either prior to or post dispensing. In such an instance, the container 1 may include a propelling mechanism 300, which propelling mechanism 300 may be configured for facilitating the delivery of the flowable and/or mixable materials 100a and/or 100b from the reservoirs 52a and 52b, through respective translating elements 30a and 30b, and out through nozzle 60. For instance, the container 1 may include a dispensing mechanism 20 having a conduit 61 connecting the translation elements 30a and 30b to an outlet of the nozzle 60, and may further include one or more controllable release valves 40a, 40b, and 40c which release valves may be controlled, via a suitably configured control element 45a, 45b, and 45c, with respect to the configurations, surface areas, and/or diameters of their opening and closing. Such a control element, for example, may have any suitable configuration so long it is adapted for opening and/or closing one or more of the controllable release valves 40a, 40b, and/or 40c, such as conjunctively or sequentially, and/or for selectively choosing between them. For instance, the valve 40 may have a toggling mechanism that can allow the contents of both cavities 52a and 52b and/or any other included cavities to flow freely into mixing chamber 2d, or may rotate, expand, or otherwise move to impinge within a feeder element 30 or passageway 41 or 61 so as to limit or otherwise control the flow out of one or more of the cavities, such that more or less of the contents of one cavity is allowed to flow more rapidly or fully through the passageways, while the contents of the other is limited and/or prevented therefrom. A configuration such as this may be adapted to work regardless of the contents within each cavity 52, such as where one cavity includes a gas, the other a liquid, both contain gases, both contain liquids, or one or both of the chambers contain a solid. Further, because of the dynamics of the system, the container 1 can be configured to allow the contents to mix, whether typically miscible or not, such as within the mixing chamber 2d, even when the two components are not readily miscible, such a oil and vinegar, etc. Hence, in a manner such as this, the valve mechanism 45 is capable of controlling and/or determining the mixing dynamics as well as the proportion and/or ratio of mixing between the various contents of the cavities 52, such as prior to release. In various instances, the valve 40 and/or control element 45 may itself be controlled, such as by an actuator 27, which actuator 27 may further be configured for controlling the propelling mechanism(s) 300, with respect to its effectuating the propelling of the materials 100a and 100b through the translation elements 30a and 30b and out of the nozzle 60, such as through one or more passageways 41 and/or 61. Particularly, in some embodiments, such as illustrated in FIG. 5A, the container 1 may include a cavity 50 that may include a sub-compartment 52, which sub-compartment may be divided into two parts 52a and 52b. For instance, the container 1 may or may not include a rigid, inelastic, and/or other bounding member 10 that resists expansion against a force, pressure, or heat. In such an instance, the rigid bounding member, where included, may bound a cavity 50 that may include a plurality of flexible sub-compartments 52a and 52b, bounded by flexible and/or expanding members 51a and 51b, that are configured as reservoirs for retaining flowable materials 100a and 100b, respectively. The cavity 50 may further include a propellant 300, such as where the propellant 300 surrounds the reservoirs 52a and 52b. In such a manner as this, one or more of the first and second reservoirs 52a and 52b may be composed of an elastic, flexible, expandable, or otherwise volumetrically adaptable bladder that is configured to fill and/or stretch and/or expand such as in response to receiving the insertion of the flowable materials, e.g., there into. This expansion, along with the propellant 300 (if included) within the cavity 50 creates a positive pressure within the lumen of the cavity 50 and against the bladders 51a and 51b. It is to be noted that although there are only two chambers containing two or more food items for mixing and/or delivery, there may be 3, 4, 5, 6, 7, or more chambers that may be included, each of which may be individually or collectively operated with respect to its delivery of its retained contents by a consumer operable control mechanism 27, as described herein, so as to vary the amounts, proportions, and/or timing of the delivery of the various contents. Hence, the elastic and/or expansive action of the reservoir materials (which may act like a mechanical propellant) and/or the propellant 300 may exert a constant pressure against the flowable materials 100a and/or 100b such that when the control mechanism 27 is actuated and one or more of control valves 40a and/or 40b are opened the flowable materials 100a and/or 100b are pushed out of their respective reservoirs 52a and 52b, into the passageways 41a and 41b, respectively, and out of passageway 61 of the nozzle 60, such as for delivery to a food item or directly to the mouth of a user. In this instance, the delivery mechanism 20 includes a mixing chamber 2d that is coupled to the translation elements 30a and 30b, and is configured for receiving the flowable materials 100a and 100b for mixing prior to exiting through the passageway 61. However, in other instances, passageway 41 may include two sub-parts 41a and 41b that would keep the flowable materials 100a and 100b from mixing prior to delivery and/or may include a toggle mechanism to allow a user to select which of the various food or drink items is delivered at which times. Additionally, the container 1 may include an inlet 48 such as for insertion of the propellant 300 into the cavity 50. Further, in some embodiments, such as illustrated in FIG. 5B, the container 1 may include a body 10 that may be divided into two parts 50a and 50b, wherein each part may be further divided into two or more sub-compartments or reservoirs, e.g., 52a and 52c as well as 52b and 52d, respectively, such as by movable dividers 51a and 51b. In such a manner as this, the first cavity portion 50a may include two or more sub-compartments, e.g., 52a and 52c, which may form a first part or portion of cavity 50, such as where the first sub-compartment 52a acts like a delivery reservoir and includes the flowable material 100a, and the second sub-compartment 52c acts like a propellant reservoir and includes the propellant 300a. Likewise, the second cavity portion 50b may include two or more sub-compartments, e.g., 52b and 52d, that may form a second part or portion of cavity 50, such as where the third sub-compartment 52b acts like a delivery reservoir and includes the flowable material 100b, and the fourth sub-compartment 52d acts like a propellant reservoir and includes the propellant 300b. In such an instance, the propellants 300a and 300b may be configured to exert a constant pressure against the dividers 51a and 51b such that when the control mechanism 27 is actuated and one or more of control valves 45a and/or 45b are opened the flowable materials 100a and 100b are pushed out of their respective reservoirs 52a and 52b, into the passageways 41a and 41b, and out of passageway 61 of the nozzle 60, such as for delivery to a food or drink item or directly to the mouth of a user. In various instances, the delivery mechanism 20 may include a mixing chamber 2d, such as for the combining of the various substances within the nozzle 60, such as where the chamber 2d is coupled to the translation elements 30a and 30b, and may be configured for receiving the flowable materials 100a and 100b prior to exiting through the passageway(s) 41a and/or 41b, such as for allowing the materials 100a and 100b to intermix and/or foam prior to delivery through the nozzle 60. In certain instances, such intermixing may be controlled with respect to modulating the various characteristics of the resultant combined material so as to control the flow of that material through the nozzle such as in relation to its flow rate, amount of flowable material, and/or in other respects that may be configured to control the flow, such as with respect to its thixotropic and/or viscos properties. For instance, as can be seen with respect to FIG. 5C, an embodiment of the container 1 is provided. In this instance, a container 1 is provided, wherein the container includes a chamber portion 50 which chamber portion includes a plurality of interior cavities 52a, 52b, 52c, and 52d, such as for containing one or more foamable and/or flowable materials to be delivered, such as directly to the mouth of a user. For these purposes, the container 1 includes a nozzle 60 having a passageway 61, which passageway 61 connects to a corresponding passageway 41, which passageway 41 connects to the cavities 52a, 52b, 52c, and 52d, such as through conduits 41a, 41b, 41c, and 41d, so as to allow the consumable materials 100a, 100b, 100c, and/or 100d to flow, be foamed, and/or intermixed, and delivered to a user of the container 1 through their respective passageways. In such an instance, each cavity 52 may be connected to the outlet 41 such as through passageways 41a, 41b, 41c, and 41d, which outlets 41 may be coupled to a mixing chamber 2d as set forth herein so as to connect the interior of the cavities 52 with the mixing chamber 2d and/or the passageway 61 of the nozzle 60. The flow through passageways 41 may each be controlled by a mechanism 45 configured for closing and/or opening of valves 45a, 45b, 45c, and/or 45d, so as to thereby control flow of the flowable and/or foamable material out of the container 1. Such flow may be controlled individually, such as by controlling the opening and its extent of each individual valve 45 separately, or the flow may be controlled collectively by opening and/or closing the valves 45a, b, c, and/or d in concert, so as to allow for the mixing and its extent of the materials 100a, b, c, and/or d, within the various respective container portions. In such an instance, the passageways 41a, b, c, and/or d may each lead to a mixing chamber 2e, within which chamber the deliverable materials 100 may be intermixed such as prior to delivery through the passageway 61 out of the nozzle 60, which delivery may be through the opening and/or closing of valve 45e. In a particular instance, as indicated in the cutaway view of the valve 45 of container 1, a control mechanism may control the flow of the materials 100a, b, c, and/or d into and through passageway 41, which control mechanism may be one or more rotating elements, fly wheels, pivotal elements, flaps, closures, diaphragms, permeable membranes, or other valve members, e.g., individual valves 45a, 45b, 45c, and 45d, capable of opening and/or closing so as to open and/or close the apertures within the chamber 50 thereby controlling the flow there through. Accordingly, the container 1 may include a valve control mechanism 45 that may include one or more, e.g., a plurality of actuators and/or motors, for controlling the opening, closing, and/or extent of the same, so as to control one or more characteristics of the flow through the valves 40. Hence, valves 40a, 40b, 40c, and/or 40d, may include respective actuators 45a, 45b, 45c, and/or 45d, that can be operated individually or collectively, or in any combination, so as to control the flow from one or more cavities 52a, 52b, 52c, and/or 52d through one or more passageways 41a, 41b, 41c, and/or 41d into mixing chamber 2e and/or out of passageway 41, such as through valve 45e, and thereby may precisely control the extent and characteristics, e.g., the proportion of mixing between the various different contained materials. For example, in various instances, the valves 40 may include a control mechanism 45, such as a tilt modulator, which modulator may be an extended element adapted for rotating and/or tilting and thereby configured for opening, partially opening, partially closing, and closing one or more of the valve elements 45a, 45b, 45c, and/or 45d, such as via the orientation, e.g., tilting, of the modulator 45, such as the angle between an axis passing longitudinally through the center of the modulator at rest and one or more axes passing normal thereto and aligned with the valves 40 and or cavities 52, such that as the modulator is tilted and/or rotated one or more of the valves 40a, b, c, and/or d may be opened and/or closed, e.g., individually or in concert, thereby opening access to the respective cavities 52. In some instances, the various valves 40 and passageways, e.g., 41, may be controlled with respect to their opening and/or closing by a switch selectable control element. Hence, as can be seen with respect to the cutaway view of the valve control mechanism 45 of the container 1, dependent upon the orientation of the controller 45, flow out of individual chambers S1, S2, S3, and/or S4 may be effectuated, or mixing of the flowable materials may be effectuated, such as where the materials in the various chambers are allowed to intermix, such that S1 and S2 can intermix, S2 and S3 can intermix, S3 and S4 can intermix, and/or S4 and S1 can intermix, or other such combinations, dependent upon the configuration of the container and the respective valves 40 and controllers 45. Further, by depressing the toggle 45 downwards towards the distal portion 16 of the container 1, all valve elements 45a, b, c, and d may be opened, thereby allowing all of the flowable materials 100a, b, c, and d to intermix, such as within chamber 2e, such as prior to delivery out of the nozzle 60 and to the mouth of a user. In various instances, one of more of the cavities 52a, 52b, 52c, and/or 52d, may have a sub-chamber, such as 52a1, 52b1, 52c1, and/or 52d1, which sub-chambers may be configured for retaining a foaming 200 and/or propelling 300 agent therein, such as for foaming of the respective materials 100 within the respective chambers, and/or for the propelling of those materials 100 out of their respective chambers 52. In certain instances, the foaming 200 and/or propelling agent 300 may be retained within a canister 310, e.g., 310a, 310b, 310c, and/or 310d, which may be communicably connected to respective chambers 52a, 52b, 52c, and/or 52d, such as by respective conduits 48a, 48b, 48c, and/or 48d, such as through the control of various control mechanisms and/or valve elements 49a, 49b, 49c, 49d, such that the materials 100 within the respective chambers may be foamed and/or flowed prior to delivery to a user. Accordingly, in view of the above, in particular instances, a system is provided wherein a flowable and/or foamable food and/or beverage material may be stored in one physical state within a canister and may therein undergo a physical change, such as prior to or upon delivery, e.g., direct delivery, to a user whereby due to the physical change the flowable and/or foamable material may be converted at least partially to another physical state, such as from a non-foamed to at least a partially foamed state. For instance, in various instances, the foamable material may be a beverage, in a liquid form, and upon the addition or intermixing of the foamable material, which in various instances may be a gas, the liquid is changed, e.g., converted, from a liquid to at least a partial colloid, such as to form a foamable material. Particularly, the foamable material may be such that it is capable of forming a matrix with one or more components of the foaming agent and/or propellant so as to form a colloid such as upon the foaming agent and/or propellant being introduced with and/or mixed with the foamable material, such as within the container. For example, the flowable and deliverable material and the foaming agent and/or propellant may be such that the two materials are at least partially soluble one within the other, such as where the foaming agent and/or propellant may at least be partially dissolvable within the foamable material so as to be captured within a matrix thereof, or vice-versa, and in various instances together may form a foamable colloid therewith. Particularly, the flowable material and propellant and/or foaming agent may be selected so as to be able to bond, e.g., chemically, with one another, such that as the more volatile component enters and/or leaves solution, bubbles may form within the matrix, which dependent on the configuration of the components and control mechanisms can result in the formation of bubbles of a predetermined size, such as small, medium, large, and extra large. The number of bubbles within the solution may also be controlled via one or more of the control mechanisms of the container, such as via activation of the consumer operable control mechanism. Such control may be for the purpose of enhancing the taste to the user, for changing the flow characteristics, e.g., flow rate, viscosity and/or thixotropic effects, of the deliverable substance, and/or for facilitating absorption such as within the biological system of the user. For instance, the insides of the container can be contoured, such as with respect to increase and/or decrease shear, thereby affecting the flow of the material proximate the bounding member of the container, so as to increase or decrease flow of various parts of the material. For example, shear may be increased so that the rate of flow of the center of the fluid material is increased relative to the flow of the material proximate the bounds of the container, or shear may be decreased so as to produce a more even flow. Thickening and/or thinning agents and/or other additives and/or flavoring agents may also be employed in a manner such as this, such as by changing the viscosity and/or of the material. In particular, a gel may be used to make the composition more viscous. Additionally, other chemical and/or mechanical elements may be included within or as part of the container such as for affecting flowability, for example, thicker, semi-solid, and/or gel like substances that would not readily be flowable may be made to flow such as by decreasing or increasing internal viscosity, decreasing its thixotropic properties, and/or increasing internal agitation of the material, e.g., mechanically, such as by increasing vibration, shaking, stirring, or pressure; or chemically, such as by increasing temperature, increasing or decreasing the retention of air within the material, or by other mechanisms configured for increasing stress within the chemical composition to be delivered, such as by decreasing and/or increasing the surface area or volume of the substance and/or the container or its component parts, such as decreasing the radius of passageways along their length and/or including shearing elements therein. As indicated, heating may be applied to cause agitation and increase flowability, and/or cooling may be applied to decrease flowability to the desired amount, such as where once flow starts, it may proceed too rapidly and thus need to be slowed down subsequent to flow being initiated. Further, additives, such as powders, ingestible beads, or other volumeizers may be included so as to decrease friction and/or adhesion and increase flow. Particularly, increased shearing may be employed so as to thin the material and/or decrease its viscosity, and increase flow. Such increasing of shearing may be at a constant, increasing, or decreasing rate over time, which will decrease or increase viscosity over that time period, respectively. Thus, the increase and/or decrease in flow may be configured so as to be time dependent, such as based on the needs and/or desires of the user. Furthermore, one or more stressors can be implemented to increase yield and/or to initiate flow. The bubbles within the suspension or liquid may also be controlled with respect to their duration before popping or persistence, which may be for a short time, medium length of time, or longer time, such as from fractions of a second to many seconds and/or many minutes, dependent on the desire of the user. More particularly, in some instances, due to a pressure and/or temperature differential the more volatile gas may leave solution rapidly, so as to form a multitude of smaller bubbles, and in other instances, the volatile gas may leave solution more slowly so as to form a lesser number of bigger bubbles. For instance, when heated, the solution becomes more turbulent wherein the more volatile component may leave the solution faster due to an increase in temperature within the container and/or the composition, and likewise as the solution cools, flowability may decrease. In some instances, the bubbles don't set within the solution, but rather pop or otherwise dissolve resulting in defoaming. Hence, based on the configuration of the container and/or the materials employed therein, the bubbles may persist from a mere fraction of seconds to seconds, minutes, several minutes, an hour, hours, etc. Consequently, in some instances, the foam is not static, but rather changes as the matrix collapses, causing the bubbles to burst, which bursting may be configured so as to occur within the mouth of the user, such as subsequent to delivery, which sensation may be experienced as pleasurable. In particular instances, an agent configured to ensure the persistence and/or size of the bubbles within the matrix may be added. Additionally, in some embodiments, the agent does not generate a foam, but rather helps maintain the structure of the foam within the container, such as by increasing the persistence and/or the extension of time within the matrix and/or the colloid. Hence, the foaminess of the substance to be controlled in any sufficient manner, such as due to the amount of foaming agent, e.g., gas, to be introduced into the substance, such as by controlling the valves controlling the release and/or flow of the foaming agent and/or propellant introduced into the deliverable substance, or controlling the amount coming out of a flow passageway, so as to control the amount and/or rate of intermixing, or by controlling the size, shape, and/or contours of a passageway, such as to control the flow characteristics. For instance, foaminess may be controlled due to the configuration of the bladder, piston, and/or other pressurizing and/or temperature controlling mechanism and may be such that the container and/or its functioning is able to control the foaminess of the composition, such as with respect to the size or volume of bubbles, uniformity of bubbles, number of bubbles, length or duration of bubbles retained within the solution, and the like. In various instances, intermixing may not be controlled but flow out of the container may be controlled. It is to be noted that the flowable material may be a liquid, such as a beverage and/or other food item made to flow. In various instances, the deliverable material may be a flowable material, such as a medicine, a medicament, and the like. In certain instances, such as for the purpose of controlling one or more flow characteristics of the materials within the container, the material to be delivered may include a thickener and/or a stabilizer, emulsifier, a gelling agent, a surfactant, a food or flavor enhancer, and/or other additive may be added to the substance to be delivered. For instance, a thickener, such as those based on polysaccharides (e.g., starches, carbohydrates, vegetable gums, and/or pectins, e.g., grapefruit pectin, and the like), sugars (e.g., simple sugars, complex sugars, oligosaccharides, agar, carrageenan, and/or galactose), and/or various proteins, such as including collagen, egg whites, other amino acids, furcellaran, and gelatin. The thickening agent may also be a flavoring agent or may include flavorless, powdered starch, such as a fecula, such as one or more of arrowroot, cornstarch, katakuri-starch, potato-starch, sago, tapioca and/or their starch derivatives. Vegetable gums may also be used as a thickener, and may include alginin, guar gum, locust bean gum, glucomannan polysaccharide gum, and/or xanthan gum. One or more pre- or probiotics and/or esters may be provided. Preservatives, scents, perfumes, essences, sweeteners, gelatin, soy lecithin, sodium phosphate, sodium stearoyl lactylate, polysorbate 80, carbo carboxymethyl cellulose, polyglycerol esters, sorbitan esters, polyglycol esters, monoglycerides, acetylated monoglycerides, lactolated monoglycerides, anti-freeze components, and the like. Other coloring agents, flavoring agents, and/or vitamins or other food supplements may be included, such as Vitamins A, B, C, D, E, and/or K and the like. In some instances, a stabilizer, such as a matrix stabilizer configured for inhibiting separation of a suspension, emulsion, and/or a foam may be included. Other volumeizing agents may also be used. In particular instances, an effervescent or other material capable of generating a gas, such as within the container may be employed. For example, an acid and/or base pair may be employed or an alcohol, such as to produce a gas and a salt within the deliverable substance. Accordingly, a container, as herein described, having at least a first cavity or reservoir and an exit passageway and/or valve associated therewith, may be provided. In various instances, a portion of the cavity may retain a flowable and/or a foamable material, such as a liquid, e.g., a beverage; and in some instances, the cavity may include a second portion that may retain a foaming agent, such as a gas, e.g., a liquid soluble gas or a mixture of gasses. In certain instances, the container may include two separate reservoirs, such as one for storing the flowable and/or foamable material, and one for storing the foaming agent. In particular instances, the container may include three or more separate reservoirs, such as one for storing the flowable and/or foamable material, one for storing the foaming agent, and/or one for storing the propelling agent. At some point prior to dispensing, such as where the flowable and/or foamable material is a liquid beverage, the material may be intermixed with a liquid soluble gas in a manner sufficient to form a foam that may then be delivered directly to the mouth of a user for consumption, such as for drinking. Hence, in various instances, the container may be a beverage container that contains a liquid beverage as well as a foaming agent, such as a gas or mixture of gases, such that prior to or upon opening of the container, e.g., actuation of the valve, such as via a control valve, a solution of the liquid and gas, e.g., in a foamed state, is released or otherwise dispensed, such as directly to the mouth of the consumer, such as via a nozzle coupled to the container, in a manner that allows for the direct drinking of the beverage by the user. For instance, in a particular embodiment, the container along with the foamable material, e.g., liquid beverage, in combination with the foaming agent and/or a propelling agent, e.g., in gaseous form, forms a pressure gradient, such as between the two or more contents within the container and/or the ambient pressure outside of the container. In such an instance, as the valve is actuated the passageway connecting the outside environment with the reservoir is opened and the foamable liquid and the gaseous foaming agent and/or propellant exit the container, e.g., through the passageway, valve, and/or nozzle. In a manner such as this, the positive or negative pressure gradient may cause the gas to go into solution and/or gas already in solution to leave the solution, which entering and/or exiting of the gas into and/or out of solution causes bubbling, which bubbling is at such an amount and rate so as to cause the liquid beverage to foam, e.g., by gas bubbles being created and/or captured within a matrix of the liquid so as to form a matrix and/or colloid. The beverage once foamed may be delivered to the user, such as via the nozzle, for direct consumption, e.g., ingestion, by the user, such as for drinking or otherwise imbibing the foamed solution. In other instances, the canister may include a flowable material that may or may not be foamable, which material may be a gaseous, liquid, powdered, and/or semi-solid imbibable drink, food, food additive, supplement, and/or other additive that is capable of being propelled out of the reservoir of the container such as via the action of a propelling agent, which propelling agent may be a chemical agent and/or mechanical mechanism. For instance, where the propellant is a chemical agent, it may be such that it exerts a force, such as a positive pressure on an intermediary agent, such as a moveable platform, that when the valve is actuated and the passageway opened the platform moves towards the opening due to the positive pressure of the chemical propellant on the platform, causing the flowable material to be expulsed from the reservoir of the container. Likewise, where the propelling agent is a mechanical mechanism, such as an expandable bladder, the potential energy created by the expansion of the bladder, such as is due to the flowable material being inserted there into, acts like a positive force that causes the expulsion of the material contained within the bladder, such as when the actuating mechanism is actuated and the valve and adjoining passageway is opened. Hence, as detailed herein, a container for containing a beverage or food or food additive product may be provided where the container includes one or more of a top portion, a bottom portion and a sidewall portion, such as a sidewall between the top and the bottom portions. The sidewall may be configured of one piece and may be circular, or may have one or more corners and be triangular, square, or other such shape. The container may include a first cavity, such as within or otherwise defined by the top, bottom, and sidewall portions, where the first cavity is sized or otherwise configured to hold an ingestible beverage or food item, which in various instances, may be a foamable liquid, such as in a pre-, mid-, or post-foamed state. As described above, the container of the system may include a valve. The valve may be any device that is capable of opening and closing and may be coupled to and/or otherwise associated with an outlet portion of the container, and/or passageway associated therewith. In various instances, the valve may be operably connected to a translation mechanism, such as a feeder tube, and/or a mixing chamber and/or a passageway, such as a passageway passing through and opening out of a nozzle. The valve may be designed to regulate, control, and/or direct the flow of the flowable material, e.g., in fluid or fluidized form, through one or more elements of the system and/or out of the container. For instance, the valve may be any valve element, such as a mechanical and/or electronic element, that is configured for regulating the passage of the flowable material through one or more of the chambers and/or passageways disclosed herein. Hence, in various instances, a valve may be an element that functions for the purpose of regulating the opening, closing, and/or size of a passageway through which the flowable material and/or propellant translates or otherwise passes. For example, a suitable valve may be adapted for opening, closing, and/or partially opening and/or closing in a manner that allows or prevents admittance of a flow, such as of the flowable material, from one part of the vessel or passageway into another part and/or out from within the vessel. In some instances, the valve may be adapted for changing one or more characteristics of the flow of the material, e.g., fluid, through the system, such as by partially obstructing or dilating the diameter of the passageway and/or by allowing various fluid components of the system to intermix, which in turn affects the flow dynamics through the system and/or its components. More particularly, when a valve is opened, the flowable material is allowed to flow from contained portions of higher pressure or temperature within the system to portions of lower pressure temperature such as within or out from the system. A typical valve may have a proximal portion and a distal portion, such as where the proximal portion of the valve extends outward from the top of the container, and the distal portion of the valve extends inwards toward one or more cavities of the container. In such an instance, the valve may be a control valve that is controllable by a consumer, such as to regulate a flow of the ingestible material from the distal portion and out through the proximal portion of the valve. For instance, the valve may be a demand valve that includes an orifice of variable dimensions that extends there through, which orifice provides for communication from the exterior to the interior of the container. In certain instances, the orifice may be configured such that there resides therein a higher-pressure chamber and a lower and/or intermediate pressure chamber (which may be at, above, or below atmospheric pressure), which chambers may be separated by a diaphragm. In certain instances, the diaphragm may be operably connected to a piston, which piston, in turn, may be operably connected to a biased element, e.g., a biased spring element, such as a spring that is biased in the compressed, closed direction (in some instances, the spring may be biased in an expanded, open direction). In such an instance, when there is an increased pressure differential, such as a drop or a rise in pressure, between the higher and lower pressure chambers, such as when a user of the container inhales, such as through a proximal portion of an accompanying nozzle or valve associated therewith, the pressure in the lower and/or intermediate chamber drops, causing the biased spring to transition from a biased to a non-biased position, or vice versa, such as from a compressed to an expanded condition (in some instances, from an expanded to a compressed condition), thus displacing the piston and/or the diaphragm causing the orifice to open and the flowable material, contained under pressure within the container, to be expulsed therefrom and delivered to the mouth of the user, such as for drinking. In some instances, the piston may be adjustable, such as via a spring or ratcheting mechanism. Further, in some instances, the valve may be a pin or a needle valve, and in other instances the valve may be a butterfly valve, a ball valve, a duplex ball valve, a gate valve, a choke valve, a diaphragm valve, a pinch valve, a piston valve, a poppet valve, a thermal expansion valve, a plug valve, and the like or a combination of the same. As indicated, in various instances, the valve may be coupled with a nozzle, such as a nozzle having a distal portion configured for being coupled with the proximal portion of the container and/or associated valve, and a proximal portion configured for delivering the ingestible material directly to the user, e.g., to the mouth of the user, such as for direct ingestion, by the user, and/or application to an additional food product. Hence, the nozzle may be composed of one or more pieces or parts, such as a part that regulates the flow of the material through and out of the nozzle, and a part that engages in direct delivery to the consumer or additional food product. For instance, one part of the nozzle may include a flow and/or pressure regulator, and another part of the nozzle may include a user interface portion, such as a duckbill portion. For example, a nozzle for use in accordance with the devices disclosed herein may be any device that is capable of being coupled to and/or otherwise associated with a portion of the container and/or valve and/or a portion of an associated feeding mechanism, such as a delivery portion thereof, such as for delivering a flowable material to a user. In certain instances, the nozzle may further be designed to affect one or more characteristics of flow, such as the flow of the flowable material, e.g., in fluid form, out of the container, passageway, valve, and/or feeding mechanism. Accordingly, in certain instances, the nozzle may be operably coupled to one or both of a valve and/or a feeding mechanism, such as a translating element, e.g., a feeder tube. As indicated, a typical nozzle and/or a passageway there through may have any shape or size, and in various embodiments, may be configured to include a simple or complex orifice or passageway that is adapted for controlling the direction, speed, mass, pressure, flow, shape, and/or characteristics of the flowable material out of the canister, such as through the valve. In various instances, the nozzle may be configured to distribute a flowable material, e.g., a liquid or gas or suspension or semi-solid, etc., over an increased area, such as to break up the fluid into droplets so as to increase the surface area of the flowable material, and/or create a decreased impact force. In other instances, the nozzle may be configured to distribute the flowable material over a decreased area, such as to congregate the fluid into a stream or other flow so as to decrease the surface area of the flowable material, and/or create an increased impact force. In such instances, the nozzle may have one or more outlets, and can be a plain orifice, shaped orifice, surface impingement, pressure swirl, solid cone, or the like, such as where the fluid being dispensed is a single fluid. Accordingly, in certain instances, the nozzle may be a single or multiple fluid nozzle, such as where two or more fluids may be mixed internally or externally, or where the nozzle is a twin fluid nozzle, such as where the nozzle allows a gas, such as a foaming agent and/or propellant, to mix with the flowable and/or foamable material, such prior to or upon ejection from the nozzle. In certain instances, this contacting can cause shearing and therefore vaporization of the fluid, such as where a higher velocity fluid contacts a lower velocity fluid moving through the system; and in other instances, the contacting can cause foaming, such as where the two materials are traversing at slow or slower speeds and/or when there is a pressure change, e.g., a pressure increase or decrease, such as prior to ejection from the nozzle. In particular instances, the nozzle can be configured such that as the valve is opened, pressure is equalized throughout the flowable material thereby allowing a contained foaming agent to leave out of solution thereby causing the flowable material to foam. Hence, in certain instances, the nozzle may be configured so as to increase one or more of the kinetic energy, pressure, and/or the internal energy of the flowable material. The nozzle may be convergent (narrowing down from a wide diameter to a smaller diameter, e.g., in the direction of the flow), so as to accelerate flow speed or rate; divergent (expanding from a smaller diameter to a larger one, e.g., in the direction of the flow), so as to decelerate flow; or a mix of the two having a convergent section and a divergent section, e.g., sequentially, one right after the other. In various embodiments, the nozzle may be choked. In certain instances, the nozzle may be a simple spray nozzle (to disperse the flowable material such as into a spray), or may be a propelling nozzle, such as a jet, e.g., a fluid or laminar jet nozzle, and in some instances, the nozzle may be a magnetic nozzle. In various instances, the nozzle may include an atomizer and/or an aspirator portion, and thus, may be an atomizing and/or aspirating, e.g., an air aspirating, nozzle. For instance, in certain embodiments, the nozzle may have a cone shape and/or may be a siphon nozzle and/or may be configured for injecting air, another gas, liquid, or solid, etc. into the stream of flowable material as it exits the nozzle, which in some instances, may be employed so as to cause the flowable material to foam or defoam. In some instances, such as where the flowable and/or foamable material includes a solute or solid component, the nozzle may be configured such that the propellant and/or flowing and/or foaming agent moves from a higher, e.g., atomizing, pressure zone to a lower pressure zone upon mixing causing a vacuum as the flowable material exits the nozzle, which vacuum then pulls additional material through the passageway. In such instances, the nozzle may be configured to control the shape of the fluid, e.g., the stream, spray, or flow, as it exits the nozzle, and in one instance, may be a swirl nozzle, such as where the nozzle is configured for directing the flow tangentially through the nozzle causing it to vortex as it exits the nozzle, such as in a cone shape. In other instances, the flow may have a dispersed, condensed, foamed, rounded, or flat pattern, such as where the cross-section discharge is used to reshape one or more components of the flow of the flowable material. In some instances, the nozzle may be a rotary nozzle having a rotating outlet so as to form a hollow cone spray of the flowable material as it is released out of the container, such as where the rotational speed determines the size of the foam, spray, and/or droplets therein. In various instances, the nozzle and/or valve may be formed as a nebulizer. In various embodiments, the container, one or more of the flowable and/or foamable material, the foaming agent, the propellant, the feeder element, valve, and/or nozzle may be configured so as to control the characteristics of the flow and/or foam being ejected from the container. For instance, one or more of these components may be configured to modulate the liquid properties, temperature, specific gravity, viscosity, surface tension, and the like of the flowable material and, thereby, modulate the flow characteristics of the foamable and/or flowable material as it exits the container. In various embodiments, the container may include a translating mechanism, for instance, a feeding member, e.g., a feeder tube, having a proximal end that is coupled with the distal portion of the valve, or other outlet of the container, and a distal end that is in communication within an interior portion of the container, or a material therein. For instance, the feeding mechanism may be in communication with one or more lumens within the container, such as where the lumen includes one or more of a flowable and/or foaming material, and/or a foaming agent, and/or a propellant. In such an instance, such a lumen may be a reservoir. In various instances, the feeding mechanism is configured for translating one or more of the flowable material, foaming agent, and/or propellant from within one portion of the cavity and/or container to a second portion of the container or other component of the system, such as an additional lumen, passageway, valve, and/or nozzle. Hence, in one embodiment, the translating element may be configured so as to be positioned in a first cavity, wherein the translating element includes one portion associated with a bounding member of the container, such as to facilitate release of the contained material(s), and further includes a second portion positioned within a cavity or lumen of the container, such as proximate the bottom of the container or lumen. Accordingly, the feeder element may include an elongated body having a proximal interface and a distal interface, such as where the proximal interface is configured for communicating with the proximal or top portion of the container, such as via the distal portion of the passageway and/or valve; and where the distal interface is configured for communicating with an ingestible food item or beverage or medicine, e.g., foamable material, within the cavity, e.g., within a first and/or second lumen within the cavity. In various embodiments, the feeder and/or translating element may be configured or otherwise adapted for transferring the flowable material, e.g., ingestible beverage, from the lumen of the first cavity to the valve of the container, such as for delivery of the ingestible material to the user or food supplement, for example prior to or post foaming of the beverage. In such an instance, the translating element may have any shape and/or size and/or configuration so long as it is capable of receiving a flowable material therein and translating it from one portion within the container to a second portion within or outside of the container, such as to a release valve and/or delivery nozzle. For instance, the translating element may have an extended, tubular body that may be straight or curved or bent (or bendable) or tortuous, such as from end to end. The diameter of the lumen of the translating element may be of any suitable dimension and may be selected so as to achieve the desired flowing and/or foaming characteristics. As indicated above, the container may include one or both of a foaming agent and/or propelling mechanism that may be connected with one or more of the first cavity or a secondary and/or third cavity, such as a secondary or tertiary cavity within a valve, or a dispensing valve, of the container. In various instances, the foaming and/or propelling mechanism may be adapted to or otherwise configured for converting the ingestible beverage from a non-foamed state to a foamed state, and may be further configured for flowing, e.g., upon consumer control of a controllable dispensing mechanism, the ingestible food or beverage, e.g., in the foamed state, through the feeding mechanism to the controllable dispensing valve and out the proximal portion of the container and/or valve, e.g., out through the nozzle, if included. In certain embodiments, the foaming and propelling mechanism includes a foaming agent, e.g., the foaming and propelling mechanism may be the same as the foaming agent, and in other embodiments, they are distinct elements that may act in concert to foam and/or propel the beverage such as within and/or out of the container. Accordingly, in various embodiments, the container may include a first cavity containing, e.g., containing the foamable material, and may include a second cavity that may be operationally or otherwise connected with the first cavity, such as by a secondary valve, e.g., a controllable feeding valve, or by a feeder element. In such an instance, the first cavity may be configured for retaining and storing the foamable beverage, and the second cavity may be configured for retaining and/or storing the foaming and/or propelling mechanism, e.g., which may be a foaming agent, such as until the consumer activates one or both of the dispensing and/or feeder control valves. In such instances, a feeder valve may be included and configured so as to control the operation of the feeding mechanism, e.g., the feeding of the foaming agent into contact with the foamable material, such as within the first or second or even a third cavity. For instance, in certain embodiments, a third cavity, e.g., a mixing cavity, may also be present such as where the third cavity is operationally or otherwise coupled with one or both of the first and/or second cavities, such as where the first and/or second cavities feed directly into the third cavity, e.g., via a tertiary control valve, such as a tertiary mixing valve; or the first and/or second cavities may feed into the third cavity, such as for the purpose of mixing the foamable material with the foaming agent, by the operation of the feeder element. As indicated above, in various instances, such a third cavity may be part of, e.g., within the bounds of the container, and/or may be a part of a control, e.g., a dispensing valve, and/or part of a dispensing nozzle. It is to be understood that any of the valves and/or nozzles disclosed herein may be configured for regulating the flow, mixing, and/or foaminess of the flowable and/or mixable materials disclosed herein, such as with respect to controlling or otherwise regulating the rate, amount, quality, and/or other characteristics of the flow, mixing, and/or foaminess of the flowable and/or mixable materials. For instance, in various embodiments, the foaminess of the material to be delivered may be controlled by the amount of propellant, e.g., gas, being introduced into the delivery chamber. Such valves may be positioned anywhere within the bounds of the container or a component thereof such as between the boundaries of the various compartments or within one or more of the translating elements and/or nozzles. In view of the different configurations of the container and/or the cavities therein, the translating member, e.g., feeder element, may be configured so as to act as a conduit directing the flow of the various flowable materials held within one or more components of the system. For instance, the translating member or feeder tube may be composed of one or more elements that are configurable for or otherwise adapted for directing a flow of one or more of the flowable materials, e.g., the one or more foamable materials and/or one or more foaming agents and/or propellants, that are held or otherwise stored within the one or more cavities of the container. One or more control valves may be included as part of the feeder element so as to further control and direct the flow of the flowable materials through the feeder element. Hence, the translating element may include a portion that contacts the flowable and/or foamable material and/or may include a portion that contacts the floawable foaming agent and/or propellant, and may include another portion that contacts a top portion of the container, such as via a dispensing valve and/or dispensing nozzle, so as to facilitate the flow and/or mixing of the flowable materials within and/or out of the container. In various embodiments, the translating member translates the one or more flowable materials through its componentry via the action of a propellant, actuation of one or more of the control valves detailed herein, and/or the creation of a vacuum, such as that created by a user sucking or blowing into one or more of a user contactable portion of a dispensing nozzle, dispensing valve, and/or proximal portion of the feeder element directly. Accordingly, a translating member of the disclosure may have any suitable configuration that may be useful in translating the flowable materials through the system such as for one or both of mixing and/or direct dispensing to the user, e.g., directly to the mouth of the user for ingestion, such as for imbibing or ingesting, or to a supplementary food item. In various instances, the translating member is configured for functioning regardless of the orientation of the canister, such as regardless of how the device is manipulated and/or used by the consumer in ingesting, e.g., drinking, the foamable material stored therein. Hence, the translating member may be composed of one or more feeder tube(s), as disclosed herein, which may be configured to assist in directing the flow of the mixable elements, assisting in mixing the elements, and for delivering the mixture to a user, such as in a flowable, foamed state, e.g. via a control valve, such as a syphon valve, or nozzle. Hence, in various embodiments, the container may include a liquid or a mixture of liquids, e.g., in a drinkable and/or foamable beverage form, and/or may include a liquid soluble gas or a mixture of gasses that may be configured as one or both of a foaming and/or a propelling agent, wherein upon contact of the liquid with the soluble gas a solution may be formed, such as a foamable solution, that may be delivered to a user, such as for drinking or otherwise ingestion, e.g. directly from the container, such as through a suitably formed delivery nozzle. As indicated, the liquid and/or liquid soluble gas may be retained within the container in the same or different compartments, can be intermixed in the same or different compartments, and/or can be translated throughout the system and/or to a user, such as through one or more suitably formed translating elements, e.g., feeder tubes, and/or one or more control valves associated therewith. In some embodiments, the container includes a first compartment for retaining both the food or beverage item and the gas, such as where the food item and/or beverage is a liquid or semi liquid or slurry and the gas are separated from one another in the canister, such as via a pressure gradient between the two, e.g., under increased pressure; and in some embodiments, the container includes a first compartment for retaining the food or beverage item and a second compartment for retaining the gas, such as where the flowable material and the gas are separated from one another in the container by a dividing wall but may be configured for communicating with one another, such as for the purpose of intermixing, such as via one or more valves, e.g., a feeding, mixing, and/or dispensing valve, and/or one or more translating elements, and/or one or more nozzle elements. In such an instance, the food or beverage item may be an ingestible item, and the gas may be at least a partially liquid soluble gas and the feeder element(s) and/or release valve(s) may be configured for intermixing the ingestible material and the soluble gas, such as to produce a foamed material, such as on release, e.g., actuation of a release mechanism of the container. As indicated, in various embodiments, the referenced second compartment may be configured for receiving an interchangeable gas reservoir, such as a cartridge containing a foaming member therein, e.g., a gas cartridge, which cartridge may be inserted into the container for discharging, and may be replaceable once the cartridge has been discharged, such as through activation of a release mechanism of the container or a component associated with the container. In a further aspect, methods for producing and/or delivering a flowable and/or foamable material is provided, such as where the foamable material is comprised of a fluid, such as a liquid or semi-fluid beverage or food item or medicine, that may be consumed, for instance, in drinkable, swallowable, and/or eatable form, or where the foamable material is at least partially prefoamed but subjected to conditions that function to increase or decrease the foaminess of the material, such as prior to delivery from a storage and/or delivery canister. The methods may include one or more steps, such as a step that includes actuating a delivery mechanism of the canister, which actuation functions to eject the flowable, foamable, and/or foamed material out of the canister. For example, the actuation of the delivery mechanism may involve the actuation of one or more of a nozzle, a valve, and/or a translation element associated with a canister configured for retaining the flowable and/or foamable material, such as where the actuation may involve activating a control element, such as by depressing or pulling a button, turning a nozzle or screw or knob, pulling a trigger, squeezing a depressible element, flipping a switch, and the like. In some instances, one or more of the components contained within the container may be under pressure, and such actuation may function to mix the contained components and/or release one or more of the contained components, such as after they have been mixed together, such as to produce at least a partially foamed material. In particular, the recited actuation may involve one or more of actuating the release of one flowable component into another flowable component contained within the container, such as by the opening of one or more valves; and/or the translating of one or more of the components such that they come into contact with one another, such as within one or more chambers within the container, valves, and/or nozzles associated therewith, such as prior to or in conjunction with actuation of the delivery mechanism and/or release from the container. In some instances, the actuation may involve an electronic control mechanism, for instance involving a control circuit that may be in a wired or wireless configuration, such as part of a processor on a microchip, such that by electronic activation of the control circuit the delivery mechanism may be activated and the components of the container may be mixed and/or released, such as for delivery of the foamable material to a user. In view of the above, in various embodiments, the container may include a bounding member, which bounding member bounds a cavity suitable for retaining a flowable and/or foamable material, and the method includes the insertion of the flowable and/or foamable material into the cavity of the container, such as by a first fill valve. For instance, the bounding member may include a proximal portion and a distal portion, which proximal and distal portions are separated by an extended portion, such as where together the proximal, extended, and distal portions are configured so as to bound the cavity, and wherein in certain embodiments, the bounding member includes at least the first fill valve. The cavity may be configured to both retain the flowable material that may be configured to promote the foaming and/or propelling of the material from the container, such as through activation of a control mechanism of the container. Accordingly, the container may include one or more valves, such as a release or delivery valve and/or an injection or fill valve, such as where the flowable material may be added in to the container through the injection or fill valve, and released from the container through the release or delivery valve. In certain embodiments, the container 1 may include a safety mechanism so as to prevent unintentional activation of the container and/or its components, so as to prevent unwanted mixing and/or delivery of the contained material(s), such as while in packaging and/or in transit. For instance, the container may include a tamper evident seal, locking ring, and/or the like. Further, in various instances, the container may include a foaming and/or propelling mechanism, which in some embodiments may be a plurality of different elements, and in other instances may be the same element. For example, in certain instances, the foaming agent and/or propellant may be a chemical agent. Accordingly, in such an instance, the method may include inserting the foaming and/or propelling agent into the container through one or more auxiliary fill or injection valves, e.g., through the first or a secondary fill valve. It is to be noted that in some instances, the foamable material and foaming and/or propelling agent may be inserted into and retained within the same compartment of the container, such as where the two components are phase separated within the same chamber of the container. In some instances, the foaming agent and/or propellant may be an electrical element or electro-mechanical element and the method may involve activating the element, such as by generating an electrical signal and/or impulse, such as by actuating a remote control mechanism, which electronic signal and/or impulse is received by the electric or mechanical element, which upon receipt activates the foaming and/or propelling mechanism that functions to foam and/or build pressure within the container, which increase in pressure may then be employed to expel the flowable material from the container, such as through the release valve. In various instances, the electrical element includes a power source, such as a battery. In various embodiments, the foaming and/or propelling mechanism(s) may be a mechanical element, such as a biasing and/or spring element, and the method may include releasing stored energy so as to foam and/or translating the foamed material out of the container. For instance, in certain embodiments, the container may include an elastic member, such as a bladder, which bladder may be a stretchable or expandable member and may be self healing, such that when the flowable material is inserted in through the container, as described above, and/or into the bladder, the bladder expands to accommodate the flowable material, however, to do so the bladder expands creating a reserve of potential energy. Such a bladder may be made of any suitable material that is capable of receiving a material therein and reversibly expanding in response thereto, such as by being deformed from a first, non-expanded condition to a second, expanded condition and thereby storing potential energy therein. Such a material, for instance, may be an elastic material. The bladder may be connected to the release valve, and the method may include activating the release valve such that as the valve is opened, the potential energy stored via the expansion of the bladder is released thereby expelling the flowable material. In such an instance, the foamable material may be inserted into the container in a foamed state or a prefoamed state, and the activating of the release valve may simply act to release the foamed material, or may further act to convert the prefoamed material into a foamed material. For instance, in such instances, the release valve and/or container may be associated with a nozzle element, which nozzle element may be adapted to control the flow of the material out through the container and/or may be configured to foam the material as it is delivered through the release valve and/or nozzle to the user. In certain instances, the release valve and/or nozzle may be associated with a translation element that is itself in communication with a reservoir, such as a reservoir containing a foaming and/or propelling agent that upon opening of the release valve and/or activation of the nozzle, the foaming and/or propelling agent is translated through the translation element to the valve and/or nozzle and thereby allowed to mix with the flowable material so as to foam and/or propel the flowable material as it exits the container. In a particular embodiment, the container may include a computing device, such as a computing device that is configured to control the operation of one or more components of the container, as disclosed herein. In such an instance, the container may include one or more sensing elements coupled to the computing device, and the method may include generating sensor data, such as data that may be sensed and/or gathered from an environment that is internal or external to the computing device, and may further include receiving such data, such as by at least one sensor or other associated electronic data input device coupled with the computing device. The data received may represent one or more attributes related to the foamable and/or flowable material, the foaming agent, the propellant, the foamed material, an internal environment condition and/or an external environmental condition (such as temperature, pressure, a characteristic of the user, etc.). In certain instances, the computing device, e.g., micro processor, may further include one or more of: at least one wireless receiver and/or transmitter, for communicating with a wireless network and/or wireless control device. In various instances, the container may include an interactive display, e.g., an interactive, touch screen display, electronically coupled to the internal processor. The method, therefore, may further include one or more of receiving of sensed data, e.g., by the internal or external controller, the data representing one or more internal or external characteristics; and/or processing, e.g., by the internal processor of the computing device, such as in accordance with a desired foaminess and/or flow rate of the foamed material. In some particular embodiments, the method may also include generating user interface, such as a graphical user interface, for display on the interactive display of the computing device such that the user may select an option as an option related to the flow rate or amount of foaminess of the material to be ingested by the user. While various embodiments of the present invention have been described above, it should be understood that they have been presented by way of example only, and not limitation. It will be apparent to persons skilled in the relevant art that various changes in form and detail can be made therein without departing from the spirit and scope of the invention. Thus, the breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents. | <SOH> BACKGROUND <EOH>Foamable materials are known in the art. For instance, whipped cream is known to be stored in a canister under pressure such that when shaken and released, the whipped cream is expulsed from the canister, such as when being applied to a food item, such as a dessert. The addition of this whipped cream to the food item is experienced by some as enhancing the flavor of the underlying food item to which it is applied, thereby making the overall consumption experience more pleasurable. As such, whipped cream has been employed in the art as a food additive and is not formulated for direct consumption, that is, whipped cream is not meant to be consumed by itself directly from the canister. Although whipped cream can be prepared by hand and be stored in any suitable manner, such as in a flexible confectioner's decorating pastry bag, often times, such as when produced for convenient mass consumption, for instance, in a ready-to-use formulation, whipped cream may be stored under pressure in a rigid canister that is capable of maintaining its contents under such pressure. For example, prior to its placement in the dispensing container, the cream is whipped in such a manner that gas bubbles are mixed within a matrix of the cream so as to produce a colloid material that in some instances may be double or triple its volume prior to being whipped and/or dispensed. Typically, in order to form a material having such a colloid consistency, the material must be capable of forming a matrix wherein bubbles may be trapped as the material is whipped, such as prior to storage within or dispensing from the canister. Traditionally, therefore, in order to be considered a foamable material, the material was assumed to need to be comprised of fat, such as at least 30% fat, such as butterfat, having a network of fat droplets wherein bubbles may be captured so as to form the colloid, such as prior to dispensing. Additionally, foamable materials, such as whipped cream, had to be stored under pressure in combination with a propellant, such as an aerosol, in a canister adapted for being able to maintain its contents under such pressures, and having a minimally configured release valve, such that in order to be dispensed the material within the canister must be inverted prior to operating the release valve. Accordingly, when properly used the canister would be inverted, the valve depressed, and the pressurized contents would then be released. Such minimally configured release valves are problematic because they allow for incorrect operation such that if operated without inversion the propellant is rapidly depleted rendering the contents inaccessible and unusable. These propellants are stored under pressure in the canister and serve two functions. First it keeps the gas suspended within the colloidal cream formulation. Secondly, it served as a propellant forcing the whipped cream out of the canister when the release valve was triggered. Typically, there is a gas-tight seal between the canister and the release valve that assists in maintaining the stored whipped cream under pressure. However, with use and/or if the seal of the canister is compromised in any way, which often happens with use and/or time, the compressed gas may leave the cream formulation, and along with the propellant, e.g., nitrous oxide, will leak out or otherwise be released from the canister resulting in the foamed material becoming defoamed making it unpleasant and unsuitable for its intended use as a food additive, if it can be released from the container at all. Propellants have also been used in conjunction with the delivery of non-foamable materials, so as to make them flowable. For instance, Cheese Whiz is a secondary food item that has been configured to be stored under pressure and delivered in a flowable manner as a topping for a secondary food item. For example, Cheese Whiz includes a cheese flavored material that is formulated in such a manner that in a suitably configured delivery canister, the cheese-like material may be delivered in a flowable form to a secondary food substrate such as a cracker, a vegetable, bread, and the like. In such an instance, the canister may include a cavity having two compartments. A first compartment containing the cheese material, and a second compartment containing a gas, where the two compartments are separated from one another by a moveable platform, so as to form a piston-like configuration. In this instance, the gas exerts a positive pressure on the platform such that when a delivery nozzle is tilted, a passageway is opened allowing the piston to move and push the cheese-like material out of the nozzle and on to the food substrate. In most of these instances, the cream, cheese, and other such flowable and dispensable materials have been formulated for delivery of the food topping to a secondary food item, such as prior to consumption of that secondary food item by the consumer. Hence, the dispensing mechanisms presently known are adapted for delivery to a secondary food item, and not configured for direct delivery to the mouth of the user. There are, however, those who have tried to employ such existing dispensing mechanisms for delivery of the food topping directly to the mouth, but with less than satisfactory results. Particularly, there are, for instance, a multiplicity of resultant problems given the configuration and mechanics of the delivery mechanisms and their intended use. For example, the attendant nozzles are not shaped nor angled for delivery to the mouth, the canister's themselves have not been ergonomically designed for such delivery, and functional operation has not be adapted to account for such usage. More particularly, users who insist on direct delivery of such secondary food toppings directly to their mouth, are required to hold the canister in an inverted position above the head so that the bottom of the container and its contents are above the nozzle; otherwise, the propellant will escape and/or delivery cannot be commenced. However, this requires the arm be raised and the neck to be tilted back and/or crimped prior to usage. Such bodily contortions are uncomfortable, cannot be engaged while mobile, such as when exercising, block one's field of vision, and are all around unpleasant. Further, in such instances, the canisters themselves become unwieldy, lack grip, and are hard to operate. Moreover, if the angle of operation is not appropriately aligned within the design dimensions of the canister, spluttering and/or resultant gas leakage can cause frustration, embarrassment, and/or lead to consequential physical damage. These results, therefore, make such usage dangerous, socially unacceptable, and open to ridicule. Specifically, fast food consumption often takes place while driving. However, to consume such flowable materials of the prior art while driving requires a tilted head position that is difficult to achieve, if possible at all, and further requires one to take his or her eyes off the road, e.g., looking upwards and not forwards, and is generally incompatible with such usage. Additionally, the canister itself, as well as the user's hand, blocks the user's field of vision. Further, the operation of the existing dispensing mechanisms requires dexterous manipulations of the actuator that interferes with concentration required for driving, and in the inverted dispensing position, the canister can collide with the headliner and/or other structures of the vehicle making driving dangerous. Similar problems can be experienced while walking, running, cycling, or participating in other forms of exercise, as well as when watching TV and/or engaging in conversation. For instance, head tilting is often times incompatible with participating in sporting events, following high-paced action, such as on a TV screen, interrupts eye contact often required for effective communication, and is a distracting gesture that may adversely affect others such as by impeding their field of view in a manner that may be considered rude and/or socially unacceptable. As seen above, whipped cream, cheese-whiz and other such flowable food topping mechanisms have focused on the application of the material to secondary food items. Presently, there are no systems that have been specifically developed and well adapted for direct delivery to the mouth of consumer of food products and beverages that have been precisely formulated for optimal taste and texture as an imbibable food substance. Accordingly, as foamed and flowable liquid, beverage, and other food materials are experienced by some to be pleasant to the taste, there is a need in the art for the storage, production, and delivery of a wider range of such materials, which can be formulated for direct delivery to and consumption by the mouth of the consumer. It has now been determined that a wide variety of directly consumable materials may be foamed by a wide variety of foaming agents, which are safe for consumption, without being overly limited by the fat content of the material to be foamed. Additionally, it has been determined that a wide array of liquids, beverages, and other food materials may be prepared so as to be flowably contained within a specially designed container for automatic delivery to a user. There is a need, therefore, for an apparatus, system, and/or delivery method that allows all such foamable and/or flowable materials to be stored in greater density, such as in a prefoamed state, and delivered direct to the consumer, such as in a manner that ensures that the foamed composition is optimally foamed substantially at the same time as delivery. This will not only allow for a greater quantity of material to be stored in a given delivery apparatus, but also ensure that the right amount of foaming agent is mixed with the right amount of foamable material so as to evoke the optimal taste experience upon delivery and consequent consumption by the consumer. Further, there is a need for an apparatus, system, and/or delivery method that allows ingestible materials to be stored in a manner that will allow them to automatically be delivered directly to the consumer, such as in a manner that ensures that the flowable composition is optimally delivered. The devices, methods, and systems of this present disclosure aim at meeting one or more of these and other related needs, while maximizing the individual's choice and enjoyment in consumable products. | <SOH> SUMMARY OF THE DISCLOSURE <EOH>The present disclosure, in its many aspects, describes devices, systems, and methods for the production and/or delivery of a foamable and/or flowable material for consumption, such as by direct application to a consumer, such as directly to the mouth of the consumer. Accordingly, in one aspect, a device and/or system for converting a material from a first, unfoamed state to a second, foamed state is provided. In another aspect, a device and/or system for converting a material from a first, non or semi-flowable state to a second, flowable state is provided. In some instances, the device and/or system may be configured for assisting delivery of a foamable and/or flowable material to a user. In another aspect, a method is provided wherein the method is directed to converting a foamable and/or flowable material from a first, non-foamed and/or semi- or non-flowable state, to a second foamed and/or flowable state, and/or for delivering the foamable and flowable material from within the container directly to the mouth of the user. In a further aspect, a foamed and/or flowable consumable product is provided, wherein the foamed and/or flowable material is derived from a material and/or produced by a process that was not heretofore known to be foamable and/or flowable in the manner presented herein. Accordingly, in additional aspects, novel devices and methods for producing them and/or using them to produce foamed and/or flowable materials, such as for consumption, are provided. Systems including such materials, devices, and methods are also provided. For instance, in a first aspect, a device for foaming, flowing, and/or containing a foamed and/or flowable material is provided. In various instances, the device includes a container. Any suitable container may be used so long as it is capable of retaining a material, such as a consumable or otherwise ingestible material, which material may be retained under pressure, such as where the pressure is added to the material, or a container retaining the material, so as to convert it from one state into another, such as from a non-foamed to a foamed state, and/or from a non- or semi-flowable to a flowable state. The container can be any suitable shape and of any suitable size, such as circular, triangular, square, rectangular, round, spherical, cylindrical, cubical, tubular, and/or a mixture of the above, and the like. For example, in one particular instance, the container may have a body, such as an extended and/or tubular body having a proximal portion and a distal portion that are separated from one another by an elongated body portion, which extended and tubular body may enclose or otherwise bound one or more cavities, such as a cavity configured for containing the foamed and/or flowable or to be foamed and flowable material and/or one or more foaming and/or propelling agents. Accordingly, in certain instances, the extended and/or tubular body is configured such that it at least partially bounds a cavity, such as a cavity that is adapted for retaining the material in one or more of its non-foamed and/or non-flowable to a foamed and/or flowable state. In such an instance, the cavity may also be bounded by one or more of a proximal and/or distal end portion. In particular, in some instances, the container is box-like and includes an elongated body formed from a plurality of opposed surfaces, such as opposed front and back surfaces, as well as left and right side surfaces, such as where the front and back surfaces are separated one from the other by the opposed side surfaces. Likewise, the box-like container may additionally include opposed top and bottom surfaces. Accordingly, in such an instance, the elongated body may include one or both of a top member and/or a bottom member, e.g., transverse to the opposed bounding surfaces, for closing a top and/or bottom portion of the elongated body, and thereby enclosing the cavity. In various other instances, the extended body may include one or more walls that are configured in a tubular shape, such as where the extended body includes a single wall that is curved so as to bound a cavity, such as where the wall includes a plurality of surfaces, such as an interior surface facing the cavity, and an outer surface opposite the interior surface. In such an instance, the wall forms a bounding member for the cavity, and in various embodiments may include one or both of a top member and/or a bottom member, e.g., transverse to the bounding wall, for closing a top and/or bottom portion of the elongated body, and thereby enclosing the cavity. In some instances, the top and/or bottom members may be removable and/or replaceable. In various instances, the bounding surfaces and/or walls may include one or more angles or curves so as to give the extended body an angled or curved configuration, thereby increasing or decreasing the interior surface area so as to better modulate the foaming and/or flowing action of the container. Regardless of the configuration, the extended body member may be configured for bounding a cavity, such as a cavity including one or more interior portions, e.g., lumens or compartments, wherein the interior surface of the extended body forms a bounding member for the lumen(s) and/or compartment(s), which lumen(s) or compartment(s) may be configured for retaining one or more of a material to be foamed, e.g., in a prefoamed state, a semi-foamed or foamed material, and/or a flowable material, e.g., in a pre-flowable, a semi-flowable or flowable state, a foaming agent, and/or a propellant. Accordingly, in various instances, a container is provided wherein the container includes a cavity having a foamable and/or flowable material retained therein, and the cavity may additionally include one or more of a foaming agent and/or a propellant and/or be connected to another cavity containing the same. In other instances, the cavity can be subdivided, e.g., by one or more partitions or dividers, into compartments or sub-compartments, such as where each sub-compartment has its own lumen. For instance, the container may have a cavity that is further divided into first, second, third, fourth, fifth, sixth, etc., lumens. For example, in some embodiments, a container is provided wherein the container includes at least a cavity with at least a first lumen and a second lumen, such as where the first lumen is configured for retaining the foamable and/or flowable material, and the second lumen is configured for retaining a foaming agent and/or propellant, such as where the first and second lumen are separate from one another. In other embodiments, a third and/or fourth lumen may be provided, such as where the third and/or fourth lumen includes a propellant and/or a mixing chamber. In various instances, the one or more lumens may include one or more materials to be mixed and/or delivered when leaving the container, and may further include one or more of a foaming agent and a propellant. Particularly, in various embodiments, the container includes a plurality of container portions, such as where the container includes a first container portion, such as for retaining the foamable material, and a second container portion, such as for retaining a foaming and/or propelling agent, where the first and second container portions are separated one from the other by one or more divider portions. In various of such instances, the first container portion may not be in communication with the second container portion, such as where the container includes an elastic member, such as a non-movable wall, a stretchable bladder, or a moveable and/or flexible diaphragm, that divides the lumen into two sections, for instance, a section containing the material to be expelled from the container, and a section containing a foaming agent and/or propellant, such as a gas. For example, the second container portion may include a wall, elastic member, or diaphragm that is substantially impermeable to the foaming agent and/or propellant, and thus may be under a positive pressure caused by the forces the gas, e.g., of the foaming and/or propelling agent exerts against the bladder and/or diaphragm. In such an instance, when the container or a passageway there through is opened a volume of the contained material under pressure may escape through the opening. Correspondingly, as the gas expands against a bladder it causes the lumen containing the material to be compressed, or where a diaphragm is included, it causes the diaphragm to be retracted, thereby reducing the volume of the lumen and allowing the contents within the cavity to be expelled. However, in various other instances, the plurality of container portions may be in communication with one another, such as by permeable interfaces, walls, and/or one or more conduits. For instance, one or more passageways and/or valves may be provided in a bounding member of the container portions, such as a wall or divider, so as to allow communication between various of the different compartments and/or the materials stored therein. Additionally, in various embodiments, one or more conduits may be present whereby the plurality of compartments or the materials within the compartments are fed into an additional compartment, such as a mixing chamber, which may or may not be part of the container, wherein in the additional compartment the two or more materials are allowed to intermix, such as to form a foamed and/or flowable material therein. For example, in one embodiment, a container is provided wherein the container includes at least a first compartment, having a lumen containing a material to be delivered, such as a foamable and/or flowable material, and a second compartment, having a lumen containing a foaming agent and/or propellant, such as where the first compartment is separated from the second compartment by a divider, wherein the divider includes a conduit or passageway that is configured for allowing and/or controlling the flow of the contents from one compartment into another compartment. In such an instance, the conduit can be an opening, such as an opening fitted with a valve, e.g., a controllable valve, whereby the opening connects the first and second compartments thereby allowing flow between the two, and the valve may further be configured for controlling the rate of that flow. The valve may have an orifice of variable dimensions, from fully open to fully closed, and variations in between, which opening and closing may be controlled by an actuator. More particularly, the actuator may be configured to control the opening and closing of the orifice of a portion of the conduit and thereby control the flow through that passageway. For instance, controlling the flow of the foaming agent to the foamable material, such as from one compartment to the other, so as to convert the foamable material from a nonfoamed state to a foamed state and/or to expel the flowable material from the lumen of the container, and/or controlling the flow of the propelling agent to the flowable material, such as from one compartment to the other, so as to convert a non or semi-flowable material from a first state to a flowable state and/or to expel the flowable material from the lumen of the container. In other embodiments, the conduit may be a plurality of conduits, such as a first conduit that is interconnected with a first chamber, and a second conduit that is interconnected with a second chamber, wherein the two conduits may themselves be interconnected with a third chamber, which third chamber may be present within the container and/or a dispensing mechanism associated therewith, whereby the first and second conduits may feed into the third chamber, e.g., a mixing chamber, thereby allowing the contents of the first and second chambers to intermix, for instance, in the third chamber, such as prior to dispensing, such as through a third conduit or other passageway. In certain of these instances, one or more of these chambers may be configured for receiving a removable storage chamber unit, such as a cartridge, for instance, a cartridge containing one or more of a foamable and/or flowable material and/or a foaming agent and/or propellant. For example, in various instances, the container may be configured to include an auxiliary chamber unit or cartridge having a foaming and/or propelling agent therein, and thus may be configured as a foaming and/or propelling member, such as where the foaming and/or propelling agent is a gas, such as nitrous oxide, nitrogen, oxygen, carbon dioxide, a noble gas, e.g., argon, butane, methane, and the like. Accordingly, once the foaming and/or propelling member is coupled with, e.g., inserted into the container, and a valve associated with one or more of the auxiliary chamber and the container is opened, the foaming agent, which may be configured as a propellant, may be released into the chamber containing the foamable material so as to intermix therewith and thereby convert the material from a non-foamed to a pre-foamed or foamed state and/or from a non or semi-flowable to a flowable state. Accordingly, in some instances, the container may include at least a first chamber for retaining a material to be foamed and/or flowably delivered, and may further include a separate compartment containing a foaming agent and/or propellant, where the separate compartment includes an actuator mechanism that is configured for releasing the foaming agent and/or propellant into the first chamber for effectuating foaming and/or release of the material within and/or from the container. The material to be delivered may be any material, such as a flowable and/or a foamable, pre-foamed, and/or foamed material. In some instances, the material may be a material capable of being foamed, such as being converted from a first, non-foamed state, into a second foamed state, and in some instances, may further be converted into one or more additional foamed states. In other instances, the material may be a material capable of being flowed, such as being converted from a first, non or semi-flowable state, into a second flowable state. For instance, in various embodiments, the material may be an ingestible material, such as a drink or food item, condiment, topping, additive, and the like, that is configured to be controllably delivered to a user of the container, such as by the operation of an actuator, for instance, by use with one or more hands of the consumer. In various instances, the deliverable material may be a flowable material, such as a medicine, a medicament, and the like. A suitable foaming agent may be any agent that is capable of converting the non-foamed material into a pre-foamed or foamed material or super-foamed material, such as when applied to or otherwise mixed with the non-foamed material. For example, a foaming agent may be a gas, liquid, solid, powder, suspension, and/or catalyst that when introduced to and/or mixed with the foamable material converts it from being substantially non-foamed into being pre-foamed or foamed and/or may convert it into a super foamed state, such as where the solution includes an increased number, density, or area of bubbles, and/or bubbles that last for a relatively longer time period within the matrix before popping or leaving the solution. A suitable propelling agent may be any one or more agents that is capable of causing the flow of a material, such as from within to outside of the container and/or a compartment thereof, and may be capable of converting a non or semi-flowable material into a flowable material, such as when applied to or otherwise mixed with the material. For example, a propellant may be any agent capable of being added to the material, e.g., the foamable and/or foamed material, and thereby facilitating the expulsion of the material from a lumen of the container. In certain instances, a plurality of agents may be employed that when mixed together form a propelling and/or foaming agent. In various instances, a foaming and/or propelling member may be included, such as where the foaming and/or propelling member may be configured as a mechanical mechanism and/or may be a chemical catalyst, such as a gas, a liquid, a suspension, a pill, a powder, and/or the like, and may further be configured for causing the movement and/or foaming and/or delivery of the ingestible material to the consumer, such as in a controlled manner. For instance, the propelling member may be configured for effectuating the movement of a foaming and/or propelling agent so as to contact and/or be at least partially subsumed within the consumable material, and/or the propelling member may be configured for effectuating the movement of the foamed and/or flowable material out of one or more compartments of the container and/or out of the container itself. Particularly, the foaming and/or propelling member may be configured for effectuating the movement of a foaming and/or propelling agent into the chamber containing the ingestible material and/or into another container portion, e.g., a mixing chamber, into which the foaming and/or flowable material may be added, such as in combination with the foaming and/or propelling agent. In more particular instances, the propelling member may be an additional material added to one or more of the chambers, such as in addition to one or more of the foaming and/or flowable material and/or foaming agent and/or propellant. For example, the foaming and/or propelling member may be any agent that is capable of creating one or more pressure and/or temperature gradients within and/or between one or more chambers or cavities of the container, which pressure gradient(s) can be employed in a manner sufficient to foam the foamable material and/or eject the foamable and/or flowable material out of the container, such as when the dispensing member, e.g., actuator, is actuated. Hence, in various embodiments, the one or more chambers of the container, e.g., the two or three chambers, along with the one or more control valves controlling communication between the chambers, may be configured for allowing and/or regulating the extent and/or rate of intermixing of the foamable and/or flowable material with the foaming agent and/or propelling agent, such as within a mixing region of the container, so as to ensure the production of a flowable and consumable end product having the optimal proportion of foamable and/or flowable material to foaming agent/propellant such that the resulting foamed and/or flowable material has the desired amount of foaminess and/or flowability. This intermixing may be performed prior to insertion of the foamed and/or flowable material into the container, after insertion within the container, such as within a single, e.g., main, chamber within the container, and/or within an auxiliary chamber, such as a mixing chamber, within or associated with the container, external to the container, and/or within a dispensing member of the container. As indicated above, where the foaming and/or flowing process takes place within the container, the foamable and/or flowable material may be within the same chamber or may be separated, such as by a partition, from the foaming agent and/or propellant, but in such a manner that the materials are capable of being intermixed, such as in a controlled fashion, upon an activation event, so as to produce the foamed and/or flowable material, and/or are capable of being expulsed out of the container. Accordingly, a conduit may be provided for allowing one or more of the materials within the container to be transported there through. Hence, in various instances, the conduit may include a control mechanism, such as a control valve, for regulating flow through the conduit, and thus, the conduit may be a control release conduit. Particularly, in various instances, a controlled release conduit may be included in one or more bounding members or partitions of the container so as to regulate the rate and extent of flow and/or intermixing of the various materials within the container. In such instances, the controlled release conduit and the container itself may be configured in such a manner so as to accommodate the physical characteristics of the foaming and/or propelling agent being employed as well as to accommodate the foaming and/or propelling action. In various instances, dependent on the identity of the foaming and/or propelling agent and/or the configuration of the container and its portions, the conduit, such as a controlled release conduit, may have any configuration suitable to creating a pressure and/or temperature differential between the inside of the container and the outside of the container and/or between various different chambers within or otherwise associated with the container, such as between the chamber containing the foamable and/or flowable material and the chamber(s) containing the foaming and/or propelling agent(s). For instance, in various embodiments, a controlled release conduit may be included where the controlled release conduit may have a mechanical configuration so as to operate mechanically. For example, the controlled release conduit may be configured as and/or otherwise be associated with a slow or quick release valve, a hand or screw pump, a screw and plate, a spring release plate, an elastic member, a diaphragm, a tear-able or puncture-able membrane, a lever, one or more of the same including a motor, a compressor, a pyrotechnic composition, piezo-electric component, or other mechanical and/or electrical element capable of increasing the pressure in at least one conduit or chamber, such as by exerting a force against the contents of that chamber, and the like. In such an instance, in certain embodiments, the foaming and/or propelling mechanism and controlled release conduit may be one in the same. In various other embodiments, the controlled release conduit may have or otherwise be associated with an electrical and/or electro-mechanical configuration so as to operate at least in part electronically. For instance, the controlled release conduit may be configured as or otherwise include an electronic slow or quick release valve, an electronic pump, electronic screw plate, an electronically activated spring release plate, an electronic lever or fan or propeller or compressor, an electronic solenoid, an electronic MEMS device, piezo-electric device, and the like. In various instances, where the conduit is controlled mechanically and/or electronically, the conduit may have control circuitry, such as a microprocessor that controls a mechanism that in turn controls the opening of the conduit and/or the size, e.g., volume, of one or more of the chambers, and thereby controls the extent and rate of expulsion and/or communication between the chambers. In such an instance, the microprocessor may include one or more of a CPU, a memory, a transmitter, a receiver, other communications module, and/or one or more sensors or gauges, such as for determining flow rate, one or more flow characteristics, and/or the amount of air, gas, or other foaming and/or propelling agent being captured within the generated foam matrix or colloid of the foamable material. In further embodiments, the foaming agent and/or propellant may be a chemical composition, and the conduit, such as a control release conduit, may be configured for facilitating the mixing of the chemical foaming and/or propelling agent with the foamable and/or flowable material, such as where the foaming and/or propelling agent is in a gaseous, liquid, gel, powder, suspension, and/or semi or solid form, and the like. For instance, the foaming and/or propelling agent may be one or more components that when intermixed with each other and/or the foamable material and/or material to be expelled from the container, cause an increase in pressure within one or more of the conduits and/or chambers of the container, which increase in pressure may be employed, via the conduit, e.g., control release conduit, or other valve, so as to pre-foam or foam the foamable material and/or facilitate in the expulsion of the material from the container, such as in response to activation of an actuator or other dispensing member. For example, the foaming and/or propelling agent may include one or more elements that when admixed causes an exothermic or endothermic or other reaction that transfers energy from one material to another in such a manner as to create a pressure differential, such as an increase or decrease in pressure, such as within a conduit and/or chamber of the container. For instance, any consumable chemical agent that undergoes a physical change, such as from a solid to a semi-solid, to a liquid and/or to a gas, with a resultant pressure change, such as an increase or decrease in pressure, for instance, due to occupying more or less space within the chamber after the change in form, may be employed in this manner. Additionally, in various instances, the foaming and/or propelling agent may include one or more elements that when admixed causes an exothermic or endothermic or other reaction that transfers energy within the system in such a manner so as to create a temperature differential, such as between the temperature prior to admixture and/or subsequent thereto, such as an increase or a decrease in temperature, such as within a chamber of the container. In various embodiments, where there is a pressure change, the resultant change in pressure may be accompanied with a change in the temperature, either higher or lower, such as of the foamable and/or propelling material, which change in temperature may be produced for the purpose of heating or cooling the foamable and/or propelling material, such as prior to dispensing. In certain instances, the addition of the foaming agent and/or propelling agent to the foamable and/or propelling material may be accompanied by a change in pressure and/or temperature such as within the container. In particular instances, the foaming and/or propelling agent may be in a gaseous form, such as carbon dioxide, nitrous oxide, hydrogen, helium, argon, other noble gas, compressed air, and the like, wherein the gas is contained within a chamber, such as an insertable and/or removable chamber, within the container, and the control release conduit controls the flow of the gas into the chamber containing the foamable and/or propelling material, whereby upon mixing of the gas with the foamable and/or propelling material a foamed and/or flowable material is produced. Accordingly, in one aspect, the disclosure is directed to the conversion of a foamable material from a first, non-foamed state to a second, foamed state, such as by the introduction of a foaming agent into the foamable material, for instance, for the production of a consumable foamed material end product having a desired amount of foaminess. For example, the foamable material and the foaming agent are selected such that when admixed the foamable material is converted from a non-foamed state to a foamed state wherein in the foamed state, the foamable material has a colloidal structure that is characterized by the amount of foaming agent that is trapped within the colloid. In such an instance, the foamable material is changed by the foaming agent, such as being converted from a liquid state to a state wherein the composition includes the foaming agent, such as in a foamed or partially foamed state. For instance, in various instances, the foamable material is a material capable of absorbing and/or otherwise retaining within its formulation at least a portion of the foaming and/or propelling agent or a reactant of the foaming and/or propelling agent. For example, in certain embodiments, the foamable material is a liquid and the foaming agent is one or more of a gas, such as a soluble gas, a dissolvable powder, a suspension, a solute, a liquid, and the like. In other embodiments, the foamable material may be one or more of a gas, such as a soluble gas, a dissolvable powder, a suspension, a solute, a liquid, and the like, and the foaming and/or propelling agent may be a liquid. Accordingly, in various embodiments, a composition is provided wherein the composition includes a formulation produced by introducing a foaming agent to a foamable material, such as to produce a foamed composition, such as where the foamable material goes from a first, non-foamed state, to a second foamed state, such as by intermixing with the foaming agent. More particularly, in certain embodiments, the composition provided is a consumable product, such as a beverage, such as a foamed beverage, or other food item to be delivered to a user of the container. In certain instances, the foaming agent and/or propellant and/or a reactant thereof may already be present within the foamable and/or flowable material, such as in a latent form that is activatable, where in such an instance, prior to activation the foaming agent and/or propellant, is quiescent within the foamable material, which may be in a non or only partially foamed or flowable state, but upon activation of the foaming agent and/or propellant, it is converted from a latent form to an active form whereby it then causes the foamable material to change from a non or partially foamed state to a foamed or super foamed and/or flowable state. In certain instances, the activatable foaming agent and/or propellant is capable of several different levels of activation and can thus convert the foamable material into a foamed and/or flowable material a multiplicity of times and/or to a multiplicity of extents, such as from partially foamed, foamed, superfoamed, and/or flowable states, and the like. Particularly, in certain instances, the foaming agent may already be present within the foamable material, such as in a latent form that is activatable, where in such an instance, prior to activation the foaming agent is quiescent within the foamable material, which may be in a non or only partially foamed state, but upon activation the foaming agent is converted from its latent form to its active form whereby it then causes the foamable material to change from a non or partially foamed state to a foamed or super foamed state. In instances, the activatable foaming agent is capable of several different levels of activation and can thus convert the foamable material into a foamed material a multiplicity of times and/or to a multiplicity of extents, such as from partially foamed, foamed, superfoamed, and the like. More particularly, in certain instances, the propellant is present within the foamable material in a latent form that is quiescent within the foamable and/or flowable material but capable of being activated, where upon activation of the propellant, it is converted from its latent form to its active form whereby it then causes the foamable material to be foamed and/or ejected or otherwise propelled out of the container or from one portion of the container to another portion of the container, such as in flowable form. In certain instances, the activatable propellant is capable of several different levels of activation and can thus act to propel the foamed material a multiplicity of times and/or to a multiplicity of different compartments, and the like. Accordingly, in various embodiments, a container is provided, wherein the container includes a foamable and/or flowable material, such as a liquid capable of being foamed and/or flowed, and further includes a foaming and/or propelling agent, such as at least a partially soluble, e.g., a liquid soluble, foaming and/or flowable agent, wherein the container is configured for allowing the foamable and/or flowable material to intermix with the foaming and/or propelling agent in such a manner that a solution of the two results. In various instances, the intermixing of the foamable and/or flowable material and the foaming and/or propelling agent results in a change in pressure and/or temperature, such as an increase or decease of pressure and/or temperature, as described herein. Hence, the container and/or its component parts may be configured so as to withstand any resultant pressure or temperature change without substantially being deformed and/or without allowing the increased or decreased pressure and/or temperature from substantially escaping its bounds prior to activated release. For example, in certain embodiments, the beverage is provided within a container, such as a container described above. In such an instance, the container may include a foamable material, or other material, to be retained within a first container portion of the container, such as in a non-foamed state, prior to expulsion therefrom and delivery to a user. In various instance, a foaming agent or other propellant may also be included, such as a foaming agent or propellant retained in a second container portion of the container. In such an instance, the second container portion may be connected to the first container portion, such as by a secondary compartment, conduit, or other dispensing mechanism that is operable, for instance, by an actuator. For instance, in such an instance, when the actuator is actuated, the foaming agent and/or propellant may be added to the contained material to be mixed therewith, thereby converting the foamable material from a non-foamed state to a foamed state and/or propelling the material out of the container, such as through a release valve. Accordingly, in various instances, the container may include an outlet, such as an outlet that is coupled with the first and/or second container portions, such that once intermixed the foamed, flowable, and/or other material may be translated from within a lumen of the container to the outside of the container, such as through a translating member, for instance, and out through the outlet for delivery to a user, e.g., for consumption. Where an additive or sweetener is included, such as a flavor, the flavor may be delivered with the material, such as in a foamed, flavored beverage form. Accordingly, in various aspects, a container is provided, where in various instances, the container is configured in such a way that an auxiliary reservoir may be coupled therewith, such as a reservoir that may include a foaming agent and/or propellant, which reservoir may be included in a separate compartment within the container, e.g., within a lumen thereof, or may otherwise be coupled with the container, or a portion thereof, e.g., such as by being inserted therein, or be associated with the outside of the bounds of the container, in such a manner that the auxiliary reservoir is in communication with a retaining lumen of the container. For instance, in certain instances, a foaming member, containing a foaming agent, or propellant, may be included, such as within an insertable and/or ejectable reservoir that is configured for being coupled to the container, such as a container having a foaming and/or propelling member receptacle therein. Hence, in these various embodiments, the container may be configured to facilitate the intermixing of the foamable and/or flowable material, such as in liquid form, with the foaming agent and/or propellant, or other material, such as where the foaming agent, or propellant, is at least partially dissolvable within the foamable and/or flowable material, and functions at least in part to assist the conversion of the foamable material from a non or partially foamed state to a foamed or super foamed state and/or functions to expel the material, foamed or otherwise, out of the container. Accordingly, in various instances, the foamable and/or flowable material may be a liquid, such as a beverage, or a gel, or other solid or fluid matrix, and the foaming agent converts the foamable material from its present state into a foamed state, such as within the canister. In other instances, the foamable material may be a foamed or a partially foamed material, e.g., within the container, and the addition of the foaming agent thereto results in the production of a super foamed material. In other instances, the material is a material that is meant to be flowed, and the addition of a propelling material assists in that flowing. As indicated above, the foaming and/or propelling process may take place within or through the container, such as within one or more compartments or passageways within the container, and/or within a chamber or passageway that is associated with the container, such as within a chamber that is part of a translating element and/or within a release valve and/or within an outlet mechanism associated with the container, such as a conduit and/or control valve. In one aspect, therefore, a system is provided, wherein the system may include one or more of: a container, as exemplified above, such as a canister that contains a material, e.g., a foamable material; one or more conduits, which conduits may include one or more valves, such as controllable release valves; one or more translating members, for translating the material, e.g., a non-foamed, partially foamed, or foamed material from the inside of the canister to the outside of the canister, e.g., through a release valve and/or nozzle; and may further include a foaming agent or propellant, which foaming agent or propellant may be contained within a separate portion of the container and/or within a foaming and/or propelling member associated therewith. In some instances, there may be a conduit, e.g., including a control valve that regulates the transmission of the foaming agent and/or propellant to the flowable and/or foamable material, or vice versa. In various instances, the foamable material may be positioned within the container after it has at least been partially or fully foamed, and in such an instance, the container may be configured for retaining the foamed material in the foamed state, and a foaming agent may be employed to make the foam super foamed or a foaming agent need not be provided. Hence, in such instances, foaming may have already occurred and/or may occur through providing a shock and/or a shake to the container, so as to assist with or further promote foaming. A shock and/or shake can also be employed to break a seal that separates the material, e.g., foamable material, from the foaming agent and/or propellant. Accordingly, the container may be configured for facilitating the intermixing of the foamable and/or flowable material, such as in liquid form, with the foaming agent and/or propellant, such as where the foaming and/or propelling agent, or an other agent associated therewith, is at least partially dissolvable within the foamable material, and functions at least in part to assist the conversion of the foamable material from a non or partially foamed state to a foamed or super foamed state. Hence, in various instances, the foamable material may be a liquid, such as a beverage, or a gel, or a semi-solid or solid, or a gas or other fluid matrix, and the foaming agent converts the foamable material from its present state into a foamed state, such as within the container. In other instances, the foamable material may be a foamed or a partially foamed material, e.g., within the container, and the addition of the foaming agent thereto results in the production of a super foamed material. As indicated above, the foaming process may take place within the container, within one or more compartments within the container, and/or within a chamber that is associated with the container, such as within a chamber that is part of a translating element and/or within a release valve and/or within an outlet mechanism associated with the container, such as control valve. In various embodiments, the propellant converts the flowable material from its then present state at rest into a flowable state, such as within the container. In various of these embodiments, the container not only facilitates the intermixing of the foamable material with the foaming agent, but may also, or alternatively, facilitate the intermixing of the foamable material with a propellant, such as when the foamable and/or propelling material is in its pre-flowable, prefoamed and/or foamed state, e.g., precedent or subsequent to the intermixing of the foamable and/or flowable material with the foaming and/or propelling agent. Accordingly, in various instances, the propellant, or an agent associated therewith, is at least partially dissolvable within the flowable, foamable, and/or foamed material, and functions in one or more of assisting the conversion of the foamable material from a non or partially foamed state to a foamed or super foamed state, and/or propelling the material from the container, such as through one or more translating elements and/or dispensing mechanisms. Hence, in various instances, the foamable and/or flowable material may be a liquid, such as a beverage, or a gel, or a semi-solid or solid, or gas or fluid matrix, the foaming agent (and/or propellant) converts the foamable material from its present state into a foamed state, such as within the container, and/or the propellant functions to expel the flowable material, e.g., the at least partially foamed material, out from the interior of the container. In other instances, the foamable material may be a foamed or a partially foamed material, e.g., within the container or canister, and the addition of the foaming agent and/or propellant thereto results in the production of a super foamed material. As indicated above, the foaming process may take place within the container, within one or more compartments within the container, and/or within a chamber that is associated with the container, such as within a chamber that is part of a translating element and/or within a release valve and/or within an outlet mechanism associated with the container, such as a control valve, and the movement of the flowable, foamable and/or foamed material through the container is facilitated by the addition of the propellant or a proponent thereof to the flowable and/or foamable material. As indicated, in one aspect, a translating element, e.g., for coupling to and/or for use with a container, such as a canister described herein, may be provided. In such an instance, the translating element may be configured as an extended member, for instance, as an extended member having an elongated, hollow and/or tubular body. The hollow extended member includes a proximal portion and a distal portion separated by a medial portion. The distal portion of the elongated body may be configured for interfacing with and/or receiving within its bounds the foamable, flowable, and/or other material, and the proximal portion may be configured for interfacing with an outlet of the canister, such as a release valve member and/or passageway associated therewith. Further, the elongated body may be configured for allowing the transmission or movement of the material, e.g., the partially or fully foamed and/or flowable material, from within the bounds of the cavity to the exterior of the cavity, such as by translating the material from the distal portion to the proximal portion of the extender tubular member. Accordingly, in various instances, a translating element or member is provided, such as where the translating member is configured as a feeder element, for example, a feeder tube that is adapted for moving or otherwise transferring the material, e.g., a foamed and/or flowable beverage, from within a cavity of the container to the outlet. In such an instance, the outlet of the container may be configured as, or otherwise be associated with, a valve, such as an actuatable release valve. For instance, a release valve that is configured for allowing and/or effectuating the movement of the foamable material from within the container to outside of the container, such as through the feeder tube, such as when the actuateable release valve is actuated, such as for consumption or ingestion of the foamable and/or flowable material directly or indirectly by a user. In various instances, the foaming agent, where included, may also function as a propellant, so as to also facilitate the expulsion of the foamable and/or flowable material out of the container, such as out through the feeder tube and/or outlet, such as a nozzle associated there with. In other instances, a propellant may be employed wherein the propellant does not substantially intermix with the foamable and/or flowable material, such as where the propellant is substantially immiscible with and/or non-soluble in the foamable and/or flowable material. Where a propellant is included, a feeder element, such as a translating element, may or may not be included within the container and it's systems. For instance, where included the propellant may be employed to facilitate the movement of the material, e.g., foamable and/or flowable material, such as in a non-foamed, partially foamed, or foamed state, through the translating element and out through the outlet, e.g., either directly or through a controllable release valve and/or associated nozzle. However, in other instances, the propellant may be employed to facilitate the movement of the flowable and/or foamable material, in a foamed, partially foamed, or non foamed state, directly out through the outlet, e.g., not via a translating tube, such as through an opening and/or a controllable release valve coupled to the opening of the container itself. Various different types of propellants and/or propelling members having various different types of configurations may be employed. In certain instances, the propellant may be the same as, or different from, the foaming agent and/or other foaming member. Any suitable propellant may be used, so long as it is capable of facilitating the movement and/or translation of the foamable material form within the container to outside of the container, and where the foamable material is provided for consumption, the foamable material and/or propellant should also be at least inert with respect to consumption, e.g., it should be consumable, such as GRAS. Further, as indicated, the foaming agent and/or propellant may already be present within the foamable material, such as in a latent form that is activateable, where in such an instance, prior to activation the foaming agent and/or propellant, is quiescent within the foamable material, which may be in a non or only partially foamed state, but upon activation of the foaming agent and/or propellant, it is converted from its latent form to an active form whereby it then causes the foamable material to change from a non or partially foamed state to a foamed or super foamed state and/or from a non-flowable to a flowable state. In certain instances, the activatable foaming agent and/or propellant is capable of several different levels of activation and can thus convert the foamable and/or flowable material into a foamed and/or flowable material a multiplicity of times and/or to a multiplicity of extents, such as from partially foamed, foamed, superfoamed, and the like. Accordingly, in various embodiments, a container or canister is provided, wherein the canister includes a foamable material, such as a liquid capable of being foamed, and/or includes a propellant, such as a soluble, e.g., a liquid soluble, gas propellant, wherein the canister is configured for allowing the foamable material to intermix with the foaming agent and/or propellant in such a manner that a solution of the two results. In various instances, the intermixing of the foamable material and the foaming agent and/or propellant results in a change in pressure and/or temperature, such as an increase or decease of pressure and/or temperature, as described above. Hence, the canister may be configured so as to withstand any resultant pressure and/or temperature change without substantially being deformed and/or without allowing the increased or decreased pressure and/or temperature from substantially escaping its bounds prior to activated release. For example, in various instances, the material of the container or canister may be one or more of a non-conductive, insulated, thermal retaining material that is adapted to retain the foamable material, e.g., once foamed, under pressure and/or within a warmed or cooled state. For instance, in certain instances, the foamable material is a liquid and one or more of the foaming agent and/or propellant is a liquid soluble gas or solute that at least to some extent intermixes with and/or is otherwise at least partially dissolvable within the liquid, so as to form a solution and/or suspension; and in various instances, the formation of the solution may result in the generation of an increased pressure gradient, such as within the canister, such as a pressure gradient that is increased as compared to outside of the canister, or as between different portions within the canister. In such an instance, the foaming agent and/or propellant going into solution may cause a pressure increase within a portion of the canister and may further thereby cause the foamable material to foam. In other instances, the foaming agent and/or propellant may already be in solution and the foaming occurs by the creation of a pressure and/or temperature gradient or other mechanism that draws the foaming agent and/or propellant out of solution, so as to equalize the pressure and/or temperature in the local environment, thereby causing the foamable material to foam, such as by the foaming agent exiting the solution, e.g., by bubbling out of solution such as where the bubbling generates the foaming action and/or causes the material to become flowable. In certain instances, the foamable and/or flowable material, e.g., a liquid portion, and the foaming and/or propelling agent, e.g., a gas portion, are contained in separate portions of the canister, and are not intermixed until exiting the canister, such that just prior to egress the foaming agent is intermixed with the foamable material, which intermixing causes the foaming material to foam, such as by the foaming agent, e.g., liquid soluble gas, forming gas bubbles within the foamable material, e.g., liquid beverage, such as by at least partially dissolving therein, prior to exiting the outlet of the canister. For instance, the container or canister may include a release valve portion that is configured for allowing the foamable material and the foaming agent to intermix, such as just prior to egress from the canister. More particularly, the canister may include at least two distinct portions, one containing the foamable material and the other containing the foaming agent. In such an instance, the canister may further include two distinct translation element portions, such as one interfacing with the foamable material and the other interfacing with the foaming agent, such as where the translating element are two separate translating elements or where the translating element is forked, such as where the translating element is configured for translating the foamable material and the foaming agent into a common receptacle, such as for intermixing, prior to release from the canister. In various instances, the outlet of the canister may be configured to feed into a valve, such as a control release valve, where the valve includes a chamber into which one or both of the foamable material and/or the foaming agent are delivered thereto, such as for intermixing and/or foaming, e.g., prior to release through the valve, for instance, upon actuation of the valve, and/or the valve may further feed into a delivery nozzle. Accordingly, in one aspect, a valve is provided, wherein the valve is configured for interfacing with a portion of a container, canister, and/or a translation member associated therewith so as to facilitate, e.g., control, the release of a flowable and/or foamable material from within the canister to outside of the canister, such as for delivery to a user, e.g., a consumer of the translated flowable material. Accordingly, the valve may have a distal portion, such as for interfacing with a portion of the canister, e.g., a portion of the canister bounding an opening therein, or a translating element associated therewith; and it may have a proximal portion, such as for interfacing with a user of the canister of the system, such as for dispensing the fluid therein, such as to a user. Typically, the valve will have an orifice or passageway extending the length of the valve, such as an orifice for translating the flowable and/or foamable material through the valve, such as for dispensing the flow of the flowable and/or foamable material out from the cavity of the canister. In various instances, the orifice may be of increasing or decreasing radius and may have one or more internal configurations, such as for creating shear with respect to the flowable and/or foamable material. In various instances, the valve may be a control valve, such as a control release valve that upon activation allows and/or facilitates the flow of the flowable and/or foamable material, e.g., in the foamed state, out of the canister, such as by interacting with the outlet of the canister and/or one or more translation members associated therewith. The valve may have any suitable configuration so long as it is capable of facilitating and/or controlling the movement and/or release of the contents of the canister out of the container, such as in a controllable manner, e.g., with respect to one or more of flow rate, density, pressure, temperature, aeration, foaminess, and/or contour of the flowable material. For instance, in one particular instance, the valve is adapted to allow the flowable and/or foamable material, such as in a beverage form, to mix with one or more of the foaming agent and/or propellant, e.g., in gas form, such as in the presence of a pressure gradient, for example, in a pressure gradient created by the valve itself, which mixing of the liquid beverage and the gas, such as in the presence of a pressure gradient, causes gas bubbles to form within the liquid, or exit therefrom, thereby creating a foam. In various instances, the amount of the foaming agent/propellant that is intermixed with and/or absorbed by the flowable and/or foamable material is controlled so as to control the nature of the flowable and/or a foamable material. It is to be noted that the above has been described with respect to a valve associated with the container or canister, however, it is understood that the valve may be part of the canister or be part of a dispensing mechanism, such as a nozzle, and/or one or more of these functions may be performed by either the valve, the nozzle, or other dispensing element. Accordingly, as indicated, the dispensing mechanism, e.g., translating passageway, valve and/or nozzle, may be adapted for increasing or decreasing the pressure of the flow, e.g., of the flowabale and/or foamed material, such as by having a passageway there through that changes dimensions, such as from larger to smaller or smaller to larger, and in some instances, the dimensions of the passageway are capable of being changed, such as where the valve is articulable thereby being able to change the dimensions and/or openings of one or more portions of the orifice thereby increasing or decreasing the pressure driving the flow of the flowable material through that portion(s) of the orifice. Additionally, the valve may be configured for increasing or decreasing foamability of the foamable material, for instance, the passageway, valve, and/or nozzle may be configured so as to include one or more additional openings such as to aerate the foamable material as it passes through the passageway, valve, and/or nozzle, such as in a controllable fashion, so as to make the foamable material more or less foamy and/or flowable. More particularly, the passageway, valve, and/or nozzle may be configured for allowing air, or another gas, such as the foaming agent and/or the propellant to intermix with the flowable material so as to modulate the foaminess and/or flowability of the material, such as when it passes through the passageway, valve, and/or nozzle. Hence, the flow of the material may be regulated so as to be a relatively fast, medium, or slow flow rate, such as by thickening, thinning, aerating, foaming, defoaming, and/or otherwise changing the characteristics of the flowable material and/or the container or its components itself. Accordingly, in certain instances, the passageway, valve, and/or nozzle are configured for changing a characteristic of the flowable and/or foamable material, such as with respect to flowability, e.g., thickness, viscosity, thixotropic effect, and the like, the taste, flavor, shape, look, and/or feel, such as in the delivery of the flowable material. For instance, the passageway, valve, and/or nozzle may be configured for contouring the shape of the flowable and/or foamed material, so as to enhance the flow, taste, flavor, shape, look, and/or feel of the flowable material, such as to make it easier to use and/or more pleasant to the user, e.g., upon delivery directly to the user such as for direct consumption by the user. For example, in various particular instances, various different types of passageways, release valves, and/or nozzles, and/or translating elements, alone or in combination, may be employed for one or more of translating and/or extracting the foamable and/or flowable material from a portion of the container; translating and/or extracting the foaming agent and/or propellant from one or more other portions of the container; and/or introducing the foaming agent and/or propellant into a common reservoir where these components can intermix, which intermixing can be fashioned in such a way as to change the flow, taste, flavor, shape, contour, look, and/or feel of the flowable material, for instance, the taste may be changed such as by adding a flavoring agent upon the mixing and/or contouring the foamed material upon release. The rate of release may also be important either for enhancing taste and/or for ensuring optimal mixing of propellant and/or foaming agent with the translatable material to ensure appropriate amount of foaming and/or flowability. Hence, in some particular instances, a system is provided wherein a material, such as an ingestible, foamable and/or flowable material is stored in one physical state within a container or canister and undergoes a physical change, such as prior to delivery, e.g., direct delivery to a user, whereby due to the physical change the foamable and/or flowable material is converted at least partially to another physical state, such as from a non-foamed and/or non-flowable state to at least a partially foamed and/or flowable state. For instance, in various instances, the foamable material may be a beverage, in a liquid form, and upon the addition or intermixing of the foamable material, the liquid is changed, e.g., converted, from a liquid to at least a partial colloid or matrix, such as to form a foamable material. More particularly, the foamable material may be such that it is capable of forming a matrix with one or more components of the foaming agent and/or propellant and may further form a colloid such as upon the foaming agent and/or propellant being introduced with and/or mixed with the foamable material, wherein the foaming agent and/or propellant may at least be partially dissolvable within the foamable material so as to be captured within the matrix and may thereby form a foamable colloid therewith. For example, a container having at least a first cavity and a passageway, conduit and/or valve may be provided where in a portion within the cavity a foamable material, such as a liquid, e.g., a beverage, is stored; and within a second portion of the cavity a foaming agent and/or propellant, such as a gas, e.g., a liquid soluble gas or a mixture of gasses, is stored, and at some point prior to dispensing the liquid beverage is intermixed with the liquid soluble gas in a manner sufficient to form a foam and/or a flowable material that may then be delivered directly to the mouth of a user for consumption, such as for drinking. Hence, in various instances, the container may be a beverage container that contains a liquid beverage as well as a foaming agent and/or propellant, such as a gas or mixture of gases, such that prior to or upon actuation of the valve, e.g., a control valve, a solution of the liquid and gas, e.g., in a foamed or semi-foamed state, is released or otherwise dispensed, such as directly to the mouth of the consumer, e.g., by single-handed activation of a delivery actuator, such as via a nozzle, in a manner that allows for the direct drinking, imbibing, or otherwise ingesting of the beverage by the user. For instance, in a particular embodiment, the container or canister along with the foamable and/or flowable material, e.g., liquid beverage and/or food, in combination with the foaming agent and/or propelling agent, e.g., in gaseous form, forms a pressure and/or temperature gradient, such as between the contents within the container and the ambient pressure outside of the container, such that as the valve is actuated the foamable liquid and/or food material and the gaseous foaming agent and/or propellant exit the container, e.g., through the valve, in a manner such that the pressure and/or temperature gradient causes the gas to go into solution and/or gas already in solution to leave the solution, which entering and/or exiting of the gas into and/or out of solution causes bubbling, which bubbling is at such an amount and rate so as to cause the liquid beverage or food item to flow and/or foam, e.g., by gas bubbles being created and/or captured within a matrix of the material, e.g., so as to form a colloid or by gas bubbles already present within the matrix to leave the solution, which foamed beverage and/or food material may be delivered to the user, such as via a nozzle, for direct consumption by the mouth of the user, such as for drinking and/or eating or otherwise imbibing the flowable and/or foamed solution. Accordingly, as detailed herein, a container for containing a beverage or food product, and/or a beverage or food product so contained, may be provided where the container includes one or more of a top, a bottom and a side wall, such as a side wall between the top and the bottom. The container may include a first cavity, such as within or otherwise defined by the top, bottom, and sidewall, where the first cavity is sized or otherwise configured to hold an ingestible material, e.g., beverage, such as a foamable liquid in a pre-, mid-, or post-foamed state. The container may include a valve mechanism having a proximal portion and a distal portion, such as where the proximal portion of the valve mechanism extends outward from the top of the container, and the distal portion of the valve mechanism extends inwards toward the first cavity of the container. In such an instance, the valve mechanism may include a valve, such as a valve configured to regulate the flow of the ingestible material from within the interior of the container to outside of the container, such as through an inlet aperture of a feeding mechanism that may be associated with the valve mechanism. Hence, the valve may be a control valve that is controllable by a consumer, such as via a consumer-operable flow controller, so as to control the valve in a manner sufficient to vary the flow, such as between no flow and a maximal flow, e.g., based on a physical force applied by the consumer to the consumer-operable flow controller. In a manner such as this, the flow of the ingestible beverage into the distal portion and out through the proximal portion of the valve may be regulated, e.g., in response to the operation of a suitably configured control mechanism. Further, in various instances, the valve mechanism may be coupled with a nozzle, such as a delivery nozzle having a distal portion configured for being coupled with the proximal portion of the valve, and a proximal portion configured for delivering the ingestible substance directly to the user, e.g., to the mouth of the user, such as for direct ingestion, e.g., drinking and/or eating, by the user. For instance, the delivery nozzle may be configured to form a pathway that extends from the container, e.g., associated with the first cavity, through the nozzle to an exit aperture that is adapted to deliver the ingestible substance to the mouth of the consumer. In such an instance, the pathway between the valve and the exit aperture of the delivery nozzle may be flexible. In particular instances, the proximal portion of the nozzle may be sized and adapted to be received in a mouth of the consumer. Accordingly, in operation, the ingestible substance may be translated from the interior of the cavity, through the pathway formed by the delivery nozzle and to the exit aperture of the delivery nozzle. In various instances, the pathway through a proximal, medial, and/or distal portion of the delivery nozzle may be angled from the pathway through one or more of the other, e.g., distal, portion of the nozzle and/or outlet thereof. The container may include a feeding mechanism, for instance, a translating member, e.g., a feeder tube, having a proximal end that is coupled with the distal portion of the valve, and a distal end positioned in the first cavity, such as proximate the bottom of the container. Hence, the feeding mechanism may be associated with the first cavity of the container so as to access the ingestible substance therein. Particularly, the feeder element may include an elongated body having a proximal interface and a distal interface, such as where the proximal interface is configured for communicating with the proximal or top portion of the container, such as via the distal portion of the valve; and where the distal interface is configured for communicating with the ingestible beverage, e.g., foamable and/or flowable material, within the first cavity. In various embodiments, the feeder and/or translating element may be configured or otherwise adapted for transferring the ingestible substance, e.g., foamable and/or flowable beverage, from the lumen of the first cavity to the valve of the container, such as for delivery of the ingestible beverage to the user, for example prior to or post foaming of the beverage. The container may include one or both of a foaming and/or propelling mechanism that may be connected with one or more of the first cavity or a secondary and/or third cavity, such as a secondary or tertiary cavity within a valve, e.g., a dispensing valve, of the container. In various instances, the foaming and/or propelling mechanism is adapted to or otherwise configured for converting an ingestible beverage and/or food item and/or medicine from a non-foamed and/or non-flowable state to a foamed and/or flowable state. Hence, the foaming and/or propelling mechanism may be configured for flowing, e.g., upon consumer control of a controllable dispensing valve, the ingestible beverage and/or food item and/or medicine, e.g., in the foamed and/or flowable state, through the feeding mechanism to the controllable dispensing valve and out the proximal portion of the valve, e.g., out through the nozzle, if included. In certain embodiments, the foaming and propelling mechanism includes a foaming agent, e.g., the foaming and propelling mechanism may be the same as the foaming agent, and in other embodiments, they are distinct elements that may act in concert to foam and/or propel the ingestible substance, e.g., beverage or other food item, such as within and/or out of the container. In some embodiments, a foaming mechanism is included wherein the foaming mechanism is coupled with the first cavity of the container and adapted to convert, e.g., using a foaming agent, the ingestible substance from a non-foamed state to a foamed state for exiting the exit aperture, e.g., of the delivery nozzle, such as in response to the operation of a controller, e.g., a consumer-operable flow controller. Accordingly, in particular embodiments, the container may include a propelling mechanism, such as a mechanism that is configured for generating a positive pressure within the first cavity, which propelling mechanism is sufficient to propel the ingestible substance through the container, e.g., a feeding mechanism where included, and out of the proximal portion of the delivery nozzle, such as for delivery of the ingestible substance to the mouth of the consumer, for example, when the valve is controlled by the consumer-operable flow controller. In certain instances, the proximal portion of the delivery nozzle at least partially includes a flexible member, such as at the exit aperture In various embodiments, the container may include a second cavity that may be operationally or otherwise connected with the first cavity, such as by a secondary valve, e.g., a controllable feeding valve, or by a feeder element. In such an instance, the first cavity may be configured for retaining and storing the flowable and/or foamable beverage or food item, and the second cavity may be configured for retaining and/or storing the foaming and/or propelling mechanism, e.g., foaming and/or propelling agent, such as until the consumer activates one or both of the dispensing and/or feeder control valves. For instance, in certain embodiments, the foaming and/or propelling mechanism may include a foaming agent and/or propellant that may be introduced into the first cavity, such as upon the operation of a consumer-operable conduit, e.g., a feeder valve, to the first cavity. In such instances, the feeder valve may be configured so as to control the feeding of the foaming and/or propelling agent into contact with the foamable and/or flowable material, such as within the first or second or even third cavity, so as to create a positive pressure therein. For example, the foaming and/or propelling mechanism may include a gas, such as a foaming agent and/or propellant, that is introduced from the second cavity to the first cavity, and/or a third cavity, such as a mixing chamber. Such introduction may take place as a result of the operation of an operable, e.g., consumer-operable, flow controller for controlling a passageway and/or a valve thereof. In various instances, the gas propellant may also be the foaming agent and may therefore function to convert the ingestible substance from a non-foamed state to a foamed state and/or a flowable state for exiting the exit aperture of the delivery nozzle. As indicated, the valve controller may operate to control the flow of an amount of the gas proportion of a mixture with the ingestible substance sufficient to convert the ingestible substance to the foamed and/or flowable state. Accordingly, in certain embodiments, a third cavity, e.g., a mixing cavity, may also be present such as where the third cavity is operationally or otherwise coupled with one or both of the first and/or second cavities, such as where the first and/or second cavities feed directly into the third cavity, e.g., via a tertiary operational flow control valve, such as a mixing valve. In such an instance, the first and/or second cavities may feed into the third cavity, such as for the purpose of mixing the foamable material with the foaming agent, by the operation of the feeder control element. Additionally, in various embodiments, a foaming mechanism may be included, where the foaming mechanism includes a foaming agent that is configured for converting the ingestible substance from a non-foamed state to a foamed state, e.g., within the first, second, and/or third cavities, prior to exiting the exit aperture of the delivery nozzle in the foamed state. As indicated above, in various instances, such a third cavity may be part of, e.g., within the bounds of the container, and/or may be a part of a control, e.g., a dispensing, valve; and/or part of a dispensing nozzle. It is to be understood that any of the passageways, valves and/or nozzles disclosed herein may be configured for regulating the flow, mixing, and/or foaminess of the flowable and/or mixable materials disclosed herein, such as with respect to controlling or otherwise regulating the rate, amount, quality, and/or other characteristics of the flow, mixing, taste, texture, and/or foaminess of the flowable and/or mixable materials. The valves may be positioned anywhere within the bounds of the container or a component thereof such as between the boundaries of the various compartments or within one or more of the translating elements and/or nozzles. In view of the different configurations of the container and/or the cavities therein, a feeding mechanism, such as a translating element, e.g., feeder tube, may be configured so as to act as a conduit directing the flow of the various flowable materials held within one or more components of the system. For instance, the translating element may be composed of one or more elements that are configurable for or otherwise adapted for directing a flow of one or more of the flowable materials, e.g., the one or more foamable materials and/or one more foaming agents and/or propellants, that are held or otherwise stored within the one or more cavities of the container. One or more control valves may be included as part of the feeder element so as to further control and direct the flow of the flowable materials through the feeder element. Hence, the translating element may include a portion that contacts the flowable and/or foamable material and/or may include a portion that contacts the flowable foaming agent and/or propellant, and may include another portion that contacts a top portion of the container, such as via a dispensing valve and/or dispensing nozzle, so as to facilitate the flow and/or mixing of the flowable and/or foamable materials within and/or out of the container. For example, a feeding member may be provided, wherein the feeding member has a proximal end that may be coupled with the distal portion of a valve mechanism, and the feeding member has a distal end that may be positioned in the first cavity, such as where the distal end has an inlet aperture. Particularly, the container may include a valve mechanism that is coupled with a delivery nozzle and further includes a feeding mechanism, such as a feeder member that is associated with the first cavity of the container so as to access the ingestible substance therein, such as where the valve mechanism includes a valve configured to regulate the flow of the ingestible substance from the first cavity and through the pathway formed by the feeding mechanism and delivery nozzle. In various embodiments, the translating mechanism includes a member that translates the one or more flowable materials through its componentry via the action of a propellant, actuation of one or more of control mechanisms, such as a consumer-operable flow controller detailed herein, and/or the creation of a pressurized chamber or vacuum, such as that created by a user sucking or blowing into one or more of a user contactable portion of a dispensing nozzle, dispensing valve, and/or proximal portion of the translating member directly. For instance, a propelling mechanism connected with a first cavity of the container may be included, wherein operation of the propelling mechanism is based on operation of a consumer-operable flow controller for controlling a valve regulating the flow through the feeding and/or dispensing mechanism of the container, which functions to propel the ingestible substance into an inlet aperture, e.g., of a delivery nozzle, through the feeding mechanism, and out of an exit aperture of a distal portion of the nozzle, such as for delivery of the ingestible substance, e.g., directly to the mouth of the consumer. In certain instances, the propelling mechanism may be capable of mechanical motion and the operable flow controller may be mechanically coupled with the valve so as to control the valve in a manner sufficient to vary the flow, e.g., between no flow and a maximal flow, proportional to a degree of a physical force applied by the user to the user-operable flow controller. In such an instance, the propelling mechanism, which may be a deformable bladder and/or an elastic member, may be coupled with the first cavity in such a manner so as to generate a pressure against the movable portion of the first cavity sufficient to propel the ingestible substance from the first cavity, through the feeding mechanism and out of the distal portion of the delivery nozzle for delivery of the ingestible substance to the user and/or to an external item when the valve is controlled by the consumer-operable flow controller. Accordingly, a translating member, e.g., a feeder tube, of the disclosure may have any suitable configuration that may be useful in translating the flowable ingestible materials through the system such as for one or both of mixing and/or direct dispensing to the user, e.g., directly to the mouth of the user for ingestion, such as for drinking. In various instances, the translating member is configured for functioning regardless of the orientation of the canister, such as regardless of how the device is manipulated and/or used by the consumer in ingesting, e.g., drinking and/or eating, the foamable material stored therein. Hence, the feeder tube(s), as disclosed herein, may be configured to assist in directing the flow of the mixable elements, assisting in mixing the elements, and for delivering the mixture to a user, such as in a flowable, foamed state, e.g. via a control valve, such as a syphon valve, or nozzle. In various instances, the container may be configured for simple activation, such as via single left or right hand of the user. Additionally, in particularly instances, the delivery mechanism, e.g., nozzle, passageway, and/or valves, may be configured with respect to the feeder mechanism and/or container and/or a cavity therein such that while the ingestible substance is delivered, the inlet aperture is proximate a portion of the container that is closest toward the center of the earth, and an angle between a vector from the inlet aperture of the feeding mechanism to the exit aperture of the delivery nozzle and a vector from the inlet aperture of the feeding mechanism to the center of the earth is greater than about 45, greater than about 60, or greater than about 90 degrees. In a particular embodiment, an apparatus such as for serving an ingestible substance is provided, wherein in the apparatus includes a container, such as a container having a at least a first cavity such as to hold an ingestible substance therein. In various instance, the first cavity may have a movable portion. In certain instances, the container may include a delivery nozzle, which nozzle may be configured so as to form a pathway through or from the container. The delivery nozzle includes a distal portion that may extend away from the container, and a proximal portion having an exit aperture extending from the pathway that is adapted to deliver the ingestible substance directly to a mouth of a user, e.g., a consumer of the ingestible sub stance. In certain embodiments, the container may additionally include a valve mechanism that may be coupled with the delivery nozzle. The container may also have a feeding mechanism that may be associated with the first cavity so as to access the ingestible substance therein, such as where the valve mechanism includes a valve that is configured to regulate the flow of the ingestible substance from the first cavity through the pathway formed by the delivery nozzle. Additionally, the container may include a consumer-operable flow controller that is mechanically coupled with the valve and configured to control the valve so as to vary the flow, e.g., between no flow and a maximal flow proportional to a degree of a physical force that is applied by the consumer to the consumer-operable flow controller. In certain instances, a propelling mechanism may be included and be coupled with the first cavity so as to generate a pressure against the movable portion of the first cavity, such as a pressure that is sufficient to propel the ingestible substance from the first cavity, such as through the feeding mechanism and out of the distal portion of the delivery nozzle for delivery of the ingestible substance to the user and/or an external item when the valve is controlled by the consumer-operable flow controller. In particular instances, the container may include a plurality of first cavities, such as where each of the plurality of first cavities is adapted to hold a different ingestible substance. As indicated above, one or more or all of the plurality of first cavities may have a movable portion therein. In such an instance, one or more propelling mechanisms may be included, where the propelling mechanism(s) may be coupled with one or more, e.g., each, of the plurality of first cavities so as to generate a pressure against the movable portion(s) of one or more of the plurality of first cavities, such as a pressure sufficient to propel the ingestible substance from one or more of the plurality of first cavities. In such an instance, the force is sufficient to push the ingestible substance through the feeding mechanism and out of the distal portion of the delivery nozzle for delivery of the ingestible substance such as when the consumer-operable flow controller is operated so as to control the valve to effectuate the release. In various instances, the propelling mechanism may include a second cavity that envelopes at least the moveable portion of the first cavity, such as where the second cavity exerts a pneumatic pressure against the movable portion of the first cavity. For instance, the second cavity may be associated with a piston that moves to exert pressure against the first cavity, such as where the moveable portion is the piston. In particular instances, a spring member may be include such as where the spring member exerts the pressure against the movable portion of the first cavity. In some instances, a consumer-operated air pump may be included and rigidly attached to the container, such as for exerting pressure against the movable portion of the first cavity upon a force exerted on the consumer-operated air pump. In such an instance, a consumer-operable flow controller is included and adapted to vary the proportion of delivery of each ingestible substance from each of the one or more of the plurality of first cavities. In certain instances, a moveable nozzle may be included such as where the nozzle rotates or pivots from one of the plurality of first cavities to another of the plurality of first cavities, such as where the pressure generated by the propelling mechanism may be selectively applied to the one or more of the plurality of first cavities. Additionally, in various embodiments, the container may include a foaming mechanism, such as where the foaming mechanism includes a foaming agent that is configured for converting the ingestible substance from a non-foamed state to a foamed state, such as prior to exiting the exit aperture of the container or a delivery nozzle associated therewith in the foamed state. For instance, a foaming mechanism having a foaming member associated therewith may be included such as where the foaming member has a foaming chamber associated with it, such as for mixing a pressurized gas with the ingestible substance so as to convert the ingestible substance from a non-foamed state to a foamed state for exiting the exit aperture of the delivery nozzle in the foamed state. A propelling mechanism may also be included where the propelling mechanism may be included in or may include a second cavity, such as a second cavity containing a pressurized propellant gas. In some instances, the foaming mechanism may include a conduit from the second cavity to the foaming chamber so as to deliver the pressurized gas to the foaming chamber. In particular instances, the foaming mechanism further includes a second valve so as to regulate the flow of the pressurized gas to the foaming chamber, such as where the conduit passes through a movable portion of the first cavity and/or where the second cavity is associated with a piston that moves to exert pressure against the first cavity. In such an instance, the conduit may be configured to pass through an aperture of the piston. In particular instances, the first and/or second cavity may be bounded by a container body that is rigid under pressure, where as the first cavity may be bounded by a more flexible and/or stretchable body. Hence, in various embodiments, the container may include a liquid or a mixture of liquids, e.g., in a drinkable and/or foamable beverage form, and/or may include a liquid soluble gas or a mixture of gasses that may be configured as one or both of a foaming and/or a propelling agent, wherein upon contact, under increased or decreased pressure and/or temperature, the liquid(s) in admixture with the soluble gas(es) may form a solution, such as a foamable and/or flowable solution, that may be delivered to a user, such as for drinking, e.g. directly from the container, such as through a suitably formed delivery nozzle. As indicated, the liquid(s) and/or liquid soluble gas(es) may be retained within the container in the same or different compartments, can be intermixed in the same or different compartments, and/or can be translated throughout the system and/or to a user, such as through one or more suitably formed translating elements, e.g., feeder tubes, and/or one or more control valves associated therewith. In some embodiments, the container includes a first compartment for retaining both a liquid and a gas, such as where the liquid and the gas are separated from one another in the container, such as via a pressure gradient between the two, e.g., under increased pressure; and in some embodiments, the container includes a first compartment for retaining the liquid, which first compartment may be flexible or semi-flexible, and a second compartment for retaining the gas, which may be rigid or semi rigid, such as where the liquid and the gas are separated from one another in the canister by a dividing wall, which may be moveable, but may be configured for communicating with one another, such as for the purpose of intermixing, such as via one or more valves, e.g., a feeding, mixing, and/or dispensing valve, and/or one or more translating elements, and/or one or more passageways and/or nozzle elements. In such an instance, the liquid may be an ingestible beverage or food item, the gas may be at least a partially liquid soluble gas, and the feeder element(s) and/or release valve(s) may be configured for intermixing the liquid and the liquid soluble gas, such as to produce a foamed and/or flowable material, such as on release, e.g., actuation of a release mechanism, e.g., an operable control mechanism, of the container. For instance, the gas may be a dissolved gas in solution of the ingestible substance. Particularly, the dissolved gas may create a propelling mechanism so as to generate a pressure within the first cavity sufficient to propel the ingestible substance through the container, e.g., a feeding mechanism associated therewith, and out of a proximal portion of a delivery nozzle. As indicated, in various embodiments, the container may include a plurality of compartments, such as a first compartment for retaining the ingestible substance, and a second compartment for retaining the foaming agent and/or propellant. In various instances, the second compartment may be configured for receiving an interchangeable gas reservoir, such as a cartridge containing a foaming and/or propelling member therein, e.g., a gas cartridge, which cartridge may be inserted into the container for discharging, and may be replaceable once the cartridge has been discharged, such as through activation of a release mechanism of the container or a component associated with the container. In various embodiments, a cap that seals over a portion of the container having an opening into an inner cavity of the container, e.g., a proximal portion of the nozzle, a feeder mechanism, and/or the container, may be included. In such instances, a retaining mechanism for retaining the cap in relation to the nozzle, feeder mechanism, and/or container may be included. A sealing mechanism such as to seal an interface between the cap and the container to seal the cavity of the nozzle, feeder mechanism, and/or container may be provided. In a further aspect, methods for producing a foamable and/or flowable material are provided, such as where the foamable and/or flowable material is comprised of a liquid, such as a beverage, or other food item or topping or medicine that may be consumed, for instance, in imbibeable and/or ingestible form, or where the foamable material is at least partially prefoamed but subjected to conditions that function to increase or decrease the foaminess of the material, such as prior to delivery from a storage and/or delivery canister. The methods may include one or more steps, such as a step that includes actuating a delivery mechanism of the container, which actuation functions to eject the foamable and/or foamed material in conjunction with one another and/or out of the container. For example, the actuation of the delivery mechanism, e.g., via a consumer operable controller, may involve the actuation of one or more of a nozzle, a valve, and/or a translation element associated with a container configured for retaining the foamable material, such as where the actuation may involve activating a control element, such as depressing or pulling a button, turning a nozzle or screw or knob, pulling a trigger, squeezing a depressible element, flipping a switch, biting a valve, pulling a tab, removing a pin or stop, operating a pressure differential valve, activating an electronically controlled valve by an electrical input sensor or signal, and the like. In some instances, one or more of the components contained within the container may be under pressure, and such actuation may function to mix the contained components and/or release one or more of the contained components, such as after they have been mixed together, such as to produce a non-foamed or at least a partially foamed material. In various instances, the container or a portion thereof may include a cap or seal that must be removed or unsealed, e.g., burst or punctured or the like, prior to delivery of the ingestible material. In particular, the recited actuation may involve one or more of releasing one flowable component into another flowable component contained within the container, such as by the operating of one or more valves that function to open one or more conduits and/or translating element(s); and/or the translating of one or more of the components such that they come into contact with one another, such as within one or more chambers within the container, passageways, valves, and/or nozzles associated therewith, such as prior to or in conjunction with actuation of the delivery mechanism and/or release from the container. In some instances, the actuation may involve an electronic control mechanism, for instance involving a control circuit that may be in a wired or wireless configuration, such as part of a processor on a microchip, such that by electronic activation of the control circuit the delivery mechanism may be activated and the components of the container may be mixed and/or released, such as for delivery of the foamable and/or flowable material to a user. Such control may be operated in a wired configuration such as by employing an integrated circuit, or may be performed wirelessly, such as through Bluetooth or Low Energy Bluetooth. | B05B704 | 20180112 | 20180927 | B05B704 | 0 | BAINBRIDGE, ANDREW PHILIP | SYSTEMS AND METHODS FOR PRODUCING A FOAMABLE AND/OR FLOWABLE MATERIAL FOR CONSUMPTION | SMALL | 0 | ACCEPTED | B05B | 2,018 |
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15,745,400 | PENDING | SYSTEM FOR DETERMINING THE LAYOUT AND ABSOLUTE AND RELATIVE POSITIONS OF ELEMENTS IN A DISTRIBUTED ANTENNA SYSTEM AND FOR USE OF THOSE ELEMENTS FOR MEASUREMENT | A distributed antenna system including a plurality of remote antenna units, a passive element coupled to at least one of the remote antenna units and an RFID system located proximate the passive element. The RFID system includes processing circuitry and measurement circuitry and the processing circuitry is configured for receiving an interrogation signal and processing the interrogation signal and providing a response. The response includes data associated with a measurement made by the measurement circuitry. | 1. A distributed antenna system comprising: a plurality of remote antenna units, a passive element coupled to at least one of the remote antenna units; an RFID system located proximate the passive element; and wherein the RFID system includes processing circuitry and measurement circuitry, the processing circuitry configured for receiving an interrogation signal and processing the interrogation signal and providing a response, the response including data associated with a measurement made by the measurement circuitry. 2. The distributed antenna system of claim 1 further comprising an interrogator for providing the interrogation signal. 3. The distributed antenna system of claim 2 wherein the interrogator is positioned proximate the remote antenna unit. 4. The distributed antenna system of claim 1 wherein the response provided by the RFID system includes identification information associated with the passive element. 5. The distributed antenna system of claim 1 wherein the RFID system is configured to receive an RF signal and to respond to RF signal with a response. 6. The distributed antenna system of claim 1 wherein the measurement circuitry is configured for measuring a signal level of an RF signal received by the RFID system, the response including data associated with the measured signal level. 7. The distributed antenna system of claim 1 further comprising at least one master unit communicatively coupled to the remote units. 8. The distributed antenna system of claim 7 wherein the master unit is configured to convert downlink signals received from a base station or signal source into one or more digital data streams for transmission to the remote antenna units. 9. A method for use with a distributed antenna system comprising a plurality of remote antenna units, the method comprising: receiving an interrogation signal at an RFID system of the distributed antenna system, the RFID system proximate a passive element coupled to at least one of the remote antennas of the distributed antenna system; making a measurement by the RFID system based on the interrogation signal; and providing, by the RFID system, a response including data associated with the measurement. 10. The method of claim 9 wherein the distributed antenna system further comprises an interrogator configured to provide the interrogation signal. 11. The method of claim 10 wherein the interrogator is positioned proximate the remote antenna unit. 12. The method of claim 9 further comprising processing the interrogation signal to determine identification information associated with the passive element; and wherein the response provided by the RFID system includes identification information associated with the passive element. 13. The method of claim 9 further comprising receiving an RF signal at the RFID system; and responding to the RF signal with a response. 14. The method of claim 9 further comprising measuring, by the RFID system, a signal level of an RF signal received by the RFID system, the response including data associated with the measured signal level. 15. The method of claim 9 wherein the distributed antenna system further comprises at least one master unit communicatively coupled to the remote units. | CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application Ser. No. 62/193,394, filed on Jul. 16, 2015, which is hereby incorporated herein by reference. FIELD OF THE INVENTION Embodiments of the invention are directed to wireless communication systems, and specifically directed to a distributed antenna system for wireless communications. BACKGROUND OF THE INVENTION Distributed antenna systems (DAS) can be used in confined areas to deploy wireless coverage and capacity to mobile devices. A DAS can include active elements such as master units, extension units, and remote units. Among the variety of active elements, a typical DAS may include passive elements as well. Examples of such passive elements are: coaxial cables, RF splitters, RF combiners, RF antennas, optical fiber, optical splitters, optical combiners, attenuators, dummy loads, cable feeds, and surge protectors. Other passive RF or optical devices can include connectors, jacks, wall jacks, and patch cords. Systems are presented for detecting the presence of passive RF or passive optical devices that are present in a DAS. The presence of such device can be facilitated through the employment of radio frequency identification (RFID) chips. One aspect includes coupling the RFID chip to the device that is to be detected. In one aspect of such systems, a coupling network is used to couple to a signal wave inside of a waveguide such as coaxial cable, optical fiber or other type of waveguide. Examples of the coupling network are resonant coupling networks, bandpass filters, low pass filters, high pass filters, and directional or non-directional couplers. One purpose of the coupling network is to pass a maximum of RF energy coming from the interrogator or RFID reader to the RFID chip. Another feature of such systems is that they block other signals used in the DAS at different frequencies than the RF interrogator frequency to avoid potential generation of intermodulation products by the potential non-linear characteristic of the RFID chip. In such systems, a DAS is provided that includes one or more passive elements. Each passive element can be associated with an RFID chip. The RFID chip may be integrated into the passive element or may be coupled, connected, or otherwise associated with the passive element. A reader may be integrated within or otherwise associated with a sub-system of the DAS that is remote from at least some of the passive elements. The reader can transceive RFID signals over a communications network of the DAS. The communications network may include, for example, coaxial cable or another transmission medium that can carry RF signals and RFID signals through the DAS. For example, the reader may transmit an RFID signal that is carried by the communications network through a coupling network to the RFID chip associated with a passive element. The RFID chip can respond to the RFID signal with a responsive signal representing an identifier of the passive element. The responsive signal can be received from the coupling network and transported by the communications network to the reader. The reader may extract the identifier from the responsive signal and provide the identifier to a controller. The passive element may not be required to be powered for a reader to detect the presence of the passive element. Both the reader and the RFID chip may be configured to be in a fixed position within the DAS, as opposed to the reader being moveable. In other aspects, the reader includes one or more readers that are moveable. An RFID chip may be any item that can respond to an RFID signal with a responsive signal representing an identifier for the item. An “RFID chip” may also be known as an “RFID tag.” One such system is described in U.S. patent application Ser. No. 13/798,517, filed Mar. 13, 2013 and entitled “Detecting Passive RF Components Using Radio Frequency Identification Tags”, which application is incorporated herein by reference in its entirety. There is a need for such a DAS system that, in addition to determining the existence and layout of various passive elements in a DAS, can further provide measurements of certain features, parameters and passive elements in the DAS. SUMMARY One embodiment is directed to a distributed antenna system. The distributed antenna system comprises a plurality of remote antenna units. A passive element is coupled to at least one of the remote antenna units. The distributed antenna system further comprises an RFID system located proximate the passive element. The RFID system includes processing circuitry and measurement circuitry. The processing circuitry is configured for receiving an interrogation signal and processing the interrogation signal and providing a response. The response includes data associated with a measurement made by the measurement circuitry. Another embodiment is directed to a method for use with a distributed antenna system comprising a plurality of remote antenna units. The method comprising receiving an interrogation signal at an RFID system of the distributed antenna system. The RFID system is proximate a passive element coupled to at least one of the remote antennas of the distributed antenna system. The method further comprises making a measurement by the RFID system based on the interrogation signal and providing, by the RFID system, a response including data associated with the measurement. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a block diagram of a distributed antenna system. FIG. 2 is a block diagram of passive elements of a distributed antenna system consistent with an embodiment of the invention. FIG. 3 is a block diagram of passive elements of a distributed antenna system consistent with another embodiment of the invention. FIG. 4 is a block diagram of an RFID system for incorporation with passive elements of a distributed antenna system consistent with embodiments of the invention. It should be understood that the appended drawings are not necessarily to scale, presenting a somewhat simplified representation of various preferred features illustrative of the basic principles of embodiments of the invention. The specific design features of the system and/or sequence of operations as disclosed herein, including, for example, specific dimensions, orientations, locations, and shapes of various illustrated components, will be determined in part by the particular intended application and use environment. Certain features of the illustrated embodiments may have been enlarged, distorted or otherwise rendered differently relative to others to facilitate visualization and clear understanding. DETAILED DESCRIPTION OF THE INVENTION The present invention provides a system incorporating RFID technology to determine the network presence and layout of the passive devices and to also use RFID technology for measurements in the DAS system. The passive RF elements of the inventive system incorporate RFID systems (chips) that are closely coupled to the otherwise passive RF elements or RF input or output. The RFID systems incorporate measurement devices or elements, including processing circuitry elements, to determine parameters of the interrogation signal or any RF signal, such as RSSI for example. The measurement system is powered by the RFID chip and is either integrated on the RFID system (typically a chip) or is connected and powered by the RFID system. The RFID measurement system receives an interrogator signal or a sequence of interrogator signals and uses the energy to prepare a response. In addition to the regular RFID response including the unique ID, the RFID system of the invention includes measurement results obtained with the measurement system at the location of the RFID system. The interrogator transceiver may be located at the feed point of the passive DAS and collects the measurement results in a processing system to process, analyze, and make determinations of the layout (interconnectivity and location), the faultless function, the presence of nearby users or interference, plus other information relevant for the operation and maintenance of the passive DAS system. FIG. 1 illustrates a block diagram depicting an embodiment of a DAS for incorporating various aspects of the invention. The DAS 10 can include one or more master units 16 as a donor device that are coupled to one or more remote antenna units 12. The DAS 10 can communicate with one or more base stations or other signal sources (not shown) via a wired or wireless communication medium as appropriate. The DAS and the master units 16 communicate uplink and downlink signals between the base stations and one or more remote antenna units 12 distributed in an environment, such as an indoor environment, to provide coverage within a service area of the DAS 10. The master units 16 can convert downlink signals received from the base station or signal source, such as RF signals, into one or more digital data streams for transmission to the remote antenna units 12. The remote antenna units 12 can convert digital data streams to RF signals. The remote antenna units 12 can amplify the downlink signals and radiate the downlink signals 24 to terminal equipment such as one or more wireless communication devices 26. Uplink signals are handled similarly in the uplink direction and are received from the devices 26 by the remote antenna units 12 and converted from RF to digital data streams and transmitted to the master units 16 and beyond. A system controller 22 can control the operation of the master units 16 for processing the signals communicated with the remote antenna units 12. The signals communicated with the remote antenna units 12 may be the uplink and downlink signals of the DAS 10 for communicating with terminal equipment. The master units 16 can provide downlink signals to the remote antenna units 12 via the links 20. The links 20 can include any communication medium suitable for communicating data via digitized signals between the master unit 16 and the remote antenna units 12. The digitized signals may be communicated electrically or optically. Non-limiting examples of a suitable communication medium for the links 20 can include copper wire (such as a coaxial cable), optical fiber, and microwave or optical communication links. Although the DAS 10 is depicted as including a couple master units 16 and remote antenna units 12 coupled to a master unit, any number (including one) of each of master unit 16 and remote antenna units 12 can be used. Furthermore, a DAS 10, according to some aspects, can be implemented without system controller 22. FIG. 2 is a block diagram of an exemplary remote antenna unit 16 configured for performing RFID detection of passive components and system measurements in accordance with aspects of the invention. The remote antenna unit 16 is coupled through an appropriate waveguide, such as a coaxial cable 30, to a splitting device 32, such as an RF splitter, and then to one or more antennas 34. The remote unit 16 uses a plurality of RFID systems 40 to detect the presence of passive RF components and make measurements in accordance with the invention. Each of the passive RF components, such as RF splitter 32 and antennas 34, has an associated RFID system. Each of the RFID systems 40 are coupled to a respective passive component via appropriate coupling circuits 42 (See FIG. 4) or some other suitable coupling circuit or device. Although three antennas 34 are depicted, any number of antennas (including one) can be used. Each of the RFID systems can include a unique, non-removable, and tamper-proof serial number, similar to an RFID tag and each of the RFID systems 40 can allow the respective passive component to be identified by a system controller 50 that is communication with an RFID interrogator/transceiver 52 or other reader/interrogator system in the remote antenna unit 16. The interrogation process can be initiated by the system controller 50. The system controller 50 can send a command to the RFID interrogator 52 to begin to probe for RFID systems 40 of the passive DAS elements. In some aspects, the RFID interrogator 52 can transmit the probing signal through an appropriate coupling device or current 54. The coupling device 54 can be a directional coupler or a non-directional coupler. In one example, the coupling device 54 can have a coupling ratio of −10 dB or smaller with respect to the coaxial cable 30 in direction to the RFID systems and associated passive elements. In other aspects, the RFID interrogator 52 can transmit the probing signal via a low pass, band pass, or high pass filter. For coupling the RFID signals in accordance with the invention, various appropriate coupling circuits or devices 42 might be used. For example, an RFID system 40 of a passive element might be coupled to another passive component, such as a coaxial cable 30 or other waveguide, via a resonant coupling circuit 42 that includes an attenuation and matching circuit. One coupling circuit 42 might use a capacitor and an inductor arrangement to have certain resonant characteristics. The resonance frequency can be the operational frequency of the RFID system 40. For frequencies separate from the resonance frequency, the coupling circuit 42 can provide a high impedance to minimize negative impacts from signals used for mobile communication via the DAS 10. Non-limiting examples of negative impacts from signals used for mobile communication can include reflection and loss to other signals on different frequencies. An attenuation and matching circuit can include attenuation devices. Other implementations are also possible. In other aspects, a Balun component, such as (but not limited to) a transformer, can be used in place of the attenuation devices. In additional or alternative aspects, the RFID system of the invention can be coupled to the coaxial cable 30 or another passive component via a non-resonant coupling circuit, such as a directional coupler. The directional coupler can be used with a coupling optimized for signals communicated with the RFID interrogator 52 and selected for suppressing potential intermodulation products generated by the RFID system 40 in the direction of one or more antennas. For providing interrogation of the RFID systems 40 of the invention, an interrogation signal can be communicated via the coaxial cable 30. The interrogation signal can experience some loss due to the nature of the coaxial cable 30 or other waveguide. One or more of the RFID systems 40 can receive an interrogation signal that has a signal level above a predetermined threshold for the RFID system. Non-limiting examples for such a threshold include signal levels between −15 dBm and −18 dBm. One or more of the RFID tags 40 can receive the interrogation signal via a respective one of the coupling circuits 42. One or more of the RFID systems 40 can then generate a responsive signal. The responsive signal can be communicated back to the RFID interrogator 52 via the coaxial cable or other waveguide. The DAS 10 may be configured as a low power DAS or a high power DAS. A low power DAS may include remote antenna units having fewer antennas. For a DAS using a low RF power, the RFID interrogator 52 can be included in each remote antenna unit and/or communicate with each remote antenna unit via a central system or devices, such as (but not limited to) the master unit 16 and a network coupling the master unit 16 to each remote antenna unit. Each RF splitter and antenna or other passive element of a respective remote antenna unit 12 can be equipped with an RFID system. The RFID interrogator 52 can transmit probing signals and receive responsive signals from the RFID systems. The implementation and protocol of the RFID standard can be used to suppress collisions in the responses from RFID tags. An element discovery can show which element and associated RFID system ID is connected to a given remote antenna unit. Periodic probing of the passive components and RFID systems can allow the detection of changes in the installation. Periodic probing of the passive components can additionally be used in accordance with one aspect to make various measurements and also to identify faulty components and devices. For a high power DAS more antennas are connected to a given remote antenna unit 12 than a low power DAS. More antennas can be connected to a given remote antenna unit 12 by increasing the amount of splitting performed by a splitting device 32. An RFID signal link budget can be evaluated to avoid the RFID interrogator signal being reduced to an insufficiently high level by the splitting. An RFID implementation having a lower loss and a higher link budget may be used. In some non-limiting embodiments, RFID implementations operating at 100-150 kHz, 13.56 MHz, 860-915 MHz, and potentially 2.4 GHz might be used. While FIG. 2 illustrates one embodiment of a remote antenna unit 12 implementing RFID systems in accordance with the invention, other implementations might utilize additional RF splitters 32, for example, in connecting the various antennas with the remote antenna unit. FIG. 3 illustrates a remote antenna unit 12 coupled with antennas 34 through multiple splitters 32. Each splitter 32 incorporates an RFID system in accordance with the invention. In accordance with one embodiment of the invention, the interrogator is incorporated into a component of the DAS, such as the remote antenna unit 12, and coupled in line through a waveguide, such as coaxial cable 30. Alternatively, as discussed herein, the interrogator might be a free standing or mobile interrogator, such as unit 60 illustrated in FIGS. 2 and 3. FIG. 4 illustrates a block diagram of an RFID system in accordance with an embodiment of the invention. As noted, the RFID system has features of a typical RFID device with respect to a unique identifier or serial number that identifies which RFID system has answered or provided a return signal to an interrogation signal from an RFID reader or interrogator. The RFID system of the invention, in addition to the ID features, also incorporates processing circuitry and measurement circuitry for doing additional measurements and processing in the system. The measurement system is powered by the RFID chip and uses the interrogator signal for powering other elements and features of the system. The processing and measurement circuitry can either be integrated with an RFID device (typically a chip) into an RFID system, as illustrated in FIG. 4, or is connected and powered by the separate RFID device. The RFID measurement system receives one or a sequence of interrogator signals and uses the energy of the interrogator signals to prepare a response. In accordance with one aspect of the invention, the RFID response would include typical unique ID information, but also includes measurement results obtained with the measurement system at the location of the RFID system. FIG. 4 shows an RFID system wherein the various components might be incorporated into a single chip or element for addressing the various features of the system in accordance with the invention. Alternatively, various elements such as the processing elements and measurement or detecting elements might be incorporated in a separate chip that is then powered by the separate RFID chip. As shown in FIGS. 2 and 3, the interrogator transceiver 52 is located at the feed point of the passive DAS for collecting the measurement results from the various RFID systems 40, and to process, analyze, and make determinations of the layout (interconnectivity and location), the faultless function, the presence of nearby users or interference and other information relevant for the operation and maintenance of the passive DAS system. To that end, referring to FIG. 4, an RFID system 40 incorporates an appropriate coupling circuit 42 for receiving a portion of an RFID interrogation signal. The system 40 includes a power generation circuit 62 that uses one or more RFID interrogation signals for providing suitable DC power 64 to other components/elements of the system 40. The RFID system 40 also includes suitable RF transceiver circuitry 66 for providing the necessary communication back and forth between the system 40 and an interrogator 52. The transceiver circuitry 66 might be wired to communicate through the coupling circuitry directly onto the coaxial cable 30 or other waveguide. Alternatively, for a mobile interrogator, the system might incorporate transceiver circuitry 66a for communication over the air in a wireless link. The transceiver circuitry 66a would be coupled to an appropriate antenna element 67 for the wireless link. In accordance with one aspect of the invention, the RFID system 40 includes measurement circuitry 68 for measuring characteristics of an RF interrogator signal or other signal that is coupled to the system 40 through coupling circuitry 42. In one embodiment, the measurement circuitry 68 might include an RF power detector for detecting levels of the RF signals (interrogator signals or other RF signals) that are captured by the system 40 through the coupling circuitry 42. System 40 also incorporates processing circuitry 70, such as a processing unit or processor, that provides signal processing at the system 40 in accordance with features of the invention. The processing circuitry 70 is coupled with memory 72 for storing and accessing information, such as the unique 10 information of the system 40. The processing circuitry can be used to control various of the other elements of the system, such as the measurement circuitry 68 and transceiver circuitry 66. In accordance with one feature of the invention, the RFID system can make a measurement of the level of signals received by the system and process that information and return it to the interrogator 52, such as to determine an amount of cable loss in the sections of the cable that might connect the passive elements to the interrogator 52. For example, referring to FIG. 2, the interrogator 52 might receive an RSSI measurement from the RFID system that is associated with an interrogation signal that was sent. The interrogation signal is sent from interrogator 52 of the remote antenna unit 16 and is received by the RFID system 40 associated with the RF splitter 32. The RFID system 40 couples off the RFID interrogation signal with the coupling circuit 42 and it is directed to appropriate measurement circuitry 68, such as a power detector. The RFID interrogation signal might also be used for providing suitable power 64 to power the processing circuitry and other elements of system 40. The power detector 68 determines the level of the received interrogation signal (RSSI) and reports the measured level to the processing circuitry 70 that processes it to formulate a response. The response signal then returns suitable information, such as ID information (indicating which RFID system is responding) and measured RSSI power levels, to the interrogator 52. The transceiver circuitry 66 is used to provide the measured information as a response. The interrogator 52 has suitable processing circuitry for evaluating the level of the interrogation signal that was originally sent and the returned RSSI information from the RFID system response for determining the loss that occurred in the cable between the remote antenna unit and the RF splitter element, or other passive element where the RFID system 40 responds. The amount of cable loss might then be used to determine if there is a fault in the cable or some other issue with the cable connection. The coupling losses associated with the interrogator and the RFID system itself may be taken into account when determining the overall cable loss for coaxial cable 30 or other waveguide. In accordance with another feature of the invention, the RFID system can be used for determining the transfer function (amplitude and phase at the frequency of the interrogation signal) between the DAS feed and a particular passive element with the RFID system. More specifically, an RF signal might be captured by the RFID system 40 of a passive element. The captured RF signal might be from the interrogator 52 or might be some other RF signal transmitted by the feeding system of the DAS. The information regarding the captured RF signal, such as a measured signal level of the RF signal, is then included in the RFID system response to the interrogator 52 for further processing by the processing circuitry of the interrogator. Through a comparison of the response with the original transmitted signal (either interrogation signal or other RF signal), the processing circuitry of the interrogator unit can determine the noted transfer function of the system at a frequency of interest. In accordance with another feature of the invention, the interrogator processing system can determine the amount of delay that occurs between the transmission of the interrogation signal, such as from the remote antenna unit, and the reception of the response from the passive element RFID system and the processing circuitry of the RFID system. In evaluating that time difference or delta, the cable distance that exists in the coaxial cable 30 between the remote antenna unit feed and a passive element such as the RF splitter 32 might then be determined. The measured distance result might experience some error associated with the processing delay in the RFID system 40. To that end, the RFID system makes a determination of the processing time delay between receipt of the interrogation signal and the transmission time of the response generated from the RFID system. The processing circuitry 70 of the system 40 can use that processing delay information and provide that delay information in the response that is sent back to the interrogator 52. For the purposes of determining the processing delay more accurately, in one embodiment, an interrogator might be used for sending a periodic probing signal and measuring the response delay of several responses. Then a min. hold function is used to determine the group delay between the interrogator and the RFID chip. For this measurement a high speed sampling technology at the interrogator for the response is required to capture the response waveform with the accuracy of nanoseconds. As a method to determine the delay the interrogator can correlate the received response from the RFID system with a stored response. From the position in time delay of the correlation peak, the group delay, and thus length to the RFID system, can be determined. In accordance with another feature of the invention, the RFID system and the processing circuitry 70 and measurement circuitry 68 therein might be triggered by the interrogator to provide desired measurement and processing of signals present at the passive element associated with a particular RFID system 40. Upon receipt of a trigger signal from the interrogator 52, the RFID system 40 measures the RSSI of any present signal at the position of that RFID system (e.g., a particular passive DAS element). That present signal might be a downlink (DL) signal that was sent by the DAS feed, a DL signal received by the passive DAS system, or an uplink (UL) signal received by the antenna feeding the trunk. Upon being appropriately triggered, the RFID system 40 makes the necessary signal measurement and provides a response to the interrogator that includes the measured information, in addition to identification information associated with a specific passive element. In another embodiment of the invention, other trigger mechanisms might be used by the RFID system 40 to take an RF measurement. For example, events that would trigger the measurement at the RFID system 40 can be time delay, RF signal level of any received signal at the RFID system measurement circuitry. Downlink signals of the DAS might be used, as well as uplink signals of a user that is located in the DAS coverage area. Alternatively, interference from a signal source that is only active for a certain period of time might be utilized as a trigger signal for the RFID system 40. The measurement circuitry and processing circuitry of the RFID system receive and evaluate the trigger signal and make desired measurements and then provide the desirable RF measurements and information in a response signal to the interrogator for further processing. Utilizing the RFID system of the invention, measurements such as cable loss and cable distance may be determined. For each passive element, such as each antenna, various measurements might be made as disclosed herein to evaluate the operation of the element and the overall DAS system. This provides troubleshooting capabilities for the DAS and the passive elements therein. For example, the DAS may store suitable element parameters that are reflective of the elements at the time of commissioning the DAS. Any faults or degradation may be determined using the invention and appropriately alarmed for the DAS system administrator to address. For example, stored tables of loss parameters and distance values for all the elements in the passive DAS may be provided and, in combination with measured data from responses from RFID systems of the passive elements, may be used for verification and troubleshooting of those elements and the passive portions of the DAS installation. In accordance with another aspect of the invention, the system responds only upon receiving several interrogation signals that would act as a trigger for making measurements or providing a response to an interrogator 52 from the RFID system 40. Specifically, several interrogation signals might be sent, either with a gap between the signals, or without a gap, and the RFID system and processing circuitry 70 would require a certain number of the interrogation signals in order to trigger an actual response from the RFID system. Utilizing several interrogation signals would improve the time synchronization of the RFID system, and provide higher accuracy between a received signal from the interrogator system, and the processing of the signal in the response of the RFID system. In that way, greater accuracy might be achieved in determining the processing time delay that is provided by the RFID system. As noted above, with greater accuracy in the processing delay, greater accuracy might be provided in determining the cable distance between two elements within the DAS. In accordance with another aspect of the invention, the RFID system might determine the origin of uplink (UL) mobile traffic. In that regard, the RFID system utilizes a level-based trigger in order to respond. A response from the RFID system, including the unique identification information from the RFID system, provides a known position within the DAS. In that way, with the known position of the RFID system, the location of the traffic that triggered a response can be further narrowed down to a specific passive component, rather than just the entire DAS coverage area. In accordance with another aspect of the invention, as illustrated in FIG. 2, an RF splitter 32 may have multiple antenna elements 34 connected thereto. In that regard, the RFID system 40 of the splitter might be coupled appropriately to each of the ports in order to either measure or capture the response of a connected RFID system of an antenna, for example, using the RF level as a trigger. The transmission of the response from an antenna RFID system, and its correlation to a specific input of the splitter can provide a determination of the specific splitter port where the antenna element is connected. Successively, all the interconnects to the splitter can be determined, documented, and used for trouble shooting. For example, an individual antenna element might respond with a message that includes information that it is an antenna that is responding. Similarly, a splitter port or other element might respond with similar information. In accordance with another feature of the invention, as illustrated in FIG. 4, the RFID system may utilize a coupling circuit 42 for coupling off an interrogator signal or other RF signal. Alternatively, an antenna 67 and appropriate transceiver circuitry 66a might also be implemented. Therefore, the RFID system of a passive element can be coupled to a specific RF feed line or waveguide, or might be coupled directly to the air. This allows probing of the RFID system, with a portable interrogator, in addition to probing the RFID system with an interrogator 52 in a remote antenna unit, as illustrated in FIGS. 2 and 3. In some scenarios, it may be desirable to receive any response from an RFID system on air, even though the interrogation signal was sent through a waveguide. For example, a portable interrogator or interrogating transceiver can be implemented in the area of passive elements of a DAS to determine the location of the various elements that are equipped with the RFID systems. By linking the position of the portable interrogator with the response received from the RFID system, the location of the passive element can be approximated. In that regard, adjusting the RF power of the interrogator transmitter to a lower value so as to only trigger closely-located elements, can improve the accuracy of the determination of the absolute location of the elements. Such location of the various elements may assist in making suitable measurements for evaluating any fault or degradation in DAS. In such a mobile interrogator scenario, the interrogation signal can be received by an over-the-air antenna 67 of the RFID system, or the interrogation signal might be sent through an antenna element 34 coupled to the remote antenna units. Any interrogation signal through antenna element 34 might then be coupled with the signal path by the coupling circuitry 42 of the RFID system 40, and processed accordingly to provide a response back to the interrogator. A passive portion of a DAS can be as simple as an antenna feed in a point-to-point scenario, or a leaky feeder system, or may be a complex passive network consisting of various of the RF elements, as listed herein, such as RF and optical splitters and combiners, coaxial cables and other waveguides, and RF antennas. Therefore, the present invention is not limited to specific type of passive element within a DAS. While the present invention has been illustrated by the description of the embodiments thereof, and while the embodiments have been described in considerable detail, it is not the intention of the applicant to restrict or in any way limit the scope of the appended claims to such detail. Additional advantages and modifications will readily appear to those skilled in the art. Therefore, the invention in its broader aspects is not limited to the specific details representative apparatus and method, and illustrative examples shown and described. Accordingly, departures may be made from such details without departure from the spirit or scope of applicant's general inventive concept. Example Embodiments Example 1 includes a distributed antenna system comprising: a plurality of remote antenna units, a passive element coupled to at least one of the remote antenna units; an RFID system located proximate the passive element; and wherein the RFID system includes processing circuitry and measurement circuitry, the processing circuitry configured for receiving an interrogation signal and processing the interrogation signal and providing a response, the response including data associated with a measurement made by the measurement circuitry. Example 2 includes the distributed antenna system of Example 1 further comprising an interrogator for providing the interrogation signal. Example 3 includes the distributed antenna system of Example 2 wherein the interrogator is positioned proximate the remote antenna unit. Example 4 includes the distributed antenna system of any of the Examples 1-3 wherein the response provided by the RFID system includes identification information associated with the passive element. Example 5 includes the distributed antenna system of any of the Examples 1-4 wherein the RFID system is configured to receive an RF signal and to respond to RF signal with a response. Example 6 includes the distributed antenna system of any of the Examples 1-5 wherein the measurement circuitry is configured for measuring a signal level of an RF signal received by the RFID system, the response including data associated with the measured signal level. Example 7 includes the distributed antenna system of any of the Examples 1-6 further comprising at least one master unit communicatively coupled to the remote units. Example 8 includes the distributed antenna system of Example 7 wherein the master unit is configured to convert downlink signals received from a base station or signal source into one or more digital data streams for transmission to the remote antenna units. Example 9 includes a method for use with a distributed antenna system comprising a plurality of remote antenna units, the method comprising: receiving an interrogation signal at an RFID system of the distributed antenna system, the RFID system proximate a passive element coupled to at least one of the remote antennas of the distributed antenna system; making a measurement by the RFID system based on the interrogation signal; and providing, by the RFID system, a response including data associated with the measurement. Example 10 includes the method of Example 9 wherein the distributed antenna system further comprises an interrogator configured to provide the interrogation signal. Example 11 includes the method of Example 10 wherein the interrogator is positioned proximate the remote antenna unit. Example 12 includes the method of any of the Examples 9-11 further comprising processing the interrogation signal to determine identification information associated with the passive element; and wherein the response provided by the RFID system includes identification information associated with the passive element. Example 13 includes the method of any of the Examples 9-12 further comprising receiving an RF signal at the RFID system; and responding to the RF signal with a response. Example 14 includes the method of any of the Examples 9-13 further comprising measuring, by the RFID system, a signal level of an RF signal received by the RFID system, the response including data associated with the measured signal level. Example 15 includes the method of any of the Examples 9-14 wherein the distributed antenna system further comprises at least one master unit communicatively coupled to the remote units. | <SOH> BACKGROUND OF THE INVENTION <EOH>Distributed antenna systems (DAS) can be used in confined areas to deploy wireless coverage and capacity to mobile devices. A DAS can include active elements such as master units, extension units, and remote units. Among the variety of active elements, a typical DAS may include passive elements as well. Examples of such passive elements are: coaxial cables, RF splitters, RF combiners, RF antennas, optical fiber, optical splitters, optical combiners, attenuators, dummy loads, cable feeds, and surge protectors. Other passive RF or optical devices can include connectors, jacks, wall jacks, and patch cords. Systems are presented for detecting the presence of passive RF or passive optical devices that are present in a DAS. The presence of such device can be facilitated through the employment of radio frequency identification (RFID) chips. One aspect includes coupling the RFID chip to the device that is to be detected. In one aspect of such systems, a coupling network is used to couple to a signal wave inside of a waveguide such as coaxial cable, optical fiber or other type of waveguide. Examples of the coupling network are resonant coupling networks, bandpass filters, low pass filters, high pass filters, and directional or non-directional couplers. One purpose of the coupling network is to pass a maximum of RF energy coming from the interrogator or RFID reader to the RFID chip. Another feature of such systems is that they block other signals used in the DAS at different frequencies than the RF interrogator frequency to avoid potential generation of intermodulation products by the potential non-linear characteristic of the RFID chip. In such systems, a DAS is provided that includes one or more passive elements. Each passive element can be associated with an RFID chip. The RFID chip may be integrated into the passive element or may be coupled, connected, or otherwise associated with the passive element. A reader may be integrated within or otherwise associated with a sub-system of the DAS that is remote from at least some of the passive elements. The reader can transceive RFID signals over a communications network of the DAS. The communications network may include, for example, coaxial cable or another transmission medium that can carry RF signals and RFID signals through the DAS. For example, the reader may transmit an RFID signal that is carried by the communications network through a coupling network to the RFID chip associated with a passive element. The RFID chip can respond to the RFID signal with a responsive signal representing an identifier of the passive element. The responsive signal can be received from the coupling network and transported by the communications network to the reader. The reader may extract the identifier from the responsive signal and provide the identifier to a controller. The passive element may not be required to be powered for a reader to detect the presence of the passive element. Both the reader and the RFID chip may be configured to be in a fixed position within the DAS, as opposed to the reader being moveable. In other aspects, the reader includes one or more readers that are moveable. An RFID chip may be any item that can respond to an RFID signal with a responsive signal representing an identifier for the item. An “RFID chip” may also be known as an “RFID tag.” One such system is described in U.S. patent application Ser. No. 13/798,517, filed Mar. 13, 2013 and entitled “Detecting Passive RF Components Using Radio Frequency Identification Tags”, which application is incorporated herein by reference in its entirety. There is a need for such a DAS system that, in addition to determining the existence and layout of various passive elements in a DAS, can further provide measurements of certain features, parameters and passive elements in the DAS. | <SOH> SUMMARY <EOH>One embodiment is directed to a distributed antenna system. The distributed antenna system comprises a plurality of remote antenna units. A passive element is coupled to at least one of the remote antenna units. The distributed antenna system further comprises an RFID system located proximate the passive element. The RFID system includes processing circuitry and measurement circuitry. The processing circuitry is configured for receiving an interrogation signal and processing the interrogation signal and providing a response. The response includes data associated with a measurement made by the measurement circuitry. Another embodiment is directed to a method for use with a distributed antenna system comprising a plurality of remote antenna units. The method comprising receiving an interrogation signal at an RFID system of the distributed antenna system. The RFID system is proximate a passive element coupled to at least one of the remote antennas of the distributed antenna system. The method further comprises making a measurement by the RFID system based on the interrogation signal and providing, by the RFID system, a response including data associated with the measurement. | H04B1717 | 20180116 | 20180726 | 76421.0 | H04B1717 | 0 | CAO, ALLEN T | SYSTEM FOR DETERMINING THE LAYOUT AND ABSOLUTE AND RELATIVE POSITIONS OF ELEMENTS IN A DISTRIBUTED ANTENNA SYSTEM AND FOR USE OF THOSE ELEMENTS FOR MEASUREMENT | UNDISCOUNTED | 0 | ACCEPTED | H04B | 2,018 |
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15,745,982 | PENDING | RETENTION ELEMENT FOR ATTACHING A FIRST DENTAL COMPONENT TO A SECOND DENTAL COMPONENT AND DENTAL ASSEMBLY COMPRISING THE RETENTION ELEMENT | The invention relates to a retention element (1) for attaching a first dental component (20), such as an abutment, to a second dental component (30), such as a dental implant. The retention element (1) comprises a coronal attachment portion (2) for attaching the retention element (1) to the first dental component (20), and an apical attachment portion (4) for attaching the retention element (1) to the second dental component (30). The retention element (1) is elastically deformable at least in all directions perpendicular to the direction from the apical attachment portion (4) towards the coronal attachment portion (2). The apical attachment portion (4) comprises at least one projection (8) extending in one or more directions substantially perpendicular to the direction from the apical attachment portion (4) towards the coronal attachment portion (2). Further, the invention relates to a dental assembly comprising the retention element (1) and to a use of the retention element (1) for attaching a first dental component (20), such as an abutment, to a second dental component (30), such as a dental implant, outside a human or animal body. | 1. A retention element configured to attach a first dental component to a second dental component, the retention element comprising: a coronal attachment portion configured to attach the retention element to the first dental component; and an apical attachment portion configured to attach the retention element to the second dental component; wherein the retention element is elastically deformable at least in all directions perpendicular to the direction from the apical attachment portion towards the coronal attachment portion, and the apical attachment portion comprises at least one projection extending in one or more directions substantially perpendicular to the direction from the apical attachment portion towards the coronal attachment portion. 2. The retention element according to claim 1, wherein the retention element has at least one portion extending from an apical end of the retention element to a coronal end of the retention element, said at least one portion being more flexible than the remainder of the retention element. 3. The retention element according to claim 1, wherein the retention element has at least one cut-out portion extending from an apical end of the retention element to a coronal end of the retention element. 4. The retention element according to claim 3, wherein the retention element is a hollow body and the at least one cut-out portion penetrates an outer wall of the retention element. 5. The retention element according to claim 1, wherein the coronal attachment portion comprises at least one projection extending in one or more directions substantially perpendicular to the direction from the apical attachment portion towards the coronal attachment portion. 6. The retention element according to claim 5, wherein the number of projections of the apical attachment portion is different from the number of projections of the coronal attachment portion. 7. The retention element according to claim 1, wherein the apical attachment portion comprises two or more projections, each extending in one or more directions substantially perpendicular to the direction from the apical attachment portion towards the coronal attachment portion. 8. The retention element according to claim 1, further comprising a through hole extending through the retention element in the direction from the coronal attachment portion towards the apical attachment portion. 9. The retention element according to claim 1, wherein the retention element has a marking. 10. The retention element according to claim 1, wherein the retention element further comprises an indication and/or tracking device. 11. The retention element according to claim 1, wherein the retention element is made of a metal, a polymer or a composite material. 12. A dental assembly comprising the retention element according to claim 1 and the first dental component. 13. The dental assembly according to claim 12, further comprising the second dental component. 14. A dental assembly comprising the retention element according to claim 1 and the second dental component. 15. A use of the retention element according to claim 1 to attach the first dental component to the second dental component. 16. The retention element according to claim 1, wherein the first dental component comprises an abutment. 17. The retention element according to claim 1, wherein the second dental component comprises a dental implant. 18. The retention element according to claim 9, wherein the marking comprises a color code. 19. The retention element according to claim 10, wherein the indication and/or tracking device comprises an RFID tag. 20. The retention element according to claim 12, wherein the first dental component comprises an abutment. 21. The retention element according to claim 13, wherein the second dental component comprises a dental implant. 22. The retention element according to claim 14, wherein the second dental component comprises a dental implant. 23. The retention element according to claim 15, wherein the first dental component comprises an abutment. 24. The retention element according to claim 15, wherein the second dental component comprises a dental implant. | FIELD OF THE INVENTION The present invention relates to a retention element for attaching a first dental component, such as an abutment, to a second dental component, such as a dental implant. Further, the invention relates to a dental assembly comprising such a retention element and the first dental component and/or the second dental component and to a use of such a retention element for attaching the first dental component to the second dental component outside a human or animal body. BACKGROUND ART Dental prostheses, such as dental crowns or dental bridges, are widely used for the treatment of partly or fully edentulous patients. These prostheses are commonly attached to dental implants placed in a patient's jaw bone with the use of an abutment arranged between implant and prosthesis. For this purpose, single-piece abutments, consisting of a single piece, or multi-piece abutments, comprising two or more separate pieces, may be employed. When providing a patient with a dental prosthesis, the abutment has to be attached to the implant placed in the patient's jaw bone. Further, for the case of a multi-piece abutment, the different pieces of the abutment have to be attached to each other. Moreover, other dental components, such as impression taking components, e.g., open or closed tray impression posts, intra-oral scanning or desk top scanning locators, healing caps, temporary restorations etc., may have to be attached to the implant in the treatment process. In these attachment processes, misfits or misalignments between the different dental components may occur, rendering the attachment complicated and causing the risk of improper placement of one or more of the components. In particular, when mounting an abutment to a dental implant, it is difficult for a clinician to assess whether the abutment is properly seated, i.e., fully engaged with the implant. If the abutment is fixed to the implant in an incorrect position, e.g., by engaging and tightening a clinical screw, problems, such as an improper placement of the dental prosthesis, the formation of undesired gaps between different components etc., can arise and the strength of the connection can be compromised. These difficulties in attaching the abutment to the implant are further aggravated if the implant is placed in the patient's upper jaw bone, due to gravity. One possible way of verifying whether the abutment is correctly seated in the implant is to take an X-ray image of the patient's jaw bone with the abutment in place. However, this approach renders the attachment process inefficient and expensive. In order to prevent fixation of the abutment to the implant in an incorrect position, it is known to provide a height lift that prevents a clinical screw from engaging with the implant if the abutment is not fully seated or if the abutment is automatically forced into its correct position while tightening the screw. In this case, the abutment cannot be secured to the implant in an improper position by the clinician. However, this means that the clinician has to repeat the steps of removing the screw, checking the position of the abutment and reinserting the screw until the screw can be engaged, thus rendering the attachment process inefficient and cumbersome. Further, there are several possible reasons why the screw may not properly engage with the implant, such as an incorrect insertion of the screw or damaged threads on the screw and/or the implant. Hence, the fact that the screw cannot be engaged is not an unambiguous indication of an incorrect placement of the abutment. U.S. Pat. No. 8,033,826 B2 discloses an abutment for use with a dental implant. The abutment comprises a prosthetic portion adapted to support a prosthesis thereon and an insert. The insert extends into a passageway of the prosthetic portion and engages the subgingival end of the prosthetic portion. The insert includes flexible retention fingers that, upon insertion into the passageway, initially contract before reaching an enlarged retention groove and then expand outwardly into the enlarged retention groove to hold the insert onto the prosthetic portion. However, in the case of the insert disclosed in U.S. Pat. No. 8,033,826 B2, only the fingers, which form a small part of the entire insert, are flexible. Hence, these fingers are prone to wear and breakage, in particular, if the insert is repeatedly engaged with and removed from the prosthetic portion. For example, in a dental laboratory, a technician will have to engage and remove a prosthetic portion or other dental components repeatedly. Moreover, for example, also in the case that a patient is provided with a temporary restoration, the insert will have to be engaged and removed a number of times. Hence, there remains a need for a reliable and efficient approach for attaching a first dental component, such as an abutment, to a second dental component, such as a dental implant, which provides a clear indication of whether the first and second dental components are properly attached to each other. SUMMARY OF THE INVENTION Accordingly, it is an object of the present invention to provide a retention element for attaching a first dental component, such as an abutment, to a second dental component, such as a dental implant, which efficiently provides reliable indication of whether the first and second dental components are properly attached to each other. Further, the invention aims to provide a dental assembly comprising such a retention element and a use of such a retention element for attaching the first dental component to the second dental component. These goals are achieved by a retention element with the technical features of claim 1, by dental assemblies with the technical features of claim 12 or 14 and by a use of the retention element with the technical features of claim 15. The invention provides a retention element for attaching a first dental component, such as an abutment to a second dental component, such as a dental implant. The retention element comprises a coronal attachment portion for attaching the retention element to the first dental component, and an apical attachment portion for attaching the retention element to the second dental component. The retention element is elastically deformable at least in all directions perpendicular to the direction from the apical attachment portion towards the coronal attachment portion. The apical attachment portion comprises at least one projection extending in one or more directions substantially perpendicular to the direction from the apical attachment portion towards the coronal attachment portion. Thus, the entire retention element is elastically deformable. The retention element is elastically deformable along its entire length. The length of the retention element extends along the longitudinal direction thereof, i.e., the direction from the apical attachment portion towards the coronal attachment portion. The entire retention element can thus be elastically deformed at least in or along all directions perpendicular to the direction from the apical attachment portion towards the coronal attachment portion, i.e., in or along all the transverse directions of the retention element. The apical attachment portion comprises at least one projection or protrusion extending from an outer surface of the remainder of the retention element in one or more directions substantially perpendicular to the direction from the apical attachment portion towards the coronal attachment portion. The at least one projection or protrusion of the apical attachment portion is configured to be received in a corresponding cavity formed in a coronal portion of the second dental component, such as a dental implant. The first dental component, such as an abutment, is attached to the second dental component, such as a dental implant, by attaching the apical attachment portion of the retention element to the second dental component and attaching the first dental component to the coronal attachment portion of the retention element. When attaching the apical attachment portion of the retention element to the second dental component, the retention element is initially elastically deformed, i.e., elastically compressed, along the transverse directions of the retention element and subsequently restored to its initial shape when the at least one projection has been received in the corresponding cavity of the second dental component, due to the restoring force of the retention element. Hence, the apical attachment portion can be attached to the second dental component by snap fit in a reliable and efficient manner. The engagement of the at least one projection of the apical attachment portion with the corresponding cavity of the second dental component provides an audible and/or tactile feedback to a user, such as a clinician or a technician, e.g., in a dental laboratory, providing a clear and unambiguous indication that the retention element, and thus also the first dental component, is properly attached to the second dental component. The whole retention element, rather than only a portion thereof, is elastically deformable along its transverse directions. In this way, a particularly high degree of flexibility of the retention element is achieved. Further, the entire retention element is elastically deformed upon attachment thereof to the second dental component, thus minimising the risk of wear or breakage of the retention element, even if the retention element is repeatedly engaged with and removed from the second dental component. Therefore, the retention element of the invention provides a clear, reliable and efficient indication of whether the first dental component is properly attached to the second dental component. The retention element may have a substantially cylindrical shape, e.g., with a substantially circular cross-section perpendicular to the direction from the apical attachment portion towards the coronal attachment portion, i.e., the longitudinal direction of the retention element. The at least one projection or protrusion of the apical attachment portion extends in one or more directions substantially perpendicular to the longitudinal direction of the retention element, i.e., in one or more transverse directions thereof. In particular, the apical attachment portion may comprise at least one projection or protrusion which extends in plural transverse directions of the retention element, i.e., extends along a portion of the outer surface of the remainder of the retention element in the circumferential direction of the retention element. The at least one projection or protrusion may extend along 10% or more, 20% or more or 30% or more of the outer circumference of the remainder of the retention element. The first dental component may be, for example, an abutment, e.g., a single-piece or a multi-piece abutment, an impression taking component, such as an open or closed tray impression post, an intra-oral scanning or desk top scanning locator, a healing cap, a temporary restoration or a final restoration. The second dental component may be, for example, a dental implant or an implant analogue, e.g., for use in a dental laboratory. For the case of a multi-piece abutment, e.g., a two-piece abutment, the first dental component may be one piece of the abutment and the second dental component may be another piece of the abutment. A base piece or unit of the multi-piece abutment may be attached to a dental implant by the retention element of the invention. The first dental component and/or the second dental component may be made of, for example, a metal, a ceramic, a polymer or a composite material. In particular, the first dental component may be an abutment made of a ceramic, a metal, a polymer or a composite material. The second dental component may be a dental implant made of, for example, a metal, such as titanium, a titanium alloy or stainless steel. The retention element of the invention may further comprise an intermediate portion arranged between the coronal attachment portion and the apical attachment portion. The retention element may have at least one portion extending from an apical end of the retention element to a coronal end of the retention element, the at least one portion being more flexible than the remainder of the retention element. This flexible portion of the retention element contributes to or even provides the elastic deformability of the retention element. Hence, the retention element can be configured in an elastically deformable manner in a simple and efficient way. The at least one portion extending from the apical end of the retention element to the coronal end of the retention element may be made or formed of a material which is more flexible than a material of the remainder of the retention element. Alternatively or additionally, the at least one portion may have a configuration or structure with a higher degree of flexibility than the configuration or structure of the remainder of the retention element. For example, the at least one portion may be made more flexible by providing, for example, perforations, recesses, openings or the like therein. Also, e.g., the at least one portion may have a smaller thickness, i.e., wall thickness, than the remainder of the retention element. The retention element may have two or more, three or more or four or more portions extending from the apical end of the retention element to the coronal end of the retention element, these portions being more flexible than the remainder of the retention element. The retention element may have at least one cut-out or recessed portion extending from the apical end of the retention element to the coronal end of the retention element. The at least one cut-out or recessed portion contributes to or even provides the elastic deformability of the retention element. Forming the retention element with such an at least one cut-out or recessed portion provides a particularly flexible configuration of the retention element. Further, the retention element has an especially simple structure. The retention element may be a hollow and/or tubular body, wherein the at least one cut-out or recessed portion penetrates an outer wall of the retention element. The retention element may have an open ring shape or open annular shape, i.e., the shape of a ring with an opening in the circumference thereof, or substantially a C-shape, in a cross-section perpendicular to the longitudinal direction of the retention element. The coronal attachment portion of the retention element may be attachable to the first dental component, such as an abutment, by friction fit. The coronal attachment portion of the retention element may comprise at least one projection or protrusion extending in one or more directions substantially perpendicular to the direction from the apical attachment portion towards the coronal attachment portion. The explanations and definitions provided above for the at least one projection or protrusion of the apical attachment portion also apply to the at least one projection or protrusion of the coronal attachment portion. The at least one projection or protrusion of the coronal attachment portion is configured to be received in a corresponding cavity formed in an apical portion of the first dental component, such as an abutment. In this way, the coronal attachment portion can be reliably and efficiently attached to the first dental component by snap fit. The at least one projection or protrusion of the coronal attachment portion extends in one or more directions substantially perpendicular to the longitudinal direction of the retention element, i.e., in one or more transverse directions thereof. In particular, the coronal attachment portion may comprise at least one projection or protrusion which extends in plural transverse directions of the retention element, i.e., extends along a portion of the outer surface of the remainder of the retention element in the circumferential direction of the retention element. The at least one projection or protrusion may extend along 10% or more, 20% or more or 30% or more of the outer circumference of the remainder of the retention element. The apical attachment portion may comprise a plurality, e.g., two or more, three of more, four or more, or five or more, projections or protrusions, each extending in one or more directions substantially perpendicular to the direction from the apical attachment portion towards the coronal attachment portion. The plurality of projections or protrusions may have the same or different extensions in the circumferential direction of the retention element. The plurality of projections or protrusions may have the same or different protruding heights from an outer surface of the remainder of the retention element, i.e., heights from this outer surface in one or more directions substantially perpendicular to the direction from the apical attachment portion towards the coronal attachment portion. The plural projections or protrusions of the apical attachment portion may be sequentially or consecutively arranged in the circumferential direction of the retention element, i.e., so that one is arranged after the other in this circumferential direction. The plural projections or protrusions may be equidistantly spaced from each other or spaced from each other at different intervals in the circumferential direction of the retention element. The plural projections or protrusions of the apical attachment portion are configured to be received in a corresponding cavity or corresponding cavities formed in the coronal portion of the second dental component, such as a dental implant. The coronal attachment portion may comprise a plurality, e.g., two or more, three or more, four or more, or five or more, projections or protrusions, each extending in one or more directions substantially perpendicular to the direction from the apical attachment portion towards the coronal attachment portion. The plurality of projections or protrusions may have the same or different extensions in the circumferential direction of the retention element. The plurality of projections or protrusions may have the same or different protruding heights from an outer surface of the remainder of the retention element, i.e., heights from this outer surface in one or more directions substantially perpendicular to the direction from the apical attachment portion towards the coronal attachment portion. The plural projections or protrusions of the coronal attachment portion may be sequentially or consecutively arranged in the circumferential direction of the retention element, i.e., so that one is arranged after the other in this circumferential direction. The plural projections or protrusions may be equidistantly spaced from each other or spaced from each other at different intervals in the circumferential direction of the retention element. The plural projections or protrusions of the coronal attachment portion are configured to be received in a corresponding cavity or corresponding cavities formed in the apical portion of the first dental implant, such as an abutment. The number of projections or protrusions of the apical attachment portion may be different from the number of projections or protrusions of the coronal attachment portion. The number of projections or protrusions of the apical attachment portion may be larger or smaller than the number of projections or protrusions of the coronal attachment portion, e.g., by one, two, three, four or five, or by one or more, two or more, three or more, four or more, or five or more. Particularly preferably, the number of projections or protrusions of the apical attachment portion is smaller than the number of projections or protrusions of the coronal attachment portion. At least one projection or protrusion of the apical attachment portion may be arranged congruently to at least one protrusion or projection of the coronal attachment portion, i.e., so that the at least one projection or protrusion of the apical attachment portion is arranged above the at least one projection or protrusion of the coronal attachment portion in the longitudinal direction of the retention element. At least one projection or protrusion of the apical attachment portion may be arranged so as to be offset or staggered from at least one projection or protrusion of the coronal attachment portion in the circumferential direction of the retention element. Further, also a combination of these two configurations is possible, i.e., some projections or protrusions may be arranged in a congruent manner and some projections or protrusions may be arranged in an offset or staggered manner. At least one projection or protrusion of the apical attachment portion may be arranged so as to at least partly overlap at least one projection or protrusion of the coronal attachment portion in the circumferential direction of the retention element. At least one projection or protrusion of the apical attachment portion may have an extension in the circumferential direction of the retention element which is the same as the extension of at least one projection or protrusion of the coronal attachment portion in the circumferential direction of the retention element. At least one projection or protrusion of the apical attachment portion may have an extension in the circumferential direction of the retention element which is different from, i.e., larger or smaller than, the extension of at least one projection or protrusion of the coronal attachment portion in the circumferential direction of the retention element. The extension of each projection or protrusion of the apical attachment portion in the circumferential direction of the retention element may be the same as or different from, i.e., larger or smaller than, the extension of each projection or protrusion of the coronal attachment portion in the circumferential direction of the retention element. Particularly preferably, the extension of each projection or protrusion of the apical attachment portion in the circumferential direction of the retention element is larger than the extension of each projection or protrusion of the coronal attachment portion in the circumferential direction of the retention element. At least one projection or protrusion of the apical attachment portion may have a protruding height from an outer surface of the remainder of the retention element, i.e., a height from this outer surface in one or more directions substantially perpendicular to the direction from the apical attachment portion towards the coronal attachment portion, which is the same as the protruding height of at least one projection or protrusion of the coronal attachment portion. At least one projection or protrusion of the apical attachment portion may have a protruding height from the outer surface of the remainder of the retention element which is different from, i.e., larger or smaller than, the protruding height of at least one projection or protrusion of the coronal attachment portion. The protruding height of each projection or protrusion of the apical attachment portion may be the same as or different from, i.e., larger or smaller than, the protruding height of each projection or protrusion of the coronal attachment portion. Particularly preferably, the protruding height of each projection or protrusion of the apical attachment portion is larger than the protruding height of each projection or protrusion of the coronal attachment portion. As has been detailed above, the retention element may have at least one portion extending from the apical end of the retention element to the coronal end of the retention element, the at least one portion being more flexible than the remainder of the retention element. The retention element may have at least one cut-out portion extending from the apical end of the retention element to the coronal end of the retention element. At least one projection or protrusion of the apical attachment portion and/or at least one projection or protrusion of the coronal attachment portion may be arranged adjacent to the at least one more flexible portion or the at least one cut-out portion of the retention element. In this way, a particularly reliable and efficient snap fit connection between the retention element and the first and/or the second dental component can be ensured. The retention element may further comprise a through hole extending through the retention element in the direction from the coronal attachment portion towards the apical attachment portion. In this case, the first dental component, such as an abutment, can be fixed to the second dental component, such as a dental implant, via the retention element by means of a fixing element, such as a screw, that passes through the through hole formed in the retention element. In particular, the first dental component may be provided with a through hole having a screw seat for retaining a head of the screw. A threaded lower portion of the screw may be inserted into a threaded bore formed in the second dental component, so that the first dental component can be reliably fixed to the second dental component via the retention element by means of the screw. By providing the retention element with such a through hole, a reversible fixed connection between the first and second dental components, i.e., a connection that can be easily released, can be obtained. The retention element may have a marking, such as a colour code. Such a marking ensures that an incorrect use of the retention element is prevented. For example, the marking, such as the colour code, may indicate an outer diameter of the apical attachment portion and/or the coronal attachment portion. The marking, e.g., the colour code, may indicate a platform size of the first dental component, e.g., an abutment, and/or the second dental component, e.g., a dental implant, which is or are to be used with the retention element. The number of projections or protrusions of the apical attachment portion may also indicate the implant platform size. For example, two protrusions may indicate a Narrow Platform (NP) size, three protrusions a Regular Platform (RP) size, and three or more protrusions a Wide Platform (WP) size. The retention element may comprise an indication and/or tracking device, such as an RFID tag. The indication and/or tracking device may provide information on the first dental component and/or second dental component to be used with the retention element, such as platform sizes, connection types, implant types, implant sizes and lengths, date of placement, primary stability etc. The indication and/or tracking device, such as an RFID tag, may be housed or received in the retention element, e.g., in a wall thereof or in a projection or protrusion of the apical attachment portion or the coronal attachment portion. The retention element may be integrally formed of a single material. The retention element may be made of, for example, a metal, such as titanium, a titanium alloy or stainless steel, a polymer or a composite material. In this way, the retention element can be configured in an elastically deformable manner in a particularly simple and reliable way. The material of the retention element may be metallic, superelastic, amorphous etc. The retention element may be manufactured, for example, by injection moulding, milling, such as CNC milling, turning etc. For example, the retention element may be manufactured by injection moulding using coloured plastic, e.g., so as to provide a colour code as a marking. If the retention element is made of a metal, such as titanium, a titanium alloy or stainless steel, the retention element may be anodised. The invention further provides a dental assembly comprising the retention element of the invention and a first dental component, such as an abutment. The explanations and definitions provided above for the retention element and the first dental component fully apply to the dental assembly of the invention. The dental assembly of the invention provides the effects and advantages already described in detail above for the retention element of the invention. The first dental component may be, for example, an abutment, e.g., a single-piece or a multi-piece abutment, an impression taking component, such as an open or closed tray impression post, an intra-oral scanning or desk top scanning locator, a healing cap, a temporary restoration or a final restoration. The first dental component may have at least one cavity formed in an apical portion thereof for receiving the at least one projection or protrusion of the coronal attachment portion of the retention element. Alternatively, the apical portion of the first dental component may be configured for attachment to the coronal attachment portion of the retention element, for example, by friction fit. The dental assembly may further comprise a second dental component. The second dental component may be, for example, a dental implant or an implant analogue, e.g., for use in a dental laboratory. For the case of a multi-piece abutment, e.g., a two-piece abutment, the first dental component may be one piece of the abutment and the second dental component may be another piece of the abutment. A base piece or unit of the multi-piece abutment may be attached to a dental implant by the retention element of the invention. The retention element may be made of the same material as the first dental component or a different material. The retention element may be made of the same material as the second dental component or a different material. If the retention element is made of a material which is different from that of the first dental component, e.g., an abutment, the retention force provided by the retention element can be appropriately chosen. The second dental component has at least one cavity formed in a coronal portion thereof for receiving the at least one projection or protrusion of the apical attachment portion of the retention element. The second dental component, such as a dental implant, may have a threaded bore for receiving a threaded portion of a screw, such as that described above, and the retention element may have a through hole extending through the retention element in the longitudinal direction of the retention element, as has been detailed above. The first dental component, such as an abutment, may be provided with a through hole having a screw seat for retaining a head of the screw. In this way, the first dental component and the retention element can be fixed to the second dental component in a reversible manner by means of the screw. The invention further provides a dental assembly comprising the retention element of the invention and a second dental component, such as a dental implant. The explanations and definitions provided above for the retention element and the second dental component fully apply to the dental assembly of the invention. The dental assembly of the invention provides the effects and advantages already described in detail above for the retention element of the invention. Moreover, the invention provides a use of the retention element of the invention for attaching a first dental component, such as an abutment, to a second dental component, such as a dental implant, inside or outside a human or animal body. For example, the retention element of the invention may be used for attaching first and second dental components to each other in a dental laboratory, e.g., using a jaw bone model. The use of the retention element of the invention provides the effects and advantages already described in detail above for the retention element of the invention. BRIEF DESCRIPTION OF THE DRAWINGS Hereinafter, non-limiting examples of the invention are explained with reference to the drawings, in which: FIG. 1 shows a retention element according to an embodiment of the present invention, wherein FIG. 1(a) is a perspective view of the retention element from a first angle, FIG. 1(b) is a perspective view of the retention element from a second angle, FIG. 1(c) is a side view of the retention element from a first side, FIG. 1(d) is a side view of the retention element from a second side, and FIG. 1(e) is a top view of the retention element; FIG. 2 shows a dental assembly according to an embodiment of the present invention, comprising the retention element shown in FIG. 1, an abutment and a dental implant, wherein FIG. 2(a) is an exploded perspective view of the dental assembly, and FIG. 2(b) is a side view of the dental assembly, showing the dental assembly in the assembled state; FIG. 3 shows the dental assembly according to the embodiment of the present invention, wherein FIG. 3(a) is a cross-sectional view of the dental assembly, showing the abutment with the retention element attached thereto prior to attachment to the dental implant, and FIG. 3(b) is a cross-sectional view of the dental assembly, showing the dental assembly in the assembled state; FIG. 4 shows the dental assembly according to the embodiment of the present invention, wherein FIG. 4(a) is a cross-sectional view of the dental assembly, illustrating a state in which the abutment is fixed to the dental implant by a screw, and FIG. 4(b) is a partly cross-sectional view of the dental assembly, showing the dental assembly in the assembled state; and FIG. 5 shows the abutment of the dental assembly according to the embodiment of the present invention, wherein FIG. 5(a) is a side view of the abutment with the retention element attached thereto, and FIG. 5(b) is a cross-sectional view of the abutment. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS Preferred embodiments of the present invention will now be described with reference to the accompanying drawings. FIG. 1 shows a retention element 1 according to an embodiment of the present invention for attaching a first dental component to a second dental component. The retention element 1 comprises a coronal attachment portion 2 for attaching the retention element 1 to the first dental component (see FIGS. 2 to 4), an apical attachment portion 4 for attaching the retention element 1 to the second dental component (see FIGS. 2 to 4), and an intermediate portion 6 arranged between the coronal attachment portion 2 and the apical attachment portion 4. The apical attachment portion 4 comprises two projections 8, each extending in plural directions substantially perpendicular to the direction from the apical attachment portion 4 towards the coronal attachment portion 2, i.e., to the longitudinal direction of the retention element 1. The retention element 1 is made of a metal, such as titanium or a titanium alloy. The retention element 1 may be manufactured, for example, by milling, such as CNC milling. The retention element 1 has a substantially cylindrical shape with a substantially circular cross-section perpendicular to the longitudinal direction of the retention element 1 (see FIGS. 1(a), (b) and (e). The retention element 1 is formed as a hollow, tubular body and has a cut-out portion 10 extending from an apical end 12 of the retention element 1 to a coronal end 14 of the retention element 1. The cut-out portion 10 penetrates an outer wall of the retention element 1, as is schematically shown in FIGS. 1(a), (b), (d) and (e). The cut-out portion 10 formed in the outer wall of the retention element 1 renders the entire retention element 1 elastically deformable in all directions perpendicular to the direction from the apical attachment portion 4 towards the coronal attachment portion 2, i.e., in all the transverse directions of the retention element 1. In particular, the retention element 1 can be elastically compressed in the transverse directions thereof when attaching the retention element 1 to the first dental component and/or the second dental component (e.g., FIG. 3). The coronal attachment portion 2 comprises five projections 16 extending in plural transverse directions of the retention element 1, as is schematically shown in FIGS. 1(a) to (e). Hence, the number of projections 8 of the apical attachment portion 4 is smaller than the number of projections 16 of the coronal attachment portion 2 by three. The projections 8 of the apical attachment portion 4 and the projections 16 of the coronal attachment portion 2 allow for the retention element 1 to be attached to the second dental component and the first dental component, respectively, by snap fit, as will be explained in detail below with reference to FIGS. 2 and 3. As is shown in FIGS. 1(a), (b), (d) and (e), the projections 8 of the apical attachment portion 4 are provided adjacent to the cut-out portion 10. In this way, a particularly reliable and efficient snap fit of the apical attachment portion 4 and the second dental component can be ensured. The extensions of the projections 8 of the apical attachment portion 4 in the circumferential direction of the retention element 1 are larger than the extensions of the projection 16 of the coronal attachment portion 2 in the circumferential direction of the retention element 1 (see FIG. 1(e)). Further, as is also shown, for example, in FIG. 1(e), protruding heights of the projections 8 of the apical attachment portion 4 from an outer surface of the remainder of the retention element 1 are larger than protruding heights of the projections 16 of the coronal attachment portion 2 from the outer surface of the remainder of the retention element 1. Two of the projections 16 of the coronal attachment portion 2 are arranged so as to fully overlap with the projections 8 of the apical attachment portion 4. The retention element 1 further comprises a through hole 18 extending through the retention element 1 in the direction from the coronal attachment portion 2 towards the apical attachment portion 4. FIGS. 2 to 4 show a dental assembly according to an embodiment of the present invention, comprising the retention element 1, a dental abutment 20 as the first dental component and a dental implant 30 as the second dental component. The abutment 20 of this dental assembly is further shown in FIG. 5. The abutment 20 is made of a metal, a ceramic, a polymer or a composite material. The implant 30 is made of a metal, for example, titanium, a titanium alloy or stainless steel. As is shown in FIGS. 2(a), 3(a), 3(b), 4(a) and 5(b), the abutment 20 has a through hole 22 extending through the abutment 20 from a coronal portion 24 to an apical portion 26 thereof. The through hole 22 comprises a screw seat 28 for resting a screw head (see FIG. 4(a)) thereon, as is schematically shown in FIGS. 3(a), 3(b), 4(a) and 5(b). The apical portion 26 of the abutment 20 is formed with an annular cavity 27 (see FIG. 5(b)) for receiving the projections 16 of the coronal attachment portion 2 of the retention element 1, as is shown in FIGS. 3(a), 3(b) and 4(a). Hence, the coronal attachment portion 2 of the retention element 1 can be securely held within the apical end of the through hole 22 by snap fit. As is shown in FIGS. 2(a) and 3(a), the implant 30 has a recess 32 formed at a coronal portion 34 of the implant 30, for receiving the retention element 1 and the apical portion 26 of the abutment 20. The coronal portion 34 of the implant 30 is formed with an annular cavity 36 (see FIG. 3(a)) for receiving the projections 8 of the apical attachment portion 4 of the retention element 1, as is shown in FIGS. 3(b), 4(a) and 4(b). Therefore, the apical attachment portion 4 of the retention element 1 can be securely held within the apical portion 34 of the implant 30 by snap fit. Further, the implant 30 has a threaded bore 38 extending below the recess 32 in the apical direction of the implant 30, as is shown in FIGS. 3(a), 3(b), 4(a) and 4(b). Moreover, the implant 30 has an outer threaded portion 39 for screwing the implant 30 into a patient's jaw bone (see FIGS. 2 to 4). When attaching the abutment 20 to the dental implant 30, the coronal attachment portion 2 of the retention element 1 is first attached to the abutment 20 by snap fit, i.e., by engaging the projections 16 with the annular cavity 27, as is shown in FIGS. 3(a) and 5(a). Subsequently, the apical portion 26 of the abutment 20 is inserted into the recess 32 of the implant 30 so that the protrusions 8 of the apical attachment portion 4 of the retention element 1 are received in the annular cavity 36 formed in the apical portion 34 of the implant 30. Hence, the retention element 1 is securely held within this apical portion 34 by snap fit, thus reliably attaching the abutment 20 to the implant 30. In the process of attaching the abutment 20, having the retention element 1 attached thereto, to the implant 30, the retention element 1 is first elastically deformed, i.e., elastically compressed, in the transverse directions thereof upon insertion of the retention element 1 into the recess 32, and subsequently restored to its initial shape, once the projections 8 are received in the annular cavity 36. This “snap in” process of the projections 8 provides an audible and tactile feedback to the user of the dental assembly, such as a clinician or a technician, e.g., in a dental laboratory, indicating that the abutment 20 with the retention element 1 attached thereto is properly seated in the implant 30 (see FIGS. 2(b), 3(b), 4(a) and 4(b)). After the abutment 20 has been properly attached to the implant 30 via the retention element 1, the abutment 20, the retention element 1 and the implant 30 are securely fixed in the attached state by inserting a screw 40 through the coronal opening of the through hole 22 of the abutment 20, passing the screw 40 through the through hole 18 of the retention element 1 and screwing the screw 40 into the threaded bore 38 of the implant 30. In the fully inserted state of the screw 40, which is illustrated in FIG. 4(a), a lower threaded portion 42 of the screw 40 is received within the threaded bore 38 of the implant 30 and a screw head 44 of the screw 40 rests on the screw seat 28 of the abutment 20, thereby firmly holding the abutment 20, the retention element 1 and the implant 30 in their relative positions. In the manner detailed above, the abutment 20 can be fixed to an implant placed in a patient's jaw bone. Specifically, the implant 30 can be screwed into the patient's jaw bone by means of the outer threaded portion 39 of the implant 30. Once the implant is osseointegrated in the jaw bone, the abutment 20 is fixed to the implant 30 through the retention element 1 and the screw 40, as has been detailed above. Further, the retention element 1 may be used for attaching first and second dental components, such as the abutment 20 and the implant 30, respectively, to each other outside a human or animal body, e.g., in a dental laboratory. In particular, in the manner detailed above, the abutment 20 can be fixed to a jaw bone model in the dental laboratory, e.g., using an implant analogue instead of the implant 30. While the dental assembly according to the embodiment of the present invention detailed above comprises an abutment as the first dental component and a dental implant as the second dental component, the retention element of the invention may be used for the attachment of various other dental components to each other, as has been explained in detail above. In particular, the first dental component may be, for example, an impression taking component, such as an open or closed tray impression post, an intra-oral scanning or desk top scanning locator, a healing cap, a temporary restoration, a final restoration etc. The second dental component may be, for example, an implant analogue, e.g., for use in a dental laboratory, as has been explained in detail above. For the case of a multi-piece abutment, e.g., a two-piece abutment, the first dental component may be one piece of the abutment and the second dental component may be another piece of the abutment. Further, a base piece or unit of the multi-piece abutment may be attached to a dental implant by the retention element of the invention. If first and second dental components such as those given above are used instead of the abutment 20 and the dental implant 30, these components are attached to each other by means of the retention element 1 substantially in the same manner as detailed above for the case of the abutment 20 and the dental implant 30. | <SOH> BACKGROUND ART <EOH>Dental prostheses, such as dental crowns or dental bridges, are widely used for the treatment of partly or fully edentulous patients. These prostheses are commonly attached to dental implants placed in a patient's jaw bone with the use of an abutment arranged between implant and prosthesis. For this purpose, single-piece abutments, consisting of a single piece, or multi-piece abutments, comprising two or more separate pieces, may be employed. When providing a patient with a dental prosthesis, the abutment has to be attached to the implant placed in the patient's jaw bone. Further, for the case of a multi-piece abutment, the different pieces of the abutment have to be attached to each other. Moreover, other dental components, such as impression taking components, e.g., open or closed tray impression posts, intra-oral scanning or desk top scanning locators, healing caps, temporary restorations etc., may have to be attached to the implant in the treatment process. In these attachment processes, misfits or misalignments between the different dental components may occur, rendering the attachment complicated and causing the risk of improper placement of one or more of the components. In particular, when mounting an abutment to a dental implant, it is difficult for a clinician to assess whether the abutment is properly seated, i.e., fully engaged with the implant. If the abutment is fixed to the implant in an incorrect position, e.g., by engaging and tightening a clinical screw, problems, such as an improper placement of the dental prosthesis, the formation of undesired gaps between different components etc., can arise and the strength of the connection can be compromised. These difficulties in attaching the abutment to the implant are further aggravated if the implant is placed in the patient's upper jaw bone, due to gravity. One possible way of verifying whether the abutment is correctly seated in the implant is to take an X-ray image of the patient's jaw bone with the abutment in place. However, this approach renders the attachment process inefficient and expensive. In order to prevent fixation of the abutment to the implant in an incorrect position, it is known to provide a height lift that prevents a clinical screw from engaging with the implant if the abutment is not fully seated or if the abutment is automatically forced into its correct position while tightening the screw. In this case, the abutment cannot be secured to the implant in an improper position by the clinician. However, this means that the clinician has to repeat the steps of removing the screw, checking the position of the abutment and reinserting the screw until the screw can be engaged, thus rendering the attachment process inefficient and cumbersome. Further, there are several possible reasons why the screw may not properly engage with the implant, such as an incorrect insertion of the screw or damaged threads on the screw and/or the implant. Hence, the fact that the screw cannot be engaged is not an unambiguous indication of an incorrect placement of the abutment. U.S. Pat. No. 8,033,826 B2 discloses an abutment for use with a dental implant. The abutment comprises a prosthetic portion adapted to support a prosthesis thereon and an insert. The insert extends into a passageway of the prosthetic portion and engages the subgingival end of the prosthetic portion. The insert includes flexible retention fingers that, upon insertion into the passageway, initially contract before reaching an enlarged retention groove and then expand outwardly into the enlarged retention groove to hold the insert onto the prosthetic portion. However, in the case of the insert disclosed in U.S. Pat. No. 8,033,826 B2, only the fingers, which form a small part of the entire insert, are flexible. Hence, these fingers are prone to wear and breakage, in particular, if the insert is repeatedly engaged with and removed from the prosthetic portion. For example, in a dental laboratory, a technician will have to engage and remove a prosthetic portion or other dental components repeatedly. Moreover, for example, also in the case that a patient is provided with a temporary restoration, the insert will have to be engaged and removed a number of times. Hence, there remains a need for a reliable and efficient approach for attaching a first dental component, such as an abutment, to a second dental component, such as a dental implant, which provides a clear indication of whether the first and second dental components are properly attached to each other. | <SOH> SUMMARY OF THE INVENTION <EOH>Accordingly, it is an object of the present invention to provide a retention element for attaching a first dental component, such as an abutment, to a second dental component, such as a dental implant, which efficiently provides reliable indication of whether the first and second dental components are properly attached to each other. Further, the invention aims to provide a dental assembly comprising such a retention element and a use of such a retention element for attaching the first dental component to the second dental component. These goals are achieved by a retention element with the technical features of claim 1 , by dental assemblies with the technical features of claim 12 or 14 and by a use of the retention element with the technical features of claim 15 . The invention provides a retention element for attaching a first dental component, such as an abutment to a second dental component, such as a dental implant. The retention element comprises a coronal attachment portion for attaching the retention element to the first dental component, and an apical attachment portion for attaching the retention element to the second dental component. The retention element is elastically deformable at least in all directions perpendicular to the direction from the apical attachment portion towards the coronal attachment portion. The apical attachment portion comprises at least one projection extending in one or more directions substantially perpendicular to the direction from the apical attachment portion towards the coronal attachment portion. Thus, the entire retention element is elastically deformable. The retention element is elastically deformable along its entire length. The length of the retention element extends along the longitudinal direction thereof, i.e., the direction from the apical attachment portion towards the coronal attachment portion. The entire retention element can thus be elastically deformed at least in or along all directions perpendicular to the direction from the apical attachment portion towards the coronal attachment portion, i.e., in or along all the transverse directions of the retention element. The apical attachment portion comprises at least one projection or protrusion extending from an outer surface of the remainder of the retention element in one or more directions substantially perpendicular to the direction from the apical attachment portion towards the coronal attachment portion. The at least one projection or protrusion of the apical attachment portion is configured to be received in a corresponding cavity formed in a coronal portion of the second dental component, such as a dental implant. The first dental component, such as an abutment, is attached to the second dental component, such as a dental implant, by attaching the apical attachment portion of the retention element to the second dental component and attaching the first dental component to the coronal attachment portion of the retention element. When attaching the apical attachment portion of the retention element to the second dental component, the retention element is initially elastically deformed, i.e., elastically compressed, along the transverse directions of the retention element and subsequently restored to its initial shape when the at least one projection has been received in the corresponding cavity of the second dental component, due to the restoring force of the retention element. Hence, the apical attachment portion can be attached to the second dental component by snap fit in a reliable and efficient manner. The engagement of the at least one projection of the apical attachment portion with the corresponding cavity of the second dental component provides an audible and/or tactile feedback to a user, such as a clinician or a technician, e.g., in a dental laboratory, providing a clear and unambiguous indication that the retention element, and thus also the first dental component, is properly attached to the second dental component. The whole retention element, rather than only a portion thereof, is elastically deformable along its transverse directions. In this way, a particularly high degree of flexibility of the retention element is achieved. Further, the entire retention element is elastically deformed upon attachment thereof to the second dental component, thus minimising the risk of wear or breakage of the retention element, even if the retention element is repeatedly engaged with and removed from the second dental component. Therefore, the retention element of the invention provides a clear, reliable and efficient indication of whether the first dental component is properly attached to the second dental component. The retention element may have a substantially cylindrical shape, e.g., with a substantially circular cross-section perpendicular to the direction from the apical attachment portion towards the coronal attachment portion, i.e., the longitudinal direction of the retention element. The at least one projection or protrusion of the apical attachment portion extends in one or more directions substantially perpendicular to the longitudinal direction of the retention element, i.e., in one or more transverse directions thereof. In particular, the apical attachment portion may comprise at least one projection or protrusion which extends in plural transverse directions of the retention element, i.e., extends along a portion of the outer surface of the remainder of the retention element in the circumferential direction of the retention element. The at least one projection or protrusion may extend along 10% or more, 20% or more or 30% or more of the outer circumference of the remainder of the retention element. The first dental component may be, for example, an abutment, e.g., a single-piece or a multi-piece abutment, an impression taking component, such as an open or closed tray impression post, an intra-oral scanning or desk top scanning locator, a healing cap, a temporary restoration or a final restoration. The second dental component may be, for example, a dental implant or an implant analogue, e.g., for use in a dental laboratory. For the case of a multi-piece abutment, e.g., a two-piece abutment, the first dental component may be one piece of the abutment and the second dental component may be another piece of the abutment. A base piece or unit of the multi-piece abutment may be attached to a dental implant by the retention element of the invention. The first dental component and/or the second dental component may be made of, for example, a metal, a ceramic, a polymer or a composite material. In particular, the first dental component may be an abutment made of a ceramic, a metal, a polymer or a composite material. The second dental component may be a dental implant made of, for example, a metal, such as titanium, a titanium alloy or stainless steel. The retention element of the invention may further comprise an intermediate portion arranged between the coronal attachment portion and the apical attachment portion. The retention element may have at least one portion extending from an apical end of the retention element to a coronal end of the retention element, the at least one portion being more flexible than the remainder of the retention element. This flexible portion of the retention element contributes to or even provides the elastic deformability of the retention element. Hence, the retention element can be configured in an elastically deformable manner in a simple and efficient way. The at least one portion extending from the apical end of the retention element to the coronal end of the retention element may be made or formed of a material which is more flexible than a material of the remainder of the retention element. Alternatively or additionally, the at least one portion may have a configuration or structure with a higher degree of flexibility than the configuration or structure of the remainder of the retention element. For example, the at least one portion may be made more flexible by providing, for example, perforations, recesses, openings or the like therein. Also, e.g., the at least one portion may have a smaller thickness, i.e., wall thickness, than the remainder of the retention element. The retention element may have two or more, three or more or four or more portions extending from the apical end of the retention element to the coronal end of the retention element, these portions being more flexible than the remainder of the retention element. The retention element may have at least one cut-out or recessed portion extending from the apical end of the retention element to the coronal end of the retention element. The at least one cut-out or recessed portion contributes to or even provides the elastic deformability of the retention element. Forming the retention element with such an at least one cut-out or recessed portion provides a particularly flexible configuration of the retention element. Further, the retention element has an especially simple structure. The retention element may be a hollow and/or tubular body, wherein the at least one cut-out or recessed portion penetrates an outer wall of the retention element. The retention element may have an open ring shape or open annular shape, i.e., the shape of a ring with an opening in the circumference thereof, or substantially a C-shape, in a cross-section perpendicular to the longitudinal direction of the retention element. The coronal attachment portion of the retention element may be attachable to the first dental component, such as an abutment, by friction fit. The coronal attachment portion of the retention element may comprise at least one projection or protrusion extending in one or more directions substantially perpendicular to the direction from the apical attachment portion towards the coronal attachment portion. The explanations and definitions provided above for the at least one projection or protrusion of the apical attachment portion also apply to the at least one projection or protrusion of the coronal attachment portion. The at least one projection or protrusion of the coronal attachment portion is configured to be received in a corresponding cavity formed in an apical portion of the first dental component, such as an abutment. In this way, the coronal attachment portion can be reliably and efficiently attached to the first dental component by snap fit. The at least one projection or protrusion of the coronal attachment portion extends in one or more directions substantially perpendicular to the longitudinal direction of the retention element, i.e., in one or more transverse directions thereof. In particular, the coronal attachment portion may comprise at least one projection or protrusion which extends in plural transverse directions of the retention element, i.e., extends along a portion of the outer surface of the remainder of the retention element in the circumferential direction of the retention element. The at least one projection or protrusion may extend along 10% or more, 20% or more or 30% or more of the outer circumference of the remainder of the retention element. The apical attachment portion may comprise a plurality, e.g., two or more, three of more, four or more, or five or more, projections or protrusions, each extending in one or more directions substantially perpendicular to the direction from the apical attachment portion towards the coronal attachment portion. The plurality of projections or protrusions may have the same or different extensions in the circumferential direction of the retention element. The plurality of projections or protrusions may have the same or different protruding heights from an outer surface of the remainder of the retention element, i.e., heights from this outer surface in one or more directions substantially perpendicular to the direction from the apical attachment portion towards the coronal attachment portion. The plural projections or protrusions of the apical attachment portion may be sequentially or consecutively arranged in the circumferential direction of the retention element, i.e., so that one is arranged after the other in this circumferential direction. The plural projections or protrusions may be equidistantly spaced from each other or spaced from each other at different intervals in the circumferential direction of the retention element. The plural projections or protrusions of the apical attachment portion are configured to be received in a corresponding cavity or corresponding cavities formed in the coronal portion of the second dental component, such as a dental implant. The coronal attachment portion may comprise a plurality, e.g., two or more, three or more, four or more, or five or more, projections or protrusions, each extending in one or more directions substantially perpendicular to the direction from the apical attachment portion towards the coronal attachment portion. The plurality of projections or protrusions may have the same or different extensions in the circumferential direction of the retention element. The plurality of projections or protrusions may have the same or different protruding heights from an outer surface of the remainder of the retention element, i.e., heights from this outer surface in one or more directions substantially perpendicular to the direction from the apical attachment portion towards the coronal attachment portion. The plural projections or protrusions of the coronal attachment portion may be sequentially or consecutively arranged in the circumferential direction of the retention element, i.e., so that one is arranged after the other in this circumferential direction. The plural projections or protrusions may be equidistantly spaced from each other or spaced from each other at different intervals in the circumferential direction of the retention element. The plural projections or protrusions of the coronal attachment portion are configured to be received in a corresponding cavity or corresponding cavities formed in the apical portion of the first dental implant, such as an abutment. The number of projections or protrusions of the apical attachment portion may be different from the number of projections or protrusions of the coronal attachment portion. The number of projections or protrusions of the apical attachment portion may be larger or smaller than the number of projections or protrusions of the coronal attachment portion, e.g., by one, two, three, four or five, or by one or more, two or more, three or more, four or more, or five or more. Particularly preferably, the number of projections or protrusions of the apical attachment portion is smaller than the number of projections or protrusions of the coronal attachment portion. At least one projection or protrusion of the apical attachment portion may be arranged congruently to at least one protrusion or projection of the coronal attachment portion, i.e., so that the at least one projection or protrusion of the apical attachment portion is arranged above the at least one projection or protrusion of the coronal attachment portion in the longitudinal direction of the retention element. At least one projection or protrusion of the apical attachment portion may be arranged so as to be offset or staggered from at least one projection or protrusion of the coronal attachment portion in the circumferential direction of the retention element. Further, also a combination of these two configurations is possible, i.e., some projections or protrusions may be arranged in a congruent manner and some projections or protrusions may be arranged in an offset or staggered manner. At least one projection or protrusion of the apical attachment portion may be arranged so as to at least partly overlap at least one projection or protrusion of the coronal attachment portion in the circumferential direction of the retention element. At least one projection or protrusion of the apical attachment portion may have an extension in the circumferential direction of the retention element which is the same as the extension of at least one projection or protrusion of the coronal attachment portion in the circumferential direction of the retention element. At least one projection or protrusion of the apical attachment portion may have an extension in the circumferential direction of the retention element which is different from, i.e., larger or smaller than, the extension of at least one projection or protrusion of the coronal attachment portion in the circumferential direction of the retention element. The extension of each projection or protrusion of the apical attachment portion in the circumferential direction of the retention element may be the same as or different from, i.e., larger or smaller than, the extension of each projection or protrusion of the coronal attachment portion in the circumferential direction of the retention element. Particularly preferably, the extension of each projection or protrusion of the apical attachment portion in the circumferential direction of the retention element is larger than the extension of each projection or protrusion of the coronal attachment portion in the circumferential direction of the retention element. At least one projection or protrusion of the apical attachment portion may have a protruding height from an outer surface of the remainder of the retention element, i.e., a height from this outer surface in one or more directions substantially perpendicular to the direction from the apical attachment portion towards the coronal attachment portion, which is the same as the protruding height of at least one projection or protrusion of the coronal attachment portion. At least one projection or protrusion of the apical attachment portion may have a protruding height from the outer surface of the remainder of the retention element which is different from, i.e., larger or smaller than, the protruding height of at least one projection or protrusion of the coronal attachment portion. The protruding height of each projection or protrusion of the apical attachment portion may be the same as or different from, i.e., larger or smaller than, the protruding height of each projection or protrusion of the coronal attachment portion. Particularly preferably, the protruding height of each projection or protrusion of the apical attachment portion is larger than the protruding height of each projection or protrusion of the coronal attachment portion. As has been detailed above, the retention element may have at least one portion extending from the apical end of the retention element to the coronal end of the retention element, the at least one portion being more flexible than the remainder of the retention element. The retention element may have at least one cut-out portion extending from the apical end of the retention element to the coronal end of the retention element. At least one projection or protrusion of the apical attachment portion and/or at least one projection or protrusion of the coronal attachment portion may be arranged adjacent to the at least one more flexible portion or the at least one cut-out portion of the retention element. In this way, a particularly reliable and efficient snap fit connection between the retention element and the first and/or the second dental component can be ensured. The retention element may further comprise a through hole extending through the retention element in the direction from the coronal attachment portion towards the apical attachment portion. In this case, the first dental component, such as an abutment, can be fixed to the second dental component, such as a dental implant, via the retention element by means of a fixing element, such as a screw, that passes through the through hole formed in the retention element. In particular, the first dental component may be provided with a through hole having a screw seat for retaining a head of the screw. A threaded lower portion of the screw may be inserted into a threaded bore formed in the second dental component, so that the first dental component can be reliably fixed to the second dental component via the retention element by means of the screw. By providing the retention element with such a through hole, a reversible fixed connection between the first and second dental components, i.e., a connection that can be easily released, can be obtained. The retention element may have a marking, such as a colour code. Such a marking ensures that an incorrect use of the retention element is prevented. For example, the marking, such as the colour code, may indicate an outer diameter of the apical attachment portion and/or the coronal attachment portion. The marking, e.g., the colour code, may indicate a platform size of the first dental component, e.g., an abutment, and/or the second dental component, e.g., a dental implant, which is or are to be used with the retention element. The number of projections or protrusions of the apical attachment portion may also indicate the implant platform size. For example, two protrusions may indicate a Narrow Platform (NP) size, three protrusions a Regular Platform (RP) size, and three or more protrusions a Wide Platform (WP) size. The retention element may comprise an indication and/or tracking device, such as an RFID tag. The indication and/or tracking device may provide information on the first dental component and/or second dental component to be used with the retention element, such as platform sizes, connection types, implant types, implant sizes and lengths, date of placement, primary stability etc. The indication and/or tracking device, such as an RFID tag, may be housed or received in the retention element, e.g., in a wall thereof or in a projection or protrusion of the apical attachment portion or the coronal attachment portion. The retention element may be integrally formed of a single material. The retention element may be made of, for example, a metal, such as titanium, a titanium alloy or stainless steel, a polymer or a composite material. In this way, the retention element can be configured in an elastically deformable manner in a particularly simple and reliable way. The material of the retention element may be metallic, superelastic, amorphous etc. The retention element may be manufactured, for example, by injection moulding, milling, such as CNC milling, turning etc. For example, the retention element may be manufactured by injection moulding using coloured plastic, e.g., so as to provide a colour code as a marking. If the retention element is made of a metal, such as titanium, a titanium alloy or stainless steel, the retention element may be anodised. The invention further provides a dental assembly comprising the retention element of the invention and a first dental component, such as an abutment. The explanations and definitions provided above for the retention element and the first dental component fully apply to the dental assembly of the invention. The dental assembly of the invention provides the effects and advantages already described in detail above for the retention element of the invention. The first dental component may be, for example, an abutment, e.g., a single-piece or a multi-piece abutment, an impression taking component, such as an open or closed tray impression post, an intra-oral scanning or desk top scanning locator, a healing cap, a temporary restoration or a final restoration. The first dental component may have at least one cavity formed in an apical portion thereof for receiving the at least one projection or protrusion of the coronal attachment portion of the retention element. Alternatively, the apical portion of the first dental component may be configured for attachment to the coronal attachment portion of the retention element, for example, by friction fit. The dental assembly may further comprise a second dental component. The second dental component may be, for example, a dental implant or an implant analogue, e.g., for use in a dental laboratory. For the case of a multi-piece abutment, e.g., a two-piece abutment, the first dental component may be one piece of the abutment and the second dental component may be another piece of the abutment. A base piece or unit of the multi-piece abutment may be attached to a dental implant by the retention element of the invention. The retention element may be made of the same material as the first dental component or a different material. The retention element may be made of the same material as the second dental component or a different material. If the retention element is made of a material which is different from that of the first dental component, e.g., an abutment, the retention force provided by the retention element can be appropriately chosen. The second dental component has at least one cavity formed in a coronal portion thereof for receiving the at least one projection or protrusion of the apical attachment portion of the retention element. The second dental component, such as a dental implant, may have a threaded bore for receiving a threaded portion of a screw, such as that described above, and the retention element may have a through hole extending through the retention element in the longitudinal direction of the retention element, as has been detailed above. The first dental component, such as an abutment, may be provided with a through hole having a screw seat for retaining a head of the screw. In this way, the first dental component and the retention element can be fixed to the second dental component in a reversible manner by means of the screw. The invention further provides a dental assembly comprising the retention element of the invention and a second dental component, such as a dental implant. The explanations and definitions provided above for the retention element and the second dental component fully apply to the dental assembly of the invention. The dental assembly of the invention provides the effects and advantages already described in detail above for the retention element of the invention. Moreover, the invention provides a use of the retention element of the invention for attaching a first dental component, such as an abutment, to a second dental component, such as a dental implant, inside or outside a human or animal body. For example, the retention element of the invention may be used for attaching first and second dental components to each other in a dental laboratory, e.g., using a jaw bone model. The use of the retention element of the invention provides the effects and advantages already described in detail above for the retention element of the invention. | A61C80063 | 20180118 | 20180726 | A61C800 | 0 | PATEL, YOGESH P | RETENTION ELEMENT FOR ATTACHING A FIRST DENTAL COMPONENT TO A SECOND DENTAL COMPONENT AND DENTAL ASSEMBLY COMPRISING THE RETENTION ELEMENT | UNDISCOUNTED | 0 | REJECTED | A61C | 2,018 |
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15,747,252 | PENDING | EDIBLE VACCINATION AGAINST MICROBIAL PATHOGENS | The present invention relates to animals and more specifically to insects. In more details the invention relates to an edible composition or insect artificial diet comprising bacteria, fungi or any fragment or spore thereof for use as a vaccine in preventing a microbial disease or infection in an insect. Still, the present invention relates to preventive methods and different uses relating to said compositions or bacteria, fungi or fragments or spores thereof. | 1.-5. (canceled) 6. A method of preventing a microbial disease or infection of an insect, wherein the method comprises feeding a queen with an artificial insect diet comprising bacteria, fungi or any fragment or spore thereof, wherein said artificial insect diet acts as a vaccine against said microbial disease or infection and wherein the insect belongs to Hymenoptera and wherein the bacteria, fungi or any fragments or spores thereof are dead, attenuated and/or avirulent. 7. The method according to claim 6, wherein said artificial insect diet is used as the only vaccine against said microbial disease or infection in the insect. 8. The method according to claim 6, wherein the insect is a honey bee. 9. (canceled) 10. The method according to claim 6, wherein the bacteria, fungi or any fragments or spores thereof are selected from the group consisting of Spiroplasma spp., Streptococcus spp., Staphylococcus spp., Enterococcus spp., Aeromonas sp., Bacillus spp., Klebsiella spp., Alcaligenes spp., Psedomonas spp., any bacteria listed in a table of FIG. 5, table of FIG. 6 or table of FIG. 7, Paenibacillus larvae, Melissococcus plutonius, Spiroplasma apis, Spiroplasma mellifera, Enterococcus faecalis, Enterococcus faecium, Bacillus bombyseptieus, Serratia marcescens, Aeromonas mundii, Bacillus thuringiensis, Beauveria spp., Isaria spp., Hirsutella ssp., Fusarium spp., Nomuraea spp., Aspergillus spp., Nosema, Vairimorpha spp., Pleisthora spp., Thelohania spp., Metarhizium spp. and Ascospaera spp. 11. The method according to claim 6, wherein amount of bacteria, fungi or any fragments or spores thereof in the artificial diet is from 1 to 20% or 1 to 10% by weight. 12. (canceled) 13. The method according to claim 6, wherein the bacteria, fungi or any fragments or spores thereof are therapeutically effective agents as such. 14. The method according to claim 6, wherein the artificial diet is for administration one, two or three times a year. 15. The method according to claim 6, wherein the microbial disease or infection is a bacterial disease or infection selected from the group consisting of Bacillus spp., Serratia spp., Aeromonas spp., Bacillus thuringiensis strains, Enterococcus spp., Paenibacillus spp., Melissococcus spp., Spiroplasma spp. disease or infection and any other bacterial diseases; or a fungal disease or infection selected from the group consisting of chalkbrood, stonebrood, dysentery, nosema disease, muscardine, aspergillosis, fusariosis, pebrine, Beauveria spp. infection, Isaria spp. infection, Hirsutella ssp. infection, Fusarium spp. infection, Nomuraea spp. infection, Aspergillus spp. infection, Nosema spp. infection, Vairimorpha spp. infection, Pleisthora spp. infection, Thelohania spp. infection, Metarhizium spp. infection and Ascospaera spp. infection. 16. The method according to claim 6, wherein the microbial disease or infection is a bacterial disease or infection selected from the group consisting of Bacillus spp., Aeromonas spp., Bacillus thuringiensis strains, Enterococcus spp., Paenibacillus spp., Melissococcus spp., Spiroplasma spp. disease or infection and any other bacterial diseases; or a fungal disease or infection selected from the group consisting of chalkbrood, stonebrood, dysentery, muscardine, aspergillosis, fusariosis, pebrine, Beauveria spp. infection, Isaria spp. infection, Hirsutella ssp. infection, Fusarium spp. infection, Nomuraea spp. infection Aspergillus spp. infection, Vairimorpha spp. infection, Pleisthora spp. infection, Thelohania spp. infection, Metarhizium spp. infection and Ascospaera spp. infection. 17. The method according to claim 16, wherein the microbial disease is American or European foulbrood. 18. An insect vaccinated by the method according to claim 6. 19-23. (canceled) | FIELD OF THE INVENTION The present invention relates to animals and more specifically to insects. In more details the invention relates to an edible composition or insect artificial diet comprising bacteria, fungi or any fragment or spore thereof for use as a vaccine in preventing a microbial disease or infection in an insect. Still, the present invention relates to preventive methods and different uses relating to said compositions or bacteria, bacterial spores or fragments thereof. The present invention further relates to preventive methods and different uses relating to said compositions or fungi, fungal spores or fragments thereof. BACKGROUND OF THE INVENTION Insects have many important roles in the environment. For example insects may be used as food for people and animals, insects help in maintaining plant and animal diversity and also have enormous effect on the crop production. Insects ultimately affect humans since ensuring healthy crops is critical for agriculture. Insects also produce useful substances such as honey, wax, lacquer and silk. Therefore, the amount and health of insects are important ecological and economical issues. A serious environmental problem is the decline of populations of pollinator insects, and a number of species of insects are now cultured primarily for pollination management in order to have sufficient pollinators in the field, orchard or greenhouse at bloom time. Insects are needed for pollination during the bloom period of the plants. Examples of well recognized pollinators are honey bees and the various species of bees but also many other kinds of pollinators are cultured and sold for managed pollination. Honey bees and other pollinators travel from flower to flower, collecting nectar, which is later converted to honey, and pollen grains. Pollinators transfer pollen among the flowers as they are working. Nectar provides the energy for bee nutrition and pollen provides the protein. When bees are rearing large quantities of brood, they gather pollen to meet the nutritional needs of the brood. The Food and Agriculture Organisation of the United Nations (FAO) estimates that out of some 100 crop species which provide 90% of food worldwide, 71 are bee-pollinated. Honey bees are by far the most important commercial pollinators. However, at the same time, they are susceptible to many diseases, and thus like many other important pollinators, are in global population decline. In special focus in apiculture is the bacterial disease foulbrood that kills honey bee larvae. Foulbrood is common in most parts of the world, including Finland, and causes marked losses in corps worldwide. Currently foulbrood can be treated e.g. by burning up the whole hive. Also, the chemical oxytetracycline hydrochloride (antibiotic Terramycin) is used for prevention of foulbrood and tylosin (antibiotic Tylan) has been registered for therapeutic treatments of American foulbrood. In addition to honey bees another example of an economically important insect is a primary producer of silk. Domestic silk moths are closely dependent on humans for reproduction, as a result of selective breeding. The silkworm is the larva or caterpillar of the domesticated silk moth (Bombyx mori). Thermal therapies have been developed for silk moth larva to control the flacherie virus disease. Also, e.g. disinfection and antibiotics are used against bacterial diseases. As an example, septicemias are common bacterial diseases in silkworms. Serratia marcescens is causing Serratia-type septicemia, Bacillus spp. is causing fuliginosa septicemia and Aeromonas bacteria is causing green thorax septicemia. The common symptoms of septicemia include that larvae become dull and motionless with reduced feeding rates, even resulting in mortality in late instar larvae. Problems of the known treatment methods of insects having microbial diseases or infections include e.g. that the hives with infected honey bees must be totally destroyed and at the same time thermal methods are unreliable and may require moving of the hives. Furthermore, use of antibiotics lead to antibiotic resistance and antibiotics also stay in the environment e.g. the honey produced by honey bees contains the antibiotic. Actually, there is a lack of effective non-antibiotic methods for preventing microbial diseases of insects. Recently, Lopez et al. (2014) have utilized trans-generational immune priming (TGIP) for priming the offspring of honey bees against infections. Indeed, Lopez et al. have shown that honey bee (Apis mellifera) queens injected with dead Paenibacillus larvae (bacterium responsible for the American foulbrood disease) produce significantly more foulbrood resistant larvae than non-injected queens. However, injecting insects at a large scale is not feasible, and the injecting techniques are not within reach of the insect farmers. Furthermore, very suitable and effective compositions are needed for continuous use. In summary, there is a need of suitable and simple tools for preventing diseases and infections caused by microbial pathogens in insects. BRIEF DESCRIPTION OF THE INVENTION An object of the present invention is to provide a method and composition for implementing the method so as to solve the above mentioned problems. The present invention provides an edible pharmaceutical composition suitable for insects and preventing microbial diseases or infections. The invention is based on the realization that immunization of insects can be utilized in preventing insect microbial diseases such as bacterial and fungal diseases by feeding the insects (e.g. larvae or adults) with said bacteria, fungi or any fragments or spores thereof. The preventive effect of the vaccine can be found in the insects fed with the vaccine composition, in the next generation or in both. An advantage of the method and arrangement of the invention is that now there is available a non-antibiotic vaccination which is effective and can be easily used. By utilizing the present invention it is easy for anyone e.g. to mix the vaccine composition into normal insect artificial diet such as food for insects (e.g. honey bees, silk moth). Furthermore, the present invention is able to reveal the detailed mechanism of how bacteria used for preventive therapeutic method are transported to insect eggs by a common insect lipoprotein vitellogenin (Vg). The objects of the invention are achieved by a method and an arrangement, which are characterized by what is stated in the independent claims. The preferred embodiments of the invention are disclosed in the dependent claims. The present invention relates to an edible composition comprising microbes selected from bacteria, fungi or any fragment or spore thereof for use as a vaccine in preventing a microbial disease or infection in an insect. The present invention also relates to bacteria, fungi, any fragment thereof or any spore thereof for oral use in preventing a microbial disease or infection of an insect. Also, the present invention relates to a method of preventing a microbial disease or infection of an insect, wherein the method comprises feeding the insect with an edible composition comprising bacteria, fungi or any fragment or spore thereof, wherein said edible composition acts as a vaccine against said microbial disease or infection. Furthermore, the present invention relates to use of bacteria, fungi or any fragment or spore thereof in an edible composition against a microbial disease or infection of an insect. Still, the present invention relates to an edible vaccine composition for insects, wherein the composition comprises bacteria, fungi or any fragments or spores thereof. And still further, the present invention relates to artificial insect diet comprising bacteria, fungi or any fragment or any spore thereof or an edible vaccine composition comprising bacteria, fungi or any fragments or spores thereof. And still furthermore, the present invention relates to a vaccine for insects, wherein the vaccine consists of bacteria, fungi, any fragments thereof and/or any spores thereof and optionally water. Also, the present invention relates to use of bacteria, fungi, any fragments thereof and/or any spores thereof, or an edible composition comprising microbes selected from bacteria, fungi or any fragment or spore thereof, in the manufacture of a medicament for preventing microbial disease or infection. And still, the present invention relates to an insect vaccinated with the edible vaccine composition of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS In the following the invention will be described in greater detail by means of preferred embodiments with reference to the attached drawings, in which FIG. 1 reveals that honey bee vitellogenin (Vg) binding to bacteria was tested by western blotting (A) and microscopy (B). Binding to candidate pathogenic molecules was further tested by surface plasmon resonance technique (C). (A) Vg-rich honey bee hemolymph (hl), Vg-rich fat body protein extract (fb), or bovine serum albumin control (BSA) were incubated with P. larvae or E. coli, after which the bacteria were washed and blotted using an antibody that detects Vg or BSA. Untreated control samples are indicated (hl, fb and BSA), and next to them are located the bacteria-incubated test samples (N=3) marked with an overhead line. Two negative controls are numbered: 1=Control for Vg aggregation (fb without bacteria), and 2=control for unspecific antibody binding to P. larvae (above) or E. coli (below). The image exposure time for the P. larvae blot was 1 s, and 5 s for the E. coli blot to better reveal its weaker bands. Vg appears as a double band of 180 and 150 kDa. (B) Representative images of P. larvae and E. coli that were incubated with hemolymph, and carefully washed and fixed (N=3). The bacteria were visualized using propidium iodide (PI; red). Vg was detected using an Alexa fluor 488 nm conjugated secondary antibody (green). The primary antibody was omitted in the secondary antibody control. (C) PG (peptidoglycan), LPS (lipopolysaccharide) and zymosan, that are parts of microbial cell walls binding to Vg immobilized on a surface plasmon resonance chip. The data are blank subtracted. Above: The X-axis shows the analyte concentration, and the Y-axis shows the binding response. The curves were fitted based on five measurements at different analyte concentrations. The dots mark the binding response at each concentration measurement point. Below: The sensogram data of the maximal concentration for each analyte. FIG. 2 shows the localization of bacterial fragments in honey bee queen ovaries in the presence (left) and absence (right) of pure Vg. Freshly detached ovaries were incubated in buffer containing fluorescent (Texas red) E. coli fragments, and imaged right after (A) or embedded for cryo-sectioning and imaging later (B-C). (A) Whole ovaries mounted and imaged immediately after incubation and washing steps. 5× magnification, the scale is 200 μm. (B) Eggs in cryo-sectioned ovaries. 10× magnification, the scale is 200 μm. (C) A single egg in a cryo-sectioned ovary; 20× magnification, the scale is 50 μm. In the Vg-incubated ovaries, eggs with internalized fluorescent material were observed. In the control (right), the bacterial fragments were, typically, found as bright aggregates on the membranes surrounding the eggs. The images represent N=6 queens. FIG. 3 shows the localization of fluorescently-labeled bacterial fragments in cryo-sectioned honey bee queen ovaries incubated in the presence of pure Vg, in the presence of hemolymph proteins other than Vg, and in the absence of any externally provided protein. (A) One ovary was incubated with Vg (left) and the other with other hemolymph proteins (right), N=3. (B) One ovary was incubated with Vg (left) and the other without any protein (right), N=3. (C) One ovary was incubated without any protein (left) and the other with other hemolymph proteins but Vg (right), N=2. The scale is 50 μm, or 200 μm (the latter is indicated with scale bars). FIG. 4 shows chromatographic fractioning of honey bee hemolymph to Vg and other proteins. S=size standard. (A) An SDS-PAGE gel with a honey bee hemolymph sample used for protein fractioning. The major proteins are (in size order) apolipophorin, vitellogenin and hexamerins. (B) Pure vitellogenin and other hemolymph proteins produced by ion-exchange chromatography. The faint ˜150 and ˜40 kDa bands in the pure vitellogenin fraction are the previously mass-spectrometrically verified vitellogenin fragmentation products [33]. (C) Hemolymph fractioning chromatogram. The X-axis shows the time with 0.5 ml/min flow rate, and the Y-axis shows the percentage of 0.45 M NaCl phosphate buffer. The fraction collected as pure Vg is highlighted grey. The other protein fraction collected is indicated below the X-axis. FIG. 5 shows a table listing examples of bacteria infecting insects (Modified from Vallet-Gely et al. 2008, Nature Reviews Microbiology 6, 302-313). FIG. 6 shows a table listing examples of bacteria infecting silk moths (silkworms) (Modified from Table 12.1. James R R and Li Z in Chapter 12 of Insect pathology (Vega F and Kaya H, Published: February 2012, ISBN: 978-0-12-384984-7)). FIG. 7 shows a table listing examples of bacteria infecting bees (Modified from Table 12.2. James R R and Li Z in Chapter 12 of Insect pathology, Vega F and Kaya H, Published: February 2012, ISBN: 978-0-12-384984-7)). FIG. 8 shows a table listing examples of fungi infecting silk moths (silkworms) (Modified from Table 12.1. James R R and Li Z in Chapter 12 of Insect pathology (Vega F and Kaya H, Published: February 2012, ISBN: 978-0-12-384984-7)). FIG. 9 shows a table listing examples of fungi infecting bees (Modified from Table 12.2. James R R and Li Z in Chapter 12 of Insect pathology, Vega F and Kaya H, Published: February 2012, ISBN: 978-0-12-384984-7)). FIG. 10 shows vaccine in the fat body of the honey bee worker. FIG. 10 reveals co-localization of Vitellogenin and vaccine analogue (pieces of bacteria—E. coli) in the fat body of worker bees after feeding on 30% sugar solution containing Texas Red labelled E. coli. a)—DAPI stained cell nuclei, b)—phalloidin stained cell cytoskeleton, c)—FITC stained Vitellogenin protein, d)—Vaccine analogue (Texas Red labelled E. coli fragments), e)—overlay to trace co-localization of vaccine and vitellogenin. DETAILED DESCRIPTION OF THE INVENTION Insects According to the present invention bacteria, fungi, bacterial fragments, fungal fragments, bacterial spores and/or fungal spores may be used for immunizing any insects which may be infected with said microbial pathogens. As used herein “insects” are a class of invertebrates within the arthropod phylum that have a chitinous exoskeleton, a three-part body (head, thorax and abdomen), three pairs of jointed legs, compound eyes and one pair of antennae. Insect refers to any stage of an insect, e.g. including but not limited to an egg, embryo, larva, pupa, adult or imago. Most specifically the insect is in the form of larva or adult. In a specific embodiment the insect is a queen. In a specific embodiment of the invention the insect is selected from the group consisting of Lepidoptera (moths and butterflies), Diptera (flies and mosquitoes), Coleoptera (beetles) and Hymenoptera (wasps, bees, ants and sawflies). In a very specific embodiment the insect belongs to Hymenoptera. In another specific embodiment of the invention the insect is a pollinator. Pollinators move pollen from the male anthers of a flower to the female stigma of a flower to accomplish fertilization of the female gametes in the ovule of the flower by the male gametes from the pollen grain. Insect pollinators include but are not limited to bees (e.g. honey bees), wasps, among others pollen wasps (Masarinae), ants, flies including but not limited to bee flies, blue bottle flies and hoverflies, midges, mosquitoes, lepidopterans (butterflies and moths) and beetles, among others flower beetles. In a specific embodiment of the invention the insects (e.g. insect pollinators) belong to the Order of Hymenoptera, Suborder Apocrita or Symphyta, with special attention, but not limited to all the species belonging to Superfamily of Aculeata or Parasitica. An edible composition or microbes of the present disclosure can be specifically, but not exclusively targeted for insects in the Superfamily of Apoidea, species belonging to Subgroups of Spechiformes or Anthophila, Families Andrenidae, Apidae, Colletidae, Dasypoidae, Halictidae, Megachilidae, Meganomiidae, Melittidae or Stenotritidae. In one embodiment of the invention the insect pollinators are bees. As used herein “bees” refers to any bees belonging to family Andrenidae, Apidae, Colletidae, Dasypodaidae, Halictidae, Megachilidae, Meganomiidae, Melittidae or Stenotritidae. In one embodiment of the invention the insect is a bee selected from the group consisting of eusocial bees, subsocial bees, quasisocial bees, semisocial bees, parasocial bees, solitary bees, honey bees, stingless bees, bumblebees, carpenter bees, hornfaced bees, orchid bees, orchard mason bees, leafcutter bees, sweat bees, mason bees, polyester bees, squash bees, dwarf carpenter bees, alkali bees, digger bees and allodapine bees. As used herein stingless bees refers to bees, which cannot sting. Stingless bees include but are not limited to bees of tribe Meliponini or family Andrenidae. Meliponines have stingers, but they are highly reduced and cannot be used for defense. As used herein “bumblebees” refer to bees that are members of the bee genus Bombus, in the family Apidae. As used herein “a honey bee” is any bee, which is a member of the genus Apis, primarily distinguished by the production and storage of honey and the construction of perennial, colonial nests from wax. For example two species of honey bees, namely A. mellifera or A. cerana indica, are often maintained by beekeepers. Honey bees include but are not limited to Apis andreniformis and Apis florea in subgenus Micrapis, Apis dorsata in subgenus Megapis, and Apis cerana, Apis koschevnikovi, Apis mellifera and Apis nigrocincta in subgenus Apis. In a very specific embodiment of the invention, the insect is selected from the group consisting of honey bees, bumblebees, wax moths and silk moths. As used herein “silk moth” refers to a lepidopteran, a moth, whose caterpillar is able to produce silk. In a specific embodiment a silk moth refers to Bombyx mori. Entomopathogenic Bacteria Bacteria that infect insects are called Entomopathogenic bacteria. As used herein “bacteria” or “bacterial” refer to prokaryotic microorganisms, which are about one-tenth the size of eukaryotic cells and are typically 0.5-5.0 micrometers in length. The bacterial cell is surrounded by a cell membrane (also known as a lipid, cytoplasmic or plasma membrane). Bacteria do not usually have membrane-bound organelles in their cytoplasm, and thus contain few large intracellular structures. They lack a true nucleus, mitochondria, chloroplasts and the other organelles present in eukaryotic cells. Bacteria may be either gram positive or gram negative bacteria. In one embodiment of the invention one or more bacteria or fragments or spores thereof used for preventing a microbial disease or infection may be selected from the group consisting of Spiroplasma spp. (e.g. S. apis, S. mellifera), Streptococcus spp., Staphylococcus spp., Enterococcus spp. (e.g. E. faecalis, E. faecium), Aeromonas sp. (e.g. A. mundii), Bacillus spp. (e.g. B. bombiseptieus, B. thuringiensis), Klebsiella spp., Alcaligenes spp., Psedomonas spp. or any bacteria listed in a table of FIG. 5, table of FIG. 6 or table of FIG. 7. In a more specific embodiment of the invention, one or more bacteria or fragments or spores thereof are selected from the group consisting of Paenibacillus larvae, Melissococcus plutonius, Spiroplasma apis, Spiroplasma mellifera, Enterococcus faecalis, Enterococcus faecium, Bacillus bombyseptieus, Serratia marcescens, Aeromonas mundii and Bacillus thuringiensis (e.g. subsp. sotto). As used herein “microbial disease or infection” refers to any disease or infection caused by a microbe, i.e. a single cell organism including but not limited to bacteria, archaea, fungi, protists and viruses. In one embodiment of the invention the microbial disease or infection is caused by bacteria. Foulbrood is one of the common diseases of bees, e.g. honey bees. Foulbrood may be American foulbrood (AFB) or the milder European foulbrood. American foulbrood (AFB), caused by the spore-forming Paenibacillus larvae, is the most widespread and destructive of the bee brood diseases. P. larvae is a rod-shaped bacterium. Bee larvae up to three days old become infected by ingesting spores present in their food. Young larvae less than 24 hours old are most susceptible to infection. Spores germinate in the gut of the larva and the vegetative bacteria begin to grow, taking nourishment from the larva. Spores will not germinate in larvae over three days old. Infected larvae normally die after their cell is sealed. The vegetative form of the bacterium will die, but not before it produces many millions of spores. American foulbrood spores are extremely resistant to desiccation and can remain viable for more than 40 years in honey and beekeeping equipment. P. larvae is highly infectious and deadly to bee brood. (See e.g. the table of FIG. 7) European foulbrood is caused by Melissococcus plutonius, a bacterium that infects the midgut of the bee (e.g. honey bee) larvae. European foulbrood is considered less serious than American foulbrood. M. plutonius is not a spore-forming bacterium, but bacterial cells can survive several months on wax foundation. Symptoms include dead. (See e.g. the table of FIG. 7) May disease of bees is caused by Spiroplasma spp. S. apis causes May disease in honey bees. The disease affects adults and causes quivering and inability to fly, moribund, or dead. Large numbers of infected adults may die in 4-5 weeks. (See e.g. the table of FIG. 7) In addition to bees other insects are also susceptible to a wide range of pathogens. A disease of insect larvae called Sotto disease or Schlaffsucht is caused by B. thuringiensis bacteria. Upon sporulation, B. thuringiensis forms crystals of proteinaceous insecticidal δ-endotoxins (called crystal proteins or Cry proteins), which are encoded by cry genes. Cry toxins have specific activities against insect species of the orders Lepidoptera (moths and butterflies), Diptera (flies and mosquitoes), Coleoptera (beetles) and Hymenoptera (wasps, bees, ants and sawflies). When insects ingest toxin crystals, their alkaline digestive tracts denature the insoluble crystals, making them soluble and thus amenable to being activated with proteases expressed in the insect gut, which liberate the toxin from the crystal. The Cry toxin is then inserted into the insect gut cell membrane, perforating the digestive tract and forming a pore. As a result the insect stops eating and starves to death. Silkworms are very susceptible to these toxins. (See e.g. the table of FIG. 6) Bacteria that cause septicemia (a morbid condition caused by the multiplication of microorganisms in the blood) e.g. in silkworms belong to many taxa. The most common bacteria include Bacillus bombyseptieous, Serratia marcescens, Aeromonas mundii, Streptococcus spp. and Staphylococcus spp. (See e.g. the table of FIG. 6). Enterococcus spp. bacteria belong to intestinal bacterial species in humans and farm animals, but are not limited to these hosts. Enterococcus spp. are found in the farm animal and human wastes, as well as in the manure used for fertilization of the crops. They interact with many organisms and have negative effects on the environment. Said bacteria typically contaminate water supplies that can lead to infected plants as well as infections in people and animals. Insects, such as flies, can transmit the bacteria from the manure of animals and other decaying organic substrates to residential settings. E.g. in silk moth Enterococcus (e.g. E. faecalis or E. faecium) causes non-uniform development of larvae. Larvae become thin and small and have diarrhea. (See e.g. the table of FIG. 6) In a specific embodiment of the invention, the microbial disease or infection is a bacterial disease or infection selected from the group consisting of Bacillus spp. (e.g. causing Fuliginosa septicemia), Serratia spp. (e.g. causing Serratia-type septicemia), Aeromonas spp. (e.g. causing Green thorax septicemia), Bacillus thuringiensis strains (e.g. causing Sotto disease or Schlaffsucht), Enterococcus spp. (e.g. causing bacterial flacherie, thoracic or wrinkling disease), Paenibacillus spp. (e.g. among others P. larvae, causing American foulbrood), Melissococcus spp. (e.g. among others M. pluton, causing European foulbrood), Spiroplasma spp. (e.g. among others S. apis, causing May disease) disease or infection and any other bacterial diseases. In another embodiment the microbial disease or infection is a bacterial disease or infection selected from the group consisting of Bacillus spp. (e.g. causing Fuliginosa septicemia), Aeromonas spp. (e.g. causing Green thorax septicemia), Bacillus thuringiensis strains (e.g. causing Sotto disease or Schlaffsucht), Enterococcus spp. (e.g. causing bacterial flacherie, thoracic or wrinkling disease), Paenibacillus spp. (e.g. among others P. larvae, causing American foulbrood), Melissococcus spp. (e.g. among others M. pluton, causing European foulbrood), Spiroplasma spp. (e.g. among others S. apis, causing May disease) disease or infection and any other bacterial diseases. In a very specific embodiment the microbial disease is American or European foulbrood. In a specific embodiment of the invention specific bacteria or fragments or spores thereof are fed to insects for preventing diseases or infections caused by said specific bacteria (or fragments or spores thereof). Entomopathogenic Fungi Fungi that infect insects are called entomopathogenic fungi. As used herein “fungal”, “fungus” and “fungi” refer to yeast and filamentous fungi i.e. moulds. In one embodiment of the invention the fungi or fragments or spores thereof used for preventing a microbial disease may be selected from Table 1 (below). The entomopathogenic fungi include Taxa from several of the main fungal groups and do not form a monophyletic group. Entomopathogenic fungi belong to the Phyla Oomycota (fungi that have cellulose in their coenocytic hyphae, without chitin and biflagellate zoospores), Chytridiomycota (groups that are without cellulose and contain chitin walls), Zygomycota (have hyphae that are multicellular, non-septate, and zygospores by the joining of gametangia), Ascomycota, Deuteromycota and Basidiomycota. Many common and/or important entomopathogenic fungi are in the order Hypocreales of the Ascomycota: the asexual (anamorph) phases Beauveria, Metarhizium, Nomuraea, Paecilomyces=Isaria, Hirsutella and the sexual (teleomorph) state Cordyceps; others (Entomophthora, Zoophthora, Pandora, Entomophaga) belong in the order Entomophthorales of the Zygomycota. TABLE 1 Classification of entomopathogenic fungi (does not include all entomopathogenic genera). Kingdom: Protoctista Phylum: Oomycota Class: Oomycetes Order: Lagenidiales Genus: Lagenidium Order: Saproleginales Genus: Aphanomycopsis Atkinsiella Couchia Leptolegina Phylum: Cytridiomycota Class: Cytridoimycotes Order: Blastocladiales Genus: Catenaria Coelomomyces Coelomycidium Order: Chytridiales Genus: Myriophagus Kingdom: Mychota Phylum: Zygomycota Class: Zygomycetes Order: Entomophthorales Genus: Basidiobolus Conidiobolus Entomophaga Erynia Massospora Neozygites Strongwellsea Zoophthora Order: Mucorales Genus: Sporodiniella Class: Trichomycetes Order: Amoebidiales Genus: Amoebidium Order: Asellariales Order: Eccrinales Order: Harpellales Phylum: Basidiomycota Class: Phragmobasidiomycetes Order: Septobasidiales Genus: Septobasidium Uredinella Phylum: Ascomycota Class: Laboulbeniomycetes Order: Laboubeniales Genus: Hesperomyces Class: Hemiascomycetes Order: Endomycetales Genus: Candida Metchnikowia Class: Loculascomycetes Order: Myringiales Genus: Myriangium Order: Pleosporales Genus: Podonectria Class: Plectomycetes Order: Ascosphaerales Genus: Ascosphaera Class: Pyrenomycetes Order: Sphaeriales Genus: Calonectria Cordyceps Cordycepioideus Hypocrella Nectria Torrubiella Phylum: Deuteromycota Class: Coelomycetes Order: Sphaeropsidles Genus: Aschersonia Tetranacrium Class: Hyphomycetes Order: Moniliales Genus: Acremonium Akanthomyces Aspergillus Beauveria Culicinomyces Engyodontium Funicularis Fusarium Gibellula Harpographium HirsuteIla Hymenostilbe Metarhizium Nomuraea Paecilomyces Sorosporella Sporothrix Stibella Syngliocladium Tertacrium Tolypocladium Verticillium Order: Mycelia sterlia Genus: Aegerita In a more specific embodiment of the invention, one or more fungi or fragments or spores thereof are selected from the group consisting of Beauveria spp. (e.g. Beauveria bassiana), Isaria spp. (e.g. I. javanica, I. farinosa, I. fumosoroseus), Hirsutella ssp. (e.g. H. necatrix), Fusarium spp., Nomuraea spp. (e.g. N. rileyi), Aspergillus spp. (e.g. A. flavus, A. ochraceus, A. oryzae, A. parasiticus, A. tamarii, A. fumigatus, A. niger), Nosema (e.g. N. apis, N. ceranae, N. bombycis, N. bombi), Vairimorpha spp., Pleisthora spp., Thelohania spp, Metarhizium spp. (e.g. M. anisopliae), Ascospaera spp. (e.g. A. apis, A. aggregata, A. torchioi). This group includes e.g. filamentous and microsporidia fungi. (See e.g. tables of FIGS. 8 and 9). In one embodiment of the invention the microbial disease or infection is caused by fungi. The most common fungal disease of bees is chalkbrood, which occurs in the larvae. Chalkbrood is caused by fungi in the genus Ascosphaera, and it affects many different taxa of bees. Indeed, Ascosphaera spp. are found associated with bees as diverse as for example A. mellifera, Megachile rotundata, M. centuncularis, Osmia lignaria, O. cornifrons, Trigona carbonaria, and Chalicodoma spp. A. apis causes chalkbrood disease in honeybees. Infected larvae die at a late stage; sometimes after the cell is capped. The dead larvae are hard, chalk-white, but often mottled with black spots (the fungal spores). (See e.g. the table of FIG. 9) Stonebrood is a fungal disease caused by Aspergillus spp. (e.g. A. fumigatus, Aspergillus flavus, Aspergillus niger). It causes mummification of the brood of a bee colony. The fungi are common soil inhabitants and are also pathogenic to other insects. The spores of the different species have different colours and when a bee larva takes in spores, they may hatch in the gut, growing rapidly to form a collar-like ring near the head. Stonebrood causes death of larvae. (See e.g. the table of FIG. 9) Nosema diseases (dysentery or nosema disease) are caused by microsporidia in the genus Nosema. Transmission of these pathogens occurs when bees ingest the spores, probably in contaminated water, pollen or honey. The main effects of these pathogens include increased bee mortality and decreased colony vigor. (See e.g. the table of FIG. 9) The muscardines are fungal diseases and are common silkworm diseases in China and Japan. The muscardine fungi produce asexual infective spores. Depending on the pathogen species, these spores are white, green, yellow, black, grey or red, and the muscardine diseases are named based on these colors (e.g. Metarhizium anisopliae causes black and Nomuraea rileyi green muscardine). Muscadines cause death of larvae. (See e.g. the table of FIG. 8) In addition to fungi causing muscardines mentioned in FIG. 8 other fungi include e.g. Isaria javanica (grey muscardine), Isaria farinose (yellow muscardine), Isaria fumosoroseus (red muscardine) and Hirsutella ssp. (e.g. H. necatrix) (grassy muscardine). Diseases caused by Aspergillus spp. are called aspergillosis. For example silkworms cadavers with aspergillosis become stiff and mycelia emerge from the integument. The fungi causing this disease in silkworms include more than ten Aspergillus species. The fungus kills the instars in two to six days. (See e.g. the table of FIG. 8) Fusarium species cause fusariosis in silk moths. Fusariosis is characterized by a fecal mass on the anus premortem and postmortem. Pebrine is caused in moths by various microsporidia e.g. by Nosema bombycis as well as Vairimorpha, Pleisthora or Thelohania species. Pebrine causes death of larvae and infected adult moths have deformed wings and distorted antennae. Adults with pebrine mate poorly and have poor egg production. (See e.g. the table of FIG. 8) In a specific embodiment of the invention, the microbial disease or infection is a fungal disease or infection selected from the group consisting of chalkbrood, stonebrood, dysentery, nosema disease, muscardine, aspergillosis, fusariosis, pebrine, Beauveria spp. (e.g. Beauveria bassiana) infection, Isaria spp. (e.g. I. javanica, I. farinosa, I. fumosoroseus) infection, Hirsutella ssp. (e.g. H. necatrix) infection, Fusarium spp. (e.g. F. verticillioides) infection, Nomuraea spp. (e.g. N. rileyi) infection, Aspergillus spp. (e.g. A. flavus, A. ochraceus, A. oryzae, A. parasiticus, A. tamarii, A. fumigatus, A. niger) infection, Nosema spp. (e.g. N. apis, N. ceranae, N. bombycis, N. bombi) infection, Vairimorpha spp. (e.g. V. ephestiae) infection, Pleisthora spp. infection, Thelohania spp. (e.g. T. solenopsae) infection, Metarhizium spp. (e.g. M. anisopliae) infection and Ascospaera spp. (e.g. A. apis, A. aggregata, A. torchioi) infection. In another embodiment the microbial disease or infection is a fungal disease or infection selected from the group consisting of chalkbrood, stonebrood, dysentery, muscardine, aspergillosis, fusariosis, pebrine, Beauveria spp. (e.g. Beauveria bassiana) infection, Isaria spp. (e.g. I. javanica, I. farinosa, I. fumosoroseus) infection, Hirsutella ssp. (e.g. H. necatrix) infection, Fusarium spp. (e.g. F. verticillioides) infection, Nomuraea spp. (e.g. N. rileyi) infection, Aspergillus spp. (e.g. A. flavus, A. ochraceus, A. oryzae, A. parasiticus, A. tamarii, A. fumigatus, A. niger) infection, Vairimorpha spp. (e.g. V. ephestiae) infection, Pleisthora spp. infection, Thelohania spp. (e.g. T. solenopsae) infection, Metarhizium spp. (e.g. M. anisopliae) infection and Ascospaera spp. (e.g. A. apis, A. aggregata, A. torchioi) infection. In a specific embodiment of the invention specific fungi or fragments or spores thereof are fed to insects for preventing diseases or infections caused by said specific fungi (or fragments or spores thereof). Compositions and Artificial Diets The present invention relates to compositions and insect artificial diets comprising bacteria, fungi, fragments and/or spores thereof. Also, the present invention relates to bacteria, fungi, fragments and/or spores thereof as such for preventing insect diseases. Most specifically, the composition or insect artificial diet of the invention comprises bacteria, fragments and/or spores thereof. As used herein, an “insect artificial diet” refers to diet, which is fed to insects and which does not occur in nature as such but is artificially prepared by methods well known to a person skilled in the art. As used herein “artificially prepared” refers to a mixture of specific macronutrients (e.g. carbohydrates, proteins and/or fatty acids) with optionally added micronutrients (e.g. various minerals, salts and/or nucleic acids) as well as optional water. Different artificial diets have been developed to mimic the natural diet and to take into account specific requirements of specific insect species for nutrients. In some embodiments artificial diet may or may not comprise plant or animal material. As it is clear to a person skilled in the art natural insect diet cannot always be fed, e.g. in the lab, for practical and economical reasons (e.g. insects need a lot of plant tissue for several weeks to complete their development and it would not be feasible to grow plants in this amounts in the greenhouses or pollinators need sugary floral nectar, what would require a lot of flowering plants in containment). The exact composition of the macro- and/or micronutrients depends on the insect species. The diet ingredients may be commercial or from the relevant vendor and mixed according to the recipes well known to a person skilled in the art. As agar is often used to solidify the diet mixture, the dry ingredients may be optionally mixed with added water and optionally heated up on the heated plate or in the microwave. After allowing the diet to cool to the room temperature it may optionally be portioned and thereafter fed to the insects. In one embodiment of the invention, in addition to bacteria, fungi or fragments or spores thereof and optional water, the insect artificial diet further comprises sugar (e.g. in the case of honey bee artificial diet). In one embodiment the sugar is in the form of sugar solution or paste. As used herein “sugar” refers to a sweet, short-chain and soluble carbohydrate. Sugar may be selected e.g. from the group consisting of monosaccharides, disaccharides and oligosaccharides, more specifically glucose, fructose, galactose, sucrose, fructose, glucose, maltose, lactose, cane sugar, beet sugar, and isomerized corn syrup. The sugar for use in the present invention may specifically be sucrose, but any formulation which is functionally and/or chemically mimetic of nectar may be employed. In one embodiment the sugar solution is water solution. Particularly specific are 50% w/v sucrose solutions. In a specific embodiment of the invention the amount of sugar in the composition or artificial insect diet of the invention is 10-95%, 20-95%, 30-95%, 40-95%, more specifically 50-95%, more specifically 60-90%, more specifically 70-90% and more specifically 75-85%, or e.g. 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% by weight. The majority of honey bee larvae eat honey, but larvae that are chosen to become future queens will be fed with royal jelly. In a specific embodiment, the artificial diet comprises royal jelly. Royal jelly is a white secretion produced by young, female worker bees. It is comprised of pollen and chemicals from the glands of worker bees. Royal jelly contains dietary supplements, fertility stimulants and other medicines, as well as B vitamins. Workers and drones are fed royal jelly during the first few days of larval development, while future queen larvae consume royal jelly throughout their development. The edible composition of the present invention may be mixed with at least any natural or artificial insect food including but not limited to any of those mentioned in this disclosure (e.g. honey, pollen, water). In a specific embodiment of the invention the amount of royal jelly in the composition or artificial insect diet of the invention is 40-95%, more specifically 50-95%, more specifically 60-90%, more specifically 70-90% and more specifically 75-85% by weight. In one embodiment of the invention the insect artificial diet is implemented with amino acids. One or more amino acids may be selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glysine, pyrrolysine, proline, selenocysteine, serine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, trypthophan and valine. In addition to bacteria, fungi or fragments or spores and optional sugar and/or optional amino acids and/or optional royal jelly, the insect artificial diet of the invention may further comprise (depending on the insect to be vaccinated), but is not limited to, one or more from the group consisting of wheat germ, Wess Salt mix, agar, methyl parabene, ascorbic acid, cellulose, pinto bean flour, soy bean flour, wheat flower, mulberry leaves powder, dried plant parts (e.g. leaves, stems, roots and/or flowers), yeast extract, brewer's yeast products and tapioca flour. Artificial diet may also optionally include protein, carbohydrate or pollen supplemental foods, any dry mixes, moist cakes, candy patties, sugar syrups, sugar candies, and dry sugar. As an example the common insect diet for herbivorous Lepidopteran larvae may comprise, but is not limited to, Pinto bean, Torula yeast, Wheat germ, Ascorbic acid, Methyl p-nydroxybenzoate, Sorbic acid, Formaldehyde 10%, Water, and/or Agar. Some specific examples of the insect artificial diet comprising vaccine compositions are shown in the examples of the present disclosure. In one embodiment of the invention, the amount of bacteria, fungi, any fragment and/or spore thereof in the composition (e.g. edible composition) or artificial insect diet of the present invention is from 1 to 100%, 1 to 90%, 1 to 80% 1 to 70%, 1 to 60%, 1 to 50%, 1 to 40%, 1 to 30%, 1 to 20%, 1 to 10% or 1 to 5% by weight. This composition or artificial diet provides a significant prevention of microbial infections and/or diseases. In a very specific embodiment, the amount of bacteria or fragments or spores thereof in the edible composition is from 90 to 100% by weight. In another very specific embodiment the amount of bacteria or fragments or spores thereof in the insect diet is from 0.1 to 10% by weight. In a further embodiment the amount of bacteria, fungi, any fragment and/or spore thereof is from 1 to 10% by weight (or 1-20%, 1-30%, 1-40%, 1-50%, 1-60%, 1-70%, 1-80% or 1-90% by weight) and the amount of sugar is about 80% by weight (or about 30%, 40%, 50%, 60%, 70% or 90% by weight). In a very specific embodiment, the amount of Melissococcus pluton or Paenibacillus larvae bacteria in the composition or insect diet of the present invention is from 1 to 10% by weight (or 1-20%, 1-30%, 1-40%, 1-50%, 1-60%, 1-70%, 1-80% or 1-90% by weight) and the amount of sugar is about 80% by weight (or about 30%, 40%, 50%, 60%, 70% or 90% by weight). The amount of the bacteria, fungi or any fragment or spore thereof in the composition or diet may be adjusted depending on the properties of other agents of the composition and the type of insect administered with the composition. Need of delivering the composition to one or more dosages, and the dosage frequency per year are determined depending on the properties of the specific composition and a condition to be treated. In a specific embodiment, bacteria, fungi or any fragment or spore thereof are the only therapeutically effective agents of the composition or the insect artificial diet. In another specific embodiment the bacteria, fungi or any fragments or spores thereof are therapeutically effective agents as such. In one specific embodiment of the invention, the composition or insect diet comprises bacteria and/or fragments or spores thereof from one or more different types of bacteria. Therefore, the composition or insect diet may comprise at least two or at least three different types of bacteria and/or fragments or spores thereof. In another specific embodiment of the invention, the composition or insect diet comprises fungi and/or fragments or spores thereof from one or more different types of fungi. Therefore, the composition or insect diet may comprise at least two or at least three different types of fungi and/or fragments or spores thereof. As used herein “bacterial or fungal fragments” refer to any fragments of the bacteria or fungi, e.g. any part, piece, or polypeptide of the bacteria, or any combination thereof. Herein, the term “polypeptide” refers to polymers of amino acids of any length. In a specific embodiment the fragments may be selected from cell wall fragments or cell recognition molecules. As used herein “cell wall fragments” refer to fragments of a cell wall i.e. fragments of a structural layer surrounding a cell. E.g. in bacteria the cell wall is composed mainly of peptidoglycans and in fungi the cell wall comprises chitin and other polysaccharides. In a specific embodiment vitellogenins (Vg) bind to said bacteria, fungi and/or fragments or spores thereof, such as cell wall fragments. As used herein “cell recognition molecules” refer to molecules taking care of interaction between cells e.g. including but not limited to surface molecules or membrane glycoproteins. In a very specific embodiment of the invention microbes or fragments or spores thereof are transferred from the insect to the egg or larvae by insect lipoproteins vitellogenins (Vg). Spores of bacteria or fungi may also be utilized in the present invention. As used herein “bacterial spore” refers to a spore or spore-like structure produced by bacteria including but not limited to endospores, Akinetes, and spores produced by Actinobacteria and Azotobacter. Spore formation in bacteria is a method of surviving unfavourable conditions. As used herein “fungal spores” refer microscopic biological particles that allow fungi to be reproduced i.e. fungal spores form part of the life cycles of fungi. In one embodiment of the invention the edible composition comprises bacterial endospores (optionally in combination with vegetative cells). In a specific embodiment bacteria, fungi or fragments or spores thereof are provided in the form of washed and/or concentrated preparations. Such preparations can be prepared by any of a wide range of known microbiological techniques. Typical methods would include growth of spores or vegetative cells to stationary phase in liquid media or on agar plates followed by separation by direct centrifugation or harvesting of the cells from the agar plates followed by centrifugation. In one embodiment of the invention the bacteria, fungi, fragments and/or spores thereof are live. In another embodiment of the invention the bacteria, fungi, fragments thereof and/or spores thereof are dead, attenuated and/or avirulent. Methods of producing or treating dead, attenuated and/or avirulent bacteria, fungi, fragments and/or spores thereof are known to a person skilled in the art and are described in various handbooks or manuals in the field. In one specific embodiment of the invention the bacteria, fungi, fragments and/or spores thereof are heat-killed e.g. at a temperature of 80-130° C. (e.g. 90° C., 105° C. or 121° C.) for 5-60 minutes (e.g. 5-20, 5-15 or 10, 20, 30, 40 or 50 minutes), optionally before or after applying them to the composition or insect diet. The composition or artificial diet may be administered to insects one or several times a year. In a specific embodiment of the invention the composition is for administration one, two or three times a year, more specifically two times per year e.g. before hibernation and after it. The composition or artificial diet may be delivered as a single dose, or in several smaller doses administered at intervals. The composition or artificial diet may be delivered to any component of the hive, or to the insect cluster itself. Compositions of the present invention are easily administered or fed to insects. In addition to bacteria, fungi, fragments and/or spores thereof, the edible composition may optionally comprise one or more acceptable (e.g. pharmaceutically acceptable) agents selected from the group consisting of carrier(s) (e.g. water, glucose or lactose), adjuvant(s), excipient(s), auxiliary excipient(s), antiseptic(s), stabilizing, thickening or coloring agent(s), perfume(s), binding agent(s), filling agent(s), lubricating agent(s), suspending agent(s), sweetener(s), flavoring agent(s), gelatinizer(s), anti-oxidant(s), preservative(s), buffer(s), pH regulator(s), wetting agent(s) and components normally found in corresponding products. However, in a very specific embodiment of the invention only bacteria, fungi, fragments thereof and/or spores thereof are needed in the composition. In a further specific embodiment the composition consists of only bacteria, fungi, fragments thereof and/or spores thereof and water. In one specific embodiment of the invention, the compositions or artificial diet may be used for example in solid, semisolid or liquid form, such as in the form of patties, syrups, drenches, dustings, pastes, tablets, pellets, capsules, solutions, emulsions, suspensions or like. Preferably the composition is for oral administration. The composition or artificial diet of the invention comprises bacteria, fungi, bacterial spores, fungal spores and/or fragments thereof in an amount sufficient to produce the desired effect. Other ingredients as well as other specific components of the compositions or artificial diet are either obtained commercially or prepared by conventional techniques known in the art. Amounts and regimens for feeding or administration of bacteria, fungi or fragments or spores thereof (e.g. in the edible composition of artificial diet) can be determined readily by those skilled in the art of preventing microbial infections of insects. Generally, the dosage of the bacteria, fungi or fragments or spores thereof will vary depending on considerations such as insect type as well as a size, stage, age, gender and general health of the insect. Also, any other therapeutically effective agents or agents having preventive effects may be utilized in the present invention. Also, other concurrent diets or compositions may be utilized in addition to the diets or compositions of the present disclosure. Frequency of feeding and nature of the effect desired as well as other variables may be adjusted by insect farmers. In a specific embodiment of the invention the edible composition is used as the only vaccine in the insect for preventing a microbial disease or infection. The compositions or artificial diet may be manufactured by any conventional processes known in the art. Generating the composition or artificial diet means that bacteria or fragments thereof may for example be added to any products or mixed with any agents. The bacteria or any fragment thereof may be added or mixed either in connection with the preparation of the composition or artificial diet or thereafter, during the finishing of the end product. The edible composition of the present invention may be mixed with at least any artificial insect food including but not limited to any of those mentioned in this disclosure. Mixing methods include any conventional mixing methods known to a person skilled in the art. In a very specific embodiment, the composition or artificial diet further comprises a vitellogenin polypeptide, fragments thereof, polynucleotide encoding the vitellogenin polypeptide or fragments thereof. Alterations of the immune response of an insect can be checked by in vitro, ex vivo or in vivo tests from any biological sample. In vivo experiments include but are not limited to the determination of a response to vaccines. As used herein vaccination refers to administration or feeding of antigenic material (a vaccine) to stimulate an immune system against a pathogen. As used herein, the term “prevent” or “preventing” refers to feeding or administration of microbes to an insect for purposes which include not only 100% or complete prevention but also partial prophylaxis and therefore also amelioration or alleviation of disorders or symptoms related to microbial infections. Preventive effect may be assessed e.g. by monitoring the symptoms mentioned in any of the tables of FIGS. 6-9. In this respect, the present invention can provide any amount of increase e.g. in the survival data compared to untreated controls. It will be obvious to a person skilled in the art that, as the technology advances, the inventive concept can be implemented in various ways. The invention and its embodiments are not limited to the examples described above but may vary within the scope of the claims. EXAMPLES Materials and Methods 1. Production of Edible Vaccination Comprising Microbes or Fragments or Spores Thereof Paenibacillus larvae genotype Eric II (strain 233/00), was acquired CCUG: Culture Collection, University of Göteborg in Sweden. The dried culture was dissolved in MYPG medium and plated out on MYPG agar plates, plates were cultivated for 7 days at 35° C. and all the bacterial cells were harvested into the 1× PBS buffer and frozen at −20° C. until further use. Two (8 cm in diameter) plates were harvested into 0.5 ml 1× PBS. Further the bacterial solution was autoclaved for 20 min at 121° C. and aliquot of it was plated out on the sterile MYPG agar to assure, that all the bacteria were dead. Prior mixing to the insect feed (here queen diet), the solution was centrifuged, where 1.5 ml of the preparation was centrifuged at 10,000 rpm for 10 min at room temperature, supernatant was removed and cells were dissolved in 100 microliters of millipore water. This preparation forms a vaccine part in the insect feed. Next the prepared mixture was added to the queen feed acquired from Imkereibedarf Uwes Bienenkorb (Königin-futterteig, #5407) to form 1% of the final mass. A vaccine composition or insect feed comprising the vaccine composition may be produced for any insect according to this Chapter 1 of materials and methods (Production of edible vaccination comprising microbes or fragments or spores thereof). The feed to be mixed with the vaccine composition may be chosen depending on the target insect. A vaccine composition comprising fungi or fragments or spores thereof may be produced according to similar methods as described in the above paragraphs of Chapter 1 of materials and methods (Production of edible vaccination comprising microbes or fragments or spores thereof). Furthermore, the vaccine composition is added to the insect artificial diet of interest. 1a) Description of the Food Preparation with Vaccine for Honey Bees For creating the edible vaccine for the honey bee queens, as an example 10 grams of sugar paste (8 grams of granulated sugar, 2 grams of water) was mixed with 100 microliters of vaccine composition. 1b) Description of the Food Preparation with Vaccine for Moths To grow larvae of the generalist herbivorous moth larvae, as an example artificial diet (casein 31.5 g, sucrose 33.76 g, wheat germ 43.76 g, Wess salt 9 g, potassium sorbate 1 g, cellulose 6.26 g, methyl paraben 1.36 g, lepidopteran vitamin mix 9 g, aureomycin 1 g, ascorbic acid 3.5 g, propyl gallate 0.2 g, 40% formaldehyde 1.5 ml, linseed oil 6.5 ml, 45% potassium hydroxide 2.5 ml, 24g agar and 750 ml water) mixed with vaccine composition can be used. 1c) Description of the Food Preparation for Moths In order to prepare the artificial diet for the silkworms as an example 100 g of powder (Dried mulberry leaf powder 25.0 g, Defatted soybean meal 36.0 g, Wheat meal 15.0 g, Corn starch 4.0 g , Soybean fiber 5.0 g, Citric acid 4.0 g, Ascorbic acid 2.0 g, Salt mixture 3.0 g, Agar 4.2 g , Vitamin mixture 399.0 mg, Sorbic acid 200.0 mg, Propionic acid 691.0 mg, Chloramphenicol 10.0 mg, b-sitosterol 500.0 mg) was dissolved in 2.6 g of double distilled water and mixed with 100 microliters of dead bacterial solution per 10 g of diet. 2. Insect Rearing and Treatment (Apis mellifera) Single hive produced Apis mellifera sibling queens were acquired from the professional bee keeper. Queens were caged with 10 worker bees in the small so called queen cages and fed with prepared queen bee vaccine, consisting of 1% of autoclaved and previously frozen sterile bacterial preparation (see above under 1. Production of edible vaccination comprising bacteria or bacterial fragments) in 10 g of feed. 6 Queens were fed with vaccine for 7 days and kept in the climate cabinet at 30° C. As control 6 queens were fed with queen diet mixed with water. Vaccine was renewed every 3 days. After one week queens were transferred to the small Apidea bee hives, consisting of ca. 350 workers. Queens were allowed to settle and start to lay eggs. After 3 days hives were open and small larvae were removed and transferred to lab, where they were infected with 3 different doses of Paenibacillus larvae spores (10, 15 and 20 spores per larvae). Mortality was reordered. Rearing or treatment conditions similar to Apis mellifera queens as described above may be utilized or modified also for other insects. 3. Western Blot with Live P. larvae and E. coli (Apis mellifera) Wintertime worker honey bee hemolymph (hl) and fat body protein extract (fb) are rich in Vg, and were used for testing Vg-binding to bacteria, adapted from the fish Vg experiment by Tong et al. (Immunobiology. Elsevier; 2010; 215: 898-902) using an antibody that detects honey bee Vg. For cell-free hl and fb sampling, see Havukainen et al. (J Exp Biol. 2011; 214: 582-592). The experiment was performed at room temperature, centrifugation steps were 3,000 g for 5 min, and wash volume was 0.5 ml of PBS, if not mentioned otherwise. P. larvae (strain 9820 purchased from Belgian Co-ordinated Collections of Micro-organisms, Gent, Belgium) grown on MYPGP agar plates for 7 days and Epicurian Gold E. coli grown in LB medium liquid culture overnight were washed and suspended in 100 μl PBS per sample. The bacteria suspensions (˜1.3×108 cells/ml) were mixed with either an equal volume of hemolymph diluted 1/10 in PBS with a protease inhibitor cocktail (Roche, Penzberg, Germany) or with fat body protein extract (5.7 mg/ml total protein in PBS with the protease inhibitors). The following negative controls were used: 1) 100 μl P. larvae and E. coli with an equal volume of PBS but no hl/fb, to detect possible unspecific antibody binding to the bacteria, 2) 100 μl fb with an equal volume of PBS, but no bacteria, to detect possible Vg aggregation, and 3) 100 μl P. larvae and E. coli treated with 100 μl 5 mg/ml bovine serum albumin (BSA; control protein). As untreated controls, we kept on ice 0.1 μl of hl, 0.5 μl of fb extract, and 1 μl of BSA. The samples were incubated at 26° C. for 50 min under agitation for Vg-bacteria binding to occur. The bacteria were washed six times. The final pellet was resuspended in 10 μl of 4 M urea in PBS, agitated for 15 min and centrifuged. The samples were blotted on a nitrocellulose membrane according to a standard horse-radish peroxidase conjugate protocol with the Vg antibody tested before (Havukainen H et al. J Exp Biol. 2011; 214: 582-592; Seehuus S-C et al. J Insect Sci. 2007; 7: 1-14) (dilution 1:25,000; Pacific Immunology, Ramona, Calif., USA), or a commercial BSA antibody (1:2000; Life Technologies, Carlsbad, Calif., USA). The bands were visualized using Immune-Star kit and ChemiDoc XRS+ imager. All blotting reagents were purchased from Bio-Rad (Hercules, Calif., USA). 4. Microscopy of P. larvae and E. coli (Apis mellifera) Vg-binding to bacteria was further tested by fluorescence microscopy. The incubation with hl was as above, except hl and bacteria volumes were both 20 μl and the number of bacterial cells was ˜3×106. All centrifugation steps were 10,000 g, +4° C., 5 min and PBS-T wash volumes were 1 ml. After hl incubation with the bacteria, the bacteria were washed and fixed with 4% paraformaldehyde for 10 min in room temperature. The cells were washed twice and blocked with 5% milk in PBS-T for 30 min in room temperature and washed again. Vg primary antibody (same as above) was used 1:50 in PBS-T and 1% milk for overnight incubation at +4° C. The samples were washed twice and incubated with Alexa fluor 488 nm anti-rabbit antibody, 1:50, for 1 h in room temperature in dark and washed three times. DNA was stained with standard propidium iodide (PI) protocol (Invitrogen). The bacteria were mounted with glycerol and imaged with Zeiss Axio Imager M2, excitations 499 nm and 536 nm, and emissions 519 nm and 617 nm. The primary antibody was omitted in the treatment of the secondary antibody control samples. 5. Surface Plasmon Resonance with LPS, PG and Zymosan (Apis mellifera) Vg was purified from honey bee hemolymph with ion-exchange chromatography as described before (Havukainen H et al. J Biol Chem. 2013, 288: 28369-81; Seehuus S-C et al. J Insect Sci. 2007; 7: 1-14). Biacore T200 instrument (GE Healthcare, Waukesha, USA) and buffers from the manufacturer were used. The analytes were bought from Sigma Aldrich: PG from S. aureus #77140, LPS from E. coli #L2630 and zymosan from S. cerevisiae #Z4250. 30 μl/ml Vg in 10 mM acetate buffer pH 4.5 was immobilized on a CM5 chip—primed and conditioned according to the manufacturer's instructions—until the response reached 5150 RU. The chip was blocked using ethanolamine. The analytes were suspended in the running buffer (0.1 M HEPES, 1.5 M NaCl and 0.5% v/v surfactant P20) and heated at 90° C. for 30 min with repeated vigorous vortexing, followed by spinning in a table centrifuge for 20 min. Zymosan was heated for an additional 30 min at 95° C. before centrifugation. PG and zymosan form a fine suspension in water solutions, and they formed a pellet during the centrifugation; their concentrations are given here as the weight added to the volume. The analytes were run with 120 s contact time and 600 s dissociation time with a 30 μl/min flow rate at 25° C. The analytes flowing in a separate channel on a naked chip was used as a blank, whose value was subtracted from the sample. After optimizing the binding-range, the following concentrations were measured. PG: 0, 0.25, 0.5, 2, 3, 5 mg/ml; LPS: 0, 0.1, 0.2, 0.9, 1.8, 3 mg/ml, and zymosan: 0, 0.5, 1, 2, 3, 4 mg/ml. PG and LPS binding did not reach binding saturation, yet, we did not exceed 5 mg/ml or 3 mg/ml concentration, respectively, to avoid analyte aggregation (see the manufacturer's information and references therein for work concentrations). 6. Microscopy of Queen Ovaries (Apis mellifera) Six one year old A. mellifera ligustica queens were anesthetized on ice. Their ovaries were dissected and washed in ice cold PBS. One of the paired ovaries per queen was then placed in control solution (50 μl PBS containing 2 mg/ml Texas Red labeled E. coli Bioparticles; Life Technologies, Carlsbad, Calif., USA) and the other ovary was placed in the same solution that contained, in addition, 0.5 mg/ml Vg purified from honey bee hemolymph (Havukainen H et al. J Biol Chem. 2013, 288: 28369-81; Havukainen H et al. J Exp Biol. 2011; 214: 582-592). The ovaries were incubated at 28° C. for 2 h under agitation. Next, the ovaries were washed twice in 1 ml ice cold PBS for 5 min under agitation. Samples of two queens were directly mounted using Fluoromount (Sigma) and observed by bright field and fluorescence (excitation 595 nm, emission 615 nm) microscopy (Axio Imager M2, Carl Zeiss AG, Oberkochen, Germany). One additional untreated control queen was imaged for detection of the autofluorescent pedical area of the ovary. The remaining four queens were embedded in Tissue-Tek (Sakura Finetek, Torrance, Calif., USA) and stored in −80° C. These ovaries were cut in 17 mm sections at −20° C., and imaged immediately after mounting. The microscopy settings were kept constant during imaging. To test whether hemolymph proteins could trigger the uptake of immune elicitors even in the absence of Vg, we modified the experimental setup to include hemolymph proteins other than Vg, the majority of which are apolipophorin and hexamerins, both known to bind to immune elicitors (Wang Z et al. PLoS Pathog. 2010, 6). The other hemolymph proteins were obtained by running ion-exchange chromatography on honey bee hemolymph and dividing the collected hemolymph fractions into Vg and non-Vg proteins (FIG. 4) (Havukainen H et al. J Biol Chem. 2013, 288: 28369-81; Havukainen H et al. J Exp Biol. 2011; 214: 582-592). Remaining small molecular weight hemolymph molecules, such as possible peptides and hormones, were removed during protein concentration using centrifugal filters with 50 kDa cutoff with both Vg and non-Vg fractions (Millipore, Billerica, Mass., USA). Fractions containing both Vg and other hemolymph proteins were discarded. The Vg and the non-Vg proteins had a final concentration of 0.5 mg/ml in the experiment. The queens were as above. The setup was as follows (all incubations contained the E. coli Bioparticles 1.5 mg/ml): one ovary was incubated with Vg and the other ovary with control solution (see above) (N=3); one with Vg and the other with non-Vg hemolymph proteins (N=3), and one ovary with non-Vg hemolymph proteins and the other with control solution (N=2). The cryo-section imaging was done as above. 7. Vaccination of Silkworm (Bombyx mori) Against the Flacherie Disease Caused by Enterococcus faecalis Flacherie (meaning “flaccidness”, expressed as lethal diarrhea) can be caused by larvae feeding on the mulberry leaves contaminated with Enterococcus faecalis. Enterococcus faecalis is an opportunistic soil dwelling entomopathogenic bacterium with global distribution. 40 ml of sterile Luria Bertoni medium (5 g NaCl, 10 g Yeast extract, 10 g Tryptone dissolved in 1 L of double distilled water) was inoculated with a single colony of Enterococcus faecalis and bacteria were allowed to grow in 30° C. for 48 hours. After that bacterial cells were harvested and dissolved in 1 ml of 1×PBS and killed by autoclaving. To ensure, that all the bacteria are dead, an aliquot was plated on the Luria Bertoni agar plates (5 g NaCl, 10 g Yeast extract, 10 g Tryptone, 15 g of Agar dissolved in 1 L of double distilled water) and checked for the colony formation. As no colonies were formed in 48 h, the killing of bacteria was considered successful. Artificial diet described in paragraph 1c) above was cooked in an autoclave for about 40 min at 105° C. The diet was cooled to room temperature and then maintained in a refrigerator (4° C.) until its utilization. Freshly laid eggs of Silkworms were placed on the diet with vaccine and allowed to hatch and start feeding on it. Larvae were kept at 25° C. with relative humidity of 75% until pupation. Results 1. Vg Binds to Bacteria and Pathogen Patterns We first verified that honey bee Vg can bind to P. larvae—the Gram-positive bacterium that causes American foulbrood disease—and to Gram-negative E. coli by using western blotting and microscopy with live bacteria and an antibody that recognizes Vg (FIG. 1A-B). In the western blot, Vg signal was found in both P. larvae and E. coli samples that had been incubated with Vg-rich honey bee hemolymph or fat body homogenate and then thoroughly washed (FIG. 1A). The Vg signal appears to be stronger in the P. larvae samples than in the case of the E. coli samples. Negative controls were used to verify that the Vg signal was not due to Vg aggregation (a sample of fat body homogenate without any bacteria; lane 1, FIG. 1A) or due to unspecific antibody binding to bacteria (samples of bacteria only; lanes numbered 2, FIG. 1A). Also, bovine serum albumin (BSA) was used as a negative control, and this protein showed no binding to either bacterial species (FIG. 1A; BSA). We did fluorescence microscopy of P. larvae and E. coli incubated with honey bee hemolymph to verify the western blot result, and Vg signal was observed covering the bacteria (FIG. 1B). The antibody controls for unspecific binding showed no signal. We then verified honey bee Vg binding to the pathogen patterns PG (predominantly a Gram-positive bacteria signature molecule), LPS (Gram-negative signature) and zymosan (yeast) using a surface plasmon resonance technique (FIG. 1C). We detected the highest binding response for PG followed by LPS, whereas the binding response to zymosan was modest. 2. Vg is Required for the Transport of Bacteria-Derived Molecules Into Eggs Next, we verified that Vg can carry pathogen-derived molecules into eggs. This was tested by incubating dissected honey bee queen ovaries with the commercially available fluorescently labeled E. coli fragments, followed by imaging the fluorescent material taken up by the ovarioles (ovarian filaments) in the absence and presence of purified Vg (FIG. 2). The uptake of bacterial material was found only in the eggs that were provided with Vg. This result is consistent with our proposition that Vg is a carrier of TGIP messages. Co-localization of Vg and vaccine analogue (pieces of bacteria—E.coli) is shown in FIG. 10. 3. Vg is Sufficient and Necessary for TGIP Finally, Vg was found to be a sufficient and necessary hemolymph protein for the transfer of immune elicitors to occur. To show this, we tested if the presence of other, non-Vg honey bee hemolymph proteins produced by ion-exchange fractioning of honey bee hemolymph can trigger the transfer of immune elicitors to the developing eggs. The major protein fractions in the samples of other proteins are apolipophorin and hexamerins that are involved in transport and storage functions (see S1 for an SDS-PAGE gel of hemolymph, pure Vg and the other non-Vg proteins, and a hemolymph fractioning chromatogram). In the case of the non-Vg hemolymph proteins, the result was negative (FIG. 3). 4. Vaccinated Beehives Show Higher Resistance to the Paenibacillus larvae Infection in the Larval Stage The vaccine fed to the queens prior to egg laying is to increase the survival of the larvae upon infection with P. larvae in a dose dependent manner. Vaccination is to be more successful against lower doses of spores (e.g. 90% survival in the case of 5 spores) in comparison to higher doses (e.g. 50% survival in the case of 20 spores), whereas in non-vaccinated hives almost all the larvae succumb to infection. Similar results on any microbe disease or infection may be obtained by utilizing any corresponding bacteria, fungi, or fragments thereof or spores thereof in any insect species. | <SOH> BACKGROUND OF THE INVENTION <EOH>Insects have many important roles in the environment. For example insects may be used as food for people and animals, insects help in maintaining plant and animal diversity and also have enormous effect on the crop production. Insects ultimately affect humans since ensuring healthy crops is critical for agriculture. Insects also produce useful substances such as honey, wax, lacquer and silk. Therefore, the amount and health of insects are important ecological and economical issues. A serious environmental problem is the decline of populations of pollinator insects, and a number of species of insects are now cultured primarily for pollination management in order to have sufficient pollinators in the field, orchard or greenhouse at bloom time. Insects are needed for pollination during the bloom period of the plants. Examples of well recognized pollinators are honey bees and the various species of bees but also many other kinds of pollinators are cultured and sold for managed pollination. Honey bees and other pollinators travel from flower to flower, collecting nectar, which is later converted to honey, and pollen grains. Pollinators transfer pollen among the flowers as they are working. Nectar provides the energy for bee nutrition and pollen provides the protein. When bees are rearing large quantities of brood, they gather pollen to meet the nutritional needs of the brood. The Food and Agriculture Organisation of the United Nations (FAO) estimates that out of some 100 crop species which provide 90% of food worldwide, 71 are bee-pollinated. Honey bees are by far the most important commercial pollinators. However, at the same time, they are susceptible to many diseases, and thus like many other important pollinators, are in global population decline. In special focus in apiculture is the bacterial disease foulbrood that kills honey bee larvae. Foulbrood is common in most parts of the world, including Finland, and causes marked losses in corps worldwide. Currently foulbrood can be treated e.g. by burning up the whole hive. Also, the chemical oxytetracycline hydrochloride (antibiotic Terramycin) is used for prevention of foulbrood and tylosin (antibiotic Tylan) has been registered for therapeutic treatments of American foulbrood. In addition to honey bees another example of an economically important insect is a primary producer of silk. Domestic silk moths are closely dependent on humans for reproduction, as a result of selective breeding. The silkworm is the larva or caterpillar of the domesticated silk moth ( Bombyx mori ). Thermal therapies have been developed for silk moth larva to control the flacherie virus disease. Also, e.g. disinfection and antibiotics are used against bacterial diseases. As an example, septicemias are common bacterial diseases in silkworms. Serratia marcescens is causing Serratia -type septicemia, Bacillus spp. is causing fuliginosa septicemia and Aeromonas bacteria is causing green thorax septicemia. The common symptoms of septicemia include that larvae become dull and motionless with reduced feeding rates, even resulting in mortality in late instar larvae. Problems of the known treatment methods of insects having microbial diseases or infections include e.g. that the hives with infected honey bees must be totally destroyed and at the same time thermal methods are unreliable and may require moving of the hives. Furthermore, use of antibiotics lead to antibiotic resistance and antibiotics also stay in the environment e.g. the honey produced by honey bees contains the antibiotic. Actually, there is a lack of effective non-antibiotic methods for preventing microbial diseases of insects. Recently, Lopez et al. (2014) have utilized trans-generational immune priming (TGIP) for priming the offspring of honey bees against infections. Indeed, Lopez et al. have shown that honey bee ( Apis mellifera ) queens injected with dead Paenibacillus larvae (bacterium responsible for the American foulbrood disease) produce significantly more foulbrood resistant larvae than non-injected queens. However, injecting insects at a large scale is not feasible, and the injecting techniques are not within reach of the insect farmers. Furthermore, very suitable and effective compositions are needed for continuous use. In summary, there is a need of suitable and simple tools for preventing diseases and infections caused by microbial pathogens in insects. | <SOH> BRIEF DESCRIPTION OF THE INVENTION <EOH>An object of the present invention is to provide a method and composition for implementing the method so as to solve the above mentioned problems. The present invention provides an edible pharmaceutical composition suitable for insects and preventing microbial diseases or infections. The invention is based on the realization that immunization of insects can be utilized in preventing insect microbial diseases such as bacterial and fungal diseases by feeding the insects (e.g. larvae or adults) with said bacteria, fungi or any fragments or spores thereof. The preventive effect of the vaccine can be found in the insects fed with the vaccine composition, in the next generation or in both. An advantage of the method and arrangement of the invention is that now there is available a non-antibiotic vaccination which is effective and can be easily used. By utilizing the present invention it is easy for anyone e.g. to mix the vaccine composition into normal insect artificial diet such as food for insects (e.g. honey bees, silk moth). Furthermore, the present invention is able to reveal the detailed mechanism of how bacteria used for preventive therapeutic method are transported to insect eggs by a common insect lipoprotein vitellogenin (Vg). The objects of the invention are achieved by a method and an arrangement, which are characterized by what is stated in the independent claims. The preferred embodiments of the invention are disclosed in the dependent claims. The present invention relates to an edible composition comprising microbes selected from bacteria, fungi or any fragment or spore thereof for use as a vaccine in preventing a microbial disease or infection in an insect. The present invention also relates to bacteria, fungi, any fragment thereof or any spore thereof for oral use in preventing a microbial disease or infection of an insect. Also, the present invention relates to a method of preventing a microbial disease or infection of an insect, wherein the method comprises feeding the insect with an edible composition comprising bacteria, fungi or any fragment or spore thereof, wherein said edible composition acts as a vaccine against said microbial disease or infection. Furthermore, the present invention relates to use of bacteria, fungi or any fragment or spore thereof in an edible composition against a microbial disease or infection of an insect. Still, the present invention relates to an edible vaccine composition for insects, wherein the composition comprises bacteria, fungi or any fragments or spores thereof. And still further, the present invention relates to artificial insect diet comprising bacteria, fungi or any fragment or any spore thereof or an edible vaccine composition comprising bacteria, fungi or any fragments or spores thereof. And still furthermore, the present invention relates to a vaccine for insects, wherein the vaccine consists of bacteria, fungi, any fragments thereof and/or any spores thereof and optionally water. Also, the present invention relates to use of bacteria, fungi, any fragments thereof and/or any spores thereof, or an edible composition comprising microbes selected from bacteria, fungi or any fragment or spore thereof, in the manufacture of a medicament for preventing microbial disease or infection. And still, the present invention relates to an insect vaccinated with the edible vaccine composition of the present invention. | A61K390208 | 20180124 | 20180802 | 94345.0 | A61K3902 | 0 | JACKSON-TONGUE, LAKIA J | EDIBLE VACCINATION AGAINST MICROBIAL PATHOGENS | SMALL | 0 | PENDING | A61K | 2,018 |
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15,747,616 | PENDING | STEERING WHEEL UNIT | A steering wheel unit, including a steering wheel body (10), an airbag housing (30) in the hub region of the steering wheel body with an airbag (38); First positioning units (40) between the steering wheel body (10) and the airbag housing (30) that position the airbag housing (30) on the steering wheel body (10) in the axial direction; Second positioning units between the steering wheel body (10) and the airbag housing (30) position the airbag housing (30) on the steering wheel body (40) in the radial plane. The second positioning unit includes at least one positioning element (52, 62) having a contact surface (56, 66a, 66b), normal or surface normals are perpendicular to the axial direction; and an opposing contact surface (58, 68a, 68b) for the contact surface (56, 66a, 66b). The positioning element (52, 62) includes at least one elastically deformable positioning section (54, 64a, 64b). | 1. A steering wheel unit comprising; a steering wheel body, an airbag housing accommodated in a hub region of the steering wheel body wherein an airbag is accommodated, first positioning units operating between the steering wheel body and the airbag housing, which the first positioning units position the airbag housing on the steering wheel body in an axial direction, second positioning units operating between the steering wheel body and the airbag housing, the second positioning units position the airbag housing on the steering wheel body in a radial plane, at least one of the second positioning units includes at least one positioning element extending in the axial direction including at least one contact surface having a surface perpendicular to the axial direction, and an opposing contact surface for the contact surface, the positioning element includes at least one positioning section including the contact surface, the positioning section is elastically deformable perpendicular to the axial direction, and a rigid movement-limiting section disposed on a side of the positioning section facing away from the contact surface and disposed spaced from the positioning section. 2. A steering wheel unit according to claim 1, further comprising the positioning element extends from a bottom of the airbag housing. 3. A steering wheel unit according to claim 2, further comprising the positioning element is formed as an integral part of the airbag housing. 4. A steering wheel unit according to claim 1, further comprising the positioning section essentially has the shape of a hollow half cylinder. 5. A steering wheel unit according to claim 1, further comprising the positioning section includes a slot that extends in the axial direction. 6. A steering wheel unit according to claim 1, further comprising the opposing contact surface includes a concave main section against which the contact surface abuts. 7. A steering wheel unit according to claim 6, further comprising in that, a secondary section connects to ends of the main section, and in that a part of the movement-limiting section is positioned between two secondary sections but is spaced away from the secondary sections. 8. A steering wheel unit according to claim 1, further comprising the positioning element includes two of the positioning sections, and in that the movement-limiting section is disposed between the two positioning sections. 9. A steering wheel unit that features three of the second positioning units, wherein two of the second positioning units are formed according to claim 6. 10. A steering wheel unit according to claim 1, further comprising at least one spring element is provided, against whose force the airbag housing can be pressed down in the direction of the steering wheel body so that the first positioning units position the airbag housing, in a non-pressed down state, on the steering wheel body in the axial direction. 11. A steering wheel unit that features one of the positioning units according to claim 8. | CROSS-REFERENCE TO RELATED APPLICATIONS This application is a 35 U.S.C. § 371 national phase application of PCT International Application No. PCT/EP2016/068717, filed Aug. 5, 2016, which claims the benefit of priority under 35 U.S.C. § 119 to German Patent Application No. 10 2015 010 099.8, filed Aug. 5, 2015, the contents of which are incorporated herein by reference in their entirety. FIELD OF THE INVENTION The invention relates to a steering wheel unit for a motor vehicle. BACKGROUND Nearly every steering wheel unit of a motor vehicle includes an airbag module. As a rule, the steering wheel unit includes a steering wheel body and an airbag module accommodated in the hub region of this steering wheel body. The airbag housing of the airbag module is covered by a cover that forms one part of the surface of the steering wheel. As a rule, the surface of the cover also serves as an actuation surface for the car horn such that when a force that exceeds a predetermined value is exerted on the cover, the horn is activated. Here there are in principle two known concepts, i.e. the so-called “floating cover” concept, wherein the housing is rigidly connected to the steering wheel body, and the cover can be pressed down relative to the housing and relative to the steering wheel body; and the so-called “floating module” concept, wherein the cover is rigidly connected to the housing, and the cover, along with the housing, can be pressed down against the steering wheel body, the housing and the steering wheel body being connected to each other by horn springs. Recently, stationary or nearly stationary systems have also become known, which do not have any horn springs, but rather wherein the housing, with a corresponding force transfer, is not moved at all, or practically not at all, against the steering wheel body. In this case, the classic horn contacts are replaced, for example, by piezo-electric elements. In the case of the aforementioned floating-module steering wheel units, positioning units are provided that position the airbag housing in both axial direction and in the radial plane on the steering wheel body. For example, with the above-mentioned type, separate first positioning units are provided for this purpose, which serve the purpose of axial positioning, and second positioning units, which serve the purpose of positioning in the radial plane, are provided. In the aforementioned document of the above-described type, three second positioning units are also provided, wherein each of these second positioning units is constructed as follows: from the bottom of the airbag housing, a pin serving as a positioning element extends in axial direction, the outer surface of the pin serving as contact surface. This pin extends into a through-hole through a component of the steering wheel body, the inner surface of which body forming the opposing contact surface for the contact surface. Due to production tolerances, it is practically impossible to avoid providing a degree of clearance between the contact surfaces and the opposing contact surfaces, which in turn can lead to noise generation and of the contact surfaces and the opposing contact surfaces. With this as a starting point, the object of the present invention is to improve a steering wheel unit of the above-described type in such manner that the positioning accuracy is improved and ideally, zero backlash is achieved between the contact surfaces and the opposing surfaces of the positioning unit (non-axial positioning unit). Furthermore, in so doing, the functional reliability of the steering wheel is to be ensured, even when the gas generator is activated. SUMMARY This object is achieved by a steering wheel in accordance with embodiments of this invention including those described herein. According to an embodiment of the invention, the positioning element of at least one second positioning unit features at least two sections, i.e. a positioning section that is elastically deformable perpendicular to the axial direction and a rigid, movement-limiting section that is arranged on a side of the positioning section facing away from the contact surface and which is arranged at a distance from the positioning section. Using the elastically deformable positioning section, a tolerance compensation and potentially also zero play are achieved. However, without additional measures, the deformability of the positioning section could, with the expansion of the airbag, and in particular in the event of a collision, lead to the airbag housing being deflected so far in the radial plane relative to the steering wheel body that an unlocking of the first positioning units could occur. In order to prevent this, the rigid movement-limitation section is provided, which permits movement of the airbag housing in the radial plane only to an extent that does not result in an unlocking of the first positioning unit. In this way, the providing of additional prevention measures can, in particular, be dispensed with. In principle, the positioning element of a second positioning unit can extend either from the airbag housing or from the steering wheel body, wherein it is preferable that the positioning element extend from the base of the airbag housing, which makes it possible, in particular, to form it as an integral part of the base of the housing, particularly when the housing is a plastic element produced wholly or in part in an injection molding process. As known in principle from the prior art, it is also preferable that the contact surface of the positioning section be formed convex. Here the positioning section preferably has the shape of a hollow half cylinder. In order to achieve that, the positioning section is not only elastically deformable but also that its width can vary elastically, the positioning section preferably has a slot extending in the axial direction. In the case of a first type, the positioning element has precisely one positioning section having a convex contact surface, and the opposing contract surface has a complementary-concave main section against which the contact surface abuts. Here, the contact surface is preferably a section of a cylinder surface. In this case, in order to further improve the deformation limitation, a secondary section is attached to each end of the main section, wherein a part of the movement-limiting section is arranged between the two secondary sections, however at a distance from them. In a second type, the positioning element has two positioning sections, between which the movement-limiting section is disposed. In a particularly preferred embodiment, the steering wheel unit has two second positioning units of the first type and a second positioning unit of the second type. In this way, a very precise positioning can be achieved at the same time as a static redundancy is avoided. The steering wheel unit can be designed as a classic “floating module steering wheel unit” wherein the airbag housing can be pressed down, against the force of spring elements, against the steering wheel body, so that the first positioning units only position the airbag, in its non-pressed down state, in the axial direction on the steering wheel body. However the invention can also be used in steering wheel units wherein no significant movement between airbag housing and steering wheel body takes place when the driver presses on the cover of the airbag housing in order to activate the horn. DESCRIPTION OF THE DRAWINGS The invention will now be explained in more detail on the basis of an exemplary embodiment with reference to the Figures. FIG. 1 shows a schematic top view of the hub region of a steering wheel unit, FIG. 2 shows a cross-section along the plane A-A in FIG. 1, FIG. 3 shows a cross-section along the plane B-B in FIG. 1, FIG. 4 shows the housing of the steering wheel unit in FIGS. 1 to 3 in a detailed perspective representation, FIG. 5 shows the housing in FIG. 4 with an installed gas generator in a top view from below, FIG. 6 shows the elements shown in FIG. 5 in a perspective representation, FIG. 7 shows a retaining plate that is part of the steering wheel body, FIG. 8 shows a second positioning unit of a first type in a representation corresponding to FIG. 7, and FIG. 9 shows a second positioning unit of a second type in a representation corresponding to FIG. 8. DETAILED DESCRIPTION FIGS. 1 and 2 show a part of a steering wheel unit which, for activation of the horn, features a so-called “floating module.” This means that the steering wheel unit is essentially formed of a steering wheel body 10 and an airbag module in a recess in the hub region of the steering wheel body 10 that can be pressed down against the force of the horn springs 20. The airbag module here features an airbag housing 30, a cover 31 that is rigidly connected to the airbag housing, an airbag 35 that is folded into the airbag housing, and a gas generator 36 that is held on the airbag housing. The airbag housing 30 is connected by the horn springs 20 to a part of the steering wheel body 10, i.e. to a retaining plate 14. This retaining plate 14 can be formed in particular of metal, wherein it can be advantageous to overmold this metal retaining plate 14, at least in sections, with plastic material. A plurality of horn contacts 23, 33 are provided, wherein, in each instance, two horn contacts of a pair face each other in the usual way. In order to retain and position the airbag housing 30 on the steering wheel body 10, a plurality of positioning units are provided. A total of three first positioning units 40 are provided, which serve the purpose of axial positioning, and in addition, three second positioning units are provided, which serve the purpose of positioning the airbag housing 30 in the radial plane. In each instance, a first and a second positioning unit are located adjacent to each other, and the positions of the positioning-unit pairs are designated in FIG. 1 with the reference numbers P, P′ and P″. All first positioning units 40 are identically constructed and are described in more detail below, in particular with reference to the FIGS. 3, 4, 6 and 7. There are two types of second positioning units, i.e. the second positioning units of the first type, which are located in the positions P and P′, and a second positioning unit of the second type, which is located in the position P″. All positioning units have a housing-side part and a steering-wheel body part. The steering-wheel body parts are in each case sections of the retaining plate 14, so they will be discussed first with reference to FIG. 7. FIG. 7 shows the retaining plate 14 in a view from above, i.e. as seen from the airbag housing 30. The retaining plate 14 features five through-holes 16a to 16e, wherein the first three through-holes 16a to 16c belong to the positioning units. Here, each of the first three through-holes 16a to 16c is both part of a first positioning unit and part of a second positioning unit. A projection 47 projects into each of the three through-holes 16a to 16c, the downward-directed surface 48 of the projection 47 (see FIG. 3) serving as a retaining surface for a first positioning element on the airbag housing side. In addition, each of the first two through-holes, 16a and b, each feature an opposing contact surface with a concave, that is to say semicircular main section 58a and secondary sections 58b and 58c that extend from this main section 58a (see, in this respect, also FIG. 8). The third through-hole 16c features two opposing contact surfaces 68a and 68b that face each other. The fourth through-hole 16d serves as a passage for a ground connection 34 (see in this respect FIG. 4), the fifth through-hole 16a serves the purpose of providing access to the ignition bushing of the gas generator 36. As can be seen in particular from FIGS. 3, 4, 6, the housing-side elements of the first positioning units 40 consist in each case of a wire bracket 42 and a plastic element 44 which is latched onto this bracket 42, the upward-facing surface 46 of the plastic element being in contact with the downward-pointing surface 48 of the associated projection 47. Assembly takes place with elastic deformation of the bracket 42. As no additional retaining elements are provided, it is important that no unlocking of the first positioning units 40 occurs during ignition of the gas generator 36 and expansion of the airbag 38. In order to ensure this, and nevertheless achieve a tolerance compensation, the two positioning units, and here, in particular, the housing-side positioning elements 52 and 62, are constructed as follows. First the two positioning elements of the first type are described. With regard to these two positioning elements, the housing-side positioning element 52 designated by the circle 50 in FIG. 3, which in each instance interacts with an opposing contact surface, consists of two sections, that is to say a positioning section 54 and a movement-limiting section 57. Both sections extend in the axial direction from the bottom of the airbag housing 30 and can, in particular, form an integral part of the same, particularly if the airbag housing is wholly or partially a plastic injection-molded part. As can be seen in particular from FIGS. 5 and 8, the positioning sections 54 are each formed as a hollow half cylinder that is divided into two symmetrically identical parts by a slot 55 running in the axial direction. This results in a certain elastic mobility of the two parts of the hollow half cylinder, both toward each other and also toward the movement-limiting section 57. The outer side (i.e. the outer surface) of the positioning section 44 forms the contact surface 56, which follows the shape of the concave main section 58a of the opposing contact surface 58. The movement-limiting section 57 is spaced from the positioning section 54, wherein the distance can be, for example, 0.8 mm. A front protrusion 57a of this movement-limiting section 57 extends essentially to the central axis of the hollow half cylinder of the positioning section 54. The movement-limiting section 57 is designed block-shaped and thus rigid. The secondary sections 58b and 58c of the opposing contact surface 58 extend above the front edge of the movement-limiting section 57. Due to the design of the positioning section 54, it has, as already mentioned, a certain elasticity, thereby enabling a tolerance compensation, by which essentially clearance-free guiding in the main section 58a of the opposing contact surface 58 is also made possible. However, the maximum deformation of the positioning section 54 is limited by the movement-limiting section 57, because if there is a deflection that is too strong, either the positioning section 54 or one of the secondary sections 58b, 58c, comes into contact with the movement-limiting section 57. This has the effect that even when there is ignition of the gas generator and subsequent expansion of the airbag in the event of a collision, during which very powerful forces can arise, the movement of the airbag housing 30 in the radial direction is limited, so that an undesired unlocking of the first positioning units is securely prevented. The second positioning unit of the second type (see in his respect FIG. 9 in particular) is constructed similarly to the second positioning unit of the first type, which was just described above. The difference here is that two opposing positioning sections 64a, 64b, are provided, between which the movement-limiting section 67 is located. Here too the positioning sections 64a, 64b are designed as slotted hollow half cylinders. The opposing contact surfaces 68a, 68b have an essentially planar form, so that that an additional tolerance compensation can take place in the direction of the arrow. Here too, the movement-limiting section 67 limits the potential deformation of the positioning sections. While the above description constitutes the preferred embodiment of the present invention, it will be appreciated that the invention is susceptible to modification, variation and change without departing from the proper scope and fair meaning of the accompanying claims. | <SOH> BACKGROUND <EOH>Nearly every steering wheel unit of a motor vehicle includes an airbag module. As a rule, the steering wheel unit includes a steering wheel body and an airbag module accommodated in the hub region of this steering wheel body. The airbag housing of the airbag module is covered by a cover that forms one part of the surface of the steering wheel. As a rule, the surface of the cover also serves as an actuation surface for the car horn such that when a force that exceeds a predetermined value is exerted on the cover, the horn is activated. Here there are in principle two known concepts, i.e. the so-called “floating cover” concept, wherein the housing is rigidly connected to the steering wheel body, and the cover can be pressed down relative to the housing and relative to the steering wheel body; and the so-called “floating module” concept, wherein the cover is rigidly connected to the housing, and the cover, along with the housing, can be pressed down against the steering wheel body, the housing and the steering wheel body being connected to each other by horn springs. Recently, stationary or nearly stationary systems have also become known, which do not have any horn springs, but rather wherein the housing, with a corresponding force transfer, is not moved at all, or practically not at all, against the steering wheel body. In this case, the classic horn contacts are replaced, for example, by piezo-electric elements. In the case of the aforementioned floating-module steering wheel units, positioning units are provided that position the airbag housing in both axial direction and in the radial plane on the steering wheel body. For example, with the above-mentioned type, separate first positioning units are provided for this purpose, which serve the purpose of axial positioning, and second positioning units, which serve the purpose of positioning in the radial plane, are provided. In the aforementioned document of the above-described type, three second positioning units are also provided, wherein each of these second positioning units is constructed as follows: from the bottom of the airbag housing, a pin serving as a positioning element extends in axial direction, the outer surface of the pin serving as contact surface. This pin extends into a through-hole through a component of the steering wheel body, the inner surface of which body forming the opposing contact surface for the contact surface. Due to production tolerances, it is practically impossible to avoid providing a degree of clearance between the contact surfaces and the opposing contact surfaces, which in turn can lead to noise generation and of the contact surfaces and the opposing contact surfaces. With this as a starting point, the object of the present invention is to improve a steering wheel unit of the above-described type in such manner that the positioning accuracy is improved and ideally, zero backlash is achieved between the contact surfaces and the opposing surfaces of the positioning unit (non-axial positioning unit). Furthermore, in so doing, the functional reliability of the steering wheel is to be ensured, even when the gas generator is activated. | <SOH> SUMMARY <EOH>This object is achieved by a steering wheel in accordance with embodiments of this invention including those described herein. According to an embodiment of the invention, the positioning element of at least one second positioning unit features at least two sections, i.e. a positioning section that is elastically deformable perpendicular to the axial direction and a rigid, movement-limiting section that is arranged on a side of the positioning section facing away from the contact surface and which is arranged at a distance from the positioning section. Using the elastically deformable positioning section, a tolerance compensation and potentially also zero play are achieved. However, without additional measures, the deformability of the positioning section could, with the expansion of the airbag, and in particular in the event of a collision, lead to the airbag housing being deflected so far in the radial plane relative to the steering wheel body that an unlocking of the first positioning units could occur. In order to prevent this, the rigid movement-limitation section is provided, which permits movement of the airbag housing in the radial plane only to an extent that does not result in an unlocking of the first positioning unit. In this way, the providing of additional prevention measures can, in particular, be dispensed with. In principle, the positioning element of a second positioning unit can extend either from the airbag housing or from the steering wheel body, wherein it is preferable that the positioning element extend from the base of the airbag housing, which makes it possible, in particular, to form it as an integral part of the base of the housing, particularly when the housing is a plastic element produced wholly or in part in an injection molding process. As known in principle from the prior art, it is also preferable that the contact surface of the positioning section be formed convex. Here the positioning section preferably has the shape of a hollow half cylinder. In order to achieve that, the positioning section is not only elastically deformable but also that its width can vary elastically, the positioning section preferably has a slot extending in the axial direction. In the case of a first type, the positioning element has precisely one positioning section having a convex contact surface, and the opposing contract surface has a complementary-concave main section against which the contact surface abuts. Here, the contact surface is preferably a section of a cylinder surface. In this case, in order to further improve the deformation limitation, a secondary section is attached to each end of the main section, wherein a part of the movement-limiting section is arranged between the two secondary sections, however at a distance from them. In a second type, the positioning element has two positioning sections, between which the movement-limiting section is disposed. In a particularly preferred embodiment, the steering wheel unit has two second positioning units of the first type and a second positioning unit of the second type. In this way, a very precise positioning can be achieved at the same time as a static redundancy is avoided. The steering wheel unit can be designed as a classic “floating module steering wheel unit” wherein the airbag housing can be pressed down, against the force of spring elements, against the steering wheel body, so that the first positioning units only position the airbag, in its non-pressed down state, in the axial direction on the steering wheel body. However the invention can also be used in steering wheel units wherein no significant movement between airbag housing and steering wheel body takes place when the driver presses on the cover of the airbag housing in order to activate the horn. | B60R212037 | 20180125 | 20180802 | 82083.0 | B60R21203 | 0 | VERLEY, NICOLE T | STEERING WHEEL UNIT | UNDISCOUNTED | 0 | ACCEPTED | B60R | 2,018 |
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15,749,254 | PENDING | METHOD FOR REARRANGING GATEWAY AND METHOD FOR GENERATING DEDICATED BEARER | An embodiment of the present description provides a method for rearranging a gateway by a node, which is in charge of a control plane, for a user equipment (UE) in a mobile communication network. The method can comprise the steps of: if a UE performs a handover and both the UE and an opponent device communicating with the UE are capable of supporting rearrangement of a gateway, determining an appropriate gateway for the UE to be rearranged; and transmitting a rearrangement indication to the UE on the basis of the determination. | 1. A method of relocating a gateway by a node, which is in charge of a control plane, for a user equipment (UE) in a mobile communication network, the method comprising: determining to relocate a gateway appropriate for the UE in a case where the UE performs a handover and when both the UE and the other party communicating with the UE have capability to support the relocation of the gateway; and delivering a relocation indication to the UE on the basis of the determination. 2. The method of claim 1, wherein the case where the UE performs the handover comprises: a case where the node in charge of the control plane is changed by the handover; a case where a group ID of the node in charge of the control plane is changed by the handover; a case where a serving gateway (S-GW) is changed by the handover; a case where an ID of a local home network is changed by the handover; and a case where the handover is a handover between a home eNodeB and an eNodeB. 3. The method of claim 1, further comprising: receiving a tracking area update (TAU) request message from the UE while the UE performs the handover, wherein the TAU request message comprises capability information indicating that both the UE and the other party communicating with the UE have the capability to support the relocation of the gateway. 4. The method of claim 1, wherein the relocation indication is transmitted when a selected gateway is different from a previous gateway as a result of selecting the gateway appropriate for the UE. 5. The method of claim 1, further comprising: after transmitting the relocation indication, receiving a connection request message of a new PDN which uses the same APN as the existing packet data network (PDN) connection from the UE. 6. The method of claim 5, further comprising: after the new PDN connection is created, receiving a disconnection request message of the existing PDN from the UE; or transmitting a delete session request message to an S-GW. 7. A method of creating a dedicated bearer, the method performed by a local gateway coupled to a home eNodeB and comprising: establishing a second packet data network (PDN) connection for a user equipment (UE) handed over from an eNodeB to a home eNodeB, wherein while the second PDN connection is established, an interface is created between a serving-gateway (S-GW) and a packet data network-gateway (P-GW) to which a first PDN connection is established with the UE before the handover; receiving a create request message of the dedicated bearer from a node in charge of a control plane in a mobile communication network through the S-GW, in order to allow a dedicated bearer, which is present in the first PDN connection before the handover, to be also created in the new second PDN connection; and transmitting a message for modifying an IP connectivity access network (IP-CAN) session to a policy and charging rule function (PCRF) through the S-GW and the P-GW, in order to create the dedicated bearer. 8. The method of claim 7, wherein the transmitting of the message for modifying the IP-CAN session by the local gateway comprises: transmitting, by the local gateway, the message for modifying the IP-CAN session to the S-GW by encapsulating the message into a specific message; delivering the specific message by the S-GW to the P-GW; and extracting, by the P-GW, the message for modifying the IP-CAN session from the specific message, and delivering the message to the PCRF. 9. A node which relocates a gateway for a user equipment (UE) in a mobile communication network and which is in charge of a control plane, the node comprising: a transceiver; and a processor controlling the transceiver, wherein the processor performs: determining to relocate a gateway appropriate for the UE in a case where the UE performs a handover and both the UE and the other party communicating with the UE have capability to support the relocation of the gateway; and delivering a relocation indication to the UE on the basis of the determination. 10. The node of claim 9, wherein the case where the UE performs the handover comprises: a case where the node in charge of the control plane is changed by the handover; a case where a group ID of the node in charge of the control plane is changed by the handover; a case where a serving gateway (S-GW) is changed by the handover; a case where an ID of a local home network is changed by the handover, and a case where the handover is a handover between a home eNodeB and an eNodeB. 11. The node of claim 9, wherein the processor receives, through the transceiver, a tracking area update (TAU) request message from the UE while the UE performs the handover, wherein the TAU request message comprises capability information indicating that both the UE and the other party communicating with the UE have the capability to support the relocation of the gateway. 12. The node of claim 9, wherein the processor receives through the transceiver a connection request message of a new PDN which uses the same APN as the existing packet data network (PDN) connection from the UE, after transmitting the relocation indication. 13. The node of claim 12, wherein after the new PDN connection is created, the processor receives a disconnection request message of the existing PDN from the UE, or transmits a delete session request message to an S-GW. 14. A local gateway coupled to a home eNodeB, comprising: a transceiver; and a processor controlling the transceiver, wherein the processor performs: establishing a second packet data network (PDN) connection for a user equipment (UE) handed over from an eNodeB to a home eNodeB, wherein while the second PDN connection is established, an interface is created between a serving-gateway (S-GW) and a packet data network-gateway (P-GW) to which a first PDN connection is established with the UE before the handover; receiving a create request message of the dedicated bearer from a node in charge of a control plane in a mobile communication network through the S-GW, in order to allow a dedicated bearer, which is present in the first PDN connection before the handover, to be also created in the new second PDN connection; and transmitting a message for modifying an IP connectivity access network (IP-CAN) session to a policy and charging rule function (PCRF) through the S-GW and the P-GW, in order to create the dedicated bearer. | CROSS-REFERENCE TO RELATED APPLICATIONS This application is the National Stage filing under 35 U.S.C. 371 of International Application No. PCT/KR2016/008976, filed on Aug. 16, 2016, which claims the benefit of U.S. Provisional Application No. 62/205,754 filed on Aug. 17, 2015, the contents of which are all hereby incorporated by reference herein in their entirety. BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to mobile communication. Related Art In 3GPP in which technical standards for mobile communication systems are established, in order to handle 4th generation communication and several related forums and new technologies, research on Long Term Evolution/System Architecture Evolution (LTE/SAE) technology has started as part of efforts to optimize and improve the performance of 3GPP technologies from the end of the year 2004. SAE that has been performed based on 3GPP SA WG2 is research regarding network technology that aims to determine the structure of a network and to support mobility between heterogeneous networks in line with an LTE task of a 3GPP TSG RAN and is one of recent important standardization issues of 3GPP. SAE is a task for developing a 3GPP system into a system that supports various radio access technologies based on an IP, and the task has been carried out for the purpose of an optimized packet-based system which minimizes transmission delay with a more improved data transmission capability. An Evolved Packet System (EPS) higher level reference model defined in 3GPP SA WG2 includes a non-roaming case and roaming cases having various scenarios, and for details therefor, reference can be made to 3GPP standard documents TS 23.401 and TS 23.402. A network configuration of FIG. 1 has been briefly reconfigured from the EPS higher level reference model. FIG. 1 shows the configuration of an evolved mobile communication network. An Evolved Packet Core (EPC) may include various elements. FIG. 1 illustrates a Serving Gateway (S-GW) 52, a Packet Data Network Gateway (PDN GW) 53, a Mobility Management Entity (MME) 51, a Serving General Packet Radio Service (GPRS) Supporting Node (SGSN), and an enhanced Packet Data Gateway (ePDG) that correspond to some of the various elements. The S-GW 52 is an element that operates at a boundary point between a Radio Access Network (RAN) and a core network and has a function of maintaining a data path between an eNodeB 22 and the PDN GW 53. Furthermore, if a terminal (or User Equipment (UE) moves in a region in which service is provided by the eNodeB 22, the S-GW 52 plays a role of a local mobility anchor point. That is, for mobility within an E-UTRAN (i.e., a Universal Mobile Telecommunications System (Evolved-UMTS) Terrestrial Radio Access Network defined after 3GPP release-8), packets can be routed through the S-GW 52. Furthermore, the S-GW 52 may play a role of an anchor point for mobility with another 3GPP network (i.e., a RAN defined prior to 3GPP release-8, for example, a UTRAN or Global System for Mobile communication (GSM) (GERAN)/Enhanced Data rates for Global Evolution (EDGE) Radio Access Network). The PDN GW (or P-GW) 53 corresponds to the termination point of a data interface toward a packet data network. The PDN GW 53 can support policy enforcement features, packet filtering, charging support, etc. Furthermore, the PDN GW (or P-GW) 53 can play a role of an anchor point for mobility management with a 3GPP network and a non-3GPP network (e.g., an unreliable network, such as an Interworking Wireless Local Area Network (I-WLAN), a Code Division Multiple Access (CDMA) network, or a reliable network, such as WiMax). In the network configuration of FIG. 1, the S-GW 52 and the PDN GW 53 have been illustrated as being separate gateways, but the two gateways may be implemented in accordance with a single gateway configuration option. The MME 51 is an element for performing the access of a terminal to a network connection and signaling and control functions for supporting the allocation, tracking, paging, roaming, handover, etc. of network resources. The MME 51 controls control plane functions related to subscribers and session management. The MME 51 manages numerous eNodeBs 22 and performs conventional signaling for selecting a gateway for handover to another 2G/3G networks. Furthermore, the MME 51 performs functions, such as security procedures, terminal-to-network session handling, and idle terminal location management. The SGSN handles all packet data, such as a user's mobility management and authentication for different access 3GPP networks (e.g., a GPRS network and an UTRAN/GERAN). The ePDG plays a role of a security node for an unreliable non-3GPP network (e.g., an I-WLAN and a Wi-Fi hotspot). As described with reference to FIG. 1, a terminal (or UE) having an IP capability can access an IP service network (e.g., IMS), provided by a service provider (i.e., an operator), via various elements within an EPC based on non-3GPP access as well as based on 3GPP access. Furthermore, FIG. 1 shows various reference points (e.g., S1-U and S1-MME). In a 3GPP system, a conceptual link that connects two functions that are present in the different function entities of an E-UTRAN and an EPC is called a reference point. Table 1 below defines reference points shown in FIG. 1. In addition to the reference points shown in the example of Table 1, various reference points may be present depending on a network configuration. TABLE 1 REFERENCE POINT DESCRIPTION S1-MME A reference point for a control plane protocol between the E-UTRAN and the MME S1-U A reference point between the E-UTRAN and the S-GW for path switching between eNodeBs during handover and user plane tunneling per bearer S3 A reference point between the MME and the SGSN that provides the exchange of pieces of user and bearer information for mobility between 3GPP access networks in idle and/or activation state. This reference point can be used intra-PLMN or inter-PLMN (e.g. in the case of Inter-PLMN HO). S4 A reference point between the SGW and the SGSN that provides related control and mobility support between the 3GPP anchor functions of a GPRS core and the S-GW. Furthermore, if a direct tunnel is not established, the reference point provides user plane tunneling. S5 A reference point that provides user plane tunneling and tunnel management between the S- GW and the PDN GW. The reference point is used for S-GW relocation due to UE mobility and if the S-GW needs to connect to a non-collocated PDN GW for required PDN connectivity S11 A reference point between the MME and the S-GW SGi A reference point between the PDN GW and the PDN. The PDN may be a public or private PDN external to an operator or may be an intra-operator PDN, e.g., for the providing of IMS services. This reference point corresponds to Gi for 3GPP access. Among the reference points shown in FIG. 1, S2a and S2b correspond to non-3GPP interfaces. S2a is a reference point providing the user plane with related control and mobility support between a PDN GW and a reliable non-3GPP access. S2b is a reference point providing the user plane with mobility support and related control between a PDN GW and an ePDG. FIG. 2 is an exemplary diagram showing the architecture of a common E-UTRAN and a common EPC. As shown in FIG. 2, the eNodeB 20 can perform functions, such as routing to a gateway while RRC connection is activated, the scheduling and transmission of a paging message, the scheduling and transmission of a broadcast channel (BCH), the dynamic allocation of resources to UE in uplink and downlink, a configuration and providing for the measurement of the eNodeB 20, control of a radio bearer, radio admission control, and connection mobility control. The EPC can perform functions, such as the generation of paging, the management of an LTE_IDLE state, the ciphering of a user plane, control of an EPS bearer, the ciphering of NAS signaling, and integrity protection. FIG. 3 is an exemplary diagram showing the structure of a radio interface protocol in a control plane between UE and an eNodeB, and FIG. 4 is another exemplary diagram showing the structure of a radio interface protocol in a control plane between UE and an eNodeB. The radio interface protocol is based on a 3GPP radio access network standard. The radio interface protocol includes a physical layer, a data link layer, and a network layer horizontally, and it is divided into a user plane for the transmission of information and a control plane for the transfer of a control signal (or signaling). The protocol layers may be classified into a first layer (L1), a second layer (L2), and a third layer (L3) based on three lower layers of the Open System Interconnection (OSI) reference model that is widely known in communication systems. The layers of the radio protocol of the control plane shown in FIG. 3 and the radio protocol in the user plane of FIG. 4 are described below. The physical layer PHY, that is, the first layer, provides information transfer service using physical channels. The PHY layer is connected to a Medium Access Control (MAC) layer placed in a higher layer through a transport channel, and data is transferred between the MAC layer and the PHY layer through the transport channel Furthermore, data is transferred between different PHY layers, that is, PHY layers on the sender side and the receiver side, through the PHY layer. A physical channel is made up of multiple subframes on a time axis and multiple subcarriers on a frequency axis. Here, one subframe is made up of a plurality of symbols and a plurality of subcarriers on the time axis. One subframe is made up of a plurality of resource blocks, and one resource block is made up of a plurality of symbols and a plurality of subcarriers. A Transmission Time Interval (TTI), that is, a unit time during which data is transmitted, is 1 ms corresponding to one subframe. In accordance with 3GPP LTE, physical channels that are present in the physical layer of the sender side and the receiver side can be divided into a Physical Downlink Shared Channel (PDSCH) and a Physical Uplink Shared Channel (PUSCH), that is, data channels, and a Physical Downlink Control Channel (PDCCH), a Physical Control Format Indicator Channel (PCFICH), a Physical Hybrid-ARQ Indicator Channel (PHICH), and a Physical Uplink Control Channel (PUCCH), that is, control channels. A PCFICH that is transmitted in the first OFDM symbol of a subframe carries a Control Format Indicator (CFI) regarding the number of OFDM symbols (i.e., the size of a control region) used to send control channels within the subframe. A wireless device first receives a CFI on a PCFICH and then monitors PDCCHs. Unlike a PDCCH, a PCFICH is transmitted through the fixed PCFICH resources of a subframe without using blind decoding. A PHICH carries positive-acknowledgement (ACK)/negative-acknowledgement (NACK) signals for an uplink (UL) Hybrid Automatic Repeat reQuest (HARQ). ACK/NACK signals for UL data on a PUSCH that is transmitted by a wireless device are transmitted on a PHICH. A Physical Broadcast Channel (PBCH) is transmitted in four former OFDM symbols of the second slot of the first subframe of a radio frame. The PBCH carries system information that is essential for a wireless device to communicate with an eNodeB, and system information transmitted through a PBCH is called a Master Information Block (MIB). In contrast, system information transmitted on a PDSCH indicated by a PDCCH is called a System Information Block (SIB). A PDCCH can carry the resource allocation and transport format of a downlink-shared channel (DL-SCH), information about the resource allocation of an uplink shared channel (UL-SCH), paging information for a PCH, system information for a DL-SCH, the resource allocation of an upper layer control message transmitted on a PDSCH, such as a random access response, a set of transmit power control commands for pieces of UE within a specific UE group, and the activation of a Voice over Internet Protocol (VoIP). A plurality of PDCCHs can be transmitted within the control region, and UE can monitor a plurality of PDCCHs. A PDCCH is transmitted on one Control Channel Element (CCE) or an aggregation of multiple contiguous CCEs. A CCE is a logical allocation unit used to provide a PDCCH with a coding rate according to the state of a radio channel A CCE corresponds to a plurality of resource element groups. The format of a PDCCH and the number of bits of a possible PDCCH are determined by a relationship between the number of CCEs and a coding rate provided by CCEs. Control information transmitted through a PDCCH is called Downlink Control Information (DCI). DCI can include the resource allocation of a PDSCH (also called a downlink (DL) grant)), the resource allocation of a PUSCH (also called an uplink (UL) grant), a set of transmit power control commands for pieces of UE within a specific UE group, and/or the activation of a Voice over Internet Protocol (VoIP). Several layers are present in the second layer. First, a Medium Access Control (MAC) layer functions to map various logical channels to various transport channels and also plays a role of logical channel multiplexing for mapping multiple logical channels to one transport channel. The MAC layer is connected to a Radio Link Control (RLC) layer, that is, a higher layer, through a logical channel. The logical channel is basically divided into a control channel through which information of the control plane is transmitted and a traffic channel through which information of the user plane is transmitted depending on the type of transmitted information. The RLC layer of the second layer functions to control a data size that is suitable for sending, by a lower layer, data received from a higher layer in a radio section by segmenting and concatenating the data. Furthermore, in order to guarantee various types of QoS required by radio bearers, the RLC layer provides three types of operation modes: a Transparent Mode (TM), an Un-acknowledged Mode (UM), and an Acknowledged Mode (AM). In particular, AM RLC performs a retransmission function through an Automatic Repeat and Request (ARQ) function for reliable data transmission. The Packet Data Convergence Protocol (PDCP) layer of the second layer performs a header compression function for reducing the size of an IP packet header containing control information that is relatively large in size and unnecessary in order to efficiently send an IP packet, such as IPv4 or IPv6, in a radio section having a small bandwidth when sending the IP packet. Accordingly, transmission efficiency of the radio section can be increased because only essential information is transmitted in the header part of data. Furthermore, in an LTE system, the PDCP layer also performs a security function. The security function includes ciphering for preventing the interception of data by a third party and integrity protection for preventing the manipulation of data by a third party. A Radio Resource Control (RRC) layer at the highest place of the third layer is defined only in the control plane and is responsible for control of logical channels, transport channels, and physical channels in relation to the configuration, re-configuration, and release of Radio Bearers (RBs). Here, the RB means service provided by the second layer in order to transfer data between UE and an E-UTRAN. If an RRC connection is present between the RRC layer of UE and the RRC layer of a wireless network, the UE is in an RRC_CONNECTED state. If not, the UE is in an RRC_IDLE state. An RRC state and an RRC connection method of UE are described below. The RRC state means whether or not the RRC layer of UE has been logically connected to the RRC layer of an E-UTRAN. If the RRC layer of UE is logically connected to the RRC layer of an E-UTRAN, it is called the RRC_CONNECTED state. If the RRC layer of UE is not logically connected to the RRC layer of an E-UTRAN, it is called the RRC_IDLE state. Since UE in the RRC_CONNECTED state has an RRC connection, an E-UTRAN can check the existence of the UE in a cell unit, and thus control the UE effectively. In contrast, if UE is in the RRC_IDLE state, an E-UTRAN cannot check the existence of the UE, and a core network is managed in a Tracking Area (TA) unit, that is, an area unit greater than a cell. That is, only the existence of UE in the RRC_IDLE state is checked in an area unit greater than a cell. In such a case, the UE needs to shift to the RRC_CONNECTED state in order to be provided with common mobile communication service, such as voice or data. Each TA is classified through Tracking Area Identity (TAI). UE can configure TAI through Tracking Area Code (TAC), that is, information broadcasted by a cell. When a user first turns on the power of UE, the UE first searches for a proper cell, establishes an RRC connection in the corresponding cell, and registers information about the UE with a core network. Thereafter, the UE stays in the RRC_IDLE state. The UE in the RRC_IDLE state (re)selects a cell if necessary and checks system information or paging information. This process is called camp on. When the UE in the RRC_IDLE state needs to establish an RRC connection, the UE establishes an RRC connection with the RRC layer of an E-UTRAN through an RRC connection procedure and shifts to the RRC_CONNECTED state. When the UE in the RRC_IDLE state needs to establish with an RRC connection includes multiple cases. The multiple cases may include, for example, a case where UL data needs to be transmitted for a reason, such as a call attempt made by a user and a case where a response message needs to be transmitted in response to a paging message received from an E-UTRAN. A Non-Access Stratum (NAS) layer placed over the RRC layer performs functions, such as session management and mobility management. The NAS layer shown in FIG. 3 is described in detail below. Evolved Session Management (ESM) belonging to the NAS layer performs functions, such as the management of default bearers and the management of dedicated bearers, and ESM is responsible for control that is necessary for UE to use PS service from a network. Default bearer resources are characterized in that they are allocated by a network when UE first accesses a specific Packet Data Network (PDN) or accesses a network. Here, the network allocates an IP address available for UE so that the UE can use data service and the QoS of a default bearer. LTE supports two types of bearers: a bearer having Guaranteed Bit Rate (GBR) QoS characteristic that guarantees a specific bandwidth for the transmission and reception of data and a non-GBR bearer having the best effort QoS characteristic without guaranteeing a bandwidth. A default bearer is assigned a non-GBR bearer, and a dedicated bearer may be assigned a bearer having a GBR or non-GBR QoS characteristic. In a network, a bearer assigned to UE is called an Evolved Packet Service (EPS) bearer. When assigning an EPS bearer, a network assigns one ID. This is called an EPS bearer ID. One EPS bearer has QoS characteristics of a Maximum Bit Rate (MBR) and a Guaranteed Bit Rate (GBR) or an Aggregated Maximum Bit Rate (AMBR). FIG. 5a is a flowchart illustrating a random access process in 3GPP LTE. The random access process is used for UE 10 to obtain UL synchronization with a base station, that is, an eNodeB 20, or to be assigned UL radio resources. The UE 10 receives a root index and a physical random access channel (PRACH) configuration index from the eNodeB 20. 64 candidate random access preambles defined by a Zadoff-Chu (ZC) sequence are present in each cell. The root index is a logical index that is used for the UE to generate the 64 candidate random access preambles. The transmission of a random access preamble is limited to specific time and frequency resources in each cell. The PRACH configuration index indicates a specific subframe on which a random access preamble can be transmitted and a preamble format. The UE 10 sends a randomly selected random access preamble to the eNodeB 20. Here, the UE 10 selects one of the 64 candidate random access preambles. Furthermore, the UE selects a subframe corresponding to the PRACH configuration index. The UE 10 sends the selected random access preamble in the selected subframe. The eNodeB 20 that has received the random access preamble sends a Random Access Response (RAR) to the UE 10. The random access response is detected in two steps. First, the UE 10 detects a PDCCH masked with a random access-RNTI (RA-RNTI). The UE 10 receives a random access response within a Medium Access Control (MAC) Protocol Data Unit (PDU) on a PDSCH that is indicated by the detected PDCCH. FIG. 5b illustrates a connection process in a radio resource control (RRC) layer. FIG. 5b shows an RRC state depending on whether there is an RRC connection. The RRC state denotes whether the entity of the RRC layer of UE 10 is in logical connection with the entity of the RRC layer of eNodeB 20, and if yes, it is referred to as RRC connected state, and if no as RRC idle state. In the connected state, UE 10 has an RRC connection, and thus, the E-UTRAN may grasp the presence of the UE on a cell basis and may thus effectively control UE 10. In contrast, UE 10 in the idle state cannot grasp eNodeB 20 and is managed by a core network on the basis of a tracking area that is larger than a cell. The tracking area is a set of cells. That is, UE 10 in the idle state is grasped for its presence only on a larger area basis, and the UE should switch to the connected state to receive a typical mobile communication service such as voice or data service. When the user turns on UE 10, UE 10 searches for a proper cell and stays in idle state in the cell. UE 10, when required, establishes an RRC connection with the RRC layer of eNodeB 20 through an RRC connection procedure and transits to the RRC connected state. There are a number of situations where the UE staying in the idle state needs to establish an RRC connection, for example, when the user attempts to call or when uplink data transmission is needed, or when transmitting a message responsive to reception of a paging message from the EUTRAN. In order for the idle UE 10 to be RRC connected with eNodeB 20, UE 10 needs to perform the RRC connection procedure as described above. The RRC connection procedure generally comes with the process in which UE 10 transmits an RRC connection request message to eNodeB 20, the process in which eNodeB 20 transmits an RRC connection setup message to UE 10, and the process in which UE 10 transmits an RRC connection setup complete message to eNodeB 20. The processes are described in further detail with reference to FIG. 6. 1) The idle UE 10, when attempting to establish an RRC connection, e.g., for attempting to call or transmit data or responding to paging from eNodeB 20, sends an RRC connection request message to eNodeB 20. 2) When receiving the RRC connection message from UE 10, eNodeB 20 accepts the RRC connection request from UE 10 if there are enough radio resources, and eNodeB 20 sends a response message, RRC connection setup message, to UE 10. 3) When receiving the RRC connection setup message, UE 10 transmits an RRC connection setup complete message to eNodeB 20. If UE 10 successfully transmits the RRC connection setup message, UE 10 happens to establish an RRC connection with eNodeB 20 and switches to the RRC connected state. In the 4th mobile communication system, an attempt to increase a cell capacity is continuously made in order to support a high-capacity service and a bidirectional service such as multimedia contents, streaming, and the like. That is, as various large-capacity transmission technologies are required with development of communication and spread of multimedia technology, a method for increase a radio capacity includes a method of allocating more frequency resources, but there is a limit in allocating more frequency resources to a plurality of users with limited frequency resources. An approach to use a high-frequency band and decrease a cell radius has been made in order to increase the cell capacity. When a cell having a small radius, such as a pico cell is adopted, a band higher than a frequency used in the existing cellular system may be used, and as a result, it is possible to transfer more information. However, since more base stations should be installed in the same area, higher cost is required. In recent years, a Femto base station such as a Home (e)NodeB 30 has been proposed while making the approach to increase the cell capacity by using the small cell. The Home (e)Node 30 has been researched based on a RAN WG3 of the 3GPP Home (e)NodeB and in recent years, the Home (e)NodeB 30 has been in earnest researched even in an SA WG. FIG. 6 is a diagram illustrating the relationship between (e)NodeB and Home (e)NodeB. The (e)NodeB 20 illustrated in FIG. 6 corresponds to a macro base station and the Home (e)NodeB 30 illustrated in FIG. 6 may correspond to the Femto base station. In the specification, (e)NodeB intends to be described based on terms of the 3GPP and (e)NodeB is used when NodeB and eNodeB are mentioned together. Further, Home (e)NodeB is used when Home NodeB and Home eNodeB are mentioned together. Interfaces marked with dotted lines are used to transmit control signals among the (e)NodeB 20, the Home (e)NodeB 30, and an MME 51. In addition, interfaced marked with solid lines are used to transmit data of the user plane. Meanwhile, recently, with an explosive increase in data, there is a problem in that congestion occurs in a core network of a mobile communication operator, that is, the S-GW 52 and P-GW 53 in the EPC. In order to solve this problem, the mobile communication operators have changed the S-GW 52 and the PDN-GW 53 to have a high capacity, or have added new equipment, which may lead to a disadvantage of requiring a significantly high cost. Further, an amount of data to be transmitted and received is exponentially increased day by day, which immediately leads to a disadvantage of overloading. Meanwhile, various methods of optimizing the S-GW 52 and the PDN-GW 53 have been proposed without having to add the mobile communication network. For example, it has been proposed a technique (i.e., selected IP traffic offload (i.e., SIPTO)) for offloading a path via nodes of a public network, i.e., a wired network, without having to perform transmission/reception via the path through the mobile communication operator's network 60. FIG. 7 shows the concept of a selected IP traffic offload (SIPTO). As can be seen with reference to FIG. 7, an SIPTO technique offloads specific IP traffic (e.g., an Internet service) of a UE 10 to nodes of a wired network 700 without having to pass through nodes in an IP service network 600 of a mobile communication operator. For example, traffic of the UE may be offloaded to the wireless network 700 such as a public communication network by applying the SIPTO to pass through a local network through a home (e)NodeB. This may be called an ‘SIPTO at local network’ scheme. Alternatively, the traffic of the UE through an (e)NodeB may be offloaded to the wired network 700 such as the public communication network. This may be called an ‘SIPTO above RAN’ scheme. FIG. 8 shows an example of a traffic path according to whether SIPTO is applied in a home (e)NodeB. Referring to FIG. 8, an SIPTO technique offloads specific IP traffic (e.g., an Internet service) of a UE 10 to nodes of a wired network, as indicated by a dotted line, without having to pass through nodes in a mobile communication operator's network 60. When the SIPTO is applied to a path through a home (e)NodeB, a function of a P-GW is additionally required in a local network in which a home (e)NodeB 30 is used. The P-GW added to the local network is called a P-GW 53′. As such, when the SIPTO technology is used, the P-GW for the UE needs to be reselected or relocated to the P-GW 53′. That is, the SIPTO technique can reduce an overload of an EPC by offloading traffic to a P-GW closest to the UE. For this, the UE shall be able to select the closest P-GW. The aforementioned SIPTO technique has been gradually improved according to the 3GPP release. First, according to the 3GPP release 10 in which the SIPTO is first standardized, a user experiences a temporary disruption of a service since seamless offloading is not supported. This will be described below in detail. First, when the UE moves to another base station, as a result of the movement, a target MME may reselect or relocate a P-GW which is more appropriate for a current location of the UE (e.g., a P-GW geographically closer to the location of the UE or a P-GW topologically closer thereto), and may determine to redirect a PDN connection of the UE to the reselected (or relocated) P-GW. As such, when the MME determines to reselect (or relocate) the P-GW, the MME performs a PDN disconnection procedure in which the UE is instructed of “reactivated requested” with respect to a PDN connection to be redirected. If it is determined to relocate all PDN connections for the UE, the MME performs a detach procedure so that the UE is instructed of “explicit detach with reattach required”. However, if there is an application being executed by the UE during the reselection (or relocation) procedure of the P-GW is performed (that is, if there is traffic to be transmitted/received via an original P-GW), a service may be temporarily disrupted due to an IP address change of the UE according to the reselection (or relocation) of the P-GW. To solve this service disruption problem, in 3GPP release 11, the MME is allowed to disconnect a PDN connection to perform P-GW reselection (or relocation) caused by SIPTO only during: i) the UE is in an idle mode; or ii) the UE performs a tracking area update (TAU) procedure in which a bearer of a user plane is not created. Accordingly, even if the UE moves in a connected mode, despite a different P-GW is more appropriate for the current location of the UE, the MME does not perform reselection (or relocation) with respect to the different P-GW. However, when the UE is in the connected mode, there is no proposed method for reselecting (or relocating) the P-GW more appropriate for the current location of the UE while minimizing a service disruption. Therefore, when the UE is in the connected mode, there is a problem in that user's traffic cannot be delivered to the more appropriate P-GW. This will be described in detail with reference to FIG. 9A and FIG. 9B. FIG. 9A shows an example in which an ‘SIPTO above RAN’ scheme is applied when a UE moves. As shown on the left side of FIG. 9A, the UE uses a PDN#1 which passes through an eNodeB#1, an S-GW#1, and a P-GW#1 by using an IP address#1. Thereafter, when the UE moves (e.g., TAU or handover), the PDN#1 passes through an eNodeB#2, an S-GW#2, and the P-GW#1. In this case, an MME performs a P-GW relocation procedure, in order to allow the PDN#1 to pass through the P-GW#2 located closer to the UE. In addition, the MME performs a procedure for deactivating the PDN#1. When the PDN#1 is deactivated, the MME allows the UE to perform a detach procedure for a reattach. After the detach procedure, the UE performs a reattach, and creates a new PDN#2. The new PDN#2 is created to pass through the P-GW#2 closer to the UE. As described above, in order to relocate the P-GW, the UE first has to perform the detach procedure, and thus a service is disrupted. FIG. 9B shows an example of applying an ‘SIPTO at local network’ scheme when a UE moves. As shown on the left side of FIG. 9B, the UE uses a PDN#1 which passes through an eNodeB#1, an S-GW#1, and a P-GW#1 by using an IP address#1. Thereafter, when the UE moves (e.g., TAU or handover), the PDN#1 passes through a home (e)NodeB, the S-GW#1, and the P-GW#1. In this case, an MME performs a P-GW relocation procedure, in order to allow the PDN#1 to pass through the P-GW located closer to the UE. In addition, the MME performs a procedure for deactivating the PDN#1. When the PDN#1 is deactivated, the MME allows the UE to perform a detach procedure for a reattach. After the detach procedure, the UE performs a reattach, and creates a new PDN#2. The new PDN#2 is created to pass through a local P-GW closer to the UE. As described above, in order to relocate the P-GW, the UE first has to perform the detach procedure, and thus a service is disrupted. Meanwhile, since the ‘conventional SIPTO at local network’ scheme does not support continuity of an IP data session, when the UE moves from the home (e)NodeB to a different base station, the PDN#2 connection is not handed over, and thus shall be re-established. Therefore, when the UE moves from the home (e)NodeB to the different base station, the home (e)NodeB releases its resource related to the UE, and requests the local P-GW to re-establish the PDN#2 connection. Then, the local P-GW drives a timer, and when the timer expires, releases the PDN#2 connection, and performs a bearer deactivation procedure. As such, since the PDN connection is disconnected, the service is disrupted. As described up to now, the conventional technique for offloading traffic, that is, the SIPTO above RAN scheme and the SIPTO at local network scheme, has to disconnect the existing PDN and create a new PDN. In this process, all services using the existing PDN are disrupted, which causes inconvenience to a user. SUMMARY OF THE INVENTION Accordingly, one disclosure of this specification is to propose a scheme capable of solving the aforementioned problems. To achieve the above purpose, a disclosure of the present specification provides a method of changing a packet data network-gateway (P-GW) to offload traffic of a user equipment (UE) in a connected mode without a service disruption. Specifically, to achieve the above purpose, a disclosure of the present specification provides a method of relocating a gateway by a node, which is in charge of a control plane, for a user equipment (UE) in a mobile communication network. The method may include: determining to relocate a gateway appropriate for the UE in a case where the UE performs a handover and both the UE and the other party communicating with the UE have capability to support the relocation of the gateway; and delivering a relocation indication to the UE on the basis of the determination. The case where the UE performs the handover may include: a case where the node in charge of the control plane is changed by the handover; a case where a group ID of the node in charge of the control plane is changed by the handover; a case where a serving gateway (S-GW) is changed by the handover; a case where an ID of a local home network is changed by the handover; and a case where the handover is a handover between a home eNodeB and an eNodeB. The method may further include receiving a tracking area update (TAU) request message from the UE while the UE performs the handover. The TAU request message may include capability information indicating that both the UE and the other party communicating with the UE have the capability to support the relocation of the gateway. The relocation indication may be transmitted when a selected gateway is different from a previous gateway as a result of selecting the gateway appropriate for the UE. The method may further include, after transmitting the relocation indication, receiving a connection request message of a new packet data network (PDN) which uses the same APN as the existing PDN connection from the UE. The method may further include: after the new PDN connection is created, receiving a disconnection request message of the existing PDN from the UE; or transmitting a delete session request message to an S-GW. On the other hand, to achieve the above purpose, a disclosure of the present specification provides a method of creating a dedicated bearer. The method may be performed by a local gateway coupled to a home eNodeB. The method may include: establishing a second packet data network (PDN) connection for a user equipment (UE) handed over from an eNodeB to a home eNodeB. Herein, while the second PDN connection is established, an interface may be created between a serving-gateway (S-GW) and a packet data network-gateway (P-GW) to which a first PDN connection is established with the UE before the handover. The method may include: receiving a create request message of the dedicated bearer from a node in charge of a control plane in a mobile communication network through the S-GW, in order to allow a dedicated bearer, which is present in the first PDN connection before the handover, to be also created in the new second PDN connection; and transmitting a message for modifying an IP connectivity access network (IP-CAN) session to a policy and charging rule function (PCRF) through the S-GW and the P-GW, in order to create the dedicated bearer. The transmitting of the message for modifying the IP-CAN session by the local gateway may include: transmitting, by the local gateway, the message for modifying the IP-CAN session to the S-GW by encapsulating the message into a specific message; delivering the specific message by the S-GW to the P-GW; and extracting, by the P-GW, the message for modifying the IP-CAN session from the specific message, and delivering the message to the PCRF. On the other hand, to achieve the above purpose, a disclosure of the present specification provides a node which relocates a gateway for a UE in a mobile communication network and which is in charge of a control plane. The node may include: a transceiver; and a processor controlling the transceiver. The processor may perform operations of: determining to relocate a gateway appropriate for the UE in a case where the UE performs a handover and both the UE and the other party communicating with the UE have capability to support the relocation of the gateway; and delivering a relocation indication to the UE on the basis of the determination. On the other hand, to achieve the above purpose, a disclosure of the present specification provides a local gateway coupled to a home eNodeB. The local gateway may include: a transceiver; and a processor controlling the transceiver. The processor may establish a second packet data network (PDN) connection for a user equipment (UE) handed over from an eNodeB to a home eNodeB. Herein, while the second PDN connection may be established, an interface is created between a serving-gateway (S-GW) and a packet data network-gateway (P-GW) to which a first PDN connection is established with the UE before the handover. The processor may receive a create request message of the dedicated bearer from a node in charge of a control plane in a mobile communication network through the S-GW, in order to allow a dedicated bearer, which is present in the first PDN connection before the handover, to be also created in the new second PDN connection. Further, the processor may transmit a message for modifying an IP connectivity access network (IP-CAN) session to a policy and charging rule function (PCRF) through the S-GW and the P-GW, in order to create the dedicated bearer. According to a disclosure of the present specification, problems of the conventional technique can be solved. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a structural diagram of an evolved mobile communication network. FIG. 2 is an exemplary diagram illustrating architectures of a general E-UTRAN and a general EPC. FIG. 3 is an exemplary diagram illustrating a structure of a radio interface protocol on a control plane between UE and eNodeB. FIG. 4 is another exemplary diagram illustrating a structure of a radio interface protocol on a user plane between the UE and a base station. FIG. 5a is a flowchart illustrating a random access process in 3GPP LTE. FIG. 5b illustrates a connection process in a radio resource control (RRC) layer. FIG. 6 is a diagram illustrating the relationship between (e)NodeB and Home (e)NodeB. FIG. 7 shows the concept of a selected IP traffic offload (SIPTO). FIG. 8 shows an example of a traffic path according to whether SIPTO is applied in a home (e)NodeB. FIG. 9A shows an example in which an ‘SIPTO above RAN’ scheme is applied when a UE moves. FIG. 9B shows an example of applying an ‘SIPTO at local network’ scheme when a UE moves. FIG. 10 is a schematic view showing a first method according to a first disclosure of the present specification. FIG. 11A and FIG. 11B are flowcharts illustrating a first method of FIG. 10 in detail. FIG. 12 is a schematic view showing a second method according to a first disclosure of the present specification. FIG. 13 is a schematic view showing a second method of FIG. 12 in a different manner. FIG. 14 shows an expected structure of a core network of a next generation mobile communication according to a second disclosure of the present specification. FIG. 15A to FIG. 15C show an expected handover of a UE in next generation mobile communication. FIG. 16 is a schematic view showing an example of applying a method according to a first disclosure of the present application to next generation mobile communication according to a second disclosure. FIG. 17 is a block diagram of a UE 100 and a network node according to an embodiment of the present invention. DESCRIPTION OF EXEMPLARY EMBODIMENTS The presented invention is described in light of UMTS (Universal Mobile Telecommunication System) and the EPC (Evolved Packet Core), but not limited to such communication systems, and may be rather applicable to all communication systems and methods to which the technical spirit of the presented invention may apply. The technical terms used herein are used to merely describe specific embodiments and should not be construed as limiting the presented invention. Further, the technical terms used herein should be, unless defined otherwise, interpreted as having meanings generally understood by those skilled in the art but not too broadly or too narrowly. Further, the technical terms used herein, which are determined not to exactly represented the spirit of the invention, should be replaced by or understood by such technical terms as being able to be exactly understood by those skilled in the art. Further, the general terms used herein should be interpreted in the context as defined in the dictionary, but not in an excessively narrowed manner. Furthermore, the expression of the singular number in the specification includes the meaning of the plural number unless the meaning of the singular number is definitely different from that of the plural number in the context. In the following description, the term ‘include’ or ‘have’ may represented the existence of a feature, a number, a step, an operation, a component, a part or the combination thereof described in the specification, and may not exclude the existence or addition of another feature, another number, another step, another operation, another component, another part or the combination thereof. The terms ‘first’ and ‘second’ are used for the purpose of explanation about various components, and the components are not limited to the terms ‘first’ and ‘second’. The terms ‘first’ and ‘second’ are only used to distinguish one component from another component. For example, a first component may be named as a second component without deviating from the scope of the presented invention. It will be understood that when an element or layer is referred to as being “connected to” or “coupled to” another element or layer, it can be directly connected or coupled to the other element or layer or intervening elements or layers may be presented. In contrast, when an element is referred to as being “directly connected to” or “directly coupled to” another element or layer, there are no intervening elements or layers presented. Hereinafter, exemplary embodiments of the presented invention will be described in greater detail with reference to the accompanying drawings. In describing the presented invention, for ease of understanding, the same reference numerals are used to denote the same components throughout the drawings, and repetitive description on the same components will be omitted. Detailed description on well-known arts which are determined to make the gist of the invention unclear will be omitted. The accompanying drawings are provided to merely make the spirit of the invention readily understood, but not should be intended to be limiting of the invention. It should be understood that the spirit of the invention may be expanded to its modifications, replacements or equivalents in addition to what is shown in the drawings. In the drawings, user equipments (UEs) are shown for example. The UE may also be denoted a terminal or mobile equipment (ME). The UE may be a laptop computer, a mobile phone, a PDA, a smart phone, a multimedia device, or other portable device or may be a stationary device, such as a PC or a car-mounted device. Definition of Terms For better understanding, the terms used herein are briefly defined before going to the detailed description of the invention with reference to the accompanying drawings. A GERAN: an abbreviation of a GSM EDGE Radio Access Network, and it refers to a radio access section that connects a core network and UE by GSM/EDGE. A UTRAN: an abbreviation of a Universal Terrestrial Radio Access Network, and it refers to a radio access section that connects the core network of the 3rd generation mobile communication and UE. An E-UTRAN: an abbreviation of an Evolved Universal Terrestrial Radio Access Network, and it refers to a radio access section that connects the core network of the 4th generation mobile communication, that is, LTE, and UE. An UMTS is an abbreviation of a Universal Mobile Telecommunication System, and it refers to the core network of the 3rd generation mobile communication. UE/MS is an abbreviation of User Equipment/Mobile Station, and it refers to a terminal device. An EPS is an abbreviation of an Evolved Packet System, and it refers to a core network supporting a Long Term Evolution (LTE) network and to a network evolved from an UMTS. A PDN is an abbreviation of a Public Data Network, and it refers to an independent network where a service for providing service is placed. A PDN connection refers to a connection from UE to a PDN, that is, an association (or connection) between UE represented by an IP address and a PDN represented by an APN. A PDN-GW is an abbreviation of a Packet Data Network Gateway, and it refers to a network node of an EPS network which performs functions, such as the allocation of a UE IP address, packet screening & filtering, and the collection of charging data. A Serving gateway (Serving GW) is a network node of an EPS network which performs functions, such as mobility anchor, packet routing, idle mode packet buffering, and triggering an MME to page UE. A Policy and Charging Rule Function (PCRF): The node of an EPS network which performs a policy decision for dynamically applying QoS and a billing policy that are different for each service flow. An Access Point Name (APN) is the name of an access point that is managed in a network and provides to UE. That is, an APN is a character string that denotes or identifies a PDN. Requested service or a network (PDN) is accessed via P-GW. An APN is a name (a character string, e.g., ‘intemet.mnc012.mcc345.gprs’) previously defined within a network so that the P-GW can be searched for. A Tunnel Endpoint Identifier (TEID): The end point ID of a tunnel set between nodes within a network, and it is set for each bearer unit of each UE. A NodeB is an eNodeB of a UMTS network and installed outdoors. The cell coverage of the NodeB corresponds to a macro cell. An eNodeB is an eNodeB of an Evolved Packet System (EPS) and is installed outdoors. The cell coverage of the eNodeB corresponds to a macro cell. An (e)NodeB is a term that denotes a NodeB and an eNodeB. An MME is an abbreviation of a Mobility Management Entity, and it functions to control each entity within an EPS in order to provide a session and mobility for UE. A session is a passage for data transmission, and a unit thereof may be a PDN, a bearer, or an IP flow unit. The units may be classified into a unit of the entire target network (i.e., an APN or PDN unit) as defined in 3GPP, a unit (i.e., a bearer unit) classified based on QoS within the entire target network, and a destination IP address unit. A PDN connection is a connection from UE to a PDN, that is, an association (or connection) between UE represented by an IP address and a PDN represented by an APN. It means a connection between entities (i.e., UE-PDN GW) within a core network so that a session can be formed. UE context is information about the situation of UE which is used to manage the UE in a network, that is, situation information including an UE ID, mobility (e.g., a current location), and the attributes of a session (e.g., QoS and priority) NAS (Non-Access-Stratum): A higher stratum of a control plane between a UE and an MME. The NAS supports mobility management, session management, IP address management, etc., between the UE and the network. RAT: an abbreviation of Radio Access Technology. Means GERAN, UTRAN, E-UTRAN, etc. MPTCP: It is an abbreviation of Multi-Path Traffic Control Protocol. A multipath TCP is a user interface such as TCP. Although a typical TCP interface is provided in this case, the existing TCP is improved so that data can be spread to several sub-flows. SIP: It is an abbreviation of Session Initiation Protocol. The SIP is a communication protocol for controlling a multimedia communication session. The most typical application using the SIP is an instant message as well as an Internet telephony for voice and video telephony. <First Disclosure of the Present Specification> Meanwhile, an embodiment proposed hereinafter may be implemented alone, or may be implemented by combining several embodiments. According to a disclosure of the present specification, a UE is improved to inform a network that it has capability to support a relocation of a P-GW. Herein, when both a transmitting side and a receiving side, e.g., a UE and an application server (AS)/application function (AF), support the relocation of the P-GW, the capability to support the relocation of the P-GW is set to “supported”. For example, when both the UE and the AS/AF use a protocol which supports session continuity, the capability to support the relocation of the P-GW is set to “supported”. For example, when the UE and the AS/AF use an MPTCP protocol or an SIP protocol, the capability to support the relocation of the P-GW may be set to “supported”. In addition, when the UE uses not only simply whether a protocol is supported but also service continuity using the protocol in a real application, the capability to support the relocation of the P-GW is set to “supported”. For example, when the UE supports the MPTCP protocol and uses the service continuity using the MPTCP in the real application, the capability to support the relocation of the P-GW is set to “supported”. If the UE supports the MPTCP protocol but cannot use a procedure for service continuity or uses it in the same way as a normal TCP, the capability to support the relocation of the P-GW is set to “not supported”. As such, the capability to support the relocation of the P-GW varies depending on the other party for communication and an application in use. Therefore, the UE always has to verify whether it has the capability to support the relocation of the P-GW with the other party for communication. For this, while communicating with the other party, the application of the UE verifies whether both of them have the capability to support the relocation of the P-GW, and reports capability information to a NAS layer. Such a verification process may be performed when a specific event occurs, for example, when communication is started or an application is executed according to the setting of the UE. In addition, when only some applications use the service continuity even if the UE does not use the service continuity in all applications currently being executed, the capability to support the relocation of the P-GW may be set to “supported”. In this case, an example of an application not using the service continuity may include a web browser or the like. FIG. 10 is a schematic view showing a first method according to a first disclosure of the present specification. As can be seen with reference to FIG. 10, a UE creates a PDN#1 through an eNodeB#1, an S-GW#1, and a P-GW#1, and exchanges data with an application function (AF). Thereafter, the UE moves to coverage of an eNodeB#2, and thus a handover procedure is performed. During the handover procedure is performed, the UE transmits a TAU request message to perform a tracking area update (TAU) procedure. Herein, the UE allows the TAU request message to include information regarding capability to support a relocation of the P-GW. As such, according to the disclosure of the present specification, it is improved to deliver the information of the capability to support the relocation of a P-GW when the UE performs the TAU procedure during the handover procedure. However, when the UE performs the TAU periodically, the information regarding the capability to support the relocation of the P-GW may not be delivered. The UE may always transmit the capability information when the TAU procedure is performed according to the handover. However, for optimization, by default, when the capability information is “not supported”, the capability information is not transmitted, and when the capability information is changed from “not supported” to “supported”, the capability information is transmitted. Upon receiving the TAU request message, an MME#2 coupled to the eNodeB#2 determines whether to relocate the P-GW for the UE on the basis of the capability to support the relocation of the P-GW, included in the TAU request message. When the UE continuously moves, the handover occurs several times, which may result in a change in an S-GW. In this case, data is delivered through many routers between the P-GW and the S-GW. Therefore, the disclosure of the present specification determines whether there is a need to relocate the P-GW in the following cases. Herein, the MME remembers the relocated P-GW. i. When both a transmitting side and a receiving side have capability to support the relocation of the P-GW, and ii. When the MME is changed by a handover, or iii. When a group ID of the MME is changed by the handover (e.g., DECOR), or iv. When the S-GW is changed by the handover, or v. When a local home network ID is changed by the handover (e.g., a change from a local P-GW#1 to a local P-GW#2), or vi. When a handover occurs from an eNodeB to a home eNodeB or from the home eNodeB to the eNodeB (i.e., a change from a P-GW to a local P-GW) The above conditions may be used independently one by one, or two or more conditions may be used in combination. As a result of selecting a P-GW appropriate for the UE by the MME, when the selected P-GW#2 is different from the previous P-GW#1, the MME delivers to the UE an indication indicating that there is a need to relocate the P-GW. Herein, the indication may be delivered by using a NAS notification message. Upon receiving the indication, the UE transmits a PDN connectivity request message to the MME in order to additionally create a PDN#2 having the same APN as that of the previously connected PDN#1. In this case, the UE sets a request type in the PDN connectivity request message to the relocation of the P-GW. When the request type in the PDN connectivity request message is set to the relocation of the P-GW, the MME may know that the NAS notification message has been successfully delivered. Meanwhile, after the PDN#2 is created, all IP flows in the PDN#1 shall be moved to the PDN#2. However, if there is a dedicated bearer in the PDN#1, the dedicated bearer is necessarily created also in the PDN#1. There are two methods for this. i. Initiation by the UE: The UE transmits a request bearer resource modification message to the MME. ii. Initiation by the MME: The MME transmits a bearer resource command to the P-GW. When the dedicated bearer is created in the new PDN#2 by using one of the above two methods, the UE performs an operation of moving traffic of the existing PDN#1 to the PDN#2 by using MPTCP/SIP signaling or the like. When all of the traffic is successfully moved to the PDN#2, no data is transmitted using the existing PDN#1. Then, there is a need to release the existing PDN#1. As such, there are two methods for releasing the existing PDN#1. i. Initiation by the UE: After the UE moves all IP flows, a PDN disconnection request message is transmitted to the MME. ii. Initiation by the MME: When the MME creates a new PDN#2 upon receiving a PDN connectivity request message including a request type which is set to the relocation of the P-GW, a timer is driven, and a delete session request message is transmitted to the S-GW when the timer expires. When the existing PDN#1 is released by using one of the above two methods, the relocation of the P-GW is complete. FIG. 11A and FIG. 11B are flowcharts illustrating a first method of FIG. 10 in detail. The flowcharts shown in FIG. 11A and FIG. 11B relate to an example in which a UE 100 relocates a P-GW by using MPTCP. When the UE 100 moves while using the PDN#1 through a P-GW#1 530a, a new PDN#2 is created through a P-GW#2 530b, and a P-GW relocation procedure is performed. Specifically, the followings are performed. First, the UE 100 cooperates with an MME#1 510a to establish the PDN#1 which passes through an eNodeB#1 200a and the P-GW#1 530a. In this case, an IP address of the UE 100 is 1.1.1.1. The UE 100 communicates with an AS by using the PDN#1. 1)-14) Thereafter, a handover procedure is performed when the UE 100 moves to coverage of an eNodeB#2 200b. During the handover procedure, the UE 100 transmits a TAU request message to perform a TAU procedure. In this case, the UE 100 allows the TAU request message to include P-GW relocation capability information. For example, when both the UE 100 and the AS support MPTCP, the UE 100 may set the P-GW relocation capability information to “supported”. 15)-16) After the handover is complete, when one or more of the above conditions are satisfied and thus the P-GW#2 530b is selected as a result of selecting a P-GW appropriate for the UE, a NAS notification message including an indication indicating that there is a need to relocate the P-GW is transmitted to the UE 100. 17)-22) Upon receiving the indication, the UE 100 creates a new PDN#2 with the same APN as the existing PDN#1. Accordingly, the IP address assigned to the UE 100 may be, for example, 1.2.2.2. 23)-27) In addition, a procedure for creating the same dedicated bearer as the dedicated bearer in the previous PDN#1 is performed. 29)-30) The UE 100 creates a sub-flow of the MPTCP and forwards a session to the new PDN#2. 31)-35) Thereafter, the UE 100 disconnects the PDN#1. As such, when the existing PDN#1 is disconnected, the relocation of the P-GW is complete. FIG. 12 is a schematic view showing a second method according to a first disclosure of the present specification. The second method relates to a situation where a UE performs a handover from an eNodeB to a home eNodeB. As such, when the handover to the home eNodeB is performed, in case of creating a new PDN which passes through a local P-GW, the local P-GW cannot support a dedicated bearer. Therefore, all IP flows using the existing PDN may not be able to be forwarded to the new PDN. To solve this problem, the second method suggests a method in which the local P-GW can create the dedicated bearer through signaling between the local P-GW and a PCRF. Herein, since there is no interface between the local P-GW and the PCRF, the second method allows the local P-GW to deliver signaling to the PCRF via the S-GW and the P-GW. For this, an additional S5 interface is allowed to be created between the S-GW and the P-GW in the process of creating the new PDN. FIG. 12 shows a process subsequent to a process in which a UE is handed over to a home eNodeB and creates a new PDN, i.e., a process of activating a dedicated bearer. The UE transmits a request bearer resource modification message to an MME. Alternatively, instead of the UE transmitting the message, the MME may transmit a bearer resource command message. The message transmitted by the UE is delivered to the local P-GW. The local P-GW performs an IP-CAN session modification procedure with respect to a PCRF to create a dedicated bearer. In this case, since there is no interface between the local P-GW and the PCRF, the local P-GW transmits to the S-GW a diameter message for modifying the IP connectivity access network (IP-CAN) session with respect to the PCRF by encapsulating it into a GTP-C message, and the S-GW delivers this to the P-GW via the additionally created S5 interface. The P-GW delivers to the PCRF the diameter message in the message received from the local P-GW. Upon receiving the diameter message from the PCRF, the P-GW delivers it to the local P-GW in the same manner. Then, the local P-GW allows to ensure QoS between the home eNodeB and the local P-GW through signaling with respect to the home eNodeB. The local P-GW transmits a create bearer request message to the S-GW. In this case, information indicating that the create bearer request message is transmitted by the local P-GW to the MME is allowed to be included, so that the S-GW does not allocate a resource for the dedicated bearer. The S-GW delivers the create bearer request message to the MME. Upon receiving the create bearer request message, the MME instructs the home eNodeB to allocate a required radio resource between the UE and the home eNodeB. 5)-6) The home eNodeB transmits an EPC dedicated bearer context activation request message to the UE according to an instruction from the MME, and receives an EPC dedicated bearer context activation accept message from the UE. 7) Then, the MME transmits a create bearer response message to the local P-GW via the S-GW to inform that radio resource allocation is successfully complete. If the dedicated bearer is successfully created, the local P-GW performs the IP-CAN with respect to the PCRF once again, and informs the PCRF that the dedicated bearer activation is complete. FIG. 13 is a schematic view showing a second method of FIG. 12 in a different manner. As shown in FIG. 13, general signaling transmitted by an MME#2 is delivered to a local P-GW via an S-GW#2. However, when the local P-GW transmits IP-CAN signaling to an S-GW for a dedicated bearer, the S-GW encapsulates the IP-CAN signaling into GTP and then relays it to the P-GW through the additional S5 interface of FIG. 12. Then, the P-GW delivers this to the PCRF. Subsequently, upon receiving a message through the PCRF, the P-GW encapsulates it into the GTP, and thereafter transmits it to the S-GW through the S5 interface. The S-GW transmits the message to the local P-GW. Accordingly, creation of the dedicated bearer is complete. Then, the local P-GW notifies the PCRF that the dedicated bearer is successfully complete through the S-GW and the P-GW. <Second Disclosure of the Present Specification> Meanwhile, it is expected to realize a data service with a minimum speed of 1 Gbps in a next generation mobile communication, so-called 5th generation mobile communication. Accordingly, an overload of a mobile communication core network is expected to be more increased. Therefore, in the so-called fifth generation mobile communication, it is urgently required to redesign the core network. FIG. 14 shows an expected structure of a core network of a next generation mobile communication according to a second disclosure of the present specification. As can be seen with reference to FIG. 14, a UE may be coupled to the core network via a next generation radio access network (RAN). The next generation core network may include a control plane (CP) function node and a user plane (UP) function node. The CP function node is a node which manages the UP function nodes and the RAN, and transmits/receives a control signal. The CP function node performs all or some parts of functions of an MME of a fourth generation mobile communication. The UP function node is a type of a gateway through which user data is transmitted/received. The function node performs all or some parts of functions of the S-GW and P-GW of the fourth generation mobile communication. An application function (AF) node is an application server located within a data network (DN). FIG. 15A to FIG. 15C show an expected handover of a UE in next generation mobile communication. As shown in FIG. 15A, the UE has a PDU session#1 directed to a data network (DN) via an UP function node#1 through a RAN. Thereafter, as shown in FIG. 15B, when the UE moves to another area, a handover is performed, thereby creating a PDU session#2 directed to the DN via the UP function node#1. As shown in FIG. 15C, when the handover is complete, only the PDU session#2 is left, and the PDU session#1 is released. As shown in FIG. 15A to FIG. 15C, when the handover is performed in the next generation mobile communication, the idea of the first disclosure of the present specification can be applied. This will be described with reference to FIG. 16. FIG. 16 is a schematic view showing an example of applying a method according to a first disclosure of the present application to next generation mobile communication according to a second disclosure. When applying the method according to the first disclosure of the present application, both an AF and a UE have to support upper layer service continuity. For example, when using protocols such as MPTCP, SIP, etc., both the UE and the AF can be used. In this case, the UE shall inform a CP function node that it has capability to support a relocation of the UP function node (or capability to support upper layer session/service continuity). Alternatively, the CP function node may identify capability of the UE and the AF when a PDU session is created or after the PDU session is created. If the CP function node identifies the capability to support the relocation of the UP function node of the UE and the AF after the PDU session is created, the UE may be informed of whether the relocation of the UP function node is supported for the created PDU session. According to the second disclosure of the present specification, the CP function node determines whether the relocation of the UP function node is necessary in the following cases. i. When both the UE and the AF have capability to support the relocation of the UP function node, and ii. When the CP function node is changed by a handover iii. When there is an UP function node closer to the UE after the handover iv. When load balancing is required between the UP function nodes v. When it is necessary to transmit data that can only be served through a specific UP function node (e.g., when it is necessary to be served through a local GW such as edge computing) Each of the above conditions may be used alone, or one or more conditions may be used in combination. As shown in FIG. 16, upon receiving an indication indicating that the relocation is necessary from the CP function node#2, the UE performs a process of newly creating a PDU session#2 with the same DN. Alternatively, when the UE determines that the reallocation of the UP function node is necessary, this may be informed to the CP function node. As such, when the PDU session#2 is newly created, two PDU sessions (i.e., PDU session#1 and PDU session#2) exist temporarily for the same DN between the UE and the DN. Then, the UE and the AF perform a process of transferring data transmitted through the existing PDU session#1 to the newly created PDU session#2. When this process ends, the UE directly releases the previously used PDU session#1. Alternatively, when the CP function node determines that the PDU session#1 is no longer used, the PDU session#1 may be released. The CP function node may determine this by using a method such as a method of using a timer value, a method of monitoring an event from the UP function node, and a method based on an indication received from the UE or the AR Although a situation where the CP function node#1 changes to the CP function node#2 due to the handover is shown in FIG. 16, the aforementioned description may also be applied to a situation where the CP function node does not change and only the UP function node changes (e.g., a situation where load balancing of the UP function node is changed from a central UP function node to the local UP function node). The content described up to now can be implemented in hardware. This will be described with reference to FIG. 17. FIG. 17 is a block diagram of a UE 100 and a network node according to an embodiment of the present invention. As shown in FIG. 17, the UE 100 includes a storing unit 101, a controller 102, and a transceiver 103. Further, the network node may be the MME 510. The network node includes a storing unit 511, a controller 512, and a transceiver 513. The storing units store the aforementioned method. The controllers control the storing units and the transceivers. More specifically, the controllers respectively execute the methods stored in the storing units. Further, the controllers transmit the aforementioned signals via the transceivers. Although exemplary embodiments of the present invention have been described above, the scope of the present invention is not limited to the specific embodiments and the present invention may be modified, changed, or improved in various ways within the scope of the present invention and the category of the claims. | <SOH> BACKGROUND OF THE INVENTION <EOH> | <SOH> SUMMARY OF THE INVENTION <EOH>Accordingly, one disclosure of this specification is to propose a scheme capable of solving the aforementioned problems. To achieve the above purpose, a disclosure of the present specification provides a method of changing a packet data network-gateway (P-GW) to offload traffic of a user equipment (UE) in a connected mode without a service disruption. Specifically, to achieve the above purpose, a disclosure of the present specification provides a method of relocating a gateway by a node, which is in charge of a control plane, for a user equipment (UE) in a mobile communication network. The method may include: determining to relocate a gateway appropriate for the UE in a case where the UE performs a handover and both the UE and the other party communicating with the UE have capability to support the relocation of the gateway; and delivering a relocation indication to the UE on the basis of the determination. The case where the UE performs the handover may include: a case where the node in charge of the control plane is changed by the handover; a case where a group ID of the node in charge of the control plane is changed by the handover; a case where a serving gateway (S-GW) is changed by the handover; a case where an ID of a local home network is changed by the handover; and a case where the handover is a handover between a home eNodeB and an eNodeB. The method may further include receiving a tracking area update (TAU) request message from the UE while the UE performs the handover. The TAU request message may include capability information indicating that both the UE and the other party communicating with the UE have the capability to support the relocation of the gateway. The relocation indication may be transmitted when a selected gateway is different from a previous gateway as a result of selecting the gateway appropriate for the UE. The method may further include, after transmitting the relocation indication, receiving a connection request message of a new packet data network (PDN) which uses the same APN as the existing PDN connection from the UE. The method may further include: after the new PDN connection is created, receiving a disconnection request message of the existing PDN from the UE; or transmitting a delete session request message to an S-GW. On the other hand, to achieve the above purpose, a disclosure of the present specification provides a method of creating a dedicated bearer. The method may be performed by a local gateway coupled to a home eNodeB. The method may include: establishing a second packet data network (PDN) connection for a user equipment (UE) handed over from an eNodeB to a home eNodeB. Herein, while the second PDN connection is established, an interface may be created between a serving-gateway (S-GW) and a packet data network-gateway (P-GW) to which a first PDN connection is established with the UE before the handover. The method may include: receiving a create request message of the dedicated bearer from a node in charge of a control plane in a mobile communication network through the S-GW, in order to allow a dedicated bearer, which is present in the first PDN connection before the handover, to be also created in the new second PDN connection; and transmitting a message for modifying an IP connectivity access network (IP-CAN) session to a policy and charging rule function (PCRF) through the S-GW and the P-GW, in order to create the dedicated bearer. The transmitting of the message for modifying the IP-CAN session by the local gateway may include: transmitting, by the local gateway, the message for modifying the IP-CAN session to the S-GW by encapsulating the message into a specific message; delivering the specific message by the S-GW to the P-GW; and extracting, by the P-GW, the message for modifying the IP-CAN session from the specific message, and delivering the message to the PCRF. On the other hand, to achieve the above purpose, a disclosure of the present specification provides a node which relocates a gateway for a UE in a mobile communication network and which is in charge of a control plane. The node may include: a transceiver; and a processor controlling the transceiver. The processor may perform operations of: determining to relocate a gateway appropriate for the UE in a case where the UE performs a handover and both the UE and the other party communicating with the UE have capability to support the relocation of the gateway; and delivering a relocation indication to the UE on the basis of the determination. On the other hand, to achieve the above purpose, a disclosure of the present specification provides a local gateway coupled to a home eNodeB. The local gateway may include: a transceiver; and a processor controlling the transceiver. The processor may establish a second packet data network (PDN) connection for a user equipment (UE) handed over from an eNodeB to a home eNodeB. Herein, while the second PDN connection may be established, an interface is created between a serving-gateway (S-GW) and a packet data network-gateway (P-GW) to which a first PDN connection is established with the UE before the handover. The processor may receive a create request message of the dedicated bearer from a node in charge of a control plane in a mobile communication network through the S-GW, in order to allow a dedicated bearer, which is present in the first PDN connection before the handover, to be also created in the new second PDN connection. Further, the processor may transmit a message for modifying an IP connectivity access network (IP-CAN) session to a policy and charging rule function (PCRF) through the S-GW and the P-GW, in order to create the dedicated bearer. According to a disclosure of the present specification, problems of the conventional technique can be solved. | H04W360011 | 20180131 | 20180809 | 62307.0 | H04W3600 | 0 | NGUYEN, BRIAN D | METHOD FOR REARRANGING GATEWAY AND METHOD FOR GENERATING DEDICATED BEARER | UNDISCOUNTED | 0 | ACCEPTED | H04W | 2,018 |
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15,749,700 | PENDING | POSITION ADJUSTING APPARATUS FOR STEERING WHEEL | In a steering wheel position adjusting device, an inner side surface of a support plate part (19a) includes a pair of protrusion parts (31a, 31b), which are positioned on both sides of the pressed-part back surfaces (24a) in a front-rear direction and interpose the pressed-part back surfaces (24a), the pressed-part back surface (24a) is positioned on a back side of a portion where the outer side surface of the support plate part (19) is pressed by a driven-side cam (35), and only tip end surfaces of the protrusion parts (31a, 31b) are changed from an unclamped state to a clamped state. In clamped state, the tip end surfaces of the protrusion parts (31a, 31b) and the pressed-part back surfaces (24a) are pressed against an outer side surface of a displacement bracket (16a). | 1. A steering wheel position adjusting device comprising: a steering column having a tubular shape and rotatably supporting a steering shaft, which supports and fixes a steering wheel at a rear end portion of the steering shaft, to an inner side of the steering column; a displacement bracket provided to the steering column; a support bracket having a pair of support plate parts which are supported to a vehicle body and interpose the displacement bracket therebetween from both sides in a width direction; a pair of pressing members arranged on both sides in the width direction of the two support plate parts, and capable of expanding and contracting an interval between the pressing members in the width direction; wherein the steering wheel position adjustment device interposes two outer side surfaces of the displacement bracket by inner side surfaces of the two support plate parts from both sides in the width direction in a clamped state where the interval between the pressing members is contracted, wherein an inner side surface of at least one support plate part of the two support plate parts includes a pressed-part back surface, which is positioned on a back side of a portion where the outer side surface of the support plate part is pressed by the pressing member, and wherein a portion, which is adjacent to the pressed-part back surface, of the inner side surface of the at least one support plate part is initially pressed against an outer side surface of the displacement bracket when changing to a clamped state from an unclamped state where the interval between the pressing members is expanded, and in this state, the pressed-part back surface is separated from the outer side surface of the displacement bracket. 2. The steering wheel position adjusting device according to claim 1, wherein the portion, which is adjacent to the pressed-part back surface, of the inner side surface of each of the two support plate parts is initially pressed against the outer side surface of the displacement bracket when changing from the unclamped state to the clamped state, and in this state, the pressed-part back surface is separated from the outer side surface of the displacement bracket. 3. The steering wheel position adjusting device according to claim 1, wherein the pressed-part back surface of the inner side surface of the support plate part is pressed against the outer side surface of the displacement bracket in the clamped state. 4. The steering wheel position adjusting device according to claim 1, wherein when changing from the unclamped state to the clamped state, portions, which are positioned on both sides of the pressed-part back surfaces and interpose the pressed-part back surfaces, of the inner side surfaces of the support plate parts is initially pressed against the outer side surfaces of the displacement bracket. 5. The steering wheel position adjusting device according to claim 1, wherein when changing from the unclamped state to the clamped state, portions of the inner side surfaces of the support plate parts on both sides in the front-rear direction of the pressed-part back surfaces are initially pressed against the outer side surfaces of the displacement bracket. 6. The steering wheel position adjusting device according to claim 5, wherein an adjustment rod is inserted, in the width direction, into a displacement-side through hole which is formed in the displacement bracket and is long hole in the front-rear direction, and into fixing-side through holes which are formed in the two support plate parts, wherein the two pressing members are provided on portions, which protrude from the outer side surfaces of the two support plate parts, of the adjustment rod, and wherein in an entire range in a case that the adjustment rod is displaced from a front end edge to a rear end edge inside the displacement-side through hole, when changing from the unclamped state to the clamped state, portions of the inner side surfaces of the support plate parts on both sides of the pressed-part back surfaces in the front-rear direction are initially pressed against the outer side surfaces of the displacement bracket. 7. The steering wheel position adjusting device according to claim 5, wherein an adjustment rod is inserted, in the width direction, into a displacement-side through hole which is formed in the displacement bracket, and into fixing-side through holes which are formed in the two support plate parts and are long holes in the upper-lower direction, wherein the two pressing members are provided on portions, which protrude from the outer side surfaces of the two support plate parts, of the adjustment rod, and wherein in an entire range in a case that the adjustment rod is displaced from an upper end edge to a lower end edge inside the fixing-side through holes, when changing from the unclamped state to the clamped state, portions of the inner side surfaces of the support plate parts on both sides of the pressed-part back surfaces in the front-rear direction are initially pressed against the outer side surfaces of the displacement bracket. 8. The steering wheel position adjusting device according to claim 7, wherein slits are formed to the support plate parts above portions, where the outer side surfaces of the support plate parts are pressed by the pressing members, of support plate parts, and wherein the silts are longer than the portions, where the outer side surfaces of the support plate parts are pressed by the pressing members, of support plate parts,. 9. The steering wheel position adjusting device according to claim 8, wherein broad parts, of which lower end edges are positioned below intermediate portions of the silts in the front-rear direction, are provided on end portions of the silts in the front-rear direction, and wherein when changing from the unclamped state to the clamped state, portions, which is closer to the fixing-side through holes than the broad parts in the front-rear direction, of the inner side surfaces of the support plate parts are initially pressed against the outer side surfaces of the displacement bracket. 10. The steering wheel position adjusting device according to claim 1, wherein a pair of protrusion parts, which protrude inward in the width direction from the pressed-part back surface in a free state, are provided on portions, which are adjacent to the pressed-part back surface, of the support plate parts. 11. The steering wheel position adjusting device according to claim 1, wherein the inner side surface of the support plate part and the outer side surface of the displacement are in contact with each other via a sandwiched member. | TECHNICAL FIELD The present invention relates to an improvement of a steering wheel position adjustment device for adjusting a position of the steering wheel according to a physique or a driving posture of a driver. BACKGROUND ART As an automobile steering device, for example, a structure as shown in FIG. 12 has been widely known. In this steering device, a steering shaft 3 is rotatably supported on an inner diameter side of a cylindrical steering column 2 which is supported on a vehicle body 1. A steering wheel 4 is fixed to a rear end portion of the steering shaft 3 protruding rearward from a rear end opening of the steering column 2. If the steering wheel 4 is rotated, the rotation thereof is transmitted to an input shaft 8 of a steering gear unit 7 through the steering shaft 3, a universal joint 5a, an intermediate shaft 6 and a universal joint 5b. If the input shaft 8 rotates, a pair of tie rods 9, 9 arranged on both sides of the steering gear unit 7 are pushed and pulled, whereby a steering angle according to an operation amount of the steering wheel 4 is provided to a pair of left and right steering wheels. Further, an example shown in drawings is an electric power steering device which uses an electric motor 10 as an auxiliary power source to reduce a force necessary for operating the steering wheel 4. In this specification and claims, a front-rear direction, a width direction (left-right direction), and an upper-lower direction refers to a front-rear direction, a width direction (left-right direction), and an upper-lower direction of a vehicle, unless particularly otherwise mentioned. In a case of a structure as shown in drawings, the steering device includes a tilt mechanism for adjusting an upper-lower position (tilt position) of the steering wheel 4 and a telescopic mechanism for adjusting a front-rear position (telescopic position) of the steering wheel 4 according to a physique and a driving posture of a driver. In order to configure the tilt mechanism, the steering column 2 is supported to the vehicle body 1 so as to be able to pivotably displaceable about a pivot shaft 11 mounted in the width direction. In order to configure the telescopic mechanism, the steering column 2 has a structure where an outer column 12 provided on a rear side and an inner column 13 provided on a front side are telescopically combined, and the steering shaft 3 has a structure where an outer shaft 14 in the rear side and an inner shaft 15 in a front side are combined to transmit torque and to be telescopic by a spline engagement and the like. A displacement bracket 16 fixedly provided on a rear end side portion of the outer column 12 is supported to a support bracket 17, which is supported to the vehicle body 1, so as to be displaceable in the upper-lower direction and the front-rear direction. The displacement bracket 16 is formed with displacement-side through holes 18, which are long in the front-rear direction (an axial direction of the outer column 12) which is a telescopic position adjustment direction. A support bracket 17 includes a pair of support plate parts 19 which interpose the displacement bracket 16 therebetween from both sides in the width direction. At portions of both support plate parts 19 which match with each other, fixing-side through holes 20 which are long in the upper-lower direction which is a tilt position adjustment direction are separately formed. Each fixing-side through hole 20 generally has a partial arc shape having the pivot shaft 11a as a center. An adjustment rod 21 is inserted into the fixing-side through holes 20 and the displacement-side through holes 18. The adjustment rod 21 is provided with a pair of pressing members in a state where the pressing members interpose the both support plate parts 19 therebetween from both sides in the width direction, and an interval between the both pressing members can be expanded and contracted by a cam device which operates based on an operation of an adjustment lever (for example, refer to FIG. 2 to be described later). When adjusting an upper-lower position or a front-rear position of the steering wheel 4, the adjustment lever is rotated in a predetermined direction, thereby expanding the interval between the pressing members so as to be an unclamped state. Accordingly, frictional force acting between inner side surfaces of the support plate parts 19 and outer side surfaces of displacement bracket 16 is reduced. At this state, within a range where the adjustment rod 21 can be displaced in the fixing-side through holes 20 and the displacement-side through holes 18, a position of the steering wheel 4 is adjusted. After the adjustment, the adjustment lever is rotated in a reverse direction of the predetermined direction, thereby contracting the interval between the pressing members so as to be a clamped state. Accordingly, the frictional force is increased to hold the steering wheel 4 at an adjusted position. In a steering device including a position adjusting device for a steering wheel, in order to enhance the support rigidity of the displacement bracket with respect to the support bracket, as disclosed in, for example, Patent Document 1, a structure has been considered which ensures that an inner side surface of support plate part having a flat surface shape is brought into contact with an outer side surface of a displacement bracket having a flat surface shape and an contact area of both side surfaces is large. However, when such a structure is adopted, as shown in FIG. 13, there is a possibility that the support plate parts 19 configuring the support bracket 17 are deformed based on pressing force of a driven-side cam 23 functioning as a pressing member when an axial dimension of the cam device 22 is expanded. Specifically, there is a possibility that portions of the support plate parts 19 except from the portions (peripheral portions) pressed by the driven-side cam 23 is warped and deformed (deformed so as to reduce force) in a direction away from the outer side surfaces of the displacement bracket 16 as indicated by an arrow in FIG. 13. Accordingly, only pressed-part back surfaces 24, which are positioned on back sides of portions where outer side surfaces are pressed by the driven-side cam 23, of inner side surfaces of the support plate parts 19 are strongly pressed against the outer side surfaces of the displacement bracket 16. Therefore, it is difficult to ensure a large contact area between the outer side surfaces of the displacement bracket 16 and the inner side surfaces of the support plate parts 19, and it is difficult to sufficiently enhance the support rigidity of the displacement bracket 16 with respect to the support bracket 17. BACKGROUND ART DOCUMENT Patent Document Patent Document 1: JP-A-2005-1546 SUMMARY OF THE INVENTION Problem to be Solved The present invention has been made in view of the above described circumstances, and an object is to realize a steering wheel position adjustment device which can enhance support rigidity of a displacement bracket with respect to a support bracket. Means for Solving the Problems A steering wheel position adjusting device of the present invention includes a steering column, a displacement bracket, a support bracket and a pair of pressing members. The steering column has a tubular (for example, cylindrical) shape and rotatably supports a steering shaft, which supports and fixes a steering wheel at a rear end portion of the steering shaft, to an inner side of the steering column. The displacement bracket is provided (for example, fixedly provided) to the steering column. The support bracket has a pair of support plate parts which are supported to a vehicle body and interpose the displacement bracket therebetween from both sides in a width direction. The two pressing members are arranged on both sides in the width direction of the two support plate parts, and capable of expanding and contracting an interval between the pressing members in the width direction. The steering wheel position adjustment device of the present invention interposes two outer side surfaces of the displacement bracket by inner side surfaces of the two support plate parts from both sides in the width direction in a clamped state where the interval between the pressing members is contracted, and position adjustment of the steering wheel is unable. Specifically in a case of the present invention, an inner side surface of at least one support plate part of the two support plate parts includes a pressed-part back surface, which is positioned on a back side of a portion where the outer side surface of the support plate part is pressed by the pressing member (the pressing member, which is arranged outside of the support plate part, of a pair of pressing members,). A portion (for example, portions on both sides in the front-rear direction when the fixing-side through hole is a long through hole in the upper-lower direction, a periphery when the fixing-side through hole is a simple round hole), which is adjacent to the pressed-part back surface of the inner side surface, of the at least one support plate part is initially pressed against (brought into pressure contact with) an outer side surface of the displacement bracket when changing (switching) to a clamped state from an unclamped state where the interval between the pressing members is expanded. Further, in this state (a state where adjacent portions are pressed), the pressed-part back surface is separated from the outer side surface of the displacement bracket. In other words, the presses-part back surface, which is positioned on the back side of a portion where the outer side surface of the support plate part is pressed by the pressing members, of the inner side surface of the at least one support plate part of the two support plate parts is separated from the outer side surface of the displacement bracket when changing to the clamped state from the unclamped state where the interval between the pressing members is expanded (at least early stage of a process of shifting from the unclamped state to the clamped state), and at least a portion adjacent to the pressed-part back surface is initially pressed against the outer side surface of the displacement bracket when changing from the unclamped state to the clamped state. In other words, with respect to the inner side surface of the at least one support plate part of the support plate parts, the pressed-part back surface is different from the portion initially pressed against the outer side surface of the displacement bracket when changing from the unclamped state to the clamped state. In a case where the present invention is implemented, for example, the portion, which is adjacent to the pressed-part back surface, of the inner side surface of each of the two support plate parts is initially pressed against the outer side surface of the displacement bracket when changing from the unclamped state to the clamped state. Further, in this state, the pressed-part back surface is separated from the outer side surface of the displacement bracket. In this case, preferably, the pressed-part back surface starts to be pressed against the outer side surface of the displacement bracket slightly before completely shifting to the clamped state, and in a stage when completely shifting to the clamped state, a contact pressure between the pressed-part back surface and the outer side surface of the displacement bracket and a contact pressure between the portion adjacent to the pressed-part back surface of the inner side surface of the support plate part and the outer side surface of the displacement bracket are almost the same. In a case where the present invention is implemented, for example, the pressed-part back surface of the inner side surface of the support plate part is pressed against the outer side surface of the displacement bracket in the clamped state. Alternatively, it is also possible that the pressed-part back surface of the inner side surface of the support plate part is not brought into contact with the outer side surface of the displacement bracket (a gap is still provided between the pressed-part back surface and the outer side surface of the displacement bracket). In a case where the present invention is implemented, for example, when changing from the unclamped state to the clamped state, portions, which are positioned on both sides the pressed-part back surfaces and interpose the pressed-part back surfaces, of the inner side surfaces of the support plate parts may be initially pressed against the outer side surfaces of the displacement bracket. In a case where the present invention is implemented, for example, when changing from the unclamped state to the clamped state, portions of the inner side surfaces of the support plate parts on both sides in the front-rear direction of the pressed-part back surfaces may be initially pressed against the outer side surfaces of the displacement bracket. In a case where the invention as described above is implemented, for example, an adjustment rod is inserted, in the width direction, into a displacement-side through hole which is formed in the displacement bracket and is long hole in the front-rear direction, and into fixing-side through holes which are formed in the two support plate parts. The two pressing members are provided on portions, which protrude from the outer side surfaces of the two support plate parts, of the adjustment rod. In an entire range in a case that the adjustment rod is displaced from a front end edge to a rear end edge inside the displacement-side through hole (regardless of the positions in the front-rear direction inside the displacement-side through hole of the adjustment rod), when changing from the unclamped state to the clamped state, portions of the inner side surfaces of the support plate parts on both sides of the pressed-part back surfaces in the front-rear direction are initially pressed against the outer side surfaces of the displacement bracket. Furthermore, when the invention as described above is implemented, for example, an adjustment rod is inserted, in the width direction, into a displacement-side through hole which is formed in the displacement bracket, and into fixing-side through holes which are formed in the two support plate parts and are long holes in the upper-lower direction. The two pressing members are provided on portions, which protrude from the outer side surfaces of the two support plate parts, of the adjustment rod. In an entire range in a case that the adjustment rod is displaced from an upper end edge to a lower end edge inside the fixing-side through holes (regardless of positions in the upper-lower direction inside the fixing-side through holes of the adjustment rod), when changing from the unclamped state to the clamped state, portions of the inner side surfaces of the support plate parts on both sides of the pressed-part back surfaces in the front-rear direction are initially pressed against the outer side surfaces of the displacement bracket. In a case where the invention as described above is implemented, for example, slits may be formed to the support plate parts above portions, where the outer side surfaces of the support plate parts are pressed by the pressing members, of support plate parts, and the silts may be longer than the portions, where the outer side surfaces of the support plate parts are pressed by the pressing members, of the support plate parts. Since such silts are formed, the two support plate parts can be easily deformed even when the adjustment rod is displaced to an upper end portion of the fixing-side through holes and clamped. Accordingly, regardless of the upper-lower position (tilt position) of the adjustment rod, during clamping, the pressed-part back surface can be securely brought into contact with the outer side surface of the displacement bracket, and the operation force of the adjustment lever can be constant. When such an invention is implemented, for example, broad parts, of which lower end edges are positioned below intermediate portions of the silts in the front-rear direction, are provided on end portions of the silts in the front-rear direction. When changing from the unclamped state to the clamped state, portions, which is closer to the fixing-side through holes than the broad parts in the front-rear direction, of the inner side surfaces of the support plate parts may be initially pressed against the outer side surfaces of the displacement bracket. In a case where the present invention is implemented, for example, a pair of protrusion parts which protrude inward in the width direction from the pressed-part back surface in a free state may be provided on portions, which interpose the pressed-part back surface and are positioned on both sides (for example, both sides in front-rear direction), of inner side surfaces of the support plate parts. Alternatively, in a case where the displacement-side through holes formed in the displacement bracket are simple circular holes, a pair of protrusion parts which protrude outward in the width direction may be provided on portions, which are on both sides in the front-rear direction and interpose the displacement-side through hole, of the outer side surfaces of the displacement bracket. In any case, a shape of the tip end surface (an inner end surface in the width direction) of each protrusion part may have a flat surface (including an oblique surface) shape, and may have a convex arc shaped cross section. Furthermore, in a case where the present invention is implemented, for example, the inner side surface of the support plate part and the outer side surface of the displacement may be brought into contact with each other via a sandwiched member made of an elastic material, such as a rubber plate or a synthetic resin plate. Effect of the Invention According to a steering wheel position adjustment device of the present invention configured as described above, it is possible to ensure a large contact area between the inner side surfaces of the support plate parts configuring the support bracket and the outer side surfaces of the displacement bracket, and enhance the support rigidity of the displacement bracket with respect to the support bracket. That is, in a case of the present invention, a portion adjacent to the pressed-part back surface, which is positioned on the back side of a portion where the outer side surface of the support plate part is pressed by the pressing member, of the inner side surface of the support plate part is initially pressed against the outer side surface of the displacement bracket when changing from the unclamped state to the clamped state. In this state, the pressed-part back surface is separated from the outer side surface of the displacement bracket. Therefore, in a case of the present invention, in the clamped state, at least a portion of the inner side surface of the support plate part adjacent to the pressed-part back surface can be pressed against the outer side surface of the displacement bracket. Therefore, as compared with a case where only the pressed-part back surface on the inner side surface of the support plate part is pressed against the outer side surface of the displacement bracket and the other part is warped and deformed as in a case of a conventional structure described above, it is possible to ensure a large contact area between the inner side surface of the plate part and the outer side surface of the displacement bracket and enhance the support rigidity of the displacement bracket with respect to the support bracket. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a partial side view of a steering device illustrating a state in which a steering wheel is positioned at an intermediate portion in a front-rear direction and an upper-lower direction according to a first embodiment of the present invention. FIG. 2 is a cross-sectional view along a line A-A of FIG. 1. FIGS. 3A and 3B is a cross-sectional view along a line B-B of FIG. 2, FIG. 3A illustrates an unclamped state, and FIG. 3B illustrates a clamped state. FIGS. 4A and 4B is a cross-sectional view along a line C-C of FIG. 2, FIG. 4A illustrates an unclamped state, and FIG. 4B illustrates a clamped state. FIGS. 5A to 5C are views corresponding to FIG. 1 and illustrate three examples in which a steering wheel is respectively displaced from a front-rear intermediate portion to an upper end edge, an upper-lower intermediate portion, and a lower end edge. FIGS. 6A to 6C are views corresponding to FIG. 1 and illustrate three examples in which a steering wheel is respectively displaced from an upper-lower intermediate portion to a rear end edge, a front-rear intermediate portion, and a front end edge. FIGS. 7A-a to 7C-c are views corresponding to D portion of FIG. 1 and illustrate nine examples in which a steering wheel is respectively displaced in a front-rear direction and an upper-lower direction. FIGS. 8A and 8B are views corresponding to FIG. 3A and FIG. 3B and illustrate a second embodiment of the resent invention. FIGS. 9A and 9B are views similar to FIG. 3A and FIG. 3B and illustrate a third embodiment of the resent invention. FIG. 10 is a view corresponding to FIG. 9B and illustrates a fourth embodiment of the resent invention. FIGS. 11A and 11B are views corresponding to FIG. 3A and FIG. 3B and illustrate a fifth embodiment of the resent invention. FIG. 12 is a view illustrating an example of a steering device for automobiles including a position adjusting device of a steering wheel as an object of the present invention. FIG. 13 is a view corresponding to FIG. 3B and illustrating problems of a conventional structure. DESCRIPTION OF EMBODIMENTS First Embodiment A first embodiment of the present invention will be described with reference to FIGS. 1 to 7. In a steering device of the embodiment, a steering shaft 3a in which a steering wheel 4 (refer to FIG. 12) is fixed on a rear end portion the steering shaft 3a is rotatably supported to an inner side of a tubular steering column 2a. An intermediate portion of the steering column 2a is supported to a support bracket 17a. The support bracket 17a is supported to a vehicle body 1 (refer to FIG. 12) so as to be able to be detached forward by a secondary collision due to a collision accident. A gear housing 25 (refer to FIG. 12) for electric power steering device is connected and fixed to a front end portion of the steering column 2a. The gear housing 25 is supported to the vehicle body 1 so as to be pivotably displaceable about a pivot shaft 11 (refer to FIG. 12) into which the gear housing 25 is inserted, and configures a tilt mechanism capable of adjusting an upper-lower position of the steering wheel 4. Furthermore, in a case of the embodiment, in addition to the tilt mechanism, a telescopic mechanism for adjusting a front-rear position of the steering wheel 4 is also incorporated. In order to configure the telescopic mechanism, the steering column 2a is configured such that a front portion of an outer column 12a is externally fitted to a rear portion of an inner column 13a so as to be relatively displaceable in an axial direction. A displacement bracket 16a having a substantially U-shaped cross section which is formed by bending a metal plate having sufficient rigidity, such as a steel plate, is fixed to an upper portion of a front end side portion of the outer column 12a by welding and the like. In a pair of flat plate shaped side plate parts 26, 26 which are parallel to each other and configure both end portions in a width direction of the displacement bracket 16a, displacement-side through holes 18a, 18a which are respectively long in a front-rear direction (an axial direction of the outer column 12a) are formed on portions which overlap with each other in the width direction. Furthermore, the steering shaft 3a is configured such that a front portion of an outer shaft 14a is externally fitted to a rear portion of an inner shaft 15 (refer to FIG. 12) by a spline engagement and the like so as to capable of transmitting torque and to relatively displaceable. A support bracket 17a is formed by connecting a plurality of parts, each of which is made of a metal plate having sufficient rigidity, such as a steel plate, by welding and the like. The support bracket 17a includes a mounting plate part 27 for supporting on the vehicle body 1, and a pair of support plate parts 19a, 19a fixed to a lower surface of the mounting plate part 27 by welding and separated in parallel to each other in the width direction. Outer side surfaces of two side plate parts 26, 26 configuring the displacement bracket 16a are interposed therebetween from both sides in the width direction by the two support plate parts 19a, 19a. On the two support plate parts 19a, 19a, fixing-side through holes 20a, 20a having partial arc shape having the pivot shaft 11 as a center are formed in portions which overlap with each other in the width direction. Specifically, in a case of the embodiment, substantially U-shaped slits 28, 28 which are long in the front-rear direction are formed on upper end edge portions of the support plate parts 19a, 19a which are positioned above the fixing-side through holes 20a, 20a. The silts 28, 28 are configured by a width-narrowed part 29 having a linear shape provided on an intermediate portion in the front-rear direction and a pair of broad parts 30, 30 each having substantially semicircular shape provided on both end portions in the front-rear direction. Lower end edges of the broad parts 30, 30 are positioned lower than a lower end edge of the width-narrowed part 29. In a case of the embodiment, portions, which are distant in the front-rear direction from portions where the slits 28, 28 are formed, of upper end edges of the support plate parts 19a, 19a are welded and fixed to a lower surface of the mounting plate part 27. Protrusion parts 31a, 31b, each having a strip shape which protrude (offset) inward in the width direction from portions where the fixing-side through holes 20a, 20a are formed, are provided on portions on both sides in the front-rear direction which interpose the fixing-side through holes 20a, 20a on the support plate parts 19a, 19a in a free state. Each of the protrusion parts 31a, 31b is formed in a partial arc shape having the pivot shaft 11 as a center similar to the fixing-side through holes 20a, 20a, and formed by pressing in an entire range from the upper end edge to the lower end edge of the support plate part 19a, 19a. Accordingly, upper end portions of the protrusion parts 31a, 31b are provided in a state of surrounding the broad parts 30, 30 respectively. Tip end surfaces (inner side surfaces) of the protrusion parts 31a, 31b are formed in a flat surface shape respectively and positioned in a same plane with each other. As shown in FIGS. 3 and 4, on the support plate parts 19a, 19a, a pair of bending part parts 32a, 32b having substantially V-shaped cross sections which protrudes outward in the width direction are provided between portions where the fixing-side through holes 20a, 20a are formed and the protrusion parts 31a, 31b. On the support plate parts 19a, 19a, a portion between the bending parts 32a, 32b where the fixing-side through holes 20a, 20a are formed is configured to a flat surface shape, width dimension thereof in the front-rear direction is set to be slightly larger than width dimensions in the front-rear direction of a driven-side cam 35 and a flange part 36 described later. In a state where a portion of the fixing-side through hole 20a, 20a and a portion of the displacement-side through hole 18a, 18a are superimposed in the width direction, an adjustment rod 21a is inserted into these through holes 18a, 20a. An interval between the support plate parts 19a, 19a can be expanded and contracted by an expansion/contraction mechanism including the adjustment rod 21a. In order to configure such an expansion/contraction mechanism, a base end portion of an adjustment lever 33 is connected and fixed to a portion protruding from an outer side surface of one support plate part 19a (the left one of FIG. 2) of the support plate parts 19a, 19a on a tip end portion of the adjustment rod 21a (the left end portion of FIG. 2, the lower end portion of FIG. 3), and a cam device 22a is provided between the outer side surface of the one support plate part 19a and the adjustment lever 33. Dimension in axial direction of the cam device 22a is expanded/contracted in the axial direction based on relative displacement between a drive-side cam 34 and a driven-side cam 35, and the driven-side cam 35 is engaged with the fixing-side through hole 20a formed in the one support plate part 19a so that the driven-side cam 35 is only displaceable along the fixing-side through hole 20a (with rotation thereof being restricted). The drive-side cam 34 is rotatable around the adjustment rod 21a by the adjustment lever 33. A nut 39 is screwed to the tip end portion of the adjustment rod 21a to prevent the cam device 22a and the like from slipping off. In contrast, a flange part 36 having an outward flange shape is fixedly provided on a base end portion (the right end portion of FIG. 2, the upper end portion of FIG. 4) of the adjustment rod 21a, and on a portion protruding from an outer side surface of the other support plate part (the right one of FIG. 2) of the two support plate parts 19a, 19a. The flange part 36 is engaged with the fixing-side through hole 20a formed in the other support plate part 19a to be only displaceable along the fixing-side through hole 20a. In a case of the embodiment having such a configuration, the driven-side cam 35 and the flange part 36 correspond to a pair of pressing members of the present invention. In a structure of the embodiment including such a tilt mechanism and a telescopic mechanism, as shown in FIGS. 5A to 5C, the adjustment rod 21a can adjust an upper-lower position of the steering wheel 4 within a range displaceable in the fixing-side through holes 20a, 20a. As shown in FIGS. 6A to 6C, the adjustment rod 21a can adjust a front-rear position of the steering wheel 4 within a range displaceable in the displacement-side through holes 18a, 18a. During the adjustment operation, the adjustment lever 33 is pivotably displaced downward (or upward), and axial dimension of the cam device 22a is contracted. Accordingly, the interval between the driven-side cam 35 and the flange part 36 which are a pair of pressing members is expanded so as to be an unclamped state. In this state, the contact pressure of contact portion between the inner side surfaces of the both support plate portions 19a, 19a and the outer side surfaces of the both side plate parts 26, 26 is reduced or lost so that the adjustment operation can be performed with a light force. On the other hand, in order to hold the steering wheel 4 at the adjusted position, after the steering wheel 4 is moved to a desired position, the adjustment lever 33 is pivotably displaced upward (or downward) to expand the axial dimension of the cam device 22a. As a result, the interval between the driven side cam 35 and the flange part 36 is contracted so as to be a clamped state. In this state, a surface pressure between contact portions is increased, and the steering wheel 4 can be held on an adjusted position. Specifically, in a case of the embodiment, when changing (switching) from an unclamped state to a clamped state, as shown in FIG. 3A, on the inner side surface of the one support plate part 19a, the tip end surfaces of the two protrusion parts 31a, 31b, which are positioned on both sides in the front-rear direction and interpose a pressed-part back surfaces 24a therebetween which is positioned on a back side of a portion where the outer side surface of the support plate part 19a is pressed by the driven-side cam 35, are initially pressed against the outer side surfaces of the side plate parts 26 of the displacement bracket 16a. In this state (a state where the tip end surfaces of the protrusion parts 31a, 31b are pressed against the outer side surfaces of the side plate parts 26), the pressed-part back surfaces 24a are separated from the outer side surfaces of the side plate parts 26. That is, until a halfway stage of the process of shifting from the unclamped state to the clamped state, the pressed-part back surface 24a is not pressed against the outer side surface of the side plate part 26. In FIGS. 5A to 7C-c, on the inner side surface of the one support plate part 19a and the outer side surface of the side plate part 26 facing each other when changing from the unclamped state to the clamped state, contact portions between the tip end surfaces of the protrusion parts 31a, 31a and the outer side surfaces of the side plate parts 26 which are the initially contacted portions are represented by inclined line lattice patterns. In a clamped state where an axial dimension of the cam device 22a is expanded and the interval between the driven-side cam 35 and the flange part 36 is contracted, as shown in FIG. 3B, the tip end surfaces of the protrusion parts 31a, 31b remain being brought into contact with the outer side surfaces of the side plate parts 26, and the two bent parts 32a, 32b are elastically deformed by pressure force through the driven-side cam 35, so that the pressed-part back surfaces 24a are pressed against the outer side surfaces of the side plate parts 26. In a case of the embodiment, the pressed-part back surfaces 24a are pressed against the outer side surfaces of the side plate parts 26 slightly before completely shifting to the clamped state. At the stage of completely shifting to the clamped state, it is ensured that the contact pressure between the pressed-part back surfaces 24a and the outer side surfaces of the displacement bracket 16a and the contact pressure between the tip end surfaces of the protrusion parts 31a, 31a and the outer side surfaces of the displacement bracket 16 are almost the same. With respect to the other support plate part 19a, similar to the one support plate part 19a, a contact state between the inner side surface of the other support plate part 19a and the outer side surface of the side plate part 26 is regulated. Specifically, as shown in FIG. 4A, when changing from the unclamped state to the clamped state, the tip end surfaces of the protrusion parts 31a, 31b, which interpose the pressed-part back surface 24 positioned on the back side of the portion where the outer side surface of the support plate part 19a is pressed by the flange part 36 and are positioned on both sides in the front-rear direction, of the inner side surface of the other support plate part 19a are initially pressed against the outer side surfaces of the side plate parts 26. In this state (a state where the tip end surfaces of the protrusion parts 31a, 31b are pressed against the outer side surfaces of the side plate parts 26), the pressed-part back surface 24a is separated from the outer side surface of the side plate part 26. That is, until the halfway stage of the process of shifting from the unclamped state to the clamped state, the pressed-part back surface 24a is not pressed against the outer side surface of the side plate part 26. With respect to the other support plate part 19a, the pressed-part back surface 24a is pressed against the outer side surface of the side plate part 26 slightly before completely shifted to the clamped state. At the stage of completely shifting to the clamped state, the contact pressure between the pressed-part back surface 24a and the outer side surface of the displacement bracket 16a and the contact pressure between the tip end surfaces of the protrusion parts 31a, 31a and the outer side surface of the displaced bracket 16a are almost the same. Furthermore, in a case of the embodiment, when changing from the unclamped state to the clamped state, in an entire range when the adjustment rod 21a is displaced from the upper end edge to the lower end edge inside two fixing-side through holes 20a, 20a, the tip end surfaces of the protrusion parts 31a, 31b of the inner side surfaces of the support plate parts 19a, 19a are initially pressed against the outer side surface of the side plate part 26. In a case of the embodiment, since both silts 28, 28 are formed on the upper end edges of the support plate parts 19a, 19a such that no welding is applied to these portions, even in a state where the adjustment rod 21a is positioned on upper end edges of both fixing-side through holes 20a, 20a (a state where the steering wheel 4 is displaced upward), the tip end surfaces of the protrusion parts 31a, 31a are reliably brought into contact with the outer side surfaces of the side plate parts 26, 26. Since a forming position and a width dimension in the front-rear direction of each of the protrusion parts 31a, 31b are appropriately regulated, within an entire range where the adjustment rod 21a is displaced from the front end edge to the rear end edge inside the displacement-side through holes 18a, 18a, when changing from the unclamped state to the clamped state, the tip end surfaces of the protrusion parts 31a, 31b of the inner side surfaces of the support plate parts 19a, 19a are initially pressed against the outer side surfaces of the side plate parts 26, 26. Specifically, in a case of the embodiment, upper end portions of the protrusion parts 31a, 31b are provided in a state of surrounding the broad parts 30, 30. Therefore, when changing from the unclamped state to the clamped state, as two support plate parts 19a, 19a are elastically deformed, portions (rear end side portion of protrusion part 31a provided on a front side and front end side portion of the protrusion part 31b provided on a rear side), which is closer to the fixing-side through holes 20a, 20a than the broad parts 30, 30 in the front-rear direction, of the tip end surfaces of the protrusion parts 31a, 31b are initially and reliably pressed against the outer side surfaces of the side plate parts 26, 26. Therefore, in the embodiment, as shown in FIG. 3A, the inner side surfaces of the support plate parts 19a, 19a are provided with the pressed-part back surfaces 24a, 24a and the tip end surfaces of the two protrusion parts 31a, 31b. The pressed-part back surfaces 24a, 24a are positioned on the back sides of portions where the outer side surfaces of the support plate parts 19a, 19a are pressed by the driven-side cam 35 and the flange part 36 in a state of surrounding the fixing-side through holes 20a, 20a. The tip end surfaces of the two protrusion parts 31a, 31b interposes the pressed-part back surfaces 24a, 24a and are positioned on both sides in the front-rear direction. In a free state, that is, an unclamped state where the interval between the driven-side cam 35 and the flange part 36 is expanded, the tip end surfaces of the two protrusion parts 31a, 31b are positioned inward in the width direction from the pressed-part back surfaces 24a, 24a, that is, closer to the outer side surfaces of the displacement brackets 16a, 16a. In a case of a steering device of the embodiment having the above structure, in the clamped state, it is possible to ensure the large contact area of the inner side surfaces of the two support plate parts 19a, 19a configuring the support bracket 17a and the outer side surfaces of the two side plate parts 26, 26 configuring the displacement bracket 16a, and enhance the support rigidity of the displacement bracket 16a with respect to the support bracket 17a. Regardless of an adjustment position of the steering wheel 4 by the tilt mechanism and the telescopic mechanism, the contact area is substantially constant, and stable holding force can be obtained. In a case of the embodiment, the tip end surfaces of the protrusion parts 31a, 31b, which interpose the pressed-part back surfaces 24a, 24a positioned on the back sides of portions where the outer side surfaces of the support plate parts 19a, 19a are pressed by the driven-side cam 35 and the flange part 36 which are pressing members and which are positioned on both sides in the front-rear direction, of the inner side surfaces of the two support plate parts 19a, 19a are initially pressed on the outer side surfaces of the two side plate parts 26, 26 when changing from the unclamped state to the clamped state. In this state, the pressed-part back surfaces 24a, 24a are separated from the outer side surfaces of the side plate parts 26, 26. In other words, when changing from the unclamped state to the clamped state (until the halfway stage of the process of shifting from the unclamped state to the clamped state), the pressed-part back surfaces 24a, 24a are separated from the outer side surfaces of the two side plate parts 26, 26. When changing from the unclamped state to the clamped state, the tip end surfaces of the protrusion parts 31a, 31b are initially pressed against the outer side surfaces of the two side plate parts 26, 26 Specifically, the bending parts 32a, 32b are elastically deformed in accordance with a transition from a state where the outer side surfaces of the two side plate parts 26, 26 contact with only the tip end surfaces of the protrusion parts 31a, 31b to a clamped state where the adjustment lever 33 is operated (the dimension of the cam device in the axial direction is expanded), so that the pressed-part back surfaces 24a, 24a are pressed against the outer side surfaces of the side plate parts 26, 26. In a case of the embodiment, in the clamped state, the tip end surfaces of the protrusion parts 31a, 31b and the pressed-part back surfaces 24a, 24a of the inner side surfaces of the support plate parts 19a, 19a can be pressed against the outer side surfaces of the side plate parts 26, 26. Therefore, compared with the above-described conventional structure where only the pressed-part back surfaces are pressed against the outer side surfaces of the displacement brackets and the other portions are warped and deformed, it is possible to ensure large contact area of the inner side surfaces of the support plate parts 19a, 19a and the outer side surfaces of the side plate parts 26, 26, and enhance the support rigidity of the displacement bracket 16a with respect to the displacement bracket 17a. In a case of the embodiment, two slits 28, 28 which are longer than the pressed portion in the front-rear direction are formed on upper end edges of portions, where the outer side surfaces are pressed by the driven-side cam 35 and the flange part 36, of the two support plate parts 19a, 19a. Accordingly, even in a case where the adjustment rod 21a is displaced to the upper section in the fixing-side through holes 20a, 20a, the support plate parts 19a, 19a can be easily elastically deformed during clamping, and the pressed-part back surfaces 24a, 24a can be reliably brought into contact with the outer side surfaces of the side plate parts 26, 26. Therefore, in a case of the embodiment, regardless of the upper-lower position (tilt position) of the adjustment rod 21a, during clamping, the pressed-part back surfaces 24a, 24a can be reliably brought into contact with the outer side surfaces of the side plate parts 26, 26 and the operation force of the adjustment lever 33 can be constant. Second Embodiment A second embodiment of the present invention will be described with reference to FIGS. 8A and 8B. In a case of the embodiment, protrusion parts 31c, 31d each having a strip shape are formed on portions of the support plate parts 19b on both sides in a front-rear direction and interposing the fixing-side through holes 20a. In a free state, protrusion parts 31c, 31d protrude (offset) inward in a width direction from portions where fixing-side through holes 20a are formed. Specifically, in a case of the embodiment, tip end surfaces of the two protrusion parts 31c, 31d have convex shaped cross sections and protrude inward in the width direction. In a case of the embodiment having such a configuration, as shown in FIG. 8A, when changing from an unclamped state to a clamped state, tip end surfaces of the protrusion parts 31c, 31d, which interpose pressed-part back surfaces 24a positioned on back sides of portions where outer side surfaces of the support plate parts 19b are pressed by a driven-side cam 35 and are positioned on both sides in the front-rear direction, of inner side surfaces of the support plate parts 19b are initially pressed against outer side surfaces of the side plate parts 26 of the displacement bracket 16a. In this state, the pressed-part back surfaces 24a are separated from the outer side surfaces of the side plate parts 26. In a clamped state where an axial dimension of a cam device 22a is expanded and an interval between the driven-side cam 35 and a flange part 36 (refer to FIG. 2) is contracted, as shown in FIG. 8B, since tip end surfaces of the protrusion parts 31c, 31d remain being brought into contact with the outer side surfaces of the side plate parts 26 and portions between the protrusion parts 31c, 31c are elastically deformed, the pressed-part back surfaces 24a are pressed against the outer side surfaces of the side plate parts 26. In a case of the embodiment having such a configuration, compared with the case of the first embodiment described above, it is possible to reduce bending process applied to the support plate parts 19b. Therefore, it is advantageous of reducing the manufacturing cost of the steering device. Other configuration and operational effects are similar to those of the first embodiment. Third Embodiment A third embodiment of the present invention will be described with reference to FIGS. 9A and 9B. In a case of the embodiment, a pair of protrusion parts is not formed on support plate parts 19c like the first and second embodiments described above. The support plate parts 19c are curved in a free state such that intermediate portions (portions where fixing-side through holes 20a are formed) in a front-rear direction protrude outward in the width direction from portions at both sides in the front-rear direction. The support plate parts 19c are provided with folding parts 37, 37 bent outward in a width direction on both end portions in the front-rear direction. In a case of the embodiment having such a configuration, as shown in FIG. 9A, when changing from an unclamped state to a clamped state, inner side surfaces of base end portions of the folding parts 37, 37, which interpose the pressed-part back surfaces 24a positioned on back sides of portions where the outer side surfaces of the support plate parts 19c are pressed by a driven-side cam 35 and are positioned at both sides in the front-rear direction, of inner side surfaces of the support plate parts 19c are initially pressed against outer side surfaces of side plate parts 26 of a displacement bracket 16a. In this state, the pressed-part back surfaces 24a are separated from the outer side surfaces of the side plate parts 26. In a clamped state where an axial dimension of a cam device 22a is expanded and an interval between the driven-side cam 35 and a flange part 36 (refer to FIG. 2) is contracted, as shown in FIG. 9B, since the inner side surfaces on base end portions of the folding parts 37, 37 remain being brought into contact with the outer side surfaces of the side plate parts 26 and portions between the folding parts in the front-rear direction on the support plate parts 19c are elastically deformed into flat surface shapes, all portions including the pressed-part back surfaces 24a are pressed against the outer side surfaces of the side plate parts 26. In a case of the embodiment having such a configuration, compared with the case of the first embodiment described above, it is possible to reduce bending process to be applied to the support plate parts 19c. To this end, it is advantageous in terms of reducing the manufacturing cost. Other configuration and operational effects are the same as those in the first embodiment. Fourth Embodiment A fourth embodiment of the present invention will be described with reference to FIG. 10. In a case of the embodiment, shapes of support plate parts 19d have same shapes as those of the support plate parts 19c of the third embodiment described above. However, in a case of the embodiment, even in a clamped state where an axial dimension of a cam device 22a is expanded and an interval between a driven-side cam 35 and a flange part 36 (refer to FIG. 2) is contracted, only inner side surfaces on base end portions of folding parts 37, 37 are pressed against outer side surfaces of side plate parts 26. In contrast, the pressed-part back surfaces 24a, which are positioned on back sides of portions where outer side surfaces of support plate parts 19d are pressed by the driven-side cam 35, of inner side surfaces of the support plate parts 19d, are not pressed against the outer side surfaces of the side plate parts 26. That is, even in a clamped state, gaps between the pressed-part back surfaces 24a and the outer side surfaces of the side plate parts 26 are provided. In a case of the embodiment having such a configuration, although it is disadvantageous from the viewpoint of increasing the contact area between the inner side surface of the support plate part 19d and the outer side surface of the side plate part 26, it is possible to select a metal plate having high rigidity as a metal plate configuring the support plate part 19d, so that it is possible to increase the support rigidity of the displacement bracket 16a with respect to the support bracket 17a. Other configuration and operational effects are the same as those in the first and third embodiments. Fifth Embodiment A fifth embodiment of the present invention will be described with reference to FIGS. 11A and 11B. In a case of the embodiment, both of inner side surfaces of support plate parts 19e and outer side surfaces of side plate parts 26 configuring a displacement bracket 16a are formed in a flat surface shape. In a case of the embodiment, a pair of resin plates 38a, 38b each of which has a partial arc shape having a pivot shaft 11 as a center (refer to FIG. 12) is sandwiched between the inner side surfaces of the support plate parts 19e and the outer side surfaces of the side plate parts 26. More specifically, the resin plates 38a, 38a are sandwiched between portions of the inner side surfaces of the support plate parts 19e on both sides in the front-rear direction which interpose the pressed-part back surfaces 24a and outer side surfaces of the side plate parts 26. In a case of the embodiment, synthetic resin plates can be used as these resin plates 38a, 38b and these resin plates 38a, 38b are fixed (for example, attached) to the inner side surfaces of the support plate parts 19e. In a case of the embodiment having such a configuration, as shown in FIG. 11A, when changing from an unclamped state to a clamped state, pressed-part back surfaces 24a, which are positioned on back sides of portions where outer side surfaces of support plate parts 19e are pressed by a driven-side cam 35, of inner side surfaces of the support plate parts 19e remain being separated from outer side surfaces of side plate parts 26, and inner side surfaces of the resin plates 38a, 38b, which interpose the pressed-part back surfaces 24a and are positioned on both sides in the front-rear direction, are initially pressed against the outer side surfaces of the side plate parts 26. In a clamped state where an axial dimension of a cam device 22 is expanded and an interval between the driven-side cam 35 and a flange part 36 (refer to FIG. 2) is contracted, as shown in FIG. 11B, since the inner side surfaces of the two resin plates 38a, 38b remain being brought into contact with the outer side surfaces of the side plate parts 26, and portions of the support plate parts 19e between a portion where the resin plates 38a, 38b are fixed in the front-rear direction are elastically deformed inward in the width direction, the pressed-part back surfaces 24a are pressed against the outer side surfaces of the side plate parts 26. In a case of the embodiment having such a configuration, the resin plates 38a and 38b are separately required, but it is not necessary to perform the bending process to be applied to the support plate portion 19e, which is advantageous reducing the manufacturing cost. Other configuration and operational effects are the same as those in the first embodiment. The present invention is not limited to the embodiments described above, and modifications and improvements can be made as appropriate. In a case where the present invention is implemented, when changing from the unclamped state to the clamped state, portions where the outer side surfaces of the displacement bracket 16a are pressed are not limited to portions which interpose the pressed-part back surfaces 24a and are positioned on both sides, and may be portions adjacent to the pressed-part back surfaces 24a. For example, protrusion parts of the above embodiments may be arranged only on one side on portions which interpose the pressed-part back surfaces 24a and are positioned on both sides. In a case where the present invention is implemented, with respect to the one support plate part of the pair of the support plate parts configuring the displacement bracket, when changing from the unclamped state to the clamped state, a configuration can be adopted in which portions adjacent to the pressed-part back surfaces press the outer side surfaces of the displacement bracket. In the above embodiment, the fixing-side through holes 20a, 20a each has a partial arc shape having the pivot shaft 11 as a center, but, for example, the fixing-side through holes 20a, 20a may each have a rectangular shape extending linearly in the upper-lower direction as long as the fixing-side through holes 20a, 20a configure a tilt mechanism. In this case, the protrusion parts 31a, 31b each having a strip shape are also formed linearly in the front-rear direction. In a case where the present invention is implemented, it is not necessary to include both the tilt mechanism and the telescopic mechanism as in the cases described in the above embodiments, and any at least one mechanism may be included. In a case where the present invention is implemented, an outer column having the displacement bracket may be provided on the front side and the inner column may be provided on the rear side. In the above embodiment, the expansion/contraction mechanism is configured by the cam device 22a, but the expansion/contraction mechanism of the present invention is not limited to this, for example, may be configured by a screw. In a case where the present invention is implemented, the position of the displacement bracket may be changed downward, or the structures of the embodiments described above may be combined as appropriate. The application is based on a Japanese Patent Application No. 2015-191604 filed on Sep. 29, 2015, the contents of which are incorporated herein by reference. DESCRIPTION OF REFERENCE NUMERALS 1: vehicle body 2, 2a: steering column 3, 3a: steering shaft 4: steering wheel 5a, 5b: universal joint 6: intermediate shaft 7: steering gear unit 8: input shaft 9: tie rod 10: electric motor 11: pivot shaft 12, 12a: outer column 13, 13a: inner column 14, 14a: outer shaft 15: inner shaft 16, 16a: displacement bracket 17, 17a: support bracket 18, 18a: displacement-side through hole 19, 19a-19e: support plate part 20, 20a: fixing-side through hole 21, 21a: adjustment rod 22, 22a: cam device 23: driven-side cam 24, 24a: pressed-part back surface 25: gear housing 26: side plate part 27: mounting plate part 28: slit 29: width-narrowed part 30: width-enlarged part 31a-31d: protrusion part 32a, 32b: bending part 33: adjustment lever 34: drive-side cam 35: driven-side cam 36: flange part 37: folding part 38a, 38b: resin plate 39: nut | <SOH> BACKGROUND ART <EOH>As an automobile steering device, for example, a structure as shown in FIG. 12 has been widely known. In this steering device, a steering shaft 3 is rotatably supported on an inner diameter side of a cylindrical steering column 2 which is supported on a vehicle body 1 . A steering wheel 4 is fixed to a rear end portion of the steering shaft 3 protruding rearward from a rear end opening of the steering column 2 . If the steering wheel 4 is rotated, the rotation thereof is transmitted to an input shaft 8 of a steering gear unit 7 through the steering shaft 3 , a universal joint 5 a, an intermediate shaft 6 and a universal joint 5 b. If the input shaft 8 rotates, a pair of tie rods 9 , 9 arranged on both sides of the steering gear unit 7 are pushed and pulled, whereby a steering angle according to an operation amount of the steering wheel 4 is provided to a pair of left and right steering wheels. Further, an example shown in drawings is an electric power steering device which uses an electric motor 10 as an auxiliary power source to reduce a force necessary for operating the steering wheel 4 . In this specification and claims, a front-rear direction, a width direction (left-right direction), and an upper-lower direction refers to a front-rear direction, a width direction (left-right direction), and an upper-lower direction of a vehicle, unless particularly otherwise mentioned. In a case of a structure as shown in drawings, the steering device includes a tilt mechanism for adjusting an upper-lower position (tilt position) of the steering wheel 4 and a telescopic mechanism for adjusting a front-rear position (telescopic position) of the steering wheel 4 according to a physique and a driving posture of a driver. In order to configure the tilt mechanism, the steering column 2 is supported to the vehicle body 1 so as to be able to pivotably displaceable about a pivot shaft 11 mounted in the width direction. In order to configure the telescopic mechanism, the steering column 2 has a structure where an outer column 12 provided on a rear side and an inner column 13 provided on a front side are telescopically combined, and the steering shaft 3 has a structure where an outer shaft 14 in the rear side and an inner shaft 15 in a front side are combined to transmit torque and to be telescopic by a spline engagement and the like. A displacement bracket 16 fixedly provided on a rear end side portion of the outer column 12 is supported to a support bracket 17 , which is supported to the vehicle body 1 , so as to be displaceable in the upper-lower direction and the front-rear direction. The displacement bracket 16 is formed with displacement-side through holes 18 , which are long in the front-rear direction (an axial direction of the outer column 12 ) which is a telescopic position adjustment direction. A support bracket 17 includes a pair of support plate parts 19 which interpose the displacement bracket 16 therebetween from both sides in the width direction. At portions of both support plate parts 19 which match with each other, fixing-side through holes 20 which are long in the upper-lower direction which is a tilt position adjustment direction are separately formed. Each fixing-side through hole 20 generally has a partial arc shape having the pivot shaft 11 a as a center. An adjustment rod 21 is inserted into the fixing-side through holes 20 and the displacement-side through holes 18 . The adjustment rod 21 is provided with a pair of pressing members in a state where the pressing members interpose the both support plate parts 19 therebetween from both sides in the width direction, and an interval between the both pressing members can be expanded and contracted by a cam device which operates based on an operation of an adjustment lever (for example, refer to FIG. 2 to be described later). When adjusting an upper-lower position or a front-rear position of the steering wheel 4 , the adjustment lever is rotated in a predetermined direction, thereby expanding the interval between the pressing members so as to be an unclamped state. Accordingly, frictional force acting between inner side surfaces of the support plate parts 19 and outer side surfaces of displacement bracket 16 is reduced. At this state, within a range where the adjustment rod 21 can be displaced in the fixing-side through holes 20 and the displacement-side through holes 18 , a position of the steering wheel 4 is adjusted. After the adjustment, the adjustment lever is rotated in a reverse direction of the predetermined direction, thereby contracting the interval between the pressing members so as to be a clamped state. Accordingly, the frictional force is increased to hold the steering wheel 4 at an adjusted position. In a steering device including a position adjusting device for a steering wheel, in order to enhance the support rigidity of the displacement bracket with respect to the support bracket, as disclosed in, for example, Patent Document 1, a structure has been considered which ensures that an inner side surface of support plate part having a flat surface shape is brought into contact with an outer side surface of a displacement bracket having a flat surface shape and an contact area of both side surfaces is large. However, when such a structure is adopted, as shown in FIG. 13 , there is a possibility that the support plate parts 19 configuring the support bracket 17 are deformed based on pressing force of a driven-side cam 23 functioning as a pressing member when an axial dimension of the cam device 22 is expanded. Specifically, there is a possibility that portions of the support plate parts 19 except from the portions (peripheral portions) pressed by the driven-side cam 23 is warped and deformed (deformed so as to reduce force) in a direction away from the outer side surfaces of the displacement bracket 16 as indicated by an arrow in FIG. 13 . Accordingly, only pressed-part back surfaces 24 , which are positioned on back sides of portions where outer side surfaces are pressed by the driven-side cam 23 , of inner side surfaces of the support plate parts 19 are strongly pressed against the outer side surfaces of the displacement bracket 16 . Therefore, it is difficult to ensure a large contact area between the outer side surfaces of the displacement bracket 16 and the inner side surfaces of the support plate parts 19 , and it is difficult to sufficiently enhance the support rigidity of the displacement bracket 16 with respect to the support bracket 17 . | <SOH> SUMMARY OF THE INVENTION <EOH> | B62D1184 | 20180201 | 20180816 | B62D1184 | 0 | VERLEY, NICOLE T | POSITION ADJUSTING APPARATUS FOR STEERING WHEEL | UNDISCOUNTED | 0 | REJECTED | B62D | 2,018 |
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15,749,887 | PENDING | ASSAYING OVARIAN CYST FLUID | A diagnostic test for ovarian cysts is based on the detection of mutations characteristic of the most common neoplasms giving rise to these lesions. With this test, tumor-specific mutations were detected in the cyst fluids of 19 of 24 (79%) borderline tumors and 28 of 31 (90%) malignant ovarian cancers. In contrast, we detected no mutations in the cyst fluids from 10 non-neoplastic cysts and 12 benign tumors. When categorized by the need for exploratory surgery (i.e., presence of a borderline tumor or malignant cancer), the sensitivity of this test was 85% and the specificity was 100%. These tests could inform the diagnosis of ovarian cysts and improve the clinical management of the large number of women with these lesions. | 1. A method, comprising: testing ovarian cyst fluid for mutations in a panel of genes frequently mutated in ovarian neoplasms, wherein the panel comprises BRAF, KRAS, and TP53. 2. The method of claim 1 wherein the panel further comprises one or more genes selected from a first group consisting of CTNNB1, PIK3CA, PTEN, ARID1A, and PPP2R1A. 3. (canceled) 4. The method of claim 1 wherein the step of testing employs gene-specific reagents. 5. The method of claim 1 wherein the step of testing employs mutation-specific reagents. 6. The method of claim 1 wherein the step of testing does not employ a whole-genome or whole-exome technique. 7. The method of claim 1 wherein the step of testing employs a whole-genome or whole-exome technique. 8. The method of claim 1 wherein the step of testing employs a whole-genome or whole-exome technique on the ovarian cyst fluid and on a sample selected from the group consisting of cyst wall and normal, non-ovarian tissue. 9. The method of claim 1 wherein BRAF600, KRAS12, KRAS13, KRAS61, or combinations thereof are tested. 10-12. (canceled) 13. The method of claim 2 wherein all genes of the first group are in the panel. 14. The method of claim 1 further comprising the step of assaying amount of DNA in the cyst fluid. 15. The method of claim 1 further comprising the step of assaying amount of CA-125 levels in plasma. 16. The method of claim 1 wherein the panel further comprises one or more genes selected from a second group consisting of AKT1, APC, BRCA1, BRCA2, CDKN2A, EGFR, FBXW7, FGFR2, MAPK1, NRAS, PIK3R1, and POLE. 17. The method of claim 13 wherein the panel further comprises one or more genes selected from a second group consisting of AKT1, APC, BRCA1, BRCA2, CDKN2A, EGFR, FBXW7, FGFR2, MAPK1, NRAS, PIK3R1, and POLE. 18-19. (canceled) 20. The method of claim 1 wherein the step of testing employs a step of adding molecular barcodes to template DNA in the ovarian cyst fluid. 21. The method of claim 1 wherein the ovarian cyst fluid is obtained by needle aspiration of an ovarian cyst. 22. The method of claim 1 wherein the ovarian cyst fluid is obtained prior to any surgical removal of the ovarian cyst. 23. The method of claim 1 wherein the ovarian cyst fluid is obtained after surgical removal of the ovarian cyst and recurrence of the ovarian cyst. 24. The method of claim 1 wherein the ovarian cyst fluid is from a cyst selected from the group consisting of: mesothelial cyst, follicular cyst, corpus luteal cyst, mucinous cystadenoma, endometriotic cyst, serous cystadenoma, serous cystadenofibroma, atypical proliferative serous tumor, atypical proliferative endometrioid tumor, serous carcinoma, mixed epithelial tumor, endometrioid carcinoma, clear cell carcinoma, metastatic tumors to the ovary, and mucinous carcinoma. 25. The method of claim 1 wherein a copy number variation, a loss of heterozygosity, or both, is determined in at least one of the genes in the panel. 26. (canceled) 27. The method of claim 1 wherein a point mutation, a rearrangement, a frameshift, or combinations thereof, is determined in at least one gene of the panel. 28-34. (canceled) | This invention was made with government support under CA 43460, 57345, and 62924 awarded by National Institutes of Health. The government has certain rights in the invention. TECHNICAL FIELD OF THE INVENTION This invention is related to the area of DNA analysis. In particular, it relates to analysis of genes in clinical samples. BACKGROUND OF THE INVENTION Ovarian cancer is the most lethal gynecologic malignancy, with 21,980 estimated new cases and 14,270 estimated deaths in the United States in 2014. Approximately 1.3% of women will be diagnosed with ovarian cancer during their lifetime (1). These cancers commonly present as an adnexal mass with cystic components, but are not associated with specific symptoms. As a result, two-thirds of ovarian cancers are diagnosed at late stage (Stage III and IV), when the 5-year survival is less than 30% (1). Complicating the diagnosis of ovarian cancer is the fact that ovarian cysts are common in women of all ages, with a prevalence of 35% and 17% in pre- and post-menopausal women, respectively (2). These cysts are frequently benign and found incidentally on routine imaging (2). Though malignancy is an unusual cause of the cysts, 30% of the cysts exhibit radiographic features suspicious for malignancy, such as solid areas or mass (2). In addition to the anxiety that such findings provoke, many women undergo unnecessary surgery for cysts that are not malignant and may not be responsible for the symptoms they have. For example, only 5% of 570 women in a large ovarian cancer screening randomized trial who underwent surgical evaluation actually had a malignancy (3). Compounding this issue is the fact that surgery for ovarian cysts requires general anesthesia and is associated with significant morbidity, causing serious complications in 15% of women. These complications include damage to nerves and ureters, bleeding, infection, perforation of adjacent viscera, as well as hormonal and fertility loss (in the case of bilateral oophorectomy) (4). Even minimal procedures such as ovarian cystectomy can affect fertility in premenopausal women by decreasing follicular response and oocyte number (5, 6). If a preoperative test could be performed that indicated whether the cystic lesion was benign or malignant, unnecessary surgery and its associated complications could be avoided in a large number of patients, particularly women of reproductive age who wish to preserve their fertility, as well as women whose medical comorbidities or functional status makes anesthesia and surgery hazardous. Ovarian cysts and tumors are classified as non-neoplastic, benign, borderline, or malignant based on microscopic examination after surgical removal (FIG. 1). Non-neoplastic cysts are by far the most common class of ovarian cyst. They are frequently functional in pre-menopausal women, arising when an egg is not released properly from either the follicle or corpus luteum and usually resolve spontaneously within several months (7). Benign cystic tumors, such as cystadenomas and cystadenofibromas, rarely progress to malignancy (8, 9). No genetic alterations have yet been identified in either non-neoplastic cysts or in benign cystic tumors (9). Neither of these cyst types requires surgery unless they are symptomatic or have undergone torsion (8). These cysts can be easily sampled with ultrasound-guided fine-needle aspiration in an outpatient setting without the need for anesthesia (10). At the other end of the spectrum are epithelial ovarian cancers, which are potentially lethal and unequivocally require surgery. A dualistic model has been proposed to classify these neoplasms (11). Type I tumors are composed of low-grade serous, low-grade endometrioid, clear cell, and mucinous carcinomas. They are clinically indolent, frequently diagnosed at early stage (Stage I or II), and develop from well-established precursor lesions (“borderline” or “atypical proliferative” tumors, as described below) (12). Type I cancers commonly exhibit mutations in KRAS, BRAF, CTNNB1, PIK3CA, PTEN, ARID1A, or PPP2R1A (11). In contrast, type II tumors are generally high-grade serous carcinomas. They are highly aggressive, most often diagnosed in late stage (Stage III or IV), and have suggested origins from the distal fallopian tube (13). Type II cancers almost always harbor TP53 mutations (14). Also unlike type I cancers, which are relatively chemo-resistant and more often treated only with surgical excision, type II cancers respond to conventional chemotherapy, particularly after maximal debulking to reduce tumor burden (15, 16). “Borderline” or “atypical proliferative” tumors lie in the middle of this spectrum, between the malignant cancers and the relatively harmless (non-neoplastic or benign) lesions. They are distinguished from carcinomas by the absence of stromal invasion and are precursors of type I cancers. In light of their potential for malignancy, the standard of care for borderline tumors is surgical excision. Following surgery, the prognosis is excellent compared to ovarian cancers, with 5-year survival rates over 85% (17). A minor but significant portion of borderline tumors recur after surgery, however, and a subset of the recurrences are found to have advanced to type I cancers (18). This progression is consistent with molecular findings: serous borderline tumors typically exhibit mutations in BRAF or KRAS, like their malignant counterparts (low-grade serous carcinoma) (19, 20). The presence of a BRAF mutation in a borderline tumor is associated with better prognosis and a low probability of progression to carcinoma (21). In contrast, KRAS mutations are associated with the progression to type I cancers (22). The examination of fluids from pancreatic, renal, and thyroid cysts is routinely used in clinical management (23-25). The fluids have historically been studied by cytology to identify malignant cysts. Ovarian cysts share many features with these other types of cysts, in that they are common, often diagnosed incidentally, and are nearly always benign. However, aspiration of ovarian cyst fluid for cytology is not standard-of-care. From a historical perspective, the difference in diagnostic management probably lies in the fact that cytology has not proven to be very informative for ovarian cysts, particularly for distinguishing benign vs. borderline tumors (26, 27). More recently, genetic analysis of specific types of cyst fluids has been considered as an aid to cytology, given that conventional cytology often has limited sensitivity and specificity (23). Based on the emerging success of the molecular genetic evaluation of other types of cysts, we reasoned that a similar approach could be applied to ovarian cysts. Evaluation of DNA from cells and cell fragments shed into the cyst fluid would presumably allow the identification of tumor-specific mutations. Unlike other, conventional markers of neoplasia such as CA-125, cancer gene mutations are exquisitely specific indicators of a neoplastic lesion (29). Moreover, the type of mutation can in some cases indicate the type of neoplastic lesion present (30). Yamada et al. have demonstrated that mutations can be detected in the cystic fluid of ovarian tumors by querying exons 4 to 9 of TP53, achieving sensitivities of 12.5% and 10%, for borderline and malignant tumors, respectively (31). Extremely sensitive methods for mutation detection, capable of identifying one mutant template allele among thousands of normal templates in a panel of genes, have recently been developed (32-34). In this study, we here applied one of these technologies to determine whether mutations could be identified in ovarian cyst fluids, and if so, whether they provided information that could in principle be used in diagnosis and management. Because there is currently no reliable way to determine whether an ovarian cyst is malignant prior to surgical excision, many women undergo unnecessary, invasive surgeries for non-malignant lesions. There is a need in the art for techniques to determine whether surgery is required or unnecessary. SUMMARY OF THE INVENTION According to one aspect of the invention a method is provided in which ovarian cyst fluid is tested for mutations in a panel of genes frequently mutated in ovarian neoplasms, wherein the panel comprises BRAF, KRAS, and TP53. According to another aspect of the invention a method is provided in which ovarian cyst fluid is tested for mutations in a panel of genes frequently mutated in ovarian neoplasms, wherein the panel comprises BRAF, KRAS, TP53, and one or more of AKT1, APC, BRCA1, BRCA2, CDKN2A, EGFR, FBXW7, FGFR2, MAPK1, NRAS, PIK3R1, and POLE. According to another aspect of the invention a method is provided in which ovarian cyst fluid is tested for mutations in a panel of genes frequently mutated in ovarian neoplasms, wherein the panel comprises BRAF, KRAS, TP53, and one or more of CTNNB1, PIK3CA, PTEN, ARID1A, and PPP2R1A. According to an additional aspect of the invention a method is provided in which ovarian cyst fluid is tested for mutations in a panel of genes frequently mutated in ovarian neoplasms, wherein the panel comprises BRAF, KRAS, TP53, AKT1, APC, BRCA1, BRCA2, CDKN2A, EGFR, FBXW7, FGFR2, MAPK1, NRAS, PIK3R1, and POLE. According to an additional aspect of the invention a method is provided in which ovarian cyst fluid is tested for mutations in a panel of genes frequently mutated in ovarian neoplasms, wherein the panel comprises BRAF, KRAS, TP53, CTNNB1, PIK3CA, PTEN, ARID1A, and PPP2R1A. According to an additional aspect of the invention a method is provided in which ovarian cyst fluid is tested for mutations in a panel of genes frequently mutated in ovarian neoplasms, wherein the panel comprises BRAF, KRAS, TP53, AKT1, APC, BRCA1, BRCA2, CDKN2A, EGFR, FBXW7, FGFR2, MAPK1, NRAS, PIK3R1, POLE, CTNNB1, PIK3CA, PTEN, ARID1A, and PPP2R1A. These and other embodiments which will be apparent to those of skill in the art upon reading the specification provide the art with powerful methods for assessing ovarian cysts without recourse to unnecessary surgeries. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1. Schematic showing classes of ovarian cysts and the diagnostic potential of the cyst fluid. Ovarian cysts and tumors are currently classified according to microscopic evaluation after surgical removal. The majority of ovarian cysts are non-neoplastic (often “functional” in premenopausal women). Ovarian tumors with combined cystic and solid components are either benign tumors, borderline tumors, or malignant cancers (type I or II). Only cysts associated with borderline tumors and cancers require surgical excision. We show here that the DNA purified from cyst fluid can be analyzed for somatic mutations commonly found in their associated tumors. The type of mutation detected not only indicates the type of tumor present but also could inform management. FIGS. 2A-2B. Mutant allele fractions. (FIG. 2A) Classification by tumor type. No mutations were found in the DNA of non-neoplastic or benign cysts (red). Of the cysts that required surgery (blue), the median mutant allele fraction was higher in the cyst fluids associated with type II cancer (60.3%) than type I (7.8%) or borderline tumors (2.4%). (FIG. 2B) Classification by tumor stage. The DNA from cyst fluids of late-stage cancers had a higher median mutant allele fraction (51.2%) than those of early-stage cancers (7.4%) or borderline tumors (2.4%). Horizontal bars depict median and IQR. FIG. 3 (Table 1.) Patient demographics. The clinical characteristics of patients in this study and their tumor characteristics are indicated. FIG. 4. (Table 2.) Mutations identified in tumors and cyst fluids. The mutations, mutant allele fractions, and amount of DNA recovered from cyst fluids are indicated. FIG. 5 (Table 3.) Detection of tumor-specific mutations in cyst fluid. The fraction of samples detected and the median fraction of mutant alleles are indicated, grouped by cyst type, cancer stage, and the need for surgery. FIG. 6 (Table 4.) Multivariate analysis for markers associated with need for surgery. The presence of a mutation, cyst DNA amount, and common serum biomarkers for ovarian cancer were analyzed for association with cysts that require surgical removal (Firth's penalized likelihood logistic regression). FIG. 7A-7C (FIG. S1.) Markers associated with the need for surgery. Cyst DNA amount and levels of commonly used ovarian cancer serum biomarkers are plotted according to the cyst type and need for surgery. (FIG. 7A) The amounts of DNA in cyst fluids was generally higher in cysts requiring surgery (blue) than those that do not (red), but no significant correlation was found (p=0.69). (FIG. 7B) CA-125 levels were significantly higher in cysts that required surgery than those that do not (p=0.01). (FIG. 7C) Serum HE4 levels was not correlated with the need for surgery (p=0.92). P-values were calculated using Firth's penalized likelihood logistic regression in a multivariate model (See Example 1). FIG. 8 (Table S1) Primer sequences used in multiplex assay; Forward primers (SEQ ID NO: 1-133); Reverse primers (SEQ ID NO: 134-266). FIG. 9A-9B Mutated genes found in the cyst fluid samples. FIG. 9A shows non-neoplastic, benign, and borderline. FIG. 9B shows malignant Type I and malignant Type II. Yellow boxes represent mutations with mutant allele frequency (MAF) between 0.1% and 1%; orange boxes represent mutations with MAF between 1 and 10%; red boxes represent mutations with MAF greater than 10% (* indicates patients with insufficient DNA for analysis; ** indicates patients with two detected mutations). DETAILED DESCRIPTION OF THE INVENTION The inventors have developed an assay for testing cyst fluids. Cyst fluids are typically aspirated by a needle, preferably a fine needle. The aspiration can be performed under the guidance of a radiological technique, such as ultrasound. Other guidance techniques can be used as convenient. Cyst fluids can typically be collected from any type of ovarian cyst or cystic neoplasm, and the term “cyst” is used here to refer to all types of ovarian growths with a cystic component. Non-neoplastic ovarian cysts typically do not require surgical removal and do not display mutations. In contrast, ovarian cysts that are associated with malignancy do require surgical removal and frequently display mutations; these mutations can further indicate the type and severity of the disease. Testing for a panel that includes markers for a broad range of ovarian cysts permits the identification of cyst type and prognosis. It also permits a clinical decision to surgically remove or not. Other markers and clinical indication can be used in combination with the ovarian cyst fluid assay results. Plasma markers such as CA-125 and HE4 can be assessed in patient plasma. Other protein or genetic markers can be used in conjunction with the ovarian cyst fluid assay. Other clinical indicators, including radiological findings and physical findings may be used in conjunction with the ovarian cyst fluid assay. Testing may be performed using any technique that is targeted for particular genes. These are not techniques that screen for any and all gene mutations. Rather, they are designed to detect mutations in certain predetermined genes. In some cases they are designed to detect certain mutations or mutations in certain codons. Any analytic technique can be used for detecting mutations as is convenient, efficient, and sufficiently sensitive to detect mutations in ovarian cyst fluid. The assays may be hybridization based, such as using specific probes or specific primers. The assays may employ labeled probes or primers. The assays may employ labeled secondary reagents that permit the primary reagents to be detected. Such labels include radiolabels, fluorescent labels, enzymatic labels, chromophores, and the like. A variety of different mutation types can be detected and may be useful in providing prognosis or management decisions. Such mutations include LOH, point mutations, rearrangements, frameshifts, point mutations, and copy number variations. Specific detection techniques for these mutation types or generic detection techniques may be used. It may be desirable to use control samples from other parts of the patient's body, such as a body fluid, like plasma, saliva, urine, feces, and the like. Alternatively other control samples may include tissues such as normal tissue from a non-ovary, or cells or tissues from the ovarian cyst wall. Cyst fluid may be obtained by any technique known in the art, including but not limited to needle aspiration. The aspiration may optionally be guided by a radiological technique such as ultrasound. Cyst fluid may be aspirated before or after initial surgical removal or subsequent surgical removal. In some embodiments, primers will incorporate unique identification DNA sequence (UID) which are molecular barcodes. These can be randomly generated and attached to templates as a means to reduce errors arising from amplification and sequencing. Probes, primers, and UIDs can incorporate non-naturally occurring modifications to DNA sequences, by internucleotide linkage modifications, by sugar modifications, and by nucleobase modifications. For example, phosphorothioate (PS) linkages can be used in which sulfur substitutes for one nonbridging phosphate oxygen. This imparts resistance to nuclease degradation. Other modifications which can be used include N3′ phosplioramidate (NP) linkages, Boranophospliate internucleotide linkages, Phosphonoacetate (PACE) linkages, Morpholino phosphoramidates, Peptide nucleic acid (PNA), 2′-O-Me nucleoside analog, 2′F-RN A modification, 2′-deoxy-2′-fluoro-β-D-arabino nucleic acid (2′F-ANA) modification and Locked nucleic acid (LNA). Other techniques which are unbiased toward particular genes can be used as well for assessing genes of interest in cyst fluid. Such techniques include whole-genome or whole exome techniques. These may include assessments by nucleotide sequencing. The nucleotide sequencing may be redundant nucleotide sequencing. Targeted sequencing methods can be used as well. The methods described here achieve high degrees of sensitivity and specificity. Sensitivity may be at least 15%, at least 20%, at least 25%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95% for borderline and malignant tumors. Specificity may be at least 15%, at least 20%, at least 25%, at least 50%, at least 60 at least 70%, at least 80%, at least 85%, at least 90%, at least 95% for borderline and malignant tumors. Removal of ovarian cyst fluid assay from the body can be accomplished before any surgery occurs. Thus the results of the assay can help guide the decision to perform surgery. If surgery has occurred to remove the ovarian cyst, and if it returns, a sample of ovarian cyst fluid may be obtained from the body at that time. The assays will typically be performed in a clinical laboratory on samples that have been removed by a skilled clinician, such as an interventional radiologist or a surgeon. The samples may be assayed immediately or they may suitable stored and or shipped for testing. It is possible that DNA will be extracted from the sample prior to shipping it to a laboratory for testing. Results will generally be communicated back from the assaying laboratory to the clinician for communication to a patient. Results may be recorded in paper or electronic medical records. Ovarian cancer is the most lethal gynecologic cancer in women. However screening is not recommended by the U.S. Preventive Services Task Force using current diagnostic approaches, which too frequently lead to “important harms, including major surgical interventions in women who do not have cancer” (Moyer and Force, 2012). We have demonstrated here that driver mutations in ovarian tumors are also present in their associated cyst fluids. Moreover, the mutant allele frequencies in the cyst fluids are relatively high (median 12.6%, IQR of 2.7% to 40.2%), facilitating their detection. There were no mutations detected in the cyst fluids that were not also present in the tumors, and vice versa. Also importantly, no mutation was identified in non-neoplastic cysts or cysts associated with benign tumors. Overall, mutations were detected in a major fraction (87%) of cysts requiring surgery but not in any cyst that did not require surgery. Our results demonstrate that mutations present in ovarian tumors are also present in their associated cyst fluids. Moreover, the mutant allele frequencies in the cyst fluids are relatively high (median 12.6%, IQR of 2.7% to 40.2%), facilitating their detection. There were no mutations detected in the cyst fluids that were not also present in the tumors, and vice versa. And most importantly, mutations were detected in a major fraction (85%) of cysts requiring surgery but not in any cyst that did not require surgery (Tables 2 and 3). Although most (85%) of the 55 cysts requiring surgery had detectable mutations in their fluidic compartment, eight did not. All of these eight cysts occurred in borderline tumors or type I cancers, while mutations were always (100%) detectable in type II cancers (Tables 2 and 3). There are two potential explanations for our failure to detect mutations in these eight cysts. First, it is possible that the mutant DNA concentration in these cysts was below the level of technical sensitivity of our assay (˜0.1% mutant allele fraction). We excluded this possibility by evaluating the tumors themselves: no mutations were detected in any of the tumors from these 8 patients. The second, and therefore more likely explanation, is that our panel of 133 amplicons, containing regions of 17 genes, was not adequate to capture the mutations that were present. Unlike type II cancers, which nearly always contain TP53 mutations (94% of the type II cancers we studied, for example), the genomic landscapes of type I cancers and borderline tumors are more heterogeneous and not as well studied (II). Further genetic evaluation of these tumors should facilitate the incorporation of additional amplicons in the panel to reach higher sensitivities. Nevertheless, the 100% sensitivity for type II cancers in our study is highly encouraging, given that these cancers account for over 90% of ovarian cancer deaths. One limitation of our study is the number of patients evaluated. Though excision of ovarian cysts is one of the most commonly performed surgical procedures, banking of cyst fluids is not common, even in academic centers. Thus, we only had relatively small numbers (n=22) of non-neoplastic cysts and benign tumors available for study. Even so, the differences in genetic alterations among the various cyst types were striking (Tables 2 and 3). Our study will hopefully stimulate collection and analyses of ovarian cyst fluids that will be able to establish smaller confidence limits around the sensitivities and specificities reported in the current study. A potential clinical limitation of our approach is the concern by gynecologists that needle puncture of a malignant ovarian cyst leads to seeding of the peritoneum. This concern is based on inconclusive evidence about the dangers of cyst rupture during surgery and is, at best, controversial (40). Moreover, leakage is expected to be much less likely when a tiny needle is inserted into the cyst under ultrasound-guidance than when cysts are manipulated during surgery. The idea that malignant cysts might shed cancer cells if needle-punctured also seems incongruent with the widespread practice of laparoscopic removal of ovarian cysts (41). Laparoscopic removal of a cyst carries a risk of cyst rupture, perhaps higher than needling (42). Finally, malignant pancreatic cysts are at least as dangerous as malignant ovarian cysts, yet the standard-of-care for pancreatic cysts involves repeated sampling of cyst fluid through endoscopic ultrasound over many years (43, 44). Though pancreatic cysts and ovarian cysts lie in different anatomical compartments, it is encouraging that aspiration of pancreatic cysts is not associated with an increased risk of mortality in patients with pancreatic cancer (45). Finally, recent advancements in methods to plug biopsy tracts, using materials such as absorbable gelatin slurry and torpedo, can further decrease the risk of tumor spillage associated with fine-needle aspirations (46, 47). On the basis of these observations and recent developments, we believe that ultrasound-guided aspiration of ovarian cyst fluids would likely be a safe and well-tolerated procedure. As noted in the background of the invention section above, seven to ten patients with benign ovarian cyst lesions undergo surgery for each case of ovarian cancer found (48). In addition to the psychological impact a potential diagnosis of cancer has on patients, surgery for benign lesions entails considerable cost and morbidity. OVA-1 is the only FDA-cleared test to date that aims to distinguish benign versus malignant adnexal mass. It measures levels of five serum markers (CA-125, β-2 microglobulin, apolipoprotein A1, prealbumin, and transferrin) and is used to stratify patients who should consult a gynecologic oncologist rather than a general gynecologist for surgery. However the test has a specificity of 43% for ovarian cancer, which is even lower than that of CA-125 alone (49). While the test might encourage patients with suspected ovarian cancer to seek specialized care, it would not decrease the number of unnecessary surgeries for women with benign adnexal masses. This study was driven by the need for a biomarker that would help distinguish malignant ovarian tumors from benign lesions and thereby reduce the number of unnecessary surgeries. Such distinction is often difficult based on symptoms and conventional diagnostic criteria. For example, in a large study of 48,053 asymptomatic postmenopausal women who underwent ultrasound examination by skilled sonographers, 8 (17%) of the 47 ovarian cancers that were identified occurred in women with persistently normal sonographic findings (Sharma et al., 2012). All eight cases were type II cancers, highlighting the potential utility of an additional assay to detect this highly lethal and aggressive type of ovarian cancer. On the other hand, of the 4367 women with abnormal sono graphic findings, less than 1% of cases proved to have malignancy upon surgery. Furthermore, of the 32 women with borderline or Type I cancers diagnosed, 22 (69%) had a serum CA-125 level within the clinically accepted normal range (≤35 units/mL). In our study, 18 of 18 (100%) type II cancers were detectable by virtue of the mutations found in cyst fluid DNA while none of the 18 benign or non-neoplastic cyst fluid contained such mutations. It is also important to note that the readout of our assay is quantitative and not dependent on the skill level of the reader (in contrast to sonography). Finally, the procedure can be performed minimally invasively in an outpatient setting. The goal of our test is not to replace clinical, radiologic, or sonographic evaluation but to augment them with molecular genetic markers. Our study, though only proof-of-principle, illustrates one route to improve management of patients with ovarian cysts. Genetic analysis is not the only such route; proteomics could also provide clues to the correct diagnosis (50, 51). One can easily imagine how such additional information could be used to inform clinical practice in conjunction with current diagnostic methods. For example, if a cyst contained low amounts of DNA, no detectable mutations, and if the patient had low CA-125 levels, our data suggest that it is very unlikely to be a borderline tumor or malignant lesion. Either no surgery, or laparoscopic rather than open surgery, could be recommended for that patient, even if there was some solid component upon imaging. The option to avoid surgery would be particularly valuable for pre-menopausal women who generally have a low risk of ovarian cancer and might wish to preserve their fertility, as well as patients who are poor surgical candidates. However, our assay in its current format cannot completely rule out malignancy because a fraction of early-stage cancer patients did not have detectable mutations in their cysts. Therefore, patients whose clinical and functional status allows them to undergo surgery and anesthesia might still choose to have a surgical procedure. On the other hand, a minimally invasive test that provides additional, orthogonal information to patients and surgeons could inform their decision about the advisability of surgery. Our data suggest that a cyst without any solid component upon imaging, and thereby unlikely via conventional criteria to be malignant, should be removed promptly if the cyst fluid contained a TP53 mutation. Radical, rather than conservative, surgery might be appropriate due to the high likelihood of an aggressive type II cancer. In contrast, if a BRAF mutation was identified, the lesion is presumably a borderline or low-grade tumor; thus conservative rather than radical surgery might be sufficient. Lastly, given that certain types of ovarian cancers (type II) tend to respond well to chemotherapy while others (type I) are relatively chemo-resistant, knowing the type of cancer present prior to surgery based on the mutation profile could help guide decisions regarding the use of neoadjuvant chemotherapy. Validation of these data in a much larger, prospective trial will of course be required before incorporation of this approach into clinical practice. The above disclosure generally describes the present invention. All references disclosed herein are expressly incorporated by reference. A more complete understanding can be obtained by reference to the following specific examples which are provided herein for purposes of illustration only, and are not intended to limit the scope of the invention. Example 1—Materials and Methods Patient Samples Cyst fluids were collected prospectively from 77 women presenting with a suspected ovarian tumor. Patients were diagnosed by transvaginal sonography or computed tomography and admitted for surgical removal of the cyst by gynecologic oncology surgeons at Sahlgrenska University Hospital, Gothenburg, Sweden. The study was approved by the ethical board of Gothenburg University and patients provided written consent. According to the approved protocol, ovarian cyst fluids were collected after removal of the cyst from the abdomen. All samples were immediately put in 4° C. for 15-30 minutes, centrifuged for 10 minutes at 500 g, and aliquoted into Eppendorf tubes. The fluids were transferred to −80° C., within 30-60 minutes after collection. All histology was reviewed by board-certified pathologists (Table 1). Plasma HE4 concentrations were determined using a commercial HE4 EIA assay (Fujirebio Diagnostics) and plasma CA-125 levels were measured using the Architect CA 125 II (Abbott Diagnostics, USA). DNA was purified from tumor tissue (either freshly-frozen, or formalin-fixed and paraffin-embedded) after microdis section to remove neoplastic components. DNA was purified from tumors and from cyst fluids using an AllPrep DNA kit (Qiagen) according to the manufacturer's instructions. Purified DNA from all samples was quantified as previously described (52). Statistical Analysis A Wilcoxon rank-sum test was used to compare the amount of DNA in the cancers and borderline tumors with the amount of DNA in the simple cysts and benign tumors. The fraction of samples detected by tumor-specific mutations in the cyst fluid, as well as their 95% confidence intervals, was calculated for each tumor type (Table 3). When the presence of a mutation in the cyst fluid was used to predict the need for surgery, the sensitivity and specificity of the test, as well as their 95% confidence intervals, were calculated. Firth's penalized likelihood logistic regression was used to quantify the association between molecular features of cyst fluids and the need for surgery (Table 4) in a multivariate model. The model predictors included the presence of mutation, log 10(ng) of cyst DNA and indicators for normal CA-125 and HE4 values. Normal CA-125 values were defined as <35 U/mL and normal HE4 values were defined as <92 pmol/L and <121 pmol/L for pre- and post-menopausal women, respectively. Statistical analyses were performed using the R statistical package (version 3.1.2). Unless noted otherwise, all patient-related values are reported as means±SD. Mutation Detection and Analysis DNA from either cyst fluids or tumors was used for multiplex PCR, as previously described (34). One-hundred-and-thirty-three primer pairs were designed to amplify 110 to 142 bp segments containing regions of interest from the following 17 genes: AKT1, APC, BRAF, CDKN2A, CTNNB1, EGFR, FBXW7, FGFR2, KRAS, MAPK1, NRAS, PIK3CA, PIK3R1, POLE, PPP2R1A, PTEN, and TP53. Primer sequences are listed in Table S1. These primers were used to amplify DNA in 25 μL reactions as previously described (34). For each sample, three multiplex reactions, each containing non-overlapping amplicons, were performed. Reactions were purified with AMPure XP beads (Beckman Coulter) and eluted in 100 μL of Buffer EB (Qiagen). A fraction (2.5 μL) of purified PCR products were then amplified in a second round of PCR, as described (34). The PCR products were purified with AMPure and sequenced on an 11lumina MiSeq instrument. We used Safe-SeqS, an error-reduction technology for detection of low frequency mutations as described to distinguish better between genuine mutations in the samples and artifactual variants arising from sequencing and sample preparation steps, (34). High quality sequence reads were selected based on quality scores, which were generated by the sequencing instrument to indicate the probability a base was called in error. The template-specific portion of the reads was matched to reference sequences. Reads from a common template molecule were then grouped based on the unique identifier sequences (UIDs) that were incorporated as molecular barcodes. Artifactual mutations introduced during the sample preparation or sequencing steps were reduced by requiring a mutation to be present in >90% of reads in each UID family (i.e., to be scored as a “supermutant”). In addition, DNA from normal individuals was used as a control to identify potential false positive mutations (see main text). Only supermutants in samples with frequencies far exceeding their frequencies in control DNA samples (i.e., >mean+5 standard deviations) were scored as positive. Example 2—Characteristics of the Tumors and Cyst Fluid Samples DNA was isolated from surgically excised ovarian cysts of 77 women. Ten of them had non-neoplastic cysts, 12 had benign tumors, 24 had borderline tumors, and 31 had cancers (13 Type I and 18 Type II). Age, histopathologic diagnosis, stage, and other clinical information are provided in Table 1. The median amount of DNA recovered from the cysts was 222 ng (interquartile range (IQR) of 53 to 3120 ng) (Table 2). There was no significant difference in the amounts of DNA between borderline tumors and type I or type II cancers (Table 2). However, the borderline tumors and cancers contained significantly more DNA than the non-neoplastic cysts or benign tumors (4453±6428 ng vs. 62±64 ng; p<0.001, Wilcoxon rank-sum test). Example 3—a Multiplex PCR-Based Test to Identify Tumor-Specific Mutations in Cyst Fluid Samples We designed a multiplex PCR-based test that could simultaneously assess the regions of 17 genes frequently mutated in ovarian tumors. The amount of DNA shed from neoplastic cells was expected to be a minor fraction of the total DNA in the cyst fluid, with most DNA emanating from normal cells. We therefore used a sensitive detection method, called Safe-SeqS (Safe-Sequencing System), to identify mutations in cyst fluid samples (34). In brief, primers were designed to amplify 133 regions, covering 9054 distinct nucleotide positions within the 17 genes of interest (Table S1). Three multiplex PCR reactions, each containing non-overlapping amplicons, were then performed on each sample. One primer in each pair included a unique identifier (UID) for each template molecule, thereby drastically minimizing the error rates associated with PCR and sequencing, as described previously (34) (Table S1). Under the conditions used in the current experiments, mutations present in >0.1% of template molecules could generally be reliably determined. We could not perform sequencing on five cysts (two simple cysts, two cystadenomas, one borderline tumor) because there was insufficient DNA (<3 ng recovered), and these were scored in a conservative fashion, as “negative” for mutations. When this test was applied to the 22 cyst fluids obtained from patients with simple cysts (n=9) or benign tumors (n=13), no mutations were identified (Tables 2 and 3). This was in stark contrast to the fluids obtained from the 18 patients with type II cancers, all of which were found to contain a mutation (Tables 2 and 3). Ten (77%) of the 13 cyst fluids from patients with type I cancers and 19 (79%) of the 24 cyst fluids from patients with borderline tumors contained at least one detectable mutation. When categorized by the need for surgery (i.e., presence of a borderline tumor or a type I or type II cancer), the sensitivity of this test was 85% (47 of 55 cysts; 95% confidence interval of 73% to 94%) and the specificity was 100% (95% confidence interval of 78% to 100%; Table 3). Ovarian cancers are generally detected only late in the course of disease, explaining the poor prognosis of patients. Accordingly, only 11 of the 31 cysts associated with cancers in our study had early (Stage I or II) disease (Table 1). As expected, most of these were type I carcinomas (n=8). Nevertheless, it was encouraging that mutant DNA could be detected in nine (82%) of these 11 patients (Table 3). Mutations could be detected in 95% of the 20 patients with Stage III or IV cancers (Table 3). A variety of control experiments were performed to confirm the integrity of these results. One informative positive control was provided by the results of sequencing of DNA from the tumors, using the identical method used to analyze DNA from the cyst fluids. Fifty-three of the 55 borderline and malignant cases had tumor available for this purpose. Every mutation identified in a tumor was found in its cyst fluid, and vice versa. As expected, the mutant allele frequencies in the tumors were often, but not always, higher than in the cyst fluid (Table 2). As another positive control, we used an independent PCR and sequencing reaction to confirm each of the cyst fluid mutations listed in Table 2. This validated not only the presence of a mutation, but also confirmed its fractional representation. The median relative difference between the fractions of mutant alleles in replicate experiments was 7.0% (IQR of 3.5% to 8.9%). Finally, four patients were found to have two independent mutations (Table 2). For example, the cyst fluid of patient OVCYST 081, who had high-grade endometrioid carcinoma, had a missense mutation (R280K) in TP53 plus an in-frame deletion of PIK3R1 at codons 458 and 459 of PIK3R1. The TP53 mutation was found in 3.0% of alleles while the PIK3R1 mutation was found in 3.7% of the alleles analyzed. Similar mutant allele frequencies among completely different mutations in the cyst fluid of three other patients provided further indicators of reproducibility (Table 2). All genetic assays were performed in a blinded manner, with the operator unaware of the diagnoses of the patients from whom the cyst fluids were obtained. In addition to DNA from normal individuals used as controls, additional negative controls were provided by the simple cysts and benign tumors. Using the identical assay, none of the DNA from their cyst fluids contained detectable mutations (Table 2). A final control was provided by the borderline and malignant tumors themselves. In general, only one or two of the 9054 base-pairs (bp) queried were mutated in any one tumor (Table 2). The other ˜9000 bp could then be independently queried in the corresponding cyst fluid, and none of these positions were found to be mutated. Example 4—Relationship Between the Type of Tumor Present and the Type of Mutation Found in the Associated Cyst Fluid Sample The mutant allele fractions in the cyst fluids tended to be higher in the type II cancers (median of 60.3%) than the type I cancers (median of 7.8%) or borderline tumors (median of 2.4%), though there was considerable overlap (Tables 2 and 3). On the other hand, the type of mutation varied considerably among these cysts. In type I tumors, the genes mutated were BRAF (n=1), KRAS (n=5), NRAS (n=1), PIK3R1 (n=1), PPP2R1A (n=1), PTEN (n=1), or TP53 (n=3). Two distinct mutations were found per sample in three type I cancers. One type I cancer had a BRAF mutation. This BRAF mutation (V600_S605>D) is unusual that it resulted from an in-frame deletion/insertion rather than the base substitution (V600E) characteristic of the vast majority of BRAF mutations reported in the literature. This mutation has been observed in a papillary thyroid cancer and a cutaneous melanoma (35, 36). The deletion results in loss of a phosphorylation site in the activation loop of BRAF, while the insertion of an aspartic acid has been suggested to increase BRAF kinase activity by mimicking an activating phosphorylation (37). In contrast, all but one type II cancers (94% of 18) had mutations in TP53; the only exception was OVCYST 081, a high-grade endometrioid carcinoma. The borderline tumors were distinguished by yet a different pattern from that of the either type I or type II cancers. Of the 19 mutations in borderline tumors, 12 (63%) were at BRAF V600E, never observed in type I or type II cancers, and the remainder were at KRAS 12 or 61 (Table 2). Example 5—Markers Associated with the Need for Surgery A multivariate analysis was used to identify the most informative molecular features of cyst fluids and to compare them to the commonly used serum biomarkers for ovarian cancer, HE4 (human epididymis protein 4) and CA-125 (38, 39) (Table 4). We defined “informative” as indicating a need for surgery (i.e., borderline tumors or type I or II cancers). The amount of DNA in cyst fluids was generally, but not significantly, higher in the cysts requiring surgery (p=0.69, Table 4), though there were many cysts not requiring surgery that had higher DNA levels than cysts requiring surgery (FIG. S1A). Similarly, the serum CA-125 levels were significantly higher in cysts requiring surgery (p=0.01, Table 4), but there were many cysts not requiring surgery that had higher levels than those requiring surgery (FIG. S1B). Serum HE4 levels were not correlated with cyst type (P=0.92, Table 4; FIG. S1C). 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Wilcox, Endoscopic ultrasound-guided fine needle aspiration biopsy of patients with suspected pancreatic cancer: diagnostic accuracy and acute and 30-day complications. The American journal of gastroenterology 98, 2663-2668 (2003). 45. S. Ngamruengphong, K. M. Swanson, N. D. Shah, M. B. Wallace, Preoperative endoscopic ultrasound-guided fine needle aspiration does not impair survival of patients with resected pancreatic cancer. Gut, (2015). 46. A. A. Tran, S. B. Brown, J. Rosenberg, D. M. Hovsepian, Tract embolization with gelatin sponge slurry for prevention of pneumothorax after percutaneous computed tomography-guided lung biopsy. Cardiovascular and interventional radiology 37, 1546-1553 (2014). 47. W. K. Tsang, W. H. Luk, A. Lo, Ultrasound-guided plugged percutaneous biopsy of solid organs in patients with bleeding tendencies. Hong Kong medical journal=Xianggang yi xue za zhi/Hong Kong Academy of Medicine 20, 107-112 (2014). 48. J. R. van Nagell, Jr., P. D. DePriest, F. R. Ueland, C. P. DeSimone, A. L. Cooper, J. M. McDonald, E. J. Pavlik, R. J. Kryscio, Ovarian cancer screening with annual transvaginal sonography: findings of 25,000 women screened. Cancer 109, 1887-1896 (2007). 49. F. R. Ueland, C. P. Desimone, L. G. Seamon, R. A. Miller, S. Goodrich, I. Podzielinski, L. Sokoll, A. Smith, J. R. van Nagell, Jr., Z. Zhang, Effectiveness of a multivariate index assay in the preoperative assessment of ovarian tumors. Obstetrics and gynecology 117, 1289-1297 (2011). 50. E. Bandiera, L. Zanotti, A. S. Fabricio, E. Bucca, E. Squarcina, C. Romani, R. Tassi, E. Bignotti, P. Todeschini, G. Tognon, C. Romagnolo, M. Gion, E. Sartori, T. Maggino, S. Pecorelli, A. Ravaggi, Cancer antigen 125, human epididymis 4, kallikrein 6, osteopontin and soluble mesothelin-related peptide immunocomplexed with immunoglobulin M in epithelial ovarian cancer diagnosis. Clinical chemistry and laboratory medicine: CCLM/FESCC 51, 1815-1824 (2013). 51. B. Kristjansdottir, K. Levan, K. Partheen, E. Carlsohn, K. Sundfeldt, Potential tumor biomarkers identified in ovarian cyst fluid by quantitative proteomic analysis, iTRAQ. Clinical proteomics 10, 4 (2013). 52. C. Rago, D. L. Huso, F. Diehl, B. Karim, G. Liu, N. Papadopoulos, Y. Samuels, V. E. Velculescu, B. Vogelstein, K. W. Kinzler, L. A. Diaz, Jr., Serial assessment of human tumor burdens in mice by the analysis of circulating DNA. Cancer research 67, 9364-9370 (2007). | <SOH> BACKGROUND OF THE INVENTION <EOH>Ovarian cancer is the most lethal gynecologic malignancy, with 21,980 estimated new cases and 14,270 estimated deaths in the United States in 2014. Approximately 1.3% of women will be diagnosed with ovarian cancer during their lifetime (1). These cancers commonly present as an adnexal mass with cystic components, but are not associated with specific symptoms. As a result, two-thirds of ovarian cancers are diagnosed at late stage (Stage III and IV), when the 5-year survival is less than 30% (1). Complicating the diagnosis of ovarian cancer is the fact that ovarian cysts are common in women of all ages, with a prevalence of 35% and 17% in pre- and post-menopausal women, respectively (2). These cysts are frequently benign and found incidentally on routine imaging (2). Though malignancy is an unusual cause of the cysts, 30% of the cysts exhibit radiographic features suspicious for malignancy, such as solid areas or mass (2). In addition to the anxiety that such findings provoke, many women undergo unnecessary surgery for cysts that are not malignant and may not be responsible for the symptoms they have. For example, only 5% of 570 women in a large ovarian cancer screening randomized trial who underwent surgical evaluation actually had a malignancy (3). Compounding this issue is the fact that surgery for ovarian cysts requires general anesthesia and is associated with significant morbidity, causing serious complications in 15% of women. These complications include damage to nerves and ureters, bleeding, infection, perforation of adjacent viscera, as well as hormonal and fertility loss (in the case of bilateral oophorectomy) (4). Even minimal procedures such as ovarian cystectomy can affect fertility in premenopausal women by decreasing follicular response and oocyte number (5, 6). If a preoperative test could be performed that indicated whether the cystic lesion was benign or malignant, unnecessary surgery and its associated complications could be avoided in a large number of patients, particularly women of reproductive age who wish to preserve their fertility, as well as women whose medical comorbidities or functional status makes anesthesia and surgery hazardous. Ovarian cysts and tumors are classified as non-neoplastic, benign, borderline, or malignant based on microscopic examination after surgical removal ( FIG. 1 ). Non-neoplastic cysts are by far the most common class of ovarian cyst. They are frequently functional in pre-menopausal women, arising when an egg is not released properly from either the follicle or corpus luteum and usually resolve spontaneously within several months (7). Benign cystic tumors, such as cystadenomas and cystadenofibromas, rarely progress to malignancy (8, 9). No genetic alterations have yet been identified in either non-neoplastic cysts or in benign cystic tumors (9). Neither of these cyst types requires surgery unless they are symptomatic or have undergone torsion (8). These cysts can be easily sampled with ultrasound-guided fine-needle aspiration in an outpatient setting without the need for anesthesia (10). At the other end of the spectrum are epithelial ovarian cancers, which are potentially lethal and unequivocally require surgery. A dualistic model has been proposed to classify these neoplasms (11). Type I tumors are composed of low-grade serous, low-grade endometrioid, clear cell, and mucinous carcinomas. They are clinically indolent, frequently diagnosed at early stage (Stage I or II), and develop from well-established precursor lesions (“borderline” or “atypical proliferative” tumors, as described below) (12). Type I cancers commonly exhibit mutations in KRAS, BRAF, CTNNB1, PIK3CA, PTEN, ARID1A, or PPP2R1A (11). In contrast, type II tumors are generally high-grade serous carcinomas. They are highly aggressive, most often diagnosed in late stage (Stage III or IV), and have suggested origins from the distal fallopian tube (13). Type II cancers almost always harbor TP53 mutations (14). Also unlike type I cancers, which are relatively chemo-resistant and more often treated only with surgical excision, type II cancers respond to conventional chemotherapy, particularly after maximal debulking to reduce tumor burden (15, 16). “Borderline” or “atypical proliferative” tumors lie in the middle of this spectrum, between the malignant cancers and the relatively harmless (non-neoplastic or benign) lesions. They are distinguished from carcinomas by the absence of stromal invasion and are precursors of type I cancers. In light of their potential for malignancy, the standard of care for borderline tumors is surgical excision. Following surgery, the prognosis is excellent compared to ovarian cancers, with 5-year survival rates over 85% (17). A minor but significant portion of borderline tumors recur after surgery, however, and a subset of the recurrences are found to have advanced to type I cancers (18). This progression is consistent with molecular findings: serous borderline tumors typically exhibit mutations in BRAF or KRAS, like their malignant counterparts (low-grade serous carcinoma) (19, 20). The presence of a BRAF mutation in a borderline tumor is associated with better prognosis and a low probability of progression to carcinoma (21). In contrast, KRAS mutations are associated with the progression to type I cancers (22). The examination of fluids from pancreatic, renal, and thyroid cysts is routinely used in clinical management (23-25). The fluids have historically been studied by cytology to identify malignant cysts. Ovarian cysts share many features with these other types of cysts, in that they are common, often diagnosed incidentally, and are nearly always benign. However, aspiration of ovarian cyst fluid for cytology is not standard-of-care. From a historical perspective, the difference in diagnostic management probably lies in the fact that cytology has not proven to be very informative for ovarian cysts, particularly for distinguishing benign vs. borderline tumors (26, 27). More recently, genetic analysis of specific types of cyst fluids has been considered as an aid to cytology, given that conventional cytology often has limited sensitivity and specificity (23). Based on the emerging success of the molecular genetic evaluation of other types of cysts, we reasoned that a similar approach could be applied to ovarian cysts. Evaluation of DNA from cells and cell fragments shed into the cyst fluid would presumably allow the identification of tumor-specific mutations. Unlike other, conventional markers of neoplasia such as CA-125, cancer gene mutations are exquisitely specific indicators of a neoplastic lesion (29). Moreover, the type of mutation can in some cases indicate the type of neoplastic lesion present (30). Yamada et al. have demonstrated that mutations can be detected in the cystic fluid of ovarian tumors by querying exons 4 to 9 of TP53, achieving sensitivities of 12.5% and 10%, for borderline and malignant tumors, respectively (31). Extremely sensitive methods for mutation detection, capable of identifying one mutant template allele among thousands of normal templates in a panel of genes, have recently been developed (32-34). In this study, we here applied one of these technologies to determine whether mutations could be identified in ovarian cyst fluids, and if so, whether they provided information that could in principle be used in diagnosis and management. Because there is currently no reliable way to determine whether an ovarian cyst is malignant prior to surgical excision, many women undergo unnecessary, invasive surgeries for non-malignant lesions. There is a need in the art for techniques to determine whether surgery is required or unnecessary. | <SOH> SUMMARY OF THE INVENTION <EOH>According to one aspect of the invention a method is provided in which ovarian cyst fluid is tested for mutations in a panel of genes frequently mutated in ovarian neoplasms, wherein the panel comprises BRAF, KRAS, and TP53. According to another aspect of the invention a method is provided in which ovarian cyst fluid is tested for mutations in a panel of genes frequently mutated in ovarian neoplasms, wherein the panel comprises BRAF, KRAS, TP53, and one or more of AKT1, APC, BRCA1, BRCA2, CDKN2A, EGFR, FBXW7, FGFR2, MAPK1, NRAS, PIK3R1, and POLE. According to another aspect of the invention a method is provided in which ovarian cyst fluid is tested for mutations in a panel of genes frequently mutated in ovarian neoplasms, wherein the panel comprises BRAF, KRAS, TP53, and one or more of CTNNB1, PIK3CA, PTEN, ARID1A, and PPP2R1A. According to an additional aspect of the invention a method is provided in which ovarian cyst fluid is tested for mutations in a panel of genes frequently mutated in ovarian neoplasms, wherein the panel comprises BRAF, KRAS, TP53, AKT1, APC, BRCA1, BRCA2, CDKN2A, EGFR, FBXW7, FGFR2, MAPK1, NRAS, PIK3R1, and POLE. According to an additional aspect of the invention a method is provided in which ovarian cyst fluid is tested for mutations in a panel of genes frequently mutated in ovarian neoplasms, wherein the panel comprises BRAF, KRAS, TP53, CTNNB1, PIK3CA, PTEN, ARID1A, and PPP2R1A. According to an additional aspect of the invention a method is provided in which ovarian cyst fluid is tested for mutations in a panel of genes frequently mutated in ovarian neoplasms, wherein the panel comprises BRAF, KRAS, TP53, AKT1, APC, BRCA1, BRCA2, CDKN2A, EGFR, FBXW7, FGFR2, MAPK1, NRAS, PIK3R1, POLE, CTNNB1, PIK3CA, PTEN, ARID1A, and PPP2R1A. These and other embodiments which will be apparent to those of skill in the art upon reading the specification provide the art with powerful methods for assessing ovarian cysts without recourse to unnecessary surgeries. | C12Q16886 | 20180202 | 20180913 | C12Q16886 | 0 | JOHANNSEN, DIANA B | ASSAYING OVARIAN CYST FLUID | SMALL | 0 | PENDING | C12Q | 2,018 |
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15,750,165 | PENDING | ELECTRONIC EXPANSION VALVE | An electronic expansion valve includes a valve seat component, including a valve seat and a valve core seat; and a valve rod component, capable of axially moving along a core cavity of the valve core seat to open or close a valve port. The valve rod component is provided with an axial through hole communicated with the valve port and a sealing surface capable of being adhered to and sealing the valve port. The valve rod component includes a valve rod and a valve core fixedly disposed at a lower end of the valve rod. The valve rod is a cylindrical body, including a small-diameter cylinder body and a large-diameter cylinder body close to the valve port. A first gap is provided between the large-diameter cylinder body and the valve core seat, and a second gap is provided between the valve core and the valve port. | 1. An electronic expansion valve, comprising: a valve seat component comprising a valve seat and a valve core seat inserted into the valve seat; a valve stem component which is axially movable along a core cavity of the valve core seat to open or close a valve port for communicating or cutting off two connection ports of the electronic expansion valve; the valve stem component has an axial through hole in communication with the valve port and a sealing surface which is configured to fit against the valve port to seal the valve port; and wherein the valve stem component comprises a valve stem and a valve core fixed to a lower end of the valve stem, and the valve stem is a cylindrical body and comprises a small-diameter segment cylinder and a large-diameter segment cylinder close to the valve port, and a first gap is provided between the large-diameter segment cylinder and the valve core seat, and a second gap is provided between the valve core and the valve port. 2. The electronic expansion valve according to claim 1, wherein each of the sizes of the first gap and the size of the second gap is in a preset range, which allows a medium pressure zone having a pressure between a refrigerant inlet pressure and a refrigerant outlet pressure to be formed at the valve port between the first gap and the second gap at the start of valve opening. 3. The electronic expansion valve according to claim 2, wherein the first gap has a size ranging from 0.1 mm to 0.5 mm. 4. The electronic expansion valve according to claim 2, wherein the second gap has a size ranging from 0.1 mm to 0.8 mm. 5. The electronic expansion valve according to claim 1, wherein the large-diameter segment cylinder has an axial dimension less than the axial dimension of the valve core. 6. The electronic expansion valve according to claim 1, wherein the two connection ports and the valve port are all provided in the valve seat, and an inner cavity of the valve seat is divided into an upper cavity and a lower cavity by the valve port; the valve core seat is inserted into the upper cavity and divides the upper cavity into a first upper cavity and a second upper cavity surrounding the first upper cavity, and a side wall of the valve core seat is provided with a flow opening via which the first upper cavity is in communication with the second upper cavity; and the second upper cavity and the lower cavity are in communication with the two connection ports respectively. 7. The electronic expansion valve according to claim 6, wherein the flow opening has a circumferential dimension tapering downward in an axial direction of the valve core seat. 8. The electronic expansion valve according to claim 7, wherein a lower portion of the flow opening is in a V-shape. 9. The electronic expansion valve according to claim 1, wherein the valve stem component further comprises a sealing ring, and the sealing ring is press-fitted between the valve stem and the valve core, and a lower end surface of the sealing ring forms the sealing surface. 10. The electronic expansion valve according to claim 2, wherein the two connection ports and the valve port are all provided in the valve seat, and an inner cavity of the valve seat is divided into an upper cavity and a lower cavity by the valve port; the valve core seat is inserted into the upper cavity and divides the upper cavity into a first upper cavity and a second upper cavity surrounding the first upper cavity, and a side wall of the valve core seat is provided with a flow opening via which the first upper cavity is in communication with the second upper cavity; and the second upper cavity and the lower cavity are in communication with the two connection ports respectively. 11. The electronic expansion valve according to claim 3, wherein the two connection ports and the valve port are all provided in the valve seat, and an inner cavity of the valve seat is divided into an upper cavity and a lower cavity by the valve port; the valve core seat is inserted into the upper cavity and divides the upper cavity into a first upper cavity and a second upper cavity surrounding the first upper cavity, and a side wall of the valve core seat is provided with a flow opening via which the first upper cavity is in communication with the second upper cavity; and the second upper cavity and the lower cavity are in communication with the two connection ports respectively. 12. The electronic expansion valve according to claim 4, wherein the two connection ports and the valve port are all provided in the valve seat, and an inner cavity of the valve seat is divided into an upper cavity and a lower cavity by the valve port; the valve core seat is inserted into the upper cavity and divides the upper cavity into a first upper cavity and a second upper cavity surrounding the first upper cavity, and a side wall of the valve core seat is provided with a flow opening via which the first upper cavity is in communication with the second upper cavity; and the second upper cavity and the lower cavity are in communication with the two connection ports respectively. 13. The electronic expansion valve according to claim 5, wherein the two connection ports and the valve port are all provided in the valve seat, and an inner cavity of the valve seat is divided into an upper cavity and a lower cavity by the valve port; the valve core seat is inserted into the upper cavity and divides the upper cavity into a first upper cavity and a second upper cavity surrounding the first upper cavity, and a side wall of the valve core seat is provided with a flow opening via which the first upper cavity is in communication with the second upper cavity; and the second upper cavity and the lower cavity are in communication with the two connection ports respectively. 14. The electronic expansion valve according to claim 2, wherein the valve stem component further comprises a sealing ring, and the sealing ring is press-fitted between the valve stem and the valve core, and a lower end surface of the sealing ring forms the sealing surface. 15. The electronic expansion valve according to claim 3, wherein the valve stem component further comprises a sealing ring, and the sealing ring is press-fitted between the valve stem and the valve core, and a lower end surface of the sealing ring forms the sealing surface. 16. The electronic expansion valve according to claim 4, wherein the valve stem component further comprises a sealing ring, and the sealing ring is press-fitted between the valve stem and the valve core, and a lower end surface of the sealing ring forms the sealing surface. 17. The electronic expansion valve according to claim 5, wherein the valve stem component further comprises a sealing ring, and the sealing ring is press-fitted between the valve stem and the valve core, and a lower end surface of the sealing ring forms the sealing surface. | This application claims priority to Chinese Patent Application No. 201510490496.X, titled “ELECTRONIC EXPANSION VALVE”, filed with the Chinese State Intellectual Property Office on Aug. 11, 2015, the entire disclosure of which is incorporated herein by reference. FIELD The present application relates to the technical field of fluid control components, and in particular to an electronic expansion valve. BACKGROUND An electronic expansion valve, as an important component for constituting a refrigeration system, is widely used in a large refrigeration unit, a large cold storage, a supermarket freezer and so on. A working process of the electronic expansion valve is generally as follows. An opening degree of a valve stem is adjusted with energizing or de-energizing of a motor, thus the flow rate of a refrigerant is adjusted. A common electronic expansion valve includes a valve seat and a valve stem. Typically, the valve seat is provided with a valve port and two connection ports. The two connection ports may be communicated through the valve port. The valve stem has a sealing surface which is capable of fitting against an end surface, at the valve port, of the valve seat to seal the valve port. The valve stem is located in a valve cavity of the valve seat. Driven by the motor, the valve stem is axially movable along the valve cavity to open or close the valve port, so as to communicate or cut off the two connection ports. Normally, a connection port in communication with the valve port may generate an axially upward acting force on the sealing surface of the valve stem. To avoid leakage at the valve port due to untight sealing, the valve stem may be provided with an axial through hole to allow an upper end and a lower end of the valve stem to be in the same pressure zone which generates an axially downward acting force on the upper end of the valve stem to balance forces received by the valve stem, thereby ensuring tightness. However, the upper end of the valve stem has a pressure receiving area greater than that of the lower end of the valve stem. As a result of the above, the valve stem is subjected to an axially downward acting force, which affects adversely valve opening capability of the electronic expansion valve. In view of this, it is a technical issue to be addressed by the person skilled in the art to improve the structure of the electronic expansion valve, which ensures not only valve port tightness but also valve opening capability. SUMMARY An object of the present application is to provide an electronic expansion valve which can ensure both valve port tightness and a valve opening capability. To address the above technical issue, it is provided according to the present application an electronic expansion valve which includes: a valve seat component including a valve seat and a valve core seat inserted into the valve seat; a valve stem component which is axially movable along a core cavity of the valve core seat to open or close a valve port for communicating or cutting off two connection ports of the electronic expansion valve; the valve stem component has an axial through hole in communication with the valve port and a sealing surface which is capable of fitting against the valve port to seal the valve port; and specifically, the valve stem component includes a valve stem and a valve core fixed to a lower end of the valve stem, and the valve stem is a cylindrical body and includes a small-diameter segment cylinder and a large-diameter segment cylinder close to the valve port, and a first gap is provided between the large-diameter segment cylinder and the valve core seat, and a second gap is provided between the valve core and the valve port. In the electronic expansion valve according to the present application, a first gap is provided between the large-diameter segment cylinder and the valve core seat, to form a first throttle passage. A second gap is provided between the valve core and the valve port, to form a second throttle passage. As such, when the valve port is opened with a small opening, due to throttling effects of the first throttle passage and the second throttle passage, a medium pressure zone having a pressure between a refrigerant inlet pressure and a refrigerant outlet pressure may be formed at the valve port. Formation of the medium pressure zone may equalize properly an air pressure to which the valve stem component is subjected, thereby improving the valve opening capability while ensuring the tightness. Each of the sizes of the first gap and the size of the second gap is in a preset range, which allows a medium pressure zone having a pressure between a refrigerant inlet pressure and a refrigerant outlet pressure to be formed at the valve port between the first gap and the second gap at the start of valve opening. The first gap has a size ranging from 0.1 mm to 0.5 mm. The second gap has a size ranging from 0.1 mm to 0.8 mm. The large-diameter segment cylinder has an axial dimension less than the axial dimension of the valve core. The two connection ports and the valve port are all provided in the valve seat, and an inner cavity of the valve seat is divided into an upper cavity and a lower cavity by the valve port; the valve core seat is inserted into the upper cavity and divides the upper cavity into a first upper cavity and a second upper cavity surrounding the first upper cavity, and a side wall of the valve core seat is provided with a flow opening via which the first upper cavity is in communication with the second upper cavity; and the second upper cavity and the lower cavity are in communication with the two connection ports respectively. The flow opening has a circumferential dimension tapering downward in an axial direction of the valve core seat. A lower portion of the flow opening is in a V-shape. The valve stem component further includes a sealing ring, and the sealing ring is press-fitted between the valve stem and the valve core, and a lower end surface of the sealing ring forms the sealing surface. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic view showing the structure of an electronic expansion valve according to an embodiment of the present application; FIG. 2 is a schematic view showing the structure of a valve seat component in FIG. 1; FIG. 3 is a schematic view showing the structure of a valve core seat in FIG. 2; FIG. 4 is a schematic view showing the structure of a valve stem component in FIG. 1; FIG. 5 is a partially enlarged view of a part A in FIG. 1; FIG. 6 is a schematic view showing assembly of a valve stem component with a position-limiting sleeve in FIG. 1; FIG. 7 is a schematic structural view showing the components in FIG. 6 in an assembled state; FIG. 8 is a partially enlarged view of a part B in FIG. 1; FIG. 9 is a schematic structural view showing cooperation of a gear system with a valve stem component in FIG. 1; FIG. 10 is a schematic view showing the structure of the gear system in FIG. 9; FIG. 11 is a schematic view showing the structure of the valve stem component in FIG. 9; and FIG. 12 is a schematic diagram showing forces of a valve stem component in FIG. 1. One-to-one correspondences between names of components and reference numerals in FIGS. 1 to 12 are as follows: 10. valve seat component, 11. valve seat, 11a. valve port, 11b. first upper cavity, 11c. second upper cavity, 11d. lower cavity, 12. valve core seat, 12a. flow opening, 12b. annular step surface, 13. first connection port pipe, 14. second connection port pipe; 20a. axial through hole, 20. valve stem component, 21. valve stem, 20b. sealing surface, 23. sealing ring, 211. small-diameter segment cylinder, 241. boss; 212a.large-diameter segment cylinder, 32. sealing washer, 22. valve core, 34. sliding-assist sheet; 24. snap, 41. gear, 31. position-limiting sleeve, 43. position-limiting lever; 33. retaining ring, 40. gear system, 42. screw rod, 50. motor. DETAILED DESCRIPTION OF EMBODIMENTS An aspect of the present application is to provide an electronic expansion valve which can ensure the tightness of a valve port and the valve opening capability. In order to make the person skilled in the art have a better understanding of solutions of the present application, the present application is described hereinafter in further detail in conjunction with the drawings and embodiments. Locality terms such as upper and lower referred to herein are all defined based on positions where parts in FIGS. 1 to 12 are located in the figures and based on relative positions between the parts, which is just for the purpose of descriptive clarity and convenience of technical solutions. It is to be understood that the locality terms used herein should not limit the scope claimed by the present application. Reference is made to FIG. 1 and FIG. 2. FIG. 1 is a schematic view showing the structure of an electronic expansion according to an embodiment of the present application, and FIG. 2 is a schematic view showing the structure of a valve seat component in FIG. 1. The electronic expansion valve includes a valve seat component 10 and a valve stem component 20. In this embodiment, the valve seat component 10 includes a valve seat 11 and a valve core seat 12. The valve seat 11 is provided with a valve port 11a, a first connection port and a second connection port. A first connection port pipe 13 and a second connection port pipe 14, connected to the first connection port and the second connection port respectively, are shown in FIGS. 1 and 2. An inner cavity of the valve seat 11 is divided into an upper cavity and a lower cavity 11d by the valve port 11a. The valve core seat 12 is mounted into the upper cavity in a plug-in manner, and divides the upper cavity into a first upper cavity 11b and a second upper cavity 11c surrounding the first upper cavity 11b. Apparently, a core cavity of the valve core seat 12 is just the first upper cavity 11b. A side wall of the valve core seat 12 is provided with a flow opening 12a via which the first upper cavity 11b is in communication with the second upper cavity 11c. The first connection port is in communication with the second upper cavity 11c, and the second connection port is in communication with the lower cavity 11d. The valve stem component 20 cooperates with the core cavity of the valve core seat 12, and is axially movable to open or close the valve port 11a, so as to communicate or cut off the first connection port and the second connection port. The valve stem component 20 has an axial through hole 20a in communication with the valve port 11a and a sealing surface 20b fitting against the valve port 11a to seal the valve port 11a. It may be understood that structure of the sealing surface 20b is fitted with the structure of the valve port 11a, and the sealing surface 20b may be a planar surface or a bevel as long as it can achieve sealing. It may be seen from FIG. 2 that, the valve port 11a is always in communication with the second connection port, that is, the second connection port is in communication with the axial through hole 20a of the valve stem component 20, and thus refrigerant in the second connection port pipe 14 is allowed to enter an upper cavity of the valve stem component 20 through the axial through hole 20a of the valve stem component 20. In order to ensure sealing, apparently, an inner wall of the valve core seat 12 is required to be sealed against the valve stem component 20, so as to ensure the upper cavity of the valve stem component 20 not to communicate with the first connection port through a gap between the valve stem component 20 and the side wall of the valve core seat 12, thereby ensuring that the first connection port can be in communication with the second connection port only after the valve port 11a is opened. Reference is made to FIG. 3, which is a schematic view showing the structure of a valve core seat in FIG. 2. The first connection port is in communication with the flow opening 12a of the valve core seat 12. Specifically, the flow opening 12a has a circumferential dimension tapering downward in an axial direction of the valve core seat 12. As such, when the valve stem component 20 is moved axially away from the valve port 11a, the first connection port may be in communication with the valve port 11a through the flow opening 12a, and as the valve stem component 20 is gradually moved upward, the area of the flow opening 12a available for the refrigerant to flow through is gradually increased, thereby achieving a function that the flow rate of the refrigerant is adjusted by axial movement of the valve stem component 20. In a specific solution, the flow opening 12a has a V shape. Of course, in practical setting, the shape of the flow opening 12a is not limited to the above shape, and may be designed specifically according to a curve of flow rate required practically and so on. Reference is made to FIG. 4, which is a schematic view showing the structure of a valve stem component in FIG. 1. The valve stem component 20 includes a valve stem 21 and a valve core 22 fixed to a lower end of the valve stem 21. The valve stem 21 is a cylindrical body, which includes a small-diameter segment cylinder 211 and a large-diameter segment cylinder 212 close to the valve port 11a. The small-diameter segment cylinder 211 is kept sealed against the valve core seat 12. In this embodiment, a sealing ring 23 is further press-fitted between the large-diameter segment cylinder 212 and the valve core 22, and a lower end surface of the sealing ring 23 is capable of fitting against an end surface, at the valve port 11a, of the valve seat 11 to seal the valve port. It may be understood that the valve core 22 is inserted into the lower cavity 11d after assembly. It is to be noted that, in practical use, the sealing ring 23 may not be provided and the lower end surface of the large-diameter segment cylinder 212 forms the sealing surface 20b sealing against the end surface, at the valve port 11a, of the valve seat 11. Reference is made to FIG. 5 which is a partially enlarged view of a part A in FIG. 1. A first gap h1 is provided between the large-diameter segment cylinder 212 and the valve core seat 12, so as to form a first throttle passage. A second gap h2 is provided between the valve core 22 and the valve port 11a, so as to form a second throttle passage. As such, when the valve is just opened and the valve port 11a is opened in a small degree, a medium pressure zone having a pressure between a refrigerant inlet pressure (the pressure of a high pressure zone) and a refrigerant outlet pressure (the pressure of a lower pressure zone) may be formed at the valve port 11a due to effects of the first throttle passage and the second throttle passage. Formation of the medium pressure zone may properly equalize an air pressure to which the valve stem component 20 is subjected, thereby improving valve opening capability while ensuring tightness. Apparently, throttling effects of the throttle passages are related to sizes of the first gap h1 and the second gap h2, and the magnitude of the pressure of the formed medium pressure zone is also related to the sizes of the first gap h1 and the second gap h2 correspondingly. Specifically, in this embodiment, forces that are subjected by the valve stem component 20 may be understood with reference to FIG. 12. FIG. 12 is a schematic diagram showing forces being subjected by a valve stem component in FIG. 1. The valve stem component in FIG. 12 is simplified and shown schematically. As is shown in FIG. 12, a dotted line on a leftmost side indicates an inner wall of the valve core seat 12, and the first gap h1 is provided between the large-diameter segment cylinder 212 of the valve stem component 20 and the valve core seat 12, and the second gap h2 is provided between the valve core 22 and the valve port 11a; refrigerant enters from the first connection port wherein the pressure is P1, and the pressure at the second connection port is P3. Since the first connection port is in communication with the second upper cavity 11c, the pressure in the second upper cavity 11c is P1. A step surface of the valve stem 21 at a joint of the large-diameter segment cylinder 212 and the small-diameter segment cylinder 211 of the valve stem 21 is subjected to an acting force from the refrigerant at the first connection port, and an effective pressure receiving area is S1. Since the second connection port is in communication with the lower cavity 11d, a pressure in the lower cavity 11d is P3, that is, a bottom of the valve core 22 is subjected to the pressure P3 and an effective pressure receiving area that the bottom portion of the valve core 22 is subjected to an acting force from the refrigerant at the second connection port is S3. In addition, since the valve stem component 20 has the axial through hole 20a, a top end of the valve stem component 20 is also subjected to a pressure P3, and a corresponding effective pressure receiving area is S4. Apparently, the effective pressure receiving area S4 is greater than the effective pressure receiving area S3 at the bottom portion of the valve core 22. As is described before, when the valve stem component 20 is moved upward axially and the valve port is caused to be opened in a small degree, a medium pressure zone, which has a pressure P2, is formed between the first throttle passage and the second throttle passage. An end surface (that is, the end surface forming the sealing surface for sealing the valve port 11a) of the large-diameter segment cylinder 212, where the large-diameter segment cylinder 212 is in cooperation with the valve core 22, is subjected to an acting force from the medium pressure zone, and a corresponding effective pressure receiving area is S2. Apparently, the effective pressure receiving area S2 is greater than the effective pressure receiving area S1 for receiving a pressure from the refrigerant at the first connection port described above. As is analyzed above, the valve stem component 20 subjects a force F=P1S1−P2S2+P3S4−P3S3. It may be seen from FIG. 12 that S1+S4=S2+S3, and it may be derived from the equation, in combination with the above equation, that: the valve stem component 20 subjects the force F=(P1−P3)S1−(P2−P3)S2, wherein S1<S2. Since P1>P2>P3, P1−P3>P2−P3. Therefore, by controlling the magnitude of P2, the force F subjected by the valve stem component 20 is allowed to be close to zero, and thus valve opening resistance is reduced and in this case the valve stem component 20 is no more subjected to an axially upward acting force, and the tightness can be further ensured. Compared with the conventional technology, the electronic expansion valve according to this embodiment is additionally provided with the first throttle passage and the second throttle passage, such that a medium pressure zone is formed at the valve port 11a when the valve port 11a is opened in a small degree. By controlling the pressure of the medium pressure zone, the forces subjected by the valve stem component 20 can be balanced, thereby reducing the valve opening resistance and improving the valve opening capability. It may be understood that in that case that the refrigerant flows in a reverse direction to the direction described above, force analysis of the valve stem component 20 is similar to the force analysis described above. The magnitude of the pressure in the medium pressure zone is related to the sizes of the first throttle passage and the second throttle passage. In a solution, the first gap h1 between the large-diameter segment cylinder 212 and the valve core seat 12 may be in a range of 0.1 mm to 0.5 mm. In a solution, the second gap h2 between the valve core 22 and the valve port 11a may be in a range of 0.1 mm to 0.8 mm. In application, the first gap h1 and the second gap h2 can be set depending on practical demands. The first gap h1 and the second gap h2 cannot be too small, so as to avoid occurrence of a jamming phenomenon during valve action. The first gap h1 and the second gap h2 cannot be too large either, so as to avoid failing to function throttling. In a further solution, the large-diameter segment cylinder 212 has an axial size less than that of the valve core 22. The pressure P2 of the medium pressure zone is related to lengths of the formed throttling passages in addition to the sizes of the gaps. If the first gap h1 is constant, as the length (i.e., an axial size of the large-diameter segment cylinder 212) of the first throttle passage reduces, a pressure gradient between the pressure P1 of the high pressure zone and the pressure P2 of the medium pressure zone may be smaller, i.e., a pressure difference between P1 and P2 may be smaller, which can further reduce an axial air pressure that impedes valve opening of the valve stem component 20, thereby facilitating improving the valve opening performance. For each of the embodiments described above, one of the inner wall of the valve core seat 12 and an outer wall of the valve stem component 20 may be provided with a mounting groove in which a sealing washer 32 is provided. The sealing washer 32 allows good tightness between the valve stem component 20 and the valve core seat 12. It is understood in conjunction with FIGS. 2 to 3 and FIGS. 6 to 8 that in a solution, the core cavity of the valve core seat 12 is in a form of a stepped hole, forming an annular step surface 12b facing a motor 50. The electronic expansion valve also includes a position-limiting sleeve 31 which is inserted into an stepped hole of the valve core seat 12. An upper end portion of the position-limiting sleeve 31 has an annular radial boss which is disposed on an upper end surface of the valve core seat 12, in this case, the inner wall of the valve core seat 12, an end surface, facing the valve port 11a, of the position-limiting sleeve 31 and the annular step surface 12b of the valve core seat 12 form the mounting groove, and the sealing washer 32 may be placed in the mounting groove. Such a construction facilitates mounting the sealing washer 32. The valve stem component 20 may be fitted into the valve core seat 12 first, and the sealing washer 32 and the position-limiting sleeve 31 are successively mounted into the valve core seat 12. Alternatively, as is shown in FIG. 6, after the sealing washer 32 and the position-limiting sleeve 31 are fitted to the valve stem component 20 to form an integral body, the integral body is mounted into the valve core seat 12. Of course, it is also possible that the mounting groove is provided in the valve stem component 20, however, in view of the strength and design requirements of the valve stem component 20, the mounting groove is preferably provided in the valve core seat 12. Furthermore, a retaining ring 33 may be further provided between the sealing washer 32 and the annular step surface 12b. The retaining ring 33 is provided such that the sealing washer 32 sliding out of the mounting groove during axial movement of the valve stem component 20 can be prevented. Furthermore, an annular sliding-assist sheet 34 is further provided in the mounting groove, and the sliding-assist sheet 34 is in contact with the outer wall of the valve stem component 20. The sealing washer 32 is located between the sliding-assist sheet 34 and the inner wall of the valve core seat 12. When there is a differential pressure between the first connection port and the second connection port, the sealing washer 32 is squeezed to deform by a pressure. The sliding-assist sheet 34 is capable of catching a squeezing force of the sealing washer 32 and fitting with the outer wall of the valve stem component 20 tightly, which ensures a valve body will not leak. In addition, the sliding-assist sheet 34 is provided such that frictional resistance in the axial movement of the valve stem component 20 is also reduced greatly. In the case that the mounting groove is formed by cooperation of the position-limiting sleeve 31 and the valve core seat 12, the assembled position-limiting sleeve 31 and the valve core seat 12 are required to be kept relatively fixed to each other, and may be fixed in a manner such as welding and threaded connection. In this embodiment, a component for driving the valve stem component 20 to move axially is a gear system 40, which is understood in conjunction with FIGS. 9 to 11. The gear system 40 includes a gear 41 and a screw rod 42. A motor 50 of the electronic expansion valve drives the gear 41 of the gear system 40 to rotate. The screw rod 42 rotates as the gear 41 rotates. The screw rod 42 is threadedly connected with the valve stem component 20. After the valve stem component 20 is positioned circumferentially, rotation of the screw rod 42 may be converted into the axial movement of the valve stem component 20. In order to circumferentially positioning the valve stem component 20, the gear system 40 further includes multiple position-limiting levers 43 for restricting the valve stem component 20 from rotating circumferentially. An upper end of the valve stem component 20 is provided with a snap 24. A boss 241 of the snap 24 is stuck between two position-limiting levers 43, and since positions of the multiple position-limiting levers 43 are fixed, the snap 24 cannot rotate, thus circumferential rotation of the valve stem component 20 is restricted, which allows the valve stem component 20 to move only in an axial direction. On the basis of this, the position-limiting levers 43 of the gear system 40 may press the above position-limiting sleeve 31 tightly against the upper end surface of the valve core seat 12 and realize the fixing of the position-limiting sleeve 31 and the valve core seat 12, which is simple and reliable and makes replacement of members such as the position-limiting sleeve 31 and the sealing washer 32 more convenient. The electronic expansion valve according to the present application is described above in detail. Specific examples are applied herein to set forth principles and embodiments of the present application, and description of the above embodiments is only used to aid in understanding methods and core ideas of the present application. It should be noted that, for the person skilled in the art, various improvements and modifications can be further made to the present application without departing from principles of the present application, and these improvements and modifications also fall within the scope of claims of the present application. | <SOH> BACKGROUND <EOH>An electronic expansion valve, as an important component for constituting a refrigeration system, is widely used in a large refrigeration unit, a large cold storage, a supermarket freezer and so on. A working process of the electronic expansion valve is generally as follows. An opening degree of a valve stem is adjusted with energizing or de-energizing of a motor, thus the flow rate of a refrigerant is adjusted. A common electronic expansion valve includes a valve seat and a valve stem. Typically, the valve seat is provided with a valve port and two connection ports. The two connection ports may be communicated through the valve port. The valve stem has a sealing surface which is capable of fitting against an end surface, at the valve port, of the valve seat to seal the valve port. The valve stem is located in a valve cavity of the valve seat. Driven by the motor, the valve stem is axially movable along the valve cavity to open or close the valve port, so as to communicate or cut off the two connection ports. Normally, a connection port in communication with the valve port may generate an axially upward acting force on the sealing surface of the valve stem. To avoid leakage at the valve port due to untight sealing, the valve stem may be provided with an axial through hole to allow an upper end and a lower end of the valve stem to be in the same pressure zone which generates an axially downward acting force on the upper end of the valve stem to balance forces received by the valve stem, thereby ensuring tightness. However, the upper end of the valve stem has a pressure receiving area greater than that of the lower end of the valve stem. As a result of the above, the valve stem is subjected to an axially downward acting force, which affects adversely valve opening capability of the electronic expansion valve. In view of this, it is a technical issue to be addressed by the person skilled in the art to improve the structure of the electronic expansion valve, which ensures not only valve port tightness but also valve opening capability. | <SOH> SUMMARY <EOH>An object of the present application is to provide an electronic expansion valve which can ensure both valve port tightness and a valve opening capability. To address the above technical issue, it is provided according to the present application an electronic expansion valve which includes: a valve seat component including a valve seat and a valve core seat inserted into the valve seat; a valve stem component which is axially movable along a core cavity of the valve core seat to open or close a valve port for communicating or cutting off two connection ports of the electronic expansion valve; the valve stem component has an axial through hole in communication with the valve port and a sealing surface which is capable of fitting against the valve port to seal the valve port; and specifically, the valve stem component includes a valve stem and a valve core fixed to a lower end of the valve stem, and the valve stem is a cylindrical body and includes a small-diameter segment cylinder and a large-diameter segment cylinder close to the valve port, and a first gap is provided between the large-diameter segment cylinder and the valve core seat, and a second gap is provided between the valve core and the valve port. In the electronic expansion valve according to the present application, a first gap is provided between the large-diameter segment cylinder and the valve core seat, to form a first throttle passage. A second gap is provided between the valve core and the valve port, to form a second throttle passage. As such, when the valve port is opened with a small opening, due to throttling effects of the first throttle passage and the second throttle passage, a medium pressure zone having a pressure between a refrigerant inlet pressure and a refrigerant outlet pressure may be formed at the valve port. Formation of the medium pressure zone may equalize properly an air pressure to which the valve stem component is subjected, thereby improving the valve opening capability while ensuring the tightness. Each of the sizes of the first gap and the size of the second gap is in a preset range, which allows a medium pressure zone having a pressure between a refrigerant inlet pressure and a refrigerant outlet pressure to be formed at the valve port between the first gap and the second gap at the start of valve opening. The first gap has a size ranging from 0.1 mm to 0.5 mm. The second gap has a size ranging from 0.1 mm to 0.8 mm. The large-diameter segment cylinder has an axial dimension less than the axial dimension of the valve core. The two connection ports and the valve port are all provided in the valve seat, and an inner cavity of the valve seat is divided into an upper cavity and a lower cavity by the valve port; the valve core seat is inserted into the upper cavity and divides the upper cavity into a first upper cavity and a second upper cavity surrounding the first upper cavity, and a side wall of the valve core seat is provided with a flow opening via which the first upper cavity is in communication with the second upper cavity; and the second upper cavity and the lower cavity are in communication with the two connection ports respectively. The flow opening has a circumferential dimension tapering downward in an axial direction of the valve core seat. A lower portion of the flow opening is in a V-shape. The valve stem component further includes a sealing ring, and the sealing ring is press-fitted between the valve stem and the valve core, and a lower end surface of the sealing ring forms the sealing surface. | F04B4922 | 20180202 | 20180913 | F04B4922 | 0 | CAHILL, JESSICA MARIE | ELECTRONIC EXPANSION VALVE | UNDISCOUNTED | 0 | ACCEPTED | F04B | 2,018 |
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15,750,842 | PENDING | POWER COORDINATION CONTROL SYSTEM, POWER COORDINATION CONTROL METHOD, AND NON-TRANSITORY STORAGE MEDIUM | Power coordination control systems (10a-10c) are provided with superimposed signal generation units (11a-11c), transmission units (12a-12c), receiving units (13a-13c) and connection relation estimation units (14a-14c). At the location of a utility consumer A (20), the superimposed signal generation unit (11a) generates a superimposed signal by superimposing a prescribed signal on a voltage supplied from a system (50). The transmission unit (12a) transmits the superimposed signal generated in the superimposed signal generation unit (11a) from the utility consumer A (20) to utility consumers B (30) and C (40). The receiving unit (13b) receives the superimposed signal at the location of the utility consumer B (30). The connection relation estimation units (14a-14c) estimate the connection relation between the utility consumer A (20) and the utility consumer B (30) on the basis of the receiving status of the superimposed signal and/or the received information received by the receiving units (13a-13c). | 1. A power coordination control system used for retrieving a connection relation between a first consumer and a second consumer connected to a first power distribution line system, the power coordination control system comprising: a superimposition signal generating unit that generates a superimposition signal acquired by superimposing a predetermined signal on a voltage supplied from the first power distribution line system in the first consumer; a transmission unit that transmits the superimposition signal generated by the superimposition signal generating unit from the first consumer to the second consumer; a receiving unit that receives the superimposition signal in the second consumer; and a connection relation estimating unit that estimates a connection relation between the first consumer and the second consumer on the basis of at least one of a receiving status of the superimposition signal and receiving information received by the receiving unit. 2. The power coordination control system according to claim 1, wherein the connection relation estimating unit estimates that the first consumer and the second consumer are connected to the first power distribution line system in a case in which the superimposition signal is received. 3. The power coordination control system according to claim 2, wherein the connection relation estimating unit estimates a power transmission distance between the first consumer and the second consumer in accordance with at least one of an attenuation rate of a signal intensity of the superimposition signal compared to a predetermined signal intensity, a delay time of the signal, and an S/N ratio. 4. The power coordination control system according to claim 1, wherein the connection relation estimating unit estimates that the second consumer are connected to a second power distribution line system other than the first power distribution line system in a case in which the superimposition signal is not received. 5. The power coordination control system according to claim 1, wherein the superimposition signal generating unit generates the superimposition signal by superimposing a predetermined high frequency component on a voltage supplied from the first power distribution line system. 6. The power coordination control system according to claim 1, wherein the superimposition signal generating unit generates the superimposition signal to which at least one of positional information and identification information of the first consumer is assigned. 7. The power coordination control system according to claim 1, further comprising a matching unit that determines a supply destination of surplus electric power generated in the first consumer or the second consumer on the basis of a result of the estimation performed by the connection relation estimating unit in a case in which the superimposition signals transmitted from a plurality of the first consumers are received. 8. The power coordination control system according to claim 7, wherein the matching unit performs supply of surplus electric power by combining the first consumer and the second consumer having low attenuation rates of the signal intensities of the superimposition signals, short delay times of the signals, or high S/N ratios according to a result of the estimation performed by the connection relation estimating unit. 9. A power coordination control method used for retrieving a connection relation between a first consumer and a second consumer connected to a first power distribution line system, the power coordination control method comprising: a superimposition signal generating step of generating a superimposition signal acquired by superimposing a predetermined signal on a voltage supplied from the first power distribution line system in the first consumer; a transmission step of transmitting the superimposition signal generated in the superimposition signal generating step from the first consumer to the second consumer; a receiving step of receiving the superimposition signal in the second consumer; and a connection relation estimating step of estimating a connection relation between the first consumer and the second consumer on the basis of at least one of a status of the superimposition signal received in the receiving step and receiving information received in the receiving step. 10. A non-transitory storage medium for storing a power coordination control program used for retrieving a connection relation between a first consumer and a second consumer connected to a first power distribution line system, wherein the power coordination control program causing a computer to execute a power coordination control method comprising: a superimposition signal generating step of generating a superimposition signal acquired by superimposing a predetermined signal on a voltage supplied from the first power distribution line system in the first consumer; a transmission step of transmitting the superimposition signal generated in the superimposition signal generating step from the first consumer to the second consumer; a receiving step of receiving the superimposition signal in the second consumer; and a connection relation estimating step of estimating a connection relation between the first consumer and the second consumer on the basis of at least one of a status of the superimposition signal received in the receiving step and receiving information received in the receiving step. 11. The power coordination control system according to claim 2, wherein the superimposition signal generating unit generates the superimposition signal by superimposing a predetermined high frequency component on a voltage supplied from the first power distribution line system. 12. The power coordination control system according to claim 3, wherein the superimposition signal generating unit generates the superimposition signal by superimposing a predetermined high frequency component on a voltage supplied from the first power distribution line system. 13. The power coordination control system according to claim 2, wherein the superimposition signal generating unit generates the superimposition signal to which at least one of positional information and identification information of the first consumer is assigned. 14. The power coordination control system according to claim 3, wherein the superimposition signal generating unit generates the superimposition signal to which at least one of positional information and identification information of the first consumer is assigned. 15. The power coordination control system according to claim 5, wherein the superimposition signal generating unit generates the superimposition signal to which at least one of positional information and identification information of the first consumer is assigned. 16. The power coordination control system according to claim 2, further comprising a matching unit that determines a supply destination of surplus electric power generated in the first consumer or the second consumer on the basis of a result of the estimation performed by the connection relation estimating unit in a case in which the superimposition signals transmitted from a plurality of the first consumers are received. 17. The power coordination control system according to claim 3, further comprising a matching unit that determines a supply destination of surplus electric power generated in the first consumer or the second consumer on the basis of a result of the estimation performed by the connection relation estimating unit in a case in which the superimposition signals transmitted from a plurality of the first consumers are received. 18. The power coordination control system according to claim 4, further comprising a matching unit that determines a supply destination of surplus electric power generated in the first consumer or the second consumer on the basis of a result of the estimation performed by the connection relation estimating unit in a case in which the superimposition signals transmitted from a plurality of the first consumers are received. 19. The power coordination control system according to claim 5, further comprising a matching unit that determines a supply destination of surplus electric power generated in the first consumer or the second consumer on the basis of a result of the estimation performed by the connection relation estimating unit in a case in which the superimposition signals transmitted from a plurality of the first consumers are received. 20. The power coordination control system according to claim 6, further comprising a matching unit that determines a supply destination of surplus electric power generated in the first consumer or the second consumer on the basis of a result of the estimation performed by the connection relation estimating unit in a case in which the superimposition signals transmitted from a plurality of the first consumers are received. | TECHNICAL FIELD The present invention relates to a power coordination control system, a power coordination control method, and a power coordination control program. BACKGROUND ART In recent years, power generation devices (for example, photovoltaic power generation devices) generating electric power using renewable energy have been used. In Japan, since a surplus electric power purchase system was enacted, electric power generated by photovoltaic power generation devices, wind power generation devices, and the like can be sold to a power company. However, there are cases in which generated electric power cannot be sold to a power company. For example, there are cases in which the amount of electric power that has been purchased by a power company exceeds a predetermined amount of electric power that can be purchased by the power company (hereinafter, referred to as output curtailment). For this reason, there are cases in which a storage battery capable of temporarily storing electric power that cannot be sold is used by a consumer. However, in a case in which the amount of electric power generated by the power generation devices is larger than the remaining capacity of a storage battery, there are cases in which the electric power generated by the power generation devices is discarded. For example, in Patent Literature 1, a power management system is disclosed which predicts a power distribution network on the basis of various kinds of information including the positional information of consumers, the positional information of facilities, and map information and calculates surplus electric power of a predetermined district using the predicted power distribution network. CITATION LIST Patent Literature [Patent Literature 1] Japanese Patent Publication No. 5576498 SUMMARY OF INVENTION Technical Problem However, the conventional power management system described above has the following problems. In the power management system disclosed in the patent publication described above, a consumer in which surplus electric power is generated may not be able to find another consumer which belongs to the same power distribution network and has a small power transmission loss therebetween. Particularly, since information relating to the power distribution network is handled as confidential information, it is difficult to ascertain whether or not power distribution line systems of consumers are the same. An object of the present invention is to provide a power coordination control system, a power coordination control method, and a power coordination control program capable of efficiently circulating the surplus electric power by searching for consumers connected to the same power distribution network among a plurality of consumers. Solution to Problem A power coordination control system according to one embodiment of the first invention is a power coordination control system used for retrieving a connection relation between a first consumer and a second consumer connected to a first power distribution line system and includes a superimposition signal generating unit, a transmission unit, a receiving unit, and a connection relation estimating unit. The superimposition signal generating unit generates a superimposition signal acquired by superimposing a predetermined signal on a voltage supplied from the first power distribution line system in the first consumer. The transmission unit transmits the superimposition signal generated by the superimposition signal generating unit from the first consumer to the second consumer. The receiving unit receives the superimposition signal in the second consumer. The connection relation estimating unit estimates a connection relation between the first consumer and the second consumer on the basis of at least one of a receiving status of the superimposition signal and receiving information received by the receiving unit. Here, a superimposition signal acquired by superimposing a predetermined signal on a system voltage is generated by the first consumer and is transmitted to the second consumer, and a connection relation between the first consumer and the second consumer is estimated on the basis of at least one of a receiving status of the superimposition signal in the second consumer and receiving information received by the receiving unit. Here, the connection relation between the first consumer and the second consumer includes relations such as whether or not they are connected to the same power distribution line system and whether a power transmission distance is long or short in accordance with a connection to the same power distribution line system. In addition, for example, predetermined values for the signal intensities of the superimposition signals transmitted and/or received between the first consumer and the second consumer are preferably known in the first and second consumers. Accordingly, when the receiving status of the superimposition signal is detected by the connection relation estimating unit, the connection relation between the first consumer and the second consumer can be estimated by comparing the predetermined value of the corresponding signal intensity with the signal intensity of the received superimposition signal and acquiring an attenuation rate. In a consumer group configured by a plurality of consumers including the first and second consumers, the first consumer and the second consumer do not represent specific consumers but mean arbitrary consumers in the consumer group including the plurality of consumers. In addition, the first consumer and the second consumer are not limited to being connected to the same power distribution line system and include consumers connected to different power distribution line systems. Furthermore, each of the first consumer and the second consumer preferably includes a transmission unit and a receiving unit. Accordingly, for example, it can be estimated whether or not the second consumer is connected to the same power distribution line system as that of the first consumer and whether or not a power transmission distance is short in accordance with the receiving status of the superimposition signal in the second consumer. Here, for example, at least one of the first consumer and the second consumer is assumed to include a power supply device that supplies electric power and a load that consumes electric power. In such a case, by setting a consumer having the shortest power transmission distance from a consumer in which surplus electric power is generated among a plurality of consumers that have received the superimposition signals as a supply destination of the surplus electric power, the surplus electric power can be used by the consumer having a small power transmission loss. As a result, a consumer connected to the same power distribution network is retrieved from among the plurality of consumers, and surplus electric power can be mutually circulated efficiently. The power coordination control system according to the second invention is the power coordination control system according to the first invention, in which the connection relation estimating unit estimates that the first consumer and the second consumer are connected to the first power distribution line system in a case in which the superimposition signal is received. Here, based on whether or not the superimposition signal has been received by the second consumer, it is estimated whether or not the second consumer is connected to the same power distribution line system as that of the first consumer. Here, in a case in which the superimposition signal transmitted from the first consumer can be received by the second consumer, it is estimated that the first consumer and the second consumer have a relationship in which there is a small power transmission loss, in other words, a high likelihood of being connected to the same power distribution line system is estimated. In this way, in a case in which the superimposition signal transmitted from the first consumer can be received by the second consumer, it can be estimated that the first consumer and the second consumer are connected to the same power distribution line system. The power coordination control system according to the third invention is the power coordination control system according to the second invention, in which the connection relation estimating unit estimates a power transmission distance between the first consumer and the second consumer in accordance with at least one of an attenuation rate of a signal intensity of the superimposition signal compared to a predetermined signal intensity, a delay time of the signal, and an signal/noise ratio (S/N ratio). Here, in a case in which the superimposition signal is received by the second consumer, a distance (power transmission distance) between the first consumer and the second consumer on a power distribution line system is estimated in accordance with at least one of the attenuation rate of the signal intensity of the superimposition signal calculated by comparing the signal intensity of the received superimposition signal with the signal intensity of the superimposition signal at the time of transmission, the delay time of the signal, and the S/N ratio. Here, for example, in a case in which the superimposition signal transmitted from the first consumer is received with a signal intensity of 80% or more by the second consumer, a relation having a small power transmission loss, in other words, a high likelihood of there being a short power transmission distance in the same power distribution line system is estimated. On the other hand, for example, in a case in which the superimposition signal transmitted from the first consumer is received with a signal intensity of 30% or less by the second consumer, between the first consumer and the second consumer, a relation having a small power transmission loss, in other words, a high likelihood of there being a long power transmission distance even in the same power distribution line system is estimated. Accordingly, in a case in which the superimposition signal transmitted from the first consumer can be received by the second consumer, a relation with respect to a degree of a distance between the first consumer and the second consumer on the same power distribution line system can be estimated. Similarly, also in a case in which the delay time until the signal is received or the S/N ratio is used, a relation with respect to the degree of the distance between the first consumer and the second consumer on the same power distribution line system can be estimated. A power coordination control system according to the fourth invention is the power coordination control system according to any one of the first to third inventions, in which the connection relation estimating unit estimates that the first consumer and the second consumer are connected to a second power distribution line system other than the first power distribution line system in a case in which superimposition signal is not received. Here, it is estimated whether or not the second consumer and the first consumer are connected to the same power distribution line system based on whether the superimposition signal is received by the second consumer. Here, in a case in which the superimposition signal transmitted from the first consumer cannot be received by the second consumer, a relation of being incapable of transmitting/receiving signals, in other words, in which there is a high likelihood of being connected to a different power distribution line system is estimated. In this way, in a case in which the superimposition signal transmitted from the first consumer cannot be received by the second consumer, it can be estimated that the first consumer and the second consumer are connected to different power distribution line systems. A power coordination control system according to the fifth invention is the power coordination control system according to any one of the first to fourth inventions, in which the superimposition signal generating unit generates the superimposition signal by superimposing a predetermined high frequency component on a voltage supplied from the first power distribution line system. Here, a predetermined high frequency component is used as a signal superimposed on a voltage. In this way, by superimposing a high frequency component on a normal voltage, a superimposition signal can be easily generated. A power coordination control system according to the sixth invention is the power coordination control system according to any one of the first to fifth inventions, in which the superimposition signal generating unit generates a superimposition signal which has at least one of positional information and identification information of the first consumer. Here, when the superimposition signal is generated by the first consumer, at least one of the positional information and the identification information of the first consumer is attached. Accordingly, the second consumer that has received the superimposition signal can recognize a consumer from which the superimposition signal has been received. A power coordination control system according to the seventh invention is the power coordination control system according to any one of the first to sixth inventions and further includes a matching unit that determines a supply destination of surplus electric power generated in the first consumer or the second consumer on the basis of a result of the estimation performed by the connection relation estimating unit in a case in which the superimposition signals transmitted from a plurality of the first consumers are received. Here, for example, in a case in which the superimposition signal transmitted from the first consumer is received by the second consumer, the second consumer that has received the superimposition signal is matched with the first consumer. As a result, for example, in a case in which surplus electric power is generated in the first consumer, the surplus electric power can be efficiently used for the second consumer to which the electric power can be supplied without a large power transmission loss. A power coordination control system according to the eighth invention is the power coordination control system according to any one of the first to seventh inventions, in which the matching unit performs supplying of surplus electric power by combining the first consumer and the second consumer, both of which have low attenuation rates of the signal intensities of the superimposition signals, short delay times of the signals, or high S/N ratios according to a result of the estimation performed by the connection relation estimating unit. Here, for example, in a case in which a plurality of superimposition signals transmitted from a plurality of first consumers are received by the second consumer, the first consumer and the second consumer that can circulate electric power the most efficiently are matched on the basis of the magnitude of the attenuation rate of the signal intensity, the delay time of the signal, the S/N ratio or the like, as described above. As a result, for example, in a case in which the surplus electric power is generated in the first consumer, the second consumer having a smallest power transmission loss is matched with the first consumer, whereby the surplus electric power can be efficiently used. A power coordination control method according to the ninth invention is a power coordination control method used for retrieving a connection relation between a first consumer and a second consumer connected to a first power distribution line system and includes a superimposition signal generating step, a transmission step, a receiving step, and a connection relation estimating step. In the superimposition signal generating step, a superimposition signal acquired by superimposing a predetermined signal on a voltage supplied from the first power distribution line system is generated in the first consumer. In the transmission step, the superimposition signal generated in the superimposition signal generating step is transmitted from the first consumer to the second consumer. In the receiving step, the superimposition signal is received in the second consumer. In the connection relation estimating step, a connection relation between the first consumer and the second consumer is estimated on the basis of at least one of a status of the superimposition signal received in the receiving step and receiving information received in the receiving step. Here, a superimposition signal acquired by superimposing a predetermined signal on a system voltage is generated by the first consumer and is transmitted to the second consumer, and a connection relation between the first consumer and the second consumer is estimated on the basis of at least one of a receiving status of the superimposition signal in the second consumer and receiving information received in the receiving unit step. Here, the connection relation between the first consumer and the second consumer includes relations such as whether or not being connected to the same power distribution line system and whether a power transmission distance is long or short in accordance with a connection to the same power distribution line system. In addition, for example, the signal intensities of the superimposition signals transmitted and/or received between the first consumer and the second consumer are preferably known in the first and second consumers as predetermined values. Accordingly, when the receiving status of the superimposition signal is detected by the connection relation estimating step, the connection relation between the first consumer and the second consumer can be estimated by comparing the corresponding signal intensity of the predetermined value with the signal intensity of the received superimposition signal and acquiring an attenuation rate. In a consumer group configured by a plurality of consumers including the first and second consumers, the first consumer and the second consumer do not represent specific consumers but mean arbitrary consumers in the consumer group including the plurality of consumers. In addition, the first consumer and the second consumer are not limited to being connected to the same power distribution line system and include consumers connected to different power distribution line systems. Furthermore, each of the first consumer and the second consumer preferably can perform the transmission step and the receiving step. Accordingly, for example, it can be estimated whether or not the second consumer is connected to the same power distribution line system as that of the first consumer and whether or not a power transmission distance is short in accordance with the receiving status of the superimposition signal in the second consumer. Here, for example, at least one of the first consumer and the second consumer is assumed to include a power supply device supplying electric power and a load consuming electric power. In such a case, by setting a consumer having the shortest power transmission distance from a consumer in which the surplus electric power is generated among a plurality of consumers that have received the superimposition signals as a supply destination of the surplus electric power, the surplus electric power can be used by a consumer having a small power transmission loss. As a result, a consumer connected to the same power distribution network is retrieved from among the plurality of consumers, and surplus electric power can be mutually circulated efficiently. A power coordination control program according to the tenth invention is a power coordination control program used for retrieving a connection relation between a first consumer and a second consumer connected to a first power distribution line system and causes a computer to execute a power coordination control method including a superimposition signal generating step, a transmission step, a receiving step, and a connection relation estimating step. In the superimposition signal generating step, a superimposition signal acquired by superimposing a predetermined signal on a voltage supplied from the first power distribution line system is generated in the first consumer. In the transmission step, the superimposition signal generated in the superimposition signal generating step is transmitted from the first consumer to the second consumer. In the receiving step, the superimposition signal is received in the second consumer. In the connection relation estimating step, a connection relation between the first consumer and the second consumer is estimated on the basis of at least one of a status of the superimposition signal received in the receiving step and receiving information received in the receiving unit step. Here, a superimposition signal acquired by superimposing a predetermined signal on a system voltage is generated by the first consumer and is transmitted to the second consumer, and a connection relation between the first consumer and the second consumer is estimated on the basis of at least one of a receiving status of the superimposition signal in the second consumer and receiving information received in the receiving unit step. Here, the connection relation between the first consumer and the second consumer includes relations such as whether or not being connected to the same power distribution line system and whether a power transmission distance is long or short in accordance with a connection to the same power distribution line system. In addition, for example, the signal intensities of the superimposition signals transmitted/received between the first consumer and the second consumer are preferably known in the first and second consumers as predetermined values. Accordingly, when the receiving status of the superimposition signal is detected by the connection relation estimating step, the connection relation between the first consumer and the second consumer can be estimated by comparing the corresponding signal intensity of the predetermined value with the signal intensity of the received superimposition signal and acquiring an attenuation rate. Furthermore, in a consumer group configured by a plurality of consumers including the first and second consumers, the first consumer and the second consumer do not represent specific consumers but mean arbitrary consumers in the consumer group including the plurality of consumers. In addition, the first consumer and the second consumer are not limited to being connected to the same power distribution line system and include consumers connected to different power distribution line systems. Furthermore, each of the first consumer and the second consumer preferably can perform the transmission step and the receiving step. Accordingly, for example, it can be estimated whether or not the second consumer is connected to the same power distribution line system as that of the first consumer and whether or not a power transmission distance is short in accordance with the receiving status of the superimposition signal in the second consumer. Here, for example, at least one of the first consumer and the second consumer is assumed to include a power supply device supplying electric power and a load consuming electric power. In such a case, by setting a consumer having a shortest power transmission distance from a consumer in which surplus electric power is generated among a plurality of consumers that have received the superimposition signals as a supply destination of the surplus electric power, the surplus electric power can be used by a consumer having a small power transmission loss. As a result, a consumer connected to the same power distribution network is retrieved from among the plurality of consumers, and surplus electric power can be mutually circulated efficiently. Advantageous Effects of Invention According to a power coordination control system of the present invention, surplus electric power can be efficiently circulated by searching for consumers connected to the same power distribution network among a plurality of consumers. BRIEF DESCRIPTION OF DRAWINGS FIG. 1 is a block diagram illustrating connection relations between a plurality of consumers and a power distribution line system configuring a power coordination control system according to one embodiment of the present invention. FIG. 2 including parts (a), (b), and (c), which are block diagrams illustrating control blocks formed inside a smart meter of each consumer configuring the power coordination control system illustrated in FIG. 1. FIG. 3 is a flowchart illustrating the flow of a power coordination control method using the power coordination control system illustrated in FIG. 1. FIG. 4 is a diagram illustrating a signal intensity of a superimposition signal transmitted from a consumer A illustrated in FIG. 1. FIG. 5 is a graph illustrating changes in the signal intensity of a superimposition signal that is transmitted from the consumer A illustrated in FIG. 1 and is received by a consumer B connected to the same distribution line system. FIG. 6 is a graph illustrating a superimposition signal that is transmitted from the consumer illustrated in FIG. 1 and cannot be received by a consumer C connected to another distribution line system. FIG. 7 is a flowchart illustrating a flow determining a combination of consumers circulating surplus electric power after estimation of a connection relation illustrated in FIG. 3. DESCRIPTION OF EMBODIMENTS Power coordination control systems 10a to 10c according to embodiments of the present invention will be described with reference to FIGS. 1 to 7. Here, a consumer A20 (first consumer) appearing in the following description means a consumer that owns a power generation device (solar panel 21) and a storage battery (power storage device 23) and has surplus electric power generated in a predetermined time period. In addition, a consumer B30 (second consumer) and a consumer C40 mean consumers that own power generating devices (solar panels 31 and 41) and storage batteries (power storage devices 33 and 43) and are predicted to have electric power deficiencies and demand occurring in predetermined time periods. In addition, these consumers A20, B30, and C40 can switch between a side on which the surplus electric power is generated and a side on which the electric power is required, and the switching may be performed at predetermined time intervals. Here, a consumer is, for example, an individual, a corporation, an organization, or the like having a contract with a power company and using electric power supplied from the power company through a system 50 (see FIG. 1) and, for example, includes an ordinary home (a detached house or an apartment), a company (an office, a factory, a facility, or the like), a local government, a government organization, and the like. In addition, a consumer includes a consumer providing electric power through in-house power generation and a consumer realizing a zero energy building (ZEB). In the following embodiments, for the convenience of description, a consumer A20 on a side generating a superimposition signal to be described later and consumers B30 and C40 on a side receiving this superimposition signal will be described as an example. However, in the present invention, the combination of the consumer A20 and the consumers B30, and C40 is not limited to a combination of one consumer-to-two consumers, and there may be a plurality of consumers, that is, three or more consumers to which superimposition signals are transmitted from one consumer A20. In the following embodiments, a system 50 (see FIG. 1) means a power system supplying electric power supplied from a power company to each consumer. In addition, in the following embodiments, each of smart meters 27, 37, and 47 (see FIG. 1) respectively means a measuring device that is installed in each consumer and is used for measuring a power generation amount, a power accumulation amount, and a power consumption amount, and for transmitting results of the measurements to a power company or the like using a communication function. By configuring the smart meters 27, 37, 47, the power company can accurately ascertain the power status of each of the consumers A20, B30, and C40 in real time and can achieve a meter reading operation automatically performed for each of predetermined periods. Furthermore, in the following embodiments, for example, in a case in which a consumer is an ordinary home, loads 24, 34, and 44 (see FIG. 1) mean power consumption bodies such as an air conditioner, a refrigerator, a microwave oven, a IH (Indirect Heating) cooking heater, a television set, and the like. In addition, for example, in a case in which a consumer is a company (a factory or the like), the loads mean power consumption bodies such as various facilities, air conditioning equipment, and the like installed in a factory. In addition, in the following embodiments, each of energy management systems 26, 36, and 46 (EMS; see FIG. 1) means a system that is installed in each consumer and is installed for reducing the amount of power consumption of each consumer. Embodiment 1 The power coordination control systems 10a to 10c according to this embodiment are systems that circulate surplus electric power by estimating connection relations between a plurality of consumers owning a power supply device and a power storage device. More specifically, the power coordination control systems 10a to 10c, as illustrated in FIG. 1, estimate connection relations between a consumer A20 (first consumer), a consumer B30 (second consumer), and a consumer C40 (second consumer) and circulate surplus power between the consumer A20 and the consumer B30. As illustrated in FIG. 1, solid lines represented inside the consumers A20, B30, and C40 represent the flows of information such as data, and dashed lines represent the flows of electricity. The configurations of the power coordination control systems 10a to 10c according to this embodiment will be described in a later stage in detail. (Consumer A) In this embodiment, the consumer A20, as illustrated in FIG. 1, is connected to the system 50 through a substation 51 and a switching unit 52a. The consumer A20 belongs to a consumer group 53a that is the same as that of the consumer B30 to be described later. Electric power is supplied to the consumers A20, B30, and the like belonging to the consumer group 53a from the system 50 through a common power distribution line system 54a. Then, in a case in which surplus electric power is generated in each of the consumers A20, B30, and the like belonging to the consumer group 53a, power is mutually circulated through the power distribution line system 54a. The consumer A20 generates a superimposition signal acquired by superimposing a predetermined high frequency component on a voltage supplied from the system 50 by using the superimposition signal generating unit 11a disposed in a smart meter 27 to be described later. Then, the consumer A20 transmits the generated superimposition signal to the other consumers B30 and C40 through a transmission unit 12a. As illustrated in FIG. 1, the consumer A20 includes: a solar panel (power generation device) 21; a photovoltaic power generation power conversion device (PCS) 22; a power generation power sensor 22a; a power storage device (storage battery) 23; a power-storage power sensor 23a; a load 24; a load power sensor 24a; a distribution board 25; an energy management system (EMS) 26; and a smart meter 27. The solar panel (power generation device) 21 is an device that generates electricity using a photo electromotive force effect using light energy of sunlight and is installed on a roof or the like of the consumer A20. The amount of power generation in the solar panel 21 can be predicted on the basis of information relating to hours of sunlight of the weather forecast. The photovoltaic power generation power conversion device (power conditioning system (PCS)) 22, as illustrated in FIG. 1, is connected to the solar panel 21 and converts a DC current generated in the solar panel 21 into an AC current. The power generation power sensor 22a, as illustrated in FIG. 1, is connected to the photovoltaic power generation power conversion device 22 and measures the amount of power generated by the solar panel 21. Then, the power generation power sensor 22a transmits a result of the measurement (the amount of generated power) to the EMS 26. The power storage device (storage battery) 23 is disposed for temporarily storing surplus electric power that has not been used by the load 24 from electric power generated by the solar panel 21. In this way, by storing remaining electric power in the power storage device 23 also in a case in which the amount of consumed power of the load 24 is small in a time period of a day in which electric power is generated by the solar panel 21, the wastefulness of discarding the generated electric power can be avoided. The power-storage power sensor 23a, as illustrated in FIG. 1, is connected to the power storage device 23 and measures the amount of electric power stored by the power storage device 23. Then, the power-storage power sensor 23a transmits a result of the measurement (the amount of stored electric power) to the EMS 26. The load 24, as described above, is a power consuming body such as an electric appliance such as an air conditioner or a refrigerator in an ordinary home or facilities or air conditioning equipment in a factory or the like and consumes electric power supplied from the system 50, electric power generated by the solar panel 21, and electric power stored by the power storage device 23. The load power sensor 24a, as illustrated in FIG. 1, is connected to the load 24 and measures the amount of electric power consumed by the load 24. Then, the load power sensor 24a transmits a result of the measurement (the amount of consumed electric power) to the EMS 26. The distribution board 25, as illustrated in FIG. 1, is connected to the power generation power sensor 22a, the power-storage power sensor 23a, the load power sensor 24a, and the smart meter 27. The distribution board 25 supplies the electric power generated by the solar panel 21 and the electric power stored by the power storage device 23 to the load 24. In addition, the distribution board 25 supplies surplus electric power generated in accordance with a time period to the system 50 through the smart meter 27. In this way, the consumer A20 can sell the surplus electric power to a power company. The energy management system (EMS) 26 is an energy management system disposed for reducing the amount of electric power consumed by the consumer A20 as described above and, as illustrated in FIG. 1, is connected to the sensors 22a, 23a, and 24a. In addition, the EMS 26 efficiently supplies the electric power generated by the solar panel 21 and the amount of power stored in the power storage device 23 to the load 24 by using detection results received from the sensors 22a, 23a, and 24a. In this way, the consumption amount of electric power supplied from the system 50 is reduced, and the power costs of the consumer A20 can be effectively reduced. The smart meter 27, as described above, measures the amount of electric power generated by the solar panel 21 owned by the consumer A20, the amount of stored power of the power storage device 23, and the amount of power consumption of the load 24. The smart meter 27, as illustrated in FIG. 1, is connected to the sensors 22a, 23a, and 24a through the distribution board 25. In addition, the smart meter 27 has a communication function (a transmission unit 12a and a receiving unit 13a (see FIG. 2)). In this way, the smart meter 27 transmits information relating to the amount of generated power, the amount of stored power, and the amount of consumed power of the consumer A20 to the power company. In addition, in this embodiment, the smart meter 27 includes the power coordination control system 10a. The configuration of the power coordination control system 10a will be described in a later stage in detail. In this embodiment, the consumer A20 will be described as a side that can supply surplus power to the outside in a predetermined time period. For this reason, in the consumer A20, currently or in a predetermined time period in the future, a sum of the amount of generated power using the solar panel 21 and the amount of stored power in the power storage device 23 is assumed to be larger than the amount of consumed power of the load 24. (Consumer B) In this embodiment, the consumer B30, as illustrated in FIG. 1, similar to the consumer A20, is connected to the system 50 through a substation 51 and a switching unit 52a. The consumer B30, as described above, belongs to the consumer group 53a that is the same as that of the consumer A20. The consumer B30, as described above, receives the superimposition signal generated by the superimposition signal generating unit 11b disposed inside the smart meter 27 of the consumer A20 using the receiving unit 13b (see FIG. 2) through the transmission unit 12a of the consumer A20. Then, the consumer B30 estimates a connection relation with the consumer A20 on the basis of the receiving status of the superimposition signal (for example, whether or not the superimposition signal has been received, the signal intensity of the received superimposition signal, and the like) using a connection relation estimating unit 14b. Here, the connection relation with the consumer A20 that is estimated by the consumer B30, for example, includes relations such as whether or not belonging to the same power distribution line system 54a and whether a distance in the power distribution line is long or short in the case of belonging to the same power distribution line system 54a. In this embodiment, as illustrated in FIG. 1, the consumer B30 in common with the consumer A20 is connected to the power distribution line system 54a. For this reason, the signal intensity of the superimposition signal transmitted from the consumer A20 is estimated to have a low attenuation rate when the superimposition signal is received by the consumer B30. The consumer B30, as illustrated in FIG. 1, includes: a solar panel (power generation device) 31; a photovoltaic power generation power conversion device (PCS) 32; a power generation power sensor 32a; a power storage device (storage battery) 33; a power-storage power sensor 33a; a load 34; a load power sensor 34a; a distribution board 35; an energy management system (EMS) 36; and a smart meter 37. The solar panel (power generation device) 31 is an device that generates electricity using a photo electromotive force effect using light energy of sunlight and is installed on a roof or the like of the consumer B30. The amount of power generation in the solar panel 31 can be predicted on the basis of information relating to hours of sunlight of the weather forecast. The photovoltaic power generation power conversion device (power conditioning system (PCS)) 32, as illustrated in FIG. 1, is connected to the solar panel 31 and converts a DC current generated in the solar panel 31 into an AC current. The power generation power sensor 32a, as illustrated in FIG. 1, is connected to the photovoltaic power generation power conversion device 32 and measures the amount of power generated by the solar panel 31. Then, the power generation power sensor 32a transmits a result of the measurement (the amount of generated power) to the EMS 36. The power storage device (storage battery) 33 is disposed for temporarily storing surplus electric power that has not been used by the load 34 among electric power generated by the solar panel 31. In this way, even in a case in which the amount of consumed power of the load 34 is small in a time period of a day time in which electric power is generated by the solar panel 31, remaining electric power is stored in the power storage device 33 and wastefulness of disposing the generated electric power can be avoided. The power-storage power sensor 33a, as illustrated in FIG. 1, is connected to the power storage device 33 and measures the amount of electric power stored by the power storage device 33. Then, the power-storage power sensor 33a transmits a result of the measurement (the amount of stored electric power) to the EMS 36. The load 34, as described above, is a power consumption bodies such as an electric appliance such as an air conditioner or a refrigerator in an ordinary home or facilities or air conditioning equipment in a factory or the like and consumes electric power supplied from the system 50, electric power generated by the solar panel 31, and electric power stored by the power storage device 33. The load power sensor 34a, as illustrated in FIG. 1, is connected to the load 34 and measures the amount of electric power consumed by the load 34. Then, the load power sensor 34a transmits a result of the measurement (the amount of consumed electric power) to the EMS 36. The distribution board 35, as illustrated in FIG. 1, is connected to the power generation power sensor 32a, the power-storage power sensor 33a, the load power sensor 34a, and the smart meter 37. The distribution board 35 supplies the electric power generated by the solar panel 31 and the electric power stored by the power storage device 33 to the load 34. In addition, the distribution board 35 supplies surplus electric power generated in accordance with a time period to the system 50 through the smart meter 37. In this way, the consumer B30 can sell the surplus electric power to a power company. The energy management system (EMS) 36 is an energy management system disposed for reducing the amount of electric power consumed by the consumer B30 as described above and, as illustrated in FIG. 1, is connected to the sensors 32a, 33a, and 34a. In addition, the EMS 36 efficiently supplies the electric power generated by the solar panel 31 and the amount of power stored in the power storage device 33 to the load 34 by using detection results received from the sensors 32a, 33a, and 34a. In this way, the consumption amount of electric power supplied from the system 50 is suppressed, and the power cost of the consumer B30 can be effectively reduced. The smart meter 37, as described above, measures the amount of electric power generated by the solar panel 31 owned by the consumer B30, the amount of stored power of the power storage device 33, and the amount of power consumption of the load 34. The smart meter 37, as illustrated in FIG. 1, is connected to the sensors 32a, 33a, and 34a through the distribution board 35. In addition, the smart meter 37 has a communication function (a transmission unit 12b and a receiving unit 13b (see FIG. 2)). In this way, the smart meter 37 transmits information relating to the amount of generated power, the amount of stored power, and the amount of consumed power of the consumer B30 to the power company. In addition, in this embodiment, the smart meter 37 includes the power coordination control system 10b. The configuration of the power coordination control system 10b will be described in a later stage in detail. In this embodiment, the consumer B30 will be described as a side that requires power supply from the outside in a predetermined time period. For this reason, in the consumer B30, currently or in a predetermined time period in the future, the amount of consumed power of the load 24 is assumed to be larger than a sum of the amount of generated power using the solar panel 31 and the amount of stored power in the power storage device 33. (Consumer C) In this embodiment, the consumer C40, as illustrated in FIG. 1, is connected to the system 50 through a substation 51 and a switching unit 52b. The consumer C40, as described above, belongs to a consumer group 53b that is different from that of the consumers A20 and B30. The consumer C40, as described above, receives the superimposition signal generated by the superimposition signal generating unit 11b disposed inside the smart meter 27 of the consumer A20 using the receiving unit 13c (see FIG. 2) through the transmission unit 12a of the consumer A20. Then, the consumer C40 estimates a connection relation with the consumer A20 on the basis of the receiving status of the superimposition signal (for example, whether or not the superimposition signal has been received, the signal intensity of the received superimposition signal, and the like) using a connection relation estimating unit 14c. Here, the connection relation with the consumer A20 that is estimated by the consumer C40, for example, includes relations such as whether or not belonging to the same power distribution line system and whether a distance in the power distribution line is long or short in the case of belonging to the same power distribution line system. In this embodiment, as illustrated in FIG. 1, the consumer C40 is connected to a power distribution line system 54b that is different from that of the consumer A20. For this reason, the signal intensity of the superimposition signal transmitted from the consumer A20 is estimated to have a high attenuation rate when the superimposition signal is received by the consumer C40, and it is estimated to be difficult to receive the superimposition signal. The consumer C40, as illustrated in FIG. 1, includes: a solar panel (power generation device) 41; a photovoltaic power generation power conversion device (PCS) 42; a power generation power sensor 42a; a power storage device (storage battery) 43; a power-storage power sensor 43a; a load 44; a load power sensor 44a; a distribution board 45; an energy management system (EMS) 46; and a smart meter 47. The solar panel 41, the photovoltaic power generation power conversion device 42; the power generation power sensor 42a, the power storage device 43; the power-storage power sensor 43a, the load 44, the load power sensor 44a, the distribution board 45, and the EMS 46 have functions similar to those owned by the consumers A20 and B30 described above. Thus, here, detailed description thereof will not be presented. The smart meter 47, as described above, measures the amount of electric power generated by the solar panel 41 owned by the consumer C40, the amount of stored power of the power storage device 43, and the amount of power consumption of the load 44. The smart meter 47, as illustrated in FIG. 1, is connected to the sensors 42a, 43a, and 44a through the distribution board 45. In addition, the smart meter 47 has a communication function (a transmission unit 12c and a receiving unit 13c (see FIG. 2)). In this way, the smart meter 47 transmits information relating to the amount of generated power, the amount of stored power, and the amount of consumed power of the consumer C40 to the power company. In addition, in this embodiment, the smart meter 47 includes the power coordination control system 10c. The configuration of the power coordination control system 10c will be described in a later stage in detail. (Configuration of Power Coordination Control Systems 10a to 10c) The power coordination control systems 10a to 10c according to this embodiment are systems for estimating mutual connection relations of the consumer groups 53a and 53b including a plurality of consumers and for circulating surplus electric power generated by the consumers A20 to C40 to consumers that can efficiently use the surplus electric power. The power coordination control systems 10a to 10c, as illustrated in FIG. 2, respectively include: superimposition signal generating units 11a to 11c; transmission units 12a to 12c; receiving units 13a to 13c; connection relation estimating units 14a to 14c; matching units 15a to 15c; and storage units 16a to 16c. The configurations of the power coordination control systems 10a, 10b, and 10c disposed inside the smart meters 27, 37, and 47 owned by the consumers A20 to C40 have the same function. Thus, in the following description, for the convenience of description, the configuration of the power coordination control system 10a disposed inside the smart meter 27 owned by the consumer A20 will be described as an example. Thus, detailed description of the configurations of the other power coordination control systems 10b and 10c will not be presented, and the configurations thereof are assumed to be similar to that of the power coordination control system 10a. The superimposition signal generating unit 11a generates a superimposition signal used for estimating connection relations between the consumer A20 and the other consumers B30 and C40. The superimposition signal is generated by superimposing a predetermined high frequency component (see FIG. 4) on a voltage supplied from the system 50. In this embodiment, the superimposition signal is generated by the superimposition signal generating unit 11a disposed inside the smart meter 27 owned by the consumer A20. The transmission unit 12a transmits a superimposition signal generated by the superimposition signal generating unit 11a to the receiving units 13b and 13c of the other consumers. In this embodiment, the superimposition signal is transmitted from the transmission unit 12a disposed inside the smart meter 27 owned by the consumer A20 to the other consumers B30 and C40. The receiving unit 13a receives a superimposition signal transmitted from the transmission unit 12b of the other consumer B30. In addition, in this embodiment, the superimposition signal transmitted from the consumer A20 is received by the receiving unit 13b of the consumer B30 connected to the same power distribution line system 54a (see FIG. 5). The connection relation estimating unit 14a estimates a connection relation with a consumer that has transmitted the superimposition signal in accordance with the receiving status of the superimposition signal received by the receiving unit 13a. For example, in this embodiment, the superimposition signal transmitted from the consumer A20 can be received by the receiving unit 13b of the consumer B30. For this reason, the consumer A20 and the consumer B30 are estimated to be connected to the same power distribution line system 54a and to have a connection relation having a low power transmission loss. On the other hand, the superimposition signal transmitted from the consumer A20 cannot be received by the receiving unit 13c of the consumer C40 (see FIG. 6). For this reason, the consumer A20 and the consumer C40 are estimated to be respectively connected to different power distribution line systems 54a and 54b and to have a connection relation having a high power transmission loss. The matching unit 15a matches a combination of the consumers A20 and B30 estimated by the connection relation estimating unit 14a to be connected to the common power distribution line system 54a. More specifically, a side transmitting a superimposition signal and a side receiving the superimposition signal that has been transmitted are matched as a combination of consumers that can transmit and receive electric power. In a case in which a superimposition signal transmitted from the consumer A20 is received by a plurality of consumers B30 and the like, the matching unit 15a determines a combination of consumers to be matched on the basis of the attenuation rate of the received superimposition signal for each consumer. In other words, in a case in which there is a plurality of consumers that can receive a superimposition signal, such consumers are estimated to be connected to the same power distribution line system 54a or to be connected to different power distribution line systems having a very close relation. In such a case, matching is performed with a consumer having a low attenuation rate of the superimposition signal prioritized among the plurality of consumers that can receive the superimposition signal. In this way, among a plurality of consumers that can receive a superimposition signal, a consumer of a connection relation estimated to have the smallest power transmission loss can be selected and matched. Accordingly, for example, the surplus electric power generated by the consumer A20 can be supplied to the consumer B30 of a connection relation having a smallest power transmission loss. As a result, surplus power generated within the consumer group 53a can be supplied to a consumer having the smallest power transmission loss, and accordingly, the surplus electric power can be effectively used. In addition, a combination of consumers performed by the matching unit 15a, for example, may be performed with a consumer such as a family member, a friend, an acquaintance, a public organization, or the like prioritized instead of being performed on the basis of the attenuation rate of the superimposition signal described above. The storage unit 16a stores information of a high frequency component and a system voltage used for the generation of a superimposition signal described above, the superimposition signal generated by the superimposition signal generating unit 11a, a transmission history of the transmission unit 12a, a receiving history of the receiving unit 13a, a result of the estimation made by the connection relation estimating unit 14a, a result of the combination made by the matching unit 15a, and the like. <Power Coordination Control Method> The power coordination control systems 10a to 10c according to this embodiment, by employing the configuration described above, perform power coordination connection control in accordance with a flowchart illustrated in FIG. 3. In Step S11, in the consumer A20, the superimposition signal generating unit 11a generates a superimposition signal acquired by superimposing a predetermined high frequency component on a voltage supplied from the system 50. Here, the superimposition signal generated by the superimposition signal generating unit 11a of the consumer A20, as illustrated in FIG. 4, is generated by superimposing a high frequency component on a system voltage in a state in which the positional information of the consumer A20 is assigned. In addition, in this embodiment, although a superimposition signal to which the positional information of the consumer A20 is assigned is generated, in a case in which a positional relation with the consumer A20 can be recognized, for example, in accordance with the attenuation rate of the signal intensity or a delay time, an S/N ratio, or the like of the receiving signal, the positional information of the consumer A20 does not need to be attached. In addition, the high frequency component to be superimposed on the system voltage illustrated in FIG. 4 is measured by the smart meter 27 owned by the consumer A20. Next, in Step S12, the consumer A20 transmits the generated superimposition signal to the other consumers B30, C40, and the like by using the transmission unit 12a. Next, in Step S13, the consumers B30 and C40 determine whether or not the receiving units 13b and 13c have received the superimposition signal transmitted from the transmission unit 12a of the consumer A20. Here, in a case in which the superimposition signal has been received, the process proceeds to Step S14. On the other hand, in a case in which the superimposition signal has not been received, the process proceeds to Step S18. Here, the consumer B30 that has received the superimposition signal can recognize a connection to the power distribution line system 54a in common with the consumer A20 from the receiving of the superimposition signal and the positional information of the consumer A20 attached to the superimposition signal. Nest, in Step S14, since the superimposition signal has been received by the receiving unit 13b of the consumer B30, the component superimposed on the system voltage is extracted from the received superimposition signal. Here, the component ΔV′ extracted from the superimposition signal received from the receiving unit 13b of the consumer B30, as illustrated in FIG. 5, is in a state in which the high frequency component (difference ΔV) illustrated in FIG. 4 is attenuated (ΔV>ΔV′). As a cause of this attenuation, a loss occurring at the time of transmitting electric power between the consumer A20 and the consumer B30 may be considered. In addition, the component extracted as a difference from the system voltage illustrated in FIG. 5 is measured by the smart meter 37 owned by the consumer B30. Next, in Step S15, the attenuation rate of the received superimposition signal (a component extracted therefrom) is calculated, and a power transmission distance on a power distribution line between the consumer A20 and the consumer B30 is estimated on the basis of this attenuation rate. Next, in Step S16, both of the information representing belonging to the common power distribution system line 54a and the information relating to the power transmission distance are transmitted from the transmission unit 12b of the consumer B30 to the receiving unit 13a of the consumer A20 on the basis of the receiving status of the superimposition signal with being superimposed on the system voltage. Next, in Step S17, it can be recognized that the transmitted superimposition signal is received by the consumer B30 connected to the same power distribution line system 54a by using the signal transmitted from the consumer B30. In this way, it can be estimated that the consumer A20 and the consumer B30 are consumers belonging to the consumer group 53a connected to the common power distribution line system 54a. Accordingly, in a case in which the surplus electric power is generated in the consumer A20 or the consumer B30, it can be mutually circulated between the consumers having a small power transmission loss. On the other hand, in Step S18, as illustrated in FIG. 6, since the receiving unit 13c of the consumer C40 could not receive (extract) a component superimposed on the superimposition signal, the consumer C cannot respond to the consumer A by superimposing the received information on the system voltage. A result of the measurement illustrated in FIG. 6 is acquired through the measurement performed by the smart meter 47 owned by the consumer C40. Here, a case may be considered in which the consumer A20 that has transmitted the superimposition signal and the consumer C40 are connected to a different power distribution line system 54b because of not receiving the superimposition signal in the consumer C40. In other words, since the consumers A20 and C40 are connected to the different power distribution line systems 54a and 54b, the high frequency component superimposed in the superimposition signal is estimated to be attenuated and disappear due to an increase in the power transmission loss at the time of passing through a columnar transformer (not illustrated in the drawing) or the like. In this way, the consumer A20 can recognize that the transmitted superimposition signal could not be received by the consumer C40. Accordingly, in the consumer A20, even in a case in which surplus electric power is generated, if the surplus electric power is supplied to the consumer C40, the power transmission loss is large, and thus, it can be recognized that a part or the whole surplus electric power attenuates. As a result, the consumer A20 compares the consumer B30 and the consumer C40, to which the superimposition signal has been transmitted, with each other and can configure the consumer B30 to which electric power can be efficiently transmitted as a supply destination or a supply source of the surplus electric power. In addition, in the storage unit 16a disposed inside the smart meter 27 owned by the consumer A20, various kinds of information included in a reply to the superimposition signal received from the consumer B30 is stored. <Matching Method> The power coordination control systems 10a to 10c, according to this embodiment, employing the configuration as described above, may match a combination of consumers that are a supply source and a supply destination of the surplus electric power between the consumers A20 and B30 both of which the connection relation therebetween is estimated in accordance with the flowchart illustrated in FIG. 7. In other words, in Step S21, it is determined whether or not the surplus electric power is generated by the consumer A20 that has received the reply of the superimposition signal from the consumer B30. The presence or absence of the surplus electric power determined here may be determined in accordance with the power supply demand status at the current time point or may be determined as an estimated value in accordance with the power supply demand status inside the consumer A20 in a predetermined time period. Here, in a case that the surplus electric power is generated in the consumer A20, the process proceeds to Step S22. The prediction of the amount of power supply in the future power supply and demand may be performed using data of hours of sunlight or the like of the weather forecast as power may be generated by using the solar panels 21 and 31 owned by the consumers A20, B30, and the like. In addition, the prediction of the amounts of power supply using the power storage devices 23 and 33 may be performed using the current amounts of power storage using the power storage devices 23 and 33. On the other hand, the prediction of the amounts of power consumption in the future power supply and demand may be performed on the basis of data of life patterns or the like of the consumers A20 and B30. Next, in Step S22, it is determined whether or not there is a plurality of consumers B30 and the like connected to the same power distribution line system 54a that is the same as that of the consumer A20. Here, in a case in which it is determined that there exists the plurality of consumers, the process proceeds to Step S23. On the other hand, in a case in which it is determined that there is only the consumer B30, the process proceeds to Step S26. Next, in Step S23, since there is a plurality of consumers B30 and the like connected to the same power distribution line system 54a as that of the consumer A20, the consumer A20 reads the contents of replies of the superimposition signal received from each of the plurality of the consumers B30 and the like from the storage unit 16a. Next, in Step S24, a consumer having a low attenuation rate of the superimposition signal is selected from among the plurality of consumers and is matched as a supply destination of the surplus electric power generated in the consumer A20. Next, in Step S25, in a predetermined time period in which surplus electric power is generated in the consumer A20, the surplus power is supplied to the consumer selected in Step S24. On the other hand, in Step S26, since the consumer connected to the same power distribution line system 54a as that of the consumer A20 is only the consumer B30, this consumer B30 is matched with the consumer A20. Next, in Step S27, in a predetermined time period in which surplus electric power is generated in the consumer A20, the surplus electric power is supplied to the consumer B30. The power coordination control systems 10a to 10c according to this embodiment, estimate mutual connection relations of the consumers A20, B30, and C40 and match consumers mutually circulating surplus electric power in accordance with a result of the estimation as described above. In this way, as a result of the estimation of the connection relation, for example, surplus electric power can be supplied to a consumer of a connection relation having a smallest power transmission loss. As a result, the surplus electric power generated in the consumer A20 can be supplied to the consumer B30 that can efficiently use the surplus electric power. Other Embodiments As above, while one embodiment of the present invention has been described, the present invention is not limited to the embodiment described above, and various changes can be made in a range not departing from the concept of the present invention. (A) In the embodiment described above, as a power coordination control method according to the present invention, while an example has been described in which the power coordination control is performed in accordance with the flowcharts illustrated in FIGS. 3 and 7. However, the present invention is not limited thereto. For example, the present invention may be realized using the power coordination control method performed in accordance with the flowcharts illustrated in FIGS. 3 and 7 as a power coordination control program executed by a computer. In addition, the present invention may be realized as a recording medium having this power coordination control program stored thereon. (B) In the embodiment described above, an example has been described in which the surplus electric power is circulated by combining one consumer B30 that belongs to the same consumer group 53a and is connected to the same power distribution line system 54a with one consumer A20. However, the present invention is not limited thereto. For example, in a case in which the amount of surplus electric power generated by the consumer A20 is larger than the amount of required electric power of the consumer B30, a plurality of consumers B30 connected to the same power distribution line system may be combined with one consumer A20. In such a case, the supply of surplus electric power can be performed from the consumer A20 in which the surplus electric power is generated in a large quantity to a plurality of consumers B30 having a small power transmission loss. Accordingly, more efficiently, the surplus electric power can be mutually circulated among the plurality of consumers. (C) In the embodiment described above, an example has been described in which surplus electric power is supplied from the consumer A20 generating a superimposition signal and transmitting the superimposition signal to the other consumers to the other consumers receiving the superimposition signals. However, the present invention is not limited thereto. For example, a consumer on the side generating and transmitting a superimposition signal and a consumer that is the supply source of surplus electric power may not coincide with each other. In other words, a consumer generating a superimposition signal and transmitting the superimposition signal to another consumer may be configured to request supply of surplus electric power from the another consumer. (D) In the embodiment described above, an example has been described in which a superimposition signal generated by the consumer A20 is transmitted to the consumer B30 and the consumer C40, and a connation relation is estimated in accordance with receiving statuses of the superimposition signal in the consumer B30 and the consumer C40. However, the present invention is not limited thereto. For example, a superimposition signal generated by the consumer B30 or the consumer C40 may be transmitted to the other consumers A20 and C40 or the consumers A20 and B30, and a connection relation may be estimated in accordance with the receiving statuses of the superimposition signal in the consumers A20 and C40 or the consumers A20 and B30. In other words, as illustrated in FIGS. 1 and 2, the consumers A20, B30, and C40 respectively include the superimposition signal generating units 11a to 11c, the transmission units 12a to 12c, the receiving units 13a to 13c, and the connection relation estimating units 14a to 14c. For this reason, the generation of a superimposition signal may be generated by any one consumer, and the generated superimposition signal may be received by any consumer. In addition, the estimation of the connection relation is not limited as being performed by a consumer that has received a superimposition signal, and the estimation may be performed by a consumer that is a transmission source as the information relating to the attenuation rate of the superimposition signal received from the consumer is replied to the consumer that is the transmission source. (E) In the embodiment described above, as illustrated in FIG. 1, an example has been described in which power generation devices such as the solar panels (photovoltaic power generation devices) 21, 31, and 41 and the power storage devices 23, 33, and 43 are used as power supply devices owned by a plurality of consumers A20, B30, and C40. However, the present invention is not limited thereto. For example, as the power supply devices owned by a plurality of consumers, other power generation devices such as wind power generation devices or geothermal power generation devices may be used, and electric vehicles (batteries built therein), heat pumps, or the like may be used. In addition, the power supply devices owned by consumers are not limited as being devices of a same kind but, power supply devices of different kinds may be owned. (F) In this embodiment, as illustrated in FIG. 2, an example has been illustrated in which the storage units 16a, 16b, and 16c storing various kinds of information are disposed inside the smart meters 27, 37, and 47 owned by the consumers A20, B30, and C40 configuring the power coordination control systems 10a to 10c. However, the present invention is not limited thereto. For example, a server disposed outside the power coordination control systems, a cloud service, or the like may be used as the storage units storing various kinds of information. (G) In the embodiment described above, an example has been described in which, when superimposition signals are to be generated by the superimposition signal generating units 11a, 11b, and 11c, predetermined high frequency components are superimposed on the system voltage. However, the present invention is not limited thereto. For example, a predetermined signal superimposed on the system voltage is not limited to a high frequency component, but any other signal may be used. INDUSTRIAL APPLICABILITY The power coordination control system according to the present invention has an effect of efficiently mutually circulating surplus electric power by searching for consumers connected to the same power distribution network among a plurality of consumers and accordingly, can be broadly applied to a system including a power distribution line system to which a plurality of consumers are connected. REFERENCE SIGNS LIST 10a, 10b, and 10c Power coordination control system 11a, 11b, and 11c Superimposition signal generating unit 12a, 12b, and 12c Transmission unit 13a, 13b, and 13c Receiving unit 14a, 14b, and 14c Connection relation estimating unit 15a, 15b, and 15c Matching unit 16a, 16b, and 16c Storage unit 20 Consumer A (first consumer) 21 Solar panel (power supply device) 22 Photovoltaic power generation power conversion device (PCS) 22a Power generation power sensor 23 Power storage device 23a Power-storage power sensor 24 Load 24a Load power sensor 25 Distribution board 26 EMS 27 Smart meter 30 Consumer B (second consumer) 31 Solar panel (power supply device) 32 Photovoltaic power generation power conversion device (PCS) 32a Power generation power sensor 33 Power storage device 33a Power-storage power sensor 34 Load 34a Load power sensor 35 Distribution board 36 EMS 37 Smart meter 40 Consumer C (second consumer) 41 Solar panel (power supply device) 42 Photovoltaic power generation power conversion device (PCS) 42a Power generation power sensor 43 Power storage device 43a Power-storage power sensor 44 Load 44a Load power sensor 45 Distribution board 46 EMS 47 Smart meter 50 System (first power distribution line system) 51 Substation 52a and 52b Switching unit 53a and 53b Consumer group 54a Power distribution line system (first power distribution line system) 54b Power distribution line system (second power distribution line system) | <SOH> BACKGROUND ART <EOH>In recent years, power generation devices (for example, photovoltaic power generation devices) generating electric power using renewable energy have been used. In Japan, since a surplus electric power purchase system was enacted, electric power generated by photovoltaic power generation devices, wind power generation devices, and the like can be sold to a power company. However, there are cases in which generated electric power cannot be sold to a power company. For example, there are cases in which the amount of electric power that has been purchased by a power company exceeds a predetermined amount of electric power that can be purchased by the power company (hereinafter, referred to as output curtailment). For this reason, there are cases in which a storage battery capable of temporarily storing electric power that cannot be sold is used by a consumer. However, in a case in which the amount of electric power generated by the power generation devices is larger than the remaining capacity of a storage battery, there are cases in which the electric power generated by the power generation devices is discarded. For example, in Patent Literature 1, a power management system is disclosed which predicts a power distribution network on the basis of various kinds of information including the positional information of consumers, the positional information of facilities, and map information and calculates surplus electric power of a predetermined district using the predicted power distribution network. | <SOH> SUMMARY OF INVENTION <EOH> | H02J346 | 20180207 | 20180809 | 94846.0 | H02J346 | 0 | CAVALLARI-SEE, DANIEL | POWER COORDINATION CONTROL SYSTEM, POWER COORDINATION CONTROL METHOD, AND NON-TRANSITORY STORAGE MEDIUM | UNDISCOUNTED | 0 | ACCEPTED | H02J | 2,018 |
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15,751,588 | PENDING | DEVICE FOR ATTACHING AND DETACHING HANDLE SURGICAL LIGHT | The present invention relates to a device for attaching and detaching a handle of a surgical light which is a medical lighting apparatus. The device, in the handle which is inserted into or separated from a surgical light shaft in a female-male coupling manner, comprises: a lock pin which protrudes in the axial direction of the surgical light shaft and is inserted into a lock hole formed on the handle so as to prevent the handle from being separated; a pin spring, supported on the surgical light shaft, for providing elastic force so that the lock pin protrudes to the outside of the surgical light shaft; a separation button which is provided on the outside of the handle and, when an external force for separating the handle from the surgical light shaft is applied, is pushed so as to enable the lock pin to be separated from the lock hole of the handle; and a button support body for supporting the separation button on the handle so that the separation button is movable to a certain degree. Therefore, the device prevents cross-infection which can occur while moving the surgical light during an operation, thereby enhancing safety and reliability of the surgical light. | 1. A device for attaching and detaching a handle of a surgical light, the handle being fitted onto or detached from a surgical light shaft in a female-male coupling manner, the device comprising: a lock pin protruding in a lateral direction of the surgical light shaft and inserted into a lock hole formed in the handle to prevent the handle from being displaced; a pin spring supported on the surgical light shaft to provide elastic force such that the lock pin protrudes outward from the surgical light shaft; a release button provided to an outer side of the handle so as to be pressed to displace the lock pin from the lock hole of the handle when external force is applied to detach the handle from the surgical light shaft; and a button supporting body for supporting the release button on the handle so as to be movable to a certain extent. 2. The device according to claim 1, wherein a pin insertion portion is formed on one lateral surface of the surgical light shaft to guide rectilinear movement of the lock pin inserted thereinto, wherein an end portion of the lock pin is positioned to penetrate the pin insertion portion, and a displacement preventing portion is assembled to prevent the lock pin from being displaced from the pin insertion portion, wherein the pin spring is configured to provide elastic force to the lock pin while being supported in the pin insertion portion. 3. The device according to claim 1, wherein the release button comprises: a support portion positioned at one side of the button such that the button supporting body may be assembled; and a pressing portion positioned at an opposite side of the button to contact the lock pin, the pressing portion protruding toward the lock pin to press the lock pin. 4. The device according to claim 1, wherein the button supporting body comprises: a button pin for perpendicularly penetrating the handle and the release button in a radial direction of the handle; and a displacement preventing portion provided at an end of the button pin to prevent the button pin from being displaced. 5. The device according to claim 4, further comprising: a return spring arranged between the displacement preventing portion and an inner side surface of the handle to provide elastic force to cause the release button to return to an original position after the release button is pressed. 6. The device according to claim 1, wherein the button supporting body comprises: a button shaft for laterally penetrating the release button and the handle to rotatably support the release button on the handle. 7. The device according to claim 6, wherein the handle is provided with a button support portion protruding to allow the release button to be coupled to the handle through the button shaft, wherein opposite side surfaces of the release button extend in a bent manner so as to be positioned on opposite sides of the button support portion, wherein the button shaft is installed so as to penetrate the opposite side surfaces of the release button and the button support portion of the handle. | TECHNICAL FIELD The present invention relates to a surgical light which is a medical lighting apparatus, and more particularly, to a device for attaching and detaching a handle of a surgical light, which can be attached to and detached from the surgical light. BACKGROUND ART Typically, a surgical light is a medical light fixture which is usually installed above an operating table so that light is projected in each direction to prevent shadows from being formed in a place where surgery is being performed. The surgical light is configured to be changeable in height and position according to various conditions such as the progress of surgery. For this purpose, the surgical light is provided with a handle, and surgery is performed by moving the surgical light to a desired position using the handle. Usually, to move the surgical light, surgical gloves are put on, and then the handle is moved to move the surgical light to a desired position. At this time, if the handle is contaminated, cross infection may occur in repeated practices of surgery. To address this issue, a cover is placed on the handle, and the surgical light is moved by manipulating the handle in the cover. However, the cover is often displaced during movement of the surgical light, and the cover is disposable, which is not economical. Although there is a handle detachably attachable to a surgical light, detachment thereof requires pressing of a button provided to the surgical light. As a result, cross infection may occur when the button is contaminated. The statement in this section is technical information that the inventor of the present application has obtained to derive the present invention or that has been acquired in deriving the present invention, and cannot be necessarily taken as known technology disclosed to the general public before the application of the present invention. DISCLOSURE Technical Problem Therefore, the present invention has been made in view of the above problems, and it is one object of the present invention to provide a device for attaching and detaching a handle of a surgical light that is provided with a detachable button on the handle to prevent cross infection which may occur in moving the surgical light during surgery and is capable of enhancing safety and reliability of the surgical light. Technical Solution In accordance with one aspect of the present invention, provided is a device for attaching and detaching a handle of a surgical light, the handle being fitted onto or detached from a surgical light shaft in a female-male coupling manner, the device comprising a lock pin protruding in a lateral direction of the surgical light shaft and inserted into a lock hole formed in the handle to prevent the handle from being displaced; a pin spring supported on the surgical light shaft to provide elastic force such that the lock pin protrudes outward from the surgical light shaft; a release button provided to an outer side of the handle so as to be pressed to displace the lock pin from the lock hole of the handle when external force is applied to detach the handle from the surgical light shaft; and a button supporting body for supporting the release button on the handle so as to be movable to a certain extent. Preferably, a pin insertion portion is formed on one lateral surface of the surgical light shaft to guide rectilinear movement of the lock pin inserted thereinto, wherein an end portion of the lock pin is positioned to penetrate the pin insertion portion, and a displacement preventing portion is installed to prevent the lock pin from being displaced from the pin insertion portion, wherein the pin spring is configured to provide elastic force to the lock pin while being supported in the pin insertion portion. Preferably, the release button comprises a support portion positioned at one side of the button such that the button supporting body may be assembled; and a pressing portion positioned at an opposite side of the button to contact the lock pin, the pressing portion protruding toward the lock pin to press the lock pin. Preferably, the button supporting body comprises a button pin for perpendicularly penetrating the handle and the release button in a radial direction of the handle; and a displacement preventing portion provided at an end of the button pin to prevent the button pin from being displaced. Preferably, the device further comprises a return spring arranged between the displacement preventing portion and an inner side surface of the handle to provide elastic force to cause the release button to return to an original position after the release button is pressed. Preferably, the button supporting body comprises a button shaft for laterally penetrating the release button and the handle to rotatably support the release button on the handle. Preferably, the handle is provided with a button support portion protruding to allow the release button to be coupled to the handle through the button shaft, wherein opposite side surfaces of the release button extend in a bent manner so as to be positioned on opposite sides of the button support portion, wherein the button shaft is installed so as to penetrate the opposite side surfaces of the release button and the button support portion of the handle. The above and other objects and advantages of the present invention will become more apparent from exemplary embodiments thereof disclosed in the Best Mode and the accompanying drawings, in which the principal solutions described above and various other solutions according to the present invention will be further illustrated and described. Advantageous Effects A device for attaching and detaching a handle of a surgical light according to the present invention is configured such that the handle can be installed simply by fitting the handle onto a shaft and be easily detached by pressing a button. Therefore, convenience of attachment and detachment of the handle may be enhanced. In addition, since the handle used in a specific surgical procedure can be easily removed by pressing the button provided on the handle, sterilized using a sterilizing device such as an autoclave, and then placed back in position, contamination of the surgical light other than the handle may be minimized, and thus the risk of cross infection may be avoided. Accordingly, safety and reliability of the surgical light may be enhanced. Further, since the handle of the present invention can be repeatedly used after being sterilized, there is no need for a cover or the like. Thus, economical efficiency may be improved according to decrease in cost. DESCRIPTION OF DRAWINGS FIG. 1 is an overall perspective view showing a surgical light with a device for attaching and detaching a handle of the surgical light according to one embodiment of the present invention. FIG. 2 is a side view showing the handle of FIG. 1, which is not installed. FIG. 3 is a cross-sectional view showing a main part of the device for attaching and detaching the handle of the surgical light according to one embodiment of the present invention. FIG. 4 is a perspective view showing the handle in the device for attaching and detaching the handle of the surgical light according to one embodiment of the present invention. FIG. 5 is an exploded perspective view showing the handle in the device for attaching and detaching the handle of the surgical light according to one embodiment of the present invention. FIG. 6 is a front view showing the handle in the device for attaching and detaching the handle of the surgical light according to one embodiment of the present invention. FIG. 7 is a cross-sectional view taken along line A-A in FIG. 6. FIG. 8 is a side view showing the handle in the device for attaching and detaching the handle of the surgical light according to one embodiment of the present invention. FIG. 9 is a plan view showing the handle in the device for attaching and detaching the handle of the surgical light according to one embodiment of the present invention. FIG. 10 is a perspective view showing a handle in a device for attaching and detaching the handle of a surgical light according to another embodiment of the present invention. FIG. 11 is an exploded perspective view showing the handle in the device for attaching and detaching the handle of the surgical light according to another embodiment of the present invention. FIG. 12 is a perspective view showing a handle in a device for attaching and detaching the handle of a surgical light according to yet another embodiment of the present invention. FIG. 13 is an exploded perspective view showing the handle in the device for attaching and detaching the handle of the surgical light according to yet another embodiment of the present invention. BEST MODE Hereinafter, preferred embodiments of the present invention will be described with reference to the accompanying drawings. FIGS. 1 to 9 are views showing a device for attaching and detaching a handle of a surgical light according to one embodiment of the present invention. FIG. 1 is an overall perspective view of the surgical light, FIG. 2 is a side view showing the handle, which is not installed yet, and FIG. 3 is a cross-sectional view of a main part of the attachment/detachment device. FIG. 4 is a perspective view of the handle, FIG. 5 is an exploded perspective view of the handle, and FIG. 6 is a front view of the handle. FIG. 7 is a cross-sectional view of the handle, FIG. 8 is a side view of the handle, and FIG. 9 is a plan view of the handle. Referring to FIG. 1, reference numeral 10 denotes a surgical light having a lighting device disposed thereunder, and reference numeral 12 denotes a support for supporting the surgical light. The surgical light 10 is provided at the lower center thereof with a surgical light shaft 20 protruding downward to a long distance, and a handle 50 may be mounted on the surgical light shaft 20. The handle 50 is attached to and detached from the surgical light shaft 20 in a female-male coupling manner. The attachment/detachment device will be described in detail with reference to FIGS. 2 to 9. Referring to FIG. 3, the device for attaching and detaching a handle of a surgical light according to an embodiment of the present invention includes a lock pin 30 protruding in a lateral direction of the surgical light shaft 20 and inserted into a lock hole 52 formed in the handle 50, a pin spring 40 supported on the surgical light shaft 20 to provide elastic force such that the lock pin 30 protrudes outward from the surgical light shaft 20, a release button 60 provided to an outer side of the handle 50 so as to be pressed to displace the lock pin 30 from the lock hole 52 of the handle 50 when external force is applied to detach the handle 50 from the surgical light shaft 20, and a button supporting body 70 for supporting the release button 60 on the handle 50 so as to be movable to a certain extent. The main components of the device for attaching and detaching the surgical light handle of this embodiment configured as above and the assembly structures thereof will be described in detail. First, the lock pin 30 and the assembly structure of the lock pin 30 are constituent parts that cause the handle 50 to be caught by the lock pin 30 so as not to be released after the handle 50 is fitted. As exemplarily shown in FIG. 3, the lock pin 30 may include a head portion 31 and a stem portion 33. Preferably, the head portion 31 is formed in a hemispherical shape in order to facilitate detachment of the handle 50 when the handle 50 is removed. Preferably, the stem portion is formed to a smaller outer diameter than the head portion 31 to allow the pin spring 40 to be mounted therearound. A pin insertion portion 22 may be formed on one lateral surface of the surgical light shaft 20 to guide rectilinear movement of the lock pin 30 inserted thereinto. The pin insertion portion 22 is formed in a hole structure having a certain depth. The lock pin 30 is inserted into and positioned in the pin insertion portion 22. Preferably, with the end portion of the stem portion 33 of the lock pin 30 positioned to penetrate the pin insertion portion 22, a displacement preventing ring 45, i.e., a snap ring or the like, is installed so as to be caught by the bottom surface of the pin insertion portion 22 and prevented from being displaced. Of course, the displacement preventing ring 45 can be replaced with any other components that prevent the lock pin 30 from being displaced, such as a nut or an engagement pin to be fastened or fixed to the end of the lock pin 30. As described above, the pin spring 40 is configured to provide elastic force to the lock pin 30 while being arranged around the stem portion 33 of the lock pin 30 and supported in the pin insertion portion 22. The pin spring 40 is preferably formed by a coil spring as illustrated in the figure. Next, the release button 60 has an approximately rectangular shape as illustrated in FIGS. 4 and 5, and the peripheral surface thereof is formed to have a skirt surface 61 extending from the top surface in a curved manner. The release button 60 includes a support portion 63 positioned at an upper side of the button and connected with the button supporting body 70, and a pressing portion 65 positioned at a lower side of the button to contact the lock pin 30 and protruding toward the lock pin 30 to press the lock pin. Here, the support portion 63 is preferably formed in a groove structure such that the head portion 72 of the button pin 71, which will be described below, is caught. Preferably, the pressing portion 65 is formed to be smaller than the lock hole 52 formed in the handle 50 so as to press the lock pin 30 completely. Preferably, the pressing portion 65 is formed in a structure having a top surface depressed in a round shape. This is intended to allow the user to correctly locate the pressing position to press the button. Next, the button supporting body 70 preferably includes a button pin 71 for perpendicularly penetrating the release button 60 and the handle 50 in the radial direction of the handle 50, and a displacement preventing ring 75 provided to an end of the button pin 71 to prevent the button pin 71 from being displaced. A button support portion 55 protrudes from the handle 50 to allow the release button 60 to be connected through the button supporting body 70. The button support portion 55 is provided with a hole 56, through which the button pin 71 is arranged. The button pin 71 may include a head portion 72 and a pin portion 73. The head portion 72 is engaged with the support portion 63 of the release button 60 and the pin portion 73 is inserted into the hole 56 of the button support portion 55 in a penetrating manner. The displacement preventing ring 75, which may be configured by an E-ring, a snap ring, or the like, is installed at the end of the button pin 71 on the back of the button support portion 55 to prevent the button pin 71 from being displaced. Preferably, the length of the button pin 71 and the installation position of the displacement prevention ring 75 are set to provide a certain clearance distance L to allow the release button 60 to be moved when the release button 60 is pressed, as shown in FIG. 3. Now, a process of attaching and detaching a handle using the attachment/detachment device according to this embodiment configured as described above will be described. Referring to FIGS. 1 and 3, when the handle 50 is pushed onto the outer side of the surgical light shaft 20 in order to mount the handle 50 on the surgical light shaft 20, the lock pin 30 is retracted as the handle 50 is fitted. When the handle is fully fitted, the lock pin 30 may be inserted into the lock hole 52 of the handle 50. Thereby, the handle 50 can be mounted on the surgical light shaft 20. In order to change the position of the surgical light 10 in this state, the surgical light can be moved using the handle 50. When the release button 60 is pressed with the thumb or the like with the handle 50 held to remove or detach the handle 50, the release button 60 is rotated about the button supporting body 70 in the pressing direction. At the same time, the pressing portion 65 presses the lock pin 30 to release the lock pin 30 from the lock hole 52. At this time, if the handle 50 is pulled downward, the handle 50 may be removed from the surgical light shaft 20. Thereafter, if necessary, the handle 50 removed as described above may be sterilized using a sterilizing device such as an autoclave, and then installed again. Next, a brief description will be given of a device for attaching and detaching a handle of a surgical light according to another embodiment of the present invention. In describing other embodiments, the same or like parts as those of the above-described embodiment are assigned the same reference numerals, and a redundant description thereof will be omitted. FIGS. 10 and 11 are a perspective view and an exploded perspective view showing a handle in a device for attaching and detaching the handle of a surgical light according to another embodiment of the present invention. All the configurations except the configuration of the button supporting body 70 are the same as those of the previous embodiment. Referring to FIGS. 10 and 11, the button supporting body 70 in this embodiment includes a return spring 77 arranged between the displacement preventing ring 75 and the inner side surface of the handle 50 to provide elastic force to the button pin 71 to cause the release button 60 to returns to an original position thereof after the release button 60 is pressed. Preferably, the return spring 77 is installed at a clearance distance L in FIG. 3. Therefore, when the release button 60 is pressed to separate the handle 50, the return spring 77 stores elastic force while being compressed. When the release button 60 is released, the release button 60 can be restored to the original position thereof by the elastic force of the return spring 77. FIGS. 12 and 13 are a perspective view and an exploded perspective view showing a handle in a device for attaching and detaching the handle of a surgical light according to yet another embodiment of the present invention. In yet another embodiment, the direction of coupling of a button supporting body 70A is different from that in the previous two embodiments. Referring to FIGS. 12 and 13, the button supporting body 70A includes a button shaft 80 for laterally penetrating the release button 60 and the handle 50 to rotatably support the release button 60 on the handle 50. To this end, the handle 50 is provided with a button support portion 55A protruding to allow the release button 60 to be coupled to the handle through the button shaft 80. The skirt surface 61 extends on opposite side surfaces of the release button 60 in a bent manner so as to be positioned on both sides of the button support portion 55A, and thus the button shaft 80 is arranged to penetrate the opposite side surfaces of the release button 60 and the button support portion 55A of the handle 50. Of course, a displacement preventing ring 85 is preferably provided at the end of the button pin 71. As described above, the technical ideas described in the embodiments of the present invention can be implemented independently, or can be implemented in combination with each other. While the present invention has been particularly shown and described with reference to exemplary embodiments thereof disposed in the Best Mode and the drawings, such descriptions are merely illustrative. Many variations and other equivalent embodiments will be apparent to those skilled in the art. Accordingly, the technical scope of the present invention should be defined by the appended claims. <Reference Numerals> 10: Surgical light 12: support 20: Surgical light shaft 22: Pin insertion portion 30: Lock pin 40: Pin spring 50: Handle 55: Button support portion 60: Release button 63: Support portion 65: Pressing portion 70: Button supporting body 71: Button pin 75: Displacement preventing ring INDUSTRIAL APPLICABILITY The present invention relates to a device for attaching and detaching a handle of a surgical light which is configured such that the handle can be installed simply by fitting the handle onto a shaft and be easily detached by pressing a button. Therefore, convenience of attachment and detachment of the handle may be enhanced. Accordingly, the present invention is applicable to all typical lights. In particular, the present invention is expected to be applied to industrial fields such as surgery or medical lighting, because it can enhance user convenience and secure health safety through sterilization and disinfection in an operating procedure. | <SOH> BACKGROUND ART <EOH>Typically, a surgical light is a medical light fixture which is usually installed above an operating table so that light is projected in each direction to prevent shadows from being formed in a place where surgery is being performed. The surgical light is configured to be changeable in height and position according to various conditions such as the progress of surgery. For this purpose, the surgical light is provided with a handle, and surgery is performed by moving the surgical light to a desired position using the handle. Usually, to move the surgical light, surgical gloves are put on, and then the handle is moved to move the surgical light to a desired position. At this time, if the handle is contaminated, cross infection may occur in repeated practices of surgery. To address this issue, a cover is placed on the handle, and the surgical light is moved by manipulating the handle in the cover. However, the cover is often displaced during movement of the surgical light, and the cover is disposable, which is not economical. Although there is a handle detachably attachable to a surgical light, detachment thereof requires pressing of a button provided to the surgical light. As a result, cross infection may occur when the button is contaminated. The statement in this section is technical information that the inventor of the present application has obtained to derive the present invention or that has been acquired in deriving the present invention, and cannot be necessarily taken as known technology disclosed to the general public before the application of the present invention. | F21V21403 | 20180212 | 20180816 | 67322.0 | F21V2140 | 0 | DUNAY, CHRISTOPHER E | DEVICE FOR ATTACHING AND DETACHING HANDLE SURGICAL LIGHT | SMALL | 0 | ACCEPTED | F21V | 2,018 |
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15,751,738 | PENDING | STACKED LAYER-TYPE MEMBER WITH INTEGRATED FUNCTIONAL COMPONENT | A fluidic valve for a sample separation apparatus for separating a fluid, wherein the fluidic valve comprises a stack of connected layer structures, a first conduit within the stack, a second conduit within the stack, a movable body within the stack, and an actuator configured for actuating the movable body to selectively bring the movable body into a flow enabling configuration in which flow of fluid between the first conduit and the second conduit is enabled, or into a flow disabling configuration in which flow of fluid between the first conduit and the second conduit is disabled. | 1. A fluidic valve for a sample separation apparatus for separating a fluid, the fluidic valve comprising: a stack of connected layer structures; a first conduit within the stack; a second conduit within the stack; a movable body within the stack; an actuator configured for actuating the movable body to selectively bring the movable body into a flow enabling configuration in which flow of fluid between the first conduit and the second conduit is enabled, or into a flow disabling configuration in which flow of fluid between the first conduit and the second conduit is disabled. 2. The fluidic valve according to claim 1, wherein at least part of the layer structures is configured as a sheet. 3. The fluidic valve according to claim 1, wherein at least part of the layer structures is configured as a patterned layer having one or more recesses constituting at least part of at least one of the first conduit and the second conduit. 4. The fluidic valve according to claim 1, wherein the movable body is configured as a ball. 5. The fluidic valve according to claim 1, wherein the movable body comprises at least one material selected from the group consisting of a ceramic, sapphire, and ruby. 6. The fluidic valve according to claim 1, wherein the movable body is configured for being forced to sealingly rest on a seat, formed by at least a part of the layer structures, by the actuator in the fluid disabling configuration, and is configured for being released from the seat when brought in the fluid enabling configuration by the actuator. 7. The fluidic valve according to claim 1, comprising a force transmission structure configured for transmitting an actuation force from the actuator to the movable body. 8. The fluidic valve according to claim 7, wherein the force transmission structure comprises an elastic material. 9. The fluidic valve according to claim 7, wherein the force transmission structure comprises an elastic membrane as at least one of the layer structures. 10. The fluidic valve according to claim 7, wherein the force transmission structure comprises an elastic pad. 11. The fluidic valve according to claim 9, wherein the elastic pad is arranged between the actuator and the elastic membrane. 12. The fluidic valve according to claim 10, wherein the elastic pad has a larger lateral extension than at least one of the actuator and the movable body. 13. The fluidic valve according to claim 1, comprising at least one of the following features: the actuator comprises a piston configured for axially moving so as to selectively actuate the movable body to be brought into the fluid enabling configuration or into the fluid disabling configuration depending on an axial position of the piston; wherein at least one of the layer structures is configured as a spring-type layer; configured as a non-return valve. 14. A sample separation apparatus for separating a fluidic sample, comprising: a fluid drive unit configured for driving at least a part of a fluid comprising a mobile phase and the fluidic sample in the mobile phase along a separation path; a separation unit arranged within the separation path and configured for separating the fluidic sample into a plurality of fractions; and fluidic valve according to claim 1 configured for selectively enabling or disabling flow of at least a part of the fluid within or into the separation path. 15. The sample separation apparatus according to claim 14, comprising at least one of the following features: the sample separation apparatus is configured as one of the group consisting of a chromatography sample separation apparatus, in particular a liquid chromatography sample separation apparatus, a gas chromatography sample separation apparatus or a supercritical fluid chromatography sample separation apparatus, and an electrophoresis sample separation apparatus, in particular a capillary electrophoresis sample separation apparatus; the sample separation apparatus comprises an injector for introducing the fluidic sample into the mobile phase between the fluid drive unit and the separation unit; the sample separation apparatus comprises a detector configured to detect separated fractions of at least a portion of the fluidic sample; the sample separation apparatus comprises a fractionating unit configured to collect separated fractions of the fluidic sample; the sample separation apparatus comprises a degassing apparatus for degassing mobile phase; the fluid drive unit is configured for driving the fluid along the separation path with a pressure of at least 200 bar. 16. A method of manufacturing a fluidic valve, the method comprising: forming a first conduit within a stack of layer structures; forming a second conduit within the stack; arranging a movable body within the stack; interconnecting the stack; configuring an actuator for actuating the movable body to selectively bring the movable body into a flow enabling configuration in which flow of fluid between the first conduit and the second conduit is enabled, or into a flow disabling configuration in which flow of fluid between the first conduit and the second conduit is disabled. 17. The method according to claim 16, wherein at least a part of the stack of layer structures is interconnected to one another by diffusion bonding. 18. A planar member, comprising: a stack of metallic layer structures connected to one another by diffusion bonding; and at least one nonmetallic functional component integrated with the stack by diffusion bonding. 19. The planar member according to claim 18, comprising at least one of the following features: wherein at least one of the at least one functional component is fixedly connected with the stack of metallic layer structures; wherein at least one of the at least one functional component is movable within the stack of metallic layer structures; configured as a high pressure resistant planar member capable of withstanding pressure of at least up to 1000 bar; wherein the at least one nonmetallic functional component is selected from the group consisting of an inorganic material, a ceramic material, a metal oxide, and a hard plastic material; wherein the at least one nonmetallic functional component is selected from the group consisting of a seat of a fluidic valve, a movable body of a fluidic valve, and a spring element. 20. (canceled) | BACKGROUND ART The present invention relates to a fluidic valve, a method of manufacturing a fluidic valve, a sample separation apparatus, a planar member, and a method of manufacturing a planar member. In liquid chromatography, a fluidic sample and an eluent (liquid mobile phase) may be pumped through conduits and a separation unit such as a column in which separation of sample components takes place. The column may comprise a material which is capable of separating different components of the fluidic sample. The separation unit may be connected to other fluidic members (like a sampler or an injector, a detector) by conduits. Before the fluidic sample is introduced into a separation path between a fluid drive unit (in particular a high pressure pump) and the separation unit, a predefined amount of fluidic sample shall be intaken from a sample source (such as a sample container) via an injection needle into a sample loop by a corresponding movement of a piston within a metering device. This usually occurs in the presence of a significantly smaller pressure than what the separation unit is run with. Thereafter, an injector valve is switched so as to introduce the intaken amount of fluidic sample from the sample loop of a metering path into the separation path between fluid drive unit and the separation unit for subsequent separation. At various positions of a liquid chromatography device, fluidic vales are used. For instance, a mixing unit for mixing a mobile phase from various solvent compositions, the above mentioned pump and the above mentioned injector may comprise one or more fluidic valves for selectively enabling or disabling flow of fluid through one or more conduits. Hence, fluidic valves are useful in a sample separation apparatus. Although conventional fluidic valves are powerful fluidic tools, there is still room for improvement of fluidic valves in terms of compactness, robustness and dead volume. Moreover, also an improvement of compactness and robustness of other members (such as valves) with functional components (such as a movable valve body of a valve) is desirable. DISCLOSURE It is an object of the invention to provide a compact and robust member (in particular a valve) with functional component (in particular a movable valve body of a valve). The object is solved by the independent claims. Further embodiments are shown by the dependent claims. According to an exemplary embodiment of the present invention, a fluidic valve (in particular for a sample separation apparatus for separating a fluid, or more generally for any fluid processing device) is provided, wherein the fluidic valve comprises a stack of (in particular integrally) connected layer structures, a first conduit (in particular defining a lumen which may accommodate fluid) within the stack, a second conduit (in particular defining a lumen which may accommodate fluid) within the stack, a movable body within the stack (i.e. a body located within the stack which can move within and relative to the stack), and an actuator configured for actuating the movable body to selectively bring the movable body into a flow enabling configuration (in particular to move or allow to move the movable body to a flow enabling position) in which flow of fluid between the first conduit and the second conduit is enabled, or into a flow disabling configuration (in particular to move or allow to move the movable body to a flow disabling position differing from the flow enabling position) in which flow of fluid between the first conduit and the second conduit is disabled. According to another exemplary embodiment of the present invention, a sample separation apparatus for separating a fluidic sample is provided, wherein the sample separation apparatus comprises a fluid drive unit configured for driving at least a part of a fluid comprising a mobile phase and the fluidic sample in the mobile phase along a separation path, a separation unit arranged within the separation path and configured for separating the fluidic sample into a plurality of fractions, and a fluidic valve having the above mentioned features configured for selectively enabling or disabling flow of at least a part of the fluid within or into the separation path. According to another exemplary embodiment of the present invention, a method of manufacturing a fluidic valve (in particular for a sample separation apparatus for separating a fluid) is provided, wherein the method comprises forming a first conduit within a stack of layer structures, forming a second conduit within the stack, arranging a movable body within the stack, interconnecting the stack, and configuring an actuator for actuating the movable body to selectively bring the movable body into a flow enabling configuration in which flow of fluid between the first conduit and the second conduit is enabled, or into a flow disabling configuration in which flow of fluid between the first conduit and the second conduit is disabled. According to still another exemplary embodiment of the present invention, a planar member is provided which comprises a stack of metallic (i.e. comprising or consisting of metallic material) layer structures connected to one another, in particular by diffusion bonding, and at least one nonmetallic (i.e. comprising or consisting of nonmetallic material) functional component integrated (for instance as an inlay) with (in particular within) the stack, in particular by diffusion bonding. According to yet another exemplary embodiment of the present invention, a method of manufacturing a planar member is provided which comprises connecting a stack of metallic layer structures to one another by diffusion bonding (in particular in combination with soldering), and integrating at least one nonmetallic functional component with (in particular within) the stack, in particular by diffusion bonding. In the context of this application, the term “fluid” may particularly denote any liquid and/or gaseous medium, optionally including also solid particles. Such a fluid may be or may comprise or may be to be mixed with fluidic sample, which is to be analyzed. Such a fluidic sample may comprise a plurality of fractions represented by molecules or particles which shall be separated, for instance small mass molecules or large mass biomolecules such as proteins. Separation of a fluidic sample into fractions may involve a certain separation criterion (such as mass, volume, chemical properties, etc.) according to which a separation can be carried out. Alternatively, the fluid may also be a mobile phase such as a solvent or a solvent composition (for instance composed of water and an inorganic solvent). In the context of this application, the term “sample separation apparatus” may particularly denote any apparatus which is capable of separating different fractions of a fluidic sample by applying a certain separation technique. The actual separation can be carried out in a separation unit of the sample separation apparatus. The term “separation unit” may particularly denote a member of a fluidic path through which a fluidic sample is transferred and which is configured so that, upon conducting the fluidic sample through the separation unit, fractions or groups of molecules of the fluidic sample will be at least partly spatially separated according to the difference in at least one of their properties. An example for a separation unit is a liquid chromatography column which is capable of trapping or retarding and selectively releasing different fractions of the fluidic sample. In the context of this application, the term “diffusion bonding” may particularly denote a connection technology for connecting stacked sheets or layers, in particular comprising metallic material, by a combination of the application of heat and high pressure. More specifically, diffusion bonding may be denoted as a solid-state welding technique, capable of joining similar and dissimilar materials including metals. It operates on the materials science principle of solid-state diffusion, wherein the atoms of two solid surfaces intermingle over time under elevated temperature (for instance in a range between 800° C. and 1200° C., for example 1100° C.). Diffusion bonding can be implemented by applying both high pressure and high temperature to the materials to be welded. According to an exemplary embodiment, a highly compact flat and planar fluidic valve is provided which is highly appropriate for microfluidic high pressure applications. This can be achieved by bonding a stack of layer structures to one another and embedding a freely and controllably movable body therein, which can be conveniently and precisely controlled with low effort from an exterior of the stack by simply operating an actuator. Such a fluidic valve may be particularly advantageously manufactured by diffusion bonding of metallic layer structures. According to another exemplary embodiment, a planar or flat and thus compact member is formed by diffusion bonding between metallic sheet material and nonmetallic material (which may be also configured as a sheet material or with a pronounced three-dimensional structure such as a ball). Surprisingly, connection of stacked metallic sheets by diffusion bonding allows to interleave or attach also one or more non-metallic structures without deterioration or damage of the manufactured planar member. Moreover, a correspondingly manufactured flat planar member shows a high robustness. In the following, further exemplary embodiments of the fluidic valve, the sample separation apparatus, the planar member, and the methods will be explained. In an embodiment, at least part of the layer structures is configured as a sheet, in particular a metal sheet (for instance steel or titanium). Metal sheets are very thin though robust and sufficiently bendable during manufacturing operation. Moreover, metal sheet are simply and reliably connectable by diffusion bonding. In an embodiment, at least part of the layer structures is configured as a patterned layer having one or more recesses constituting at least part of the first conduit and the second conduit. Patterning layers, for instance by etching, punching, laser cutting, etc. is a simple and accurate way of defining fluidic conduits or channels in a layer stack. It allows to manufacture both straight and curved conduits, and even complex bifurcations and fluidic networks. In an embodiment, the movable body is configured as a ball. By such a ball or sphere geometry, activation of the movable body by a piston-type actuator works reliably regardless of a rotation state of the movable body. In an embodiment, the movable body is made of a ceramic material, sapphire, or ruby. Such materials are capable of withstanding high pressure values (of several hundred bar, for instance up to 1200 bar) which may occur in modern sample separation procedures (in particular in terms of HPLC) while at the same time being capable of providing a leakage free sealing with a seat in which the movable body may rest in a fluid flow disabling operation mode. Moreover, the mentioned materials are capable of withstanding the high temperature and pressure conditions during diffusion bonding of metal sheets. In an embodiment, the movable body is configured for being forced to rest on a seat formed by at least a part of the layer structures by the actuator in the fluid disabling configuration (in particular fluid disabling position) and is configured for being released from the seat for being brought into the fluid enabling configuration (in particular for assuming the fluid enabling position) by the actuator. In order to drive the movable body into the seat, force or pressure may be applied from the actuator onto the movable body (either directly or preferably indirectly via a force transmission mechanism). In the absence of force or pressure applied from the actuator onto the movable body, the movable body is able to move out of the seat (for instance under the influence of flowing fluid which may lift the movable body out of the seat), thereby opening a fluid passage between the first conduit and the second conduit. In an embodiment, the actuator comprises a piston configured for axially moving (for instance for reciprocating)—when driven by a drive unit (such as an electric motor) or by the muscle force of a user—so as to selectively actuate the movable body to be transferred into the fluid enabling configuration (in particular to move into the fluid enabling position) or into the fluid disabling configuration (in particular a fluid disabling position) depending on an axial position of the piston. Such a reciprocating piston, which may move upwardly or downwardly under control of a user or a drive unit (such as a processor-controlled motor) of the fluidic valve or the sample separation apparatus, may assume two different functional positions, one relating to a fluid flow enabling operation mode and the other one relating to a fluid flow disabling operation mode of the fluidic valve. It is also possible that the fluid flow between the first conduit and the second conduit is enabled only to a certain degree by allowing the movable body to move out the seat only for a limited extent, defined by a correspondingly controllable piston position. In an embodiment, the fluidic valve comprises a force transmission structure, in particular a force distribution structure, configured for transmitting, in particular for distributing, an actuation force from the actuator to the movable body. Such a force transmission structure may act as a force-travel transformer and as a mechanical interface between the piston and the movable body. In an embodiment, the force transmission structure is elastic, i.e. has elastic properties. Therefore, force transmitted from the piston to the movable body can be applied to the movable body in a smooth and gentle way damping force peaks, since the elastic force transmission structure also functions as a damping element due to its elastic properties. In an embodiment, the force transmission structure comprises an elastic membrane as at least one of the layer structures. Such an elastic membrane may be a thin bendable film being deformable when applying force or pressure by the piston. Such a membrane may, on the one hand, contribute to the sealing of the fluid flow channel between the first conduit and the second conduit and may, on the other hand, operate in a smooth way on the movable body. In an embodiment, the force transmission structure comprises an elastic pad. For example, the elastic pad may be made of elastic polyurethane material. It may serve as a damping cushion for transmitting and spatially distributing force from the piston to the membrane, and from there to the movable body. In particular, the elastic pad may be arranged between the piston and the elastic membrane. In an embodiment, the elastic pad has a larger lateral extension (i.e. a larger extension within a plane perpendicular to a motion direction of the piston) than at least one of the actuator and the movable body. The elastic pad may therefore balance out spatial inaccuracies concerning the relative position and orientation between piston and movable body. In an embodiment, at least one of the layer structures is configured as a spring-type layer (for instance made of spring steel or a ceramic material). Such a spring-type layer may for example generate a biasing force biasing the movable body into a valve seat. Thus, such a spring-type layer may additionally contribute to the fluid-tight sealing between movable body and seat. Depending on its configuration and arrangement, the spring-type layer may bias the fluidic valve either into a normally open state (i.e. being open as a default state, thus enabling fluid flow in the absence of a piston force) or into a normally closed state (i.e. being closed as a default state, thus disabling fluid flow in the absence of a piston force). Surprisingly, the integration of a spring-type layer into a stack of layers connected to one another by diffusion bonding does not deteriorate the spring properties. In an embodiment, the fluidic valve is configured as a non-return valve. Such a non-return valve (which may also be denoted as check valve or one-way valve) is a valve that (in particular when opened) allows fluid (i.e. liquid or gas) to flow through it in only one direction, but not in the opposite direction. In an embodiment, at least a part of the stack of layer structures is connected to one another by diffusion bonding. Diffusion bonding can be implemented, according to an exemplary embodiment of the invention, by applying both high pressure and high temperature to the stacked sheets to be welded. Diffusion bonding can hence be advantageously applied to weld layered stacks of thin metal foils, which may also be recessed for conduit formation or the like. Surprisingly, conduit recesses within the stack can be advantageously maintained during diffusion bonding without deterioration. In an embodiment, the fluidic valve according to an exemplary embodiment may be implemented at or in a mixing unit for mixing a mobile phase from various solvent compositions upstream of a fluid drive unit, and/or may be implemented at or in a fluid drive unit, and/or may be implemented at or in a proportioning valve, and/or may be implemented at or in an injector for injecting the fluidic sample into a mobile phase. Of course, fluidic valves according to exemplary embodiments of the invention may also be implemented in very different technical environments. In an embodiment, a thickness of each of the layer structures may be in a range between 20 μm and 500 μm, in particular in a range between 50 μm and 200 μm. Preferably, outer layers of the stack may have a higher thickness (for instance between 150 μm and 250 μm) than interior layers of the stack (for instance between 50 μm and 150 μm). Embodiments of the above described fluid valve may be implemented in conventionally available HPLC systems, such as the Agilent 1200 Series Rapid Resolution LC system or the Agilent 1100 HPLC series (both provided by the applicant Agilent Technologies—see www.agilent.com—which shall be incorporated herein by reference). One embodiment of a sample separation apparatus, in which one or more of the above described fluidic valves may be implemented, comprises a pumping apparatus as fluid drive unit or mobile phase drive having a pump piston for reciprocation in a pump working chamber to compress liquid in the pump working chamber to a high pressure at which compressibility of the liquid becomes noticeable. This pumping apparatus may be configured to know (by means of operator's input, notification from another module of the instrument or similar) or elsewise derive solvent properties, which may be used to represent or retrieve actual thermal properties of fluidic content, which is anticipated to be in a sampling apparatus. The separation unit of the sample separation apparatus preferably comprises a chromatographic column (see for instance http://en.wikipedia.org/wiki/Column chromatography) providing the stationary phase. The column may be a glass or steel tube (for instance with a diameter from 50 μm to 5 mm and a length of 1 cm to 1 m) or a microfluidic column (as disclosed for instance in EP 1577012 or the Agilent 1200 Series HPLC-Chip/MS System provided by the applicant Agilent Technologies). The individual components are retained by the stationary phase differently and at least partly separate from each other while they are propagating at different speeds through the column with the eluent. At the end of the column they elute one at a time or at least not entirely simultaneously. During the entire chromatography process the eluent may be also collected in a series of fractions. The stationary phase or adsorbent in column chromatography usually is a solid material. The most common stationary phase for column chromatography is silica gel, surface modified silica gel, followed by alumina. Cellulose powder has often been used in the past. Also possible are ion exchange chromatography, reversed-phase chromatography (RP), affinity chromatography or expanded bed adsorption (EBA). The stationary phases are usually finely ground powders or gels and/or are microporous for an increased surface. The mobile phase (or eluent) can be a pure solvent or a mixture of different solvents (such as water and an organic solvent such as ACN, acetonitrile). It can be chosen for instance to minimize the retention of the compounds of interest and/or the amount of mobile phase to run the chromatography. The mobile phase can also be chosen so that the different compounds or fractions of the fluidic sample can be separated effectively. The mobile phase may comprise an organic solvent like for instance methanol or acetonitrile, often diluted with water. For gradient operation water and organic is delivered in separate bottles, from which the gradient pump delivers a programmed blend to the system. Other commonly used solvents may be isopropanol, THF, hexane, ethanol and/or any combination thereof or any combination of these with aforementioned solvents. The fluidic sample may comprise but is not limited to any type of process liquid, natural sample like juice, body fluids like plasma or it may be the result of a reaction like from a fermentation broth. The pressure, as generated by the fluid drive unit, in the mobile phase may range from 2-200 MPa (20 to 2000 bar), in particular 10-150 MPa (100 to 1500 bar), and more particular 50-120 MPa (500 to 1200 bar). The sample separation apparatus, for instance an HPLC system, may further comprise a detector for detecting separated compounds of the fluidic sample fluid, a fractionating unit for outputting separated compounds of the fluidic sample, or any combination thereof. Further details of such an HPLC system are disclosed with respect to the Agilent 1200 Series Rapid Resolution LC system or the Agilent 1100 HPLC series, both provided by the applicant Agilent Technologies, under www.agilent.com which shall be in cooperated herein by reference. Embodiments of the invention can be partly or entirely embodied or supported by one or more suitable software programs, which can be stored on or otherwise provided by any kind of data carrier, and which might be executed in or by any suitable data processing unit. Software programs or routines can be preferably applied in or by the control unit. In an embodiment, at least one of the at least one functional component is integrally connected with the stack of metallic layer structures, in particular by diffusion bonding. Such a functional component may be a non-metallic inlay which may be put into a recess of a metallic layer, for instance according to Damascene technology. By such an integrated connection, one or more of the metallic layer structures on the one hand and the respective functional component on the other hand are connected to one another so as to be fixed one other, in particular in an inseparable manner. Surprisingly, such an intimate connection between metallic and nonmetallic elements can be established with higher mechanical reliability and robustness by diffusion bonding. For example, a nonmetallic (for instance ceramic) valve seat layer may be connected to neighboured metallic conduit layers by diffusion bonding. In an embodiment, at least one of the at least one functional component is movable within the stack of metallic layer structures. Additionally or alternatively to the previously described embodiment, the interconnection of the metallic layer structures together with the nonmetallic functional component(s) in between may be carried out in such a manner that the functional component remains a separate (and separately movable) body in the readily manufactured planar member regardless of the harsh conditions (such as high pressure and high temperature) which may act thereon during the manufacturing procedure. This for instance allows to manufacture a movable valve body from a nonmetallic material which may freely move within a stack of metallic sheets by diffusion bonding, which surprisingly neither deteriorates integrity of the nonmetallic functional component in an interior of the planar member nor its capability of moving during operation. In an embodiment, the planar member is configured as a high pressure resistant planar member, in particular capable of withstanding pressure of at least up to 1000 bar. It has been found surprisingly that even a connection of metallic sheets with nonmetallic structures by diffusion bonding results in an extremely robust planar member. Thus, the manufactured planar member may be used for applications in which high exterior and/or interior pressure is exerted to the planar member or parts thereof during operation. For example, the planar member may be configured and used as a fluidic valve having the above-mentioned features, which can be made subject to high pressure values of up to 1000 bar or more for example in the field of high performance liquid chromatography. In an embodiment, the at least one nonmetallic functional component comprises or consists of at least one of group consisting of an inorganic material, a ceramic material, a metal oxide, and a hard material (such as a hard plastic material). Examples of nonmetallic materials which are appropriate for diffusion bonding are zirconium oxide, aluminum oxide, sapphire, ruby. In particular, a ceramic may be an inorganic, nonmetallic solid comprising metal, nonmetal or metalloid atoms primarily held in ionic and covalent bonds. The crystallinity of ceramic materials ranges from highly oriented to semi-crystalline, and often completely amorphous. In an embodiment, the at least one nonmetallic functional component (206) comprises at least one of the group consisting of a seat of a fluidic valve, a movable body of a fluidic valve, and a spring element. However, many other applications are possible. In an embodiment, the described planar member may be configured as a fluidic valve having the above described features. In particular, the stack of metallic layer structures of the planar member may correspond to the stack of connected layer structures of the fluidic valve, the stack of metallic layer structures of the planar member may correspond to the stack of connected layer structures (optionally including the conduits) of the fluidic valve, and the at least one nonmetallic functional component of the planar member may correspond to the movable body and/or a valve seat of the fluidic valve. BRIEF DESCRIPTION OF DRAWINGS Other objects and many of the attendant advantages of embodiments of the present invention will be readily appreciated and become better understood by reference to the following more detailed description of embodiments in connection with the accompanied drawings. Features that are substantially or functionally equal or similar will be referred to by the same reference signs. FIG. 1 illustrates a sample separation apparatus according to an exemplary embodiment of the invention. FIG. 2 shows a fluidic valve according to an exemplary embodiment. FIG. 3 shows constituents of a fluidic valve according to an exemplary embodiment. FIG. 4 shows a detailed view of a part of a fluidic valve according to an exemplary embodiment. FIG. 5 and FIG. 6 show cross-sectional views of planar members according to exemplary embodiments of the invention manufactured using diffusion bonding and illustrated before a connection between various layer structures. The illustration in the drawing is schematic. Before describing the figures in further detail, some basic considerations of the present invention will be summarized based on which exemplary embodiments have been developed. According to an exemplary embodiment of the invention, a high pressure valve is provided which can be manufactured in diffusion bonded sheet-metal technology. According to this technology, microfluidic planar structures can be interconnected by diffusion welding to thereby obtain a high pressure robust planar microfluidic valve. In such an embodiment, it is also possible to bond ceramic components (and/or components from other nonmetallic materials) with other structures in a high pressure resistant manner. In particular, sapphire balls or spheres can be mounted in a movable way within a planar layer structure prior to a diffusion welding procedure, which can be carried out subsequently to obtain a bonding without damage or deterioration. This allows to manufacture a non-return valve in a planar layer structure architecture. In the event of high pressure load, high forces may be exerted to membrane type outer layers of planar structures. Under certain circumstances, it may be possible that such kind of membranes cannot withstand such forces without deterioration or damage. However, when mechanically supporting such membranes from an exterior position with a hydraulic counterforce, the forces acting onto the membrane from an exterior position and from an interior position, may at least partially compensate each other. In an embodiment, such a counterpart can be generated by a cushion type elastic member (for instance from polyurethane). An external piston may be implemented as actuator for the valve and may exert a force onto the elastic member which can be translated or conveyed into an interior of the stacked layer or laminate type valve, to act on the membrane. By an appropriate dimensioning, this architecture allows to obtain a force-distance transducer reducing the required actuation force for the valve. In an embodiment, it is also possible to combine a force-opened valve with a pin (for instance made of sapphire) arranged in an inlet channel region of the valve, which pin may be actuable via a membrane system from an exterior position of the valve. Advantageously, a spring type element may be arranged within the planar structure so as to equip the valve with a certain degree of elasticity. Such a spring element may be made of a metal alloy (keeping its spring properties even after a bonding procedure) or from an elastic ceramic foil. Referring now in greater detail to the drawings, FIG. 1 depicts a general schematic of a sample separation apparatus 10 configured as a liquid chromatography system. A high pressure pump as a fluid drive unit 20 receives a mobile phase from a solvent supply 25, typically via a degasser 27, which degases the solvent and thus reduces the amount of dissolved gases in the mobile phase. The fluid drive unit 20 drives the mobile phase through a separation unit 30 (such as a chromatographic column) comprising a stationary phase. A sampling unit or sample injector 40 can be provided between the mobile phase drive or fluid drive unit 20 and the separation unit 30 in order to subject or add (often referred to as sample introduction) a fluidic sample into the mobile phase. A fluidic valve (or a combination of valves) denoted as injector valve 92 is switchable between different switching positions (or combinations of positions), one of which relating to an intake of fluidic sample within the sample injector 40 at a low pressure, while another switching position relates to an introduction of previously intaken fluidic sample into a main path or separation path between fluid drive unit 20 and separation unit 30 for separation of the fluidic sample under high pressure provided by the fluid drive unit 20. The stationary phase of the separation unit 30 is configured for separating compounds of the sample liquid. A detector 50 is provided for detecting separated compounds or fractions of the fluidic sample. A fractionating unit 60 can be provided for collecting separated compounds of fluidic sample individually. While the mobile phase can be comprised of one solvent only, it may also be mixed from plural solvents, as indicated schematically in a detail of the solvent supply 25 shown in FIG. 1. Two different solvents (such as water and an organic solvent) are stored in solvent containers 82, 84 and are supplied to a mixing unit 86 in which the two solvents are mixed at a mixing point 88. Two fluidic valves 90, which may selectively open or close and may be configured according to an exemplary embodiment of the invention, may be located between the solvent containers 82, 84 and the mixing point 88. The mixing might be a low pressure mixing and provided upstream of the fluid drive unit 20, so that the fluid drive unit 20 already receives and pumps the mixed solvents as the mobile phase. Alternatively, the fluid drive unit 20 may be comprised of plural individual pumping units, with plural of the pumping units each receiving and pumping a different solvent or mixture, so that the mixing of the mobile phase (as received by the separation unit 30) occurs at high pressure and downstream of the fluid drive unit 20 (or as part thereof). The composition (mixture) of the mobile phase may be kept constant over time, the so called isocratic mode, or varied over time, the so called gradient mode. As can be taken from a further detail of the fluid drive unit 20 illustrated in FIG. 1, the fluid drive unit 20 may be composed of two serially arranged piston pump units 94, 96 each having a piston 66, 68 reciprocating within a respective pump housing 62, 64. Operation of the piston pump units 94, 96 may be synchronized or coordinated. A respective one of two fluidic valves 90, which may selectively open or close and may be configured according to an exemplary embodiment of the invention, is located upstream of the piston pump unit 94 and between the piston pump unit 94 and the piston pump unit 96. The above description shows that one or multiple fluidic valves 90 (which may be in particular On/Off valves or non-return valves) may be implemented in a fluid processing apparatus, such as the sample separation apparatus 10 operating in accordance with the principle of liquid chromatography. A data processing unit or control device 70, which can be a PC or workstation or an instrument-embedded micro-processor, can be coupled (as indicated by the dotted arrows) to one or more of the devices in the sample separation apparatus 10 in order to receive information and/or control operation. For example, the control device 70 may control operation of the fluid drive unit 20 (for instance setting control parameters) and receive therefrom information regarding the actual working conditions (such as output pressure, flow rate, etc. at an outlet of the pump). The control device 70 may also control operation of the solvent supply 25 (for instance setting the solvent/s or solvent mixture to be supplied) and/or the degasser 27 (for instance setting control parameters such as vacuum level) and may receive therefrom information regarding the actual working conditions (such as solvent composition supplied over time, flow rate, vacuum level, etc.). The control device 70 may further control operation of the sample injector 40 (for instance controlling sample injection or synchronization sample injection with operating conditions of the fluid drive unit 20). The separation unit 30 may also be controlled by the control device 70 (for instance selecting a specific flow path or column, setting operation temperature, etc.), and send—in return—information (for instance operating conditions) to the control device 70. Accordingly, the detector 50 may be controlled by the control device 70 (for instance with respect to spectral or wavelength settings, setting time constants, start/stop data acquisition), and send information (for instance about the detected sample compounds) to the control device 70. The control device 70 may also control operation of the fractionating unit 60 (for instance in conjunction with data received from the detector 50). The injector valve 92 and the fluidic valve 90 are also controllable by the control device 70 for selectively enabling or disabling specific fluidic paths within sample separation apparatus 10. FIG. 2 shows a fluidic valve 90 according to an exemplary embodiment of the invention which is configured as a non-return valve. The fluidic valve 90 can be implemented in the way as described above referring to FIG. 1, or at any other desired position within the sample separation apparatus 10 or in any other fluidic member or device. For instance, it may also be possible to configure the injector valve 92 from one or more fluidic valves 90 as shown in FIG. 2 or having an adapted configuration. The fluidic valve 90 shown in FIG. 2 comprises a stack of connected layer structures 200, for instance made of steel or titanium. Each of the layer structures 200 may have, for instance, a thickness in a range between 20 μm and 500 μm. The various layer structures 200 may be bonded to one another to form a planar laminate. During manufacture of the fluidic valve 90, the stack of layer structures 200 is connected to one another by diffusion bonding so as to obtain a flat and planar high pressure robust configuration. Since the layer structures 200 are configured as sheets (some of them as metal sheets), the fluidic valve 90 is plate-shaped and hence very flat, thereby obtaining a vertically compact arrangement. As will be described below in further detail, some of the layer structures 200 are configured as patterned layers having recesses. The fluidic valve 90 comprises a first conduit 202 (in the shown embodiment an inlet channel) configured as a recess within the stack and a second conduit 204 (in the shown embodiment an outlet channel) configured as a further recess within the stack. The function of the first conduit 202 and of the second conduit 204 can also be exchanged in each embodiment described in this application, i.e. the first conduit 202 may also function as outlet channel (i.e. may be connected to a fluidic drain), whereas the second conduit 204 may also function as inlet channel (i.e. may be connected to a fluidic source). The fluidic valve 90 may be configured or operate to function as a one-way valve, i.e. enabling only a fluid flow from the fluid inlet to the fluid outlet, or may be configured or operate to function as a two-way valve, i.e. enabling a flow from the first conduit 202 towards the second conduit 204, or from the second conduit 204 towards the first conduit 202. When the fluidic valve 90 is in an open state, fluid (in particular a liquid) is enabled to flow from the first conduit 202 into the second conduit 204. When the fluidic valve 90 is in a closed state, fluid is disabled to flow from the first conduit 202 into the second conduit 204. For switching the fluidic valve 90 between the closed state and the open state, a movable body 206 (such as a ball or sphere, but which may alternatively be configured as a pin or any other structure, and which may be preferably made of sapphire material) is located within the stack and can be moved from an exterior of the stack by an actuator 208. The movable body 206, made of sapphire, is configured for being forced to rest on a seat 210 (which may be made of a ceramic material, preferably ZrO2 or a composition of ZrO2 and Y2O3) which is formed as well as part of the layer structures 200. The actuator 208 is here embodied as a movable piston and may be made from a magnetic material so as to be movable by correspondingly powering a solenoid or electromagnet (not shown). The closed position of the valve 90 can be initiated by a downward motion of the piston according to FIG. 2 so that the piston actuator 208 sealingly presses the movable body 206 into seat 210. The open position of the valve 90 can be initiated by an upward motion of the piston according to FIG. 2 so that the piston actuator 208 releases the movable body 206 and no longer presses the latter against the seat 210, thereby allowing a fluid flow. The motion of the movable body 206 may hence be triggered or effected by a motion of the actuator 208. In the fluid disabling position, the movable body 206 sealingly sits on the seat 210 and thereby prevents flow of fluid between the first conduit 202 and the second conduit 204. However, in the absence of a vertical pressing force from the actuator 208 onto the movable body 206 against the seat 210, the movable body 206 is free to be released from the seat 210 and can therefore assume the fluid enabling position in which fluid may flow from the first conduit 202 through a central through hole in the seat 210 into the second conduit 204. To accomplish its actuation function, the actuator 208 comprises the piston which is configured for axially moving (see double arrow 280) so as to selectively actuate the movable body 206 to move into the fluid enabling position or into the fluid disabling position depending on an axial position of the piston. More precisely, the fluidic valve 90 is configured for actuating the movable body 206 using a force transmission mechanism located between piston actuator 208 and movable body 206 to selectively move into a flow enabling position (i.e. an upper position of the actuator 208 according to FIG. 2) in which flow of fluid between the first conduit 202 and the second conduit 204 is enabled, or into a flow disabling position (i.e. a lower position of the actuator 208 according to FIG. 2) in which flow of fluid between the first conduit 202 and the second conduit 204 is disabled. In order to apply spatially distributed pressure to the movable body 206, an elastic force transmission structure 212 of the force transmission mechanism is arranged between the actuator 208 and the movable body 206 and is configured for transmitting an actuation force from the actuator 208 to the movable body 206. More specifically, the force transmission structure 212 serves as a force distribution or spreading structure distributing or spreading the force applied via a relatively small contact surface 282 of the piston actuator 208 to a larger contact surface of an elastic membrane 214 of the force transmission structure 212, wherein the membrane 214 acts directly on the movable body 206. The force transmission structure 212 thus comprises the flexible or elastic membrane 214 as one of the layer structures 200 and comprises an elastic pad 216 (for instance made of elastic polyurethane material). The elastic pad 216 is arranged between the actuator 208 and the elastic membrane 214. As can be taken from FIG. 2, the elastic pad 216 has a larger lateral extension, D, than a smaller lateral extension, d, of the actuator 208. The elastic pad 216 acts as a hydraulic medium to distribute the piston pressure homogeneously on the elastic membrane 214 and supports the elastic membrane 214. The force transmission structure 212 acts as a force-travel transformer. The bulky electric pad 216, exerting a counterforce on the elastic membrane 214, also mechanically stabilizes the sensitive elastic membrane 214 which might otherwise get torn or break in the presence of a high pressure of for instance 1200 bar. From bottom to top, the stacked layer laminate according to FIG. 2 comprises a bottom cover sheet 230, covered with a patterned sheet 232 in which a recess 218 forms part of the first conduit 202 and being, in turn, covered with a seal sheet 234 in which a further recess 236 is provided which forms another part of the first conduit 202 and being, in turn, covered with a spacer layer 238 (composed of a central ceramic body 240 constituting the seat 210 and a surrounding spacer annulus 242). The spacer layer 238 is covered by a patterned seal layer 244 having a central recess 246 partially for accommodating the movable body 206 and partially for forming a fluidic interface between the first conduit 202 and the second conduit 204. A further patterned sheet 248 has a recess which constitutes the second conduit 204. A patterned spacer sheet 250 is arranged on top of the further patterned sheet 248. The spacer sheet 250 is covered by the elastic membrane 214. A central portion of the elastic membrane 214 is covered by and elastically coupled to the elastic pad 216, whereas an annularly surrounding portion of the elastic membrane 214 is immovably sandwiched between the spacer sheet 250 and a top cover sheet 252. The actuator 208 configured as reciprocating piston (i.e. being capable to move upwardly or downwardly) is longitudinally guided by a guide body 254 having an accommodation recess in which the actuator 208 is accommodated. The bottom cover sheet 230 and the top cover sheet 252 are thick metal sheets functioning as a casing and mechanically stabilizing the fluidic valve 90. It should be said that many alternatives are possible concerning the configuration of FIG. 2. For instance, it is possible to provide two membranes 214 sandwiching the movable body 206 (for instance from a top side and from a bottom side) and being actuable by two pistons (for instance from a top side and from a bottom side). FIG. 3 shows an explosive view of constituents of a planar fluidic valve 90 according to another exemplary embodiment of the invention. According to the embodiment of FIG. 3, one of the layer structures 200 is configured as a spring-type layer 300 which may be made for instance of a spring-type steel or ceramic material. The movable body 206 rests on top of the spring-type layer 300 and biases the fluidic valve 90 into a normally open state. In other words, the spring force of the spring-type layer 300 keeps the movable body 206 away from the seat 210. Only when the piston actuator 208 (not shown in FIG. 3) presses the movable body 206 onto the seat 210, the fluidic valve 90 is converted into the closed state. The spring-type layer 300 hence strengthens the elastic properties of the fluidic valve 90 and contributes to a biasing of the fluidic valve 90 into the open position. According to FIG. 3, the seat 210 is illustrated as a full layer with a central recess. However, it may be advantageous to configure the seat 210 as ceramic inlay to be inserted into a central recess of a metallic layer (see reference numeral 242 in FIG. 2) in Damascene technology and to integrally fix this structure by diffusion bonding. An advantage of such a configuration is that fitting issues and thermal stress induced by different thermal expansion properties of the ceramic material of the seat 210 on the one hand and vertically surrounding metallic material on the other hand can be suppressed. Referring to FIG. 3, the components according to reference numerals 212 (hydroformed bellow), 250 (spacer sheet), 300 (spring-type layer, for instance made of steel) and the movable body 206 (such as a sapphire ball) can be bonded with valve manifold. Alternatively, at least a part of these components may also form a separate mounted assembly. FIG. 4 shows a detailed view of a part of a fluidic valve 90 according to an exemplary embodiment of the invention. In the embodiment according to FIG. 4, the metallic material of the top cover sheet 252 presses again PEEK (Polyetheretherketone) material of the flexible membrane 214. Furthermore, the ceramic body 240 is made of a combination of ZrO2 andY2O3. FIG. 5 show a cross-sectional view of a planar member, here configured as part of a fluidic valve 90, according to an exemplary embodiment of the invention manufactured using diffusion bonding. The illustration according to FIG. 5 relates to a situation before a connection between various layer structures. The planar member comprises a stack of metallic layer structures 200, for instance made of steel or titanium, and being connected to one another by diffusion bonding. If desired, the connection strength may be further improved by connecting the metallic layer structures 200 by soldering (and additionally, if desired, by adhesive). Additionally, a nonmetallic functional component 206, which can be made of zirconium oxide, is immovably integrated within the stack. The nonmetallic functional component 206 may be configured as a valve seat. The nonmetallic functional component 206 according to FIG. 5 is integrally connected with the stack of metallic layer structures 200 by diffusion bonding. The nonmetallic functional component 206 according to FIG. 5 is embedded in one of the metallic layer structures 200 in accordance with Damascene technology. The planar member of FIG. 5 is configured as a high pressure resistant planar member 90 which is capable of withstanding pressure of at least up to 1000 bar. FIG. 6 show a cross-sectional view of a planar member, configured as part of a fluidic valve 90, according to another exemplary embodiment of the invention manufactured using diffusion bonding. The illustration according to FIG. 6 relates to a situation before a connection between various layer structures. A main difference between the embodiment of FIG. 5 and the embodiment of FIG. 6 is that according to FIG. 6 the nonmetallic functional component 206 may be configured to be movable within the layer structures 200, in particular as a movable valve body. The nonmetallic functional component 206 according to FIG. 6, which can be made of sapphire or ruby, is embedded within a void within the stack of metallic layer structures 200 by diffusion bonding. The dimension of the void is larger than a dimension of the functional component 206. Correspondingly, the nonmetallic functional component 106 according to FIG. 6 is movable within the void of the stack of metallic layer structures 200 after completion of the manufacturing procedure of the planar member. It should be noted that the term “comprising” does not exclude other elements or features and the “a” or “an” does not exclude a plurality. Also elements described in association with different embodiments may be combined. It should also be noted that reference signs in the claims shall not be construed as limiting the scope of the claims. | <SOH> BACKGROUND ART <EOH>The present invention relates to a fluidic valve, a method of manufacturing a fluidic valve, a sample separation apparatus, a planar member, and a method of manufacturing a planar member. In liquid chromatography, a fluidic sample and an eluent (liquid mobile phase) may be pumped through conduits and a separation unit such as a column in which separation of sample components takes place. The column may comprise a material which is capable of separating different components of the fluidic sample. The separation unit may be connected to other fluidic members (like a sampler or an injector, a detector) by conduits. Before the fluidic sample is introduced into a separation path between a fluid drive unit (in particular a high pressure pump) and the separation unit, a predefined amount of fluidic sample shall be intaken from a sample source (such as a sample container) via an injection needle into a sample loop by a corresponding movement of a piston within a metering device. This usually occurs in the presence of a significantly smaller pressure than what the separation unit is run with. Thereafter, an injector valve is switched so as to introduce the intaken amount of fluidic sample from the sample loop of a metering path into the separation path between fluid drive unit and the separation unit for subsequent separation. At various positions of a liquid chromatography device, fluidic vales are used. For instance, a mixing unit for mixing a mobile phase from various solvent compositions, the above mentioned pump and the above mentioned injector may comprise one or more fluidic valves for selectively enabling or disabling flow of fluid through one or more conduits. Hence, fluidic valves are useful in a sample separation apparatus. Although conventional fluidic valves are powerful fluidic tools, there is still room for improvement of fluidic valves in terms of compactness, robustness and dead volume. Moreover, also an improvement of compactness and robustness of other members (such as valves) with functional components (such as a movable valve body of a valve) is desirable. | <SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>Other objects and many of the attendant advantages of embodiments of the present invention will be readily appreciated and become better understood by reference to the following more detailed description of embodiments in connection with the accompanied drawings. Features that are substantially or functionally equal or similar will be referred to by the same reference signs. FIG. 1 illustrates a sample separation apparatus according to an exemplary embodiment of the invention. FIG. 2 shows a fluidic valve according to an exemplary embodiment. FIG. 3 shows constituents of a fluidic valve according to an exemplary embodiment. FIG. 4 shows a detailed view of a part of a fluidic valve according to an exemplary embodiment. FIG. 5 and FIG. 6 show cross-sectional views of planar members according to exemplary embodiments of the invention manufactured using diffusion bonding and illustrated before a connection between various layer structures. detailed-description description="Detailed Description" end="lead"? The illustration in the drawing is schematic. Before describing the figures in further detail, some basic considerations of the present invention will be summarized based on which exemplary embodiments have been developed. According to an exemplary embodiment of the invention, a high pressure valve is provided which can be manufactured in diffusion bonded sheet-metal technology. According to this technology, microfluidic planar structures can be interconnected by diffusion welding to thereby obtain a high pressure robust planar microfluidic valve. In such an embodiment, it is also possible to bond ceramic components (and/or components from other nonmetallic materials) with other structures in a high pressure resistant manner. In particular, sapphire balls or spheres can be mounted in a movable way within a planar layer structure prior to a diffusion welding procedure, which can be carried out subsequently to obtain a bonding without damage or deterioration. This allows to manufacture a non-return valve in a planar layer structure architecture. In the event of high pressure load, high forces may be exerted to membrane type outer layers of planar structures. Under certain circumstances, it may be possible that such kind of membranes cannot withstand such forces without deterioration or damage. However, when mechanically supporting such membranes from an exterior position with a hydraulic counterforce, the forces acting onto the membrane from an exterior position and from an interior position, may at least partially compensate each other. In an embodiment, such a counterpart can be generated by a cushion type elastic member (for instance from polyurethane). An external piston may be implemented as actuator for the valve and may exert a force onto the elastic member which can be translated or conveyed into an interior of the stacked layer or laminate type valve, to act on the membrane. By an appropriate dimensioning, this architecture allows to obtain a force-distance transducer reducing the required actuation force for the valve. In an embodiment, it is also possible to combine a force-opened valve with a pin (for instance made of sapphire) arranged in an inlet channel region of the valve, which pin may be actuable via a membrane system from an exterior position of the valve. Advantageously, a spring type element may be arranged within the planar structure so as to equip the valve with a certain degree of elasticity. Such a spring element may be made of a metal alloy (keeping its spring properties even after a bonding procedure) or from an elastic ceramic foil. Referring now in greater detail to the drawings, FIG. 1 depicts a general schematic of a sample separation apparatus 10 configured as a liquid chromatography system. A high pressure pump as a fluid drive unit 20 receives a mobile phase from a solvent supply 25 , typically via a degasser 27 , which degases the solvent and thus reduces the amount of dissolved gases in the mobile phase. The fluid drive unit 20 drives the mobile phase through a separation unit 30 (such as a chromatographic column) comprising a stationary phase. A sampling unit or sample injector 40 can be provided between the mobile phase drive or fluid drive unit 20 and the separation unit 30 in order to subject or add (often referred to as sample introduction) a fluidic sample into the mobile phase. A fluidic valve (or a combination of valves) denoted as injector valve 92 is switchable between different switching positions (or combinations of positions), one of which relating to an intake of fluidic sample within the sample injector 40 at a low pressure, while another switching position relates to an introduction of previously intaken fluidic sample into a main path or separation path between fluid drive unit 20 and separation unit 30 for separation of the fluidic sample under high pressure provided by the fluid drive unit 20 . The stationary phase of the separation unit 30 is configured for separating compounds of the sample liquid. A detector 50 is provided for detecting separated compounds or fractions of the fluidic sample. A fractionating unit 60 can be provided for collecting separated compounds of fluidic sample individually. While the mobile phase can be comprised of one solvent only, it may also be mixed from plural solvents, as indicated schematically in a detail of the solvent supply 25 shown in FIG. 1 . Two different solvents (such as water and an organic solvent) are stored in solvent containers 82 , 84 and are supplied to a mixing unit 86 in which the two solvents are mixed at a mixing point 88 . Two fluidic valves 90 , which may selectively open or close and may be configured according to an exemplary embodiment of the invention, may be located between the solvent containers 82 , 84 and the mixing point 88 . The mixing might be a low pressure mixing and provided upstream of the fluid drive unit 20 , so that the fluid drive unit 20 already receives and pumps the mixed solvents as the mobile phase. Alternatively, the fluid drive unit 20 may be comprised of plural individual pumping units, with plural of the pumping units each receiving and pumping a different solvent or mixture, so that the mixing of the mobile phase (as received by the separation unit 30 ) occurs at high pressure and downstream of the fluid drive unit 20 (or as part thereof). The composition (mixture) of the mobile phase may be kept constant over time, the so called isocratic mode, or varied over time, the so called gradient mode. As can be taken from a further detail of the fluid drive unit 20 illustrated in FIG. 1 , the fluid drive unit 20 may be composed of two serially arranged piston pump units 94 , 96 each having a piston 66 , 68 reciprocating within a respective pump housing 62 , 64 . Operation of the piston pump units 94 , 96 may be synchronized or coordinated. A respective one of two fluidic valves 90 , which may selectively open or close and may be configured according to an exemplary embodiment of the invention, is located upstream of the piston pump unit 94 and between the piston pump unit 94 and the piston pump unit 96 . The above description shows that one or multiple fluidic valves 90 (which may be in particular On/Off valves or non-return valves) may be implemented in a fluid processing apparatus, such as the sample separation apparatus 10 operating in accordance with the principle of liquid chromatography. A data processing unit or control device 70 , which can be a PC or workstation or an instrument-embedded micro-processor, can be coupled (as indicated by the dotted arrows) to one or more of the devices in the sample separation apparatus 10 in order to receive information and/or control operation. For example, the control device 70 may control operation of the fluid drive unit 20 (for instance setting control parameters) and receive therefrom information regarding the actual working conditions (such as output pressure, flow rate, etc. at an outlet of the pump). The control device 70 may also control operation of the solvent supply 25 (for instance setting the solvent/s or solvent mixture to be supplied) and/or the degasser 27 (for instance setting control parameters such as vacuum level) and may receive therefrom information regarding the actual working conditions (such as solvent composition supplied over time, flow rate, vacuum level, etc.). The control device 70 may further control operation of the sample injector 40 (for instance controlling sample injection or synchronization sample injection with operating conditions of the fluid drive unit 20 ). The separation unit 30 may also be controlled by the control device 70 (for instance selecting a specific flow path or column, setting operation temperature, etc.), and send—in return—information (for instance operating conditions) to the control device 70 . Accordingly, the detector 50 may be controlled by the control device 70 (for instance with respect to spectral or wavelength settings, setting time constants, start/stop data acquisition), and send information (for instance about the detected sample compounds) to the control device 70 . The control device 70 may also control operation of the fractionating unit 60 (for instance in conjunction with data received from the detector 50 ). The injector valve 92 and the fluidic valve 90 are also controllable by the control device 70 for selectively enabling or disabling specific fluidic paths within sample separation apparatus 10 . FIG. 2 shows a fluidic valve 90 according to an exemplary embodiment of the invention which is configured as a non-return valve. The fluidic valve 90 can be implemented in the way as described above referring to FIG. 1 , or at any other desired position within the sample separation apparatus 10 or in any other fluidic member or device. For instance, it may also be possible to configure the injector valve 92 from one or more fluidic valves 90 as shown in FIG. 2 or having an adapted configuration. The fluidic valve 90 shown in FIG. 2 comprises a stack of connected layer structures 200 , for instance made of steel or titanium. Each of the layer structures 200 may have, for instance, a thickness in a range between 20 μm and 500 μm. The various layer structures 200 may be bonded to one another to form a planar laminate. During manufacture of the fluidic valve 90 , the stack of layer structures 200 is connected to one another by diffusion bonding so as to obtain a flat and planar high pressure robust configuration. Since the layer structures 200 are configured as sheets (some of them as metal sheets), the fluidic valve 90 is plate-shaped and hence very flat, thereby obtaining a vertically compact arrangement. As will be described below in further detail, some of the layer structures 200 are configured as patterned layers having recesses. The fluidic valve 90 comprises a first conduit 202 (in the shown embodiment an inlet channel) configured as a recess within the stack and a second conduit 204 (in the shown embodiment an outlet channel) configured as a further recess within the stack. The function of the first conduit 202 and of the second conduit 204 can also be exchanged in each embodiment described in this application, i.e. the first conduit 202 may also function as outlet channel (i.e. may be connected to a fluidic drain), whereas the second conduit 204 may also function as inlet channel (i.e. may be connected to a fluidic source). The fluidic valve 90 may be configured or operate to function as a one-way valve, i.e. enabling only a fluid flow from the fluid inlet to the fluid outlet, or may be configured or operate to function as a two-way valve, i.e. enabling a flow from the first conduit 202 towards the second conduit 204 , or from the second conduit 204 towards the first conduit 202 . When the fluidic valve 90 is in an open state, fluid (in particular a liquid) is enabled to flow from the first conduit 202 into the second conduit 204 . When the fluidic valve 90 is in a closed state, fluid is disabled to flow from the first conduit 202 into the second conduit 204 . For switching the fluidic valve 90 between the closed state and the open state, a movable body 206 (such as a ball or sphere, but which may alternatively be configured as a pin or any other structure, and which may be preferably made of sapphire material) is located within the stack and can be moved from an exterior of the stack by an actuator 208 . The movable body 206 , made of sapphire, is configured for being forced to rest on a seat 210 (which may be made of a ceramic material, preferably ZrO 2 or a composition of ZrO 2 and Y 2 O 3 ) which is formed as well as part of the layer structures 200 . The actuator 208 is here embodied as a movable piston and may be made from a magnetic material so as to be movable by correspondingly powering a solenoid or electromagnet (not shown). The closed position of the valve 90 can be initiated by a downward motion of the piston according to FIG. 2 so that the piston actuator 208 sealingly presses the movable body 206 into seat 210 . The open position of the valve 90 can be initiated by an upward motion of the piston according to FIG. 2 so that the piston actuator 208 releases the movable body 206 and no longer presses the latter against the seat 210 , thereby allowing a fluid flow. The motion of the movable body 206 may hence be triggered or effected by a motion of the actuator 208 . In the fluid disabling position, the movable body 206 sealingly sits on the seat 210 and thereby prevents flow of fluid between the first conduit 202 and the second conduit 204 . However, in the absence of a vertical pressing force from the actuator 208 onto the movable body 206 against the seat 210 , the movable body 206 is free to be released from the seat 210 and can therefore assume the fluid enabling position in which fluid may flow from the first conduit 202 through a central through hole in the seat 210 into the second conduit 204 . To accomplish its actuation function, the actuator 208 comprises the piston which is configured for axially moving (see double arrow 280 ) so as to selectively actuate the movable body 206 to move into the fluid enabling position or into the fluid disabling position depending on an axial position of the piston. More precisely, the fluidic valve 90 is configured for actuating the movable body 206 using a force transmission mechanism located between piston actuator 208 and movable body 206 to selectively move into a flow enabling position (i.e. an upper position of the actuator 208 according to FIG. 2 ) in which flow of fluid between the first conduit 202 and the second conduit 204 is enabled, or into a flow disabling position (i.e. a lower position of the actuator 208 according to FIG. 2 ) in which flow of fluid between the first conduit 202 and the second conduit 204 is disabled. In order to apply spatially distributed pressure to the movable body 206 , an elastic force transmission structure 212 of the force transmission mechanism is arranged between the actuator 208 and the movable body 206 and is configured for transmitting an actuation force from the actuator 208 to the movable body 206 . More specifically, the force transmission structure 212 serves as a force distribution or spreading structure distributing or spreading the force applied via a relatively small contact surface 282 of the piston actuator 208 to a larger contact surface of an elastic membrane 214 of the force transmission structure 212 , wherein the membrane 214 acts directly on the movable body 206 . The force transmission structure 212 thus comprises the flexible or elastic membrane 214 as one of the layer structures 200 and comprises an elastic pad 216 (for instance made of elastic polyurethane material). The elastic pad 216 is arranged between the actuator 208 and the elastic membrane 214 . As can be taken from FIG. 2 , the elastic pad 216 has a larger lateral extension, D, than a smaller lateral extension, d, of the actuator 208 . The elastic pad 216 acts as a hydraulic medium to distribute the piston pressure homogeneously on the elastic membrane 214 and supports the elastic membrane 214 . The force transmission structure 212 acts as a force-travel transformer. The bulky electric pad 216 , exerting a counterforce on the elastic membrane 214 , also mechanically stabilizes the sensitive elastic membrane 214 which might otherwise get torn or break in the presence of a high pressure of for instance 1200 bar. From bottom to top, the stacked layer laminate according to FIG. 2 comprises a bottom cover sheet 230 , covered with a patterned sheet 232 in which a recess 218 forms part of the first conduit 202 and being, in turn, covered with a seal sheet 234 in which a further recess 236 is provided which forms another part of the first conduit 202 and being, in turn, covered with a spacer layer 238 (composed of a central ceramic body 240 constituting the seat 210 and a surrounding spacer annulus 242 ). The spacer layer 238 is covered by a patterned seal layer 244 having a central recess 246 partially for accommodating the movable body 206 and partially for forming a fluidic interface between the first conduit 202 and the second conduit 204 . A further patterned sheet 248 has a recess which constitutes the second conduit 204 . A patterned spacer sheet 250 is arranged on top of the further patterned sheet 248 . The spacer sheet 250 is covered by the elastic membrane 214 . A central portion of the elastic membrane 214 is covered by and elastically coupled to the elastic pad 216 , whereas an annularly surrounding portion of the elastic membrane 214 is immovably sandwiched between the spacer sheet 250 and a top cover sheet 252 . The actuator 208 configured as reciprocating piston (i.e. being capable to move upwardly or downwardly) is longitudinally guided by a guide body 254 having an accommodation recess in which the actuator 208 is accommodated. The bottom cover sheet 230 and the top cover sheet 252 are thick metal sheets functioning as a casing and mechanically stabilizing the fluidic valve 90 . It should be said that many alternatives are possible concerning the configuration of FIG. 2 . For instance, it is possible to provide two membranes 214 sandwiching the movable body 206 (for instance from a top side and from a bottom side) and being actuable by two pistons (for instance from a top side and from a bottom side). FIG. 3 shows an explosive view of constituents of a planar fluidic valve 90 according to another exemplary embodiment of the invention. According to the embodiment of FIG. 3 , one of the layer structures 200 is configured as a spring-type layer 300 which may be made for instance of a spring-type steel or ceramic material. The movable body 206 rests on top of the spring-type layer 300 and biases the fluidic valve 90 into a normally open state. In other words, the spring force of the spring-type layer 300 keeps the movable body 206 away from the seat 210 . Only when the piston actuator 208 (not shown in FIG. 3 ) presses the movable body 206 onto the seat 210 , the fluidic valve 90 is converted into the closed state. The spring-type layer 300 hence strengthens the elastic properties of the fluidic valve 90 and contributes to a biasing of the fluidic valve 90 into the open position. According to FIG. 3 , the seat 210 is illustrated as a full layer with a central recess. However, it may be advantageous to configure the seat 210 as ceramic inlay to be inserted into a central recess of a metallic layer (see reference numeral 242 in FIG. 2 ) in Damascene technology and to integrally fix this structure by diffusion bonding. An advantage of such a configuration is that fitting issues and thermal stress induced by different thermal expansion properties of the ceramic material of the seat 210 on the one hand and vertically surrounding metallic material on the other hand can be suppressed. Referring to FIG. 3 , the components according to reference numerals 212 (hydroformed bellow), 250 (spacer sheet), 300 (spring-type layer, for instance made of steel) and the movable body 206 (such as a sapphire ball) can be bonded with valve manifold. Alternatively, at least a part of these components may also form a separate mounted assembly. FIG. 4 shows a detailed view of a part of a fluidic valve 90 according to an exemplary embodiment of the invention. In the embodiment according to FIG. 4 , the metallic material of the top cover sheet 252 presses again PEEK (Polyetheretherketone) material of the flexible membrane 214 . Furthermore, the ceramic body 240 is made of a combination of ZrO 2 andY 2 O 3 . FIG. 5 show a cross-sectional view of a planar member, here configured as part of a fluidic valve 90 , according to an exemplary embodiment of the invention manufactured using diffusion bonding. The illustration according to FIG. 5 relates to a situation before a connection between various layer structures. The planar member comprises a stack of metallic layer structures 200 , for instance made of steel or titanium, and being connected to one another by diffusion bonding. If desired, the connection strength may be further improved by connecting the metallic layer structures 200 by soldering (and additionally, if desired, by adhesive). Additionally, a nonmetallic functional component 206 , which can be made of zirconium oxide, is immovably integrated within the stack. The nonmetallic functional component 206 may be configured as a valve seat. The nonmetallic functional component 206 according to FIG. 5 is integrally connected with the stack of metallic layer structures 200 by diffusion bonding. The nonmetallic functional component 206 according to FIG. 5 is embedded in one of the metallic layer structures 200 in accordance with Damascene technology. The planar member of FIG. 5 is configured as a high pressure resistant planar member 90 which is capable of withstanding pressure of at least up to 1000 bar. FIG. 6 show a cross-sectional view of a planar member, configured as part of a fluidic valve 90 , according to another exemplary embodiment of the invention manufactured using diffusion bonding. The illustration according to FIG. 6 relates to a situation before a connection between various layer structures. A main difference between the embodiment of FIG. 5 and the embodiment of FIG. 6 is that according to FIG. 6 the nonmetallic functional component 206 may be configured to be movable within the layer structures 200 , in particular as a movable valve body. The nonmetallic functional component 206 according to FIG. 6 , which can be made of sapphire or ruby, is embedded within a void within the stack of metallic layer structures 200 by diffusion bonding. The dimension of the void is larger than a dimension of the functional component 206 . Correspondingly, the nonmetallic functional component 106 according to FIG. 6 is movable within the void of the stack of metallic layer structures 200 after completion of the manufacturing procedure of the planar member. It should be noted that the term “comprising” does not exclude other elements or features and the “a” or “an” does not exclude a plurality. Also elements described in association with different embodiments may be combined. It should also be noted that reference signs in the claims shall not be construed as limiting the scope of the claims. detailed-description description="Detailed Description" end="tail"? | G01N3020 | 20180209 | 20180830 | G01N3020 | 0 | HOPKINS, BRANDI N | STACKED LAYER-TYPE MEMBER WITH INTEGRATED FUNCTIONAL COMPONENT | UNDISCOUNTED | 0 | PENDING | G01N | 2,018 |
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15,752,138 | PENDING | WIRELESS POWER TRANSFER SYSTEM AND DRIVING METHOD THEREFOR | The present invention provides a method of driving a power transfer unit wirelessly transferring power, the method including: detecting a voltage and a current of the power transfer unit; detecting a change in the voltage and the current; and sensing that a battery receiving wireless power from the power transfer unit is being fully charged on the basis of the change in the voltage and the current. | 1. A method of driving a power transfer unit wirelessly transferring power, the method comprising: determining a change in a voltage and a current of the power transfer unit; and determining whether a battery in a power receiver unit receiving wireless power from the power transfer unit is being fully charged on the basis of a change in the voltage and the current. 2. The method of claim 1, wherein the determining of a change in a voltage and a current measures values of the voltage for a predetermined time and detects whether the measured values of the voltage are reduced, and measures values of the current for a predetermined time and determines whether the measured values of the current are maintained. 3. The method of claim 2, wherein the determining whether the current is reduced determines whether the voltage is reduced step by step. 4. The method of claim 3, wherein when the batter is being fully charged, wireless power transfer is stopped. 5. The method of claim 1, wherein the voltage of an output voltage of a DC/DC converter of the power transfer unit, and the current is an output current of a DC/DC converter of the power transfer unit. 6. The method of claim 1, wherein a change in a voltage of the power transfer unit is determined on the basis of an output voltage instruction value of the DC/DC converter. 7. The method of claim 1, wherein, the voltage and the current are an input voltage and an input current of a transfer-side coil of the power transfer unit. 8. A method of driving a power receiver unit charging a batter by wirelessly receiving power from a power transfer unit, the method comprising: reducing step by step a current applied to the battery when a charge amount of the battery is a first charge amount to a second charge amount larger than the first charge amount; determining whether power is transferred from the power transfer unit recognizing a reduction of the current; and determining that the battery has been fully charged when power transfer from the power transfer unit is stopped. 9. The method of claim 8, wherein the first charge amount is a charge amount indicating a full charge start state of the battery, the second charge amount is a charge amount indicating a full charge completion state of the battery, and when the charge amount of the battery is within the range of the first to second charge amounts, the battery is being fully charged. 10. The method of claim 8, wherein a voltage applied to the battery in the reducing of a current applied to the battery is constant. 11. A power transfer wirelessly transferring power to a power receiver unit, comprising: a DC/DC converter; and a controller determining whether a battery of a power receiver unit, which receives wireless power from the power transfer unit, is being fully charged on the basis of a change in an output signal of the DC/DC converter. 12. The power transfer unit of claim 11, wherein the output signal is an output current and an output voltage of the DC/DC converter. 13. The power transfer unit of claim 12, further comprising a detector detecting the output current and the output voltage. 14. The power transfer unit of claim 12, further comprising a detector detecting the output current, wherein the controller adjusts an output voltage for the DC/DC converter on the basis of an output voltage instruction value, and the controller determines a change in the output voltage on the basis of the output voltage instruction value. 15. The power transfer unit of claim 12, wherein whether the output current is constant and the output voltage is reduced step by step for a predetermined time is determined. 16. The power transfer unit of claim 14, wherein whether the output current is constant and the output voltage instruction value is reduced step by step for a predetermined time is determined. 17. The power transfer unit of claim 11, wherein when the power transfer unit determines that the battery is being fully charged, the power transfer unit stops wireless power transfer after a predetermined time passes. 18. The power transfer unit of claim 11, wherein the power receiver unit comprises: a receiver-side coil receiving the power; a battery charged with the power; and a battery manager controlling the battery, wherein the battery manager reduces step by step a current applied to the battery when a charge amount of the battery is a first charge amount to a second charge amount larger than the first charge amount, and determines that the battery has been fully charged when power transfer from the power transfer unit recognizing the reduction of the current is stopped. 19. The power transfer unit of claim 18, wherein the battery manager determines that the first charge amount is a charge amount indicating a full charge start state of the battery, that the second charge amount is a charge amount indicating a full charge completion state of the battery, and that the battery is being fully charged when the charge amount of the battery is within the range of the first to second charge amounts. 20. The power transfer unit of claim 18, wherein the power receiver unit receives a message of stopping wireless power transfer from the power transfer unit recognizing the reduction of the current. | TECHNICAL FIELD The present invention relates to a wireless power transfer system and a method of driving the wireless power transfer system. BACKGROUND ART In general, various electronic devices are equipped with a battery and use the power stored in the battery. The batteries of electronic devices can be replaced and can also be recharged. To this end, electronic devices have a contact terminal for connecting an external charger. That is, electronic devices are electrically connected with a charger through the contact terminal. However, since the contact terminals of electronic device are exposed to the outside, they may be contaminated by dirt or a short circuit may occur due to humidity. In these cases, there is a problem that the batteries of electronic devices are not charged due to poor contact between a contact terminal and a charger. In order to solve this problem, wire power transfer (WPT) has been proposed to wirelessly charge electronic devices. Wireless power transfer, which is a technology of transferring power through a space without a wire, is a technology that maximizes convenience in supplying power to mobile devices and digital appliances. A wireless power transfer system has advantages such as saving energy by controlling power consumption in real time, overcoming a spatial limit in power supply, and reducing the amount of waste of batteries by recharging batteries. A magnetic induction method and a magnetic resonance method are representative of methods of implementing a wireless power transfer system. The magnetic induction method is a non-contact energy transfer technology that supplies a current to one of two coils disposed close to each other to generate magnetic flux, thereby generating an electromotive force at the other coil, and can use frequencies of hundreds of kHz. The magnetic resonance method, which is a technology that uses only an electric field or a magnetic field without using electromagnetic waves or a current, has over several meters of available power transfer distance and can use bands of several MHz. A wireless power transfer system includes a transmitter that wirelessly transfers power and a receiver that receives power and charges loads such as a battery. A charge method by receivers, that is, any one of the magnetic induction method and the magnetic resonance method can be selected and transmitters that can wirelessly transfer power in correspondence to the charge methods by receivers have been developed. When the battery of a receiver is fully charged, a transmitter does not recognize this fact and keeps transferring power, so power is lost and the temperature of the transmitter and receiver is increased due to heat generation thereof. DISCLOSURE Technical Problem An embodiment provides a wireless power transfer system for solving the problem of a loss of power and heat generation when it is not recognized that a battery has been fully charged, by stopping wireless power transfer by sensing that the battery has been fully charged, using a power receiver unit, even if a power transfer unit does not receive a separate message from the power receiver unit. Technical Solution An embodiment provides a method of driving a power transfer unit wirelessly transferring power, the method including: determining a change in a voltage and a current of the power transfer unit; and determining whether a battery in a power receiver unit receiving wireless power from the power transfer unit is being fully charged on the basis of a change in the voltage and the current. An embodiment provides a method of driving a power transfer unit, in which the determining of a change in a voltage and a current measures values of the voltage for a predetermined time and detects whether the measured values of the voltage are reduced, and measures values of the current for a predetermined time and determines whether the measured values of the current are maintained. An embodiment provides a method of driving a power transfer unit, in which the determining whether the current is reduced determines whether the voltage is reduced step by step. An embodiment provides a method of driving a power transfer unit, in which when the battery is being fully charged, wireless power transfer is stopped. An embodiment provides a method of driving a power transfer unit, in which the voltage of an output voltage of a DC/DC converter of the power transfer unit, and the current is an output current of a DC/DC converter of the power transfer unit. An embodiment provides a method of driving a power transfer unit, in which a change in a voltage of the power transfer unit is determined on the basis of an output voltage instruction value of the DC/DC converter. An embodiment provides a method of driving a power transfer unit, in which the voltage and the current are an input voltage and an input current of a transfer-side coil of the power transfer unit. An embodiment provides a method of driving a power receiver unit charging a batter by wirelessly receiving power from a power transfer unit, the method including: reducing step by step a current applied to the battery when a charge amount of the battery is a first charge amount to a second charge amount larger than the first charge amount; determining whether power is transferred from the power transfer unit recognizing a reduction of the current; and determining that the battery has been fully charged when power transfer from the power transfer unit is stopped. An embodiment provides a method of driving a power receiver unit, in which the first charge amount is a charge amount indicating a full charge start state of the battery, the second charge amount is a charge amount indicating a full charge completion state of the battery, and when the charge amount of the battery is within the range of the first to second charge amounts, the battery is being fully charged. An embodiment provides a method of driving a power receiver unit, in which a voltage applied to the battery in the reducing of a current applied to the battery is constant. An embodiment provides a power transfer unit wirelessly transferring power, including: a DC/DC converter; and a controller determining whether a battery of a power receiver unit, which receives wireless power from the power transfer unit, is being fully charged on the basis of a change in an output signal of the DC/DC converter. An embodiment provides a power transfer unit, in which the output signal is an output current and an output voltage of the DC/DC converter. An embodiment provides a power transfer unit, the power transfer unit further including a detector detecting the output current and the output voltage. An embodiment provides a power transfer unit, the power transfer unit further including a detector detecting the output current, in which the controller adjusts an output voltage for the DC/DC converter on the basis of an output voltage instruction value, and the controller determines a change in the output voltage on the basis of the output voltage instruction value. An embodiment provides a power transfer unit, in which whether the output current is constant and the output voltage is reduced step by step for a predetermined time is determined. An embodiment provides a power transfer unit, in which whether the output current is constant and the output voltage instruction value is reduced step by step for a predetermined time is determined. An embodiment provides a power transfer unit, in which when the power transfer unit determines that the battery is being fully charged, the power transfer unit stops wireless power transfer after a predetermined time passes. An embodiment provides a power receiver unit wirelessly receiving power from a power transfer unit, including: a receiver-side coil receiving the power; a battery charged with the power; and a battery manager controlling the battery, in which the battery manager reduces step by step a current applied to the battery when a charge amount of the battery is a first charge amount to a second charge amount larger than the first charge amount, and determines that the battery has been fully charged when power transfer from the power transfer unit recognizing the reduction of the current is stopped. An embodiment provides a power receiver unit, in which the battery manager determines that the first charge amount is a charge amount indicating a full charge start state of the battery, that the second charge amount is a charge amount indicating a full charge completion state of the battery, and that the battery is being fully charged when the charge amount of the battery is within the range of the first to second charge amounts. An embodiment provides a power receiver unit, in which the power receiver unit receives a message of stopping wireless power transfer from the power transfer unit recognizing the reduction of the current. Advantageous Effects According to an embodiment, even if a power transfer unit does not receive a separate message from a power receiver unit, it is possible to sense that a battery of the power receiver unit has been fully charged. Accordingly, it is possible to remove a risk due to non-reception of a message between the power transfer unit and the power reception unit. Further, when the power transfer unit receives a full charge message after the power receiver unit is fully charged, it is possible to prevent unnecessary waste of power between the units. Further, since the power transfer unit determines whether to stop wireless power transfer by determining by itself the charge state of a load, it is possible to a loss of power and heat generation due to non-recognition of full charge completion of the battery. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is diagram showing a magnetic induction equivalent circuit. FIG. 2 is diagram showing a magnetic resonance equivalent circuit. FIGS. 3A and 3B are block diagrams showing a power transfer unit that is one of sub-systems constituting a wireless power transfer system; FIGS. 4A and 4B are block diagrams showing a power receiver unit that is one of sub-systems constituting a wireless power transfer system; FIG. 5 is a diagram showing the operation flow of a wireless power transfer system, based on the operation state of a power transfer unit according to an embodiment; FIG. 6 is a diagram showing the operation flow of a wireless power transfer system, based on the operation state of a power transfer unit according to another embodiment; FIG. 7 is a diagram showing the operation flow of a wireless power transfer system according to another embodiment; FIGS. 8A and 8B are equivalent circuit diagrams of a power transfer unit and a power receiver unit; FIG. 9 is a flowchart of driving a power transfer unit according to an embodiment; FIG. 10 is a flowchart of driving a power receiver unit according to an embodiment; and FIG. 11 is a graph showing the magnitude of a current applied to a battery in accordance with a full charge state of the battery over time. BEST MODE FOR THE INVENTION A wireless power transfer system including a power transfer unit having a function of wirelessly transmitting power and a power receiver unit wirelessly receiving power according to an embodiment of the present invention is described hereafter in detail with reference to the drawings. Embodiments to be described hereafter are provided as examples for sufficiently communicating the spirit of the present invention to those skilled in the art. Accordingly, the present invention is not limited to the following embodiments and may be implemented by other ways. The sizes, thicknesses, etc. of devices may be exaggerated for convenience in the drawings. The like reference numerals indicate substantially the like components throughout the specification. Embodiments may include a communication system that selectively uses various frequency bands from a low frequency (50 kHz) to a high frequency (15 MHz) to wirelessly transfer power and can exchange data and control signals for system control. Embodiments can be applied to various industrial fields such as a mobile terminal industry using electronic devices, which use or require a battery, a smart watch industry, a computer and notebook industry, an appliance industry, an electric vehicle industry, a medical device industry, and a robot industry. Embodiments may consider a system that can transfer power to one or more devices, using one or more transfer coils. According to embodiments, it is possible to the problem of a deficit of power in a battery for mobile devices such as a smartphone and a notebook, and for example, when a smartphone and a notebook are used on a wireless charger pad on a table, batteries are automatically charged and can be used for a long time. Further, it is possible to charge and use various mobile devices regardless of charging terminals that are different by mobile device manufacturers only by installing a wireless charger pad in public places such as a cafe, an airport, a taxi, an office, and a restaurant. Further, when a wireless power transfer technology is applied to home appliances such as a cleaner and an electric fan, it is not required to look for a power cable, disarranged electric wires cannot be cleared in houses, electric wires in building can be reduced, and spatial availability can be increased. Further, at present, it takes long time to charge an electric vehicle with the electricity for home use, but if high power is transmitted by a wireless power transfer technology, the charging time can be reduced. Furthermore, if a wireless charging facility is installed on the floor of a parking place, it is possible to clear up the inconvenience that there is a need for preparing a power cable around an electric vehicle. Terminologies and abbreviations that are used in embodiments are as follows. Wireless power transfer system: A system that provides wireless power transfer in a magnetic field area. Wireless power transfer system-charger; Power transfer unit (PTU): A device that provides wireless power transfer to a power receiver unit in a magnetic field area and it may be referred to a transfer device or a transmitter. Wireless power receiver system-device; Power receiver unit (PRU): A device that receives wireless power transfer from a power transfer unit in a magnetic field area and it may be referred to as a reception device or a receiver. Charging area: An area where wireless power transfer is performed in a magnetic field area and it may change in accordance with the sizes of application products, requested power, and an operation frequency. S scattering parameter: A ratio of an output voltage to an input voltage in frequency distribution and it may be a ratio of an output port to an input port (transmission; S21), or a reflection value of each of input/output ports, that is, an output value (reflection; S11, S22) that is reflected back by its input. Quality factor (Q): Q in resonance is a quality of frequency selection, the higher the Q, the better the resonance characteristic, and Q may be expressed as a ratio of energy kept in an resonator and lost energy. The principle of wirelessly transferring power may be classified into a magnetic induction method and a magnetic resonance method. The magnetic induction method is a non-contact energy transfer technology that puts a source inductor Ls and a load inductor Ll and supplies a current to the source inductor Ls to generate magnetic flux, thereby generating an electromotive force at the load inductor Ll. The magnetic resonance method is a technology that wirelessly transfers energy using a resonance scheme in which two resonators are coupled and magnetic resonance is generated by a natural frequency between the resonators, so the resonators are vibrated at the same frequency, thereby generating an electric field and a magnetic field within the same wavelength range. FIG. 1 is diagram showing a magnetic induction equivalent circuit. Referring to FIG. 1, in the magnetic induction equivalent circuit, a power transfer unit may be implemented by a source voltage Vs and a source resistor Rs according to a device that supplies power, a source capacitor Cs for impedance matching, and a source coil Ls for magnetic coupling with a power receiver unit, and the power receiver unit may be implemented by a load resistor Rl that is an equivalent resistor, a load capacitor Cl for impedance matching, and a load coil Ll for magnetic coupling with the power transfer unit, in which the degree of magnetic coupling of the source coil Ls and the load coil Ll can be expressed as mutual inductance Msl. When a ratio S21 of an output voltage to an input voltage is obtained from a magnetic induction equivalent circuit composed of only coils without a source capacitor Cs and a load capacitor Cl for impedance matching and the maximum power transfer condition is found from the ratio, the maximum power transfer condition satisfies the following Equation 1. Ls/Rs=Ll/Rl Equation 1 When a ratio of the inductance of the transfer coil Ls and the source resistor Rs and a ratio of the inductance of the load coil Ll and the load resistor Rl are the same in Equation 1, the maximum power transfer is possible. In a system having only inductance, there is no capacitor that can compensate for reactance, so the reflection value S11 of an I/O port cannot be 0 at the point where the maximum power is transmitted, and the power transmission efficiency can be largely changed in accordance with mutual inductance Msl. Accordingly, a source capacitor Cs may be added to a power transfer unit as a compensation capacitor for impedance matching and a load capacitor Cl may be added to the power receiver unit. The compensation capacitors Cs and Cl, for example, may be connected in series or in parallel to a reception coil Ls and a load coil Ll, respectively. Further, not only the compensation capacitors, but passive devices such as additional capacitors and inductors may be further added to the power receiver unit and the power transfer unit for impedance matching. FIG. 2 is diagram showing a magnetic resonance equivalent circuit. Referring to FIG. 2, in the magnetic resonance equivalent circuit, the power transfer unit is implemented by a source coil forming a closed circuit by connecting a source voltage Vs, a source resistor Rs, and a source inductor Ls in series, and a transfer-side resonant coil forming a closed circuit by connecting a transfer-side resonant inductor L1 and a transfer-side resonant capacitor C1 in series. Further, a power receiver unit is implemented by a load coil forming a closed circuit by connecting a load resistor Rl and a load inductor Ll and a reception-side resonant coil forming a closed circuit by connecting a reception-side resonant inductor L2 and a reception-side resonant capacitor C2 in series. Further, the source inductor Ls and the transfer-side resonant inductor L1 are magnetically coupled with a coupling coefficient K01, the load inductor Ll and the load-side resonant inductor L2 are magnetically coupled with a coupling coefficient K23, and the reception-side resonant inductor L1 and the reception-side resonant inductor L2 are magnetically coupled with a coupling coefficient K12. An equivalent circuit according to another embodiment may be composed of only a transfer-side resonant coil and a reception-side resonant coil without a source coil and/or a load coil. According to the magnetic induction method, when the resonant frequencies of two resonator are the same, most of the energy of the resonator of a power transfer unit is transmitted to the resonator of the power receiver unit, so the power transmission efficiency can be improved, and the efficiency in the magnetic resonance method is improved when the following Equation 2 is satisfied. k/Γ>>1 (k is a coupling coefficient and Γ is a damping rate) Equation 2 In the magnetic resonance method, a device for impedance matching may be added to increase the efficiency and the impedance matching device may be a passive device such as an inductor and a capacitor. A wireless power transfer system for transmitting power, using the magnetic induction method or the magnetic resonance method, on the basis of the wireless power transfer principle described above is described hereafter. <Power Transfer Unit> FIGS. 3A and 3B are block diagrams showing a power transfer unit that is one of sub-systems constituting a wireless power transfer system. Referring to FIG. 3A, a wireless power transfer system according to an embodiment may include a power transfer unit 1000 and a power receiver unit 2000 that wirelessly receives power from the power transfer unit 1000. The power transfer unit 1000 may include: a transfer-side power converter 101 that outputs an AC signal by performing power conversion on an input AC signal; a transfer-side resonant circuit unit 102 that provides power to the power receiver unit 2000 in a charging area by generating a magnetic field on the basis of the AC signal output from the transfer-side power converter 101; a transfer-side controller 103 that controls power conversion of the transfer-side power converter 101, adjusts the amplitude and frequency of the output signal from the transfer-side power converter 101, performs impedance matching of the transfer-side resonant circuit unit 102, senses impedance, voltage, and current information from the transfer-side power converter 101 and the transfer-side resonant circuit unit 102, and can perform wireless communication with the power receiver unit 2000. The transfer-side power converter 101 may include at least one of a power converter that converts an AC signal into a DC signal, a power converter that outputs a DC by varying the level of a DC, and a power converter that converts a DC into an AC. The transfer-side resonant circuit unit 102 may include a coil and an impedance matching unit that can resonate with the coil. The transfer-side controller 103 may include a sensing unit for sensing impedance, voltage, and current information, and a wireless communication unit. Further, referring to FIG. 3, the power transfer unit 1000 may include a transfer-side AC/DC converter 1100, a transfer-side DC/AC converter 1200, a transfer-side impedance matching unit 1300, a transfer coil unit 1400, and a transfer-side communication & control unit 1500. The transfer-side AC/DC converter 1100, which is a power converter that converts an AC signal provided from the outside into a DC signal under control of the transfer-side communication & control unit 1500, may include a rectifier 1110 and a transfer-side DC/DC converter 1120 that are sub-systems. The rectifier 1110, which is a system that converts a provided AC signal into a DC signal, for example, may be a diode rectifier that has relatively high efficiency in high-frequency operation, a synchronous rectifier that can be implemented into one chip, or a hybrid rectifier that can save the manufacturing cost and a space and has high degree of freedom of dead time. However, the rectifier is not limited thereto and any system that converts an AC into a DC can be applied. The transfer-side DC/DC converter 1120, which adjusts the level of a DC signal provided from the rectifier 1110 under control of the transfer-side communication & control unit 1500, for example, may be a buck converter that decreases the level of an input signal, a boost converter that increases the level of an input signal, or a buck boost converter or a cuk converter that deceases or increases the level of an input signal. The transfer-side DC/DC converter 1120 may include: an inductor and a capacitor that function as a switch device and a power conversion medium, which perform power conversion control function, or that perform a power smoothing function; and a transformer that adjusts a voltage gain or performs an electrical separation function (insulating function). Further, the transfer-side DC/DC converter 1120 can remove a ripple component or a pulsation component included in an input AC signal (an AC component included in a DC signal). The difference between a command value of an output signal of the transfer-side DC/DC converter 1120 and the actual output value can be adjusted through feedback, which may be achieved by the transfer-side communication & control unit 1500. The transfer-side DC/AC converter 1200, which is a system that can convert a DC signal output from the transfer-side AC/DC converter 1100 into an AC signal and can adjust the frequency of the converted AC signal under control of the transfer-side communication & control unit 1500, for example, may be a half bridge inverter or a full bridge inverter. The wireless power transfer system may include various amplifiers that convert a DC into an AC, and for example, there are A-class, B-class, AB-class, C-class, E-class, and F-class amplifiers. The transfer-side DC/AC converter 1200 may include an oscillator that generates a frequency of an output signal and a power amplifier that amplifies an output signal. The transfer-side AC/DC converter 1100 and the transfer-side DC/AC converter 1200 may be replaced by an AC power supplier, or may be removed or replaced by other components. The transfer-side impedance matching unit 1300 improves flow of a signal by minimizing a reflected wave at points having different impedances. The two coils of the power transfer unit 1000 and the power receiver unit 2000 are spatially separated, so there is a lot of leakage of magnetic field, so it is possible to improve power transmission efficiency by correcting the impedance difference between two connection terminals of the power transfer unit 1000 and the power receiver unit 2000. The transfer-side impedance matching unit 1300 may be composed of at least one of an inductor, a capacitor, and a resistor and can adjust an impedance value for impedance matching by varying inductance of the inductor, capacitance of the capacitor, and a resistance value of the resistor under control by the communication & control unit 1500. When the wireless power transfer system transfers power, using the magnetic induction method, the transfer-side impedance matching unit 1300 may have a serial constant structure of a parallel resonant structure, and it is possible to minimize a loss of energy by increasing the induction coupling coefficient between the power transfer unit 1000 and the power receiver unit 2000. When the wireless power transfer system transfers power, using the magnetic resonance method, the transfer-side impedance matching unit 1300 can correct in real time impedance matching according to a matching impedance change on an energy transfer line when the distance between the power transfer unit 1000 and the power receiver unit 2000 is changed or the characteristics of a coil is changed by metallic foreign objects (FO) or interaction of a plurality of device, in which as the correcting method, multi-matching that uses a capacitor, matching that uses multi-antennas, and matching that uses multi-loops, etc. may be used. The transfer-side coil 1400 may be implemented by a plurality of coils or one coil, and when a plurality of transfer-side coils 1400 is provided, they may be spaced from each other or overlap each other. Further, when the transfer-side coils overlap each other, the overlap areas may be determined in consideration of a difference in magnetic flux. When the transfer-side coil 1400 is manufactured, internal resistance and radiation resistance, and in this case, when the resistance component is small, the quality factor and the transfer efficiency can be increased. The communication & control unit 150 may include a transfer-side controller 1510 and a transfer-side communication unit 1520. The transfer-side controller 1510 can adjust an output voltage of the transfer-side AC/DC converter 1100 (or the current flowing through a transfer coil Itx_coil) in consideration of one or more of a requested amount of power of the power receiver unit 2000, the current changing amount, a voltage Vrect at the output terminal of the rectifier of the power receiver unit, charging efficiency of each of a plurality of power receiver units, and a wireless power method. Further, it is possible to create a frequency and switching waves for driving the transfer-side DC/AC converter 1200 and control power to be transferred, in consideration of the maximum power transfer efficiency. Further, it is possible to control the entire operation of the power receiver unit 2000, using an algorithm, a program, or an application that is required to control and read out from a storage unit (not shown) of the power receiver unit 2000. The transfer-side controller 1510 may be referred to as a microprocessor, a micro control unit, or a micom. The transfer-side communication unit 1520 can communicate with a reception-side communication unit 2620 and may use a near field communication method such as Bluetooth, NFC, and Zigbee. The transfer-side communication unit 1520 and the reception-side communication unit 2620 can transmit and receive charge situation information, charge control instructions to and from each other. The charge situation information may include the number of the power receiver units 2000, a battery level, the number of times of charging, a battery capacity, a batter ratio, the power transfer amount of the power receiver unit 1000, etc. The transfer-side communication unit 1520 can receive a charge function control signal for controlling a charge function of the power receiver unit 2000 and the charge function control signal may be a control signal that enables or disables the charge function by controlling the power receiver unit 2000. The transfer-side communication unit 1520 may perform communication in an out-of-band type configured in a separate module, but it is not limited thereto and may perform communication in an in-band type in which a power receiver unit uses a feedback signal that is transmitted to a power transfer unit, using a power signal transmitted from the power transfer unit and the power transfer unit transmits a signal to the power receiving unit, using frequency shift of the power signal transmitted from the power transfer unit. For example, a power receiver unit may transmit information such as start of charge, end of charge, and a battery state to a transmitter through a feedback signal by modulating the feedback signal. The transfer-side communication unit 1520 may be configured separately from the transfer-side controller 1510 and the reception-side communication unit of the power receiver unit 2000 may be included in a controller 2610 of the power receiver unit or may be separately configured. A power transfer unit 1000 of a wireless power transfer system according to another embodiment may further include a detector 1600. The detector 1600 can detect at least one of an input signal of the transfer-side AC/DC converter 1100, an output signal of the transfer-side AC/DC converter 1100, an input signal of the transfer-side DC/AC converter 1200, an output signal of the transfer-side DC/AC converter 1200, an input signal of the transfer-side impedance matching unit 1300, an output signal of the transfer-side impedance matching unit 1300, an input signal of the transfer-side coil 1400, and an output signal of the transfer-side coil 1400. For example, the signals may include at least one of information about a current, information about a voltage, and information about impedance. Detected signals are fed back to the communication & control unit 1500 and the communication & control unit 1500 can control the transfer-side AC/DC converter 1100, transfer-side DC/DC converter 1120, and transfer-side impedance matching unit 1300 on the basis of the feedback. The communication & control unit 1500 can perform foreign object detection (FOD) on the basis of the detection result. The detected signal may be at least one of a voltage and a current. The detector 1600 may be configured as hardware different from the communication & control unit 1500 or may be implemented as one piece of hardware. <Power Receiver Unit> FIGS. 4A and 4B are block diagrams showing a power receiver unit (or a receiver) that is one of sub-systems constituting a wireless power transfer system. Referring to FIG. 4A, a wireless power transfer system according to an embodiment may include a power transfer unit 1000 and a power receiver unit 2000 that wirelessly receives power from the power transfer unit 1000. The power transfer unit 2000 may include: a reception-side resonant circuit 201 that receives an AC signal transmitted from the power transfer unit 1000; a reception-side power converter 202 that outputs a DC signal by performing power conversion on an AC current from the reception-side resonant circuit unit 201; and a reception-side controller 203 that can sense current voltages of a load 2500, which is charged by receiving a DC signal output from the reception-side converter 202, and the reception-side resonant circuit unit 201, perform impedance matching of the reception-side resonant circuit unit 201, or control power conversion of the reception-side power converter 202, and can adjust the level of an output signal of the reception-side power converter 202, sense an input or output voltage or current of the reception-side power converter 202, control whether to supply the output signal of the reception-side power converter 202 to the load 2500, or communicate with the power transfer unit 1000. The reception-side power converter 202 may include a power converter that converts an AC signal into a DC signal, a power converter that outputs a DC by varying the level of a DC, and a power converter that converts a DC into an AC. Referring to FIG. 4B, a wireless power transfer system according to an embodiment may include a power transfer unit (or a transmitter) 1000 and a power receiver unit (or a receiver) 2000 that wirelessly receives power from the power transfer unit 1000. The power receiver unit 2000 may include a reception-side resonant circuit unit 2120 composed of a reception-side coil unit 2100 and a reception-side impedance matching unit 2200, a reception-side AC/DC converter 2300, a DC/DC converter 2400, a load 2500, and a reception-side communication & control unit 2600. The reception-side AC/DC converter 2300 may be referred to as a rectifier that rectifies an AC signal into a DC signal. The reception-side coil unit 2100 can receive power through the magnetic induction method or the magnetic resonance method. The reception-side coil unit 2100 may include one or more of an induction coil or a resonant coil, depending on the power reception method. For example, the reception-side coil unit 2100 may be disposed in a mobile terminal together with an antenna for near field communication (NFC). The reception-side coil unit 2100 may be the same as the transfer-side coil unit 1400 and the dimensions of the receiving antenna may depend on the electrical characteristic of the power receiver unit 200. The reception-side impedance matching unit 2200 perform impedance matching between the power transfer unit 1000 and the power receiver unit 2000. The reception-side AC/DC converter 2300 generates a DC signal by rectifying an AC signal output from the reception-side coil unit 2100. The output voltage of the reception-side AC/DC converter 2300 may be referred to as a rectified voltage Vrect, and the reception-side communication & control unit 2600 can detect or change the output voltage of the reception-side AC/DC converter 2300 and can transmit state parameter information such as information about a minimum rectified voltage Vrect_min (or referred as a minimum output voltage Vrect_min)that is the minimum value of the output voltage of the reception-side AC/DC converter 2300, a maximum rectified voltage Vrect_max (or referred to as a maximum output voltage Vrect_max) that is the maximum value of the output voltage, and an optimum rectified voltage Vrect_set (or referred to as an optimum output voltage Vrect_set) that has any one voltage value of values between the minimum value and the maximum value. The reception-side DC/DC converter 2400 can adjust the level of the DC signal output from the reception-side AC/DC converter 2300 to fit the capacity of the load 2500. The load 2500 may include a battery, a display, a voice output circuit, a main processor, a battery manager, and various sensors. The load 2500, as in FIG. 4A, may include at least a battery 2510 and a battery manager 2520. The battery manager 2520 can adjust a voltage and a current that are applied to the battery 2510 by sensing the chare phase of the battery 2510. The reception-side communication & control unit 2600 can be activated by wake-up power from the transfer-side communication & control unit 1500, communicate with the transfer-side communication & control unit 1500, and control the operation of the sub-systems of the power receiver unit 2000. One or a plurality of power receiver units 2000 may be provided and can wirelessly simultaneously receive energy from the power transfer unit 1000. That is, in a wireless power transfer system using the magnetic resonance method, a plurality of target power receiver units 2000 can receive power from one power transfer unit 1000. The transfer-side matching unit 1300 of the power transfer unit 1000 can adaptively perform impedance matching among a plurality of power receiver units 2000. This can be applied in the same way even though a plurality of independent reception-side coil units is provided in the magnetic induction method. When a plurality of power receiver units 2000 is provided, they may be systems that use the same power reception method or different power reception types. In this case, the power transfer unit 1000 may be a system that transfers power, using magnetic induction or magnetic resonance, or a system that uses both of magnetic induction and magnetic resonance. The relationship between the magnitude and the frequency of a signal in a wireless power transfer system is described. In wireless power transfer using the magnetic induction method, in the power transfer unit 1000, the transfer-side AC/DC converter 1100 can receive and convert an AC signal of a tens of or hundreds of voltage (for example 110V˜220V) at a tens of or hundreds of hertz (for example, 60 Hz) into a DC signal of a several to hundreds or hundreds of voltage (for example 10V˜20V) and output the DC signal, and the transfer-side DC/AC converter 1200 can receive a DC signal and output an AC signal at KHz (for example 125 KHz). The reception-side AC/DC converter 2300 of the power receiver unit 2000 can receive and convert an AC signal at KHz (for example, 125 KHz) into a DC signal of a several to hundreds or hundreds of voltage (for example 10V˜20V) and output the DC signal, and the reception-side DC/DC converter 2400 can output and transmit a DC signal suitable for the load 2500, for example, a DC signal of 5V to the load 2500. In wireless power transfer using the magnetic resonance method, in the power transfer unit 1000, the transfer-side AC/DC converter 1100 can receive and convert an AC signal of a tens of or hundreds of voltage (for example 110V˜220V) at a tens of or hundreds of hertz (for example, 60 Hz) into a DC signal of a several to hundreds or hundreds of voltage (for example 10V˜20V) and output the DC signal, and the transfer-side DC/AC converter 1200 can receive a DC signal and output an AC signal at MHz (for example 6.78 MHz). The reception-side AC/DC converter 2300 of the power receiver unit 2000 can receive and convert an AC signal at MHz (for example, 6.78 MHz) into a reception-side DC signal of a several to hundreds or hundreds of voltage (for example 10V ˜20V) and output the reception-side DC signal, and the reception-side DC/DC converter 2400 can output and transmit a DC signal suitable for the load 2500, for example, a DC signal of 5V to the load 2500. <Operation State of Power Transfer Unit> FIG. 5 is a diagram showing the operation flow of a wireless power transfer system, based on the operation state of a power transfer unit according to an embodiment. Referring to FIG. 5, a power transfer unit according to an embodiment may have 1) a selection phase, 2) a ping phase, 3) an identification and configuration phase, 4) a power transfer phase, and 5) an end of charge phase. [Selection Phase] (1) In the selection phase, the power transfer unit 1000 can perform a detection process to select a power receiver unit in a sensing area or a charge area. (2) The sensing area or the charge area, as described above, may refer to areas in which an object can influence a power characteristic of the transfer-side power converter 101. Compared with the ping phase, a detection process for selecting a power receiver unit 2000 in the selection phase is a process of checking whether there is an object in a predetermined range by sensing a change in a power amount for generating wireless power signal by the power converter of the power transfer unit 1000 instead of receiving a response from the power receiver unit 2000, using a power control message. The detection process in the selection phase may be referred to as an analog ping because it detects an object using not a digital format packing, but a wireless power signal in the ping phase to be described below. (3) In the selection phase, the power transfer unit 1000 can sense an object coming into and going out of the sensing area or charge area. The power transfer unit 1000 can discriminate the power receiver unit 2000 that can wirelessly transfer power and other objects (for example, a key and a coin) in objects in the sensing area or charge area. As described above, the distances to which power can be wirelessly transferred are different, depending on the induction coupling method and the resonant coupling method, so the sensing areas where an object is detected in the selection phase may be different. (4) First, when power is transferred in accordance with an induction coupling method, the power transfer unit 1000 in the selection phase can monitor an interface surface (not shown) to sense disposition and removal of objects. The power transfer unit 1000 can also sense the location of a power receiver unit placed on the interface surface. (5) When the power transfer unit 1000 includes one or more transfer coils, it can enter the ping phase from the selection phase and perform a method of checking whether a response to a detection signal has been transmitted from the object, using the coils, and there after, it can enter the identification phase and perform a method of checking whether identification information is transmitted from the object. The power transfer unit 1000 can determine a coil to use for wireless power transfer on the basis of the location of the power receiver unit 2000 obtained through this process. (6) When power is transferred in a resonant coupling method, the power transfer unit 1000 in the selection phase can detect an object by sensing a change in one or more of the frequency, current, and voltage of the power converter due o the object in the sensing area or charge area. (7) The power transfer unit 1000 in the selection phase can detect an object, using at least one of detection methods using the induction coupling method and the resonant coupling method. (8) The power transfer unit 1000 can perform an object detection process according to the power transfer methods and then select the method that detected the object from the coupling methods for wirelessly transferring power to progress to other phases. (9) The power transfer unit 1000 in the selection phase generates a wireless power signal for detecting an object and a wireless power signal for digital detection, identification, configuration, and power transfer in the latter phases, and characteristics such as the frequency and the intensity of the wireless power signals may be different. This is for reducing power consumption by the power transfer unit 1000 in an idle phase or for being able to generate a specialized signal to detect an object because the selection phase of the power transfer unit 1000 corresponds to an idle phase for detecting an object. [Ping Phase] (1) In the ping phase, the power transfer unit 1000 can perform a process of detecting a power receiver unit 2000 in a sensing unit or a charge unit through a power control message. Compared with the process of detecting a power receiver unit 2000, using characteristics etc. of a wireless power signal in the selection phase, a detection process in the ping phase may be referred to as digital ping. (2) The power transfer unit 1000 can generate a wireless power signal for detecting a power receiver unit 2000, demodulate a wireless power signal modulated by the power receiver unit 200, and obtain a power control message in a digital data format corresponding to a response to the detection signal from the demodulated wireless power signal. (3) The power transfer unit 1000 can recognize the power receiver unit 2000 that is an objective of power transfer, by receiving the power control message corresponding to a response to the detection signal. (4) The detection signal that is generated to perform a digital detection process by the power transfer unit 1000 in the ping phase may be a wireless power signal that is generated by applying power signal at a specific operating point for a predetermined time. The operating point may mean the frequency, duty cycle, and amplitude of a voltage that is applied to the transfer-side coil unit 1400. The power transfer unit 1000 can attempt to generate the detection signal generated by applying a power signal at the specific operating point for a predetermined time and receive a power control message from the power receiver unit 2000. (5) The power control message corresponding to a response to the detection signal may be a message showing the strength of the wireless power signal received by the power receiver unit 2000. For example, the power receiver unit 2000 can transmit a signal strength packet including a message showing the strength of the wireless power signal received as a response to the detection signal. The packet may include a header showing that it is a packet and a message showing the strength of the power signal received by the power receiver unit 2000. The strength of the power signal in the message may be a value showing the degree of induction coupling or resonant coupling for power transfer between the power transfer unit 1000 and the power receiver unit 2000. (6) The power transfer unit 1000 can enter the identification and pin phase by extending the digital ping after finding out the power receiver unit 2000 by receiving a response message to the detection signal. That is, the power transfer unit 1000 can receive a necessary power control message in the identification and ping phase to maintain a power signal at the specific operating point after finding out the power receiver unit 2000. However, when the power transfer unit 1000 could not find out the power receiver unit that can transfer power, the operation state of the power transfer unit 1000 can return to the selection phase. [Identification and Configuration Phase] (1) In the identification and configuration phase, the power transfer unit 1000 can be controlled to efficiently transfer power by receiving identification information and/or configuration information transmitted from the power receiver unit 2000. (2) In the identification and configuration phase, the power receiver unit 2000 can transmit a power control message including identification information thereof. To this end, the power receiver unit 2000, for example, can transmit an identification packet including a message showing the identification information of the power receiver unit 2000. The packet may include a header showing that it is a packet showing identification information and a message including the identification information of the power receiver unit 2000. The message may include information showing the version of a contract for wireless power transfer, information for identifying the manufacturer of the power receiver unit 2000, information showing whether there is an extended device identifier, and basic device identifier. When it is shown that there is an extended device identifier in the information showing whether there is an extended device identifier, an extended identification packet including the extended device identifier may be separately transmitted. The packet may include a header showing that it is a packet showing an extended device identifier and a message including the extended device identifier. When an extended device identifier is used, as described above, identification information of the manufacturer, and information based on the basic device identifier and the extended device identifier may be used to identify the power receiver unit 2000. (3) In the identification and configuration phase, the power receiver unit 2000 can transmit a power control message including information about estimated maximum power. To this end, the power receiver unit 2000, for example, can transmit a configuration packet. The packet may include a header showing that it is a configuration packet and a message including information about the estimated maximum power. The message may include a power class, information about the estimated maximum power, an indicator showing a method of determining a current of a main cell of the power transfer unit 1000, and the number of selective configuration packets. The indicator may show whether the current of the main cell of the power transfer unit 1000 is determined in accordance with the contract for wireless power transfer. (4) The power transfer unit 1000 can create a power transfer contract that is used for charge and the power receiver unit 2000 on the basis of the identification information and/or configuration information. The power transfer contract may include limits on parameters that determine a power transfer characteristic in the power transfer phase. (5) The power transfer unit 1000 can end the identification and configuration phase and returns to the selection phase before entering the power transfer phase. For example, the power transfer unit 1000 can end the identification and configuration phase to find out another power receiver unit 2000 that can wirelessly receive power. [Power Transfer Phase] (1) The power transfer unit 1000 in the power transfer phase transfers power to the power receiver unit 2000. (2) The power transfer unit 1000 can receive a power control message from the power receiver unit 2000 and adjust the characteristic of power supplied to the transfer coil unit 1400 in response to the received power control message while transferring power. For example, the power control message that is used to adjust the characteristic of the transfer coil may be included in a control error packet. The packet may include a header showing that it is a control error packet and a message including a control error value. The power transfer unit 1000 can adjust power that is supplied to the transfer coil in accordance with the control error value. That is, the current that is applied to the transfer coil may be maintained when the control error value is 0, can be reduced when the control error value is a negative value, and can be increased when the control error value is a positive value. (3) In the power transfer phase, the power transfer unit 1000 can monitor parameters in the power transfer contract created on the basis of the identification information and/or configuration information. As the result of monitoring the parameters, when power transfer to the power receiver unit 2000 violates the limits included in the power transfer contract, the power transfer unit 1000 can cancel the power transfer and return to the selection phase. (4) The power transfer unit 1000 can end the power transfer phase on the basis of the power control message transmitted from the power receiver unit 2000. For example, when a battery is fully charged while the power receiver unit 2000 charges the battery using transferred power, the power receiver unit 2000 can transmit a power control message that request stopping of wireless power transfer to the power transfer unit 1000. In this case, the power transfer unit 1000 can end wireless power transfer and return to the selection phase after receiving the message that requests stopping of power transfer. Alternatively, the power receiver unit 2000 can transmit a power control message that request renegotiation or reconfiguration to update the previously created power transfer contract. The power receiver unit 2000 can transmit a message that request renegotiation of the power transfer contract when a larger or smaller amount of power than the current transferred amount of power is required. In this case, the power transfer unit 1000 can end wireless power transfer and return to the identification and configuration phase after receiving the message that requests renegotiation of the power transfer contract. To this end, the message that the power receiver unit 2000 transmits may be an end power transfer packet. The packet may include a header showing that it is an end power transfer packet and a message including end power transfer code showing the reason of the ending. The end power transfer code may show any one of charge complete, an internal fault, over temperature, over voltage, over current, battery failure, reconfiguration, no response, and unknown error. Alternatively, when the power transfer unit 1000 senses that the load 2500 is being fully charged, it can end power transfer regardless of whether a message has been received from the power receiver unit 2000. <Operation State of Power Transfer Unit> FIG. 6 is a diagram showing the operation flow of a wireless power transfer system, based on the operation state of a power transfer unit according to another embodiment. Referring to FIG. 6, a power transfer unit according to another embodiment may have 1) a standby phase, 2) a digital ping phase, 3) an authentication phase, 4) a power transfer phase, and 5) an end of charge phase. [Standby] (1) When power is supplied to the power transfer unit 1000 and the power transfer unit 1000 is started, the power transfer unit 1000 may be in a standby phase. The power transfer unit 1000 in the standby phase can detect an object (for example, a power receiver unit 2000 or a metallic foreign object (FO)) in a sensing area or a charge area. Further, the power transfer unit 1000 can detect whether an object has been removed from the charge area. (2) The power transfer unit 1000 can detect an object in the charge area by monitoring a change in magnetic flux, a change in capacitance between an object and the power transfer unit 1000, a change in inductance, or a shift of a resonant frequency, but it is not limited thereto. (3) When detecting the power receiver unit 2000 in the charge area, the power transfer unit 1000 can progress to the digital ping phase that is the next step. (4) When a foreign object (FO) such as a metallic foreign object is in the charge area, the power transfer unit 1000 can detect the foreign object. (5) When the power transfer unit 1000 could not obtain sufficient information for discriminating the power receiver unit 2000 and the foreign object in the standby phase, the power transfer unit 1000 can progress to the digital ping phase or the authentication phase and check whether it is the power receiver unit 2000 or a foreign object (FO). [Digital Ping] (1) In the digital ping phase, the power transfer unit 1000 connects to a power receiver unit 2000 that can be charged and checks whether the power receiver unit 2000 can be charged with wireless power provided from the power transfer unit 1000. The power transfer unit 1000 can create and output digital pin having a predetermined frequency and timing to be connected with the chargeable power receiver unit 2000. (2) When a sufficient power signal for digital ping is transmitted to the power receiver unit 200, the power receiver unit 2000 can respond to the digital ping by modulating the power signal in accordance with a communication protocol. When the power transfer unit 1000 receives an effective signal from the power receiver unit 2000, the power transfer unit 1000 can progress to the authentication phase without the power signal removed. When an end of charge (EOC) is received from the power receiver unit 2000 or when the power transfer unit 1000 senses that the load 2500 is being fully charged, the power transfer unit 1000 can progress to the end of charge phase. (3) When an effective power receiver unit 2000 is not detected or when a response time of an object to the digital ping exceeds a predetermined time, the power transfer unit 1000 can remove the power signal and return to the standby phase. Accordingly, when a foreign object is disposed in the charge area, the foreign object cannot make any response, so the power transfer unit 1000 can return to the standby phase. [Identification] (1) When a response of the power receiver unit 2000 according to the digital ping of the power transfer unit 1000 is finished, the power transfer unit 1000 can check compatibility between the power transfer and receiver units 1000 and 2000 by transmitting power transfer unit authentication information to the power receiver unit 2000. When compatibility is found, the power receiver unit 2000 can transmit authentication information to the power transfer unit 1000. Further, the power transfer unit 1000 can check power receiver unit authentication information of the power receiver unit 2000. (2) When the mutual authentication is finished, the power transfer unit 1000 can progress to the power transfer phase, or when authentication failed or a predetermined authentication time is exceeded, it can return to the standby phase. [Power Transfer] (1) The communication & control unit 1500 of the power transfer unit 1000 can provide charge power to the power receiver unit 2000 by controlling the power transfer unit 1000 on the basis of control data provided from the power receiver unit 2000. (2) The power transfer unit 1000 can verity whether it goes out of an appropriate operation range or there is a problem with stability according to FOD. (3) When power transfer unit 1000 receives a charge end request signal from the power receiver unit 2000 or senses that the load 2500 is being fully charged, or when a predetermined critical temperature value is exceeded, the power transfer unit 1000 can stop power transfer and progress to the end of charge phase. (4) When the situation is changed into a situation not suitable for transferring power, the power signal can be removed and the standby phase can be returned. When the power receiver unit 2000 is removed and enters again the charge area, the cycle described above can be performed again. (5) The power transfer unit 1000 can return to the authentication phase from the charge state of the load 2500 of the power receiver unit 2000 and can provide a charge power adjusted on the basis of phase information of the load to the power receiver unit 2000. [End of Charge (EOC)] (1) When the power transfer unit 1000 receives information showing that the power receiver unit 2000 has been charged, or senses that the load 2500 is being fully charged, or receives information showing that the temperature of the power receiver unit 2000 has increased to a predetermined temperature or more, the power transfer unit 1000 can progress to the end of charge phase. (2) When the power transfer unit 1000 receives charge complete information from the power receiver unit 2000, or immediately after sensing that the load 2500 is being fully charged or when a predetermined time has passed after the sensing, the power transfer unit 1000 can stop power transfer and can stand by for a predetermined time. After the predetermined time passes, the power transfer unit 1000 can enter the digital ping phase to connect with the power receiver unit 2000 in the charge area. (3) When the power transfer unit 1000 receives information showing that the predetermined temperature is exceeded from the power receiver unit 2000, the power transfer unit 1000 can stand by for a predetermined time. After the predetermined time passes, the power transfer unit 1000 can enter the digital ping phase to connect with the power receiver unit 2000 in the charge area. (4) The power transfer unit 1000 can monitor whether the power receiver unit 2000 has been removed from the charge area for a predetermined time, and when the power receiver unit 2000 is removed from the charge area, the power transfer unit 1000 can return to the standby phase. FIG. 7 is a diagram showing the operation flow of a wireless power transfer system according to another embodiment. Operation State of Power Transfer Unit Referring to FIG. 7, a power transfer unit 1000 according to another embodiment may have at least 1) a configuration mode 2) a power save mode, 3) a low power mode, 4) a power transfer mode, and 5) a latch fault mode. [Configuration Mode] (1) When power is supplied to the power transfer mode 1000 (Power Up), the configuration mode can be entered. (2) The power transfer unit 1000 itself can check the system. (3) The power transfer unit 1000 can maintain a current Itx_in that is applied to the transfer-side coil 1400 at a specific current value (for example, 20 mArms) or less, and if the input current Itx_in of the transfer-side coil 1400 is larger than the specific current value, it is possible to reduce the input voltage Itx_in of the transfer-side coil 1400 to the specific current value or less within specific time (for example, 50 ms) after the power transfer unit 1000 entered the configuration mode. (4) The power transfer unit 1000 can enter the power save mode within predetermined time (for example, 4s) after it entered the configuration mode. [Power Save Mode] (1) In the power save mode, the power transfer unit 1000 can apply different power beacons to the transfer-side coil 1400 at each period. (2) The power beacons may include a short beacon and a long beacon and the short beacon can have a power amount required for detecting various power receiver units 2000. The long beacon can have a power amount required for driving the communication & control unit 2600 of the power receiver unit 2000. The long beacon can have a power amount that can maintain a sufficient voltage for inducing a response of the power receiver unit 2000 at the power receiver unit 2000. The short beacon can have a first period and the long beacon can have a second period. The short beacon may include a plurality of short beacons having different power amounts and the long beacon may include a plurality of long beacons having different power amounts. (3) The power transfer unit 1000 can detect a change in reactance of input impedance Ztx_in, resistance of the input impedance Ztx_in, or the input impedance Ztx_in of the transfer-side coil 1400 and the transfer-side impedance matching unit 1300 while applying a shot beacon. (4) When the power transfer unit 1000 detects a change in reactance of the input impedance Ztx_in, resistance of the input impedance Ztx_in, or the input impedance Ztx_in, it can immediately apply a long beacon. (5) The power transfer unit 1000 can be driven by the long beacon of the power transfer unit 1000, and the power transfer unit 1000 can communicate with the power receiver unit 2000 on the basis of a predetermined method. When the power transfer unit 1000 receives advertisement from the power receiver unit 2000, it can enter the low power mode. (6) When the power transfer unit 1000 could not detect a change in the input impedance Ztx_in itself or in reactance or resistance of the input impedance Ztx_in, it can maintain the power save mode. (7) When the power transfer unit 1000 detected a change in the input impedance Ztx_in itself or in reactance or resistance of the input impedance Ztx_in, it can determine that an object exists in the charging area and enter the low power mode. [Low Power Mode] (1) In the low power mode, the power transfer unit 1000 and the power receiver unit 2000 can be connected by a predetermined communication method (for example, Bluetooth low energy (BLE) and can transmit and receive data, and the power receiver unit 2000 can join a wireless power network that the power transfer unit 1000 manages. The power transfer unit 1000 can enter the power transfer mode. The power transfer unit 1000 can sense an object positioned on a transfer pad, using a beacon signal, and determine whether the object is a device that can wirelessly receive power. The beacon signal may use a short beacon and a long beacon. The power receiver unit 2000 (or the reception-side communication & control unit) receiving the long beacon signal can be woken up (or powered up) and can transmit an advertisement (PRU advertisement) to the power transfer unit 1000. (2) The power transfer unit 1000 receiving the advertisement (PRU advertisement) from the power receiver unit 2000 can form connection between the power transfer unit 1000 and the power receiver unit 2000 by transmitting a connection request signal to the power receiver unit 2000. 2-1) When the power receiver unit 2000 receives the connection request signal from the power transfer unit 1000, the power receiver unit 2000 can transmit power receiver unit power receiver unit parameter information to the power transfer unit 1000 (or the power transfer unit 1000 can read information from the power receiver unit 2000) and the power transfer unit 1000 can also transmit power transfer unit parameter information to the power receiver unit 2000 (or the power transfer unit 1000 can write information on the power receiver unit 2000). The PRU parameter information, which is information about the output voltage Vrect of the reception-side AC/DC converter 2300, may include the minimum output voltage Vrect_min, the maximum output voltage Vrect_max, and the optimum output voltage Vrect_set. The optimum output voltage may have any one voltage value of values over the minimum output voltage Vrect_min and under the maximum output voltage Vrect_max. 2-2) In detail, the power transfer unit can receive a power receiver unit static parameter from the power receiver unit 2000. The power receiver unit static parameter may be state information previous fixed as a signal indicating the state of the power receiver unit 2000. The power receiver unit static parameter may include selective filed information, protocol information, information about the output voltage Vrect of the reception-side AC/DC converter 2300, information about the output power of the reception-side AC/DC converter 2300. 2-3) The power transfer unit 1000 receiving the power receiver unit static parameter can transmit a power transmitter unit parameter (PTU static parameter) to the power receiver unit 2000. The power transmitter unit parameter (PTU static parameter) may be a signal indicating the capability of the power transfer unit 1000. 2-4) The power transfer unit 1000 can receive a power receiver unit dynamic parameter (PRU dynamic parameter) from the power receiver unit 2000. The power receiver unit dynamic parameter may include at least one item of parameter information measured by the power receiver unit 2000. For example, the power receiver unit dynamic parameter may include information about the output voltage Vrect of the reception-side AC/DC converter 2300. The power receiver unit dynamic parameter can include and provide a set voltage value rearranged in accordance with the wireless charge situation to the power transfer unit 1000 and the power transfer unit 1000 can update a power receiver unit control table on a registry, that is, an initially set voltage value of the power receiver unit static parameter to fit the situation on the basis of the rearranged set voltage value. The power transfer unit 1000 can control power transfer on the basis of the recently updated set value. 2-5) The power receiver unit dynamic parameter may include selective field information, information about the output voltage Vrect_dyn of the reception-side AC/DC converter 2300, the minimum output voltage Vrect_min_dyn of the reception-side AC/DC converter 2300, the maximum output voltage Vrect_max_dyn of the reception-side AC/DC converter 2300, the optimum output voltage Vrect_set_dyn of the reception-side AC/DC converter 2300, and the output current of the reception-side AC/DC converter 2300, information about the output current of the reception-side DC/DC converter 2400, temperature information, alert information (PRU alert), etc. 2-6) The alert information may include information such as over voltage, over current, over temperature, charge complete, wire charge terminal lead-in detection (TA detect), SA mode/NSA mode transition, and restart request. (3) When an object in the charging area is not the power receiver unit 200, but a metallic foreign object, data transmission and reception cannot be made between the power transfer unit 1000 and the object. Accordingly, when the power transfer unit 1000 could not receive a response from the object for a predetermined time, it can determine that the object is a foreign object and enter the latch fault mode. [Latch Fault Mode] (1) When the power transfer unit 1000 enters the latch fault mode, the power transfer unit 1000 can periodically apply a short beacon to the reception-side coil unit 400 (that is, transmit a short beacon to the power receiver unit 2000). (2) When the power transfer unit 1000 detected a change in the input impedance Ztx_in itself or in reactance or resistance of the input impedance Ztx_in from the short beacon, it can determine that an object is out of the charging area and enter the power save mode or a configuration state. (3) When the power transfer unit 1000 could not detect a change in the input impedance Ztx_in itself or in reactance or resistance of the input impedance Ztx_in, it can determine that the object has not been recovered and inform a user that the current state of the power transfer unit 1000 is an error state. Accordingly, the power transfer unit 1000 may include a lamp or an output unit that displays an alert such as an alarm. (4) The latch fault mode may have various latch fault mode enter conditions other than the case in which an object is a foreign object. For example, when there is an error situation corresponding to the alarm information, the power transfer unit 1000 can enter the latch fault mode. [Power Transfer Mode] (1) The power transfer unit 1000 enters the power transfer mode, and the power transfer unit 1000 can output power receiver unit control information (PRU control) on the basis of the parameter information received from the power receiver unit 2000. The power receiver unit control information (PRU control) may include information that enables/disables charge of the power receiver unit 2000 and permission information. When the power transfer unit 1000 can provide power enough to charge the power receiver unit 2000, it can output the power receiver unit control information (PRU control) including enabling information. (2) The power transfer unit 1000 can provide the power receiver unit control information power receiver unit control information (PRU control) to the power receiver unit 2000 at least periodically or in accordance with a necessity of changing the state of the power receiver unit 2000. The power receiver unit 2000 can change the state on the basis of the power receiver unit control information (PRU control) and output the power receiver unit dynamic parameter to the power transfer unit 1000 to report the state of the power receiver unit 2000. For example, the power receiver unit control information (PRU control) may include adjustment information to change the maximum power value Pmax of the power receiver unit 2000 and the power receiver unit 2000 can transmit changed information to the power transfer unit 1000 by adjusting at least one of requested voltage/current information and the optimum output voltage of the reception-side AC/DC converter 2300 in accordance with the adjustment information. As another embodiment, the power receiver unit control information (PRU control) may include adjustment information for changing the information about the output voltage Vrect of the reception-side AC/DC converter 2300 of the power receiver unit 2000 and the power receiver unit 2000 can adjust the requested voltage/current information or the optimum output voltage Vrect_set_dyn and the output voltage Vrect of the reception-side AC/DC converter 2300 and then transmit information about the adjustment to the power transfer unit 1000. (3) The power receiver unit 2000 is permitted to be charged and power can be transferred from the power transfer unit 1000 to the power receiver unit 2000. The power transfer unit 1000 can periodically receive the power receiver unit dynamic parameter from the power receiver unit 2000. The power receiver unit dynamic parameter may include the state and temperature information of the wireless power receiver unit. (4) The power receiver unit control information may include information for controlling the output voltage Vrect of the reception-side AC/DC converter 2300 of the power receiver unit 2000. Alternatively, when the power transfer unit 1000 senses that the load 2500 is being fully charged, it can end power transfer regardless of whether information about full charge of the load 2500 has been received from the power receiver unit 2000. Operation State of Power Receiver Unit Referring to FIG. 7, the power receiver unit 2000 according to an embodiment may have at least 1) a null state, 2) a boot state, and 3) an on-state. [Null State] (1) The power receiver unit 2000 can become a null state when the output voltage Vrect of the reception-side AC/DC converter 2300 is less than a boot output voltage Vrect_boot. (2) The power receiver unit 2000 can enter the null state when power is supplied to the power receiver unit 2000 (Power UP) and the output voltage Vrect of the reception-side AC/DC converter 2300 is less than the boot output voltage Vrect_boot. (3) After going out of the null state, the power receiver unit 2000 can enter the null state when the output voltage Vrect of the reception-side AC/DC converter 2300 becomes an output voltage under a lock-out voltage (under voltage lock Out; Vrect_UVLO). The output voltage under a lock-out voltage (Vrect_UVLO) may be smaller than the boot output voltage (Vrect_boot). [Boot State] (1) The power receiver unit 2000 (or the reception-side communication & control unit) receiving a long beacon can be woken up (or powered up). When the power receiver unit 2000 has not been completely charged, it can transmit (or broadcast) an advertisement signal (PRU advertisement) and can wait a connection request from the power transfer unit 1000. (2) The advertisement signal (PRU advertisement) can be periodically transmitted (or broadcasted) and the period may be changed over time. The power receiver unit 2000 can periodically transmit (or broadcast) the advertisement signal until it receives a connection request signal from the power transfer unit 1000. (3) The power transfer unit 1000 can transmit a connection request signal for connecting to the power receiver unit 2000 on the basis of information included in the advertisement signal (PRU advertisement). When receiving the connection request signal for the advertisement signal (PRU advertisement) from the power transfer unit 1000 power receiver unit 2000, the power receiver unit 2000 and the power transfer unit 1000 can form connection. The power receiver unit 2000 can transmit a power receiver unit static parameter, receive a power transfer unit static signal from the power transfer unit 1000, and transmit a power receiver unit dynamic parameter to the power transfer unit 1000. [On-State] (1) The power receiver unit 2000 receives power receiver unit control information (PRU control) from the power transfer unit 1000, and when it is enabled by the power receiver unit control information (PRU control), it becomes the on-state and can receive power from the power transfer unit 1000. (2) The power receiver unit 2000 can provide state information thereof by transmitting a power receiver unit dynamic parameter to the power transfer unit 1000. Procedure of Setting Charge Voltage (1) When wireless charge permission information about the power transfer unit 1000 is included in the power receiver unit control unit (PRU control) provided from the power transfer unit 1000 to the power receiver unit 2000, wireless charging can be started. (2) The power transfer unit 1000 can transmit charge power on the basis of the power receiver unit static parameter. (3) The power transfer unit 1000 can adjust the charge power on the basis of the power receiver unit dynamic parameter reflecting the state information of the power receiver unit 2000. The charge power adjustment is an operation of the power receiver unit 2000 corresponding to description about the low power state and the power transfer state, so it is not described in detail. However, the description may be applied also to embodiments of the power receiver unit 2000. [Method of Sensing Progress of Full Charge Step of Load] FIGS. 8A and 8B are equivalent circuit diagrams of a power transfer unit and a power receiver unit. Referring to FIG. 8A, the transfer-side impedance matching unit 1300 and the transfer coil unit 1400 of the power transfer unit 1000 can be expressed as an equivalent circuit of a transfer-side resistor Rtx, a transfer-side capacitor Ctx, and a transfer-side inductor Itx, and the transfer-side capacitor Ctx, and transfer-side inductor Ltx are expressed in series, but they are not limited thereto and may be expressed in parallel. An output power Pin from the transfer-side DC/AC converter 1200 can be provided to the transfer-side impedance matching unit 1300 and the transfer coil unit 1400. The output power can be determined by product of an output voltage Vin (or it may be referred to as an input voltage to the transfer-side impedance matching unit 1300 or the transfer coil unit 1400) and an output current Iin (or it may be referred to as an input current to the transfer-side impedance matching unit 1300 or the transfer coil unit 1400) of the DC/AC converter 1200. The reception-side coil unit 2100 and the reception-side impedance matching unit 2200 of the power receiver unit 2000 can be expressed as an equivalent circuit of a reception-side inductor Lrx and a reception-side capacitor Crx, and the reception-side inductor Lrx and reception-side capacitor Crx are expressed in series, but are not limited thereto and may be expressed in parallel. transfer-side of the power transfer unit 1000 can be magnetically coupled to the reception-side inductor Lrx of the power receiver unit 2000. 2) A input resistance Ra that is a natural number part of input impedance Za of a DC/DC converter 2400 of the power receiver unit 2000 when the load 2500 is seen from an input port of the DC/DC converter 2400 can be expressed as Equation 3 by output power Prx of the DC/DC converter 2400 and an input voltage of the DC/DC converter 2400, that is, a output voltage Vrect of the reception-side AC/DC converter 2300. R a = V rect 2 P rx Equation 3 The output power Prx can be defined as product of the effective values of the output voltage Vrect and a output current Irx of the reception-side AC/DC converter 2300. Accordingly, output power Prx of the reception-side AC/DC converter 2300 can be considered as being provided to the load 2500 via the DC/DC converter 2400. Input impedance Zin1 (input impedance of the resonant circuit unit 102) when the power receiver unit 2000 is seen from an input port of the transfer-side impedance matching unit 1300 in a resonant state of the power transfer unit 1000 and the power receiver unit 2000 can be expressed as Equation 4. Real { Z in } = ω 2 K 2 L tx L rx R a = P rx V rect 2 ω 2 K 2 L tx L rx Equation 4 Input power Pin that is output from the transfer-side DC/AC converter 1200 and the transfer-side impedance matching unit 1300 (that is, input power of the resonance circuit unit 102) can be expressed as Equation 5. P in = V in 2 Real { Z in } = V rect 2 V in 2 P rx ω 2 K 2 L tx L rx Equation 5 A transfer efficiency can be expressed as Equation 6 from the ratio of input power Pin and output power Prx. P in = P rx transfer efficiency Equation 6 Equation 7 can be obtained from Equations 5 and 6. P in = V in 2 Real { Z in } = V rect 2 V 2 in P rx ω 2 K 2 L tx L rx = P rx transfer efficiency Equation 7 Equation 8 can be obtained by arranging Equation 7. V in = P rx ω K V rect L tx L rx transfer efficiency Equation 8 The input power Pin satisfies Equation 9. According to Equation 9, it can be seen that, assuming that the coupling coefficient K and the transfer efficiency are constant, when the reception-side output power Prx, is increased, the transfer-side input voltage Vin is increased, while the reception-side output power Prx is increased, the transfer-side input voltage Vin is decreased. Accordingly, it can be seen that reception-side output power Prx and the transfer-side input voltage Vin are in proportion to each other. P in = I in 2 Real ( Z in ) = I in 2 P rx V rect 2 ω 2 K 2 L tx L rx = P rx transfer efficiency Equation 9 Equation 10 is satisfied by arranging Equation 9 for an input current Iin. I in = V rect ω K 1 transfer efficiency × L tx L rx Equation 10 According to Equation 10, it can be seen that the transfer-side input current Iin is irrelevant to the reception-side output power Prx, the transfer-side input current Iin is maintained when the output voltage Vrect of the reception-side AC/DC converter 2300, the coupling coefficient K, and the transfer efficiency are constant. Although, in the above description referring to Equations 3 to 10, the transfer-side input voltage Vin and the transfer-side input current Iin are the voltage and current applied to the transfer coil unit 1400, in detail, the voltage and current applied to the transfer-side impedance matching unit 1300, they are not limited thereto and may be applied in the same way to the output voltage and output current of the transfer-side DC/DC converter 1120 or the input voltage and the input current of the transfer-side DC/AC converter 1200. Referring to FIG. 8A, in accordance with another embodiment, the power transfer unit 1000 may further include a DC/DC converter 801, a current sensor 803, an amplifier 805, and a controller 807. The amplifier 805 can be connected in series to a transfer-side resistor Rtx and a transfer-side capacitor Ctx. The controller 807 can sense an input voltage V′in from the DC/DC converter 801. The current sensor 803 can measure input impedance Z′in from the DC/DC converter 801. The controller 807 can sense the magnitude of the input voltage I′in from the input impedance Z′in sensed through the current sensor 803. It is possible to measure an input voltage Vin and an input current Iin by measuring the input voltage V′in and input current I′in of the input impedance Z′in that is in proportion to the input impedance Zin of the power transfer unit 1000. According to the power transfer unit 1000, when the input voltage Vin and the input current Iin are directly measured, as in FIG. 8A, a problem may occur in terms of cost and loss. The power transfer unit 1000 can solve the problem by measuring the input voltage V′in and input current I′in of the input impedance Z′in that is in proportion to the input impedance Zin through the DC/DC converter 801, the current sensor 803, the amplifier 805, and the controller 807. FIG. 9 is a diagram showing the operation flow of a power transfer unit according to an embodiment and FIG. 10 is a diagram showing the operation flow of a power receiver unit according to an embodiment. A step in which the power transfer unit 1000 determines whether the power receiver unit 2000 has been full charged is described with reference to FIGS. 9 and 10. The power transfer unit 1000 performs 1) a step of detecting an output signal from the power transfer unit 1000 (S110), 2) a step of determining a change in the output signal (S130), and 3) a step of sensing that the battery 2510 receiving wireless power from the power transfer unit 1000 is being fully charged on the basis of the voltage and current (S150), thereby being able to determine whether the battery has been fully charged (S170). The step of detecting an output signal from the power transfer unit (S110) can detect an output voltage and an output current of the power transfer unit 100 or detect an output current o the power transfer unit 1000, in which the output voltage of the power transfer unit 1000 can be estimated on the basis of an output voltage instruction value to be described below. The step of determining a change in voltage and current, in detail, may be a step that determines whether the voltage has changed and the current has been maintained for a predetermined time. In more detail, the step of determining whether the voltage has changed may be a step that determines whether the voltage continuously decreases. That is, when the power transfer unit 1000 determines that a voltage decreases, but a current is maintained, it senses that the battery 2510 is being fully charged and can stop wireless power transfer. The voltage and current may be the output voltage and output current of the DC/DC converter 1120 of the power transfer unit 1000. Alternatively, whether the output voltage changes may be determined on the basis of whether the output voltage instruction value of the DC/DC converter 1120 changes. The output voltage instruction value is a target value of the output voltage of the DC/DC converter 1120 and the DC/DC converter 1120 can be controlled by the transfer-side controller 1510 to be able to output an output voltage corresponding to the output voltage instruction value. When the reception-side output power Prx decreases as the battery 2510 is being fully charged, the power transfer unit 1000 can decrease the transfer-side input voltage Vin such that the power amount transferred from the transfer coil unit 1400, that is, the transfer-side input power Pin decreases. In this case, the transfer-side controller 1510 can decrease the output voltage instruction value such that the output voltage of the DC/DC converter 1120 decreases. Accordingly, it is possible to determine that the output voltage of the DC/DC converter 1120 decreases by determining whether the output voltage instruction value decreases. Alternatively, the voltage and current may be the input voltage and current of the transfer-side coil unit 1400 of the power transfer unit 1000. When the power transfer unit 100 determines that the battery 2510 is being fully charged and stops wireless power transfer, the power transfer unit 100 can transmit a wireless power transfer stop message to the power receiver unit 2000. A method of driving the power receiver unit 2000 charging the battery 2510 wirelessly receiving power from the power transfer unit 100 is described. The power receiver unit 2000 can perform 1) a step of determining whether the charge amount of the battery 2510 is a first charge amount to a second charge amount larger than the first charge amount (S210), 2) a power reception step of decreasing a current applied to the battery 2510 when the charge amount of the battery 2510 is the first charge amount to the second charge amount (S230) (the current may be decreased step by step), 3) a step of determining that power reception from the power transfer unit 1000 sensing the decrease of the current has been stopped (S250), and 4) a charge end step that determines that the battery 2510 has been fully charged by determining that power reception from the power transfer unit 100 has been stopped (S270). In this case, the first charge amount may be a charge amount indicating start of full charge of the battery 2510, the second charge amount may be a charge amount indicating completion of full charge of the battery 2510, and when the battery 2510 is in the first to second charge amount, it may be being fully charged. In the power reception step (S230), the voltage applied to the battery 2510 may be constant. The power receiver unit 2000 determines by itself whether the battery 2510 has been fully charged after it was being fully charged and transmits a message including information showing that the battery 2510 has been fully charged, so the power transfer unit 1000 can check whether the battery 2510 has been fully charged and stop wireless power transfer. However, according to an embodiment of the present invention, the power transfer unit 1000 can determine by itself whether the battery 2510 has been fully charged even if the power receiver unit 2000 does not transmit separate full charge state information to the power transfer unit 1000. Further, the power receiver unit 2000 can determine whether the battery 2510 has been fully charged, by determining that wireless power has not been received, without checking by itself the charge amount of the battery 2510 in order to determine whether the battery 2150 has been fully charged. An example of a method of checking a full charge state by determining whether the battery 2510 is being fully charged is described in detail. FIG. 11 is a graph showing the magnitude of a current applied to a battery in accordance with a full charge state of the battery over time. Charging the battery 2510 of the load 2500 can be finished through a charge state that is a first step, a full charge state that is a second step, a full charge-progressing state that is a third step, and a full charge completion state that is a fourth step, that is, charging can be completed through the first to fourth steps. A voltage and current that are applied to the battery 2510 in accordance with the first to fourths steps are described. The voltage that is applied to the battery 2510 in accordance with the first to fourth steps may have a fixed value (or an approximately constant value). The current that is applied to the battery 2510 may have a constant current value in the first step and may be reduced continuously or step by step through the second to fourth steps. For example, referring to FIG. 11, a voltage and a current applied to the battery 2510 during charging that is the first step may be 5V and 50 mA, respectively, and the voltage and current applied to the battery 2510 in the full charge start state that is the second step may be 5V and reduced to 350 mA, respectively. The voltage and current applied to the battery 2510 in the full charge-progressing state that is the third step may be 5V and decreased to 200 mA, respectively. The voltage and current applied to the battery 2510 in the full charge completion state that is the fourth step may be 5V and decreased to 50mA, respectively. That is, the current applied to the battery 2510 may be decreased step by step through the first to fourth steps. The first to fourth steps are divided for the convenience of description but may be more finely divided, and the degree of decrease in current may be changed by more finely dividing the full charge-progressing state that is the third step. In this case, the current can be continuously decreased through the steps. The current that flows to the battery 2510 may be reduced step by step under control of the battery manager 2520. As the battery 2510 is gradually fully charged, in order to prevent overcharging, the battery manager 2520 reduces the charge speed by reducing the current amount applied to the battery 2510 when the battery 2510 is almost fully charged. Unlike the figure, the current applied to the battery 2510 is constant in the charge-progress state that is the first step, but the current is not limited thereto and may be changed in a predetermined range. The charge amount of the battery 2510 for discriminating the first step and the second step may depend on the kind of the battery 2510. For example, the charge amount of the battery 2510 may be less than 90% in the first step, 90% in the second step, larger than 90% and less than 98% in the third step, and 90% or more in the fourth step. When the charge capability of the battery 2510 becomes a predetermined value or more while the battery 2510 is being charged, the full charge start state may be entered, and after the full charge-progressing state, the full charge completion state may be entered. In this process, the output power Prx applied to the load 2500 may be defined as product of the voltage and current applied to the battery 2510, and the output power Prx may also be reduced step by step in correspondence to the decrease of the current, as the current is reduced step by step in full charge-progressing. When the output power Prx is reduced in accordance with Equation 6 with the transfer efficiency maintained, the input power Pin can also be reduced in correspondence to the reduction of the output power Prx. Further, since the input current Iin is constant regardless of the reduction of the output power Prx, the input voltage Vin can be reduced in correspondence to the reduction of the input power Pin that is defined as product of the input voltage Vin and input current Iin. Accordingly, the transfer-side controller 1510 can determine the full charge-progressing progressing state of the battery 2510 by determining a change in the input voltage Vin and input current detected by the detector 1600. That is, the power transfer unit 1000 can determine that the battery 2510 is being fully charged by measuring the output voltage Vin1 and output current Iin1 of the transfer-side AC/DC converter 1100 or the input voltage Vin2 and input current Iin2 of the transfer coil unit 1400. In detail, the detector 1600 of the power transfer unit 1000 can detect the output current Iin1 of the transfer-side AC/DC converter 1100 or the input current Iin1 of the transfer-side DC/AC converter 1200. Further, the detector 1600 can detect the output voltage Vin1 of the transfer-side AC/DC converter 1100 or the output voltage Vin1 of the transfer-side DC/AC converter 1200. Further, it is possible to detect the output voltage Vin2 of the transfer-side DC/AC converter 1200, the output current Iin2, or the input voltage Vin2 and input current Iin2 applied to the transfer coil unit 1400. When the detector 1600 determines that the voltage is decreased step by step but the current is constant for a predetermined time period on the basis of the detected voltage and current, it can determine the battery is being fully charged. When the power transfer unit 1000 determines that the battery 2510 is being fully charged, it can stop wireless power transfer immediately or after a predetermined time passes. The point of time when the predetermined time passed may be the same as the point of time when the battery 2510 is fully charged, or a point of time before or after the point of time. According to the embodiment, when the coupling coefficient K is changed, both of the input voltage Vin and the input current are changed, but in the full charge-progressing state, the input current Iin is fixed and the input voltage Vin is changed. Accordingly, using this fact, the power transfer unit 1000 can determine whether to keep performing wireless power transfer by determining whether the batter 2510 is being fully charged. Further, before the power receiver unit 2000 provides information showing full charge completion to the power transfer unit 1000 when the battery 2510 is fully charged, the power transfer unit 1000 stops wireless power transfer, whereby it is possible to save power. Further, it is possible to prevent the problem that the transfer-side communication unit 1520 could not determine the full charge information of the battery 2510 from the power receiver unit 2000, thereby causing unnecessary power transfer and heat generation. Although exemplary embodiments of the present invention were described above, it should be understood that the present invention may be changed and modified in various ways by those skilled in the art without departing from the spirit and scope of the present invention described in the following claims. Therefore, the technical scope of the present invention is not limited to the exemplary embodiments described herein, but should be determined by claims. INDUSTRIAL APPLICABILITY The present invention can be used in the field of a wireless power transfer system. | <SOH> BACKGROUND ART <EOH>In general, various electronic devices are equipped with a battery and use the power stored in the battery. The batteries of electronic devices can be replaced and can also be recharged. To this end, electronic devices have a contact terminal for connecting an external charger. That is, electronic devices are electrically connected with a charger through the contact terminal. However, since the contact terminals of electronic device are exposed to the outside, they may be contaminated by dirt or a short circuit may occur due to humidity. In these cases, there is a problem that the batteries of electronic devices are not charged due to poor contact between a contact terminal and a charger. In order to solve this problem, wire power transfer (WPT) has been proposed to wirelessly charge electronic devices. Wireless power transfer, which is a technology of transferring power through a space without a wire, is a technology that maximizes convenience in supplying power to mobile devices and digital appliances. A wireless power transfer system has advantages such as saving energy by controlling power consumption in real time, overcoming a spatial limit in power supply, and reducing the amount of waste of batteries by recharging batteries. A magnetic induction method and a magnetic resonance method are representative of methods of implementing a wireless power transfer system. The magnetic induction method is a non-contact energy transfer technology that supplies a current to one of two coils disposed close to each other to generate magnetic flux, thereby generating an electromotive force at the other coil, and can use frequencies of hundreds of kHz. The magnetic resonance method, which is a technology that uses only an electric field or a magnetic field without using electromagnetic waves or a current, has over several meters of available power transfer distance and can use bands of several MHz. A wireless power transfer system includes a transmitter that wirelessly transfers power and a receiver that receives power and charges loads such as a battery. A charge method by receivers, that is, any one of the magnetic induction method and the magnetic resonance method can be selected and transmitters that can wirelessly transfer power in correspondence to the charge methods by receivers have been developed. When the battery of a receiver is fully charged, a transmitter does not recognize this fact and keeps transferring power, so power is lost and the temperature of the transmitter and receiver is increased due to heat generation thereof. | <SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is diagram showing a magnetic induction equivalent circuit. FIG. 2 is diagram showing a magnetic resonance equivalent circuit. FIGS. 3A and 3B are block diagrams showing a power transfer unit that is one of sub-systems constituting a wireless power transfer system; FIGS. 4A and 4B are block diagrams showing a power receiver unit that is one of sub-systems constituting a wireless power transfer system; FIG. 5 is a diagram showing the operation flow of a wireless power transfer system, based on the operation state of a power transfer unit according to an embodiment; FIG. 6 is a diagram showing the operation flow of a wireless power transfer system, based on the operation state of a power transfer unit according to another embodiment; FIG. 7 is a diagram showing the operation flow of a wireless power transfer system according to another embodiment; FIGS. 8A and 8B are equivalent circuit diagrams of a power transfer unit and a power receiver unit; FIG. 9 is a flowchart of driving a power transfer unit according to an embodiment; FIG. 10 is a flowchart of driving a power receiver unit according to an embodiment; and FIG. 11 is a graph showing the magnitude of a current applied to a battery in accordance with a full charge state of the battery over time. detailed-description description="Detailed Description" end="lead"? | H02J7007 | 20180212 | 20180823 | 77522.0 | H02J700 | 0 | TSO, EDWARD H | WIRELESS POWER TRANSFER SYSTEM AND DRIVING METHOD THEREFOR | UNDISCOUNTED | 0 | REJECTED | H02J | 2,018 |
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15,753,778 | PENDING | Rotating Coalescing Element with Directed Liquid Drainage and Gas Outlet | A rotating coalescer having an ejected coalesced liquid separating device is described. The separating device prevents re-entrainment of liquid into a stream of filtered gas. The rotating coalescer includes a rotating filter element or coalescing cone stack positioned within a rotating coalescer housing. The outer surface of the rotating filter element or the outlet of the coalescing cone stack is displaced from the inner surface of the rotating coalescer housing. The gap between the rotating filter element or the coalescing cone stack and the rotating coalescer housing allows for ejected coalesced liquid, such as oil, to accumulate on the inner surface of the rotating coalescer housing for drainage and allows for filtered gas, such as air, to exit through a clean gas outlet of the rotating coalescer housing. | 1. A filtration system comprising: a filtration system housing having an inlet and an outlet, a rotating coalescer element positioned within the filtration system housing and in fluid communication with the inlet and the outlet, the rotating coalescer element configured to separate a suspended liquid from a fluid received through the inlet, the rotating coalescer element including: a first endplate, second endplate, a coalescing device positioned between the first endplate and the second endplate, and a rotating coalescer housing extending between and coupled to the first endplate and the second endplate, the rotating coalescer housing radially displaced from an outer surface of the coalescing device such that a gap exists between an inner wall of the rotating coalescer housing and the outer surface of the coalescing device, the rotating coalescer housing including a clean gas outlet adjacent the first endplate and a liquid outlet adjacent the second endplate, the rotating coalescer housing including a circumferential ring positioned near the gas outlet that prevents separated liquid accumulated on the inner wall from passing through the clean gas outlet. 2. The filtration system of claim 1, wherein the coalescing device includes a fibrous filter media. 3. The filtration system of claim 1, wherein the coalescing device includes a coalescer cone stack. 4. The filtration system of claim 1, wherein the rotating coalescer housing is narrower at a first end adjacent to the gas outlet and wider at a second end adjacent to the liquid outlet. 5. The filtration system of claim 4, wherein the accumulated liquid is drained from the rotating coalescer element against the force of gravity. 6. The filtration system of claim 1, wherein the rotating coalescer element is a high-speed rotating coalescer element that creates a radial g-force at the inner wall of the rotating coalescer housing of at least 1000 times the force of gravity. 7. The filtration system of claim 1, wherein the fluid is crankcase blowby gas received from an internal combustion engine. 8. The filtration system of claim 1, wherein the second endplate comprises a plurality of drains. 9. The filtration system of claim 1, wherein the rotating coalescer housing comprises a support rib projecting from the inner wall to provide support to the coalescing device. 10. The filtration system of claim 9, wherein the support rib comprises a through-hole configured to allow filtered fluid to pass through the support rib. 11. A rotating coalescer element configured to separate a suspended liquid from a fluid, the rotating coalescer element comprising: a first endplate, a second endplate, a coalescing device positioned between the first endplate and the second endplate, and a rotating coalescer housing extending between and coupled to the first endplate and the second endplate, the rotating coalescer housing radially displaced from an outer surface of the coalescing device such that a gap exists between an inner wall of the rotating coalescer housing and the outer surface of the coalescing device, the rotating coalescer housing including a clean gas outlet adjacent the first endplate and a liquid outlet adjacent the second endplate, the rotating coalescer housing including a circumferential ring positioned near the gas outlet that prevents separated liquid accumulated on the inner wall from passing through the clean gas outlet. 12. The rotating coalescer element of claim 11, wherein the coalescing device includes a fibrous filter media. 13. The rotating coalescer element of claim 11, wherein the coalescing device includes a coalescer cone stack. 14. The rotating coalescer element of claim 11, wherein the rotating coalescer housing is narrower at a first end adjacent to the gas outlet and wider at a second end adjacent to the liquid outlet. 15. The rotating coalescer element of claim 14, wherein the accumulated liquid is drained from the rotating coalescer element against the force of gravity. 16. The rotating coalescer element of claim 11, wherein the rotating coalescer element is a high-speed rotating coalescer element that creates a radial g-force at the inner wall of the rotating coalescer housing of at least 1000 times the force of gravity. 17. The rotating coalescer element of claim 11, wherein the fluid is crankcase blowby gas received from an internal combustion engine. 18. The rotating coalescer element of claim 11, wherein the second endplate comprises a plurality of drains. 19. The rotating coalescer element of claim 11, wherein the rotating coalescer housing comprises a support rib projecting from the inner wall to provide support to the coalescing device. 20. The rotating coalescer element of claim 19, wherein the support rib comprises a through-hole configured to allow filtered fluid to pass through the support rib. | CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62/211,538, entitled “ROTATING COALESCING ELEMENT WITH DIRECTED LIQUID DRAINAGE AND GAS OUTLET,” by Schwandt et al., filed on Aug. 28, 2015 and the contents of which are herein incorporated by reference in the entirety and for all purposes. TECHNICAL FIELD The present application relates to rotating coalescing elements. BACKGROUND During operation of an internal combustion engine, a fraction of combustion gases can flow out of the combustion cylinder and into the crankcase of the engine. These gases are often called “blowby” gases. The blowby gases include a mixture of aerosols, oils, and air. If vented directly to the ambient, the blowby gases can harm the environment. Accordingly, the blowby gases are typically routed out of the crankcase via a crankcase ventilation system. The crankcase ventilation system may pass the blowby gases through a coalescer (i.e., a coalescing filter element) to remove a majority of the aerosols and oils contained in the blowby gases. The coalescer includes filter media. The filtered blowby gases (“clean” gases) are then either vented to the ambient (in open crankcase ventilation systems) or routed back to the air intake for the internal combustion engine for further combustion (in closed crankcase ventilation systems). Some crankcase ventilation systems utilize rotating coalescers that increase the filter efficiency of the coalescing filter elements by rotating the filter media during filtering. In rotating filter cartridges, the contaminants (e.g., oil droplets suspended and transported by blowby gases) are separated inside the filter media of the filter cartridge through the particle capture mechanisms of inertial impaction, interception, diffusion, and gravitational forces onto the fibers. By rotating the filter media, inertial impaction and gravitational forces are enhanced by the additional centrifugal force. Additionally, the rotation of the filter cartridge can create a pumping effect, which reduces the pressure drop through the filtration system. Rotating filter cartridges may include fibrous filters as well as centrifugal separation devices. The centrifugal forces caused by the rotation tend to eject coalesced liquid droplets along the entire axial height of the filter media. Depending on the location of ejection and the speed of rotation, the separated liquid droplets may be re-entrained into the flow stream of filtered air. Further, the ejected liquid droplets may be collected on a stationary surface of the coalescer housing at an undesirable area. This increased liquid carry-over of the rotating coalescer can reduce the efficiency of the filtration system. Further, the increased liquid carry-over can make it difficult to position a gas flow outlet for the coalescer housing directly opposite of the rotating coalescer outer diameter due to direct ejection of the coalesced droplets towards the outlet. SUMMARY One example embodiment relates to a filtration system. The filtration system includes a filtration system housing having an inlet and an outlet. A rotating coalescer element is positioned within the filtration system housing and in fluid communication with the inlet and the outlet. The rotating coalescer element is configured to separate a suspended liquid from a fluid received through the inlet. The rotating coalescer element includes a first endplate, a second endplate, and a coalescing device positioned between the first endplate and the second endplate. The rotating coalescer element further includes a rotating coalescer housing extending between and coupled to the first endplate and the second endplate. The rotating coalescer housing is radially displaced from an outer surface of the coalescing device such that a gap exists between an inner wall of the rotating coalescer housing and the outer surface of the coalescing device. The rotating coalescer housing includes a clean gas outlet adjacent the first endplate and a liquid outlet adjacent the second endplate. The rotating coalescer housing including a circumferential ring positioned near the gas outlet that prevents separated liquid accumulated on the inner wall from passing through the clean gas outlet. Another example embodiment relates to a rotating coalescer element. The rotating coalescer element is configured to separate a suspended liquid from a fluid. The rotating coalescer element includes a first endplate, a second endplate, and a coalescing device positioned between the first endplate and the second endplate. The rotating coalescer element further includes a rotating coalescer housing extending between and coupled to the first endplate and the second endplate. The rotating coalescer housing is radially displaced from an outer surface of the coalescing device such that a gap exists between an inner wall of the rotating coalescer housing and the outer surface of the coalescing device. The rotating coalescer housing includes a clean gas outlet adjacent the first endplate and a liquid outlet adjacent the second endplate. The rotating coalescer housing including a circumferential ring positioned near the gas outlet that prevents separated liquid accumulated on the inner wall from passing through the clean gas outlet. These and other features, together with the organization and manner of operation thereof, will become apparent from the following detailed description when taken in conjunction with the accompanying drawings, wherein like elements have like numerals throughout the several drawings described below. BRIEF DESCRIPTION OF THE FIGURES FIG. 1 shows a cross-sectional view of a filtration system is shown according to an example embodiment. FIG. 2 shows a cross-sectional view of the rotating filter element of the filtration system of FIG. 1. FIG. 3 shows a perspective view of the rotating filter element of the filtration system of FIG. 1. FIG. 4 shows another perspective view of the rotating filter element of the filtration system of FIG. 1. FIG. 5 shows another cross-sectional view of the rotating filter element of the filtration system of FIG. 1. FIG. 6 is a cross-sectional view of a rotating coalescer element according to an example embodiment. FIG. 7 is a cross-sectional view of a rotating filter element according to another example embodiment. DETAILED DESCRIPTION Referring to the figures generally, a rotating coalescer having an ejected coalesced liquid separating device is described. The separating device prevents re-entrainment of liquid into a stream of filtered gas. The rotating coalescer includes a rotating filter element or coalescing cone stack positioned within a rotating coalescer housing. The outer surface (i.e., the clean side) of the rotating filter element or the outlet of the coalescing cone stack is displaced from the inner surface of the rotating coalescer housing. The gap between the rotating filter element or the coalescing cone stack and the rotating coalescer housing allows for ejected coalesced liquid, such as oil, to accumulate on the inner surface of the rotating coalescer housing for drainage and allows for filtered gas, such as air, to exit through a clean gas outlet of the rotating coalescer housing. In some arrangements, the rotating coalescer housing includes a rib that prevents accumulated liquid from flowing through the clean gas outlet. In further arrangements, the inner surface of the rotating coalescer housing is angled to assist with drainage of the accumulated liquid. Referring to FIG. 1, a cross-sectional view of a filtration system 100 is shown according to an example embodiment. The filtration system 100 includes a filtration system housing 102 having an inlet 104 and an outlet 106. The filtration system housing 102 is a stationary housing. The inlet 104 receives fluid to be filtered, such as crankcase blowby gases, and the outlet 106 outputs filtered fluid to a system, such as an internal combustion engine (e.g., a diesel internal combustion engine). The filtration system 100 includes a rotating filter element 108. The rotating filter element 108 is a rotating coalescer element. The rotating filter element 108 includes filter media 110. The filter media 110 shown in FIG. 1 is arranged in a cylindrical shape. The filter media 110 is a coalescing fibrous filter media. The rotating filter element 108 includes a first endplate 112 and a second endplate 114. The filter media 110 is positioned between the first endplate 112 and the second endplate 114. In some arrangements, the filter media 110 is sealed to the first endplate 112 and the second endplate 114. The rotating filter element 108 further includes a rotating coalescer housing 116. The rotating coalescer housing 116 extends between and is coupled to the first endplate 112 and the second endplate 114. The rotating coalescer housing 116 is radially displaced from an outer surface of the filter media 110. Generally, the rotating filter element 108 separates a suspended liquid in the fluid. In arrangements where the filtration system 100 is a crankcase ventilation system, the rotating filter element 108 separates oils and aerosols suspended in the crankcase blowby gases. The rotating filter element 108 is described in further detail below with respect to FIGS. 2 through 7. Referring to FIGS. 2 through 5, various views of the rotating filter element 108 are shown. As shown best in FIGS. 2 and 5, the rotating filter element 108 includes a central axis 118. During operation, the rotating filter element 108 rotates about a central axis. Fluid to be filtered enters the filtration system housing 102 through the inlet 104. The fluid flows through the filter media 110 as shown by flow arrows 120 in FIG. 5. As the fluid passes through the filter media 110, liquid droplets dispersed in the fluid are coalesced and separated from the fluid by the filter media 110. Due to the rotation of the rotating filter element 108 and the centrifugal force imparted on the separated liquid, the separated liquid may be ejected from the outlet face of the filter media 110. As noted above, the inner wall of the rotating coalescer housing 116 is separated from the outlet face of the filter media 110 (e.g., by a distance D). The separation distance D permits the ejected liquid to accumulate along the inner wall of the rotating coalescer housing 116 while still providing space for the filtered fluid to flow out of the rotating filter element 108. As the separated liquid accumulates on the inner wall of the rotating coalescer housing 16, the separated liquid may form a film of liquid along the inner wall of the rotating coalescer housing 116. The separated liquid flows to a drain (as designated by the drainage arrow 122). The filtered fluid exits the rotating filter element 108 through a plurality of gas outlets 124 formed between the first endplate 112 and the rotating coalescer housing 116. The accumulated liquid along the inner wall of the rotating coalescer housing 116 exits the rotating filter element 108 through a plurality of liquid outlets 126 formed in the rotating coalescer housing 116 and a plurality of drains 128 formed in the second endplate 114. As shown best in FIG. 3, the liquid outlets 126 are formed near the opposite end of the rotating coalescer housing 116 from the gas outlets 124. As described in further detail below, the rotating coalescer housing 116 includes features that assist in preventing the accumulated fluid from flowing out of the gas outlets 124. In some arrangements, the rotating coalescer housing 116 and the first endplate 112, or at least a portion there of, are formed as a single piece of injection molded thermoplastic. In some arrangements, the inner wall of the rotating coalescer housing 116 includes a circumferential ring 130 positioned near the gas outlets 124 of the rotating filter element 108. The circumferential ring 130 prevents the separated liquid from flowing through the gas outlets 124. Due to the rotation of the rotating filter element 108, the film of accumulated liquid that forms along the inner wall of the rotating coalescer housing 116 can only reach a certain thickness. The height of the circumferential ring 130 with respect to the inner wall of the rotating coalescer housing 116 is greater than the maximum thickness of the film of accumulated liquid thereby preventing the liquid from exiting the rotating filter element through the gas outlets 124. In further arrangements, the rotating coalescer housing 116 may be angled at a draft angle a away from the gas outlets 124. In such arrangements, the rotating coalescer housing is narrower at the end adjacent to the gas outlets 124 (i.e., the first endplate 112) and wider at the end adjacent to the liquid outlets 126 (i.e., the second endplate 114). Thus, the rotating coalescer housing 116 may be slightly conical, convex, or concave in shape. During rotation, the centrifugal forces on the accumulated liquid will move the accumulated along angled wall of the rotating coalescer housing 116 in an axial direction towards the liquid outlets 126 and away from the gas outlets 124. In some arrangements, the centrifugal forces on the accumulated liquid in the axial direction are greater than gravity. In such arrangements, the gas outlet 124 and the liquid outlet can be flipped in the direction of gravity (e.g., as shown in FIG. 7). Neglecting viscous and/or shear forces from the flow of gas between the filter media 110 and the rotating coalescer housing 116, the accumulated liquid on the inner wall of the rotating coalescer housing 116 forms a “near vertical” liquid film, where the equilibrium surface angle with respect to axis =a (if no drainage occurred and the accumulated liquid were trapped within the rotating filter element 108) would be approximately tan−1(1/Gradial), where the Gradial is defined by equation (1) below. ω2*R=Gradial≥˜1000 (1) In equation 1, ω is the rotational speed of the rotating filter element 108 during operation and R is the distance between the central axis 118 and the inside of the rotating coalescer housing 116. Accordingly, the height of the circumferential ring 130, the draft angle α, or a combination thereof creates an effective angle greater than tan−1(1/Gradial) to achieve drainage in the desired direction (i.e., away from the gas outlets 124 and towards the liquid outlets 126. For example, for a Gradial of approximately 1000, the draft angle 132 is approximately 0.06 degrees. Still referring to FIGS. 1 through 5, in some arrangements, the rotating coalescer housing 116 includes a plurality of support ribs 132 projecting from the inner surface of the rotating coalescer housing 116 to the outlet face of the filter media 110. The support ribs 132 provide support to the flexible fibrous media 110 during rotation of the filter element 108 to prevent excessive deformation of the filter media 110 during high speed rotation. In order to allow filtered fluid to exit through the gas outlets 124, the support ribs 132 may include a number of first through-holes that allow the filtered fluid to pass between the support ribs 132. Alternatively, gas outlets 124 may be positioned between adjacent sets of support ribs 132 and between the outermost support ribs 132 and the first and second endplates 112 and 114. Additionally, to allow the accumulated liquid to drain, the support ribs 132 include a number of second through-holes that allow the accumulated liquid to pass between the support ribs 132. Alternatively, liquid outlets 126 may be positioned between adjacent sets of support ribs 132 and between the outermost support ribs 132 and the first and second endplates 112 and 114. In some arrangements, an axial rib ring extends 134 from the gas outlet end of the rotating coalescer housing 116 adjacent to the filter media 110. The axial rib ring 134 extends into the rotating coalescer housing 116 beyond the axial location of the circumferential ring 130, which prevents accumulated liquid from migrating to the gas outlets 124. The axial rib ring 134 acts as a weir that prevents accumulated liquid exiting the filter media 110 from ejecting directly to the gas outlets 124. Referring to FIG. 6, a cross-sectional view of a rotating coalescer element 600 is shown according to an example embodiment. The rotating coalescer element 600 is similar to the rotating filter element 108 of filtration system 100. Accordingly, like numbering is used between the rotating coalescer element 600 of FIG. 6 and the rotating filter element of FIGS. 1 through 5. The only difference between the rotating coalescer element 600 and the rotating filter element 108 is that the rotating coalescer element 600 does not utilize filter media to separate a liquid suspended in the fluid flowing through the rotating coalescer element 600. Rather, the rotating coalescer element 600 utilizes a centrifuge cone stack 602. The centrifuge cone stack 602 includes a plurality of axially spaced centrifuge cones 604. Each of the cones is angled with respect to the radial direction. As the gas passes through the space between each of the axially spaced centrifuge cones 604, the angle of the individual axially spaced centrifuge cones 604 causes an abrupt change in direction of the gas. The abrupt change of direction separates the suspended liquid due to the higher inertia of the liquid as compared to the gas. FIG. 7 shows a cross-sectional view of a rotating filter element 700 according to an example embodiment. The rotating filter element 700 is similar to the rotating filter element 108 of filtration system 100. Accordingly, like numbering is used between the rotating filter element 700 of FIG. 7 and the rotating filter element of FIGS. 1 through 5. As shown in FIG. 7, the rotating filter element 700 is oriented in the opposite direction with respect to gravity 702 than the rotating filter element 108. Accordingly, the accumulated liquid is drained from the rotating filter element 700 against the force of gravity. The drainage is achieved because the centrifugal force on the accumulated liquid is high enough to overcome the force of gravity. The orientation of the filter element 700 permits a top inlet of the gas-liquid mixture into the device and a bottom clean gas outlet. Such an arrangement may be preferred for certain crankcase ventilation applications in which the source of the aerosol laden blowby gas to be cleaned is above the location of the rotating coalescing device. The above-described rotating coalescer and filter elements may be used in crankcase ventilation systems. In some arrangements, the above-described rotating coalescer and filter elements are used in high-speed rotating coalescer arrangements in which the radial g-force at the inner diameter of the rotating coalescer housing 116 is at least 1000 times the force of gravity. The above-described rotating coalescer and filter elements provide a number advantages in accordance with various embodiments. By changing the shape of the rotating coalescer housing (e.g., the rotating coalescer housing 116), separated liquid can be directed to a desired location by harnessing axial and radial components of the centrifugal force created by the rotation. This allows for an unlimited amount of locations for accumulated liquid to be ejected from the rotating coalescer housing. This minimizes or eliminates the risk of accumulated liquid becoming re-entrained into the filtered fluid via the gas outlet. Similarly, by utilizing the centrifugal forces to move the accumulated liquid, the coalescing element could be operated at any angle, provided that the outlet liquid ejected from the rotating body is captured in an area of the stationary housing which directs the ejected liquid away and does not allow it to recombine with the clean gas outlet. It should be noted that any use of the term “example” herein to describe various embodiments is intended to indicate that such embodiments are possible examples, representations, and/or illustrations of possible embodiments (and such term is not intended to connote that such embodiments are necessarily extraordinary or superlative examples). As used herein, the term “about” or “approximately” when coupled to a number or a range means plus or minus five percent of the modified number or range. When a range is described as being between two numbers, the range is intended to be inclusive of the two numbers that define the range. The terms “coupled” and the like as used herein mean the joining of two members directly or indirectly to one another. Such joining may be stationary (e.g., permanent) or moveable (e.g., removable or releasable). Such joining may be achieved with the two members or the two members and any additional intermediate members being integrally formed as a single unitary body with one another or with the two members or the two members and any additional intermediate members being attached to one another. References herein to the positions of elements (e.g., “top,” “bottom,” “above,” “below,” etc.) are merely used to describe the orientation of various elements in the FIGURES. It should be noted that the orientation of various elements may differ according to other example embodiments, and that such variations are intended to be encompassed by the present disclosure. It is important to note that the construction and arrangement of the various example embodiments are illustrative only. Although only a few embodiments have been described in detail in this disclosure, those skilled in the art who review this disclosure will readily appreciate that many modifications are possible (e.g., variations in sizes, dimensions, structures, shapes and proportions of the various elements, values of parameters, mounting arrangements, use of materials, colors, orientations, etc.) without materially departing from the novel teachings and advantages of the subject matter described herein. For example, elements shown as integrally formed may be constructed of multiple parts or elements, the position of elements may be reversed or otherwise varied, and the nature or number of discrete elements or positions may be altered or varied. The order or sequence of any process or method steps may be varied or re-sequenced according to alternative embodiments. Additionally, features from particular embodiments may be combined with features from other embodiments as would be understood by one of ordinary skill in the art. Other substitutions, modifications, changes and omissions may also be made in the design, operating conditions and arrangement of the various example embodiments without departing from the scope of the present invention. | <SOH> BACKGROUND <EOH>During operation of an internal combustion engine, a fraction of combustion gases can flow out of the combustion cylinder and into the crankcase of the engine. These gases are often called “blowby” gases. The blowby gases include a mixture of aerosols, oils, and air. If vented directly to the ambient, the blowby gases can harm the environment. Accordingly, the blowby gases are typically routed out of the crankcase via a crankcase ventilation system. The crankcase ventilation system may pass the blowby gases through a coalescer (i.e., a coalescing filter element) to remove a majority of the aerosols and oils contained in the blowby gases. The coalescer includes filter media. The filtered blowby gases (“clean” gases) are then either vented to the ambient (in open crankcase ventilation systems) or routed back to the air intake for the internal combustion engine for further combustion (in closed crankcase ventilation systems). Some crankcase ventilation systems utilize rotating coalescers that increase the filter efficiency of the coalescing filter elements by rotating the filter media during filtering. In rotating filter cartridges, the contaminants (e.g., oil droplets suspended and transported by blowby gases) are separated inside the filter media of the filter cartridge through the particle capture mechanisms of inertial impaction, interception, diffusion, and gravitational forces onto the fibers. By rotating the filter media, inertial impaction and gravitational forces are enhanced by the additional centrifugal force. Additionally, the rotation of the filter cartridge can create a pumping effect, which reduces the pressure drop through the filtration system. Rotating filter cartridges may include fibrous filters as well as centrifugal separation devices. The centrifugal forces caused by the rotation tend to eject coalesced liquid droplets along the entire axial height of the filter media. Depending on the location of ejection and the speed of rotation, the separated liquid droplets may be re-entrained into the flow stream of filtered air. Further, the ejected liquid droplets may be collected on a stationary surface of the coalescer housing at an undesirable area. This increased liquid carry-over of the rotating coalescer can reduce the efficiency of the filtration system. Further, the increased liquid carry-over can make it difficult to position a gas flow outlet for the coalescer housing directly opposite of the rotating coalescer outer diameter due to direct ejection of the coalesced droplets towards the outlet. | <SOH> SUMMARY <EOH>One example embodiment relates to a filtration system. The filtration system includes a filtration system housing having an inlet and an outlet. A rotating coalescer element is positioned within the filtration system housing and in fluid communication with the inlet and the outlet. The rotating coalescer element is configured to separate a suspended liquid from a fluid received through the inlet. The rotating coalescer element includes a first endplate, a second endplate, and a coalescing device positioned between the first endplate and the second endplate. The rotating coalescer element further includes a rotating coalescer housing extending between and coupled to the first endplate and the second endplate. The rotating coalescer housing is radially displaced from an outer surface of the coalescing device such that a gap exists between an inner wall of the rotating coalescer housing and the outer surface of the coalescing device. The rotating coalescer housing includes a clean gas outlet adjacent the first endplate and a liquid outlet adjacent the second endplate. The rotating coalescer housing including a circumferential ring positioned near the gas outlet that prevents separated liquid accumulated on the inner wall from passing through the clean gas outlet. Another example embodiment relates to a rotating coalescer element. The rotating coalescer element is configured to separate a suspended liquid from a fluid. The rotating coalescer element includes a first endplate, a second endplate, and a coalescing device positioned between the first endplate and the second endplate. The rotating coalescer element further includes a rotating coalescer housing extending between and coupled to the first endplate and the second endplate. The rotating coalescer housing is radially displaced from an outer surface of the coalescing device such that a gap exists between an inner wall of the rotating coalescer housing and the outer surface of the coalescing device. The rotating coalescer housing includes a clean gas outlet adjacent the first endplate and a liquid outlet adjacent the second endplate. The rotating coalescer housing including a circumferential ring positioned near the gas outlet that prevents separated liquid accumulated on the inner wall from passing through the clean gas outlet. These and other features, together with the organization and manner of operation thereof, will become apparent from the following detailed description when taken in conjunction with the accompanying drawings, wherein like elements have like numerals throughout the several drawings described below. | B01D460031 | 20180220 | 20180830 | 90291.0 | B01D4600 | 0 | JONES, CHRISTOPHER P | Rotating Coalescing Element with Directed Liquid Drainage and Gas Outlet | UNDISCOUNTED | 0 | ACCEPTED | B01D | 2,018 |
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15,754,367 | PENDING | RECEPTION DEVICE, BROADCAST SYSTEM, RECEPTION METHOD, AND PROGRAM | A service information processing unit acquires, from service information of content, current information that indicates luminance information of a video at a current time point and preannouncement information that indicates luminance information of the video after a given time from the current time point, a level control unit, when a luminance range indicated by the preannouncement information changes from a luminance range of the video at the current time point, changes a luminance range more gently compared to a change of the luminance range, and a display unit displays the video in the luminance range defined by the level control unit. | 1. A reception device comprising: a service information processing unit that acquires, from service information of content, current information that indicates luminance information of a video at a current time point and preannouncement information that indicates luminance information of the video after a given time from the current time point; a level control unit that, when a luminance range indicated by the preannouncement information changes from a luminance range of the video at the current time point, changes a luminance range more gently compared to a change of the luminance range; and a display unit that displays the video in the luminance range defined by the level control unit. 2. The reception device according to claim 1, wherein when the luminance range specified by the preannouncement information is expanded from the luminance range of the video at the current time point, the level control unit changes the luminance range over a longer time compared to a case where the luminance range indicated by the preannouncement information is reduced. 3. The reception device according to claim 1, wherein when the luminance range indicated by the preannouncement information is wider than the luminance range of the video at the current time point, the level control unit gradually reduces maximum luminance of the video to given luminance within the given time. 4. The reception device according to claim 3, wherein the level control unit gradually releases luminance reduction to the given luminance after the given time has lapsed. 5. The reception device according to claim 3, wherein in a case where an effective duration time is further set to the luminance information indicated by the preannouncement information, the level control unit gradually releases luminance reduction to the given luminance when the duration time has further lapsed after the given time. 6. The reception device according to claim 1, further comprising a display control unit that, when the luminance range indicated by the preannouncement information changes, notifies a change of the luminance range. 7. A broadcast system including a transmission device and a reception device, wherein the transmission device transmits content and service information of the content that includes current information that indicates luminance information of a video at a current time point and preannouncement information that indicates luminance information of the video after a given time from the current time point, and the reception device includes: a service information processing unit that acquires the current information and the preannouncement information from the service information; a level control unit that, when a luminance range indicated by the preannouncement information changes from a luminance range of the video at the current time point, changes a luminance range more gently compared to a change of the luminance range; and a display unit that displays the video in the luminance range defined by the level control unit. 8. A reception method in a reception device, the reception method comprising: acquiring, from service information of content, current information that indicates luminance information of a video at a current time point and preannouncement information that indicates luminance information of the video after a given time from the current time point; and when a luminance range indicated by the preannouncement information changes from a luminance range of the video at the current time point, changing a luminance range, in which the video is displayed, more gently compared to a change of the luminance range. 9. A non-transitory computer readable recording medium storing a program causing a computer of a reception device to execute: acquiring, from service information of content, current information that indicates luminance information of a video at a current time point and preannouncement information that indicates luminance information of the video after a given time from the current time point; and when a luminance range indicated by the preannouncement information changes from a luminance range of the video at the current time point, changing a luminance range, in which the video is displayed, more gently compared to a change of the luminance range. | TECHNICAL FIELD An embodiment of the present invention relates to a reception device, a broadcast system, a reception method, and a program that comfortably control luminance when broadcast videos whose dynamic ranges are different are switched. This application claims priority based on Japanese Patent Application No. 2015-164794 filed in Japan on Aug. 24, 2015, the content of which is incorporated herein. BACKGROUND ART With development of a sensor technique and an image processing technique, interest in an HDR (High Dynamic Range; also referred to as a wide-band dynamic range) video is enhanced and it is attempted to exploit the HDR video. The HDR video is a video that has luminance in a wider range than that of a normal video. On the other hand, the normal video is called an LDR (Low Dynamic Range) video or an SDR (Standard Dynamic Range) video. The HDR video is expected to be introduced in broadcast service in the future. However, the HDR video is not always provided in the broadcast service. It is expected that the HDR video or the SDR video is used properly depending on a program. In this case, not only in a normal program, but between advertisements (CM: Commercial Advertisement) mainly aiming at advertising of various goods and service, a luminance range of a video that is broadcasted is switched between the HDR and the SDR in some cases. Thus, a reception device is required to cope with a change of the luminance range as the program is switched. Then, a technical requirement under which a transmission device adds luminance information which indicates whether a luminance range is the HDR or the SDR to content to be broadcasted and a reception device sets various parameters on the basis of the luminance information has been standardized. The parameters include peak luminance, and contrast, for example. The parameters are set aiming that a video that is adjusted to have luminance and contrast as intended by a transmission side is viewed on a reception side. PTL 1 describes a reception device including a trigger detection unit that detects a trigger for a start of CM broadcasting and a trigger for an end of CM broadcasting from a television broadcast signal. When the trigger for the start of CM broadcasting is detected, the reception device calculates a feature quantity of the television broadcast signal immediately after the trigger. When the calculated feature quantity is stored in a CM database with indication of being a CM, the reception device determines that the television broadcast signal is a CM. The reception device causes a CM database unit to store a time until the trigger for the end of CM broadcasting is detected after the trigger for the start of CM broadcasting is detected and the calculated feature quantity, and when the number of times that the time and the feature quantity are detected is a given number of times or more, the reception device causes the CM database unit to store the feature quantity and indication of being a CM. CITATION LIST Patent Literature PTL 1: Japanese Unexamined Patent Application Publication No. 2011-109395 SUMMARY OF INVENTION Technical Problem However, when luminance suddenly changes in accordance with detection of luminance information as content is switched, a viewer who views a video may be made uncomfortable or his/her physical condition may be affected. An error on a transmission side or an error of luminance information due to a defect of the reception device may cause an unnecessary change of luminance. The invention was made in view of such circumstances and provides a reception device, a broadcast system, a reception method, and a program that are able to prevent or reduce uncomfortableness or a poor physical condition of a viewer due to a sudden change in luminance. Solution to Problem The invention was made to solve the aforementioned problems and provides a reception device including: a service information processing unit that acquires, from service information of content, current information that indicates luminance information of a video at a current time point and preannouncement information that indicates luminance information of the video after a given time from the current time point; a level control unit that, when a luminance range indicated by the preannouncement information changes from a luminance range of the video at the current time point, changes a luminance range more gently compared to a change of the luminance range; and a display unit that displays the video in the luminance range defined by the level control unit. Advantageous Effects of Invention According to an embodiment of the invention, it is possible to prevent or reduce uncomfortableness or a poor physical condition of a viewer due to a sudden change in luminance. BRIEF DESCRIPTION OF DRAWINGS FIG. 1 is a schematic block diagram illustrating a configuration of a broadcast system according to a first embodiment. FIG. 2 illustrates an example of a relationship between a signal level and luminance. FIG. 3 illustrates another example of a relationship between a signal level and luminance. FIG. 4 is a schematic block diagram illustrating a configuration of a transmission device according to the first embodiment. FIG. 5 illustrates an example of a data structure of an MPT. FIG. 6 illustrates an example of a data structure of a video component descriptor. FIG. 7 illustrates an example of setting of a luminance flag. FIG. 8 illustrates an example of a data structure of an MH-EIT. FIG. 9 is a schematic block diagram illustrating a configuration of a reception device according to the first embodiment. FIG. 10 illustrates an example of a time change of a luminance range of a video. FIG. 11 illustrates an example of control for a luminance range according to the first embodiment. FIG. 12 is a flowchart indicating control for a luminance range according to the first embodiment. FIG. 13 is a view for explaining a preannouncement flag. FIG. 14 illustrates an example of control for a luminance range according to a second embodiment. FIG. 15 illustrates an example of control for a luminance range according to the second embodiment. FIG. 16 illustrates an example of a time change of a luminance range of a video. FIG. 17 is a flowchart indicating control for a luminance range according to the second embodiment. FIG. 18 illustrates an example of a time change of a luminance range of a video. FIG. 19 is a flowchart indicating control for a luminance range according to a third embodiment. DESCRIPTION OF EMBODIMENTS Hereinafter, embodiments of the invention will be described with reference to drawings. First Embodiment First, an outline of a broadcast system 1 according to a first embodiment of the invention will be described. FIG. 1 is a schematic block diagram illustrating a configuration of the broadcast system 1 according to the present embodiment. The broadcast system 1 is configured by including a transmission device 20 and a reception device 10. The transmission device 20 transmits broadcast program data, which indicates a broadcast program, to a reception device via a broadcasting transmission path BT. The broadcasting transmission path BT is a transmission path in which the broadcast program data is unilaterally and simultaneously transmitted to multiple unspecified reception devices 10. The broadcasting transmission path BT is, for example, a broadcast wave that has a given frequency band. The broadcasting transmission path BT may be configured by including a broadcast satellite BS that relays the broadcast wave. In a part of the broadcasting transmission path BT, a network, for example, a dedicated line or a VPN (Virtual Private Network) may be included. The reception device 10 receives broadcast program data that is transmitted via the broadcasting transmission path BT. The reception device 10 displays a video based on video data that constitutes the received broadcast program data. The reception device 10 is electronic equipment, for example, such as a television reception device, that is able to receive broadcast program data and display a video related to the received broadcast program data. Though the numbers of transmission devices 20 and reception devices 10 are typically multiple, description will be given below by assuming that each of the numbers is one. A case where the broadcast system 1 uses an MMT (MPEG Media Transport) system as a media transport system is taken as an example. The broadcast system 1 is able to broadcast a plurality of broadcast programs whose dynamic ranges of luminance are different from each other. In other words, an HDR broadcast program and an SDR broadcast program are broadcasted in the broadcast system 1. The HDR broadcast program is a broadcast program in which an HDR video whose luminance range is an HDR is included as a component. The SDR broadcast program is a broadcast program in which an SDR video whose luminance range is an SDR is included as a component. Video data indicating the HDR video and video data indicating the SDR video are respectively called HDR video data and SDR video data. (Luminance of Video) There are two types of luminance; optical luminance and image luminance. The optical luminance is a physical amount indicating brightness of a light source. The optical luminance is used for indicating brightness of a display, for example. In the present embodiment, a luminance range of 0 to 6000 cd/m2 is referred to as the HDR and a luminance range of 0 to 300 cd/m2 is referred to as the SDR, for example. That is, the HDR indicates a wider dynamic range of the optical luminance than that of the SDR. Note that, the luminance ranges of the HDR and the SDR are not limited to the aforementioned ranges, and may be defined as any ranges in accordance with the broadcast system, for example. Hereinafter, the dynamic range of the optical luminance is simply called a dynamic range in some cases. The image luminance means luminance represented by a signal level indicating brightness of a video or a relative value thereof. Hereinafter, each of the optical luminance and the image luminance is simply called luminance in some cases. The broadcast system 1 transmits broadcast program data that includes HDR video data or SDR video data. The HDR video data is constituted by a video format defined by the Rec. ITU-R (International Telecommunication Union-Radiocommunication Sector) BT. 2020, for example. The video format is called an HDR format. The HDR format is able to be applied also to the SDR video data and used for a UHDTV (Ultra-High Definition Television). A case where the video data is data represented by a color space of YCbCr will be described below, for example. In this case, a video source may be data represented by another color space such as a color space of RGB. In the HDR format, a signal level of the image luminance and the HDR as the luminance range are associated with each other. For example, as illustrated in FIG. 2, in the HDR format, the signal level of the image luminance of 0 to 50% corresponds to the optical luminance of 0 to 300 cd/m2, and the signal level of the image luminance of 50 to 100% corresponds to the optical luminance of 300 to 6000 cd/m2, for example. Thus, in the HDR video data transmitted by the HDR format, the signal level of the image luminance may take a range of 0 to 100%. Hereinafter, a possible range of the signal level for video data is referred to as a level range. In the present example, a minimum value (for example, black level) and a maximum value (for example, nominal peak) of a signal value of each pixel that constitutes the HDR video data respectively correspond to 0% and 100%. In a case where the signal value of each pixel is represented by 12 bits, the signal values of the black level and the nominal peak are respectively 64 and 3840, for example. The SDR video data has a video format defined by the Rec. ITU-R BT. 709, for example. The video format is called an SDR format. The SDR format is used for an HDTV (High Definition Television). In the SDR format, a signal level of the image luminance and the SDR are associated with each other. For example, as illustrated in FIG. 3, in the SDR format, the level range of 0 to 100% corresponds to the optical luminance of 0 to 300 cd/m2. The signal level of the image luminance of the SDR video data may take a range of 0 to 100%. In the present example, a minimum value and a maximum value of a signal value of each pixel that constitutes the SDR video data respectively correspond to 0% and 100%. In a case where the signal value of each pixel is represented by 10 bits, the signal values of the black level and the nominal peak are respectively 16 and 960, for example. In the following description, a case where the optical luminance corresponding to a range of 0 to 50% in the range of the image luminance of the HDR video mainly has a range (0 to 300 cd/m2) of the optical luminance corresponding to the range (0 to 100%) of the image luminance of the SDR video is taken as an example. Next, a display unit 15 (FIG. 9) included in the reception device 10 will be described. The display unit 15 may be constituted as a display device separate from the reception device 10. The display unit 15 is a display capable of displaying videos of both the HDR and the SDR as the range of the optical luminance. Specifically, in a case where the signal level of the image luminance in an HDR video signal that is input is 0 to 50 [%], the display unit 15 performs display with the optical luminance of 0 to 300 [cd/m2]. In a case where the signal level is 50 to 100 [%], the display unit 15 performs display with the optical luminance of 300 to 6000 [cd/m2]. Specifically, the display unit 15 performs display with the optical luminance according to the signal level of the image luminance on the basis of an electro optical transfer function (EOTF) exemplified in FIG. 2, for example. The EOTF is a function that describes a correspondence relation between the signal value of the luminance input to the display and the luminance displayed by the display. (Outline of Processing) Next, an outline of processing from when video data for a broadcast program is captured till when a video is displayed on the display unit 15 will be described. Here, for example, it is set that an image capturing device (not illustrated) for video data captures objects SU1 and SU2 and pieces of optical luminance of the objects SU1 and SU2 are respectively 200 and 2000 [cd/m2]. While the optical luminance of the object SU1 is in the range of the SDR, the optical luminance of the object SU2 exceeds an upper limit of the SDR. As a component of broadcast program data, the transmission device 20 transmits, to the reception device 10, the captured video data as SDR video data or HDR video data. The reception device 10 acquires the video data from the broadcast program data received from the transmission device 20 and outputs the acquired video data to the display unit 15. In a case where the video data is the SDR video data, a signal level of the object SU1 is in a range of 0 to 100%. On the other hand, a signal level corresponding to the optical luminance of the object SU2 exceeds 100% and is thus 100%. Therefore, while the display unit 15 displays the object SU1 with the optical luminance within a range of 200 cd/m2, the optical luminance with which the object SU2 is displayed is suppressed to an upper limit thereof, 300 cd/m2. In a case where a video source is the HDR video data, the signal levels of the objects SU1 and SU2 are within ranges of 0 to 50% and 50 to 100%. Therefore, the display unit 15 displays the objects SU1 and SU2 respectively with pieces of optical luminance of 200 and 2000 [cd/m2] that are equal to the pieces of optical luminance obtained by the capturing. As described above, in the HDR video displayed by HDR display, the luminance range in which the optical luminance obtained by the capturing corresponds to the signal level of the image luminance is wider than that of the SDR video. Thus, the object SU1 and the object SU2 are represented with different optical luminance. In a case where the luminance range of the video is switched between the HDR and the SDR, the reception device 10 changes, with respect to the display unit 15, setting of a range of the signal level and the EOTF which indicates a relationship between signal luminance and optical luminance. Since the luminance range of the video that is able to be represented is switched by changing the setting, the luminance of the video changes. The change in the luminance of the video may bring a cause of making a viewer uncomfortable or affecting his/her physical condition. Then, the reception device 10 according to the present embodiment acquires, from service information of a broadcast program, luminance information of a video included in the broadcast program, and when a luminance range indicated by the luminance information changes and the broadcast program is changed, immediately changes setting of the luminance range from the luminance range before the change to a luminance range after the change. When the luminance range indicated by the luminance information changes and the program is not changed, the reception device 10 gradually changes the setting of the luminance range from the luminance range before the change to a luminance range after the change. The reception device 10 causes the display unit 15 to display the video with a defined luminance range. (Configuration of Transmission Device) Next, a configuration of the transmission device 20 according to the present embodiment will be described. FIG. 4 is a schematic block diagram illustrating the configuration of the transmission device 20 according to the present embodiment. The transmission device 20 multiplexes broadcast program data and service information and transmits, on a broadcast wave, the multiplexed data obtained through the multiplexing. The transmission device 20 is configured by including a service information acquisition unit 210, a broadcast content acquisition unit 220, a multiplexing unit 230, a modulation unit 240, and a transmission unit 250. The service information acquisition unit 210 acquires service information. The service information is information about provision of broadcast service, such as a provision form or configuration of a broadcast program. The service information is, for example, MMT-SI (Service Information) in the MMT system. The MMT-SI information includes, for example, an MPT (MMT Package Table) and an MH-EIT (MH-Event Information Table). The MPT is a table that includes information indicating an asset that is a component of the broadcast program, that is, a list of videos or sounds, or a providing condition thereof. The MH-EIT is a table that includes information about the program, for example, information indicating a name of the program, broadcast date and time, explanation for broadcast content, or the like. A luminance flag indicating luminance information of the video to be broadcasted is included in the MPT, for example. In other words, the luminance flag indicates whether the luminance range is the HDR or the SDR. The MH-EIT (MH-Event Information Table) that is a table for transmitting information about the program, such as a name of the program, broadcast date and time, or explanation for broadcast content is included. The service information acquisition unit 210 outputs the acquired service information to the multiplexing unit 230 every given time (for example, 0.1 to 0.5 ms). The service information is updated in accordance with progress of the program, but when not updated, the same service information may be iterated multiple times. Thereby, the broadcast program is able to be presented on the basis of a broadcast signal received at any time point by the reception device 10. The broadcast content acquisition unit 220 acquires broadcast program data. The broadcast program data is data indicating content of the broadcast program. The broadcast program data includes, for example, video data, sound data, and the like that are provided in the broadcast program. The broadcast content acquisition unit 220 outputs the acquired broadcast program data to the multiplexing unit 230. The multiplexing unit 230 multiplexes the service information input from the service information acquisition unit 210 and the broadcast program data input from the broadcast content acquisition unit 220 to generate multiplexed data. The multiplexing unit 230 outputs the multiplexed data that is generated to the modulation unit 240. The modulation unit 240 modulates the multiplexed data input from the multiplexing unit 230, generates a broadcast signal having a given broadcast frequency band, and outputs the generated broadcast signal to the transmission unit 250. The transmission unit 250 outputs, to the broadcasting transmission path BT, a transmission signal input from the modulation unit 240. Thereby, the broadcast signal that carries the multiplexed data in which the broadcast program data and the service information are multiplexed is transmitted via the broadcasting transmission path BT. The broadcast signal is transmitted as a broadcast wave, for example. (MPT) Next, a data structure of an MPT will be described. FIG. 5 illustrates an example of the data structure of the MPT. The MPT is configured by including an asset type (asset_type) and an asset descriptor area (asset_descriptors_byte) of each asset. The asset type (asset_type) is information indicating a type of an asset. For example, an asset in which “hvc1” is described as the asset type indicates a video and an asset in which “mp4a” is described as the asset type indicates sound. The asset descriptor area is an area in which a descriptor describing information about an asset is stored. In the asset descriptor area, a video component descriptor (Video_Component_Descriptor) is described, for example. (Video Component Descriptor) Next, a video component descriptor will be described. FIG. 6 illustrates an example of a data structure of the video component descriptor. The video component descriptor is a descriptor indicating a parameter or explanation related to a video component. The video component descriptor includes an unused parameter (reserved) and component description (text_char). In the present embodiment, a luminance flag as luminance information is described in either the unused parameter (reserved) or the component description (text_char). With the luminance flag, whether the luminance range of a video to be broadcasted is the HDR or the SDR is specified. (Luminance Flag) FIG. 7 illustrates an example of setting of a value of the luminance flag. The luminance flag (video_hdr_flag) has 1-bit information and may have a value of 1 or 0 as exemplified in FIG. 7. The value of 0 indicates that the luminance range is the SDR and the value of 1 indicates that the luminance range is the HDR. The luminance range specified with the luminance flag is set to each of a broadcast program, a segment (also called a session) that constitutes one broadcast program, a CM included in one broadcast program, and the like in some cases. (MH-EIT) Next, an MH-EIT will be described. FIG. 8 illustrates an example of a data structure of the MH-EIT. In the example illustrated in FIG. 8, the MH-EIT (MH-Event_Information_Table( ) includes an event identification (event_ID), a start time (start_time), and a duration time (duration). The event identification indicates an identification number of an event. Specifically, the event identification indicates identification information of a program, for example. The start time indicates a start time of the event. That is, the start time indicates a start time (date and time) of the program. The duration time indicates a duration time of the event. That is, the duration time indicates a length of broadcast time of the program. The MH-EIT also includes a descriptor area (descriptor ( )) of each event identification. The descriptor area is an area in which a descriptor is stored. The MH-EIT is able to include a video component descriptor, for example. The descriptor area is also able to include an MH-extended event descriptor (MH-Extended_Event_Descriptor ( )). In the MH-extended event descriptor, detailed information about each program is described. The detailed information may include, in addition to a performer, a creator, and the like, information of each segment (also called a session) that is a part of a program, such as a provision start time, a duration time, a luminance flag, and the like. (Reception Device) Next, a configuration of the reception device 10 according to the present embodiment will be described. FIG. 9 is a schematic block diagram illustrating the configuration of the reception device 10 according to the present embodiment. The reception device 10 is configured by including a broadcast reception unit 11, an input unit 12, an amplification unit 14, a display unit 15, a storage unit 16, and a control unit 17. The broadcast reception unit 11 receives, among broadcast signals transmitted from the transmission device 20 via the broadcasting transmission path BT, a broadcast signal that is transmitted on a channel specified by a channel tuning signal from a channel tuning unit 178 of the control unit 17. The broadcast reception unit 11 is configured by including a tuner that receives a broadcast wave, for example. The tuner receives a broadcast wave of a frequency band corresponding to the channel specified by the channel tuning signal. The broadcast reception unit 11 outputs the received broadcast signal to a demodulation unit 171 of the control unit 17. To the input unit 12, an operation signal generated by an operation of a user is input. The input unit 12 is configured by including an infrared interface that receives an operation signal from a control device (remote controller) RC by an infrared ray, for example. The operation signal specifies information of on/off of a power supply, a channel on which a broadcast wave is received, a sound volume, luminance, contrast, or the like, for example. The input unit 12 outputs the operation signal to the control unit 17. Note that, the input unit 12 is constituted by including a physical member for receiving the operation of the user, for example, such as various buttons, knobs, and the like, and may generate an operation signal according to the operation. The amplification unit 14 reproduces sound based on sound data input from a sound processing unit 173 of the control unit 17. The amplification unit 14 is configured by including a speaker, for example. The display unit 15 reproduces a video based on video data input from a video processing unit 174 of the control unit 17. The display unit 15 is a display capable of displaying an HDR video based on HDR video data and an SDR video based on SDR video data as described above. The storage unit 16 stores various data such as setting data used in the control unit 17 and data acquired by the control unit 17. The storage unit 16 is configured by including various storage media such as a RAM (Random Access Memory) and a ROM (Read-only Memory). The storage unit 16 may be configured by including a storage medium (for example, BD (Blu-ray (registered trademark) Disc)) in which received video data of a broadcast program or video data of content of a movie or the like produced in advance is stored. In the storage unit 16, broadcast program data and service information which is multiplexed with the broadcast program data may be stored in association with each other. The control unit 17 performs various processing related to an operation of the reception device 10. The control unit 17 is configured by including the demodulation unit 171, a separation unit 172, the sound processing unit 173, the video processing unit 174, and a display processing unit 175. The display processing unit 175 is configured by including an SI processing unit 176, a display control unit 177, the channel tuning unit 178, and a level control unit 179. The control unit 17 is configured by including a control circuit such as a CPU (Central Processing Unit). The control unit 17 may realize a function of the demodulation unit 171, the separation unit 172, the sound processing unit 173, the video processing unit 174, the display processing unit 175, or the like by executing processing specified by a command indicated by a control program read out from the storage unit 16. The demodulation unit 171 demodulates a broadcast signal input from the broadcast reception unit 11 and generates multiplexed data. A demodulation scheme used by the demodulation unit 171 is a demodulation scheme according to a modulation scheme used in the modulation unit 240 (FIG. 4). The demodulation unit 171 outputs the multiplexed data that is generated to the separation unit 172. The separation unit 172 separates broadcast program data and service information from the multiplexed data input from the demodulation unit 171. The separation unit 172 also separates sound data and video data from the broadcast program data. The separation unit 172 outputs the separated sound data to the sound processing unit 173 and outputs the separated video data to the video processing unit 174. The separation unit 172 outputs the separated service information to the display processing unit 175. The sound processing unit 173 decodes the sound data (that has been coded) input from the separation unit 172 and generates decoded sound data. A sound decoding scheme used by the sound processing unit 173 is a sound decoding scheme (for example, MPEG-4 audio) according to a coding scheme used for coding of the sound data. The sound processing unit 173 outputs the sound data generated by decoding to the amplification unit 14. The video processing unit 174 decodes the video data (that has been coded), which is input from the separation unit 172, in a luminance range indicated by luminance information input from the SI processing unit 176 and generates decoded video data. A video decoding scheme used by the video processing unit 174 is a video decoding scheme (for example, HEVC: High Efficiency Video Coding) according to a coding scheme used for coding of the video data. In the following description, a video indicated by the video data input from the separation unit 172 is called a broadcast video in some cases. The video processing unit 174 adjusts a display manner of the broadcast video under control of the display processing unit 175. As the display manner, for example, presence/absence of various graphic screens (such as a caution screen, a menu screen, and a guide screen), luminance or contrast of a broadcasted video, that is, of a video indicated by generated video data, or the like is adjusted. The video processing unit 174 superimposes a graphic screen indicated by graphic screen data input from the video processing unit 174 with the decoded video and generates the superimposed video as an adjusted video. For a pixel whose signal level is in a luminance range indicated by luminance range setting input from the level control unit 179 among pixels indicated by the video data, the video processing unit 174 keeps the signal level without change. For a pixel whose signal level is greater (or smaller) than the luminance range indicated by the luminance range setting input from the level control unit 179 among pixels indicated by the video data, the video processing unit 174 sets the signal level as a maximum value (or a minimum value) of the signal level of each luminance range. The video processing unit 174 outputs video data that indicates the adjusted video to the display unit 15. The display processing unit 175 performs processing related to display of a video. The display processing unit 175 is configured by including the SI processing unit 176, the display control unit 177, the channel tuning unit 178, and the level control unit 179. The SI processing unit 176 analyzes service information input from the separation unit 172. Specifically, the SI processing unit 176 extracts a video component descriptor of an MPT from the service information and acquires luminance information by referring to a value set to a luminance flag. The SI processing unit 176 outputs the acquired luminance information to the video processing unit 174, the display control unit 177, and the level control unit 179. The SI processing unit 176 extracts an MH-EIT from the service information and outputs program information indicated by the extracted MH-EIT to the display control unit 177 and the level control unit 179. The display control unit 177 controls whether to display a graphic screen to be displayed on the display unit 15, acquisition or changing of the graphic screen, and the like on the basis of one or both of the operation signal from the input unit 12 and the information from the SI processing unit 176. As the graphic screen, there is a caution screen, a menu screen, or the like, for example. As the menu screen, there is a video setting screen for setting luminance or contrast for display on the display unit 15. As the caution screen, there is a luminance change caution screen for notifying a change, that is, expansion or reduction of the luminance range. The luminance change caution screen for notifying expansion of the luminance range may include, for example, a message of “Video is made brighter suddenly!” or the like as a message for giving a caution about a sudden increase in the luminance due to expansion of the luminance range. Graphic screen data indicating various graphic screens is stored in advance in the storage unit 16. As the graphic screen, there is a screen that is displayed in accordance with a change of the luminance range of the broadcast video or a screen whose content varies depending on the luminance range of the broadcast video. For example, when the luminance range indicated by luminance information changes, the display control unit 177 starts display of the luminance change caution screen and stops the display after a given time (for example, 5 seconds) has lapsed. When starting the display of the luminance change caution screen, the display control unit 177 reads out, from the storage unit 16, luminance change caution screen data for indicating the luminance change caution screen and outputs the luminance change caution screen data that is read out to the video processing unit 174. As the video setting screen, there is an HDR video setting screen to be displayed when the luminance range of the broadcast video is the HDR or an SDR video setting screen to be displayed when the luminance range of the broadcast video is the SDR. This is because a range of luminance and a range of contrast that are able to be set vary when the luminance range changes. When the luminance range indicated by the luminance information is the HDR and an operation signal to specify display of the video setting screen is input from the input unit 12, the display control unit 177 reads out HDR video setting screen data from the storage unit 16. The display control unit 177 outputs the HDR video setting screen data that is read out to the video processing unit 174. When the luminance range indicated by the luminance information is the SDR and an operation signal to specify display of the video setting screen is input from the input unit 12, the display control unit 177 reads out SDR video setting screen data from the storage unit 16. The display control unit 177 outputs the SDR video setting screen data that is read out to the video processing unit 174. That is, in accordance with the change of the luminance range, the display control unit 177 changes the video setting screen to be displayed. The channel tuning unit 178 identifies a channel, on which a broadcast signal is received, by the operation signal input from the input unit 12. The channel tuning unit 178 generates a channel tuning signal to specify the identified channel and outputs the generated channel tuning signal to the broadcast reception unit 11. The level control unit 179 controls a signal level of the broadcast video on the basis of luminance information and program information that are input from the SI processing unit 176. When a luminance range indicated by the luminance information changes and a program indicated by the program information is changed, the level control unit 179 immediately switches setting of the luminance range set to the video processing unit 174 from the luminance range before the change to a luminance range after the change. In this case, the level control unit 179 outputs setting of the switched luminance range to the video processing unit 174. On the other hand, when the luminance range indicated by the luminance information changes and the program indicated by the program information is not changed, the display control unit 177 gradually changes the setting of the luminance range from the luminance range before the change to a luminance range after the change. In this case, the level control unit 179 successively outputs, to the video processing unit 174, the setting of the luminance range that is defined for each frame. As a result, the level control unit 179 is able to define, with respect to the video processing unit 174, a range of the signal level of the broadcast video as a range of the signal level according to the luminance range defined by the level control unit 179. (Time Change of Luminance Range) Next, an example of a time change of a luminance range of a video that constitutes a broadcast program will be described. FIG. 10 illustrates an example of a time change of a luminance range of a video. In the example illustrated in FIG. 10, a program A that includes an SDR video is broadcasted from a time t0 to a time t1, a program B is broadcasted from the time t1 to a time t6, and a program C that includes an SDR video is broadcasted from the time t6 to a time t7. In the program B, the luminance range of the video is switched. The luminance range may change as a session (also called a segment) that is a part of the program is switched. In the example illustrated in FIG. 10, the luminance range is switched from the HDR to the SDR at times t2, t4, and t6 and switched from the SDR to the HDR at times t3 and t5. In FIG. 10, a mark ▴ assigned to times t1 and t7 indicates a timing when the level control unit 179 immediately changes setting of the luminance range. At the times, a change of the program is accompanied by a change of the luminance range notified with SI information. A mark 4 assigned to times t2, t3, t4, and t5 indicates a timing when the level control unit 179 gradually changes the setting of the luminance range over a given time τ (for example, 2 to 3 seconds). In the following description, the time τ is called a luminance transition time. Note that, the display control unit 177 may perform switching of a graphic screen (display of the luminance change caution screen, the video setting screen) according to the change of the luminance range in the same manner regardless of whether or not the change of the program is accompanied. (Control for Luminance Range) Next, control for a luminance range by the level control unit 179 according to the present embodiment will be described. FIG. 11 illustrates an example of control for a luminance range according to the present embodiment. In the example illustrated in FIG. 11, a case where a luminance range specified by SI information is switched at a time t3 from the SDR to the HDR without being accompanied by a change of a program is exemplified. In the example, the level control unit 179 gradually expands the luminance range from the SDR (0 to 300 cd/m2) to the HDR (0 to 6000 cd/m2) from the time t3 to a time t3+τ (refer to FIG. 11(a)). The level control unit 179 gradually changes a maximum value of the signal level that constitutes video data from the signal level (50% in the example illustrated in FIG. 11(b)) according to the luminance (300 cd/m2) that corresponds to the maximum value of the signal level of the SDR into the signal level (100% in the example illustrated in FIG. 11(b)) according to the luminance (6000 cd/m2) that corresponds to the maximum value of the signal level of the HDR, for example. The change is only required to be performed in a continuous manner, for example, linearly with respect to a time change. The continuous manner does not always mean to be mathematically continuous, and the meaning is sufficiently satisfied when one is conscious that the luminance changes in a continuous manner. For example, it is only required that a rate of the change (that is, an amount of the change between frames that are adjacent to each other) of the maximum value of the signal level is smaller than a given threshold of the rate of the change. The level control unit 179 successively sets the defined maximum value to the video processing unit 174. When a signal value exceeding the set maximum value is detected among signal values of pixels that are decoded, the video processing unit 174 defines (clipping) the signal value as the maximum value to limit the signal value between a given minimum value and the set maximum value. On the other hand, in a case where the luminance range specified by SI information is switched from the HDR to the SDR without being accompanied by a change of a program, the level control unit 179 may change the maximum value of the signal level from the maximum value of the HDR to the maximum value of the SDR over the luminance transition time τ in a continuous manner as described above. In this case, the level control unit 179 starts such processing at a time earlier than a time (for example, time t4), at which the luminance range changes from the HDR to the SDR, by the luminance transition time τ. Note that, the video data transmitted by the transmission device 20 may be obtained by multiplying a signal value by an OETF (Opto-Electronic Transfer Function) in advance in order to offset characteristics of the EOTF (reference EOTF) in a specific display device. The level control unit 179 uses a given correction coefficient to correct a signal value that is limited, so that a last output value (luminance) from the display unit 15 has a constant magnification with respect to an original input value of the video data. The correction is called gamma correction in some cases. The correction coefficient may be provided as a conversion table indicating a relationship between the input value and the output value. The correction coefficient may be different between the SDR and the HDR. For example, the level control unit 179 may immediately switch the correction coefficient of the SDR to the correction coefficient of the HDR at the time t3 when it is instructed to change the luminance range from the SDR to the HDR. The level control unit 179 may immediately switch the correction coefficient of the HDR to the correction coefficient of the SDR at the time t4 when it is instructed to change the luminance range from the HDR to the SDR. The level control unit 179 uses a correction coefficient corresponding to a signal value whose maximum value is limited and corrects the signal value. Next, control for a luminance range according to the present embodiment will be described. FIG. 12 is a flowchart indicating control for a luminance range according to the present embodiment. (Step S101) The separation unit 172 separates service information from multiplexed data that is carried by a received broadcast signal. The SI processing unit 176 analyzes the separated service information and acquires luminance information and program information. Then, the procedure proceeds to processing of step S102. (Step S102) The level control unit 179 determines whether or not the luminance range indicated by the luminance information changes from the HDR to the SDR or from the SDR to the HDR. When it is determined that there is a change (step S102, YES), the procedure proceeds to processing of step S103. When it is determined that there is no change (step S102, NO), the procedure returns to processing of step S101. (Step S103) The level control unit 179 refers to the program information to determine whether or not the program that has been broadcasted up to that time ends and a new program starts. When it is determined that a new program starts (step S103, YES), the procedure proceeds to processing of step S104. When it is determined that a new program does not start (step S103, NO), the procedure proceeds to processing of step S105. (Step S104) The level control unit 179 immediately switches setting of the luminance range of a video from setting of the luminance range before the change to setting of a luminance range after the change. Then, the procedure returns to processing of step S101. (Step S105) The level control unit 179 gradually changes the setting of the luminance range of the video from setting of the luminance range before the change to setting of the luminance range after the change over a given luminance transition time T. Then, the procedure returns to processing of S101. Modified Example Control for a luminance range according to the present embodiment may be performed as described below. (I) A luminance transition time τHS when the luminance range specified by SI information is reduced from the HDR to the SDR may be shorter than a luminance transition time τSH when the luminance range is expanded from the SDR to the HDR. For example, in a case where the luminance transition time τSH is 2 seconds, the luminance transition time τHS may be 0.5 second or less. In a case where the luminance range specified by SI information is reduced from the HDR to the SDR, the level control unit 179 may immediately switch the setting of the luminance range. This is because there is a greater need to gradually change the setting as a safety design in the case of expansion of the luminance range from the SDR to the HDR, which causes a sudden increase in the luminance or contrast. This is also because, according to visual perception of a human, the increase in the luminance or contrast typically gives a stronger impression to the viewer compared to a case where the luminance or contrast is reduced, and thus brings a more significant cause of making the viewer uncomfortable or affecting his/her physical condition. In a case where the luminance range is reduced from the HDR to the SDR, a start of processing of the reduction needs to be applied to video data that is received at a time (for example, time t4-τHS) earlier than a time (for example, time t4) when the luminance range changes from the HDR to the SDR by the luminance transition time τHS, so that a start of processing needs to be delayed by at least the luminance transition time τHS. By reducing or eliminating the luminance transition time τHS, a delay time required from reception of a broadcast signal to display of a video is shortened. (II) The level control unit 179 may successively acquire luminance information included in SI information every given time, and determine a change of a luminance range by using luminance information acquired a plurality of times up to that time. Here, for example, when the luminance range indicated by the luminance information changes and the changed luminance range is then iterated a given number of times (number of times of determination), the level control unit 179 decides the change of the luminance range with respect to the changed luminance range. The level control unit 179 changes the setting of the luminance range as described above on the basis of the decided change of the luminance range. Thereby, the level control unit 179 is able to prevent an unnecessary change of the luminance range due to a temporal error of luminance information caused by noise, erroneous transmission, or the like. At this time, the number of times of determination for determining that the luminance range is expanded from the SDR to the HDR may be greater than the number of times of determination for determining that the luminance range is reduced from the HDR to the SDR. The more number of times of determination makes the determination related to expansion of the luminance range more difficult than the determination related to the reduction, and is thus more effective for a safety design to prevent uncomfortableness or a poor physical condition of the viewer. Though a case where the reception device 10 displays a video of a broadcast program based on video data that is carried by a broadcast signal is mainly exemplified above, the aforementioned control for the luminance range may be applied to a case where a video based on video data recorded in the storage unit 16 in advance is displayed. In this case, instead of an input of video data and service information corresponding to the video data from the separation unit 172, in accordance with an input of an operation signal indicating an instruction of recording reproduction from the input unit 12, the video processing unit 174 reads out video data and service information from the storage unit 16. In this case, the SI processing unit 176 also acquires the service information stored in the storage unit 16, instead of an input of the service information from the separation unit 172. Note that, no change of the luminance range indicated by luminance information is generally caused in video data that is produced in advance. Even when there is a change of the luminance range, the change is not caused frequently. Thus, the display control unit 177 may display a menu screen to select any of the following control modes on the basis of an operation signal from the input unit 12. The control modes are (i) mode 1: setting of the luminance range is gradually changed over the luminance transition time τ in accordance with the change of the luminance range, (ii) mode 2: setting of the luminance range is immediately changed in accordance with the change of the luminance range, and (iii) mode 3: the change of the luminance range is ignored and setting of a certain luminance range is used. The display control unit 177 sets the selected control mode to the level control unit 179 and the level control unit 179 performs the aforementioned control for the luminance range in accordance with the level control mode that is set. As described above, the reception device 10 according to the present embodiment includes the SI processing unit 176 that acquires, from service information of content, luminance information of a video included in the content. The reception device 10 also includes the level control unit 179 that, when setting of a luminance range changes in accordance with a change of a luminance range indicated by luminance information, changes the setting of the luminance range more gently when the content does not change compared to a case where the content changes. The reception device 10 includes the display unit 15 that displays the video on the basis of the setting of the luminance range defined by the level control unit 179. According to such a configuration, compared to the change of the luminance range accompanying switching of the content, the change of the luminance range accompanying an instruction given in the middle of the content is reduced more. Thus, it is possible to prevent or reduce uncomfortableness or a poor physical condition of the viewer caused by a sudden change in the luminance during viewing of the content or a sudden change in the luminance due to an unnecessary change of the luminance range because of an error or the like. When the content changes, the level control unit 179 immediately changes the setting of the luminance range before the change to setting of a luminance range after the change. According to such a configuration, by quickly responding to the change of the luminance range also upon switching of the content, the content is able to be viewed in a luminance range intended by a broadcasting company or a content creator in a content beginning portion that gives a strong impression to the viewer. When the luminance range indicated by the luminance information is expanded, the level control unit 179 changes the setting of the luminance range over a longer time compared to a case where the luminance range indicated by the luminance information is reduced. According to such a configuration, it is possible to reduce a sudden increase in the luminance that becomes a main cause of uncomfortableness or a poor physical condition of the viewer and reduce a processing time required to reduce the luminance range that results in uncomfortableness or a poor physical condition of the viewer. The reduction of the processing time makes it possible for the viewer to view the content in a luminance range intended by a broadcasting company or a content creator as much as possible. The level control unit 179 successively acquires luminance information and decides a change of the luminance range on the basis of iteration of the luminance range indicated by the luminance information. According to such a configuration, it is possible to prevent an unnecessary change of the luminance range due to erroneous setting or erroneous transmission of the luminance information. Thus, it is possible to prevent uncomfortableness or a poor physical condition of the viewer due to a sudden unnecessary change in the luminance. When the number of times of iteration of the luminance range after the luminance range changes is a given number of times or more, the level control unit 179 decides the change of the luminance range, and a given number of times related to expansion of the luminance range is greater than a given number of times related to reduction of the luminance range. According to such a configuration, it is possible to prevent a sudden unnecessary increase in the luminance that becomes a main cause of uncomfortableness or a poor physical condition of the viewer. Second Embodiment Next, a second embodiment of the invention will be described. A configuration and processing that are the same as those of the embodiment described above are given the same reference signs and description thereof is incorporated by reference. The broadcast system 1 according to the present embodiment is configured by including the reception device 10 and the transmission device 20 as illustrated in FIG. 1. As luminance flags indicating luminance information of a video to be broadcasted, the transmission device 20 according to the present embodiment transmits, to the broadcasting transmission path BT, a current flag that indicates luminance information of the video at that time and a preannouncement flag that indicates luminance information of the video when a given time has lapsed after that time by including in service information. The reception device 10 acquires the current flag and the preannouncement flag from the service information received via the broadcasting transmission path BT. When a luminance range indicated by the current flag is different from a luminance range indicated by the preannouncement flag, the reception device 10 gradually changes setting of the luminance range from setting of the luminance range indicated by the current flag to setting of the luminance range indicated by the preannouncement flag within a given time. With the luminance defined on the basis of the changed setting of the luminance range, the reception device 10 displays a video related to video data that is carried by a broadcast signal. (Preannouncement Flag) Next, a preannouncement flag will be described. The preannouncement flag is luminance information that indicates a change of the luminance range after a given time ΔT (for example, five seconds) from that time. On the other hand, a current flag corresponds to the luminance flag described above. FIG. 13 exemplifies a case where a CM constituted by an SDR video is broadcasted from a time t12 to a time t13 and a program constituted by an HDR video is broadcasted from the time t13. In the example, a preannouncement flag is provided at a time t13−ΔT. The preannouncement flag is information indicating that the luminance range of the video changes from the SDR to the HDR at the time 13 after the given time ΔT from the time t13−ΔT. The level control unit 179 performs control for the luminance rage as described above by referring to the preannouncement flag and thereby reduces a sudden change in the luminance accompanying the change of the luminance range. The preannouncement flag is transmitted being included in service information. The service information in which the preannouncement flag is included may be input from outside of the transmission device 20 to the service information acquisition unit 210 (FIG. 4) of the transmission device 20 or may be generated uniquely. The service information acquisition unit 210 acquires, from the broadcast content acquisition unit 220, broadcast program data of a broadcast program that is broadcasted at each time and specifies a time when the luminance range changes by referring to luminance information of video data included in the broadcast program data. Then, with respect to a time (the time t13−ΔT in the example illustrated in FIG. 13) the given time ΔT before the specified time (the time t13 in the example illustrated in FIG. 13), the service information acquisition unit 210 generates a preannouncement flag that indicates a change of the luminance range at the specified time. The service information acquisition unit 210 includes the generated preannouncement flag, for example, in a video component descriptor of an MPT that is transmitted at a time before the given time ΔT. (Display of Graphic Screen) When the preannouncement flag is input from the SI processing unit 176, the display control unit 177 (FIG. 9) may cause the display unit 15 to display a luminance change caution screen related to a change of the luminance range whose change is specified by the preannouncement flag. Here, the display control unit 177 reads out, from the storage unit 16, luminance change caution screen data related to the luminance range after the change, and outputs the luminance change caution screen data that is read out to the video processing unit 174. Thereby, the change of the luminance range from the luminance range at that time is notified to the viewer. When an operation signal to specify display of a video setting screen is input after the preannouncement flag is input, the display control unit 177 may cause the display unit 15 to display a video setting screen related to the luminance range after the change that is indicated by the preannouncement flag. In this case, the display control unit 177 reads out, from the display unit 15, video setting screen data related to the luminance range after the change and outputs the video setting screen data that is read out to the video processing unit 174. Thereby, it is possible to prevent a setting operation in a luminance range that becomes unnecessary due to the change of the luminance range and prompt a setting operation in a new luminance range. (Control for Luminance Range) Next, control for a luminance range by the level control unit 179 (FIG. 9) according to the present embodiment will be described. FIG. 14 illustrates an example of control for a luminance range according to the present embodiment. In the example illustrated in FIG. 14, with content being changed from a CM to a given program at a time t13, a luminance range specified by SI information is expanded from the SDR to the HDR, and with the content being changed from the program to another given program at a time t14, the luminance range specified by the SI information is reduced from the HDR to the SDR. On the other hand, a preannouncement flag that indicates a change of the luminance range from the HDR to the SDR at the time t13 is set at a time t13−ΔT and a preannouncement flag that indicates a change of the luminance range from the SDR to the HDR at the time t14 is set at a time t14−ΔT. Then, when the preannouncement flag is input from the SI processing unit 176 at the time t13−ΔT, the level control unit 179 starts processing for gradually reducing a maximum value of the luminance that is able to be displayed by the display unit 15 from a reference value (for example, 300 cd/m2) of the SDR to a given control value (for example, 100 cd/m2) over the given time ΔT. Thereby, the luminance range of an HDR video that starts at the time t13 is 0 to 200 cd/m2 and is smaller than 0 to 6000 cd/m2 as the luminance range when control is not performed. As a result, the change of the luminance from the time t13−ΔT to the time t13 is reduced more compared to a case where control is not performed. Meanwhile, the level control unit 179 ignores the preannouncement flag that is input from the SI processing unit 176 at the time t14−ΔT. At the time t14, the level control unit 179 starts processing for gradually increasing the maximum value of the luminance that is able to be displayed by the display unit 15 from a reference value (for example, 100 cd/m2) of the SDR to a given control value (for example, 300 cd/m2) over the given time ΔT. Thereby, the luminance range of the HDR video that is displayed till the time t14 is 0 to 2000 cd/m2. Thus, the change of the luminance from the time t14 to t14+ΔT is reduced compared to the case where control is not performed. In order to control the luminance range of the video, the level control unit 179 controls an amplification factor of an amplification circuit (amplifier) that constitutes the display unit 15, for example, as setting of the luminance range. The amplification circuit is a circuit that amplifies a voltage value according to an input signal value of each of pixels and outputs the resultant to the pixel. In the example illustrated in FIG. 14, the level control unit 179 linearly reduces the amplification factor, which is set to the display unit 15, from a reference value to ⅓ of the reference value from the time t13−ΔT to the time t13. The level control unit 179 linearly increases the amplification factor from ⅓ of the reference value to the original reference value from the time t14 as a time when the current flag is input to the time t14+ΔT. In the example illustrated in FIG. 14, however, the luminance range of the HDR video is 0 to 2000 cd/m2, and is thus narrower than the luminance range of 0 to 6000 cd/m2 that is originally expected. Then, when the luminance range specified by the current flag changes from the SDR to the HDR, the level control unit 179 gradually changes the setting of the luminance range in which the luminance range is reduced to the original setting of the luminance range over the given time ΔT. When a preannouncement flag indicating a change of the luminance range from the HDR to the SDR is input, the level control unit 179 gradually changes the original setting of the luminance range to the setting in which the luminance range is reduced, over the given time T. In an example illustrated in FIG. 15, the level control unit 179 gradually changes the setting of the luminance range in which the luminance range is reduced to the original setting from the time t13 when the current flag is input to a time t13+ΔT. The level control unit 179 gradually changes the setting of the luminance range to the setting, in which the luminance range is reduced, over the given time ΔT from the time t14−ΔT to the time t14. Thereby, the change of the luminance range is reduced and the HDR video is displayed in the luminance range of 0 to 6000 cd/m2 that is originally expected. Note that, for a correction coefficient related to gamma correction, at a time (for example, the time t13) related to a change of the luminance range, which is specified by the preannouncement flag, the level control unit 179 may set, to the video processing unit 174, a correction coefficient related to the luminance range after the change. At this time, the correction coefficient that is set till that time is immediately switched to a correction coefficient according to a format of video data to be decoded. (Time Change of Luminance Range) FIG. 16 illustrates an example of a time change of a luminance range of a video. In the example illustrated in FIG. 16, a program A is broadcasted from a time t20 to a time t21, a program B is broadcasted from the time t21 to a time t24, and a program C is broadcasted from the time t24 to a time t27. In the program A, an SDR video is broadcasted in all sections from the time t20 to the time t21. In the program B, an HDR video is broadcasted in a section from the time t21 to a time t22 and a section from a time t23 to the time t24. A CM that is constituted by an SDR video is inserted in a section from the time t22 to the time t23. In the program C, an SDR video is broadcasted in a section from the time t24 to a time t25 and a section from a time t26 to the time t27. A CM that is constituted by an HDR video is inserted in a section from the time t25 to the time t26. A time between the time t25 and the time t26 is 30 seconds. In FIG. 16, a mark □ assigned to a time t21−ΔT, a time t22−ΔT, a time t23−ΔT, and a time t24−ΔT indicates a time when the reception device 10 receives a preannouncement flag. On the basis of the preannouncement flag, the level control unit 179 performs control for the luminance range as described with use of FIG. 14 or 15. Upon acquisition of the preannouncement flag at the time t21−ΔT, for example, the level control unit 179 gradually makes a change to setting, in which the luminance range is reduced, from the time t21−ΔT to the time t21 and gradually makes a change to setting, in which the luminance range is expanded, from the time t21 to the time t21−ΔT (refer to FIG. 15). Upon reception of the preannouncement flag, the display control unit 177 causes the display unit 15 to display a luminance change caution screen that indicates a change to the luminance range, which is specified by the preannouncement flag. When an operation signal to specify display of a video setting screen is input to the display control unit 177, the display control unit 177 causes the display unit 15 to display the video setting screen related to the luminance range after the change that is specified by the preannouncement flag. Note that, the preannouncement flag may further include information of a duration time and may be information indicating a change of the luminance range by a duration time that is specified. In the example illustrated in FIG. 16, the preannouncement flag received at a time t25−ΔT includes information of a duration time (30 minutes) from the time t25 to the time t26. At the time t25−ΔT, the level control unit 179 starts control for the luminance range when the luminance range changes from the SDR to the HDR, and additionally, at a time t26−ΔT that is a time indicated by a black square, the level control unit 179 starts control for the luminance range when the luminance range is returned from the HDR to the SDR that is the original luminance range. The time t26 is a time after 30 seconds as the duration time from the time t25 that is a time when broadcasting of a CM starts. Under such control, the level control unit 179 gradually makes a change to the setting, in which the luminance range is reduced, from the time t26−ΔT to the time t26 and gradually makes a change to the setting, in which the luminance range is expanded, from the time t26 to a time t26+ΔT (refer to FIG. 15). Thereby, in a case where a video (typically, for a short time period of 15 seconds, 30 seconds, or the like) whose duration time is defined in advance like a specific scene or a CM is broadcasted, it is not necessary to further set a preannouncement flag when the video ends. Setting of a preannouncement flag in editing of a program is simplified. Next, control for a luminance range according to the present embodiment will be described. FIG. 17 is a flowchart indicating control for a luminance range according to the present embodiment. In processing illustrated in FIG. 17, after step S101 (FIG. 12) ends, the procedure proceeds to processing of step S111. (Step S111) The display processing unit 175 determines whether or not a preannouncement flag is included in luminance information. When it is determined that a preannouncement flag is included (step S111, YES), the procedure proceeds to processing of step S112. When it is determined that a preannouncement flag is not included (step S111, NO), the procedure returns to processing of step S101. (Step S112) The display control unit 177 causes the display unit 15 to display a luminance change caution screen (caution screen) related to a change to a luminance range that is specified to be changed by the preannouncement flag. When an operation signal to specify display of a video setting screen is input, the display control unit 177 causes the display unit 15 to display a video setting screen (menu switch) related to a luminance range after the change that is indicated by the preannouncement flag. Then, the procedure proceeds to step S113. (Step S113) The level control unit 179 gradually makes a change to setting, in which the luminance range is reduced, over a given time till a time when luminance information changes. Immediately after that, the level control unit 179 may gradually make a change to setting, in which the luminance range is expanded, over the given time (FIG. 15). Then, the procedure proceeds to step S114. (Step S114) The level control unit 179 determines whether or not information of a video duration time is included in the acquired preannouncement flag. When it is determined that the information is included (step S114, YES), the procedure proceeds to step S115. When it is determined that the information is not included (step S114, NO), the procedure returns to step S101. (Step S115) The level control unit 179 gradually makes a change to the setting, in which the luminance range is reduced, over the given time until the duration time during which a change is specified by the preannouncement flag has lapsed after a time when luminance information changes (till a time when the luminance information changes next time). However, such processing is omitted when processing for making a change to the setting in which the luminance range is expanded is not performed at step S113. The level control unit 179 gradually makes a change to the setting (original setting), in which the luminance range is expanded, over the given time when the duration time during which a change is specified by the preannouncement flag has lapsed after the time when the luminance information changes. Then, the procedure returns to step S101. Note that, though a case where both the time during which a change is made to the setting in which the luminance range is expanded and the time during which a change is made to the setting in which the luminance range is reduced are ΔT is exemplified in the description above, there is no limitation thereto. Both the times may be shorter than ΔT as long as being sufficient to reduce uncomfortableness or a poor physical condition of the viewer, for example, 2 to 3 seconds. The time during which a change is made to the setting in which the luminance range is reduced may be shorter than the time during which a change is made to the setting in which the luminance range is expanded. The time during which the setting of the luminance range changes may be longer when the luminance range changes from the SDR to the HDR compared to a case where the luminance range changes from the HDR to the SDR. As described above, this is because there is a greater need to gradually change the setting as a safety design in the case of expansion of the luminance range that causes a sudden increase in the luminance or contrast, compared to the case of the reduction of the luminance range. Though a case where a preannouncement flag is provided as preannouncement information separate from a current flag is exemplified in the description above, there is no limitation thereto. For example, in a case where a video component descriptor is described in an MH-EIT that is used as program information, the level control unit 179 and the display control unit 177 may use, as preannouncement information for a change of the luminance range, a luminance flag that is set to the video component descriptor. This is because, in the MH-EIT, for each program or segment that is a unit finer than the program, the video component descriptor is described in association with a start time and a duration time of a video that is a component of the program or the segment. For acquiring a luminance flag, the level control unit 179 and the display control unit 177 may read out the luminance flag from a luminance information table (described later) that is formed in the storage unit 16. As described above, the reception device 10 according to the present embodiment includes the SI processing unit 176 that acquires, from service information of content, current information that indicates luminance information of a video at a current time point and preannouncement information that indicates luminance information of the video after a given time from the current time point. The reception device 10 includes the level control unit 179 that, when a luminance range indicated by the preannouncement information changes from a luminance range of the video at the current time point, changes the luminance range more gently compared to a change of the luminance range indicated by the preannouncement information. The reception device 10 includes the display unit 15 that displays the video in the luminance range defined by the level control unit 179. According to such a configuration, it is possible to start processing for reducing a change of the luminance range before a scheduled change of the luminance range. Thus, by reducing a change of the luminance without causing delay of processing, it is possible to prevent or reduce uncomfortableness or a poor physical condition of the viewer. When the luminance range specified by the preannouncement information is expanded from the luminance range of the video at the current time point, the level control unit 179 changes the luminance range over a longer time compared to a case where the luminance range specified by the preannouncement information is reduced. According to such a configuration, it is possible to reduce expansion of the luminance range that becomes a main cause of uncomfortableness or a poor physical condition of the viewer and reduce a processing time to reduce the luminance range that results in uncomfortableness or a poor physical condition of the viewer. The reduction of the processing time makes it possible to view the content in a luminance range intended by a broadcasting company or a content creator as much as possible. When the luminance range indicated by the preannouncement information is wider than the luminance range of the video at the current time point, the level control unit 179 gradually reduces maximum luminance of the video to given luminance within a given time. According to such a configuration, it is possible to reduce a sudden increase in the luminance after the given time specified by the preannouncement information. Thus, uncomfortableness or a poor physical condition of the viewer is prevented or reduced. After the given time has lapsed, the level control unit 179 gradually releases the reduction of the luminance to the given luminance. According to such a configuration, it is possible to prevent or reduce uncomfortableness or a poor physical condition of the viewer, which is caused again by an increase of the luminance, and it is possible to view the content in a luminance range intended by a broadcasting company or a content creator as much as possible. When an effective duration time is further set to the luminance information indicated by the preannouncement information, the level control unit gradually releases the luminance reduction to the given luminance, when the duration time has further lapsed after the given time. According to such a configuration, it becomes unnecessary to further set preannouncement information, so that the setting of the preannouncement information is simplified. Thus, processing and an operation that are related to setting of service information according to editing of a program are reduced. The reception device 10 further includes the display control unit that, when the luminance range indicated by the preannouncement information changes, notifies the change of the luminance range. According to such a configuration, a preannouncement of the change of the luminance range is given to the viewer, so that the viewer is prompted to take an action of avoiding a sudden change in the luminance, for example, to avoid viewing. Third Embodiment Next, a third embodiment of the invention will be described. A configuration and processing that are the same as those of the embodiments described above are given the same reference signs and description thereof is incorporated by reference. The broadcast system 1 according to the present embodiment is configured by including the reception device 10 and the transmission device 20 as illustrated in FIG. 1. The reception device 10 acquires, from service information related to a broadcast program, luminance information of a video included in the broadcast program provided by each channel By referring to the acquired luminance information, the reception device 10 determines whether or not a luminance range of a video of content received on a selected channel changes from a luminance range of content received at a current time point. When determining that there is a change, the reception device 10 gradually changes setting of the luminance range to setting of a luminance range after the change and displays the video with use of the changed setting. The service information acquisition unit 210 (FIG. 4) of the transmission device 20 according to the present embodiment acquires service information that includes an MH-EIT in which a video component descriptor is described as program information. A luminance flag is set to the video component descriptor as described above. In the MH-EIT, for each program or segment, the video component descriptor is described in association with a start time and a duration time of a video that is a component of the program or segment. Thus, in the MH-EIT, for each program or segment, the luminance flag is used for the association as luminance information indicating a luminance range of the video. In the reception device 10 according to the present embodiment, the SI processing unit 176 (FIG. 9) extracts, for each channel, a set of a program or segment, a start time, a duration time, and a luminance flag from an MH-EIT that is input from the separation unit 172. The SI processing unit 176 stores, for each channel, the extracted set in the storage unit 16 in order of the start time to thereby form a luminance information table. The broadcast reception unit 11 includes a tuner capable of receiving broadcast signals of a plurality of channels in parallel. The broadcast reception unit 11 outputs, to the demodulation unit 171, a broadcast signal corresponding to a channel specified by a channel tuning signal from the channel tuning unit 178 among the received broadcast signals. As decoding units that decode video data, the video processing unit 174 may include an SDR decoding unit that decodes SDR video data input from the separation unit 172 and acquires decoded SDR video data and an HDR decoding unit that decodes HDR video data and acquires decoded HDR video data. With use of correction coefficients corresponding to the HDR and the SDR, the video processing unit 174 may perform gamma correction for each of the HDR video data and the SDR video that are decoded. According to such a configuration, a broadcast signal of only one channel is able to be received, thus making it possible to eliminate interruption of a video that is caused immediately after channel switching or interruption of a video that is caused by changing a luminance range. The level control unit 179 refers to the luminance information table stored in the storage unit 16 to determine whether or not, in the selected channel, the luminance range indicated by the luminance information changes with switching of a program or segment at that time. In the level control unit 179, there is a case where the channel specified by the channel tuning signal input from the channel tuning unit 178 changes from the channel that is selected at that time. In this case, the level control unit 179 determines whether or not the luminance range indicated by the luminance information in the channel after the change changes from the luminance range indicated by the luminance information in the channel immediately before the change. When determining that the luminance range changes, the level control unit 179 gradually changes the setting of the luminance range from the luminance range before the change to the luminance range after the change over a given luminance transition time T. For changing the setting of the luminance range, the level control unit 179 may change a maximum value of a signal level in a continuous manner with respect to a time change, for example, as described with use of FIG. 11. The level control unit 179 outputs, to the video processing unit 174, the setting of the luminance range that is defined for each frame. By adjusting a signal level indicated by video data on the basis of the setting of the luminance range that is input from the level control unit 179 as described above, the video processing unit 174 causes the display unit 15 to display a video in the luminance range. When the level control unit 179 determines that the luminance range changes, the display control unit 177 causes the display unit 15 to display a luminance change caution screen related to the luminance range after the change. When an operation signal to specify display of a video setting screen is input to the display control unit 177, the display control unit 177 causes the display unit 15 to display a video setting screen related to the luminance range after the change. (Time Change of Luminance Range) FIG. 18 illustrates an example of a time change of a luminance range of a video. In the example illustrated in FIG. 18, on a channel CH-1, a program 1-A is broadcasted from a time t30 to a time t33 and a program 1-B is broadcasted from the time t33 to a time t35. On a channel CH-2, a program 2-A is broadcasted from the time t30 to a time t31, a program 2-B is broadcasted from the time t31 to the time t33, a program 2-C is broadcasted from the time t33 to a time t34, and a program 2-D is broadcasted from the time t34 to the time t35. On a channel CH-3, a program 3-A is broadcasted from the time t30 to a time t32, a program 3-B is broadcasted from the time t32 to the time t34, and a program 3-C is broadcasted from the time t34 to the time t35. Among the programs, in the programs 1-A, 1-B, 2-A, 2-B, 2-D, and 3-A, an SDR video is broadcasted. In the programs 2-C, 3-B, and 3-C, an HDR video is broadcasted. Here, a case where the channel CH-3 is selected from the time t30 to a time t3x and the channel CH-1 is selected from the time t3x to the time t35 is taken as an example. According to luminance information about the channel CH-3 obtained by referring to a luminance information table, the luminance range of the video is expanded from the SDR to the HDR at the time t32 indicated by a mark ◯. At this time, the level control unit 179 determines that the luminance range changes from the SDR to the HDR. The level control unit 179 gradually changes the setting of the luminance range from setting of the SDR to setting of HDR over a given luminance transition time τ. The display control unit 177 causes the display unit 15 to display a luminance change caution screen indicating that the luminance range changes to the HDR. In a case where an operation signal to specify display of a video setting screen is input, the display control unit 177 causes the display unit 15 to display a video setting screen indicating that the luminance range is the HDR. At the time t3x indicated by a mark ●, a channel tuning signal to specify switching from the channel CH-3 to the channel CH-1 is input to the level control unit 179. According to luminance information about the channel CH-1 obtained by referring to the luminance information table, the luminance range of the video is reduced from the HDR to the SDR. At this time, the level control unit 179 determines that the luminance range changes from the HDR to the SDR. The level control unit 179 gradually changes the setting of the luminance range from the setting of the HDR to the setting of the SDR over the given luminance transition time τ. The display control unit 177 causes the display unit 15 to display a luminance change caution screen indicating that the luminance range changes to the SDR. In a case where an operation signal to specify display of a video setting screen is input, the display control unit 177 causes the display unit 15 to display a video setting screen indicating that the luminance range is the SDR. Next, control for a luminance range according to the present embodiment will be described. FIG. 19 is a flowchart indicating control for a luminance range according to the present embodiment. In processing illustrated in FIG. 19, after step S101 (FIG. 13) ends, the procedure proceeds to processing of step S121. (Step S121) The SI processing unit 176 extracts a set of a program or segment, a start time, a duration time, and a luminance flag (HDR/SDR information), which is extracted for each channel from an MH-EIT that is input from the separation unit 172. The SI processing unit 176 stores, for each channel, the extracted set in order of the start time to thereby update a luminance information table. Then, the procedure proceeds to processing of step S121. (Step S122) The level control unit 179 refers to the luminance information table stored in the storage unit 16 and determines whether or not the program or segment is switched in the same channel with lapse of time. When it is determined that the switching is performed (step S122, YES), the procedure proceeds to step S124. When it is determined that the switching is not performed (step S122, NO), the procedure proceeds to step S123. (Step S123) The level control unit 179 determines whether or not a channel indicated by a channel tuning signal input from the channel tuning unit 178 is switched from the channel that is selected up to that time. When it is determined that the switching is performed (step S123, YES), the procedure proceeds to step S124. When it is determined that the switching is not performed (step S123, NO), the procedure returns to step S122. (Step S124) The level control unit 179 determines whether or not luminance information of a video broadcasted on a channel after the change is switched from the luminance information of the video broadcasted on the channel before the change. When it is determined that the switching is performed (step S124, YES), the procedure proceeds to step S125. When it is determined that the switching is not performed (step S124, NO), the procedure returns to step S122. (Step S125) The display control unit 177 causes the display unit 15 to display a luminance change caution screen (caution screen) related to the change to the luminance range for which it is determined that the switching is performed. When an operation signal to specify display of a video setting screen is input, the display control unit 177 causes the display unit 15 to display a video setting screen (menu switching) related to the luminance range for which it is determined that the switching is performed. Then, the procedure proceeds to step S126. (Step S126) The level control unit 179 gradually changes the setting of the luminance range of the video from setting related to the luminance range before the change to setting of the luminance range after the change over a given luminance transition time τ. Then, the procedure returns to processing of step S101. Note that, in the present embodiment, instead of referring to the luminance information table stored in the storage unit 16 and determining switching of the program or segment at that time, the level control unit 179 may determine switching of the program or segment when a given time ΔT has lapsed after that time. When determining that the luminance range changes, the level control unit 179 gradually changes the setting of the luminance range from the setting of the luminance range of the video up to that time to setting of the luminance range of the video after the given time ΔT. For changing the luminance range, the level control unit 179 may change a gain of the display unit 15 as the setting of the luminance range in a continuous manner with respect to a time change, for example, as described with use of FIG. 14 or 15. The display control unit 15 adjusts a signal level of the gain set by the level control unit 179 and displays the video with the adjusted signal level. As described above, the reception device 10 includes the SI processing unit 176 that acquires, from service information of content transmitted by a broadcast signal, luminance information of a video provided by each channel. The reception device 10 includes the level control unit 179 that determines, on the basis of the luminance information, whether or not a luminance range of a video provided on a channel that is selected changes from a luminance range of a video at a current time point, and when determining that the luminance range changes, changes the setting of a luminance range to setting of the luminance range after the change over a given time. The reception device 10 includes the display unit 15 that displays the video on the basis of the setting of the luminance range that is defined by the level control unit 179. According to such a configuration, it is possible to determine whether or not a luminance range changes upon a change of a channel on the basis of luminance information of a video that is acquired in advance. Thus, it is possible to eliminate or reduce delay of processing related to the change of the luminance range associated with the change of the channel and prevent or reduce uncomfortableness or a poor physical condition of the viewer. The reception device 10 further includes the broadcast reception unit 11 that receives broadcast signals of a plurality of channels and selects a broadcast signal of the channel that is selected from among the broadcast signals of the plurality of channels. According to such a configuration, it is possible to avoid interruption and restart of a video that is caused by channel switching and continue display of the video in which a change of a luminance range is reduced. Thus, it is possible to prevent or reduce uncomfortableness or a poor physical condition of the viewer due to a sudden change in the luminance that accompanies the interruption and restart of the video. The reception device 10 further includes the display control unit 177 that notifies, when the luminance range changes, the change of the luminance range. According to such a configuration, a preannouncement of the change of the luminance range that accompanies channel switching is given to the viewer, so that the viewer is prompted to take an action of avoiding a sudden change in the luminance, for example, to avoid viewing. As above, the embodiments of the invention have been described in detail with reference to the drawings, but the specific configuration is not limited to the aforementioned embodiments and includes, for example, a design that falls within the gist of the invention. Any of the configurations described in the aforementioned embodiments may be combined. For example, the reception device 10 may execute the processing illustrated in FIG. 12 or the processing illustrated in FIG. 17, and steps S121 and S123 to S126 of FIG. 19. In the processing illustrated in FIG. 17, the reception device 10 may use, as a preannouncement flag, luminance information that is stored in the luminance information table in association with a broadcast start time. In the control for the luminance range performed at step S105 of FIG. 12 or step S126 of FIG. 19, instead of controlling a maximum value of a signal level that is set to the video processing unit 174 as setting of the luminance range, the level control unit 179 may control a gain of the display unit 15. In the example illustrated in FIG. 11, the level control unit 179 reduces the gain of the display unit 15 from a given reference value to 1/20 (=300/6000) of the reference value at the time t3, and then linearly changes the gain of the display unit 15 to the reference value up to the time t3+τ. In this case, the video processing unit 174 uses a given maximum value of the luminance range specified by luminance information and clipping based on the maximum value from the level control unit 179 is able to be omitted. In the control for the luminance range performed at steps S113 and 115 of FIG. 17, instead of controlling the gain of the display unit 15 as setting of the luminance range, a maximum value of a signal level that is set to the video processing unit 174 may be controlled. In the example illustrated in FIG. 15, the level control unit 179 changes the maximum value of the signal level at the time t13 from a given maximum value of the SDR to ½ (corresponding to the signal level of 50%, 300 cd/m2) of a given maximum value of the HDR. At this time point, maximum luminance does not change with the switching from the SDR to the HDR. Then, the level control unit 179 linearly changes the maximum value of the signal level to the given maximum value of the HDR up to the time t13+ΔT. The level control unit 179 linearly changes the maximum value of the signal level from the given maximum value of the HDR to ½ thereof from the time t14−ΔT to the time t14. Then, at the time t14, the level control unit 179 changes the maximum value of the signal level to the given maximum value of the SDR. Though the video processing unit 174 performs clipping of the signal value on the basis of the maximum value defined by the level control unit 179, the luminance of an entire video does not change and there exist signal levels having common luminance before and after the luminance range changes. This makes it possible to reduce or eliminate deterioration of image quality. Note that, various numerical values in the aforementioned embodiments are merely examples and the values are not limited. For example, the numerical values such as 50% and 100% as the signal levels and 300 cd/m2 and 6000 cd/m2 as the luminance that are illustrated in FIG. 2 may be other numerical values (for example, 70% and 100% as the signal levels and 800 cd/m2 and 6000 cd/m2 as the luminance). For example, the numerical values such as 100 cd/m2 and 2000 cd/m2 as the luminance that are illustrated in FIG. 14 may be other numerical values (for example, 75 cd/m2 and 1500 cd/m2 as the luminance). Note that, though description has been given in the aforementioned embodiments for an example in which the broadcast system 1 uses the MMT system as the media transport system, there is no limitation thereto. The broadcast system 1 may use a media transport system, for example, such as an MPEG-2 TS system or an RTP (Real-time Transport Protocol) system. Note that, the invention described above may be carried out in the following aspects. (1) A reception device including: a service information processing unit that acquires, from service information of content, current information that indicates luminance information of a video at a current time point and preannouncement information that indicates luminance information of the video after a given time from the current time point; a level control unit that, when a luminance range indicated by the preannouncement information changes from a luminance range of the video at the current time point, changes a luminance range more gently compared to a change of the luminance range; and a display unit that displays the video in the luminance range defined by the level control unit. (2) The reception device according to (1), in which when the luminance range specified by the preannouncement information is expanded from the luminance range of the video at the current time point, the level control unit changes the luminance range over a longer time compared to a case where the luminance range indicated by the preannouncement information is reduced. (3) The reception device according to (1) or (2), in which when the luminance range indicated by the preannouncement information is wider than the luminance range of the video at the current time point, the level control unit gradually reduces maximum luminance of the video to given luminance within the given time. (4) The reception device according to (3), in which the level control unit gradually releases luminance reduction to the given luminance after the given time has lapsed. (5) The reception device according to (3) or (4), in which in a case where an effective duration time is further set to the luminance information indicated by the preannouncement information, the level control unit gradually releases luminance reduction to the given luminance when the duration time has further lapsed after the given time. (6) The reception device according to any one of (1) to (5), further including a display control unit that, when the luminance range indicated by the preannouncement information changes, notifies a change of the luminance range. (7) A broadcast system including a transmission device and a reception device, in which the transmission device transmits content, and service information of the content that includes current information that indicates luminance information of a video at a current time point and preannouncement information that indicates luminance information of the video after a given time from the current time point, and the reception device includes: a service information processing unit that acquires the current information and the preannouncement information from the service information; a level control unit that, when a luminance range indicated by the preannouncement information changes from a luminance range of the video at the current time point, changes a luminance range more gently compared to a change of the luminance range; and a display unit that displays the video in the luminance range defined by the level control unit. (8) A reception method in a reception device, the reception method including the steps of: acquiring, from service information of content, current information that indicates luminance information of a video at a current time point and preannouncement information that indicates luminance information of the video after a given time from the current time point; and when a luminance range indicated by the preannouncement information changes from a luminance range of the video at the current time point, changing a luminance range, in which the video is displayed, more gently compared to a change of the luminance range. (9) A program causing a computer of a reception device to execute the steps of: acquiring, from service information of content, current information that indicates luminance information of a video at a current time point and preannouncement information that indicates luminance information of the video after a given time from the current time point; and when a luminance range indicated by the preannouncement information changes from a luminance range of the video at the current time point, changing a luminance range, in which the video is displayed, more gently compared to a change of the luminance range. The reception device 10 and the transmission device 20 described above may be realized by recording a program for realizing functions of the reception device 10 and the transmission device 20 on a computer-readable recording medium and causing a computer system to read the program recorded on the recording medium for execution. Here, “causing a computer system to read the program recorded on the recording medium for execution” encompasses installing the program in the computer system. The “computer system” here is defined to include an OS and hardware components such as a peripheral device. Further, the “computer system” may include a plurality of computer devices connected via a network including a communication line such as the Internet, WAN, LAN, a dedicated line, or the like. The “computer-readable recording medium” refers to a portable medium such as a flexible disk, a magneto-optical disk, a ROM, and a CD-ROM, and a storage device such as a hard disk built into the computer system. Thus, the recording medium storing the program may be a non-transitory recording medium such as a CD-ROM. The recording medium also includes internal and external recording media capable of being accessed from a distribution server that distributes the aforementioned program. A code of the program stored in the recording medium of the distribution server may be different from a code of a program written in a format executable by a terminal device. That is, any format can be used to store the program in the distribution server as long as the program is able to be downloaded from the distribution server and installed in the terminal device in an executable format. Note that, the program may be configured to be divided into plural pieces and integrated in the terminal device after being downloaded at different timings from each other, and the divided programs may be distributed from different distribution servers from each other. Furthermore, the “computer-readable recording medium” includes a medium that retains the program for a certain time period, such as a volatile memory (RAM) within a server or the computer system serving as a client in a case where the program is transmitted through a network. In addition, the aforementioned program may be configured to realize a part of the functions described above. The aforementioned program may also be a program capable of realizing the functions described above in combination with a program already recorded in the computer system, that is, a so-called difference file (difference program). INDUSTRIAL APPLICABILITY As described above, the reception device, the broadcast system, the reception method, and the program according to the invention are useful for controlling luminance of a video that is broadcasted. REFERENCE SIGNS LIST 1 broadcast system 10 reception device 11 broadcast reception unit 12 input unit 14 amplification unit 15 display unit 16 storage unit 17 control unit 171 demodulation unit 172 separation unit 173 sound processing unit 174 video processing unit 175 display processing unit 176 SI processing unit 177 display control unit 178 channel tuning unit 179 level control unit 20 transmission device 210 service information acquisition unit 220 broadcast content acquisition unit 230 multiplexing unit 240 modulation unit 250 transmission unit BT broadcasting transmission path BS broadcast satellite RC control device | <SOH> BACKGROUND ART <EOH>With development of a sensor technique and an image processing technique, interest in an HDR (High Dynamic Range; also referred to as a wide-band dynamic range) video is enhanced and it is attempted to exploit the HDR video. The HDR video is a video that has luminance in a wider range than that of a normal video. On the other hand, the normal video is called an LDR (Low Dynamic Range) video or an SDR (Standard Dynamic Range) video. The HDR video is expected to be introduced in broadcast service in the future. However, the HDR video is not always provided in the broadcast service. It is expected that the HDR video or the SDR video is used properly depending on a program. In this case, not only in a normal program, but between advertisements (CM: Commercial Advertisement) mainly aiming at advertising of various goods and service, a luminance range of a video that is broadcasted is switched between the HDR and the SDR in some cases. Thus, a reception device is required to cope with a change of the luminance range as the program is switched. Then, a technical requirement under which a transmission device adds luminance information which indicates whether a luminance range is the HDR or the SDR to content to be broadcasted and a reception device sets various parameters on the basis of the luminance information has been standardized. The parameters include peak luminance, and contrast, for example. The parameters are set aiming that a video that is adjusted to have luminance and contrast as intended by a transmission side is viewed on a reception side. PTL 1 describes a reception device including a trigger detection unit that detects a trigger for a start of CM broadcasting and a trigger for an end of CM broadcasting from a television broadcast signal. When the trigger for the start of CM broadcasting is detected, the reception device calculates a feature quantity of the television broadcast signal immediately after the trigger. When the calculated feature quantity is stored in a CM database with indication of being a CM, the reception device determines that the television broadcast signal is a CM. The reception device causes a CM database unit to store a time until the trigger for the end of CM broadcasting is detected after the trigger for the start of CM broadcasting is detected and the calculated feature quantity, and when the number of times that the time and the feature quantity are detected is a given number of times or more, the reception device causes the CM database unit to store the feature quantity and indication of being a CM. | <SOH> SUMMARY OF INVENTION <EOH> | H04N977 | 20180222 | 20180830 | 63354.0 | H04N977 | 0 | NATNAEL, PAULOS M | RECEPTION DEVICE, BROADCAST SYSTEM, RECEPTION METHOD, AND PROGRAM | UNDISCOUNTED | 0 | ACCEPTED | H04N | 2,018 |
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15,755,344 | PENDING | METHOD AND DEVICE TO TRANSFER A VIDEO STREAM BETWEEN A HOST DEVICE AND AN ELECTRONIC DESCRAMBLING DEVICE | A method to transfer a video stream from a host device comprising a controller configured for bulk transfers to a descrambling device, comprises: forming a chain out transfer comprising a chain out header linked with multiple chain out descriptors, the first chain out descriptor pointing to an out description packet containing at least one producer ID, the second and subsequent chain out descriptor pointing to chunks from the video stream, the last chain out descriptor being configured to generate an interrupt; forming a chain in transfer comprising a chain in header linked with a plurality of chain in descriptors, each chain in descriptor pointing to a descrambled chunk; requesting the controller to process the chain; receiving the description packet by the descrambling device and using key data associated with the chunks to descramble them; receiving by the controller the descrambled chunks and triggering an interrupt on the last chunk. | 1. A method to descramble at least one video stream, originating from at least one producer having a producer ID, by an electronic descrambling device connected to a host device, said host device comprising a controller configured for bulk out and bulk in transfers, comprising the steps of, at the host device: for the at least one producer, defining multiple chunks of data from the video stream; forming a chain out transfer, the chain out transfer comprising a chain out header linked with a plurality of chain out descriptors, the first chain out descriptor pointing to an out description packet containing the producer ID of the at least one producer, the second and subsequent chain out descriptors pointing to respective chunks of data, each chunk of data being of a particular producer; forming, by the host device, a chain in transfer, the chain in transfer comprising a chain in header linked with a plurality of chain in descriptors, each chain in descriptor pointing to a descrambled chunk of data, and the last chain in descriptor being configured to generate an interrupt; transferring the chain out transfer by the controller to the electronic descrambling device, thus transferring to the electronic descrambling device the scrambled data chunks; at the electronic descrambling device: receiving the description packet by the electronic descrambling device and identifying by the electronic descrambling device key data associated with the scrambled chunks; using the key data to descramble the scrambled data chunks; returning the descrambled data chunks to the host device; at the host device: receiving the chain in transfer by the controller, thus receiving from the electronic descrambling device the descrambled data chunks; storing the received descrambled data chunks at an address indicated by the correspond chain in descriptor; and triggering an interrupt in response to reception of the last descrambled chunk. 2. The method of claim 1, wherein the at least one video stream is compliant with a Moving Picture Experts Group (MPEG) standard. 3. The method of claim 1, wherein the electronic descrambling device is a universal serial bus dongle. 4. The method of claim 2, wherein the at least one MPEG stream comprises a Multi Program transport stream (MPTS) comprising a plurality of sub-streams having each a program ID, and intended for a consumer, said method comprising the steps of: inserting in the transfer chain description packet the program ID of each sub-stream, the chain of in transfer containing at least one chunk for each consumer associated with each program ID; and informing each consumer that the transferred chunk is descrambled. 5. The method of claim 2, wherein the at least one MPEG stream is formed by a Single Program Transport Stream (SPTS) having one packet identifier (PID). 6. The method of claim 4, wherein at least a first and a second MPEG stream are transferred to the electronic descrambling device, each having a producer ID unique per MPEG stream, the method comprising the steps of: inserting in the first chain out descriptor the producer ID of the first stream and the producer ID of the second stream; and inserting in the second chain out descriptor a chunk of data of the from the first MPEG stream and in the third chain out descriptor a chunk of data of the from the second MPEG stream. 7. The method of claim 5, wherein a transfer chain can contain different type of producer selected among, SPTS, MPTS, or RAW mpeg, each identified using its producer ID. 8. The method of claim 1, wherein the key data are transferred to the electronic descrambling device through a dedicated channel, each key data being dedicated to one PID, the key data being used with the data chunk of that particular program. 9. The method of claim 1, wherein the descrambled chunk is re-encrypted by a channel key shared between the host device and the electronic descrambling device. 10. A host device having an interface with an electronic descrambling device to transfer at least one video stream, originating from at least one producer having a producer ID, from the host device to the interface with the electronic descrambling device, said host device comprising a controller configured for bulk out and bulk in transfers, said controller being configured to: for the at least one producer, define multiple chunks of data from the video stream; form a chain out transfer, the chain out transfer comprising a chain out header linked with a plurality of chain out descriptors, the first chain out descriptor pointing to an out description packet containing the producer ID of the at least one producer, the second and subsequent chain out descriptors pointing to respective chunks of data, each chunk of data being of a particular producer; form a chain in transfer, the chain in transfer comprising a chain in header (iqH) linked with a plurality of chain in descriptors, each chain in descriptor pointing to a descrambled chunk of data, and the last chain in descriptor being configured to generate an interrupt; transfer the chain out transfer to the electronic descrambling device, thus transferring to the electronic descrambling device the scrambled data chunks; receive the chain of in transfer, thus receiving from the electronic descrambling device the descrambled data chunks; store the received descrambled data chunks at an address indicated by the corresponding chain in descriptor; and trigger an interrupt in response to reception of the last descrambled chunk. 11. The host device of claim 10, wherein the video stream is compliant with an MPEG standard and comprises a Multi Program transport stream comprising a plurality of sub-streams having each a packet identifier (PID), and intended for a consumer, the system being further configured to: insert in the transfer chain description packet the program ID of each program, the chain of in transfer containing at least one chunk for each consumer associated with each PID, inform each consumer that the transferred chunk is descrambled. 12. The host device of claim 10, wherein a first and a second video stream are transferred to the electronic descrambling device, each having a producer ID unique per video stream, the host device being configured to: insert in the transfer chain description packet the producer ID of the first stream and the producer ID of the second stream; insert in chain of out transfer a first consumer identification of the first stream and a second consumer identification of the second stream; configure at least two chunks in the chain in transfer, one of the first stream and one for the second stream; and inform the first and the second consumers that the transferred chunks are descrambled. 13. The host device of claim 8, further configured to decrypt the descrambled chunk with a channel key shared between the host device and the electronic descrambling device. | INTRODUCTION Multimedia contents may be transmitted in various ways from a provider to an end user. In order to protect this valuable content, scrambling (encrypting) may be performed to the content so that only authorized persons can have access to it. Reception of the scrambled multimedia content may be done on different devices such as a personal computer, a tablet, a smartphone, or other devices that may not have the necessary descrambling (decrypting) capabilities to access the content. BRIEF DESCRIPTION OF THE INVENTION In one embodiment, an electronic descrambling device may be connected to a host device and configured to descramble multimedia content. An electronic descrambling device is a portable module comprising electronic chips connected via a communication port with the host device. It is generally called “dongle”. The electronic chip comprises a descrambling engine and memories to temporary store the incoming data chunk. According to a particular embodiment, the electronic descrambling device is a USB dongle and the video stream is a MPEG stream. Currently, transfer protocols to an electronic descrambling device are not adapted to the continuous exchange of data at a bit rate compatible with video streams. They have been designed to accommodate the transfer of storage data. To address this problem, it is proposed a method to descramble at least one video stream originating from at least one producer, having a producer ID, by an electronic descrambling device connected to a host device, said host device comprising a controller comprising a bulk pipe out and a bulk pipe in transfer, comprising, at the host device: for each producer, defining a chunk of data from the video stream, forming a chain of out transfer, the chain of out transfer comprising a chain out header (oqH) linked with a plurality of chain out descriptors (oqTD), the first chain out descriptor pointing to a out description packet containing the at least one producer ID, the second and subsequent chain out descriptor pointing to the chunk of data, each chunk of data being of a particular producer, forming, by the host device, a chain of in transfer, the chain of in transfer comprising a chain in header (iqH) linked with a plurality of chain in descriptors (iqTD), each chain in descriptor pointing to a descrambled chunk of data, and the last chain in descriptor being configured to generate an interrupt, transferring the chain of out transfer by the controller to the electronic descrambling device, thus transferring to the electronic descrambling device the scrambled data chunk, at the electronic descrambling device: receiving the description packet by the electronic descrambling device and identifying by the electronic descrambling device key data associated with the at least one chunk, using the key data to descramble the scrambled data chunk, returning the descrambled data to the host device, at the host device: receiving the chain of in transfer by the controller, thus waiting from the electronic descrambling device the chunk descrambled data, storing the received descrambled data chunk at an address indicated by the correspond chain in descriptor (iqTD), triggering an interrupt by the reception of the last descrambled chunk. The format of the multimedia content is preferably an MPEG stream. An MPEG stream typically comprises several sub-streams having each a different packet identifier (PID). Examples of sub-streams are audio, video, data, and caption. Sub-streams pertain to the same multimedia content from a channel. A MPEG stream can comprise several channels, the description of each sub-stream being located into the Program Map Table (PMT). As far as the scrambling of data is concerned, the keys loaded into the electronic descrambling device are dedicated to a sub-stream and identified using the producer ID and the PID. BRIEF DESCRIPTION OF THE FIGURES The following detailed description will be better understood thanks to the attached figures in which: FIG. 1 illustrates a block diagram of the host device in connection with the electronic descrambling device, FIG. 2 illustrates the format of the chain in and out queue according one example of the invention, FIG. 3a illustrates a first embodiment of the transfer chain, FIG. 3b illustrates a second embodiment of the transfer chain, FIG. 4 illustrates the management of the queues in a buffer, FIG. 5 illustrates an example of the modules in a electronic descrambling device. DETAILED DESCRIPTION FIG. 1 illustrates the different components of one embodiment of the invention. The Host (which may be for example a home multimedia receiver) comprises various layers. The top layer may be the TV Native Application. A Middleware layer may include a DVB Middleware and the Media Player modules. The OS Drivers may be lower layers containing the Stream Management Unit in charge of executing one embodiment of the invention. The communication layer SoC may be configured for the handling of the MPEG streams and may include the communication module (USB controller) with the electronic descrambling device. In the following description, the electronic descrambling device will be named “dongle”. FIG. 2 describes one example of the formatting of a chain for a controller, in particular a USB controller. The application layer, in the host device, receives the MPEG stream (or a plurality of MPEG streams) and formats the chain in and chain out (CT) in order to instruct the USB controller. The chain out starts with a chain out header (oqH) playing the role of the link with the chain out descriptors (oqTD1 to oqTDn). The first chain out descriptor (oqTD1) is pointing to the out description packet containing the at least one producer ID. The application layer is in charge of composing the chains and extracts the producer ID from the MPEG stream. The application layer then loads the producer ID into the out description packet (oDP). The first chain out descriptor (odTD1) points to the second chain out descriptor (odTD2). This second chain out descriptor (and the following chain out descriptors) points to the chunk of data extracted from the MPEG stream. The application layer handling the MPEG stream splits the stream into chunks of data and loads them into the buffer memory at an address loaded into the chain out descriptor. The application layer can load more than one chunk into the chain in accordance with the maximum number of chain out descriptors handled by the chain. According to the example of FIGS. 3a and 3b, when the application layer is processing more than one MPEG stream, the producer ID of each stream is loaded into the out descriptor packet (oDP). This is illustrated by the FIG. 3b in which three streams are processed and the producer ID1, the producer ID2 and the producer ID3 are loaded into the out descriptor packet. The MPTS1 Data, forming the first data chunk, is then pointed by the second chain out descriptor (oqTD2), the MPTS2 Data, forming the second data chunk, is then pointed by the third chain out descriptor (oqTD) and the MPTS3 Data, forming the third data chunk, is then pointed by the fourth chain out descriptor (oqTD1). The application layer also configures the chain in. The chain in and chain out are connected together and form a single event. Once configured, the application layer calls the USB controller to execute the chain operations. The chain in is a chain starting with a chain in header (iqH) linked with a plurality of chain in descriptors (iqTD). Each chain in descriptor points to a chunk of data resulting from the processing (i.e. descrambling) by the USB dongle. The last chain in descriptor (iqTDn) is configured to trigg an interrupt when the USB controller receives the last chunk of processed data by the USB dongle. Each chain in descriptor is associated with a MPEG stream. Depending of the implementation of the USB controller, the size of data chunk can vary. According to one example, a data chunk comprises a plurality of packets. Each packet represents a USB transaction. According to one example of forming a chain of packets, each packet has a size equal to the nominal size (e.g. 512 Bytes), except the last packet. The non-nominal size of the packet indicates that this is the last packet of the data chunk. This is illustrated in the FIG. 2 by the box DCo1 to DCop. The last packet of the data chunk has a size different than the nominal size, thus indicating that it is the last packet of the data chunk. According to another example of realization, the chain out transfer is configured such as the producer ID is placed in the data chunk, into the first packet. The producer ID is placed in a data header preceding the data chunk and both are concatenated by the USB controller and transferred in a single USB transaction. This is the case illustrated at the FIG. 3A. The first chain out descriptor points to at least two packets, one being the packet containing the producer ID and the second one (and further ones) being the packets of the data chunk of the MPEG stream. The chain in is the same as in the first example. When the USB controller is supporting both 3a and 3b, 3a and 3b share a common field in their respective header allowing the dongle USB controller to differentiate between a 3a and a 3b chain of descriptor. This allows a host to choose the most efficient transfer for a specific processing. Once the chain out and in is configured, the USB controller receives a signal from the application layer and the chain is processed. The transfer to the USB dongle is executed by the USB controller for example using the bulk in and out transfer. The USB controller activates and transfers the data as instructed. The USB dongle receives the chain out and retrieves the producer ID from the corresponding packet. With the producer ID, the USB dongle can retrieve the key data corresponding to the data chunk. The USB dongle receives through another USB channel, key data related to the MPEG streams to proceed. The USB dongle comprises a key table populated with the key data for each MPEG stream. According to a first example, the key table comprises for each producer ID, the key data related to this producer. Preferably, the key data comprises an odd and an even key, one being currently used and the other one ready for the next key change. A bit in the chunk data indicates the current key to be used. This key table can further contain a packet identifier PID (or program ID) in case one producer ID is associated with a plurality of key data. The table will be then as follows: Producer ID PID ID Key odd Key even PRID1 PID12 Value Value PRID1 PID15 Value Value PRID2 PID3 Value Value PRID3 PID10 Value Value An example of the value of the keys is a 128 bits pseudorandom number. In the above example, the producer PRID1 is associated with an MPEG stream comprising two sub-streams needing key data to be descrambled. Each sub-stream is identified by a PID identifier or program ID (in our example PID12 and PID15), each sub-stream being associated with different key data. The key table is received by the host device from an authorization server or can be extracted from one or more MPEG stream. According to an embodiment of the invention, the USB dongle comprises the key(s) necessary to decrypt the encrypted key data. The encrypted key data can be in the form of ECM (Entitlement Control Message) extracted from the MPEG stream by the host and transferred to the USB dongle. According to another embodiment, the host can request a license file from an authorization server and can pass the license file to the USB dongle once received from the authorization server. The license file is decrypted and the key data are used to populate the key table. The USB dongle can comprise a personal key to decrypt the encrypted key data (license or ECM). Once the USB dongle has descrambled the data chunk using the corresponding key data, the descrambled data chunk are sent to the host device, in particular to the USB controller. The latter stores the received data at the address indicated in the first chain out descriptor. As a consequence, a data chunk DCo1 is transferred by the USB controller to the USB dongle and when the USB dongle returns the data chunk DCi1, the USB controller stores it at the address indicated by the first chain in descriptor iqTD1. When the last data chunk has been stored in the chain in queue the USB controller initiates an interrupt to inform the application layer. The application layer can then retrieve the descrambled data chunk and can deliver it to a consumer such as a multimedia player. It is to be noted that a MPEG stream is loaded into a stream buffer as illustrated at the FIG. 4. The host can process several MPEG streams in parallel and the FIG. 4 illustrates two MPEG streams from two producers (Producer#1, Producer#2). The application layer is in charge of the management of the Stream Buffer#1 and #2. A buffer is dedicated to one producer and the application layer mainly deals with the pointers of the buffer. The buffer is filled with data coming from an MPEG source. When the chain in and chain out are defined, the USB controller process the data chunk (chunk#1 for the Producer#1 and chunk#2 for the Producer#2) so that more than one MPEG source can be processed in parallel. The consumer is using the buffer architecture and handles its own pointers to the descrambled data. According to the illustrated example, the stream buffer is the same for the scrambled and descrambled data. However, in accordance with another example, the buffer for the scrambled data is independent to the buffer of the descrambled data. In this case, the USB controller, while receiving the descrambled chunk from the USB dongle, stores them into the in buffer. This formatting and handling of chain buffer is particularly adapted to USB 2.0 transmission. However, other protocol layer can be used to transfer the data based on stream buffer and chain pointer and descriptor as described above. FIG. 5 illustrates a block diagram of the dongle. The dongle comprises four main blocks, the I/O interface block, the processing block PRO_M, the memory MEM and the descrambling module DES_M. The I/O interface is connectable with the host device to receive the data via the dedicated USB signals. The processing block PRO_M is in charge of directing the flow of data entering and exiting via the I/O Interface to the memory MEM. The memory acts as a buffer memory and the pointers (in and out pointers) are handled by the processing block. The data chunks are stored in the memory and the pointer for this chunk is passed to the descrambling module. The processing block also keep track of the producer ID for said chunk of data and loads the related keys into the descrambling module. The descrambling module, when the chunk is descrambled, stores the descrambled chunk and sends a signal to the processing module. The pointer is then passed to the I/O interface which routes the descrambled chunk into the I/O Interface. The processing block is in charge of executing the chain's instruction. The structure of the chain is known by the processing block and the elements of the chain extracted so that the processing block knows for each data chunk, which producer ID is related to. For that purpose, the processing block is connected with a key memory K_MEM to store the keys received from the host device via the USB Interface. According to another embodiment, the keys memory K_MEM is directly connected to the descrambling module and this module, when the processing block instructs to descramble a data chunk identified by producer ID, loads the keys related to said producer ID in the key registers. Although an overview of the inventive subject matter has been described with reference to specific example embodiments, various modifications and changes may be made to these embodiments without departing from the broader spirit and scope of embodiments of the present invention. For example, various embodiments or features thereof may be mixed and matched or made optional by a person of ordinary skill in the art. Such embodiments of the inventive subject matter may be referred to herein, individually or collectively, by the term “invention” merely for convenience and without intending to voluntarily limit the scope of this application to any single invention or inventive concept if more than one is, in fact, disclosed. The embodiments illustrated herein are believed to be described in sufficient detail to enable those skilled in the art to practice the teachings disclosed. Other embodiments may be used and derived therefrom, such that structural and logical substitutions and changes may be made without departing from the scope of this disclosure. The Detailed Description, therefore, is not to be taken in a limiting sense, and the scope of various embodiments is defined only by the appended claims, along with the full range of equivalents to which such claims are entitled. | <SOH> INTRODUCTION <EOH>Multimedia contents may be transmitted in various ways from a provider to an end user. In order to protect this valuable content, scrambling (encrypting) may be performed to the content so that only authorized persons can have access to it. Reception of the scrambled multimedia content may be done on different devices such as a personal computer, a tablet, a smartphone, or other devices that may not have the necessary descrambling (decrypting) capabilities to access the content. | <SOH> BRIEF DESCRIPTION OF THE INVENTION <EOH>In one embodiment, an electronic descrambling device may be connected to a host device and configured to descramble multimedia content. An electronic descrambling device is a portable module comprising electronic chips connected via a communication port with the host device. It is generally called “dongle”. The electronic chip comprises a descrambling engine and memories to temporary store the incoming data chunk. According to a particular embodiment, the electronic descrambling device is a USB dongle and the video stream is a MPEG stream. Currently, transfer protocols to an electronic descrambling device are not adapted to the continuous exchange of data at a bit rate compatible with video streams. They have been designed to accommodate the transfer of storage data. To address this problem, it is proposed a method to descramble at least one video stream originating from at least one producer, having a producer ID, by an electronic descrambling device connected to a host device, said host device comprising a controller comprising a bulk pipe out and a bulk pipe in transfer, comprising, at the host device: for each producer, defining a chunk of data from the video stream, forming a chain of out transfer, the chain of out transfer comprising a chain out header (oqH) linked with a plurality of chain out descriptors (oqTD), the first chain out descriptor pointing to a out description packet containing the at least one producer ID, the second and subsequent chain out descriptor pointing to the chunk of data, each chunk of data being of a particular producer, forming, by the host device, a chain of in transfer, the chain of in transfer comprising a chain in header (iqH) linked with a plurality of chain in descriptors (iqTD), each chain in descriptor pointing to a descrambled chunk of data, and the last chain in descriptor being configured to generate an interrupt, transferring the chain of out transfer by the controller to the electronic descrambling device, thus transferring to the electronic descrambling device the scrambled data chunk, at the electronic descrambling device: receiving the description packet by the electronic descrambling device and identifying by the electronic descrambling device key data associated with the at least one chunk, using the key data to descramble the scrambled data chunk, returning the descrambled data to the host device, at the host device: receiving the chain of in transfer by the controller, thus waiting from the electronic descrambling device the chunk descrambled data, storing the received descrambled data chunk at an address indicated by the correspond chain in descriptor (iqTD), triggering an interrupt by the reception of the last descrambled chunk. The format of the multimedia content is preferably an MPEG stream. An MPEG stream typically comprises several sub-streams having each a different packet identifier (PID). Examples of sub-streams are audio, video, data, and caption. Sub-streams pertain to the same multimedia content from a channel. A MPEG stream can comprise several channels, the description of each sub-stream being located into the Program Map Table (PMT). As far as the scrambling of data is concerned, the keys loaded into the electronic descrambling device are dedicated to a sub-stream and identified using the producer ID and the PID. | H04N214181 | 20180226 | 20180830 | 57644.0 | H04N21418 | 0 | AMBAYE, SAMUEL | METHOD AND DEVICE TO TRANSFER A VIDEO STREAM BETWEEN A HOST DEVICE AND AN ELECTRONIC DESCRAMBLING DEVICE | UNDISCOUNTED | 0 | ACCEPTED | H04N | 2,018 |
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15,755,454 | PENDING | STORAGE SYSTEM | A storage system is provided that has a plurality of flash packages and a storage controller that controls read/write processing between a host and the flash packages. When data identical to data written in a second address of a second flash package of the plurality of flash packages is written to a first address of a first flash package of the plurality of flash packages, the storage system may store the second address in the first package in association with the first address, and perform deduplication. When the first flash package stores the second address in association with the first address and a read request for the first address is received from the storage controller, the first flash package may return the second address to the storage controller. In response to receiving the second address, the storage controller may acquire target read data from the second flash package. | 1. A storage system comprising: a plurality of flash packages each having a plurality of nonvolatile storage media; and a storage controller configured to execute read/write processing between a host and the plurality of flash packages, wherein: the storage system is configured to store, when data identical to data written in a second address of a second flash package of the plurality of flash packages is written to a first address of a first flash package of the plurality of flash packages, the second address in the first package in association with the first address; and the first flash package is configured to return, when the second address is stored in association with the first address, the second address to the storage controller in response to receiving a read request for the first address from the storage controller; the storage controller is configured to issue, in response to receiving the second address from the first flash package, a read request to the second flash package and receive target read data from the second flash package. 2. The storage system of claim 1, wherein: the storage controller is configured to receive, from the plurality of flash packages, historical information of write requests accepted by the flash packages; and the storage system is configured to detect, based on the historical information, that identical data is written in a plurality of areas of the plurality of flash packages. 3. The storage system of claim 2, wherein: the historical information includes addresses of the flash packages for which write requests have been issued by the storage controller and a characteristic amount of the write data designated by the write requests; and the storage system is configured to determine, in a case that the characteristic amount included in the historical information created by the first flash package and the characteristic amount of data stored in the second flash package are identical, that data identical to the first flash package is written in the second flash package. 4. The storage system of claim 3, wherein: in response to receiving, from the storage controller, a write request for the write data, the flash package is configured to: calculate a characteristic amount of the write data, and create the historical information including an address of the flash package included in the write request, a characteristic amount of the write data, and a characteristic amount of pre-update data of the write data. 5. The storage system of claim 4, wherein the storage system is configured to: determine whether data having an identical characteristic amount to the characteristic amount of the pre-update data included in the historical information is stored in any of the plurality of flash packages; and transmit, to the flash package that created the historical information, in a case that data having the same characteristic amount as the characteristic amount of the pre-update data is not stored in the plurality of flash packages, information indicating that the pre-update data may be deleted. 6. The computer system of claim 3, wherein: each of the plurality of flash packages is configured to manage information related to characteristic amounts of a predetermined range and addresses of the flash packages in which data having the characteristic amount are stored, in response to receiving the write request and the write data, the flash package is configured to: calculate a characteristic amount of the received write data, create the historical information including a write destination address of the write data and the characteristic amount, and transmit, to the storage controller, the historical information, the storage controller that received the historical information is configured to: identify, from among the plurality of flash packages, the flash package that manages the characteristic amount included in the historical information, and transmit, to the identified flash package, the historical information, the flash package that has received the historical information is configured to determine whether data having an identical characteristic amount as the characteristic amount of the write data included in the historical information is stored in any of the plurality of flash packages, the second flash package is configured to transmit, in a case that it is determined that data having an identical characteristic amount as the characteristic amount of the write data is stored in the second address, the second address to the first flash package via the storage controller, and the first flash package is configured to store the second address in association with the first address. 7. The storage system of claim 6, wherein: the first flash package and the second flash package belong to a same RAID group; in a case that the address of the first flash package in which the write data is written and the address of the second flash package in which data having an identical characteristic amount as the characteristic amount of the write data are identical, the flash package that received the historical information is configured not to transmit, to the first flash package, an address within the second flash package in which identical data is stored. 8. The storage system of claim 3, wherein: the storage system further includes a plurality of real storage systems having a storage controller and a plurality of flash packages connected to the storage controller, the first flash package is connected to a first storage controller in the plurality of real storage systems and the second flash package is connected to a second storage controller in the plurality of real storage systems, the first flash package is configured to return, when the second address is stored in association with the first address, the second address to the first storage controller in response to receiving a read request for the first address from the first storage controller, the first storage controller is configured to issue, in response to receiving the second address from the first flash package, a request to the second storage controller to read data from the second flash package, and the second storage controller is configured to read target read data from the second flash package and return it to the first storage controller. 9. The storage system of claim 8, wherein: each of a plurality of storage controllers is configured to manage information related to characteristic amounts of a predetermined range and addresses of the flash packages in which data having the characteristic amount are stored, in response to receiving the write request and the write data, the first flash package is configured to: calculate a characteristic amount of the received write data, create the historical information including a write destination address of the write data and the characteristic amount, and transmit, to the first storage controller, the historical information, in a case that the storage controller that manages the characteristic amount included in the historical information is the second storage controller, the first storage controller is configured to transmit the historical information to the second storage controller, and the second storage controller that has received the historical information is configured to determine whether data having an identical characteristic amount as the characteristic amount of the write data included in the historical information is stored in any of the plurality of flash packages. 10. The storage system of claim 8, wherein: each of the plurality of flash packages is configured to manage information related to characteristic amounts of a predetermined range and addresses of the flash packages in which data having the characteristic amount are stored, in response to receiving the write request and the write data, the first flash package is configured to: calculate a characteristic amount of the received write data, create the historical information including a write destination address of the write data and the characteristic amount, and transmit, to the first storage controller, the historical information, in a case that the flash package that manages the characteristic amount included in the historical information is connected to the second storage controller, the first storage controller is configured to transmit the historical information to the second storage controller, and the second storage controller that has received the historical information is configured to transmit the historical information to the flash package that manages the characteristic amount included in the historical information. 11. A flash package connected to a storage controller that processes a data access request from a host, wherein the flash package is configured to: manage information related to characteristic amounts of a predetermined range and addresses of the flash packages in which data having the characteristic amount are stored, in response to receiving a write request and write data from the storage controller, calculate a characteristic amount of the received write data, create historical information including a write destination address of the write data and the characteristic amount, and transmit, to the storage controller, the historical information, and in response to receiving, from the storage controller, the historical information having a characteristic amount included in the range managed by the flash package, determine, based on the historical information, whether or not a flash package having data identical to the write data written in the first flash package exists among the plurality of flash packages connected to the storage controller, and transmit, to the first flash package, in a case that it is determined that the second flash package of the plurality of flash packages has data identical to the write data, an address within the second flash package in which identical data is stored. 12. The flash package of claim 11, wherein the flash package is configured to: provide a volume to the storage controller, and return, to the storage controller, the address of the flash package having the data identical to the data written in the address in the volume in response to receiving a read request for an address in the volume after receiving an address within the flash package having data identical to the data written in the address in the volume. 13. A flash package of claim 11, wherein the flash package is configured to: determine, in a case that the characteristic amount included in the historical information and the characteristic amount of the data stored in the second flash package are identical, that the second flash package has identical data to the write data in response to receiving the historical information from the storage controller. 14. A flash package of claim 11, wherein the flash package is configured to: calculate, in response to receiving the write request and the write data from the storage controller, a characteristic amount of the write data from the write data, and create the historical information including an address of the flash package included in the write request, a characteristic amount of the write data, and a characteristic amount of pre-update data of the write data. | TECHNICAL FIELD The present invention relates to a deduplication technique in a storage system. BACKGROUND ART As storage devices that make use of flash memory as a storage medium are overwhelmingly faster than HDDs and the like, they are rapidly gaining in popularity in recent years as bit costs decrease. In addition, conventional storage systems have utilized a plurality of storage devices, such as HDDs, in order to achieve high reliability and high performance. Accordingly, it is common for pluralities of storage devices that use flash memory as a storage medium to be utilized in storage systems, and for storage controllers to control these storage devices that use flash memory as a storage medium. In addition, some storage devices that use flash memory as a storage medium have form factors and interfaces compatible with HDDs. These are referred to as SDDs. In contrast, there are also devices that do not have compatibility with HDDs. The present invention is directed to both types, and is hereinafter referred to as a flash package. As the bit cost of flash memory is higher than that of magnetic disks or the like, there is a need to reduce the stored data capacity and increase the apparent capacity. In storage systems, a deduplication technique is one technique for reducing data storage capacity. In this technique, the storage controller checks whether multiple sets of data with the same contents are stored in the storage system. In the case that there is a plurality of sets of data with the same content (duplicate data), only one of them is left in the storage system and the remaining data is deleted. In this way, the amount of data stored in a storage device may be reduced. For example, Patent Document 1 discloses a deduplication technique in a storage device having a plurality of flash memory modules mounted therein. The storage device disclosed in Patent Document 1 is equipped with a plurality of storage devices called flash memory modules. In addition, the storage device disclosed in Patent Document 1 divides data into data units called stripe units, and distributes and stores the divided data in a plurality of flash memory modules. When deduplication processing is performed, the storage controller performs deduplication on data of a size equal to or larger than a stripe unit with a range extending over a plurality of flash memory modules. Then, the flash memory modules perform deduplication for data of a size equal to or smaller than a stripe unit with respect to the data in the flash memory module. In the technique disclosed in Patent Document 1, as duplication elimination is performed with a range extending over a plurality of storage devices, the effect of reducing the data amount is greater in comparison with cases where deduplication processing targeting only the data of the storage device is performed. In contrast, in recent years, capacity virtualization functions have become widespread in storage systems. A capacity virtualization function is a function for providing a host side with a virtual capacity larger than the physical capacity of the storage devices possessed by the storage system, and in general, is a function possessed by the storage controller in the storage system. This is because when the user actually uses storage, the amount of data actually stored in the user volume with respect to the capacity of the user volume (storage device as seen by the user) defined by the user is based on a characteristic that it does not readily reach the capacity of the user volume. That is, when the capacity virtualization function is not used, the user needs to reserve a physical storage area equal to the capacity of the volume at the time of volume definition. When the capacity virtualization function is used, at the time of volume definition, the user does not necessarily have to prepare a physical storage area corresponding to the capacity of the volume. When a data write actually occurs in the volume, the storage area is allocated to the volume for the first time. As a result, since the capacity of the storage device to be prepared in advance can be reduced, and the user need not strictly define the volume capacity but rather simply define a value having a large margin, usability can be improved. Patent Document 2 discloses a technique of providing a capacity virtualization function not only in a storage controller but also in a flash package in a storage system having a plurality of flash packages. Furthermore, in the storage system disclosed in Patent Document 2, it is also disclosed that the flash package may compress the data. In general, since the compression ratio of data varies depending on the content of data, it is difficult to predict the data size after compression. Also, if the data is updated, the compression ratio naturally changes. For this reason, Patent Document 2 discloses a technique for changing the size (virtual capacity) of the volume provided by the flash package to the storage controller due to the change in the compression rate. CITATION LIST Patent Literature [Patent Document 1 ] U.S. Patent Application Publication No. 2009/0089483 [Patent Document 2 ] U.S. Patent Application Publication No. 2012/0317333 SUMMARY OF INVENTION Technical Problem As the storage data amount of the storage system increases, the load of the deduplication processing increases. In the technique disclosed in Patent Document 1, the deduplication processing targeting data in a range extending over a plurality of storage devices is performed by the storage controller. Accordingly, as the amount of stored data increases, the storage controller can become a performance bottleneck. In contrast, if the deduplication process is performed in the storage device, the data targeted by the deduplication process is limited to the data in the storage device, and the deduplication efficiency is not improved. A challenge to be solved by the present invention is to provide, in a large-scale storage system including a number of flash packages, a storage system capable of reducing the impact on the performance of the entire storage system while reducing the storage data capacity and storing data of a capacity greater than the apparent capacity. Solution to Problem A storage system according to an embodiment of the present invention includes a plurality of flash packages and a storage controller that controls read and write processes between a host and the flash packages. When data identical to the data written in a second address of a second flash package is written in a first address of a first flash package of the plurality of flash packages, the storage system stores the second address in the first flash package in association with the first address and performs deduplication. In a state where the second address is stored in association with the first address, when a read request is received for the first address from the storage controller, the first flash package may return the second address to the storage controller. Upon receiving the second address, the storage controller may acquire the target read data from the second flash package by issuing a read request to the second flash package. Advantageous Effects of Invention According to the present invention, in a large-capacity storage system in which a large number of flash packages are connected, it is possible to execute deduplication of data between flash packages, reduce data storage amounts while suppressing performance deterioration of the storage controller, and store a greater amount of data than the physical capacity. BRIEF DESCRIPTION OF DRAWINGS FIG. 1 is a diagram illustrating a configuration of an information system including a storage system according to a first or second embodiment. FIG. 2 is a diagram illustrating a configuration of a flash package. FIG. 3 is a conceptual diagram illustrating a relationship between a logical volume, a virtual page, a real page, and a flash package group. FIG. 4 is a conceptual diagram illustrating a relationship between a flash volume and a real block. FIG. 5 is a diagram illustrating information stored in a shared memory of a storage system according to a first embodiment. FIG. 6 is a diagram illustrating a format of logical volume information. FIG. 7 is a diagram illustrating a format of real page information. FIG. 8 is a diagram illustrating a format of flash package information. FIG. 9 is a diagram illustrating a format of flash package group information. FIG. 10 is a diagram illustrating the structure of a free real page management information queue. FIG. 11 is a diagram illustrating a format of hash value storage information. FIG. 12 is a diagram illustrating information stored in a package memory of a flash package according to the first embodiment. FIG. 13 is a diagram illustrating the format of package information. FIG. 14 is a diagram illustrating a format of chip information. FIG. 15 is a diagram illustrating the format of real block information. FIG. 16 is a diagram illustrating the structure of a free real block information queue. FIG. 17 is a diagram illustrating a format of virtual block group information. FIG. 18 is a conceptual diagram illustrating a state of a virtual segment when deduplication processing is performed. FIG. 19 is a diagram illustrating a format of historical information. FIG. 20 is a diagram illustrating the structure of hash index information. FIG. 21 is an explanatory diagram of a leaf segment. FIG. 22 is a diagram illustrating a program stored in the memory of the storage controller in the first embodiment. FIG. 23 is a diagram illustrating a processing flow of a read processing execution unit in the first or second embodiment. FIG. 24 is a diagram illustrating a processing flow of a write request receiving unit. FIG. 25 is a diagram illustrating a processing flow of a write-after process execution unit. FIG. 26 is a diagram illustrating a processing flow of a deduplication scheduling unit according to the first embodiment. FIG. 27 is an explanatory diagram of the contents of a first list and a second list. FIG. 28 is an explanatory diagram of contents of erasure candidates. FIG. 29 is an explanatory diagram of the contents of duplication candidates. FIG. 30 is a diagram illustrating a program stored in a package memory of a flash package according to the first embodiment. FIG. 31 is a diagram illustrating a processing flow of a data read processing execution unit. FIG. 32 is a diagram illustrating a processing flow of a hash designation read execution unit. FIG. 33 is a diagram illustrating a processing flow (1) of the data write processing execution unit. FIG. 34 is a diagram illustrating a processing flow (2) of the data write processing execution unit. FIG. 35 is a diagram illustrating a processing flow of a historical information transmission unit. FIG. 36 is a diagram illustrating a processing flow of a deduplication execution unit. FIG. 37 is a diagram illustrating a processing flow of a deduplication determination unit. FIG. 38 is a diagram illustrating a processing flow of a deduplication scheduling unit according to the second embodiment. FIG. 39 is a diagram illustrating a configuration of an information system including a virtual storage system according to a third or fourth embodiment. FIG. 40 is a diagram illustrating a format of storage system information. FIG. 41 is a diagram illustrating a processing flow of a read processing execution unit in Embodiment 3 or 4. FIG. 42 is a diagram illustrating a processing flow of an external package read execution unit in Embodiment 3 or 4. FIG. 43 is a diagram illustrating a processing flow of a deduplication scheduling unit in the third embodiment. FIG. 44 is a diagram illustrating a format of hash value storage information in the fourth embodiment. FIG. 45 is a diagram illustrating a processing flow of a deduplication schedule section according to the fourth embodiment. DESCRIPTION OF EMBODIMENT(S) Hereinafter, embodiments will be described with reference to the drawings. Before entering into a description of the embodiments, various terms used in the embodiments will be described. “Volume” refers to the storage space provided by a target device, such as a storage system or a storage device, to an initiator of a host computer or the like. When the initiator issues a data write request to the area on the volume, the data is stored in the physical storage area allocated to that area. In the storage system according to the embodiment described below, the capacity virtualization function is implemented in each of the storage controllers and the storage devices (flash package). In the present specification, volumes defined by the storage controller using the capacity virtualization function and volumes provided to the host are called “logical volumes”. In contrast, the volumes that the flash package provides to the storage controller, and the volumes defined using the capacity virtualization function are called “flash volumes”. The capacity virtualization function of the storage controller is referred to as a higher-level capacity virtualization function, and the capacity virtualization function of the flash package is referred to as a lower-level capacity virtualization function. No physical storage area is allocated to the area on the logical volume (or flash volume) in the initial state (immediately after the volume is defined). At the point in time when the host (or storage controller) issues a data write request to the area on the logical volume (or flash volume), the storage controller (or flash package) dynamically determines the physical storage area to be allocated to that area. In the embodiments described herein, the smallest unit when allocating a physical storage area to a logical volume is called a “page”. In general, a page refers to the minimum unit of read/write processing in a flash memory, but in the embodiments described herein, the unit of reads/writes in the flash memory is called a “segment” rather than a page. A storage area allocated to a logical volume is called a “real page”, and an area on a logical volume to which a real page is allocated is called a “virtual page”. In the flash memory, the data erase unit is called a “block”. Because a block contains multiple segments, the size of the block is an integer multiple of the segment size. In contrast, the page (real page) in the embodiments described below is a concept not directly related to blocks or segments, and there is not necessarily a correlation between the page size and the size of a block (or segment). However, in the following embodiments, for simplicity of explanation, examples in which the real page has a relationship of at least an integer multiple of the segment will be described. The flash package defines a “flash volume” using the capacity virtualization function. In the embodiments described below, the unit for allocating the physical storage area to the flash volume is a segment. That is, a segment is equal to the smallest unit of read/write processing in the flash memory. The physical storage area allocated to the flash volume is called a “real segment”, and the area on the flash volume to which the real segment is allocated is called a “virtual segment”. “Updating” in the storage area refers to rewriting (overwriting) the contents of the data stored in the storage area with new contents. Before a certain storage area is updated, the data stored in the storage area is called “original data” or “old data”. In contrast, data newly written in the storage area is called “updated data” or “post-update data”. In the present embodiment, in the case that there are a plurality of data sets having identical contents in a storage device such as a storage system, “deduplication” refers to a process of leaving only one of those data sets in the storage device, and deleting the other data sets from the storage device. In the storage system according to the embodiments described below, the unit of deduplication is a segment. Herein, the unit of deduplication refers to a minimum size of each data set when comparing the differences of two (or more) data sets. That is, in the embodiments described below, data comparison is performed on a segment basis. When there are a plurality of actual segments in which identical data is written, only one real segment is left. In the storage system according to the embodiments described below, there are cases where the deduplication processing is performed by the flash package. Also, in the event that the capacity virtualization function is used, as by this flash package, when the identical data contents are written to a plurality of virtual segments on the flash volume (one or more), a common real segment is allocated to each virtual segment in which the identical data contents are written. In the present embodiment, the “characteristic amount” of data indicates a value obtained by subjecting data to a predetermined calculation. The type of the predetermined calculation is not necessarily limited to a specific one. However, it is necessary to guarantee that the same value will always be derived when a predetermined operation is performed on a plurality of data sets having identical contents. As an example of an operation corresponding to this condition, there is the hash function SHA-256, for example. A value calculated using a hash function is called a hash value. A hash value is an example of a characteristic amount. As the size of a hash value is very small in comparison with the size of the original data (for example, a few hundredths of the size), it can be used when determining differences between a plurality of data sets (for example, deduplication processing), for example. In the embodiments described below, a hash function such as SHA-256 may be used for calculating the characteristic amount unless otherwise noted. In the embodiment, when the hash value H is obtained by applying the hash function to a data set A, the value H is referred to as the characteristic amount of the data set A or the hash value of the data set A. Conversely, the data set A may be referred to as “data having a hash value H”. In the present embodiment, “collision” means that, when a predetermined operation is performed on each of a plurality of different data sets to generate a characteristic amount, each generated characteristic amount generated is the same. When characteristic amounts are used for comparison between data sets, it is not desirable for collision to occur. The hash values generated by the hash function SHA-256 mentioned above has a feature that the probability of the occurrence of collision is extremely low. First Embodiment FIG. 1 illustrates a configuration of an information system in this embodiment. The information system may include a storage system 100, a host 110, and a SAN (Storage Area Network) 120 that connects both of these. The host 110 is a computer on which a user application runs, and is configured to perform reads and writes for necessary data with the storage system 100 via the SAN 120. For example, the SAN 120 may be a network conforming to a standard such as Fiber Channel Also, the present invention may be effective even if the host 110 and the storage system 100 are connected directly. The storage system 100 may include at least one storage controller 200, a cache memory 210, a shared memory 220, a flash package 230, and at least one connecting device 250 that connects these components. In FIG. 1, the storage devices in the storage system 100 are all flash packages 230, but the storage system 100 may include other kinds of storage devices such as HDDs. Further, in the present embodiment, the capacities of the flash packages 230 are all set to be equal. However, as another embodiment, the capacity of each flash package 230 mounted in the storage system 100 may be different. The storage controller 200 may include a processor 260 and a memory 270 for processing read/write requests issued from the host 110. One of the features of the storage system 100 according to the present embodiment is that the flash package 230 executes the deduplication processing. Generally, in the deduplication process, when data (referred to as data set A) is newly written in a storage device such as the storage system 100, a characteristic amount such as a hash value is calculated. In the case that data having the same characteristic amount as the characteristic amount of the data set A exists (the data is provisionally referred to as data set B), the data set A and the data set B are compared bit by bit. If the result of the comparison indicates that data set A and data set B are the same, the data set A is not stored in the storage device, and the storage capacity is reduced. The characteristic amount is used to narrow down the candidates for which the contents of the data should be compared. In the storage system 100 according to this embodiment, the flash package 230 performs the calculation of the characteristic amount. However, as another embodiment, the calculation of the characteristic amount may be performed by the storage controller 200. The connecting device 250 is a mechanism for connecting each component in the storage system 100. In addition, in the present embodiment, in order to achieve high reliability, it is assumed that each flash package 230 is connected to a plurality of storage controllers 200 by a plurality of connecting devices 250. However, the present invention is also applicable when one flash package 230 is connected to only one connecting device 250. The cache memory 210 and the shared memory 220 are usually composed of a volatile memory such as a DRAM, but here it is assumed that they are made nonvolatile by a battery or the like. However, the present invention is applicable even if the cache memory 210 and the shared memory 220 are not nonvolatile. In the cache memory 210, among the data stored in the flash packages 230, data frequently accessed from the storage controller 200 is stored. Further, the storage controller 200 uses the cache memory 210 as what is known as a write-back cache. That is, the storage controller 200 writes the data received together with the write request from the host 110 to the cache memory 210, and at that time, responds to the host 110 that the write request has been completed. Writing data from the cache memory 210 to the flash package 230 may be performed asynchronously with write requests from the host 110. However, as another embodiment, what is known as a write-through method (a method of responding to the host 110 that the write request is completed when the write data is stored in the flash package 230) may be used. The shared memory 220 may store control information of the cache memory 210, important management information of the storage system 100, contact information between the storage controllers 200, synchronization information, and the like. Each flash package 230 according to the present embodiment may form a volume (storage space), and provide this volume area to the storage controller 200. That is, the storage controller 200 may recognize the flash package 230 as one storage device. Also, in the present embodiment, the volume formed by the flash package 230 may be referred to as a “flash volume”. In addition, to achieve high reliability, the storage controller 200 may have a Redundant Array of Inexpensive/Independent Disks/Devices (RAID) function capable of recovering the data of the flash package 230. In the RAID function, a group (what is known as a RAID group) composed of a plurality of (for example, four) flash packages 230 is defined, and in the event that one flash package 230 in the RAID group fails, the storage controller 200 can recover the data contents stored in the failed flash package 230 based on the information stored in the remaining flash packages 230 in the RAID group. In the present embodiment, a RAID group including a plurality of flash packages 230 is referred to as a flash package group 280. Multiple flash package groups 280 may be defined. It should be noted that the present invention is applicable even if the storage controller 200 does not have the RAID function. In addition, the present invention is applicable even if a storage device other than the flash package 230, for example, a storage device such as an HDD (Hard Disk Drive) is included in the storage system 100. FIG. 2 illustrates the configuration of a flash package 230. The flash package 230 may include a plurality of flash chips 300 that use nonvolatile semiconductor memory as a storage medium, and also include a package processor 310, a package memory 320, a buffer 330, a package bus 340, a package bus transfer device 350, and a hash circuit 370. Note that, in the present embodiment, an example in which the flash package 230 does not have compression/decompression functionality will be described. However, the flash package 230 may have a compression/decompression functionality. The hash circuit 370 may calculate a hash value (characteristic amount) of data written from the storage controller 200 to the flash package 230. In the present embodiment, a hash algorithm with a very low collision probability, such as SHA-256, is used in calculating the hash value. Accordingly, if the hash values generated from two data sets are equal, it can be determined that the contents of the two sets of data are equal. However, as another embodiment, a hash algorithm other than SHA-256 may be used. The package processor 310 may receive a read/write request from the storage controller 200 and execute a corresponding process. The buffer 330 may store data to be read/written between the storage controller 200 and the flash chip 300. In the present embodiment, it is assumed that the buffer 330 is volatile memory. Upon receiving a write request and a write data from the storage controller 200, the package processor 310 writes the received write data to the flash chip 300, and subsequently notifies the storage controller 200 that the write process has been completed. However, the present invention is applicable even if the buffer 330 is a nonvolatile memory and the write request received from the storage controller 200 is completed at the point when the write request received from the storage controller 200 is written in the buffer 330. In the package memory 320, programs executed by the package processor 310, management information of the flash chip 300, and the like are stored. As the management information of the flash package 230 is important information, it is desirable that the management information can be evacuated to a specific flash chip 300 at the time of planned shutdowns. In addition, in order to prepare for sudden failures, it may be preferable to have a battery that can be used to evacuate the management information to a specific flash chip 300 even if a failure or the like occurs. Storing all information relating to deduplication in the package memory 320 increases the capacity of the package memory 320, which can result in higher costs. Accordingly, in the flash package 230 according to the present embodiment, it is assumed that all the information is stored in the flash chip 300 and only a portion of the information is stored in the package memory 320. However, as another embodiment, all the information may be stored in the package memory 320. The package bus 340 is a bus that performs data transfer between the buffer 330 and the flash chip 300, and one or of these buses may exist. In order achieve improved performance, the flash package 230 generally has a plurality of package buses 340, but the present invention is applicable even if there only one. A package bus transfer device 350 may exist for each package bus 340 and execute data transfer between the buffer 330 and the flash chip 300 according to instructions of the package processor 310. The hash circuit 370 may be connected to the buffer 330 and calculate a hash value of data written from the storage controller 200 according to instructions of the package processor 310. The flash chip 300 may, for example, be a nonvolatile semiconductor memory chip such as a NAND type flash memory. As is well known, the unit of data reading/writing in flash memory is a segment (although generally referred to as a page, in the present specification, it is referred to as a segment). Further, data erasure may be performed for each block, which is a set of segments (referred to as a real block in the present embodiment). In the flash chip 300, there are a plurality of dies, which are aggregates of real blocks, and a plurality of segments are present in each actual block. In the present, a segment existing in a real block is referred to as a “real segment”. In the area on the flash volume, the area to which a real segment is allocated is referred to as a “virtual segment”. The flash package 230 manages each flash chip 300 with an assigned identification number. The identifier of the flash chip 300 is called a chip ID. In addition, identification numbers are also assigned to each die and each real block. The die identification number is called a die number, and the real block identifier is called a block number. The die number is a unique identification number within the flash chip 300 to which the die belongs, and the block number is an identification number unique among the dies to which the real block belongs. Also, the identification number assigned to the real segment in the real block is called a relative segment number. The relative segment number of the first real segment in the real block is 0, and the subsequent real blocks are numbered in the order 1, 2 . . . n. Subsequently, the information managed by the storage system 100 in this embodiment will be described, but before that, the configuration of the logical volume and the flash volume will be described. In the present embodiment, it is assumed that the storage controller 200 supports a high-level capacity virtualization function. However, the present invention is applicable even if the storage controller 200 does not include a higher-level capacity virtualization function. Normally in higher-level capacity virtualization functions, the allocation unit of a storage area is called a page. It should be noted that in the present embodiment, the space of the logical volume is divided into units of virtual pages, and the storage area of the flash package group 280 is divided into real pages. The relationship between the logical volume, the virtual page, the real page, and the flash package group 280 will be described with reference to FIG. 3. The storage controller 200 can define one or more logical volumes and provide them to high level devices such as the host 110. Also, as described above, the storage controller 200 may divide and manage the storage space of each logical volume in predetermined unit areas referred to as a plurality of virtual pages (FIG. 3: VP0, VP1, VP2). It should be noted that the size of a virtual page is stored in the virtual page capacity 2600 (described later) in the shared memory 220. Further, in the storage system 100 according to the present embodiment, although the capacity of all the virtual pages is the same, a configuration in which virtual pages of different sizes exist in the storage system 100 may also be used. The virtual page is a concept used only for managing the storage space of the logical volume inside the storage controller 200. When accessing the storage area of the logical volume, the host 110 specifies the storage area to be accessed by using an address such as an LBA (Logical Block Address). When the host 110 issues an access request to the logical volume, the storage controller 200 converts the LBA designated by the host 110 into a virtual page number (identification number attached to each virtual page) and a relative address (offset address at the top of the virtual page). This conversion can be realized by dividing the LBA by the virtual page size. Assuming that the size of the virtual page is P (MB), the area of P (MB) from the top position of the logical volume is managed as virtual page #0 (where #0 represents the virtual page number), the next P (MB) is managed as virtual page #1. After that, similarly, the areas of P (MB) are managed as virtual pages #2, #3 . . . #n, respectively. Immediately after the storage controller 200 defines a logical volume, no physical storage area is allocated to each virtual page. The storage controller 200 may allocate a physical storage area to the virtual page only when it receives a write request for the virtual page from the host 110. The physical storage area allocated to the virtual page is called a real page. FIG. 3 illustrates a state in which a real page RP0 is allocated to the virtual page #0 (VP0). A real page is an area formed using storage areas of a plurality of flash volumes of the flash package group 280. In FIG. 3, reference numerals 230-1, 230-2, 230-3, and 230-4 each represent flash volumes of the respective flash packages 230. In addition, the RAID type of the flash package group 280 illustrated in FIG. 3 is a 3D+1 P configuration of RAID 4 (a RAID group including three data drives and one parity drive). The storage controller 200 divides the flash volumes (230-1, 230-2, 230-3, 230-4) of the flash packages 230 belonging to the flash package group 280 into a plurality of fixed-size storage areas called stripe blocks and manages them. For example, in FIG. 3, each region described as 0(D), 1(D), 2(D) . . . n(D), or P0, P1 . . . Pn represents a stripe block. In addition, in the present embodiment, although an example is described in which the size of the stripe block is equal to the size of the virtual segment of the flash volume, as another embodiment, configurations in which the sizes of the stripe block and the virtual segment are different are also possible. In FIG. 3, the stripe blocks described as P0, P1 . . . Pn among the stripe blocks are stripe blocks for storing redundant data (parity) generated by the RAID function, and are called “parity stripes”. In contrast, the stripe blocks described as 0(D), 1(D), 2(D) . . . n(D) are stripe blocks in which data written from the host 110 (data which is not redundant data) is stored. These stripe blocks are called “data stripes”. In the parity stripes, redundant data generated using a plurality of data stripes is stored. Hereinafter, a set of parity stripes and data stripes used for generating redundant data stored in the parity stripes is referred to as a “stripe line”. In the case of the storage system 100 according to the present embodiment, for example, redundant data (parity) generated using data stripes 0(D), 1(D), and 2(D) is stored in the parity stripe P0, and data stripes 0(D), 1(D), 2(D) and parity stripe P0 belong to the same stripe line. That is, each stripe block belonging to one stripe line exists at the same position (address) on the flash volume (230-1, 230-2, 230-3, 230-4). However, as another embodiment, a configuration in which each stripe block belonging to the same stripe line exists at a different address on the flash volume may be utilized. In the storage system 100 according to the present embodiment, as shown in FIG. 3, real pages (for example RP0, RP1) are composed of one or a plurality of stripe lines. In addition, when a real page is assigned to a virtual page, only data stripes (0(D), 1(D), etc.) are allocated, and no parity stripe is allocated. Accordingly, the total size of the area where the write data is stored on the real page is equal to the size of the virtual page. That is, (the size of the real page−parity storage area of the real page)=the virtual page size. Although only a configuration example of RAID 4 is depicted in FIG. 3, in a case where the RAID type of the flash package group 280 is RAID 1, for example, the real page size may be twice the virtual page size (virtual page capacity 2600). The relationship (mapping) between each area in the virtual page and each area in the real page is as depicted in FIG. 3. That is, areas (0(D), 1(D), 2(D)) excluding parity from the top stripe of the real page are allocated to the top area of the virtual page. After that, the areas (3(D), 4(D), 5(D) . . . n(D)) excluding parity from the second and subsequent stripes of the real page are allocated in order to the area of the virtual page. In this way, since the mapping between each area in the virtual page and each area in the real page is regularly mapped, the storage system 100 can uniquely derive the flash package 230 associated with the access position and the area (data stripe) within the flash package 230 by obtaining the virtual page number and the relative address in the virtual page (the offset address from the top of the virtual page) from the access position (LBA) on the logical volume designated by the access request from the host 110. In addition to the data stripe associated with the access position, the parity stripe belonging to the same stripe line as the data stripe may be uniquely determined. However, the mapping between each area in the virtual page and each area in the real page is not limited to the mapping method described here. In the capacity virtualization technique, when defining each logical volume, the total storage capacity of each logical volume can be defined to be larger than the capacity of the real storage medium. Accordingly, in general, the number of virtual pages is larger than the number of real pages. Even in the storage device according to the embodiments of the present invention, the number of virtual pages can be made larger than the actual page number. It should be noted that the real pages allocated to each virtual page in the logical volume are not necessarily limited to the real pages in the same flash package group 280. The real page allocated to the virtual page #0 and the real page allocated to the virtual page #1 may be real pages in different flash package groups 280, respectively. However, in this embodiment, an example will be described in which all the real pages to be allocated to each virtual page of one logical volume are allocated from a flash package group 280 having the same RAID type. Next, the flash volume will be explained. In the present embodiment, each of the flash packages 230 may have a capacity virtualization function (lower-level capacity virtualization function) and perform deduplication processing. Accordingly, the flash package 230 can provide the storage controller 200 with a flash volume apparently having a capacity larger than the actual physical capacity (the total capacity of the flash chip 300). FIG. 4 illustrates the relationship between a flash volume V1 and the real block. The flash package 230 may manage the flash volume V1 by dividing the flash volume V1 into regions equal in size to “m” actual blocks. In the present embodiment, this area is referred to as “virtual block group”. Also, for convenience, an area within the virtual block group whose size is equal to the size of the real block is referred to as a “virtual block”. That is, the virtual block group can be said to be a storage area composed of m virtual blocks. Each virtual block group may be assigned an identification number, which is called a virtual block group number. In addition, a virtual block group having a virtual block group number of “n” (where n is an integer value of 0 or more) is referred to as “virtual block group #n”. This notation method is also used for objects (segments, pages, etc.) other than the virtual block group. When the size of the real block (or virtual block) is B (KB), the area of m×B (KB) from the top of the flash volume V1 is managed as virtual block group #0, and regions of m×B (KB) may be managed as virtual block groups in the order #1, #2 . . . #n. In the present embodiment, when the flash package 230 receives a write request for a virtual block group to which a real block has not yet been allocated, the real block is allocated for the first time. In addition, the flash package 230 according to the present embodiment may allocate a maximum of (m+1) real blocks to one virtual block group. Hereinafter, the reason why the maximum allocatable number of real blocks is set to m+1 in this embodiment will be described below. Consider a case where a method of allocating m real blocks to a virtual block group is utilized. In addition, consider that data is written in all areas of the virtual block group, and at that time data can hardly be deduplicated. In this case, m real blocks may be allocated to the virtual block group, but then there will be almost no available capacity in the real block. At this time, it is assumed that the flash package 230 receives a request (an ordinary write request) from the storage controller 200 for rewriting a portion of the data in the block. Since the flash memory block cannot be rewritten, the flash package 230 must read all the data of the block into the buffer 330, update only the portion where the rewrite request has occurred in the buffer 330, delete the block, and subsequently store the data in the entire block. When the above operations (reading, erasing, and writing of blocks) are executed ever time the flash package 230 receives a write request, the processing time becomes excessive, and cannot be said to be practical. In order to solve this problem, in the flash package 230 according to the present embodiment, by allocating one surplus real block to the virtual block group to reserve a free area, additional writing can be performed to the free area. When the free area becomes small and it is no longer included in the rewriting data, an erasure process is performed. In this way, since it is sufficient to execute one erasure process for a plurality of (e.g., “n”) write requests, the performance can be improved. In addition, reducing the number of times of erasure processing may also be associated with longer flash memory service life. As described above, the access (read/write) unit of the flash memory is a “segment”. Accordingly, the flash package 230 may divide and manage the space of the flash volume V1 for respective areas equal to the size of a segment. These areas may be referred to as “virtual segments”. In FIG. 4, virtual segment #0, virtual segment #1 . . . virtual segment #n represent virtual segments. Virtual segment may also be units of deduplication processing. When the flash package 230 receives an access request from the storage controller 200 for the flash volume V1, first, the flash package 230 converts the address designated by the access request into an identifier for designating a virtual segment. There are a plurality of types of identifiers (internal virtual segment number, relative virtual segment number, virtual segment address) used by the flash package 230 for designating virtual segments. The internal virtual segment number is an identifier that can uniquely identify a virtual segment in the flash package 230. The internal virtual segment number of the virtual segment positioned at the top of the flash volume V1 is set to 0. Then, consecutive numbers 1, 2, . . . n are sequentially used for the internal virtual segment numbers of the subsequent virtual segments. In FIG. 4, the numbers (#1, #s, etc.) attached to each virtual segment represent internal virtual segment numbers. The relative virtual segment number is an identifier that can uniquely identify a virtual segment within the virtual block group. The relative virtual segment number of the first virtual segment in each virtual block group is set to 0. Then, consecutive numbers of 1, 2, . . . n are sequentially used for the relative virtual segment numbers of the subsequent virtual segments. The virtual segment address is an address generated by concatenating the identifiers of the flash packages (called package ID) with the internal virtual segment number. When a virtual segment address is provided, it is possible to uniquely identify one virtual segment in the storage system 100. Next, information managed by the storage system 100 in the present embodiment will be described. FIG. 5 depicts information related to the present embodiment among the information stored in the shared memory 220 of the storage system 100. Hash value storage information 2400 is stored in the shared memory 220 in at least the logical volume information 2000, real page information 2100, free real page management information pointer 2200, flash package group information 2300, flash package information 2500, and virtual page capacity 2600. The information sets other than the hash value storage information 2400 are information necessary for realizing the higher-level capacity virtualization technique. Each information set will be described below. FIG. 6 illustrates the format of the logical volume information 2000. The logical volume information 2000 is information existing for each logical volume and is information for managing attribute information of the logical volume. Hereinafter, logical volumes whose attribute information is managed by a particular logical volume information 2000 is referred to as a “management target logical volume”. The logical volume information 2000 includes a logical volume ID 2001, a logical capacity 2002, a logical volume RAID type 2003, and a real page pointer 2004. The logical volume ID 2001 indicates the ID of the management target logical volume. Generally, the host 110 specifies the identifier of a logical volume (for example, an identifier such as a logical unit number (LUN)), an address (LBA) in a logical volume, and a length of the data to be read/written, and issues an access request (read request or write request). In the logical volume ID 2001, an identifier of the logical volume specified when the host 110 issues an access request to the logical volume is stored. The logical capacity 2002 is the capacity of the management target logical volume. The logical volume RAID type 2003 represents the RAID type of the managed logical volume. The information stored in the logical volume RAID type 2003 includes not only the RAID type such as RAID 0 and RAID 1, but when storing redundant data of one capacity for N capacities as in RAID 5, the concrete numerical value of N is also included. However, this is not to say that any arbitrary RAID type can be specified, and it is necessary for it to be a RAID type of at least one flash package group 280. When allocating a real page to the virtual page of the management target logical volume, the storage controller 200 selects the real page from the flash package group 280 whose RAID type of the flash package group 280 is the same as the logical volume RAID type 2003. The real page pointer 2004 is a pointer to the page management information (real page information 2100 to be described later) of the real page allocated to the virtual page of the management target logical volume. The number of the real page pointers 2004 is the number of virtual pages of the management target logical volume (which is a number obtained by dividing the logical capacity 2002 by the virtual page capacity 2600, or that number+1 if there is a remainder). If the number of virtual pages of the management target logical volume is n, then there are n real page pointers 2004 (there are real page pointers from 2004-0 to 2004-(n−1)). Among the plurality of real page pointers 2004 (2004-0 to 2004-(n−1)) in the logical volume information 2000, a pointer to the page management information (real page information 2100, to be described later) of the real page allocated to the virtual page #(k−1) is stored in the kth real page pointer 2004-(k−1) from the top. In addition, the trigger to allocate real pages is not when a logical volume is defined, but the trigger of actually receiving a data write request for a virtual page. Accordingly, the real page pointer 2004 corresponding to a virtual page that has not yet been written has an invalid value (NULL). FIG. 7 depicts the format of the real page information 2100. The real page information 2100 is for managing information about real pages, and one real page information 2100 exists for each real page. The real page information 2100 includes a package group 2101, a real page address 2102, a free page pointer 2103, and a page data storage amount 2104. Note that in the process of describing the following real page information 2100, a real page managed by a particular real page information 2100 is called a “management target real page”. In the package group 2101, the identifier of the flash package group 280 to which the management target real page belongs is stored. Hereinafter, the identifier of the flash package group 280 is referred to as a “package group ID”. In the real page address 2102, information on the position (address) where the management target real page exists is stored. The address stored in the real page address 2102 is a relative address in the flash package group 280 to which the management target real page belongs. The free page pointer 2103 is information used in the case that the management target real page is not assigned to the virtual page. In the present embodiment, a real page that is not assigned to a virtual page is referred to as a “free real page” or “free page”. In the case that a management target real page is not allocated to the virtual page, real page information 2100 of another free page is stored in the free page pointer 2103. When the management target real page is allocated to the virtual page, the free page pointer 2103 has a null (NULL) value. The page data storage amount 2104 is the amount of data stored in the management target real page. However, this information is not attribute information regarding (the storage area of) the flash package 230 allocated to the management target real page, but attribute information regarding the data of the virtual pages to which the management target real page is allocated. Therefore, when another real page is allocated to this virtual page and the data of the current real page is copied to the new real page, it is necessary to transfer over the page data storage amount 2104 as the management information of the new real page. FIG. 8 illustrates the format of the flash package information 2500. The flash package information 2500 is information for managing the flash package 230, and includes a flash package ID 2501, a flash package virtual capacity 2502, and a block capacity 2503. A flash package information 2500 exists for each flash package 230. Hereinafter, the flash package 230 managed by a particular flash package information 2500 is referred to as a management target flash package. The flash package ID 2501 is an identifier (referred to as a package ID) of the management target flash package. The flash package virtual capacity 2502 is the size of the area provided to the storage controller 200 in the storage area of the flash volume formed by the management target flash package, and in the present embodiment, this size is referred to as a “virtual capacity.” In the present invention, it is an advantage that the flash package virtual capacity 2502 is adjusted according to the deduplication rate of the flash package 230 or the like. In the present embodiment, the flash package 230 determines this capacity, but it may also be determined by the storage controller 200. In response to receiving notification from the flash package 230 that the virtual capacity has changed, the storage controller 200 may set this value in the flash package virtual capacity 2502. The block capacity 2503 is the size of a block. Accordingly, the value obtained by dividing the flash package virtual capacity 2502 by the block capacity 2503 is the number of blocks of the flash package 230. Referring once again to FIG. 4, the relationship between the flash volume and the virtual capacity will be briefly described. The flash package 230 according to the present embodiment provides the storage controller 200 with an area having a size equal to the virtual capacity (flash package virtual capacity 2502) in the flash volume V1. In principle, any arbitrary area of the flash volume V1 may be provided to the storage controller 200, but in the present embodiment, an example is described of providing a continuous area starting from the top of the flash volume V1 (area A; the size of this region is equal to the virtual capacity) as depicted in FIG. 4. The virtual capacity may be larger than the total storage capacity of all the flash chips 300 of the flash package 230. In FIG. 4, the storage controller 200 can access only the area A (the area equal in size to the virtual capacity) on the flash volume V1. Also, the virtual capacity can fluctuate as described above. As the size of the virtual capacity (that is, the area A) increases, the accessible area increases. Adjustment of the virtual capacity of the flash package 230 may be performed in the same manner as that described in Patent Document 2, for example. It is assumed that data is written to n virtual segments out of the virtual segments on the flash volume V1. The written data is stored in the actual segments of the flash chip 300 (put differently, it may be said that the actual segments are consumed). When deduplication is hardly performed, a number of real segments close to n are consumed. In this case, it is desirable that the virtual capacity be about the same as the total of the actual segments in the flash package 230. However, when the deduplication process is performed, only actual segments less than the virtual segment on which data is written are consumed. For example, there are cases where only n/10 actual segments may be consumed. In this case, if the virtual capacity is equal to the total of the real segments in the flash package 230, a large number of real segments go unused, and the storage area cannot be effectively utilized. In this case, if a storage capacity greater than the total of the actual segments (for example, 10 times the total storage capacity of the actual segments) is provided to the storage controller 200 as the virtual capacity, the storage area (actual segments) in the flash package 230 can be effectively utilized. That is, when the virtual capacity is adjusted (expanded or reduced) according to the ratio (referred to as the deduplication rate) of the amount of virtual segments in which data is written and the amount of consumed real segments, the storage area in the flash package 230 (actual segments) can be effectively utilized. However, since the specific method of adjusting the virtual capacity is not directly related to the present invention, a detailed description thereof will be omitted herein. In addition, the flash package 230 may reserve an area called a “hidden area” at the end of the flash volume V1. The hidden area may be provided for storing hash index information 3500, as will be described later. The storage controller 200 cannot access the hidden area. However, a program executed by the flash package 230 (at least a program that performs reference updates of the hash index information 3500) can access the hidden area. FIG. 9 illustrates the format of flash package group information 2300. The flash package group information 2300 may be used to manage information on the flash package group 280. One flash package group information 2300 may exist for each flash package group 280. The flash package group information 2300 may include a flash package group ID 2301, a package group RAID type 2302, a real page number 2303, a free real page number 2304, and a flash package pointer 2305. Hereinafter, the flash package group 280 managed by a particular flash package group information 2300 is referred to as “management target package group”. The flash package group ID 2301 is an identifier of the management target package group. The package group RAID type 2302 is the RAID type of the management target package group. This RAID type is as described in the explanation of the logical volume RAID type 2003. The real page number 2303 and the free real page number 2304 indicate the total number of real pages of the management target package group and the number of free real pages, respectively. The flash package pointer 2305 is the package ID of the flash package 230 belonging to the management target package group. The number of flash package pointers 2305 included in the flash package group information 2300 is equal to the number of flash packages 230 belonging to the management target package group. In addition, this number is determined by the package group RAID type 2302. Next, the free real page management information pointer 2200 will be described. The free real page management information pointer 2200 is information provided for each flash package group 280. FIG. 10 depicts a set of free real pages managed by the free real page management information pointer 2200. This structure is called a free real page management information queue 2201. In addition, the real page information 2100 corresponding to the free real pages is referred to as free real page information 2100. The free real page management information pointer 2200 points to the free real page information 2100 at the top of the free real page management information queue 2201 (that is, the free real page management information pointer 2200 stores the address of the top free real page information 2100). Next, the top free page pointer 2103 in the first real page information 2100 points to the next free real page information 2100. In FIG. 10, although the free page pointer 2103 of the last free real page information 2100 indicates the free real page management information pointer 2200, a null value may also be stored. In response to receiving a write request for a virtual page to which no real page is allocated, the storage controller 200 selects one of the flash package groups 280 having the same RAID type (package group RAID type 2302) as the logical volume RAID type 2003 of the logical volume to which the virtual page belongs, selects a free real page possessed by the selected flash package group 280, and assigns it to a virtual page. For example, it may be preferable to select a free real page from the free real page management information pointer 2200 of the flash package group 280 that has the largest number of free real pages. Next, the format of the hash value storage information 2400 will be described with reference to FIG. 11. In the storage system 100 according to the present embodiment, hash values used for determination of deduplication are stored in the flash chip 300. One feature of the storage system 100 according to the present embodiment is that the hash values are distributed and stored in a plurality of flash packages 230. Most of the hash values change each time data is updated. In addition, the hash values have a smaller capacity than the data. Accordingly, if the hash values are consolidated and stored in a specific area, the number of block erasures in that area becomes large in comparison with the data, and there is a high likelihood that the erasure count of the flash memory will reach its limit number early. This is the reason why the storage system 100 distributes and stores the hash values in a plurality of flash packages 230. Another feature of the storage system 100 according to the present embodiment is that both the hash value and the data are stored in the flash package 230. In this way, the flash package 230 balances the erasure count of both the actual segment that stores the data and the actual segment that stores the hash value by (local) wear leveling. Since the order of updating the hash value and the order of updating the data are roughly the same, the number of updates of the entire real segment of the flash package 230 can be made to be approximately the same order as the number of times the data is updated. The hash value storage information 2400 is information indicating which flash package 230 stores and manages each hash value. In the storage system 100 according to the present embodiment, a hash space (a range of values that a hash value can take; for example, if the value obtained by a hash function used in the storage system 100 can take a value from 0 to (2h−1), then the size of the hash space is 2h) is divided by a number (assumed to be k) sufficiently larger than the flash package 230, and information regarding the hash value belonging to each division unit is stored in any of the flash packages 230 in the storage system 100 (the reason for dividing by a sufficiently large number is that the size of the information regarding the hash value may be split up depending on each division unit, and the update frequency of the information also becomes unbalanced. For example, if the space of the hash value is 2 to the 32th power, the hash space is divided into a number sufficiently larger than the number of flash packages 230 (the number of flash packages is about one thousand at most); for example, divided into tens of thousands). The hash value storage information 2400 has a plurality of sets of hash ranges 2401 and flash package IDs 2402. Here, a set of a hash range 2401 and a flash package ID 2402 is referred to as an extent 2410. In FIG. 11, extents 2410-1, 2410-2 . . . , 2410-k are described. The number of extents 2410 is k. When the size of the hash space is 2h, the first hash range 2401 is 0 to 2h÷k−1, and the second is 2h÷k to 2×2h÷k−1. The ith is (i−1)×2h÷k to i×2h÷k−1. In the flash package ID 2402, the package ID of the flash package 230 is stored. For example, this means that when the hash value range stored in the hash range 2401 in a particular extent 2410 is a to b and the flash package ID 2402 in the extent 2410 is p, the hash value of the range a to b is stored in the flash package #p. Also in this case, the hash value in the range of a to b is called the “hash value in charge of flash package #p”. Next, the management information possessed by the flash package 230 will be described. The flash package 230 stores most of the management information in the package memory 320. FIG. 12 depicts the information included in the package memory 320. Information included in the package memory 320 includes package information 3000, chip information 3100, virtual block group information 3200, real block information 3300, free real block information pointer 3600, flash package group information 2300, hash value storage information 2400, historical information 3400, and non-leaf segment hash index information 3500. As the hash value storage information 2400 and the flash package group information 2300 are substantially the same as the hash value storage information 2400 and the flash package group information 2300 of the storage controller 200, the description of the contents thereof is omitted here. Note that the flash package group information 2300 of all the flash package groups 280 included in the storage system 100 is stored in the package memory 320. The hash value storage information 2400 and the flash package group information 2300 may be provided to the flash packages 230 from the storage controller 200 at the time of initialization, for example. Each time the storage controller 200 updates the hash value storage information 2400 and the flash package group information 2300, the storage controller 200 provides the updated information to each flash package 230. The reason why each flash package 230 has the same information as the hash value storage information 2400 of the storage controller 200 in the storage system 100 according to the present embodiment is that, at the time of the deduplication processing, it is necessary for each flash package 230, and not just the storage system 100, to be aware of the information regarding the hash values that each flash package 230 is in charge of. Also, the reason why the flash package 230 has the same information as the flash package group information 2300 managed by the storage controller 200 is that, when the flash package 230 makes a deduplication determination, it identifies data that should not be deduplicated. For example, when deduplication processing is performed on data belonging to the same stripe line, redundancy is lost, and data may not be regenerated in the event of failure of the flash package 230. Accordingly, the flash package 230 according to the present embodiment does not perform the deduplication processing for data belonging to the same stripe line. At that time, the flash package 230 uses the flash package group information 2300 to determine whether or not a plurality of data sets belong to the same stripe line. FIG. 13 illustrates the format of the package information 3000. The package information 3000 may include a package ID 3001, a virtual package capacity 3002, a real package capacity 3003, a flash block capacity 3004, a package free block number 3005, an internal information storage block number 3009, and an internal information storage address 3010. The package ID 3001 is an identifier of the flash package 230. The virtual package capacity 3002 is the virtual capacity of the flash package 230. The real package capacity 3003 is the capacity of the physical storage area (real blocks or real segments of the flash chip 300) of the flash package group 280. However, this capacity is a sum of a capacity for storing write data from the storage controller 200, a capacity for storing information used for deduplication, a capacity for evacuating information in the package memory 320, and a capacity of an area used for purposes of reclamation (spare area) or the like. The flash block capacity 3004 is the size of a block, which is an erase unit of the flash memory. The number of free blocks 3005 is the number of free blocks in the flash package 230. The internal information storage block number 3009 is the number of blocks of real blocks (these real blocks will be referred to as “internal information storage blocks”) of the package information 3000, the chip information 3100, the virtual block group information 3200, the real block information 3300, the historical information 3400, the non-leaf segment hash index information 3500, and the free real block information pointer 3600 stored in the package memory 320 to be evacuated in the event of a power off or a failure occurrence. The internal information storage address 3010 is the address of the internal information storage block. As the package information 3000, the chip information 3100, the virtual block group information 3200, and the real block information 3300 are important information, they may be stored n times. Also, as evacuation is not performed a greater number of times, the erasure count of the real blocks, etc., are not considered to be problematic. FIG. 14 depicts the format of chip information 3100. The chip information 3100 is information for managing the attribute information of the flash chip 300. The chip information 3100 is information that exists for each flash chip 300. The chip information 3100 may have a chip ID 3101, a chip real block number 3102, a number of free real blocks in the chip 3103, and a connection bus ID 3104. Hereinafter, the flash chip 300 to be managed by particular chip information 3100 is referred to as a “management target chip”. The chip ID 3101 is the chip ID of the management target chip. The chip real block number 3102 is the number of real blocks possessed by the management target chip. The number of free real blocks in the chip 3103 indicates the number of free real blocks in the management target chip. Note that the free real block number refers to a real block not allocated to a virtual block group. The connection bus ID 3104 is an identifier of the package bus 340 to which the management target chip is connected. FIG. 15 illustrates the format of the real block information 3300. The real block information 3300 is information that exists for each real block. The real block information 3300 may include a real block identifier 3301, a free real block pointer 3302, a real block free capacity 3304, and a real segment bitmap 3305. In the following description, a real block to be managed by particular real block information 3300 will be referred to as a “management target real block”. The real block identifier 3301 is an identifier of the management target real block. In this embodiment, the identifier of the real block is expressed as a combination of the chip ID, die number, and block number of the flash chip 300 to which the real block belongs in order to uniquely identify the real block in the flash package 230. The free real block pointer 3302 points to the real block information 3300 of the real block in the next free state when the real target block to be managed is not allocated to the virtual block group (in a free state). The real block free capacity 3304 indicates the current free space of the management target real block. The package processor 310 can store the write data in a free area of the management target real block when it receives write data from the storage controller 200 of a size less than or equal to the real block free capacity 3304 of the management target real block. After storing the write data, the package processor 310 subtracts the size of the stored data from the real block free capacity 3304. Note that, as the smallest write unit of the flash memory is a segment, the size of the stored data is an integral multiple of a segment (actual segment). The actual segment bitmap 3305 is N-bit size information when the number of real segments in the real block is N. When the kth bit in the real segment bitmap 3305 is 1 (ON), this means that the kth actual segment from the top in the management target real block is in use (allocated to a virtual segment), when it is 0 (OFF), this means that the kth actual segment from the top in the management target real block is unused (not allocated to a virtual segment). Next, the free real block information pointer 3600 will be described. A free real block information pointer 3600 exists for each flash chip 300. FIG. 16 illustrates a set of free real blocks managed by the free real block information pointer 3600. This structure is called a free real block information queue 1700. The free real block information pointer 3600 points to the real block information 3300 of the top free real block within the free real block information queue 1700 (that is, the free real block information pointer 3600 stores an address on the package memory 320 in which the real block information 3300 of the top free real block is stored). Next, the free real block pointer 3302 in the real block information 3300 of the top free real block points to the real block information 3300 of the next free real block. In FIG. 16, the free real block pointer 3302 of the real block information 3300 of the free real block information 3300 at the end of the free real block information queue 1700 indicates the free real block information pointer 3600, but may also be a null value. In response to receiving a write request for a virtual segment within a virtual block group to which no real block is allocated, the package processor 310 searches for a free real block from the free real block information pointer 3600 corresponding to any one of the flash chips 300 and allocates it to the virtual block group. For example, it may be desirable that a free real block is selected from the flash chip 300 that has the largest number of free real blocks (number of free real blocks in the chip 3103). FIG. 17 illustrates the format of the virtual block group information 3200. The virtual block group information 3200 is information for managing a virtual block group, and is information that exists for each virtual block group. It is assumed that the virtual block group information 3200 is arranged in order of the addresses of the virtual block group in the package memory 320. The top virtual block group information 3200 in the package memory 320 is management information for virtual block group #0. The kth virtual block group information 3200 from the top in the package memory 320 is management information for the virtual block group #(k−1). The virtual block group information 3200 may include a virtual block group identifier 3201, a real block information pointer 3202, a data storage amount 3203, a new virtual segment pointer 3205, a new hash value 3206, an old virtual segment pointer 3210, an old hash value 3211, an erasure prevention virtual segment number 3207, an erasure prevention address 3208, and an erasure prevention hash value 3209. Hereinafter, the virtual block group managed by the virtual block group information 3200 will be referred to as a “management target virtual block group”. In the present embodiment, an example is described in which the unit of the deduplication processing is a segment. However, the present invention is also applicable when the unit of deduplication is not a segment. The storage system 100 according to the present embodiment checks, for each virtual segment in which update data is written, whether or not data having the same hash value as the hash value of the update data written in the relevant virtual segment has already been stored in one of the flash packages 230. If such data already exists, the update data is not stored (but rather deleted). This has the effect of reducing the amount of data stored in the flash package 230. The virtual block group identifier 3201 is an identifier of the management target virtual block group. The real block information pointer 3202 is a pointer to the real block information 3300 (an address on the package memory 320 in which the real block information 3300 is stored) of the real block allocated to the management target virtual block group. There may be m+1 real block information pointers 3202. When no real blocks are allocated, the real block information pointer 3202 is a null value. In a case that the number of real blocks allocated to the virtual block group is p (m+1 or less), p real block information pointers 3202 from the top are valid (not null values). The data storage amount 3203 represents the amount of data stored in the management target virtual block group. The maximum capacity is (capacity of real blocks×(m+1)). In the case of flash memory, when the content of a virtual segment is updated, the update data is stored in a real segment different from the real segment previously allocated to the virtual segment. Accordingly, data (most recent data and pre-update data) written to the same virtual segment exists in a plurality of locations. Therefore, there are cases where the data storage amount 3203 may become larger than the total size of the virtual segments within the virtual block group. The new virtual segment pointer 3205, the new hash value 3206, the erasure prevention virtual segment count 3207, the erasure prevention address 3208, the erasure prevention hash value 3209, the old virtual segment pointer 3210, and the old hash value 3211, which will be subsequently described, are information that is provided for each virtual segment. Hereinafter, these pieces of information may be collectively referred to as “virtual segment management information”. Each of the new virtual segment pointer 3205, the new hash value 3206, the old virtual segment pointer 3210, and the old hash value 3211 are information that exist within the virtual block group information 3200 in a number equal to the number of virtual segments in the virtual block group. Note that, in the Figures, there are locations where the reference number of the new virtual segment pointer 3205 is listed as “3205-s”. This indicates that the relative virtual segment number is the new virtual segment pointer of the virtual segment of “s”. This reference number assignment rule is also applied to the new hash value 3206, the old virtual segment pointer 3210, the old hash value 3211, the erasure prevention virtual segment number 3207, the erasure prevention address 3208, and the erasure prevention hash value 3209. The new virtual segment pointer 3205 represents the address of the area currently allocated to the virtual segment. To be precise, address information for the area (actual segment or virtual segment) in which the storage controller 200 stores the most recent data (updated data) among the data written to the virtual segments is stored in the new virtual segment pointer 3205. The new hash value 3206 is a hash value of the most recent data written in the virtual segment. In particular, it is a hash value of data stored in the area specified by the new virtual segment pointer 3205. In the new virtual segment pointer 3205, the old virtual segment pointer 3210, and the erasure prevention address 3208, either information directly indicating an actual segment or information indicating a virtual segment is stored. Information directly indicating a real segment is information composed of a combination of an identifier (real block identifier 3301) of a real block in which data is stored and a relative address (relative segment number) of that real block, and this information may be referred to as a real segment address. For example, in the example depicted in FIG. 18, the most recent data written in the virtual segment #x of the flash package 230-A is stored in the real segment #1 (representing a real segment with a relative segment number of 1) of the real block #0. In that case, a set of the real block identifier 3301 of the real block #0 and the relative segment number (1) of the real block #0 are stored in the new virtual segment pointer (3205) of the virtual segment #x. In response to receiving a read request for the virtual segment #x from the storage controller 200, the flash package 230-A can identify the real segment (real segment #1 in the real block #0) in which the read target data is stored by referring to the new virtual segment pointer (3205) of the virtual segment #x. In contrast, a virtual segment address is used as information indicating a virtual segment. When the virtual segment deduplication processing is performed, there are cases where the virtual segment address may be stored in the new virtual segment pointer 3205. In FIG. 18, for example, it is assumed that the same data as the data written in the virtual segment #x is written in the virtual segment #y, and the deduplication processing is performed. In this case, the virtual segment address of the virtual segment #x of the flash package 230-A is stored in the new virtual segment pointer (3205) of the virtual segment #y. In the present embodiment, when the virtual segment address of the virtual segment #x is stored in the new virtual segment pointer 3205 (of the virtual segment #y) as in the state shown in FIG. 18, the virtual segment #y is stated to be “referring to the virtual segment #x”. Also, the virtual segment #x may be expressed as “a virtual segment referenced by the virtual segment #y”. In addition, when the virtual segment address of the virtual segment #x is stored in the old virtual segment pointer 3210 (of the virtual segment #y) or the erasure prevention address 3208, it can be stated that “virtual segment #y refers to virtual segment #x”. It should be noted that these same expressions can be used for real segments. For example, in FIG. 18, the real segment address of the real segment #1 of the real block #0 is stored in the new virtual segment pointer 3205 of the virtual segment #x. In this case, it can be stated that “the real segment #1 is referenced by the virtual segment #x”. Note that in the present embodiment, in order that the flash package 230 (package processor 310) can recognize whether the information stored in the new virtual segment pointer 3205 (or the old virtual segment pointer 3210 or the erasure prevention address 3208) is a real segment address or a virtual segment address, the format of the real segment address and the virtual segment address may be defined. For example, it may be preferable that the uppermost bit of the real segment address always be “1,” and the uppermost bit of the virtual segment address always be “0”. When the storage controller 200 issues a read request for the virtual segment #y to the flash package 230-B in the state shown in FIG. 18, the flash package 230-B may recognize that the virtual segment address of the virtual segment #x is stored in the new virtual segment pointer (3205) by referring to the new segment pointer (3205) of the virtual segment #y. In this case, the flash package 230-B may return the read virtual segment address and the like to the storage controller 200. In response to receiving this information, the storage controller 200 may issue a read request with the returned virtual segment address (virtual segment #x) as the access destination, and thereby obtain the target read data (that is, access redirection performed). Details thereof will be described later. The old virtual segment pointer 3210 may store, from among the data written in the virtual segment, address information for an area in which pre-update data is stored. The old hash value 3211 is a hash value of the data stored in the area specified by the old virtual segment pointer 3210. In FIG. 18, the old virtual segment pointer (3210) of the virtual segment #x may point to the real segment #0 of the real block #b. This means that the pre-update data of the virtual segment #x is stored in the real segment #0 of the real block #b. As a general rule, when an update to a virtual segment occurs, data (pre-update data) written in the virtual segment in the past may be erased. However, when deduplication processing is performed, a state may occur in which other virtual segments refer to this pre-update data (it is pointed to by the new virtual segment pointer 3205 of another virtual segment or the like) (for example, in FIG. 18, the virtual segment #x of the flash package 230-A is referred to by the virtual segment #y of the flash package 230-B). In this case, as the pre-update data cannot be erased, the old virtual segment pointer 3210 and the old hash value 3211 are used for storing (saving) this data. When further updates occur in the virtual segment, it becomes necessary to evacuate the contents stored in the old virtual segment pointer 3210 and the old hash value 3211 as well. Accordingly, the erasure prevention address 3208 and the erasure prevention hash value 3209 described later are utilized. Note that, although an example was described in the present embodiment in which a new virtual segment pointer 3205, a new hash value 3206, an old virtual segment pointer 3210, and an old hash value 3211 exist for each virtual segment, it is also possible to provide the same information for two or more virtual segments. The erasure prevention address 3208 and the erasure prevention hash value 3209 may be used for evacuating the values of the old virtual segment pointer 3210 and the old hash value 3211. The number of old virtual segment pointers 3210 and old hash values 3211 that need to be evacuated is not necessarily 1. Accordingly, one or more erasure prevention addresses 3208 and erasure prevention hash values 3209 may be provided for one virtual segment. In addition, the number of erasure prevention virtual segments 3207 indicates the number of virtual segments that should not be erased (that is, the number of sets of the erasure prevention address 3208 and the erasure prevention hash value 3209). In the example of the virtual block group information 3200 depicted in FIG. 17, there are two of each of the erasure prevention address (3208-s1, 3208-s1) and the erasure prevention hash values of the (s+1)th virtual segment (the virtual segment with relative virtual segment number s) in the virtual block group. In this case, the value of the number of erasure prevention virtual segments (3207-s) becomes 2. As described above, information such as the new virtual segment pointer 3205, the old virtual segment pointer 3210, and the erasure prevention address 3208 are provided for each virtual segment, and as a result, there are cases where a plurality of real segments (or virtual segments) may be assigned to a single virtual segment. As described above, the most recent data (updated data) among the data written from the storage controller 200 to the virtual segment is stored in the real segment pointed to by the new virtual segment pointer 3205. Accordingly, when receiving the read request from the storage controller 200, as a general rule, the flash package 230 may read out and return the data of the real segment pointed to by the new virtual segment pointer 3205 as described above. However, when access redirection occurs, it may be necessary to return the pre-update data (that is, the data stored in the actual segment pointed to by the old virtual segment pointer 3210 and the erasure prevention address 3208). This specific method will be described later. In the following description, among the data written in the virtual segment, the data stored in the real segment pointed to by the new virtual segment pointer 3205 of the virtual segment will be referred to as “data after update of the virtual segment” or “virtual segment update data”. In contrast, the data stored in the real segment pointed to by the old virtual segment pointer 3210 or erasure prevention address 3208 of the virtual segment is referred to as “data prior to update of the virtual segment” or “old data of the virtual segment”. Note that the storage system 100 according to the present embodiment may use the hash function SHA-256 to calculate a hash value of data to be written in the virtual segment by. In SHA-256, the probability of occurrence of collision is extremely low. Accordingly, in the storage system 100 according to this embodiment, when there are a plurality of data sets having the same hash value, it is assumed that the contents of these data sets are the same, and deduplication processing is performed. However, in addition to the hash value comparison, the present invention can also be applied to a case where deduplication determination is made by comparing the entire contents of each data set (in units of bits or bytes). Next, the historical information 3400 illustrated in FIG. 19 will be described. In the storage system 100 according to the present embodiment, the deduplication processing is executed asynchronously with the write processing of the host 110. Accordingly, the flash package 230 may maintain historical information 3400 indicating the history of the write processing. The historical information 3400 may include a historical information number 3401, a write address 3402, an original hash value 3403, and an updated hash value 3404. The write address 3402 is a virtual segment address of a virtual segment in which write data is written from the storage controller 200. Hereinafter, the write address 3402 may be referred to as “virtual segment address 3402”. The original hash value 3403 and the updated hash value 3404 may represent the hash value of the data (original data or updated data) written in the virtual segment specified by the write address 3402. The updated hash value 3404 is information indicating the hash value of the updated data. In contrast, the original hash value 3403 is information indicating the hash value of the original data. Hereinafter, a set of the write address 3402, the original hash value 3403, and the updated hash value 3404 is referred to as a “write history”. The historical information number 3401 is information indicating the number of write histories (sets of the write address 3402, original hash value 3403, and updated hash value 3404) stored in the historical information 3400, and the initial value is 0. Each time the flash package 230 receives a write request from the storage controller 200 and performs write processing, the write history is added to the historical information 3400 and the value of the historical information number 3401 is increased. The write history is stored in the historical information 3400 in the order of the time when the write request was received. The write history stored immediately after the historical information number 3401 is the oldest write history. In response to receiving a historical information transmission request from the storage controller 200, the flash package 230 transmits the historical information 3400 to the storage controller 200 and clears all the information in the historical information 3400 (the historical information number 3401 is set to 0. Also, each write history may also be erased). Next, the hash index information 3500 will be described. As described above, in the storage system 100 according to the present embodiment, the range of the hash value assigned to each flash package 230 is predetermined. The hash index information 3500 is information for specifying the flash package 230 (to be precise, the virtual segment address) in which data having the hash value is stored when a hash value is provided. In the hash index information 3500, a hash value assigned to the flash package 230 and information on the storage position of the data having the hash value are stored. The structure of the hash index information 3500 is depicted in FIG. 20. Basically, this structure has the same structure as B+Tree, etc., used for indices managed by DBMSs (database management system). The leaf segment 3501 corresponds to a leaf node in a tree structure such as B+Tree. In the present embodiment, each node existing on the route from the root node of the B+Tree to the leaf node is called a hierarchical segment 3509. Information (each layer segment 3509) other than the leaf segment 3501 is stored in the package memory 320 (and internal information storage block). In contrast, the leaf segment 3501 is stored in the flash chip 300. However, as described above, the flash package 230 has an area (hidden area) where the leaf segments 3501 are stored on the flash volume. A program that refers to or updates the leaf segment 3501 (such as the deduplication determination unit 12300 described later) issues a read request or a write request to a virtual segment on the hidden area, thereby reading and writing the leaf segment 3501. As a result, the leaf segment 3501 is written to the flash chip 300 (real segment allocated to the virtual segment). Accordingly, the size of the leaf segment 3501 is the same size as the virtual segment. In the leaf segment 3501, only an amount of information less than the size of the virtual segment may be stored. In this case, by padding with invalid data such as “0,” the program for updating the leaf segment 3501 may make the leaf segment 3501 have the same size as the virtual segment, and store it in the flash chip 300. The leaf segment 3501 stores a hash value and a set of storage positions of data having that hash value. A virtual segment address is used as information for expressing the storage position of the data. Accordingly, hereinafter, the storage position of data having a hash value H is referred to as a “virtual segment having a hash value H”. Information regarding the range of the hash values stored in the leaf segment 3501 is included in a parent node (hierarchical segment 3509) of the leaf segment 3501. The range of the hash values stored in the leaf segment 3501 will be described with reference to FIG. 20. In FIG. 20, the leaf segment 3501-1 and the leaf segment 3501-2 are connected to a hierarchical segment 3509-1, which is a common parent node. The hierarchical segment 3509 includes one or more sets (equal to the number of leaf segments 3501 connected to the hierarchical segment 3509) of a leaf address 3507 and a minimum value Min (hash)) 3508 of the hash values. The leaf address 3507 is a pointer to the leaf segment 3501. The value used for the pointer to the leaf segment 3501 is the virtual segment address (since the leaf segment 3501 is written to the virtual segment). The minimum value of the hash value to be stored in the leaf segment 3501 pointed to by the leaf address 3507 is stored in the Min (hash) 3508. In the structural example of FIG. 20, for example, when 0 is stored in Min (hash) 3508-1 and k (where k is a value larger than 0) is stored in Min (hash) 3508-2, hash values in the range from 0 to (k−1) are stored in the leaf segment 3501-1 pointed to at the leaf address 3507-1, and hash values having a value of k or more are stored in the leaf segment 3501-2. Therefore, by referring to the contents (Min (hash) 3508) of each hierarchical segment 3509, it is possible to identify the leaf segment 3501 in which the hash value of the search target is stored. However, in the initial state, hash values are not stored in the leaf segment 3501. After the write data is stored in the flash package 230 and the hash value of the write data is calculated, the hash values are stored in the leaf segment 3501, which will be described in detail later. Incidentally, one or more sets of leaf addresses 3507 and Min (hash) 3508 are also included in the hierarchical segment 3509, which is the parent node of the hierarchical segment 3509 (for example, the hierarchical segment 3509-1 of FIG. 20). In this case, an address on the memory (package memory 320) in which the lower hierarchical segment 3509 is placed is used as the leaf address 3507. In the Min (hash) 3508 corresponding to this leaf address 3507, the minimum value among the plurality of Min (hash) 3508 stored in the lower hierarchical segment 3509 is stored. In this method, a higher hierarchical segment 3509 is formed, and the structure of the highest hierarchical segment 3509, that is, the root node, can store information regarding the entire space of the hash value. Details of the information stored in the leaf segment 3501 will be described with reference to FIG. 21. One or more sets of a registered hash value 3502, a registered data number 3503, a segment number 3504, a registered address 3505, and an invalid flag 3506 are stored in the leaf segment 3501. Hereinafter this set is referred to as entry 3510. In the example of FIG. 21, an example is illustrated in which three entries 3510 are stored. However, the number of entries 3510 in the leaf segment 3501 may be less than 3, or may be 4 or more. In addition, a plurality of sets of the registered address 3505 and the invalid flag 3506 may be stored in the entry 3510 in some cases. In the example of FIG. 21, three sets of the registered address 3505 and the invalid flag 3506 are stored in the entry 3510-1. Hereinafter, the information stored in the entry 3510 will be described. As described above, hash values are stored in the leaf segment 3501. In particular, hash values are stored in the registered hash value 3502 in the entry 3510. One hash value may be stored in one entry 3510. For example, when n hash values are stored in a leaf segment 3501, n entries 3510 are provided in the leaf segment 3501, and a hash value is stored in the registered hash value 3502 of each entry 3510. Also, immediately after the registered hash value 3502, the registered data number 3503 is stored. The registered data number 3503 indicates the number of virtual segments (referred to as overlapping segments) having the same hash value as the hash value stored in the registered hash value 3502 in the entry 3510. However, the registered data number 3503 does not include the number of virtual segments that are not subject to deduplication processing. After the number of registered data 3503, the segment number 3504, the registered address 3505, and the invalid flag 3506 are stored. The registered address 3505 may be the virtual segment address of the virtual segment having the hash value stored in the registered hash value 3502 in the entry 3510. The invalid flag 3506 may be information indicating whether or not a valid value is stored in the immediately preceding registered address 3505. When “1” (ON) is stored in the invalid flag 3506, this indicates that a valid value is not stored in the immediately preceding registered address 3505. In the segment number 3504, the number of sets of the registered address 3505 and the invalid flag 3506 stored in the entry 3510 is stored. In principle, immediately after the deduplication process is performed, there may be only one virtual segment having the same hash value in the storage system 100 (that is, there may be only one registered address 3505 in the entry 3510). However, in the storage system 100 according to the present embodiment, when virtual segments having the same hash value exist on the same stripe line, the deduplication processing is not performed on these virtual segments for the reasons described above. In the case that a virtual segment having the same hash value as the virtual segment designated by the first registered address 3505 exists on the same stripe line, the flash package 230 stores the virtual segment addresses of the virtual segments in the second and subsequent registered addresses 3505. A detailed description of this processing will be described later. As mentioned earlier, the registered data number 3503 does not include the number of virtual segments that are not subject to deduplication processing. In the registered data number 3503, a virtual segment specified by the first registered address 3505 and the sum of the virtual segments existing on a strip line different from this virtual segment that also have the same hash value are stored (that is, the virtual segments that became targets of the deduplication processing). When all the virtual segments having the same hash value as the virtual segment identified by the first registered address 3505 exist on the same stripe line, the registered data number 3503 is one. When new data is written to the virtual segment from the storage controller 200, if a hash value of the data does not exist in the hash index information 3500, an entry 3510 for storing the hash value is added to the leaf segment 3501. However, if the entry 3510 cannot be stored in one leaf segment 3501, a leaf segment 3501 is added. Then, the information that has been stored in the leaf segment 3501 (or the hierarchical segment 3509) may be rearranged. However, since this operation is a known operation similar to insertion of data into tree structures such as B+Trees, the description thereof will be omitted herein. Next, the processing executed by the storage controller 200 and the flash package 230 will be described using the above-described management information. First, the processing performed by the storage controller 200 will be described. As a general rule, the processing performed by the storage controller 200 is realized by the processor 260 in the storage controller 200 executing a program. In addition, this program may be stored in the memory 270. FIG. 22 illustrates a program related to the present embodiment stored in the memory 270. The program related to the present embodiment may include a read process execution unit 4000, a write request acceptance unit 4100, a write-after process execution unit 4200, and a deduplication scheduling unit 4300. These programs may be programs used to realize upper level wear leveling techniques and capacity virtualization techniques. Note that, in the following description of each process, there are locations where the processing is explained using the program (the read processing execution part 4000 etc.) as the subject. However, in reality, this refers to a case where processing is performed by the program (the read processing execution unit 4000 or the like) being executed by the processor 260. Note that, as described above, in the storage system 100 according to the present embodiment, the flash package 230 may execute the wear leveling function and the lower-level capacity virtualization function. However, as another embodiment, the storage controller 200 may execute the wear leveling function and the lower-level capacity virtualization function. In this case, a program that implements the wear leveling function and the lower level capacity virtualization function may be executed by the storage controller 200. Accordingly, since the storage controller 200 executes both the higher-level program (a program for implementing the higher-level capacity virtualization function and the like) and the lower-level program, although the interfaces between the programs may differ, the contents executed by the higher-level program do not differ a great deal. Accordingly, in the present embodiment, the read processing execution unit 4000, the write request receiving unit 4100, the write-after processing unit 4200, and the deduplication schedule unit 4300 will be described in detail based on the premise that the low-level wear leveling technique and the capacity virtualization technique are implemented by the flash package 230. In addition, in the present embodiment, the data access range designated by the read request or the write request from the host 110 is explained on the premise that it coincides with the virtual segment boundary, which is the read/write unit of the flash memory. Of course, even if the access range designated from the host 110 does not coincide with the virtual segment boundary, the logical volume can be accessed. For example, when a partial area of the virtual segment is designated as a write area, the flash package 230 may read out the entire virtual segment, update only the designated partial area, and write the entire virtual segment. FIG. 23 is a processing flow of the read processing execution unit 4000. The read processing execution unit 4000 is executed when the storage controller 200 receives a read request from the host 110. Step 5000: The read process execution unit 4000 (the processor 260) calculates, based on the address of the read target area designated by the received read request, the virtual page # of the virtual page corresponding to the read target area and the relative address in the virtual page. Step 5001: The read processing execution unit 4000 checks whether the data to be read is stored in the cache memory 210 (a hit). This technique is known in the art. If it is a hit (Step 5001: Yes), then step 5011 is performed. If it is not a hit (Step 5001: No), then step 5002 is performed. Step 5002: Here, it is necessary to load the data to be read into the cache memory 210. First, the read processing execution unit 4000 identifies the real page information 2100 of the real page allocated to the read target virtual page by referring to the real page pointer 2004 of the logical volume information 2000. It should be noted that the real page assigned to the virtual page to be read is referred to as a “read target real page” in the following description. Step 5003: Based on the package group 2101 and the real page address 2102 of the identified real page information 2100, the read process execution unit 4000 may calculate the flash package group 280 to which the read target real page belongs and the address in the flash package group 280 where the (top of the) read target real page is located. Step 5004: Based on the relative address in the virtual page obtained in step 5001 and the package group RAID type 2302, the read processing execution unit 4000 calculates the location in the real page where the read target data is stored (in particular, the relative address in the real page). Then, the read processing execution unit 4000 may uses the calculated relative address in the real package, the package group RAID type 2302 and the flash package pointer 2305 to identify the flash package 230 in which the read target data is stored as well as the address within the flash package 230. Step 5005: The read process execution unit 4000 may issue a read request to the address of the flash package 230 specified in step 5004. Step 5006: The read processing execution unit 4000 may wait for data to be sent from the flash package 230. Step 5007: As a result of issuing the read request, there are cases where a response indicating that data is deduplicated may be returned from the flash package 230. In this case, the response may include a set of virtual segment addresses and hash values. In step 5007, the read processing execution unit 4000 may determine whether or not a response indicating that the data is deduplicated is returned from the flash package 230. If so, (Step 5007: Yes), the read processing execution unit 4000 next executes Step 5009. Otherwise (Step 5007: No), read data is returned from the flash package 230. In this case, Step 5008 is executed next. Step 5008: The read processing execution unit 4000 may reserve an area in the cache memory 210 for storing the read target data, and stores the data sent from the flash package 230 in the reserved area. Subsequently, Step 5011 may be performed. Step 5009: This step is executed when a response (a response including a set of virtual segment addresses and hash values) indicating that data is deduplicated is returned from the flash package. The virtual segment address included in the response is information indicating the flash package 230 and the virtual segment in which the read target data is actually stored. In this case, the read processing execution unit 4000 issues a read request (a “hash designation read request,” which will be described later) designating the virtual segment address and the hash value included in the response to the flash package 230 in which the data is actually stored (as the virtual segment address included in the response includes the package ID, the flash package 230 can be identified). Step 5010: The read processing execution unit 4000 waits for data to be sent from the flash package 230. When data transfer from the flash package 230 is initiated, the read process execution unit 4000 may executes Step 5008. Step 5011: The read processing execution unit 4000 may read the read target data from the cache memory 210 and transfer it to the host 110, thereby completing the processing. FIG. 24 is a processing flow of the write request receiving unit 4100. The write request receiving unit 4100 is executed when the storage controller 200 receives a write request from the host 110. Step 6000: The write request receiving unit 4100 (processor 260) calculates the virtual page # of the virtual page corresponding to the write target area and the relative address in the virtual page based on the address of the write target area specified by the received write request. Step 6001: The write request acceptance unit 4100 identifies the logical volume information 2000 of the logical volume designated by the write request. Then, the write request receiving unit 4100 checks whether or not the real page is allocated to the virtual page identified in step 6000 by referring to the real page pointer 2004 in the identified logical volume information 2000. If a real page has been allocated, step 6002 is skipped and then step 6003 is executed. Step 6002: The write request receiving unit 4100 allocates a real page to the virtual page corresponding to the write target area. At this time, the write request receiving unit 4100 refers to the logical volume RAID type 2003 of the logical volume information 2000 identified in Step 6001, the package group RAID type 2303 of each flash package group information 2300, and the free real page number 2304, etc., to determines which flash package group 280 to which the real page will be allocated. Thereafter, the write request receiving unit 4100 refers to the free real page management information pointer 2200 of the determined flash package group 280 and configures the real page pointer 2004 of the virtual page to which the write target area belongs to indicate the top free real page information 2100. In this way, the real page is allocated to the virtual page to which the write target area belongs. Note that the free real page management information pointer 2200 is modified so as to indicate the next real page information 2100 (the real page information 2100 indicated by the free page pointer 2103 in the real page real page information 2100 assigned to the virtual page), and further, the free page pointer 2103 in the real page information 2100 of the real page allocated to the virtual page is made to be null. In addition, the write request receiving unit 4100 reduces the number of free real pages 2304 of the flash package group management information corresponding to the real pages. In the present embodiment, although an example has been described in which the process of allocating a virtual page to a real page is executed when a write request is received, this allocation process may be executed until the data is stored in the flash package 230. Step 6003: The write request receiving unit 4100 stores the write data designated by the write request from the host 110 in the cache memory 210. Note that, when storing the write data in the cache memory 210, the write request receiving unit 4100 attaches the write position information of the write data (the ID of the flash package 230, the address on the flash volume (LBA), etc.) and stores it. Thereafter, the process completes. As the flash package group 280 has a RAID configuration, it is necessary to generate redundant data corresponding to the write data stored in the cache memory 210 (redundant data to be stored in the parity stripe belonging to the same stripe line as the data stripe storing the write data). However, as this is a well-known process, it will not be described in detail herein. Generation of redundant data may be performed, for example, immediately after step 6003. When the processor 260 creates the redundant data, it temporarily stores the redundant data in the cache memory 210. Further, as described above, in addition to the data stripe storing data, the parity stripe to store the redundant data corresponding to the data is uniquely determined from the address on the virtual page. Note that, when storing the redundant data in the cache memory 210, the processor 260 attaches the write position information to the redundant data in the same manner as for the write data. The write data and the redundant data are written to the flash package 230 by the write-after process executing unit 4200, but, from the viewpoint of the flash package 230, as both of them are data to be written to the flash package 230, it is not necessary to distinguish them from each other. Therefore, the write-after process execution unit 4200 does not perform different processes in the case of writing the write data and the case of writing the redundant data. However, from the viewpoint of deduplication processing, as redundant data is generated as a result of logical operations (exclusive OR or the like) of a plurality of data sets, the probability that deduplication can be performed (the probability that the same data exists elsewhere) is low in comparison to normal data. For this reason, in order to reduce the overhead of deduplication, it is not necessary to include it as a target of deduplication. In this case, when writing the redundant data, the storage controller 200 may attach information indicating that the data is not a target of the deduplication processing to the flash package 230. The flash package 230 that received this indication may not subject the redundant data to deduplication. FIG. 25 is a processing flow of the write-after process execution unit 4200. The write-after process execution unit 4200 is a process executed by the processor 260 with a predetermined timing. For example, the write-after process execution unit 4200 may be executed periodically. Or, the write-after process execution unit 4200 may be executed when an amount of dirty data in the cache memory 210 exceeds a predetermined amount. The write-after process execution unit 4200 may execute a process of writing the write data or the redundant data received from the host 110 into the flash package 230. However, the write-after process executing unit 4200 processes both the write data and the redundant data as data to be written in the flash package 230 without distinguishing them from each other. Step 7000: The write-after process execution unit 4200 (processor 260) searches the cache memory 210 and determines data to be written to the flash package 230. The write-after process execution unit 4200 may extract write location information attached to the found data. It should be noted that an example will be described herein of a case where the range of the area written by the write-after process execution unit 4200 does not extend over a plurality of flash packages 230. Step 7001: The write-after process execution unit 4200 may issue a write request to the appropriate flash package 230 based on the write location information. In addition, when writing redundant data, at this time the write-after process executing unit 4200 may issue an instruction indicating that this data (the redundant data) should not be included as a target of deduplication. Step 7002: The write-after process execution unit 4200 may wait for completion of the write request. When a completion report regarding the write request is returned from the flash package 230, the write-after process execution unit 4200 may end the process. FIG. 26 is a processing flow of the deduplication scheduling unit 4300. The deduplication scheduling unit 4300 may acquire the historical information 3400 accumulated in all the flash packages 230 in the storage system 100 and schedule deduplication processing. This process may be executed at appropriate intervals. Step 12000: The deduplication schedule section 4300 may issue a historical information transmission request to each flash package 230 in the storage system 100, and wait for the historical information 3400 to be sent from each flash package 230. In response to receiving the historical information transmission request, the flash package 230 may return the historical information 3400 to the storage controller (deduplication scheduling unit 4300). The processing performed by the flash package 230 will be described later. Step 12001: The deduplication scheduling unit 4300 may refer to the historical information 3400 sent from each of the flash packages 230 to create a list 1 and a list 2. The list 1 and the list 2 will be described below with reference to FIG. 27. As described above, in the historical information 3400, one or more sets (referred to as a “write history”) of the write address 3402, the original hash value 3403, and the updated hash value 3404 are included. As illustrated in FIG. 27, list 1 is a set of records generated by removing the updated hash value 3404 from each write history. List 2 is a set of records generated by removing the original hash value 3403 from each write history. Note that there may be cases where multiple updates are made with respect to the same virtual segment (multiple pieces of write history for the same virtual segment may be included in the historical information 3400). In the case that multiple updates are made to the same virtual segment (when there are multiple write histories), the deduplication scheduling unit 4300 may extract the first write history (the oldest) and the last write history (the newest) from among the plurality of write histories having the same write address 3402. Then, the deduplication schedule section 4300 registers the record generated by removing the updated hash value 3404 from the former in the list 1 and the record generated by removing the original hash value 3403 from the latter in the list 2. However, when the hash value of the old data is a null value, the deduplication scheduling unit 4300 does not register the old hash value and the address of the virtual segment in the list 1. Step 12002: Here, the deduplication schedule section 4300 divides the information in List 1 and List 2 into information to be transmitted to each flash package 230 based on the hash value (original hash value 3403 or updated hash value 3404). Hereinafter, among the information in the divided list 1, the information to be transmitted to the flash package #f is referred to as “list 1-f”, and the information to be transmitted to the flash package #f among the information in the list 2 is referred to as “list 2-f”. The method of dividing the information is described below. For example, in the list 1, when the range of the hash values assigned to the flash package #f is a to b, the records in which the (pre-update) hash value 3403 is included within the range of a to b are extracted as information to be transmitted to the flash package #f, and set as list 1-f. Similarly, in the list 2, records in which the (updated) hash value 3404 is included within the range of a to be are extracted as information to be transmitted to the flash package #f, and set as list 2-f. Step 12003: The deduplication scheduling unit 4300 may issue a deduplication determination request to each flash package 230. At that time, the deduplication schedule section 4300 may transfer the list 1 and the list 2 divided for each flash package 230 to the flash package 230 together with the deduplication determination request (for example, the list 1-f and the list 2-f may be sent to the flash package #f). Thereafter, the time deduplication scheduling unit 4300 waits for a response from each flash package 230. When the flash package 230 (flash package #f, for example) receives the list 1-f together with the deduplication determination request, it may determine, for each virtual segment address 3402 registered in the list 1-f, whether or not to erase the old data of the virtual segment designated by the virtual segment address 3402, and return the result to the storage controller 200 (deduplication scheduling unit 4300). The returned result information is referred to as “erasure candidates.” FIG. 28 illustrates an example of erasure candidates. The erasure candidates are information instructing the flash package 230 to erase the old data of the virtual segments. In the present embodiment, deletion of the old data of the virtual segments refers to a process of setting the value of the old virtual segment pointer 3210 (or erasure prevention address 3208) of the virtual segment to an invalid value (NULL). As a result of this processing, the segment (for example, the real segment) pointed to by the old virtual segment pointer 3210 (or the erasure prevention address 3208) is in a state not allocated to the virtual segment, such that the old data of the virtual segment is substantially deleted. Also, the real segments previously allocated to the virtual segments may be used for another purpose after erasing the real block (including the real segments) by garbage collection processing or the like performed in the flash package 230. As this process is well-known, the explanation thereof will be omitted herein. The erasure candidates are a list of records including a virtual segment address 3601, a hash value 3602, and an erasure flag 3603. If the erasure flag 3603 in the record is “1”, this indicates that the old data of the virtual segment designated by the virtual segment address 3601 of the record may be deleted. If the erasure flag 3603 in the record is “0”, this indicates that the old data of the virtual segment designated by the virtual segment address 3601 of the record should not be erased. In addition, the hash value 3602 is the hash value of the old data of the virtual segment designated by the virtual segment address 3601. In response to receiving the list 2-f (along with the deduplication determination request), the flash package 230 (flash package #f, for example) determines, for each virtual segment address 3402 registered in the list 2-f, whether or not deduplication processing can be performed on the update data of the virtual segment designated by the virtual segment address 3402, and returns the result to the storage controller 200 (deduplication scheduling unit 4300). The returned information may be referred to as “duplication candidates”. Note that, in the present embodiment, “deduplication of virtual segments” or “deduplication of update data of virtual segments” refers to a process of storing a virtual segment address of the virtual segment having the same data as the real segment in the new virtual segment pointer 3205 of the target segment, instead of the real segment pointed to by the new virtual segment pointer 3205 of a particular virtual segment (called a target segment). In this way, the real segments that have been allocated to the target segment so far (pointed to by the new virtual segment pointer 3205) are substantially deleted. FIG. 29 illustrates an example of duplication candidates. The duplication candidates are information instructing the flash package 230 to perform deduplication processing of virtual segments. The duplication candidates are a list of records including a virtual segment address 3701, a duplication flag 3702, and a duplicate Addr 3703. When the duplication flag 3702 in the record is “1”, this indicates that the update data of the virtual segment specified by the virtual segment address 3701 of the record can be deduplicated, and that the data of the area specified by the virtual segment address 3701 can be deleted. In addition, in this case, the address (virtual segment address) of the virtual segment having the same hash value as that of the virtual segment designated by the virtual segment address 3701 is stored in the duplicate Addr 3703. Also, if the duplication flag 3702 in the record is “0”, this indicates that the update data of the virtual segment designated by the virtual segment address 3701 of the record cannot be subjected to the deduplication process. Step 12004: The deduplication scheduling unit 4300 classifies each record in the erasure candidates received from each flash package 230 based on the flash package 230 to which they should be transmitted. The classification at this time may be performed based on the virtual segment address 3601. The virtual segment address may include the identifier (package ID) of the flash package 230. When the package ID included in the virtual segment address 3601 is “f”, it is determined to transmit that record to the flash package #f. Also, the list of records to be sent to the flash package #f is referred to as “erasure candidates-f”. Step 12005: The deduplication schedule section 4300 classifies each record within the received duplication candidates based on the flash package 230 to which they should be transmitted. This classification is performed based on the virtual segment address 3701, similarly to the classification performed in Step 12004. Hereinafter, among the records of the duplication candidates, the list of records to be transmitted to the flash package #f is referred to as “duplication candidates-f”. Step 12006: The deduplication scheduling unit 4300 may issue a deduplication execution request to each flash package 230. At that time, the deduplication scheduling unit 4300 may send the duplication candidates and the erasure candidates classified (created) in Steps 12004 and 12005 to the flash package 230 together with the deduplication execution request (for example, duplication candidates-f and erasure candidates-f are sent to the flash package #f), and wait for a response to come back. That is, the storage controller 200 (the deduplication scheduling unit 4300) may transfer the duplication candidates and the erasure candidates received from each flash package 230 to the destination flash package based on the virtual segment address (3601, 3701). Put differently, it can be said that the flash package 230 is transmitting the created duplication candidates and erasure candidates to each flash package 230 via the storage controller 200. When the duplication candidates and the erasure candidates are transmitted, the flash package 230 erases old data of the virtual segments specified by the virtual segment address 3601 included in the records of which the erasure flag 3603 is “1”, and deduplication processing is executed for the virtual segments specified by the virtual segment address included in the records in which the duplication flag 3702 is “1.” A detailed description of this processing will be described later. Step 12007: The deduplication scheduling unit 4300 completes the process when responses are received from each flash package 230. Next, the operations executed by the flash package 230 will be described. The operations of the flash package 230 are executed by the package processor 310, and the programs are stored in the package memory 320. FIG. 30 illustrates a program related to the present embodiment stored in the package memory 320. The program related to the present embodiment includes a data read processing execution unit 12600, a data write processing execution unit 12100, a historical information transmission unit 12200, a deduplication determination unit 12300, a deduplication execution unit 12400, and a hash designation read execution unit 12500. The processing flow of each program will be described below. In the following description of each process, there may be locations where the processing is explained using the program (data read processing execution unit 12600 etc.) as the subject. However, in reality, this refers to a case where processing is performed by the program (data read processing execution unit 12600 or the like) being executed by the package processor 310. FIG. 31 is a processing flow of the data read processing execution unit 12600. The data read processing execution unit 12600 is executed when a read request is received from the storage controller 200. In addition, this process may also be used when the deduplication determination unit 12300 reads out the leaf segments 3501. In the processing flow of FIG. 31 illustrated in the present embodiment, a processing flow of reading data stored in one virtual block group is depicted. However, in the present invention, it is also effective to read data stored across a plurality of virtual block groups by a read request. In addition, there are two kinds of read requests issued by the storage controller 200 according to the present embodiment. In the first read request, a read target area (an area specified by an address and a data length) is specified. In contrast, in the second read request, a hash value is specified in addition to the read target area. Hereinafter, the first read request will be referred to as an “ordinary read request”, and the second read request will be referred to as a “hash designation read request”. The processing flow illustrated in FIG. 31 is performed when an ordinary read request is received from the storage controller 200. Step 13000: The data read processing execution unit 12600 (package processor 310) may calculate, from the read target address designated by the received read request, the relative address in the virtual block group to which the read target area belongs and the virtual block group to be accessed. When the read target address is expressed by an LBA, the data read processing execution unit 12600 may calculate read target address×512÷(m×flash block capacity 3004). The quotient calculated by this calculation is the virtual block group number, and the remainder is the relative address within the virtual block group. In this way, the data read processing execution unit 12600 can specify the virtual block group (virtual block group information 3200) to be read. Step 13001: In this step, the data read processing execution unit 12600 may convert the relative address in the virtual block group obtained in Step 13000 into a relative virtual segment number, and further use it to identify the new virtual segment pointer 3205 of the access target virtual segment. Step 13002: The data read processing execution unit 12600 may identify whether the address stored in the new virtual segment pointer 3205 is a real segment address. When the obtained address is a real segment address (Step 13002: No), the data read processing execution unit 12600 next executes Step 13003. Otherwise (Step 13002: Yes), Step 13008 is executed. Step 13003: As described above, the real segment address includes a set of the identifier of the real block in which the data is stored and the relative address (relative segment number) in the real block. The data read processing execution unit 12600 identifies the flash chip 300 in which the access target area exists and the location (address) in the flash chip 300 from the information included in the real segment address. Step 13004: The data read processing execution unit 12600 may identify the package bus 340 to which the flash chip 300 is connected by referring to the chip information 3100 of the flash chip 300 specified in Step 13003, and recognize the corresponding package bus transfer device 350. Step 13005: The data read processing execution unit 12600 may instruct the package bus transfer device 350 recognized in Step 13004 to transfer the data from the flash chip 300 to the buffer 330. Step 13006: Subsequently, the data read processing execution unit 12600 may wait until the transfer is completed. Step 13007: The data read processing execution unit 12600 may send the read data requested from the storage controller 200 stored in the buffer 330 to the storage controller 200, and ends the process. Step 13008: When this step is executed, the virtual segment address is stored in the new virtual segment pointer 3205 specified in Step 13001. The data read processing execution unit 12600 may return the contents of the new virtual segment pointer 3205 and the new hash value 3206 to the storage controller 200 and complete the process. Note that, as a result of checking the virtual segment address stored in the new virtual segment pointer 3205, it is possible that the virtual segment address is an address pointing to a virtual segment in its own flash package (the flash package 230 in which the data read processing execution unit 12600 is executed). In this case, the data to be read is in the flash package itself. Accordingly, in this case, instead of returning the contents of the new virtual segment pointer 3205 and the new hash value 3206, the data read processing execution unit 12600 may search for the data stored in the flash package 230 and send the retrieved data to the storage controller 200. FIG. 32 is a processing flow of the hash designation read execution unit 12500. This processing is performed when the flash package 230 receives a hash designation read request from the storage controller 200 (when Step 5009 is executed). As described above, the hash designation read request includes a hash value in addition to the information (address) of the access target area. Note that, in the following description, the hash designation read request is abbreviated as a “read request”. Step 13500: This processing is the same as that of Step 13000. As a result of this processing, the hash designation read execution unit 12500 may identify the relative virtual segment number in the virtual block group corresponding to the access target area. Here, a case will be described in which the identified relative virtual segment number is “s”. A virtual segment whose relative virtual segment number is “s” may be expressed as “virtual segment #s”. Step 13501: The hash designation read execution unit 12500 may compare the hash value designated by the received read request with the new hash value 3206, the old hash value 3211, and the erasure prevention hash value 3209 of the virtual segment #s. If the hash value designated by the read request matches the new hash value 3206, the hash designation read execution unit 12500 may acquire the information (address) stored in the new virtual segment pointer 3205 of the virtual segment #s . If the hash value designated by the read request matches the old hash value 3211, the hash designation read execution unit 12500 may acquire the information (address) stored in the old virtual segment pointer 3210 of the virtual segment #s. In contrast, if the hash value specified by the read request matches the erasure prevention hash value 3209, the hash designation read execution unit 12500 may acquire the information (address) stored in the erasure prevention address 3208 of the virtual segment #s. Note that, when a plurality of erasure prevention hash values 3209 and erasure prevention addresses 3208 are provided in the virtual segment #s, the hash designation read execution unit 12500 may compare and collate the hash value designated by the read request with the respective erasure prevention hash values 3209. Step 13503: The address acquired in Step 13501 is a real segment address. The data read processing execution unit 12600 identifies, from the actual segment address obtained in step 13501, the identifier of the flash chip 300 in which the read target data is stored and the address in the flash chip 300. This is the same process as that of Step 13003. Step 13504: Processing similar to that of Step 13004 is performed. Step 13505: Processing similar to that of Step 13005 is performed. Step 13506: Processing similar to that of Step 13006 is performed. Step 13507: Process similar to that of Step 13007 is performed. As a result, data is returned to the storage controller 200. Next, with reference to FIG. 33 and FIG. 34, the processing flow of the data write processing execution unit 12100 will be described. The data write processing execution unit 12100 is executed when the flash package 230 receives a write request from the storage controller 200. Further, this processing flow may also be executed when the deduplication determination unit 12300 writes a leaf segment. Note that, in the process flow of FIG. 33 and FIG. 34 illustrated in the present embodiment, a process is illustrated of a case in which the range designated by the write request is included in one virtual block group and does not extend over a plurality of virtual block groups. However, the present invention is also applicable when a write request is received for an area spanning a plurality of virtual block groups. Step 14000: The data write processing execution unit 12100 (package processor 310) may calculate, from the address to be written by the received write request, the relative address within the virtual block group to be accessed and the virtual block group to which the write target area belongs. This is similar to the calculation performed in Step 13000. Further, the data write processing execution unit 12100 may identify the virtual segment corresponding to the write target area by converting the relative address in the virtual block group to which the write target area belongs to a relative virtual segment number. Hereinafter, this virtual segment is referred to as a “write target virtual segment”. In addition, here, the new virtual segment pointer 3205 of the write target virtual segment is also identified. In the present embodiment, an example will be described in which the write range specified by the write request from the storage controller 200 coincides with the virtual segment boundary. Of course, the present invention is also applicable when only a portion of the virtual segment is designated by the write request from the storage controller 200. Note that, when a partial area of the flash virtual segment is designated, the flash package 230 may read the entire virtual segment to the buffer 330 or the like, update only the specified partial area in the buffer 330, and write the updated data for one virtual segment to the virtual segment. Step 14001: The data write processing execution unit 12100 may receive the write data specified by the write request from the storage controller 200 and stores it in the buffer 330. In addition, the data write processing execution unit 12100 may calculate a hash value of the data by using the hash circuit 370. Step 14002: The data write processing execution unit 12100 may acquire the first real block information pointer 3202 from the virtual block group information 3200 (hereinafter referred to as “target virtual block group information”) of the virtual block group to which the virtual segment that is the write target belongs. Then, the data write processing execution unit 12100 may check whether this value is null, that is, whether a real block is allocated. If a real block is allocated (Step 14002: No), the data write processing execution unit 12100 may next executes Step 14005. If a real block has not been allocated (Step 14002: Yes), then Step 14003 is executed. Step 14003: The data write processing execution unit 12100 may assign a real block in a free state to the virtual block group to which the virtual segment that became the write target belongs. Herein, it is assumed that the allocated real block is erased and the data is not stored. In particular, the data write processing execution unit 12100 may refer to the number of free real blocks in the chip 3103 etc., of each set of chip information 3100 and determine a target flash chip 300 to acquire a free real block. Thereafter, the data write processing execution unit 12100 may refer to the free real block information pointer 3600 of the determined flash chip 300 and obtain a pointer to the top real block information 3300. Then, the data write processing execution unit 12100 may store the obtained pointer in the first real block information pointer 3202 of the target virtual block group information. This assigns the first real block to the virtual block group. Note that the free real block information pointer 3600 may be modified to indicate the next real block information 3300 (the real block information 3300 indicated by the free real block pointer 3302 in the real block information 3300 of the real block allocated to the virtual block group), and further, the free real block pointer 3302 in the real block information 3300 of the real block allocated to the virtual block is made null. In addition, the data write processing execution unit 12100 may reduce the number of free real blocks in the chip 3103 of the chip information 3100 corresponding to the real block. Then, the data write processing execution unit 12100 may set the real block free capacity 3304 corresponding to the allocated real blocks to the capacity of the real block. Here, data is written from the top of the allocated real block. Step 14004: The data write processing execution unit 12100 may generate the real segment address of the first real segment of the allocated real block. In particular, by combining the identifier of the real block and the relative address within the real block (in this case, the relative address becomes 0), the real segment address can be generated. Then, the data write processing execution unit 12100 may set the generated actual segment address in the new virtual segment pointer 3205 of the write target virtual segment. In this way, the real segment may be allocated to the write target virtual segment. In addition, the data write processing execution unit 12100 may set the hash value calculated in Step 14001 to the new hash value 3206 of the write target virtual segment. Further, the data write processing execution unit 12100 may set the old virtual segment pointer 3210 and old hash value 3211 of the write target virtual segment to null values. In addition, the data write processing execution unit 12100 may set 0 in the data storage amount 3203. Subsequently, the data write processing execution unit 12100 may execute Step 14010. Step 14005: The data write processing execution unit 12100 may identify the real block information 3300 corresponding to the real block that will become the write target. This is the real block information 3300 pointed to by the real block information pointer 3202 at the end of the real block information pointer 3202 in which a valid value (non-NULL value) is stored in the virtual block group information 3200. The data write processing execution unit 12100 may check, based on the real block free capacity 3304 of the identified real block information 3300 and the length of the write data stored in the buffer 330, whether the received data can be written in the free area of the real block. If writing is possible (Step 14005: No), then Step 14008 is executed. Otherwise, the data write process execution unit 12100 next executes Step 14006. Step 14006: This step is a step executed when the length of the write data is greater than the free area of the real block set as the write target. In this step, the data write processing execution unit 12100 may determine whether (m+1) real blocks are allocated to the virtual block group (determine whether all (m+1) real block information pointers 3202 in the virtual block group information 3200 are non-NULL values). When (m+1) real blocks are allocated, the data write processing execution unit 12100 may execute step 14013. Step 14007: This step is a step of allocating a real block in a free state to a corresponding virtual block group, and the same processing as in Step 14003 is performed. Step 14008: The data write processing execution unit may 12100 check the old virtual segment pointer 3210 of the write target virtual segment in the virtual block group information 3200, and if the value is a null value, the new virtual segment pointer 3205 and the new hash value 3206 of the write target virtual segment may be copied to the old virtual segment pointer 3210 and the old hash value 3211, respectively (when the old virtual segment pointer 3210 is not a null value, information is not copied to the old virtual segment pointer 3210 and the old hash value 3211). Note that, when the write request for the relevant virtual segment is received for the first time, the old virtual segment pointer 3210 and the old hash value 3211 of the relevant virtual segment are null values. The fact that the old hash value 3211 is a null value indicates that the hash value thereof is invalid. Step 14009: The data write processing execution unit 12100 may determine the last real block (the real block indicated by the last real block information pointer 3202 whose real block information pointer 3202 is not a null value) among the real blocks allocated to the virtual block group to be a write target. In addition, the data write processing execution unit 12100 may set the hash value calculated in Step 14001 as the new hash value 3206 of the write target virtual segment. Step 14010: The data write processing execution unit 12100 may add the new hash value 3206 of the write target virtual segment, the old hash value 3211, and the write target virtual segment address to the historical information 3400, and increment the historical information number 3401 by one. In addition, the data write processing execution unit 12100 may determine, based on the real block free capacity 3304 of the data write target real block, the address to write this time (a real segment address; that is, a combination of a chip ID, a die number, a block number, and a relative segment number within a real block). As the data write processing execution unit 12100 sequentially writes data in order from the top real segment of the real block, if the real block free capacity 3304 and the size of the real block are known, the relative address in the real block (relative segment number) to be written this time can be easily determined. The data write processing execution unit 12100 may set this address as the new virtual segment pointer 3205 of the write target virtual segment. Further, the data write processing execution unit 12100 may turn on, in the actual segment bitmap 3305, the bit corresponding to the real segment which is the current write target. Step 14011: The data write processing execution unit 12100 may set a request to the transfer apparatus to write the write data in the buffer 330 in the write target real segment, and wait for the write to complete. Step 14012: The data write processing execution unit 12100 may reduce the real block free capacity 3304 corresponding to the write target real blocks by the value corresponding to the total size of the real segments that have been written this time. Further, the data write processing execution unit 12100 may add the capacity of the virtual segment set as the write target to the data storage amount 3203. Then, the data write process execution unit 12100 may report completion of the process to the storage controller 200, and complete the process. Step 14013: Here, a process (a garbage collection process, as it is known) may be performed to move valid data in the real blocks previously allocated to the virtual block group to a new free real block. In particular, the data write processing execution unit 12100 may read out valid information, that is, only the data stored in the real segments pointed to by the new virtual segment pointer 3205, the old virtual segment pointer 3210, and the erasure prevention address 3208, from among the real blocks allocated to the virtual block group so far, write the read data to a new free real block, and update the virtual block group information 3200. More particularly, the data write processing execution unit 12100 may store a pointer to the real block information 3300 of the real block in which the data is written in the real block information pointer 3202, and set the address of the (real segment of) the real block in which the data is written in the new virtual segment pointer 3205, the old virtual segment pointer 3210, and the erasure prevention address 3208. In addition, the real block free capacity 3304 and the real segment bit map 3305 are also set for the real block information 3300 of the real blocks to which data is newly written. Note that the newly allocated real blocks are selected according to a wear leveling algorithm (an algorithm for balancing the number of erasures of each real block). As wear leveling is a well-known technique, it will not be described here in detail. In addition, the real blocks that have been allocated to the virtual block group so far are erased and managed as free real blocks. Thereafter, Step 14005 may be executed. FIG. 35 is a processing flow of the historical information transmitting unit 12200. The historical information transmitting unit 12200 is executed when a historical information transmission request is sent from the storage controller 200 (Step 12000). Step 15000: The historical information transmitting unit 12200 sends the historical information 3400 to the storage controller 200. Step 15001: The historical information transmitting unit 12200 initializes the historical information 3400. In particular, the historical information transmitting unit 12200 clears the area in the package memory 320 in which the historical information 3400 was stored. Subsequently, the process completes. FIG. 36 is a processing flow of the deduplication execution unit 12400. The deduplication execution unit 12400 is a processing flow that is executed when the deduplication execution request, the erasure candidates and the duplication candidates described above are sent from the storage controller 200 (Step 12006) (to be precise, the erasure candidates and the duplication candidates classified in Step 12004 and Step 12005 are sent to the flash package 230. For example, the flash package #x may receive erasure candidate-x and duplication candidate-x, but in the following description, the erasure candidate-x and the duplication candidate-x are simply referred to as an “erasure candidate” and a “duplication candidate”, respectively). Step 16000: The deduplication execution unit 12400 divides the record of the erasure candidate sent from the storage controller 200 into records with erasure flags 3603 of “1” and records of “0”. Step 16001: In this step, processing is performed on records with erasure flags 3603 of “1”. Hereinafter, an example will be described of a case where there is one record with an erasure flag 3603 of “1” as a result of executing Step 16000. In the description of Step 16001, the virtual segment specified by the virtual segment address 3601 of this record is referred to as a “target virtual segment”. The deduplication execution unit 12400 may obtain, from the virtual segment address 3601 of the record, the virtual block group to which the target virtual segment belongs and the relative virtual segment number of the target virtual segment. An example will be described below of a case where the obtained relative virtual segment number is “s”. Next, by referring to the virtual block group information 3200 of the specified virtual block group, the deduplication execution unit 12400 may read the old hash value 3211 (3211-s) and the erasure prevention hash value 3209 (3209-s) of the target virtual segment and compare them with the hash value 3602. When the hash value 3602 matches the old hash value 3211-s, the deduplication execution unit 12400 determines whether or not the address stored in the old virtual segment pointer 3210-s is the real segment address. If it is the real segment address, the deduplication execution unit 12400 may subtract the size of the virtual segment from the data storage amount 3203. In addition, the deduplication execution unit 12400 identifies the real block information 3300 of the real block having the real segment in which the old data was stored by referring to the address stored in the old virtual segment pointer 3210-s (more particularly, the real block identifier included in the real segment address) and the real block information pointer 3202. Then, in the real segment bitmap 3305 of the real block information 3300, the deduplication execution unit 12400 turns off the bit corresponding to the real segment in which the old data was stored. If the address stored in the old virtual segment pointer 3210-s is not the actual segment address, this process is not performed. Next, the deduplication execution unit 12400 sets the old virtual segment pointer 3210-s and the old hash value 3211-s to null. As a result, the area (the real segment pointed to by the old virtual segment pointer 3210-s) in which the old data had been stored (evacuated) and which was allocated to the virtual segment may be substantially deleted. When the hash value 3602 matches the erasure prevention hash value 3209-s, the deduplication execution unit 12400 sets the erasure prevention hash value 3209-s and the erasure prevention address 3208-s to null, and decreases the erasure prevention virtual segment number 3207 by 1. In this way, the area (the real segment pointed to by the erasure prevention address 3208-s) in which the old data had been stored (evacuated), and which was allocated to the virtual segment may be substantially deleted. In addition, the deduplication execution unit 12400 may subtract the size of the virtual segment from the data storage amount 3203, and turn off the bit of the actual segment bitmap 3305 corresponding to the real segment that had been pointing to the erasure prevention address 3208-s. This is the same as the processing performed for the old virtual segment pointer 3210-s described above. Further, the deduplication execution unit 12400 may front-fill the erasure prevention hash value 3209 and the erasure prevention address 3208, which are stored behind the nullified erasure prevention hash value 3209-s and erasure prevention address 3208-s, up to the nullified erasure prevention hash value 3209 and erasure prevention address 3208. Step 16002: In this step, processing is performed on records with erasure flags 3603 of “0”. In the following, as in Step 16001, an example will be described of a case in which there is one record with an erasure flag 3603 of “0”. In addition, the virtual segment specified by the virtual segment address 3601 of this record is referred to as a “target virtual segment”. The deduplication execution unit 12400 may obtain the virtual block group to which the target virtual segment belongs and the relative virtual segment number of the target virtual segment from the virtual segment address 3601 of the record. An example of a case where the obtained relative virtual segment number is “s” will be described below. The deduplication execution unit 12400 may update the virtual block group information 3200 of the specified virtual block group. In particular, the deduplication execution unit 12400 may increment the erasure prevention virtual segment number 3207-s by one. Further, the deduplication execution unit 12400 may copy the old virtual segment pointer 3210 and the old hash value 3211 to the area of the erasure prevention address 3208 and the erasure prevention hash value 3209. Further, the deduplication execution unit 12400 may set the old virtual segment pointer 3210 and the old hash value 3211 to null. Step 16003: Here, processing related to duplication candidates is executed. If the duplication candidates include a record whose duplication flag 3702 is “0”, that record is ignored. If the duplication flag 3702 contains a record of “1”, deduplication processing should be performed for the virtual segment specified by the virtual segment address 3701 of the record. Hereinafter, an example will be described of a case where one duplication flag 3702 “1” is included in the duplication candidates. In the following example, an example is described in which the relative virtual segment number of the virtual segment (referred to as the target virtual segment) specified by the virtual segment address 3701 of the record is “s”. The deduplication execution unit 12400 may update the virtual block group information 3200 of the virtual block group to which the target virtual segment belongs. In particular, the deduplication execution unit 12400 nullifies the new virtual segment pointer 3205-s, and reduces the size of the virtual segment from the data storage amount 3203. In addition, the deduplication execution unit 12400 turns off the real segment bitmap 3305 corresponding to the real segment indicated by the new virtual segment pointer 3205-s in the same manner as the processing in Step 16001. Further, the deduplication execution unit 12400 sets the value of the duplicate Addr 3703 to the new virtual segment pointer 3205-s. In this way, the new virtual segment pointer 3205-s points to a virtual segment having the same hash value, and the deduplication processing of the target virtual segment is performed. Note that virtual segments having the same hash values may exist in the same flash package 230 or may be present in another flash package 230. Upon completion of Step 16003, the deduplication execution unit 12400 notifies the storage controller 200 that the processing has been completed and ends the process. Note that, in the above description, although an example was described in which there is only one record of the erasure candidates (or duplication candidate records) to be processed in each step, but in cases where there are a plurality of records (or duplication candidate records) to be deleted, the above-described processing is performed for each record. FIG. 37 is a processing flow of the deduplication determination unit 12300. The deduplication determination unit 12300 is a processing flow executed when the deduplication determination request, the list 1, and the list 2 described above are sent from the storage controller 200 (Step 12003). The deduplication determination unit 12300 may receive a list of hash values assigned to the flash package 230 (for example, the flash package #x receives a list 1-x and a list 2-x). Step 17000: In this step, processing related to the list 1-x is executed. The deduplication determination unit 12300 reads records one by one from the list 1-x, determines, whether or not to erase the old data of the virtual segment based on the virtual segment address 3402 and (pre-update) hash value 3403 stored in each record, and creates records for the erasure candidates. Hereinafter, an example of processing performed when a certain record in the list 1-x is read out will be described. In addition, in the following, an example will be described in which the (pre-update) hash value 3403 of the read record is H. Further, the virtual segment specified by the virtual segment address 3402 of the read record is referred to as a “target segment”, and the virtual segment address (i.e., virtual segment address 3402) of the target segment is referred to as a “target segment address”. When the (pre-update) hash value 3403 is H, the deduplication determination unit 12300 searches the hash index information 3500, identifies the leaf segment 3501 in which the information of the hash value H is stored, and reads the leaf segment 3501 to the buffer 330. At this time, the deduplication determination unit 12300 reads the virtual segment in which the leaf segment 3501 is stored by calling the data read processing execution unit 12600. Subsequently, the deduplication determination unit 12300 may identify, from the read leaf segment 3501, the entry 3510 whose registered hash value 3502 is H. Further, the deduplication determination unit 12300 may determine whether or not a registered address 3505 having a value equal to the target segment address exists in the entry 3510, and perform different processing depending on the determination result. First, a description will be provided of a case where there is a registered address 3505 equal to the value of the target segment address. In this case, there may be cases where the existing registered address 3505 is the top registered address 3505 in the entry 3510, as well as cases where it is not. If the registered address 3505 which is equal to the value of the target segment address is not the top registered address 3505 in the entry 3510, the old data of the target segment may be deleted. As the addresses of virtual segments for which deduplication processing has not been performed are stored in the second and subsequent registered addresses 3505 in the entry 3510 (the virtual segment address of the virtual segment belonging to the same stripe line as the first registered address 3505 is stored), no problem occurs even if the old data of these virtual segments is deleted. Accordingly, at this time, the deduplication determination unit 12300 creates, as the record of the erasure candidate, a record in which the target segment address is stored in the virtual segment address 3601, H is written to the hash value 3602, and 1 is stored in the erasure flag 3603. The deduplication determination unit 12300 may turn on the invalidation flag 3506 corresponding to the registered address 3505 that is equal to the value of the target segment address. At the same time, NULL may be stored in the registered address 3505. Further, the deduplication determination unit 12300 may reduce the number of segments 3504 by one. Note that editing of the entry 3510 performed here (updating of segment number 3504 and the like) is performed for the contents of the entry 3510 read onto the buffer 330. In contrast, when the registered address 3505 at the top of the entry 3510 is equal to the value of the target segment address, the old data of the target segment may or may not be deleted. When the number of registered data 3503 is 1, this indicates that there are no virtual segments having a hash value H other than the virtual segment specified by the target segment address (or the top registered address 3505). Therefore, in this case, the old data of the target segment may be erased. Also, even if the registered data number 3503 is 1, if the segment number 3504 is 2 or more, then there are a plurality of virtual segments having the hash value H. In this case, however, all the virtual segments having the hash value H exist in the same stripe line in a particular flash package group 280. As deduplication processing is not performed for virtual segments belonging to the same stripe line, they may be deleted. In contrast, when the registered data number 3503 is 2 or more, this indicates that there is a virtual segment referring to the target segment (it has been deduplicated). In that case, the old data of the target segment should not be deleted. Accordingly, when the registered data number 3503 is 1, the deduplication determination unit 12300 creates, as a record of the erasure candidate, a record in which the target segment address is stored in the virtual segment address 3601, H is stored in the hash value 3602, and 1 is stored in the erasure flag 3603. Further, the deduplication determination unit 12300 deletes, from the leaf segment 3501, the entry 3510 whose registered hash value 3502 is H. This is because the virtual segment having the hash value H, which was also the virtual segment to be subjected to the deduplication processing, has disappeared. When the registered data number 3503 is 2 or more, the deduplication determination unit 12300 creates, as a record of the erasure candidate, a record in which the target segment address is stored in the virtual segment address 3601, H is stored in the Hash value 3602, and 0 is stored in the erasure flag 3603 (that is, it does not allow the target segment to be erased). At this time, the deduplication determination unit 12300 does not modify the contents of the entry 3510. Next, a description will be provided of a case where there is no registered address 3505 equal to the value of the target segment address in the entry 3510. In this case, the target segment is a virtual segment referring to the virtual segment specified by the registered address 3505 at the top of the entry 3510. Conversely, as the target segment is not being referred to by another virtual segment, the old data of the target segment may be erased. Accordingly, the deduplication determination unit 12300 creates, as a record of the erasure candidate, a record in which the target segment address is stored in the virtual segment address 3601, H is stored in the hash value 3602, and 1 is stored in the erasure flag 3603. Further, the deduplication determination unit 12300 may reduce the data registered number 3503 by one. Updating of the number of registered data 3503 performed here is also performed on the contents of the entry 3510 read onto the buffer 330. The above processing is performed for all the records in the list 1. After the processing described above is performed for all the records in the list 1, the deduplication determination unit 12300 writes the edited (updated) leaf segments 3501 on the buffer 330. At this time, the deduplication determination unit 12300 calls the data write processing execution unit 12100 shown in FIG. 33 and FIG. 34 in order to execute the write. As can be understood from the description of the data write processing execution unit 12100, when writing to the virtual segment is performed, the write data is written in a real segment (free real segment) different from the actual segment allocated to the virtual segment. Step 17001: In this step, processing related to list 2 is executed. The deduplication determination unit 12300 reads records one by one from the list 2-x, performs the deduplication determination based on the virtual segment address 3402 and (updated) hash value 3404 stored in each record, and creates records for the duplication candidates. Hereinafter, an example will be described of the processing performed when a certain record in the list 2-x is read. As in the case of the description of step 17000, an example will be described below of a case where the (updated) hash value 3404 of the read record is H. Further, the virtual segment specified by the virtual segment address 3402 of the read record is referred to as a “target segment,” and the virtual segment address (that is, the virtual segment address 3402) of the target segment is referred to as a “target segment address”. In a case where the (updated) hash value 3404 is H, the deduplication determination unit 12300 searches the hash index information 3500, identifies the leaf segment 3501 that may possibly store the information of the hash value H, and reads them to the buffer 330. As in step 17000, at this time, the deduplication determination unit 12300 reads the leaf segments 3501 by calling the data read processing execution unit 12600. Subsequently, the deduplication determination unit 12300 may determine whether there is an entry 3510 in the read leaf segments 3501 in which the registered hash value 3502 is H. If a corresponding entry 3510 is not found, deduplication cannot be performed (as this means that there is no duplicate data). In this case, the deduplication determination unit 12300 creates, as the duplication candidate record, a record in which the target segment address is stored in the virtual segment address 3701, 0 is written in the overlap Flag 3702, and NULL is stored in the duplicate Addr 3703. In addition, the deduplication determination unit 12300 may record the hash value H and the virtual segment address in the leaf segment 3501 read onto the buffer 330. In particular, the deduplication determination unit 12300 may newly create an entry 3510 in which H is stored in the registered hash value 3502. Further, the deduplication determination unit 12300 may sets the registered data number 3503 and the segment number to 1, set the target segment address to the first registered address 3505 in the entry 3510, and turn off the invalid flag 3506. If there is an entry 3510 whose registered hash value 3502 is H, there is a possibility that deduplication can be performed. In this case, the deduplication determination unit 12300 may compare the virtual segment address recorded in the top registered address 3505 in the entry 3510 with the target segment address, and determine whether both belong to the same stripe line. In this determination, the flash package group information 2300 is used. In particular, in the case that the virtual segment address recorded in the registered address 3505 and the package ID included in the target segment address are both those of the flash package 230 in the same flash package group 280, and the virtual segment address recorded in the registered address 3505 is equal to the internal virtual segment number included in the target segment address, then it can be determined that both belong to the same stripe line. When both belong to the same stripe line, the deduplication determination unit 12300 determines not to perform the deduplication processing of the target segment. Accordingly, the deduplication determination unit 12300 creates, as the duplication candidate record, a record in which the target segment address is stored in the virtual segment address 3701, 0 is written in the overlap flag 3702, and NULL is stored in the duplicate Addr 3703. Further, the deduplication determination unit 12300 updates the entry 3510 in the leaf segment 3501 read into the buffer 330. In particular, the deduplication determination unit 12300 may increment the value of the segment number 3504 by 1, set the new registered address 3505 in the added set to the target segment address, and turn off the invalid flag 3506. If both do not belong to the same stripe line, the target segment may be deduplicated. The deduplication determination unit 12300 may create, as the duplication record, a record in which the target segment address is stored in the virtual segment address 3701, 1 is stored in the duplication flag 3702, and the content of the top registered address 3505 in the entry 3510 is stored in the duplicate Addr 3703. Further, the deduplication determination unit 12300 may increment the registered data number 3503 in the entry 3510 by one. The above processing is performed for all the records in the list 2. Thereafter, the deduplication determination unit 12300 writes the edited (updated) leaf segment 3501 on the buffer 330. As described in step 17000, the deduplication determination unit 12300 may execute the write by calling the data write processing execution unit 12100 depicted in FIG. 33 and FIG. 34. Step 17002: The deduplication determination unit 12300 may return the list of the erasure candidates and the duplication candidates created in Step 17000 and Step 17001 to the storage controller 200, and then complete the processing. The above is the processing of the deduplication determination unit 12300. In the above description, an example was described in which writing (writing to the actual segment) of the edited (updated) leaf segment 3501 on the buffer 330 is performed after completion of Step 17000, and writing of the edited (updated) leaf segments 3501 on the buffer is performed after completion of step S7001. However, in Steps 17000 and 17001, the same leaf segments 3501 to be processed (referenced or updated) may be included. Accordingly, the deduplication determination unit 12300 may not write the leaf segment 3501 to the actual segment at the time of completion of the step 17000, but may collectively perform the writing in Step 17001. This concludes the explanation of the storage system according to this embodiment. In the storage system according to the present embodiment, deduplication of data between flash packages can be executed, so duplication elimination can be performed efficiently. In principle, as the flash package executes the deduplication processing, there is an advantage that the storage controller does not become a performance bottleneck. In the storage system according to the present embodiment, only the data addresses corresponding to the hash values are exchanged between the storage controller and the flash package for the deduplication process. Then, the storage controller may transfer a plurality of hash values and data addresses with one command, thereby reducing the number of accesses to the flash package from the storage controller. In addition, in the storage system that performs the deduplication processing, as in the hash index of the storage system according to the above-described embodiment, it is necessary to store the information (hereinafter referred to as an index) of the area in which the data having the hash values is stored. As these sets of information are large, storing them in an expensive storage medium such as DRAM or the like increases the bit cost of the storage device. Therefore, in the storage system according to this embodiment, these sets of information are stored in the flash memory of the flash package. The index is modified each time a data write (update) from the host occurs. For this reason, if the indexes are consolidated and stored in a specific flash package, the number of updates of the flash package becomes large, which tends to be a performance bottleneck and can shorten the lifetime of the flash memory. In the storage system according to the above-described embodiment, the indices may be distributed and stored in a plurality of flash packages, and the distributed and stored indexes may be managed (referenced or updated) by the respective flash packages. Accordingly, processing related to the indices does not concentrate in a specific controller (or flash package). Also, as the areas (segment) on the flash memory to which the indices are written are also managed as targets of wear leveling processing, the number of erasures may be controlled so as to not deviate between the segments in which an index is written and the segments in which the data is written. In addition, the overhead associated with index update processing is large. Normally, when the data is updated, the hash value is also modified from a different value (old hash value to new hash value). Accordingly, once the data is updated, the following three update processes occur with respect to the index: 1) updating the hash value of the data to the new hash value, 2) adding the address of the data to the set of data having the new hash value, and 3) deleting the address of the data from the set of data having the old hash value. When trying to perform these updates with the storage controller, the flash memory access for reading out these pieces of information takes place three times and flash memory access occurs three times for the writing process, resulting in a large overhead. In the storage system according to the embodiment described above, when transferring the write processing history and the hash value of the write data used in the deduplication processing between the storage controller and the flash package, the write processing history and the hash value may be aggregated and collectively transferred. Therefore, the overhead of information transfer can be reduced. Second Embodiment Subsequently, the second embodiment will be described. The hardware configuration of the information system in the second embodiment is the same as that of the information system (FIG. 1) in the first embodiment. In addition, in the following description, the same reference numerals used in the first embodiment may be used when specifying the same elements as those of the information system according to the first embodiment. The storage system according to the first embodiment and the storage system according to the second embodiment have the following main differences. The flash package according to the first embodiment has a program (duplication elimination determination unit 12300) for determining whether or not deduplication is possible, and by executing the deduplication determination unit 12300, it was determined whether or not duplication elimination was possible based on the information transmitted from the storage controller 200 (list 1, list 2). In contrast, in the storage system according to the second embodiment, the storage controller 200 may include a program (in the second embodiment, this is referred to as “deduplication determination unit 12300’) for executing the same processing as the deduplication determination unit 12300 described in the first embodiment. Then, the storage controller 200 may execute the deduplication determination unit 12300′, thereby determining whether or not deduplication is possible. Conversely, the flash package according to the second embodiment does not have the deduplication determination unit 12300. Subsequently, the difference between the management information possessed by the storage system according to the first embodiment and the management information possessed by the storage system according to the second embodiment will be described. Unlike the flash package according to the first embodiment, the flash package 230 according to the second embodiment does not have the hash index information 3500. Instead, in the storage system according to the second embodiment, the storage controller 200 manages the hash index information 3500, and the hash index information 3500 is stored in the shared memory 220. Accordingly, in the flash package 230 according to the second embodiment, it is not always necessary to provide a hidden area in the flash volume. In the second embodiment, the format of the hash index information 3500 of the storage controller 200 is the same as that described in the first embodiment. However, in the hash index information 3500 according to the second embodiment, the fact that the address on the shared memory 220 in which the leaf segment 3501 is stored is used as the leaf address 3507, which is a pointer to the leaf segment 3501, is different from the hash index information in the first embodiment (in the hash index information in the first embodiment, the virtual segment address was used as the leaf address). In addition, the flash package 230 according to the second embodiment does not need to have the flash package group information 2300 and the hash value storage information 2400. In contrast, the storage controller 200 according to the second embodiment may have the flash package group information 2300 as in the first embodiment, but it is not necessary for it to have the hash value storage information 2400. In the storage system according to the second embodiment, the storage controller 200 refers to/updates the hash index information 3500. Note that, in the storage system according to the first embodiment, as each flash package 230 had the hash index information 3500, a number of hash index information 3500 equal to the number of flash packages 230 were present in the storage system. In contrast, in the storage system according to the second embodiment, the storage controller 200 only needs to have one hash index information 3500. Also, in the second embodiment, an example will be described in which the hash index information 3500 is stored in the shared memory 220. However, the hash index information 3500 may be stored in the cache memory 210 instead of the shared memory 220. Alternatively, in the storage system according to the second embodiment, the hash index information 3500 may be configured to be stored in a storage area of a storage device such as the flash package 230 or an HDD. Next, the processing executed by the storage controller 200 according to the second embodiment will be described. As described above, the flash package according to the second embodiment differs from the flash package in the first embodiment only in that it does not have the deduplication determination unit 12300, and does not execute the deduplication determination unit 12300. Accordingly, the description of the processing executed by the flash package according to the second embodiment will be omitted. The storage controller 200 according to the second embodiment stores at least a read processing execution unit 4000, a write request receiving unit 4100, a write-after processing execution unit 4200, a deduplication scheduling unit 4300′, and a deduplication determination unit 12300′ in the memory 270 (not shown). The read process execution unit 4000, the write request receiving unit 4100, and the write-after process execution unit 4200 are the same programs as those described in the first embodiment. That is, when receiving a write request or read request from the host 110, the processing performed by the storage system 100 according to the second embodiment is the same as that described in the first embodiment. The deduplication scheduling unit 4300′ is a program similar to the deduplication schedule section 4300 described in the first embodiment, but there are minor differences. These differences will be primarily explained below. A flow of processing performed by the deduplication scheduling unit 4300′ will be described with reference to FIG. 38. Steps 12000 and 12001 are the same as those described in the first embodiment (Step 12000 to Step 12001 in FIG. 26). Accordingly, the explanation thereof is omitted herein. After Step 12001 is completed, the deduplication scheduling unit 4300′ then executes Step 12003′. Step 12003′: This step is a substitute for the Step 12003 explained in the first embodiment. In Step 12003′, the deduplication scheduling unit 4300′ makes a determination as to whether deduplication is possible or not using the list 1 and the list 2 created in Step 12001. At this time, the deduplication scheduling unit 4300′ determines whether or not deduplication is possible by calling the deduplication determination unit 12300′. The deduplication determination unit 12300′ performs the same processing as that of the deduplication determination unit 12300 described in the first embodiment to determine whether or not to delete old data (pre-update data), to determine whether deduplication of update data is possible or not, and outputs the erasure candidates and the duplications candidate (similar to that described in the first embodiment). After Step 12003′, the deduplication scheduling unit 4300′ executes Steps 12004 to 12007. Steps 12004 to 12007 are the same as the Steps 12004 to 12007 described in the first embodiment, so the description thereof will be omitted herein. Subsequently, the flow of processing of the deduplication determination unit 12300′ will be described. The main difference between the deduplication determination unit 12300 described in the first embodiment and the deduplication determination unit 12300′ in the second example is that the deduplication determination unit 12300′ is executed by the processor 260 of the storage controller 200. As the processing flow of the deduplication determination unit 12300′ is the same as the processing flow of the deduplication determination unit 12300 described in the first embodiment, illustration of the flowchart thereof is omitted here, description will be performed with reference to FIG. 37 used in the first embodiment. Also, the following description will focus on the differences between the processing of the deduplication determination unit 12300′ from the processing of the deduplication determination unit 12300 described in the first embodiment. The deduplication determination unit 12300′ starts processing based on a trigger of being called by the deduplication scheduling unit 4300′. At this time, the deduplication determination unit 12300′ receives the list 1 and the list 2 from the deduplication schedule unit 4300′. In the first embodiment, the deduplication schedule unit 4300 divided the list 1 and the list 2 (based on the hash values) and transmitted the divided list 1 and the divided list 2 to the deduplication determination unit 12300 of the flash package 230. The deduplication scheduling unit 4300 according to the second embodiment does not divide the list 1 and the list 2. Accordingly, at this time, the deduplication determination unit 12300′ receives the undivided lists 1 and 2 from the deduplication scheduling unit 4300′. The processing performed after the deduplication determination unit 12300′ receives the list 1 and the list 2, particularly the Steps 17000 and 17001 of FIG. 37, are substantially similar to those described in the first embodiment. Note that, in Steps 17000 and 17001, the hash index information 3500 may be updated, but in the second embodiment, as the hash index information 3500 is stored in the shared memory 220, it is unnecessary to perform processing such as reading the contents of the leaf segment 3501 from the virtual segment (or the real segment assigned to it) to the buffer and writing the updated contents on the buffer to the virtual segment as in the deduplication determination unit 12300 of the first embodiment, which differs from that described in the first embodiment. As a result of execution of Step 17000 and Step 17001, erasure candidates and duplication candidates are generated. The deduplication determination unit 12300 in the first embodiment returns the erasure candidates and the duplication candidates (from the flash package 230) to the storage controller 200 after the end of Step 17001, but the deduplication determination unit 12300′ in the second embodiment transmits the generated erasure candidates and duplication candidates to the calling program (deduplication scheduling unit 4300′). Thereafter, the deduplication determination unit 12300′ terminates the processing. By performing the above processing, the storage system according to the second embodiment can perform deduplication processing similarly to the storage system according to the first embodiment. Third Embodiment FIG. 39 illustrates a hardware configuration of the information system according to the third embodiment. The information system according to the third embodiment includes a plurality of real storage systems (100-1, 100-2 . . . ), one or more hosts 110, and a SAN 120 that connects them. The hardware configuration of each real storage system (100-1, 100-2 . . . ) is the same as that of the storage system 100 described in the first or second embodiments, and includes at least one storage controller 200, a cache memory 210, a shared memory 220, a flash package 230, and one or more connecting devices 250 connecting these elements (these elements are not shown in FIG. 39). In the following description, when collectively referring to each real storage system (100-1, 100-2 . . . ), it is referred to as “real storage system 100”. In FIG. 39, an element 190 of the real storage system 100 is a communication interface for connecting the real storage system 100 to the SAN 120. In the present embodiment, this is called a “port”. Each real storage system 100 may include one or more ports 190. The port 190 is used by the real storage system 100 to transmit and receive data to and from the host 110 and the other real storage system 100. The real storage system 100 according to the third embodiment may transmit and receive data and requests between the real storage systems 100, and the real storage system 100 transmits and receives data and requests via the port 190 at that time. The storage system according to the first embodiment or the second embodiment also has a port, but the description of the port is omitted in the first and second embodiments. Further, the information system according to the third embodiment may include a storage management server 180, and the storage management server 180 is connected to each real storage system 100 via a local area network (LAN) 130. The real storage system 100 according to the third embodiment may have the same function as the function of the storage system 100 according to the first embodiment. Therefore, as described in the first embodiment, the real storage system 100 may define one or more logical volumes and provide them to the host 110 or the like. The fact that the real storage system 100 divides and manages the storage space of each logical volume into a plurality of virtual pages, and the fact that the real page is formed from the area of the flash package group 280 and the real pages are allocated to the virtual page are the same as in the first embodiment. In addition to the functions of the storage system 100 according to the first embodiment, the real storage system 100 according to the third embodiment also has a function of using (sharing) the storage areas of the respective real storage systems 100 with each other. Accordingly, in the third embodiment, the collection of the real storage systems 100 that can use this storage area with each other are referred to as a “virtual storage system 1000”. The virtual storage system 1000 may be defined, for example, by a user (administrator) of the information system. When the administrator determines the set of the real storage systems 100 belonging to one virtual storage system 1000, the storage management server 180 is used to notify each real storage system 100 of a set of identification numbers (for example, manufacturing numbers, etc.) of the real storage systems 100 that are to belong to one virtual storage system 1000. By receiving this information, each real storage system 100 can recognize each real storage system 100 that will belong to the virtual storage system 1000. One example of a configuration in which each real storage system 100 shares storage areas with each other is a configuration in which deduplication is performed across a plurality of real storage systems 100. In the following, an example of a configuration in which deduplication is performed across a plurality of real storage systems 100 will be described with reference to FIG. 18, which was used also in the first embodiment. It is assumed that the flash package 230-A shown in FIG. 18 is mounted in the real storage system 100-1, while the real storage system 100-2 is equipped with the flash package 230-B. It is assumed that the same data as the data written in the virtual segment #x of the flash package 230-A is written in the virtual segment #y of the flash package 230-B. In this case, the real segment in the flash package 230-B is once allocated to the virtual segment #y of the flash package 230-B, and the written data is stored in the allocated actual segment. In the subsequent deduplication process, the flash package 230-B stores the virtual segment address of the virtual segment #x of the flash package 230-A in the new virtual segment pointer (3205) of the virtual segment #y, such that the virtual segment #y is made to refer to the virtual segment #x. Then, the real segment that was previously allocated to the virtual segment #y can no longer be allocated to the virtual segment #y (however, as described in the first embodiment, in the case that there is another virtual segment referring to the virtual segment #y in the virtual storage system 1000, the address of the real segment is evacuated to the erasure prevention address 3208 of the virtual segment #y (or old virtual segment pointer 3210), and the state where the real segment is allocated to the virtual segment #y is maintained). Subsequently, when the host 110 issues a read request including the virtual segment #y in the read target range, data is read out from the flash package 230-A having the virtual segment #x and returned to the host 110. This process will be described later. As described above, the deduplication across the plurality of real storage systems 100 is performed in the virtual storage system 1000 according to the third embodiment, such that it can be anticipated that the efficacy of reducing the data amount will be greater than the storage systems according to the first or second embodiments. As another example in which each real storage systems 100 share a storage area with each other, there may be a configuration in which each real storage system 100 shares real pages. For example, the real storage system 100-1 may have a function of allocating a real page of the real storage system 100-2 to the virtual page of the logical volume defined by the real storage system 100-1, such that when the write data for the virtual page of the logical volume defined by the real storage system 100-1 is received from the host 110, the write data may be stored in the real page of the real storage system 100-2. However, as this function is not directly related to deduplication processing, the description of this function is abbreviated herein. Also in the following description, explanation will be made assuming that the real storage system 100 does not have this function. Next, the management information possessed by the real storage system 100 according to the third embodiment will be described. First, the real storage system 100 retains at least the management information (management information depicted in FIG. 5) described in the first embodiment in the shared memory 220. In addition to this, the real storage system 100 also retains information (storage system information 2700 to be described later) regarding each real storage system 100 in the virtual storage system 1000 in the shared memory 220. The contents of the storage system information 2700 will be described with reference to FIG. 40. The storage system information 2700 is a set of the information of the flash packages 230 of each real storage system 100 in the virtual storage system 1000 and information of the ports of each real storage system 100. Also, a set of information for a flash package 230 possessed by one real storage system 100 in the virtual storage system 1000 and port information is referred to as “real storage system information 2710”. The storage system information 2700 includes real storage system information 2710 of all the real storage systems 100 in the virtual storage system 1000. The contents of the real storage system information 2710 will be described with reference to FIG. 40. The real storage system information 2710 includes a real storage system ID 2711, a port address 2712, and a flash package ID 2713. The real storage system ID 2711 is an identification number (for example, a manufacturing number or the like) of the real storage system 100. The port address 2712 may be an identifier of a port possessed by the real storage system 100 and is, for example, an N_Port ID or WWN (World Wide Name). The real storage system 100 according to the third embodiment may issue a data transmission/reception request (a request such as an external package read request to be described later) to another real storage system 100 via the SAN 120. At this time, it issues an access request designating the port of the real storage system 100 that is the target of the request transmission. Port address 2712 is used for that purpose. When the real storage system 100 includes a plurality of ports, a plurality of port addresses 2712 may be stored in the real storage system information 2710. The flash package ID 2713 is the package ID of the flash package 230 of the real storage system 100. Typically, the real storage system 100 is equipped with a plurality of flash packages 230. Package IDs for all the flash packages 230 of the real storage system 100 are stored in the real storage system information 2710. Note that, in the virtual storage system 1000 according to the third embodiment, an identifier unique within the virtual storage system 1000 is used as the package ID for each flash package 230. The storage system information 2700 is information that all the real storage systems 100 in the virtual storage system 1000 have. The contents of the storage system information 2700 of each real storage system 100 in the virtual storage system 1000 are the same. Subsequently, the hash value storage information 2400 included in the real storage system 100 according to the third embodiment will be described. However, since the format of the hash value storage information 2400 is the same as that described in the first embodiment (FIG. 11), the figure illustration thereof is omitted herein. In the virtual storage system 1000 according to the third embodiment, similarly to the first embodiment, each flash package 230 makes a determination as to whether or not deduplication is possible, and the hash values are stored in the flash package 230 (as described in the first embodiment, the hash values are stored in the leaf segment 3501 in the hash index information 3500). Also, as in the first embodiment, the ranges of the hash values assigned to each flash package 230 are different for each flash package 230. As with the hash value storage information 2400 described in the first embodiment, the hash value storage information 2400 of the virtual storage system 1000 according to the third embodiment stores information regarding the range of the hash values handled by each flash package 230. As in the first embodiment, in the virtual storage system 1000 according to the third embodiment, the hash value storage information 2400 may be stored in the shared memory 220 of each real storage system 100 and the package memory 320 of each flash package 230. The format of the hash value storage information 2400 according to the third embodiment is the same as that described in the first embodiment, and a plurality of sets of the hash range 2401 and the flash package ID 2402 are included. The difference between the hash value storage information 2400 of the real storage system 100 according to the third embodiment and the hash value storage information 2400 of the storage system 100 according to the first embodiment is that, although the hash value storage information 2400 included in the storage system 100 according to the first embodiment includes only the information of the hash value assigned to each flash package in the storage system 100, the hash value storage information 2400 included in the real storage system 100 according to the third embodiment includes information on hash values assigned to all the flash packages 230 of each real storage system in the virtual storage system 1000. Next, the management information possessed by the flash package 230 will be described. The type of management information possessed by the flash package 230 according to the third embodiment is the same as the management information (FIG. 12) possessed by the flash package 230 according to the first embodiment. Also, the format of each set of management information is the same between the first embodiment and the third embodiment. However, the management information possessed by the flash package 230 according to the first embodiment and the management information possessed by the flash package 230 according to the third embodiment have the following differences. The flash package 230 according to the first embodiment retains the flash package group information 2300 of all the flash package groups 280 in the storage system 100, but the flash package 230 according to the third embodiment retains the flash package group information 2300 of all the flash package groups 280 managed by each real storage system 100 in the virtual storage system 1000. Subsequently, the processing executed by the storage controller 200 and the flash package 230 in the virtual storage system 1000 according to the third embodiment will be described. First, the processing performed by the storage controller 200 will be described. The main program executed by the storage controller 200 according to the third embodiment includes a read processing execution unit 4000′, a write request receiving unit 4100, a write-after processing execution unit 4200, a deduplication scheduling unit 4300″, and an external package read execution unit 4400 (not shown). As the write request receiving unit 4100 and the write-after process execution unit 4200 are the same as those described in the first embodiment, the description thereof is omitted herein. Similar to the read processing execution unit 4000 described in the first embodiment, the read processing execution unit 4000′ is a program executed when a read request is received from the host 110. The deduplication scheduling unit 4300″ is a program that performs the same processing as the deduplication scheduling unit 4300 described in the first embodiment. The external package read execution unit 4400 is a program executed when the real storage system 100 receives a request (external package read request) from another real storage system. Hereinafter, a flow of processing executed by the read processing execution unit 4000′, the deduplication scheduling unit 4300″, and the external package read execution unit 4400 will be described. First, the processing flow of the read processing execution unit 4000′ in the third embodiment will be described with reference to FIG. 41. In the virtual storage system 1000 according to the third embodiment, the real storage system 100 that has received the read request from the host 110 may issue a request (external package read request) to another real storage system 100 in the virtual storage system 1000. In the following description, the real storage system 100 that has received the read request from the host 110 is referred to as “real storage A”, and the real storage system 100 to which the real storage A issues the external package read request is referred to as “Real storage B”. Each step shown in FIG. 41 is a process executed by the read processing execution unit 4000′ of the real storage system 100 (that is, real storage A) that has received a read request from the host 110. Accordingly, in the following explanation, this indicates that the locations described with the read processing execution unit 4000′ as the subject are the processes executed by the real storage A. The read processing execution unit 4000′ may execute Steps 50091 to 50093 instead of Step 5009, which was performed in the read processing execution unit 4000 in the first embodiment. The other processes (Step 5000 to Step 5007, Step 5008, Step 5010, Step 5011) are the same as those described in the first embodiment. Hereinafter, Steps 50091 to 50093 will be primarily described. In Step 5006, when a response indicating that data was deduplicated is returned from the flash package 230 of the real storage A to the storage controller 200 of the real storage A (Step 5007: Yes), the read processing execution unit 4000′ performs Step 50091. As described in the first embodiment, the response indicating that the data was deduplicated may include a set of the virtual segment address and the hash value. In Step 50091, the read processing execution unit 4000′ may determine, by referring to the storage system information 2700, whether the virtual segment address included in the response indicating that the data was deduplicated is a virtual segment address of a flash package 230 of the real storage A or a virtual segment address of a flash package 230 of another real storage system 100. As the package ID of the flash package 230 is included in the virtual segment address, the read processing execution unit 4000′ can determine, by ascertaining which of the real storage system information 2710 of the storage system 2700 the package ID in the virtual segment address included in the response is included in, to which virtual segment address of the flash package 230 of the real storage system 100 the virtual segment address belongs. If the virtual segment address included in the response is the virtual segment address of the flash package 230 possessed by the real storage A (Step 50091: No), the read processing execution unit 4000′ may issue a hash designation read request to the flash package 230 of the real storage A (Step 50092). Step 50092 is the same processing as that of Step 5009 described in the first embodiment. Thereafter, the read processing execution unit 4000′ may execute Step 5010, Step 5008, and Step 5011, and end the process. When the virtual segment address included in the response is the virtual segment address of the flash package 230 of a real storage system 100 other than the real storage A (for example, real storage B) (Step 50091: Yes), the read processing execution unit 4000′ requests the real storage B to acquire the data in the flash package 230 (Step 50093). The request issued here is called “external package read request”. In Step 50093, the read process execution unit 4000′ may issue the external package read request to the real storage B via the SAN 120. The information included in the external package read request are the virtual segment address, the hash value, and the port address of the real storage system 100 (real storage B). The processing performed in Step 50093 will be described in detail. In the following description, an example of a case will be described where the package ID (included in the virtual segment address) included in the response indicating that the data was deduplicated is “p”. The read processing execution unit 4000′ may identify the real storage system information 2710 whose flash package ID 2713 is “p” from among the real storage system information 2710 in the storage system information 2700. Subsequently, the read processing execution unit 4000′ acquires the port address 2712 included in the identified real storage system information 2710. Further, the read processing execution unit 4000′ creates an external package read request using the acquired port address 2712, the virtual segment address, and the hash value included in the response indicating that the data is deduplicated, and sends the external package read request to the real storage B via the SAN 120. Details of the processing performed in the real storage system 100 (real storage B) that has received the external package read request will be described later. Thereafter, the read processing execution unit 4000′ waits until the response (response including the read data) is returned from the real storage B (step 5010). When the response is returned, the read processing execution unit 4000′ may execute Steps 5008 and 5011 and end the processing. Subsequently, the flow of processing performed in the real storage system 100 that has received the external package read request will be described with reference to FIG. 42. Upon receiving the external package read request, the real storage system 100 initiates execution of the external package read execution unit 4400. Step 8001: The external package read execution unit 4400 may check whether the read target data designated by the external package read request is stored in the cache memory 210 (hit). This is a known technique. If it is hit (Step 8001: Yes), the external package read execution unit 4400 returns the data stored in the cache memory 210 to the real storage system 100 of the request source (Step 8005), and ends the processing. If it is not hit (Step 5001: No), then step 8002 is performed. Step 8002: This processing is similar to the Step 5009 described in the first embodiment. The external package read execution unit 4400 creates a hash designation read request using the virtual segment address and the hash value designated by the external package read request, and issues the created hash designation read request to the flash package 230 in which the read target data is stored. Since the package ID of the flash package 230 in which read target data is stored is stored in the virtual segment address specified by the external package read request, the external package read execution unit 4400 can specify the flash package 230 of the request issue destination. Step 8003: The external package read execution unit 4400 waits for data to be sent from the flash package 230. Step 8004: The external package read execution unit 4400 may reserve an area for storing the read target data in the cache memory 210, and store the data sent from the flash package 230 in the reserved area. Step 8005: The external package read execution unit 4400 returns the data stored in the cache memory 210 to the real storage system 100 of the request source, and the processing is completed. Next, the processing flow of the deduplication scheduling unit 4300″ will be described. The deduplication scheduling unit 4300″ is a program executed by all the real storage systems 100 included in the virtual storage system 1000. In the third embodiment, execution of the deduplication scheduling unit 4300″ is initiated simultaneously in each real storage system 100 included in the virtual storage system 1000. For example, the storage management server 180 may periodically transmit a command instructing the start of execution of the deduplication scheduling unit 4300″ to all the real storage systems 100 in the virtual storage system 1000, and each real storage system 100 may initiate execution of the deduplication scheduling unit 4300″ according to the instruction from the storage management server 180. Alternatively, a particular one of the real storage systems 100 may periodically send an instruction instructing the start of execution of the deduplication scheduling units 4300″ to all the real storage systems 100 in the virtual storage system 1000. FIG. 43 illustrates a processing flow of the deduplication scheduling unit 4300″ executed by a specific one of the real storage systems 100 in the virtual storage system 1000 (hereafter, this will be referred to as “real storage A”). Steps 12000 to 12002 are the same as the processing of the deduplication scheduling unit 4300 described in the first embodiment (FIG. 26), so the description thereof will be omitted herein. Step 12021: The deduplication schedule section 4300″ of the real storage A transmits those items that should be sent to another real storage system 100 from among the list 1 and the list 2 created and divided in the Steps 12001 to 12002 to the other real storage systems 100. In the following description, as in the first embodiment, the set of records determined in Step 12002 to be transmitted to the flash package #f among the records in the list 1 will be denoted as “list 1-f”, and similarly, the set of records determined in Step 12002 to be sent to the flash package #f from among the records in list 2 will be denoted as “list 2-f”. In addition, in the explanation of FIG. 43, an example is described in Step 12021 in which the deduplication scheduling unit 4300″ of the real storage A transmits the list 1-f and the list 2-f to the real storage system 100 having the flash package #f. By referring to the storage system information 2700, the deduplication scheduling unit 4300″ of the real storage A may identify the port address 2712 of the real storage system 100 having the flash package #f, and transmit the list 1-f and the list 2-f to the port address 2712 of the identified real storage system 100. The transmission of the list 1-f and the list 2-f is performed via the SAN 120. However, as another embodiment, the list 1-f and the list 2-f may be transmitted via the LAN 130. Note that, in Step 12002, as a result of the deduplication scheduling unit 4300″ of the real storage A creating the divided lists 1 and 2, there may be cases where, for example, there are no records of list 1 (or records of list 2) to be sent to a particular real storage system 100 (hereinafter referred to as “actual storage C”). In such a case, the deduplication scheduling unit 4300″ of the real storage A may create one record in which invalid values (NULL) are stored in the virtual segment address 3402 and the (pre-update) hash value 3403 in Step 12021, and transmit the created record to the real storage C. When there are no records for list 1 (or records for list 2) to be sent to the real storage C, if the real storage A does not send anything to the real storage C, the real storage C cannot determine whether there are no records for list 1 (or records for list 2) to be sent from the real storage A to the real storage C, or if the records transmitted from the real storage A failed to reach the real storage C due to a failure or the like. Accordingly, when there are no records for list 1 (or records for List 2) to be sent to the real storage C, the real storage A creates a record in which invalid values (NULL) are stored and transmits it to the real storage C. Step 12022: The deduplication scheduling unit 4300″ of the real storage A waits until all the real storage systems 100 (excluding real storage A) in the virtual storage system 1000 receive the divided lists 1 and 2. Then, after the deduplication scheduling unit 4300″ of the real storage A receives the divided lists 1 and 2 from all the real storage systems 100 in the virtual storage system 1000, it then executes Steps 12003 to 12005. As Steps 12003 to 12005 are the same as the processing described in the first embodiment, the description thereof will be omitted herein. However, in the third embodiment, when the deduplication scheduling unit 4300″ of the real storage A transmits the list 1 and the list 2 divided in Step 12003 to each flash package 230, in addition to list 1 and list 2 (the list 1 and list 2 created and divided in Steps 12001, 12002) created in the real storage A, the list 1 and the list 2 received from the other real storage system 100 in Step 12022 are also transmitted to the flash package 230. Also, in the following description, the set of records to be transmitted to the flash package #f among the records included in the erasure candidates received from each flash package 230 in Step 12003 is referred to as “erasure candidates-f” as in the first embodiment. Likewise, the set of records to be transmitted to the flash package #f among the records in the duplication candidates is referred to as “duplication candidates-f”. Step 12051: The deduplication scheduling unit 4300″ of the real storage A selects the items that should be sent to another real storage system 100 from among the erasure candidates and duplication candidates classified in Steps 12004 to 12005, and transmits them to another real storage system 100. Similar to Step 12021, the deduplication scheduling unit 4300″ of the real storage A refers to the storage system information 2700 to identify the port address 2712 of the real storage system 100 having the flash package #f, and transmits the erasure candidates-f and the duplication candidates-f to the identified real storage system 100. Note that in some cases there may be no erasure candidate records (or duplication candidate records) to be transmitted to a particular real storage system 100 (provisionally referred to as “real storage C”). In that case, the deduplication scheduling unit 4300″ creates one record in which an invalid value (NULL) is stored, for example, in the virtual segment addresses 3601 (or the virtual segment addresses 3701) as in the method described in Step 12021, and the record in which these invalid values are stored is transmitted to the real storage C. Step 12052: The deduplication scheduling unit 4300″ of the real storage A receives the classified erasure candidates and duplication candidates from the other real storage systems 100 in the virtual storage system 1000. Thereafter, the deduplication scheduling unit 4300″ of the real storage A executes Steps 12006 to 12007. Steps 12006 to 12007 are substantially similar to the processing described in the first embodiment. In the third embodiment, however, in Step 12006, in addition to transmitting the erasure candidates and the duplication candidates created in the real storage A to the flash package 230, the deduplication schedule section 4300″ of the real storage A transmits the erasure candidates and the duplication candidates received from the other real storage systems 100 to the flash package 230. Note that, as the processing executed in the flash package 230 according to the third embodiment is substantially similar to that described in the first embodiment, the description of the processing executed in the flash package 230 will be omitted herein. The above is the description of the processing executed in the virtual storage system 1000 in the third embodiment. In the virtual storage system 1000 according to the third embodiment, by performing the above-described processing, deduplication of a plurality of real storage systems 100 may become possible. Fourth Embodiment Subsequently, the fourth embodiment will be described. As the hardware configuration of the information system in the fourth embodiment is the same as that of the information system in the third embodiment, the figure illustration thereof is omitted herein. Also, in the following description, the same reference numerals used in the third embodiment are used when specifying the same elements as those of the information system according to the third embodiment. As in the virtual storage system according to the third embodiment, the virtual storage system according to the fourth embodiment performs deduplication across a plurality of real storage systems 100. However, in the virtual storage system (or the real storage system) according to the fourth embodiment, the storage controller 200 performs a portion of the processing that was performed in the flash package according to the third embodiment (or the first embodiment). The flash package according to the first or third embodiment included a program (deduplication determination unit 12300) for determining whether or not deduplication processing was possible, and performed the deduplication possibility determination based on the information (list 1, list 2) sent from the storage controller 200. In contrast, as in the storage system described in the second embodiment, the storage controller 200 of the fourth embodiment determines whether or not deduplication processing can be performed. Accordingly, the storage controller 200 may include a program similar to the deduplication determination unit 12300′ described in the second embodiment (in the fourth embodiment, this was referred to as deduplication determination unit 12300″). Conversely, the flash package according to the fourth embodiment does not include the deduplication determination unit 12300. Similar to the flash package 230 according to the second embodiment, the flash package 230 according to the fourth embodiment does not include the hash index information 3500. Instead, in the virtual storage system according to the fourth embodiment, each real storage system 100 in the virtual storage system has the hash index information 3500 in its shared memory 220. Further, the flash package 230 according to the fourth embodiment need not include the flash package group information 2300 and the hash value storage information 2400. In contrast, the real storage system 100 according to the fourth embodiment may include the flash package group information 2300 in the shared memory 220. However, the real storage system 100 also retains the flash package group information 2300 of the flash package group 280 possessed by other real storage systems 100 in the virtual storage system 1000. In addition, the real storage system 100 according to the fourth embodiment may include hash value storage information 2400′ instead of the hash value storage information 2400 described in the first embodiment and the like. The format of the hash value storage information 2400′ will be described with reference to FIG. 44. In the hash value storage information 2400 described in the first embodiment and the like, information regarding the range of the hash values assigned to each flash package 230 was stored. In contrast, the hash value storage information 2400′ stores information regarding the range of hash values handled by each real storage system 100. It should be noted that the meaning (definition) of “hash values handled by the real storage system 100” is the same as “hash value handled by the flash package”. For example, when the real storage system #p (the real storage system 100 having the identification number p) determines whether deduplication is possible for a virtual segment whose hash value ranges are from a to b, this is expressed as “the range of the hash values handled by the real storage system #p is a to b”. The hash value storage information 2400′ has a plurality of sets of a hash range 2401′ and a real storage system ID 2402′. Here, the set of the hash range 2401′ and the real storage system ID 2402′ is referred to as an extent 2410′. For example, in a case that the hash value range stored in the hash range 2401′ in a certain extent 2410′ is a to b and the real storage system ID 2402′ in the extent 2410′ is p, this means that the range of the hash value handled by the real storage system #p is a to b, and when performing the deduplication possibility determination described later, the real storage system #p determines whether or not deduplication is possible for virtual segments having hash value ranges from a to b. Also in this case, the range of the hash values stored in the hash index information 3500 created and managed by the real storage system #p is a to b. The hash value storage information 2400′ is information stored in the shared memory 220 of all the real storage systems 100 in the virtual storage system 1000. Also, the content of the hash value storage information 2400′ of each real storage system 100 is the same. Next, the processing executed by the storage controller 200 according to the fourth embodiment will be described. Note that the flash package according to the fourth embodiment is the same as the flash package according to the second embodiment. That is, the flash package according to the fourth embodiment is different from the flash package in the first or third embodiments only in that it does not have the deduplication determination unit 12300 and does not execute the deduplication determination unit 12300. Accordingly, the description of the processing executed by the flash package according to the fourth embodiment will be omitted herein. The storage controller 200 according to the fourth embodiment includes at least a read processing execution unit 4000′, a write request receiving unit 4100, a write-after processing execution unit 4200, a deduplication scheduling unit 4300′″, an external package read execution unit 4400, and a deduplication determination unit 12300′ (not shown). Both the read process execution unit 4000′ and the external package read execution unit 4400 are the same as those described in the third embodiment. The write request receiving unit 4100 and the write-after process executing unit 4200 are the same as those described in the first embodiment and the like. The deduplication determination unit 12300′ is the same as that described in the second embodiment. For this reason, the description thereof will be omitted herein. The processing flow of the deduplication schedule section 4300′″ will be described with reference to FIG. 45. Steps 12000 and 12001 are the same as the processing from Step 12000 to Step 12001 in FIG. 26, so the description thereof will be omitted herein. Step 12002′: The deduplication schedule section 4300′″ refers to the hash value storage information 2400′ to divide the information in the list 1 and the information in the list 2 into information to be transmitted to each real storage system 100. An example of an information division method using hash value storage information 2400′ will be described below. For example, consider that there is an extent 2410′ in which the real storage system ID 2402′ is “f” and the hash range 2401′ is a to b in the hash value storage information 2400′. In this case, in the record of list 1, the record in which the (pre-update) hash value 3403 is included in the range of a to b is extracted and determined to be the information to be transmitted to the real storage system #f. Each record in list 2 is also divided in the same way. In the following description, among the records in the list 1, the set of records determined to be transmitted to the real storage system #f in step 12002′ is denoted as “list 1-f”. Likewise, the set of records determined to be transmitted to the real storage system #f among the records in the list 2 will be referred to as “list 2-f”. Step 12021′: The deduplication schedule section 4300′″ sends the items that should be sent to another real storage system 100 from among the list 1 and the list 2 divided in the Step 12002′ to another real storage system 100. This process is the same as the process described in the third embodiment (Step 12021). Note that, as in the third embodiment, if there is no divided list 1 (or list 2) to be transmitted to another real storage system 100, the deduplication schedule unit 4300′″ creates a record in which an invalid value (NULL) is stored, and transmits it to another real storage system 100. Step 12022′: Deduplication schedule section 4300′″ receives the divided list 1 and divided list 2 from the other real storage system 100. Upon receiving the divided list 1 and the divided list 2 from all the real storage systems 100 in the virtual storage system, the deduplication scheduling unit 4300′″ then executes Step 12003″. Step 12003″: The processing performed in this step is the same processing as that of Step 12003′ described in the second embodiment. In step 12003″, the deduplication scheduling unit 4300′″ uses the list 1 and list 2 it created as well as the list 1 and list 2 received from other real storage systems 100 to perform the deduplication possibility determination. At this time, the deduplication scheduling unit 4300′″ calls the deduplication determination unit 12300′ to perform the deduplication possibility determination. As the content of the processing performed by the deduplication determination unit 12300′ is the same as that described in the second embodiment, the description thereof is omitted herein. As Steps 12004 to 12005 are the same as the processing described in the first embodiment (Steps 12004 to 12005 in FIG. 26), the description thereof will be omitted herein. Step 12051, Step 12052: As this processing is the same as Step 12051 and Step 12052 described in the third embodiment, the description thereof will be omitted herein. After step 12052, the deduplication scheduling unit 4300′″ executes Step 12006 and Step 12007, and ends the process. As Steps 12006 and 12007 are the same as those described in the first embodiment and the like, the description thereof will be omitted herein. The above is the processing flow of the deduplication scheduling unit 4300′″. Although the embodiments of the present invention have been described above, these are examples for explaining the present invention, and the scope of the present invention is not limited to these examples. That is, the present invention can be implemented in a variety of other forms. For example, in the above-described embodiments, although an example was described in which the flash package has a function for performing deduplication processing or the like, a configuration in which an HDD is provided in the storage system instead of the flash package, and the HDD may perform each process that was performed by the flash package in the above embodiments. Also, in the above-described embodiments, an example was described in which the hash value assigned to a certain flash package is stored only in the flash package (hash index information). However, as another embodiment, in order to increase availability, a copy of the hash index information created in a certain flash package may be stored in another flash package. For example, each time a flash package A updates its own hash index information, it may transmit the update information to a flash package B, and a copy of the hash index information managed by the flash package A may be stored in the flash package B. In addition, in the above-described embodiment, explanation was performed on the premise that all the data was included as deduplication targets. However, for data with low probability of deduplication such as RAID redundant data, it is preferable not to perform deduplication determination, and so the processing of the above-described embodiments may be modified as such. For example, when the storage controller 200 writes redundant data to the flash package 230, it may attach information to the write request indicating that deduplication is not required (hereinafter simply referred to as a “flag”). For the virtual package, the flash package 230 may prepare an area for storing the fact that the flag is received for each virtual segment in the virtual block group information 3200. In response to receiving the flag at the time of receiving the write request, the flash package 230 may record the flag in the virtual segment management information in the virtual block group information 3200, and need not calculate the hash value of the data at the time of executing Step 14001. Then, the deduplication determination unit 12300 and the deduplication execution unit 12400 need not perform the deduplication determination or the like on the virtual segment in which the flag is stored. REFERENCE SIGNS LIST 100: storage system, 110: host, 120: storage area network (SAN), 200: storage controller, 210: cache memory, 220: shared memory, 230: flash package, 250: connecting device, 260: processor, 270: memory, 280: flash package group, 300: flash chip, 310: package processor, 320: package memory, 330: buffer, 340: package bus, 350: package bus transfer device, 370: hash circuit, 2000: logical volume information, 2100 : real page information, 2300: flash package group information, 2400: hash value storage information, 2500: flash package 3000: package information, 3100: chip information, 3200: virtual block group information, 3300: real block information, 3400: historical information, 3500: hash index information, 3600: free real block information pointer, 4000: read processing execution unit, 4100: write request receiving unit, 4200: write-after processing execution unit, 4300: deduplication scheduling unit, 12100: data write processing execution unit, 12200: historical information transmission unit, 12300: deduplication determination unit, 12400: deduplication execution unit, 12500: hash specification read execution unit, 12600: data read processing execution unit | <SOH> BACKGROUND ART <EOH>As storage devices that make use of flash memory as a storage medium are overwhelmingly faster than HDDs and the like, they are rapidly gaining in popularity in recent years as bit costs decrease. In addition, conventional storage systems have utilized a plurality of storage devices, such as HDDs, in order to achieve high reliability and high performance. Accordingly, it is common for pluralities of storage devices that use flash memory as a storage medium to be utilized in storage systems, and for storage controllers to control these storage devices that use flash memory as a storage medium. In addition, some storage devices that use flash memory as a storage medium have form factors and interfaces compatible with HDDs. These are referred to as SDDs. In contrast, there are also devices that do not have compatibility with HDDs. The present invention is directed to both types, and is hereinafter referred to as a flash package. As the bit cost of flash memory is higher than that of magnetic disks or the like, there is a need to reduce the stored data capacity and increase the apparent capacity. In storage systems, a deduplication technique is one technique for reducing data storage capacity. In this technique, the storage controller checks whether multiple sets of data with the same contents are stored in the storage system. In the case that there is a plurality of sets of data with the same content (duplicate data), only one of them is left in the storage system and the remaining data is deleted. In this way, the amount of data stored in a storage device may be reduced. For example, Patent Document 1 discloses a deduplication technique in a storage device having a plurality of flash memory modules mounted therein. The storage device disclosed in Patent Document 1 is equipped with a plurality of storage devices called flash memory modules. In addition, the storage device disclosed in Patent Document 1 divides data into data units called stripe units, and distributes and stores the divided data in a plurality of flash memory modules. When deduplication processing is performed, the storage controller performs deduplication on data of a size equal to or larger than a stripe unit with a range extending over a plurality of flash memory modules. Then, the flash memory modules perform deduplication for data of a size equal to or smaller than a stripe unit with respect to the data in the flash memory module. In the technique disclosed in Patent Document 1, as duplication elimination is performed with a range extending over a plurality of storage devices, the effect of reducing the data amount is greater in comparison with cases where deduplication processing targeting only the data of the storage device is performed. In contrast, in recent years, capacity virtualization functions have become widespread in storage systems. A capacity virtualization function is a function for providing a host side with a virtual capacity larger than the physical capacity of the storage devices possessed by the storage system, and in general, is a function possessed by the storage controller in the storage system. This is because when the user actually uses storage, the amount of data actually stored in the user volume with respect to the capacity of the user volume (storage device as seen by the user) defined by the user is based on a characteristic that it does not readily reach the capacity of the user volume. That is, when the capacity virtualization function is not used, the user needs to reserve a physical storage area equal to the capacity of the volume at the time of volume definition. When the capacity virtualization function is used, at the time of volume definition, the user does not necessarily have to prepare a physical storage area corresponding to the capacity of the volume. When a data write actually occurs in the volume, the storage area is allocated to the volume for the first time. As a result, since the capacity of the storage device to be prepared in advance can be reduced, and the user need not strictly define the volume capacity but rather simply define a value having a large margin, usability can be improved. Patent Document 2 discloses a technique of providing a capacity virtualization function not only in a storage controller but also in a flash package in a storage system having a plurality of flash packages. Furthermore, in the storage system disclosed in Patent Document 2, it is also disclosed that the flash package may compress the data. In general, since the compression ratio of data varies depending on the content of data, it is difficult to predict the data size after compression. Also, if the data is updated, the compression ratio naturally changes. For this reason, Patent Document 2 discloses a technique for changing the size (virtual capacity) of the volume provided by the flash package to the storage controller due to the change in the compression rate. | <SOH> SUMMARY OF INVENTION <EOH> | G06F30641 | 20180226 | 20180906 | 99144.0 | G06F306 | 0 | PEUGH, BRIAN R | STORAGE SYSTEM | UNDISCOUNTED | 0 | ACCEPTED | G06F | 2,018 |
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15,756,634 | PENDING | FAN APPARATUS | A fan apparatus has a drive circuit for an electrically-driven rotor, and includes a drive signal generating circuit portion for the electrically-driven rotor; an output stage including an upper MOSFET and a lower MOSFET; and a motor portion to be driven by the output stage. One of the upper MOSFET and the lower MOSFET is a braking MOSFET, while another of the upper MOSFET and the lower MOSFET is a non-braking MOSFET. The fan apparatus further includes a back-electromotive force supply portion arranged to supply, to the braking MOSFET, power by a back-electromotive force caused by rotation of the motor portion while a power supply voltage for the electrically-driven rotor is not being supplied; and an electromagnetic brake portion arranged to electromagnetically brake the motor portion by causing the braking MOSFET to enter an ON state through the power supplied by the back-electromotive force supply portion. | 1. A fan apparatus having a drive circuit for an electrically-driven rotor, the fan apparatus comprising: a drive signal generating circuit portion for the electrically-driven rotor; an output stage including an upper MOSFET and a lower MOSFET; and a motor portion to be driven by the output stage; wherein one of the upper MOSFET and the lower MOSFET is a braking MOSFET, while another of the upper MOSFET and the lower MOSFET is a non-braking MOSFET; and the fan apparatus further comprises: a back-electromotive force supply portion arranged to supply, to the braking MOSFET, power by a back-electromotive force caused by rotation of the motor portion while a power supply voltage for the electrically-driven rotor is not being supplied; and an electromagnetic brake portion arranged to electromagnetically brake the motor portion by causing the braking MOSFET to enter an ON state through the power supplied by the back-electromotive force supply portion. 2. The fan apparatus according to claim 1, further comprising: a power supply voltage monitoring circuit portion arranged to detect whether the power supply voltage is being supplied; a control power supply voltage generation portion arranged to generate a control power supply voltage from the power supply voltage; a diode arranged between a power output terminal of the control power supply voltage generation portion and a gate terminal of the braking MOSFET, and having an anode connected to the power output terminal and a cathode connected to the gate terminal; and a drive circuit arranged to receive supply of the control power supply voltage and a drive signal outputted from the drive signal generating circuit portion, and arranged to drive the gate terminal of the braking MOSFET; wherein the drive signal generating circuit portion is arranged to control the non-braking MOSFET to enter an OFF state when the power supply voltage monitoring circuit portion has detected an interruption of supply of the power supply voltage. 3. The fan apparatus according to claim 1, wherein the back-electromotive force supply portion includes: a parasitic diode in the non-braking MOSFET; a series circuit including a resistor and a back-electromotive force supply diode having one end connected to a cathode of the parasitic diode and another end connected to a ground side of the power supply voltage; and a supply line arranged to supply, to the gate terminal of the braking MOSFET, power supplied to the series circuit through the parasitic diode. 4. The fan apparatus according to claim 3, wherein the back-electromotive force supply portion further includes a constant voltage diode connected between the ground side of the power supply voltage and a point of junction of the series circuit and the supply line. 5. The fan apparatus according to claim 4, wherein a breakdown voltage of the constant voltage diode is determined on a basis of the control power supply voltage generated from the power supply voltage. | BACKGROUND OF THE INVENTION 1. Field of the Invention The present disclosure relates to a fan apparatus. 2. Description of the Related Art A technique of braking a rotation of a motor caused by an external force to reduce the rotation rate thereof has been known. For example, a technique described in JP-A 2013-188000 has been known. However, the technique described in JP-A 2013-188000 requires power to be supplied from an external source to reduce the rotation rate of a motor caused by an external force, and is therefore unable to achieve a reduced power consumption. An embodiment of the present invention has as an object to reduce the rotation rate of a motor caused by an external force while achieving a reduced power consumption. SUMMARY OF THE INVENTION A fan apparatus according to an embodiment of the present disclosure has a drive circuit for an electrically-driven rotor, and includes a drive signal generating circuit portion for the electrically-driven rotor; an output stage including an upper MOSFET and a lower MOSFET; and a motor portion to be driven by the output stage. One of the upper MOSFET and the lower MOSFET is a braking MOSFET, while another of the upper MOSFET and the lower MOSFET is a non-braking MOSFET. The fan apparatus further includes a back-electromotive force supply portion arranged to supply, to the braking MOSFET, power by a back-electromotive force caused by rotation of the motor portion while a power supply voltage for the electrically-driven rotor is not being supplied; and an electromagnetic brake portion arranged to electromagnetically brake the motor portion by causing the braking MOSFET to enter an ON state through the power supplied by the back-electromotive force supply portion. The above and other elements, features, steps, characteristics and advantages of the present disclosure will become more apparent from the following detailed description of the preferred embodiments with reference to the attached drawings. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a diagram illustrating an embodiment of the present disclosure, and is a circuit diagram illustrating an example circuit configuration of a fan apparatus. FIG. 2 is a diagram illustrating example waveforms of drive signals generated by a drive signal generating circuit portion. FIG. 3 is a diagram illustrating example signal waveforms when supply of a power supply voltage is interrupted. FIG. 4 is a diagram illustrating example back-electromotive force supply paths of the fan apparatus. FIG. 5 is a diagram illustrating example waveforms indicative of potential changes caused by a back-electromotive force after an interruption of power supply. FIG. 6 shows a graph representing an example of the rotation rate of a motor portion in the case where a brake is not applied after the interruption of the power supply. FIG. 7 shows a graph representing an example of the rotation rate of the motor portion in the case where a brake is applied after the interruption of the power supply. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, a fan apparatus 100 according to an embodiment of the present disclosure will be described with reference to the accompanying drawings. Note that the scope of the present disclosure is not limited to embodiments described below, but includes any modification thereof within the scope of the technical idea of the present disclosure. FIG. 1 is a circuit diagram illustrating an example circuit configuration of the fan apparatus 100. The fan apparatus 100 includes a regulator circuit portion 1, a drive signal generating circuit portion 2, transistors 3 and 4, transistors 13 and 14, a motor portion 19, a capacitor 20, a diode 21, and an output stage. The output stage includes upper MOSFETs 15 and 16 and lower MOSFETs 17 and 18. Note that, although the output stage is a single-phase full-bridge circuit in this example, this is not essential to the present disclosure. For example, in the case where the motor portion 19 is a three-phase motor, the output stage may be a three-phase full-bridge circuit. In the case where a power supply voltage V is supplied, an electric drive current id1 is supplied to the motor portion 19 when each of the upper MOSFET 15 and the lower MOSFET 18 of the output stage is in an ON state, and each of the upper MOSFET 16 and the lower MOSFET 17 of the output stage is in an OFF state. In addition, in the case where the power supply voltage V is supplied, an electric drive current id2 is supplied to the motor portion 19 when each of the upper MOSFET 15 and the lower MOSFET 18 of the output stage is in the OFF state, and each of the upper MOSFET 16 and the lower MOSFET 17 of the output stage is in the ON state. Each of the upper MOSFETs 15 and 16 is a p-channel MOSFET, which is arranged to enter the OFF state when an H (high) level signal is supplied to a gate terminal thereof, and enter the ON state when an L (low) level signal is supplied to the gate terminal thereof. Each of the lower MOSFETs 17 and 18 is an n-channel MOSFET, which is arranged to enter the ON state when an H level signal is supplied to a gate terminal thereof, and enter the OFF state when an L level signal is supplied to the gate terminal thereof. Note that each of the lower MOSFETs 17 and 18 may be hereinafter referred to as a braking MOSFET as appropriate, and each of the upper MOSFETs 15 and 16 may be hereinafter referred to as a non-braking MOSFET as appropriate. The regulator circuit portion 1 generates a control power supply voltage A for the drive signal generating circuit portion 2 from the power supply voltage V supplied to the fan apparatus 100. The drive signal generating circuit portion 2 generates each of drive signals B, C, D, and E used to drive the output stage on the basis of the control power supply voltage A supplied from the regulator circuit portion 1. The drive signal generating circuit portion 2 includes a power supply voltage monitoring circuit portion 2-1. The power supply voltage monitoring circuit portion 2-1 detects whether the power supply voltage V is being supplied. Specifically, the power supply voltage monitoring circuit portion 2-1 monitors the potential of the power supply voltage V, and, in the event of a lowering of the power supply voltage V, notifies the drive signal generating circuit portion 2 of the lowering. If the power supply voltage monitoring circuit portion 2-1 detects a lowering of the power supply voltage V, the drive signal generating circuit portion 2 stops outputting the drive signals B, C, D, and E. Specifically, if the power supply voltage V is lowered to a specific potential or less, the drive signal generating circuit portion 2 causes each of the drive signals B, C, D, and E to be in a Hi-Z (high-impedance) state. The transistor 3 drives the upper MOSFET 15. Specifically, the transistor 3 is an NPN transistor. A base terminal of the transistor 3 is connected to the drive signal generating circuit portion 2, a collector terminal of the transistor 3 is connected to a gate terminal of the upper MOSFET 15 through a resistor 5, and an emitter terminal of the transistor 3 is connected to a ground side of the power supply voltage V, i.e., to a ground potential GND. If an H-level drive signal B is supplied from the drive signal generating circuit portion 2 to the base terminal of the transistor 3, the transistor 3 enters an ON state, and shifts the gate terminal of the upper MOSFET 15 to an L level. Meanwhile, if an L-level drive signal B is supplied from the drive signal generating circuit portion 2 to the base terminal of the transistor 3, the transistor 3 enters an OFF state, and shifts the gate terminal of the upper MOSFET 15 to an H level through the power supply voltage V supplied through a resistor 7. The transistor 4 drives the upper MOSFET 16 in accordance with the drive signal C supplied from the drive signal generating circuit portion 2. The above-described specific example of the transistor 3 can also be applied to the transistor 4, and therefore, an explanation of a specific example of the transistor 4 is omitted. The transistor 13 drives the lower MOSFET 17 in accordance with the drive signal D supplied from the drive signal generating circuit portion 2. Specifically, the transistor 13 is an NPN digital transistor. A base terminal of the transistor 13 is connected to the drive signal generating circuit portion 2, a collector terminal of the transistor 13 is connected to a gate terminal of the lower MOSFET 17 through a resistor 10, and an emitter terminal of the transistor 13 is connected to the ground potential GND. If an H-level drive signal D is supplied from the drive signal generating circuit portion 2 to the base terminal of the transistor 13, the transistor 13 enters an ON state, and shifts the gate terminal of the lower MOSFET 17 to an L level. Meanwhile, if an L-level drive signal D is supplied from the drive signal generating circuit portion 2 to the base terminal of the transistor 13, the transistor 13 enters an OFF state, and shifts the gate terminal of the lower MOSFET 17 to an H level through the control power supply voltage A supplied through the diode 21 and a resistor 9. The transistor 14 drives the lower MOSFET 18 in accordance with the drive signal E supplied from the drive signal generating circuit portion 2. The above-described specific example of the transistor 13 can also be applied to the transistor 14, and therefore, an explanation of a specific example of the transistor 14 is omitted. The capacitor 20 is connected between the power supply voltage V and the ground potential GND to stabilize the power supply voltage V. The motor portion 19 is arranged to rotate a fan, which is not shown, through the electric drive currents id1 and id2 supplied from the output stage. A back-electromotive force may occur in the motor portion 19 due to an external force, such as an air flow, causing the fan to rotate. An electric current generated by the back-electromotive force in the motor portion 19 flows into the power supply voltage V through the upper MOSFET 15 or 16, i.e., a parasitic diode in a non-braking MOSFET. Next, with reference to FIG. 2, examples of the drive signals generated by the drive signal generating circuit portion 2 will now be described below. FIG. 2 is a diagram illustrating example waveforms of the drive signals generated by the drive signal generating circuit portion 2. In this example, supply of the power supply voltage V continues from time t0 to time t7, and is interrupted at time t7, as indicated by waveform Wv in the figure. The power supply voltage V is, for example, 54 [V]. In accordance with the supply of the power supply voltage V and the interruption thereof, the control power supply voltage A is at an operating potential from time t0 to time t7, and is at a stop potential from time t7 onward, as indicated by waveform WA in the figure. The operating potential of the control power supply voltage A is, for example, 12 [V]. The stop potential of the control power supply voltage A is, for example, 0 [V]. Waveforms WB, WC, WD, and WE of the drive signals B, C, D, and E, respectively, are shown in the figure. Each of the drive signals B, C, D, and E is switched between an H level and an L level in accordance with control by the drive signal generating circuit portion 2. In this example, when the drive signal B is at the H level, the drive signal C is at the L level, the drive signal D is at the H level, and the drive signal E is at the L level. Meanwhile, when the drive signal B is at the L level, the drive signal C is at the H level, the drive signal D is at the L level, and the drive signal E is at the H level. The drive signal generating circuit portion 2 drives the motor portion 19 by switching the level of each drive signal sequentially from time t0 to time t7. Referring to FIG. 2, when the supply of the power supply voltage V is interrupted at time t7, the control power supply voltage A shifts from the operating potential to the stop potential. Once the control power supply voltage A shifts to the stop potential, the drive signal generating circuit portion 2 stops outputting the drive signals B, C, D, and E. As a result, each of the drive signals B, C, D, and E is in the Hi-Z state from time t7 onward. Here, details of an operation of the circuitry at time t7 will be described below with reference to FIG. 3. FIG. 3 is a diagram illustrating example signal waveforms when the supply of the power supply voltage V is interrupted. If the supply of the power supply voltage V is interrupted at time t71, the control power supply voltage A is lowered from time t71, and reaches the stop potential at time t72. The drive signal D is at the H level at time t71. The drive signal E is at the L level at time t71. After time t71, each of the drive signals D and E is in the Hi-Z state. In the lower MOSFET 17, a parasitic capacitance exists between the gate terminal and a source terminal thereof. When the drive signal D is in the Hi-Z state, a potential D2 at the gate terminal of the lower MOSFET 17 is maintained at the H level as indicated by waveform WD2 in the figure by an electric charge stored in the parasitic capacitance of the lower MOSFET 17. The lower MOSFET 17 is in the ON state when the potential D2 at the gate terminal exceeds a threshold potential VthD2 as indicated by waveform W71 in the figure. That is, the lower MOSFET 17 is maintained in the ON state from time t71 to time t7off with the parasitic capacitance between the gate terminal and the source terminal keeping the potential D2 at the gate terminal exceeding the threshold potential VthD2. In the lower MOSFET 18, a parasitic capacitance exists between the gate terminal and a source terminal thereof. When the drive signal E is in the Hi-Z state, a potential E2 at the gate terminal of the lower MOSFET 18 is maintained at the H level as indicated by waveform WE2 in the figure by an electric charge stored in the parasitic capacitance of the lower MOSFET 18. That is, similarly to the lower MOSFET 17, the lower MOSFET 18 is maintained in the ON state from time t71 to time t7off with the parasitic capacitance between the gate terminal and the source terminal keeping the potential E2 at the gate terminal exceeding a threshold potential VthE2. That is, both the lower MOSFETs 17 and 18 are maintained in the ON state from time t71 to time t7off. The diode 21 prevents the electric charge stored in each parasitic capacitance from flowing into the regulator circuit portion 1 or the drive signal generating circuit portion 2. Accordingly, the gate terminal potentials D2 and E2 do not decrease rapidly, but are maintained for some period. The ON state of the lower MOSFETs 17 and 18 continues until the gate terminal potentials D2 and E2 decrease to the threshold potentials VthD2 and VthE2 or less, respectively. In each of the lower MOSFETs 17 and 18, a parasitic diode exists between a drain terminal and the source terminal. An anode of the parasitic diode is arranged on the side of the source terminal connected to the ground potential GND, while a cathode of the parasitic diode is arranged on the side of the drain terminal connected to the motor portion 19. That is, the parasitic diode allows an electric current to flow from the ground potential GND to the motor portion 19. The existence of the parasitic diodes and the ON state of both the lower MOSFETs 17 and 18 combine to cause both ends of a winding of the motor portion 19 to be connected to the ground potential GND. Therefore, according to the fan apparatus 100, the interruption of the supply of the power supply voltage V causes an electromagnetic brake to be applied to the motor portion 19, reducing the rotation rate of the fan. The braking of the motor portion 19 by the braking MOSFETs at the interruption of the power supply has been described above. Next, braking of the motor portion 19 after the interruption of the power supply will now be described below. Referring back to FIG. 1, the fan apparatus 100 includes a back-electromotive force supply portion. The back-electromotive force supply portion includes a diode D1, a resistor R1, and a supply line LN1. The diode D1, the resistor R1, and the supply line LN1 are connected in series between the power supply voltage V and the braking MOSFETs. In the example illustrated in FIG. 1, an anode of the diode D1 is connected to the power supply voltage V, while a cathode of the diode D1 is connected to the resistor R1. One end of the resistor R1 is connected to the cathode of the diode D1, while another end of the resistor R1 is connected to a junction point P. The junction point P is connected to the gate terminal of the lower MOSFET 17 through the resistor R9 and the resistor R10. In addition, the junction point P is connected to the gate terminal of the lower MOSFET 18 through a resistor R11 and a resistor R12. Here, after time t8 in FIG. 2, that is, after the interruption of the power supply, the electric charges in the parasitic capacitances of the braking MOSFETs may decrease to such an extent that the braking MOSFETs cannot be maintained in the ON state by the electric charges in the parasitic capacitances alone. That is, in the fan apparatus 100, the electric charges in the parasitic capacitances of the braking MOSFETs alone may sometimes not suffice to cause the electromagnetic brake to be applied to the motor portion 19 after the interruption of the power supply. A mechanism by which the fan apparatus 100 causes the electromagnetic brake to be applied to the motor portion 19 after the interruption of the power supply will now be described below with reference to FIGS. 4 and 5. FIG. 4 is a diagram illustrating example back-electromotive force supply paths of the fan apparatus 100. As described above, after time t7 in FIG. 2, that is, after the interruption of the power supply, the drive signal generating circuit portion 2 keeps each of the drive signals B, C, D, and E in the Hi-Z state. Therefore, after the interruption of the power supply, each of the upper MOSFETs 15 and 16 and the lower MOSFETs 17 and 18 is in the OFF state. Suppose that an external force causes the fan to rotate at time t8 in FIG. 2. In this case, a back-electromotive force occurs in the motor portion 19 due to the rotation of the fan. This back-electromotive force causes the motor portion 19 to generate an electric current ic1 or an electric current ic2. The electric current ic1 and the electric current ic2 will be hereinafter referred to collectively as an electric current ic unless they need to be differentiated from each other. As noted above, the parasitic diode exists in each of the upper MOSFETs 15 and 16 and the lower MOSFETs 17 and 18. Even when in the OFF state, each of the upper MOSFETs 15 and 16 and the lower MOSFETs 17 and 18 allows the electric current ic to flow from the side of the ground potential GND to the side of the power supply voltage V through the parasitic diode. The electric current ic1 flows from the ground potential GND into the power supply voltage V through the parasitic diode of the lower MOSFET 17, the motor portion 19, and the parasitic diode of the upper MOSFET 16. That is, the electric current ic1 flows along a back-electromotive force supply path Rt1. Meanwhile, the electric current ic2 flows from the ground potential GND into the power supply voltage V through the parasitic diode of the lower MOSFET 18, the motor portion 19, and the parasitic diode of the upper MOSFET 15. That is, the electric current ic2 flows along a back-electromotive force supply path Rt2. As noted above, the power supply voltage V and the junction point P are connected to each other through the diode D1 and the resistor R1. The electric current ic which flows into the power supply voltage V through the back-electromotive force supply path Rt1 or the back-electromotive force supply path Rt2 flows into the junction point P through the diode D1 and the resistor R1. That is, the electric current ic flows into the junction point P through a back-electromotive force supply path Rt. With the above arrangement, a potential at the junction point P increases. A change in the potential at the junction point P will now be described below with reference to FIG. 5. FIG. 5 is a diagram illustrating example waveforms indicative of potential changes caused by the back-electromotive force after the interruption of the power supply. A waveform WA of the control power supply voltage A continues to maintain the stop potential from time t81 to time t84 after the interruption of the power supply. As a result, each of the drive signals D and E is in the Hi-Z state from time t81 to time t84. In this example, the back-electromotive force occurs in the motor portion 19 between time t81 and time t83. The back-electromotive force causes the electric current ic to flow into the junction point P through the back-electromotive force supply path Rt, causing the potential at the junction point P to increase from time t81 to time t82. Between the junction point P and the ground potential GND, a cathode of a constant voltage diode ZD1 is connected to the junction point P, and an anode of the constant voltage diode ZD1 is connected to the ground potential GND. This constant voltage diode ZD1 is, for example, a Zener diode, and restricts the potential at the junction point P to a Zener voltage VZD1 or less. As a result, the potential at the junction point P is maintained at values equal to or lower than the Zener voltage VZD1 from time t82 to time t83. The potential D2 at the gate terminal of the lower MOSFET 17 varies in accordance with the change in the potential at the junction point P. Once the potential D2 at the gate terminal exceeds the threshold potential VthD2, the lower MOSFET 17 enters the ON state. In this example, the potential D2 at the gate terminal exceeds the threshold potential VthD2 from time t8on to time t8off. In this case, the lower MOSFET 17 is in the ON state from time t8on to time t8off as indicated by waveform V117. The potential E2 at the gate terminal of the lower MOSFET 18 also varies, in a manner similar to that of the potential D2 at the gate terminal. That is, the potential E2 at the gate terminal varies in accordance with the change in the potential at the junction point P. Once the potential E2 at the gate terminal exceeds the threshold potential VthE2, the lower MOSFET 18 enters the ON state. In this example, the potential E2 at the gate terminal exceeds the threshold potential VthE2 from time t8on to time t8off. In this case, the lower MOSFET 18 is in the ON state from time t8on to time t8off as indicated by waveform W18. That is, each of the lower MOSFETs 17 and 18 is in the ON state from time t8on to time t8off. When both the braking MOSFETs have entered the ON state, an electromagnetic brake occurs in the motor portion 19, reducing the rotation rate of the fan. In this fan apparatus 100, the Zener voltage VZD1 of the constant voltage diode ZD1 and the resistance value of the resistor R1 are determined as follows. The power supply voltage V is higher in voltage than the control power supply voltage A. In this example, the power supply voltage V is 54 [V], and the control power supply voltage A is 12 [V]. The control power supply voltage A is applied to the junction point P through the diode 21. Here, while the power supply voltage V is being supplied to the fan apparatus 100, the voltage is applied to the junction point P through the diode D1 and the resistor R1 of the back-electromotive force supply portion. The Zener voltage VZD1 of the constant voltage diode ZD1 is determined on the basis of permissible values of the voltage applied to the junction point P while the power supply voltage V is being supplied. Specifically, the Zener voltage VZD1 is determined on the basis of the control power supply voltage A. For example, when the control power supply voltage A is 12 [V], the Zener voltage VZD1 of the constant voltage diode ZD1 is 12 [V]. That is, a breakdown voltage of the constant voltage diode ZD1 is determined on the basis of the control power supply voltage A used for control and generated from the power supply voltage V. The Zener voltage VZD1 of the constant voltage diode ZD1 is lower than the power supply voltage V. Therefore, while the power supply voltage V is being supplied, an electric current iz flows from the power supply voltage V to the ground potential GND through the diode D1 and the resistor R1 of the back-electromotive force supply portion and the constant voltage diode ZD1. This electric current iz does not contribute to the driving of the motor portion 19. A reduction in power consumption of the fan apparatus 100 can be achieved by reducing the electric current iz. The electric current iz is given by (power supply voltage V−Zener voltage VZD1)/(resistance value of resistor R1). Accordingly, in the fan apparatus 100, a reduction in the electric current iz can be achieved by a relatively large resistance value of the resistor R1. The resistance value of the resistor R1 is, for example, 47 [kΩ)]. A result of a test on braking after the interruption of the power supply will now be described below with reference to FIGS. 6 and 7. FIG. 6 shows a graph representing an example of the rotation rate of the motor portion 19 in the case where a brake is not applied after the interruption of the power supply. FIG. 7 shows a graph representing an example of the rotation rate of the motor portion 19 in the case where a brake is applied after the interruption of the power supply. In this test, the supply of the power supply voltage V is interrupted at time t10, and thereafter, the motor portion 19 is caused to rotate by an external force at time t11. Specifically, a wind is applied to the fan of the fan apparatus 100 at time t11 to cause the fan to rotate by wind power. In the case where a brake is not applied after the interruption of the power supply, the rotation rate of the motor portion 19 is increased to 2800 [rpm] (46.7 [r/s]) after time t11 as illustrated in FIG. 6. Meanwhile, in the case where a brake is applied after the interruption of the power supply, the rotation rate of the motor portion 19 is increased to 1600 [rpm] (26.7 [r/s]) after time t11 as illustrated in FIG. 7. That is, in the fan apparatus 100, the brake applied after the interruption of the power supply reduces the rotation rate of the motor portion 19 by 1400 [rpm] (23.3 [r/s]). As described above, the fan apparatus 100 is able to reduce the rotation rate of the motor caused by an external force without the need for power supplied from an external source. That is, the fan apparatus 100 is able to achieve a reduced power consumption, and is also able to reduce the rotation rate of the motor caused by an external force. In addition, the fan apparatus 100 applies a brake at the interruption of the power supply, in addition to the brake after the interruption of the power supply. Also with the brake at the interruption of the power supply, the fan apparatus 100 reduces the rotation rate of the motor caused by an external force without the need for power supplied from an external source. That is, the fan apparatus 100 is able to achieve a reduced power consumption, and is also able to reduce the rotation rate of the motor caused by an external force. Note that, although each of the upper MOSFETs 15 and 16 is a non-braking MOSFET, and each of the lower MOSFETs 17 and 18 is a braking MOSFET in the exemplary embodiment described above, this is not essential to the present disclosure. Each of the upper MOSFETs 15 and 16 and each of the lower MOSFETs 17 and 18 may alternatively be a braking MOSFET and a non-braking MOSFET, respectively. While preferred embodiments of the present invention have been described above, it is to be understood that variations and modifications will be apparent to those skilled in the art without departing from the scope and spirit of the present invention. The scope of the present invention, therefore, is to be determined solely by the following claims. | <SOH> BACKGROUND OF THE INVENTION <EOH> | <SOH> SUMMARY OF THE INVENTION <EOH>A fan apparatus according to an embodiment of the present disclosure has a drive circuit for an electrically-driven rotor, and includes a drive signal generating circuit portion for the electrically-driven rotor; an output stage including an upper MOSFET and a lower MOSFET; and a motor portion to be driven by the output stage. One of the upper MOSFET and the lower MOSFET is a braking MOSFET, while another of the upper MOSFET and the lower MOSFET is a non-braking MOSFET. The fan apparatus further includes a back-electromotive force supply portion arranged to supply, to the braking MOSFET, power by a back-electromotive force caused by rotation of the motor portion while a power supply voltage for the electrically-driven rotor is not being supplied; and an electromagnetic brake portion arranged to electromagnetically brake the motor portion by causing the braking MOSFET to enter an ON state through the power supplied by the back-electromotive force supply portion. The above and other elements, features, steps, characteristics and advantages of the present disclosure will become more apparent from the following detailed description of the preferred embodiments with reference to the attached drawings. | F04D2506 | 20180301 | 20180913 | F04D2506 | 0 | DINH, THAI T | FAN APPARATUS | UNDISCOUNTED | 0 | ACCEPTED | F04D | 2,018 |
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15,757,023 | PENDING | COMPOSITIONS COMPRISING OMEGA-3 FATTY ACIDS, 17-HDHA AND 18-HEPE AND METHODS OF USING SAME | The present invention relates to a polyunsaturated fatty acid composition comprising Omega-3 fatty acids, 17-HDHA and 18-HEPE. The composition can furthermore comprise DPA and/or an acceptable carrier and can be present in a capsule or other suitable dosage unit. The invention also relates to the process of obtaining the composition and methods for using same. | 1. A polyunsaturated fatty acid composition comprising: about 20% to about 95%, by weight, Omega-3 fatty acids; and 17-HDHA and 18-HEPE in a total amount of about 0.0005% to about 1%, by weight, wherein the composition comprises not more than about 0.005%, by weight, pro-inflammatory compounds. 2. The composition of claim 1 further comprising an acceptable carrier. 3. The composition of claim 1 wherein the composition is present in a capsule or other suitable dosage unit. 4. The composition of claim 1 wherein the Omega-3 fatty acids comprise DHA and/or EPA. 5. The composition of claim 1 wherein: DHA is present in an amount of about 30% to about 45% by weight of the composition; EPA is present in an amount of about 10% to about 26% by weight of the composition; 17-HDHA is present in an amount of about 0.0004% to about 0.04%, by weight of the composition; and 18-HEPE is present in an amount of about 0.0003% to about 0.04%, by weight of the composition, wherein the composition comprises not more than about 0.005%, by weight, pro-inflammatory compounds. 6. The composition of claim 1 further comprising DPA. 7. The composition of claim 1 further comprising 14-HDHA and optionally 7R,14S-dihydroxy-4Z, 8E, 10E,12Z,16Z,19Z-docosahexaenoic acid (“MaR1”). 8-10. (canceled) 11. The composition of claim 1, wherein the Omega-3 fatty acids, 17-HDHA, and/or 18-HEPE are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. 12-14. (canceled) 15. A dietary supplement, nutraceutical product, nutritional composition for infant formulae and/or prenatal formulae, pharmaceutical composition, vaccine, chemotherapeutic coadjutant or medical food composition comprising the composition of claim 1. 16-18. (canceled) 19. A process for obtaining a polyunsaturated fatty acid composition from a crude oil comprising: i. chemically esterifying crude oil with ethanol and a basic catalyst, at a temperature of about 55° C. to about 75° C. to produce esterified oil; ii. distilling the esterified oil, under vacuum of about 0.01 mbar to 0.6 mbar and temperature of about 130° C. to 190° C. for about 10 seconds to about 5 minutes to separate fatty acids shorter than twenty carbons to obtain a distilled esterified oil comprising about 20% to about 95% by weight EPA and/or DHA, and about 0.0005% to 1% 17-HDHA and 18-HEPE; and iii. subjecting the polyunsaturated fatty acid composition obtained in step ii to supercritical fluid extraction with CO2 as a supercritical fluid at a temperature of about 39° C. to 46° C. and pressure of about 80 bar to 115 bar to remove oxidation, decomposition and/or degradation products as oligomers, dimers, polymers and conjugated dienes from the composition. 20. (canceled) 21. The process of claim 19 wherein step ii is made in several stages in series and/or further comprises distilling the esterified oil obtained in step ii to remove fatty acids containing more than 23 carbon atoms in the corresponding fatty acid chains before step iii. 22. The process of claim 19 further comprising bleaching the polyunsaturated fatty acid composition under vacuum with bleaching earths and diatomaceous earths. 23. The process of claim 19 further comprising transesterifying the polyunsaturated fatty acid composition in ethyl ester form to obtain a composition containing a mixture of tri-glycerides, mono-glycerides and di-glycerides. 24. (canceled) 25. The process of claim 19 further comprising deodorizing the polyunsaturated fatty acid composition by applying a countercurrent flow of nitrogen or water steam to the composition under vacuum. 26. (canceled) 27. A process for obtaining a polyunsaturated fatty acid composition from a concentrated esterified oil comprising: i. distilling the concentrated esterified oil under vacuum of about 0.01 mbar to 0.6 mbar and at a temperature of about 130° C. to 190° C. for about 10 seconds to about 5 minutes to separate fatty acids having fewer than 20 carbon atoms in the corresponding fatty acid chain to obtain a distilled esterified oil comprising about 20% to about 95% by weight EPA and/or DHA, and about 0.0005% to about 1% 17-HDHA and 18-HEPE; ii. subjecting the distilled esterified oil obtained in step i to supercritical fluid extraction with CO2 as a supercritical fluid at a temperature of about 20° C. to 40° C. and at a pressure of about 80 bar to about 115 bar to remove oxidation, decomposition and degradation products as oligomers, dimers, polymers and conjugated dienes from the composition. 28. (canceled) 29. The process of claim 27 wherein step i is made in several stages in series and/or further comprises distilling the distilled esterified oil obtained in step i to remove fatty acids having more than 23 carbon atoms in the corresponding fatty acid chain before step ii. 30-42. (canceled) 43. The composition of claim 1 for increasing phagocytic activity of macrophages, enhancing macrophage polarization toward pro-resolution phenotype, and/or resolving inflammation associated with a disease in a subject in need thereof. 44-45. (canceled) 46. The composition of claim 43, wherein the disease is selected from Crohn's disease, irritable bowel disease (“IBD”), ulcerative colitis, fatty liver, wound healing, arterial inflammation, sickle-cell disease, arthritis, psoriasis, urticaria, vasculitis, asthma, ocular inflammation, pulmonary inflammation, dermatitis, cardiovascular diseases, AIDS, Alzheimer's disease, atherosclerosis, cancer, type 2 diabetes, hypertension, infectious diseases, leukemia/lymphoma, metabolic syndrome, neonatology, neuromuscular disorders, obesity, perinatal disorders, rheumatic diseases, stroke, surgical transplantation, vascular disorders, periodontal diseases, brain injury, trauma and neuronal inflammation. 47. The composition of claim 1 for elevating SPM levels in plasma of a human subject. 48. The composition of claim 47, wherein the SPM comprises RvD1. 49-54. (canceled) | PRIORITY CLAIM This application is a 35 USC § 371 U.S. National Stage Application of International Patent Application No. PCT/US2016/050397, filed Sep. 6, 2016, which claims priority to U.S. Provisional Application No. 62/213,958, filed Sep. 3, 2015, the entirety of each which is hereby incorporated by reference herein. TECHNICAL FIELD The present disclosure relates to a polyunsaturated fatty acid composition comprising 17-HDHA and 18-HEPE among other Omega-3 fatty acids. The compositions can furthermore comprise DPA and/or an acceptable carrier and can be present in a capsule or other suitable dosage unit. Processes of obtaining and using the compositions are also provided. BACKGROUND Inflammation is an unspecific response in defense of external pathogen agents to eliminate them and repair damaged tissues. Inflammation is a complex physiologic process that could be considered as acute or chronic depending on the duration of this process. Chronic inflammation is maintained over time, as a result of a lack of resolution of the acute initial phase of the inflammatory response or progressive initiation associated with diseases such as rheumatoid arthritis, atherosclerosis, tuberculosis, cancer, vascular diseases, metabolic syndrome, and neurological diseases as Alzheimer among others. Resolution of the inflammation is a different process from the anti-inflammatory process. Resolution of inflammation can be defined as the interval between maximum neutrophil infiltration to the point when they are lost from the tissue. Complete resolution is the ideal outcome of inflammation, although, if not properly regulated, it can lead to chronic inflammation, fibrosis, and loss of function. Pathologists divide the inflammatory response into initiation and resolution. The natural mechanism of the resolution of inflammation has acquired a high relevance during the last years due to the inflammation being recognized as an important characteristic of the above diseases. Resolution was considered to be a passive process before the discovery and identification of specialized pro-resolving mediators. Effective clearance of microbial infections and damaged tissue is self-limited and followed by resolution of inflammation. Resolution can be defined at the cellular level as the disappearance of accumulated polymorphonuclear leukocytes, and at the macroscopic level as reconstitution of tissue architecture and restoration of normal function. Complete restoration of tissue integrity after bacterial infection is directly related to the efficiency of microbe clearance and then to leukocyte clearance. Several mechanisms appear to drive the disappearance of inflammatory leukocytes. Apoptosis of leukocytes is one important route of elimination. Once phagocytosis is complete, leukocytes undergo programmed cell deaths in response to locally released mediators which regulate the rate of apoptosis. As polymorphonuclear leukocytes die, they simultaneously function as cytokine sinks and sequester earlier released pro-inflammatory cytokines. Apoptotic neutrophils are subsequently phagocytozed by macrophages (efferocytosis) in a so-called non-phlogistic fashion (i.e., in the absence of further generation of pro-inflammatory mediators), but with increased formation of anti-inflammatory mediators such as transforming growth factor-β (TGF-β), lipoxin A4 (LXA4) and interleukin-10. Another important route of elimination of leukocytes is egress from the inflamed tissue, as shown for eosinophils in pulmonary inflammation. Macrophages which have eliminated apoptotic neutrophils disappear in turn by either apoptosis or egress via the lymphatic system as inflammation resolves. Development of new products to facilitate the resolution of the inflammation, especially in chronic diseases associated with an important inflammatory component, such as Crohn's disease, irritable bowel disease (IBD), fatty liver, wound healing, arterial inflammation, sickle-cell disease, arthritis, psoriasis, urticaria, vasculitis, asthma, ocular inflammation, pulmonary inflammation, dermatitis, cardiovascular diseases, AIDS, Alzheimer's disease, atherosclerosis, cancer, type 2 diabetes, hypertension, infectious diseases, leukemia/lymphoma, metabolic syndrome, neonatology, neuromuscular disorders, obesity, perinatal disorders, rheumatic diseases, stroke, surgical transplantation, vascular disorders, periodontal diseases, brain injury, trauma and neuronal inflammation, among others, is greatly needed. SUMMARY In several embodiments, the present disclosure provides a polyunsaturated fatty acid composition comprising about 20% to about 95%, by weight, Omega-3 fatty acids, and 17-HDHA and 18-HEPE in a total amount of about 0.0005% to about 1% by weight of the composition. In some embodiments, the composition can further comprise DPA and/or an acceptable carrier and can be present in a capsule or other suitable dosage unit. In one embodiment, the present disclosure provides a polyunsaturated fatty acid composition comprising about 20% to about 95%, by weight, Omega-3 fatty acids, and a collective amount of about 0.0005% to about 1% of 17-HDHA and 18-HEPE, by weight. In another embodiment, the present disclosure provides a dietary supplement, pharmaceutical product, nutraceutical product, medical food, infant formulae and/or prenatal formulae composition comprising a composition as disclosed herein. In another embodiment, the present disclosure provides a process for obtaining a composition as disclosed herein from an oil using a method selected from chromatography, extraction, distillation and/or vacuum rectification. In another embodiment, the present disclosure provides a process for obtaining a composition as disclosed herein from a crude oil, the process comprising: (i) chemically esterifying crude oil with ethanol and a basic catalyst, at a temperature of about 55° C. to about 75° C. to produce esterified oil; (ii) distilling the esterified oil under vacuum of about 0.01 mbar to 0.6 mbar and at a temperature of about 130° C. to 190° C. for about 10 seconds to about 5 minutes to separate fatty acids shorter than 20 carbon atoms to obtain a distilled esterified oil comprising about 20% to about 95% by weight EPA and/or DHA, and about 0.0005% to about 1% by weight 17-HDHA and 18-HEPE (collectively); and (iii) subjecting the polyunsaturated fatty acid composition obtained in step (ii) to supercritical fluid extraction with CO2 as a supercritical fluid at a temperature of about 39° C. to about 46° C. and pressure of about 80 bar to about 115 bar to remove oxidation, decomposition and/or degradation products as oligomers, dimers, polymers and conjugated dienes from the composition. In another embodiment, the present disclosure provides a process for obtaining a composition as disclosed herein from a concentrated esterified oil, the process comprising: (i) distilling the concentrated esterified oil under vacuum of about 0.01 mbar to 0.6 mbar and at a temperature of about 130° C. to 190° C. for about 10 seconds to about 5 minutes to separate fatty acids having fewer than 20 carbon atoms in the corresponding fatty acid chain to obtain a distilled esterified oil comprising about 20% to about 95% by weight EPA and/or DHA, and about 0.0005% to about 1% by weight 17-HDHA and 18-HEPE (collectively); (ii) subjecting the distilled esterified oil obtained in step (i) to supercritical fluid extraction with CO2 as a supercritical fluid at a temperature of about 20° C. to 40° C. and at a pressure of about 80 bar to about 115 bar to remove oxidation, decomposition and degradation products as oligomers, dimers, polymers and conjugated dienes from the composition. In another embodiment, the present disclosure provides a method of increasing phagocytic activity of macrophages in a subject comprising administering to the subject a phagocytic activity enhancing amount of a composition as disclosed herein. In another embodiment, the present disclosure provides a method of enhancing macrophage polarization toward a pro-resolution phenotype in a subject comprising administering to the subject a macrophage polarization-enhancing amount of a composition as disclosed herein. In another embodiment, the present disclosure provides a method of resolving inflammation associated with a disease in a subject in need thereof comprising administering to the subject an inflammation-resolving amount of a composition as disclosed herein. In another embodiment, the present disclosure provides a method of elevating SPM levels in plasma of a human subject comprising administering to the human subject an SPM-elevating amount of a composition as disclosed herein. In another embodiment, the present disclosure provides use of a composition as disclosed herein as a vaccine coadjuvant. In another embodiment, the present disclosure provides use of a composition as disclosed herein as a chemotherapeutic coadjuvant. In another embodiment, the present disclosure provides use of a composition as disclosed herein in the manufacture of a medicament for increasing phagocytic activity of macrophages in a subject. In another embodiment, the present disclosure provides use of a composition as disclosed herein in the manufacture of a medicament for enhancing macrophage polarization toward a pro-resolution phenotype in a subject. In another embodiment, the present disclosure provides use of a composition as disclosed herein in the manufacture of a medicament for resolving inflammation associated with a disease in a subject in need thereof. In another embodiment, the present disclosure provides use of a composition as disclosed herein in the manufacture of a medicament for elevating SPM levels in plasma of a human subject. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1A: Biosynthesis of lipoxins and aspirin-triggered lipoxins from arachidonic acid. FIG. 1B: Biosynthesis of E-series resolvins: RvE1 and RvE2 from EPA. FIG. 1C: Biosynthesis of D series resolvins and aspirin-triggered D series resolvins. FIG. 1D: Biosynthesis of protectins: PD1 (the mono-hydroxylated product 17S-hydroxy-DHA), the mono-hydroxylated product 17S-hydroxy-DHA, and the double oxygenation product 10S,17S-dihydroxy-DHA, an isomer of NPD1/PD1. FIG. 1E: Formation of maresins: Mar-1 (7,14S-dihydroxy-DHA); also, an isomer 7S,14S-dihydroxy-DHA, a novel double dioxygenation product from this biosynthetic pathway. FIG. 2: Percentage of increase of phagocytosis over vehicle comparative. This figure shows the comparison of macrophage activation in an in vitro model of three oil fractions in ethyl ester form compared to the values obtained with Mar-1 (1 nM). In this model 100% activity is assigned to Mar-1 (1 nM) over phagocytic activity. FIG. 3: Levels of RvD1 (pg/ml) measured in human plasma samples. This figure shows the values of RvD1 measured in plasma in subjects administered a composition containing EPA, DHA, 17-HDHA and 18-HEPE compared with a placebo. FIGS. 4A and 4B: Total and average flux values. These figures show an analysis of bioluminescence total flux of the bioluminescence value (bottomless) and the evolution of medium signal value (bottomless) in an inflammatory murine model administered by gavage krill oil and compared with indomethacin and control. FIGS. 5A and 5B: Total and average flux values. These figures show an analysis of bioluminescence total flux of the bioluminescence value (bottomless) and the evolution of medium signal value (bottomless) in an inflammatory murine model administered by gavage LM03-3 oil and compared with indomethacin and control. FIGS. 6A and 6B: Total and average flux values. These figures show an analysis of bioluminescence total flux of the bioluminescence radiation value (bottomless) and the evolution of medium radiance value (bottomless) in an inflammatory murine model administered by gavage algae oil and compared with indomethacin and control. DETAILED DESCRIPTION The use of numerical values specified in this application, unless expressly indicated otherwise, are stated as approximations through the minimum and maximum values specified within the stated ranges, and preceded by the word “about.” The disclosure of ranges is intended as a continuous range including every value between the minimum and maximum values recited as well as any ranges that can be formed through such values. The numerical values presented in this application represent various embodiments of the present invention. In various embodiments, the present invention provides a polyunsaturated fatty acid composition comprising about 20% to about 95%, by weight, of Omega-3 fatty acids and about 0.0005% to about 1%17-HDHA and 18-HEPE (collectively) by weight of the composition. Omega-3 fatty acids are a family of polyunsaturated fatty acids considered as essential fatty acids, because they cannot be synthesized by mammals. The main components of this family are EPA (5Z,8Z,11Z,14Z,17Z eicosapentaenoic acid), DHA (4Z,7Z,10Z,13Z,16Z,19Z docosahexaenoic acid), and ALA (9Z,12Z,15Z octadecatrienoic acid). Other important components of the family of omega-3 fatty acids are n-3 DPA (7Z,10Z,13Z,16Z,19Z-docosapentaenoic acid). The compound n-3 DPA is an elongated metabolite/intermediate of EPA and an intermediate product between EPA and DHA. In various embodiments, the Omega-3 fatty acids in the composition comprise EPA and/or DHA in an amount between about 20% to about 95% by weight of the composition. In various embodiments, the Omega-3 fatty acids in the composition comprise EPA in an amount between about 20% to about 95% by weight of the composition. In various embodiments, the Omega-3 fatty acids in the composition comprise DHA in an amount between about 20% to about 95% by weight of the composition. In various embodiments, the composition comprises EPA in an amount between about 10% to about 26% by weight and DHA in an amount of about 30% to about 45% by weight of the composition. SPMs are a new genus with several families of potent endogenous bioactive products derived from precursors essential fatty acids EPA, DHA, ARA and DPA that are biosynthesized by positional and stereospecific incorporation of one, two or three molecules of molecular oxygen into a polyunsaturated fatty acid using EPA, DHA, ALA and DPA as substrates into a catalyzed reaction involving fatty acid lipoxygenases, cyclooxygenase type-2, when acetylated by aspirin, and several cytochrome P450 oxidases. The SPMs include several families of mediators, lipoxins, resolvins, protectins and maresins. Specific potent members of these families include among others: Lipoxin A4: LXA4; 5S,6R,15S-trihydroxy-7E,9E,11Z,13E-eicosatetraenoic acid 15-epi-lipoxin A4: 15-epi-LXA4; (5S,6R,7E,9E,11Z,13E,15R)-5,6,15-trihydroxyicosa-7,9,11,13-tetraenoic acid Lipoxin B4: LXB4, 5S,14R,15S-trihydroxy-6E,8Z,10E,12E-eicosatetraenoic acid 15-epi-lipoxin B4: 15-epi-LXB4; 5S,14R,15R-trihydroxy-6E,8Z,10E,12E-eicosatetraenoic acid Resolvin E1: RvE1; 5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid 18S-Resolvin E1: 18S-RvE1; 5S,12R,18S-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid 20-hydroxy-Resolvin E1: 20-hydroxy-RvE1, 5S,12R,18S,20-tetrahydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid Resolvin E2: RvE2; 5S,18R-dihydroxy-6E,8Z,11Z,14Z,16E-eicosapentaenoic acid 18S-Resolvin E2: 18S-RvE2, 5S,18S-dihydroxy-6E,8Z,11Z,14Z,16E-eicosapentaenoic acid 18S-Resolvin E3: 18S-RvE3, 17R,18S-dihydroxy-5Z,8Z,11Z,13E,15E-eicosapentaenoic acid 18R-Resolvin E3: 18R-RvE3; 17R,18R-dihydroxy-5Z,8Z,11Z,13E,15E-eicosapentaenoic acid Maresin 1: MaR1, 7R,14S-dihydroxy-4Z,8E,10E,12E,16Z,19Z-docosahexaenoic acid 7S-Maresin 1: 7S-MaR1, 7S,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoic acid 13R,14S-Maresin 2: 13R,14S-MaR2, 13R,14S-dihydroxy-4Z,7Z,9E,11E,16Z,19Z-hexaenoic acid 14S-hydroperoxy-4Z,7Z,10Z,12E,16Z,19Z-docosahexaenoic acid Protectin DX: PDX; 10S,17S-dihydroxy-4Z,7Z,11E,13Z,15E,19Z-docosahexaenoic acid 14S, 21R-diHDHA: 14S,21R-dihydroxy-4Z,7Z,10Z,12E,16Z,19Z-docosahexaenoic acid 14R,21S-diHDHA: 14R,21S-dihydroxy-4Z,7Z,10Z,12E,16Z,19Z-docosahexaenoic acid 14R,21R-diHDHA: 14R,21R-dihydroxy-4Z,7Z,10Z,12E,16Z,19Z-docosahexaenoic acid 14S, 21S-diHDHA: 14S,21S-dihydroxy-4Z,7Z,10Z,12E,16Z,19Z-docosahexaenoic acid 16,17-diHDHA: 16,17S-dihydroxy-4Z,7Z,10Z,12E,14E,19Z-docosahexaenoic acid 16,17-Epoxy-DHA: 16,17-Epoxy-4Z,7Z,10Z,12E,14E,19Z-docosahexaenoic acid 17S-HDHA: 17S-hydroxy-4Z,7Z,10Z,13Z,15E,19Z-docosahexaenoic acid 7,8-epoxy-17S-HDHA: 17S-hydroxy-4Z,7Z,10Z,13Z,15E,19Z-docosahexaenoic acid Protectin D1: PD1; 10R,17S-dihydroxy-4Z,7Z,11E,13E,15Z,19Z-docosahexaenoic acid 10S,17S-HDHA: 10S,17S-dihydroxy-4Z,7Z,11E,13Z,15E,19Z-docosahexaenoic acid 16,17S-diHDHA: 16,17S-dihydroxy-4Z,7Z,10Z,12E,14E,19Z-docosahexaenoic acid 16,17-Epoxy-DHA: 16,17-Epoxy-4Z,7Z,10Z,12E,14E,19Z-docosahexaenoic acid Resolvin D1: RvD1, 7S,8R,17S-trihydroxy-docosa-4Z,9E,11E,13Z,15E,19Z-hexaenoic acid Resolvin D2: RvD2; 7S,16R,17S-trihydroxy-docosa-4Z,8E,10Z,12E,14E,19Z-hexaenoic acid Resolvin D3: RvD3; 4S,11,17S-trihydroxy-5E,7E,9E,13Z,15E,19Z-docosahexaenoic acid Resolvin D4: RvD4; 4S,5,17S-trihydroxy-6E,8E,10E,13E,15Z,19Z-docosahexaenoic acid Resolvin D5: RvD5; 7S,17S-dihydroxy-5Z,8E,10Z,13Z,15E,19Z-docosahexaenoic acid Resolvin D6: RvD6; 4S,17S-dihydroxy-5E,7Z,10Z,13Z,15E,19Z-docosahexaenoic acid AT-Resolvin D1: AT-RvD1; 7S,8R,17R-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid AT-Resolvin D2: AT-RvD2; 7S,16R,17R-trihydroxy-4Z,8E,10Z,12E,14E,19Z-docosahexaenoic acid AT-Resolvin D3: AT-RvD3; 4D,11,17R-trihydroxy-5E,7E,9E,13Z,15E,19Z-docosahexaenoic acid AT-Resolvin D4: AT-RvD4; 4S,5,17R-trihydroxy-6E,8E,10E,13E,15Z,19Z-docosahexaenoic acid 10S,17S-HDPAn-6: 10S,17S-dihydroxy-4Z,7Z,11E,13Z,15E-docosapentaenoic acid 7,17-HDPAn-6: 7,17-dihydroxy-4Z,8E,10Z,13Z,15E-docosapentaenoic acid 7,14-HDPAn-6: 7,14-dihydroxy-4Z,8E,10Z,12Z,16Z-docosapentaenoic acid 10S,17S-HDPAn-6: 10S,17S-dihydroxy-7Z,11E,13Z,15E,19Z-docosapentaenoic acid 7,17-HDPAn-6: 7,17-dihydroxy-8E,10Z,13Z,15E,19Z-docosapentaenoic acid 15S-HETE: 15S-hydroxy-5Z,8Z,11Z,13E-eicosatetraenoic acid 15R-HETE: 15R-hydroxy-5Z,8Z,11Z,13E-eicosatetraenoic acid 5S-HEPE: 5S-hydroxy-6E,8Z,11Z,14Z,17Z-eicosapentaenoic acid 5R-HEPE: 15R-hydroxy-5Z,8Z,11Z,13E,17Z-eicosapentaenoic acid 11S-HEPE: 11S-hydroxy-5Z,8Z,12E,14Z,17Z-eicosapentaenoic acid 11R-HEPE: 11R-hydroxy-5Z,8Z,12E,14Z,17Z-eicosapentaenoic acid 12S-HEPE: 12S-hydroxy-5Z,8Z,10E,14Z,17Z-eicosapentaenoic acid 12R-HEPE: 12R-hydroxy-5Z,8Z,10E,14Z,17Z-eicosapentaenoic acid 15S-HEPE: 15S-hydroxy-5Z,8Z,11Z,13E,17Z-eicosapentaenoic acid 15R-HEPE: 15R-hydroxy-5Z,8Z,11Z,13E,17Z-eicosapentaenoic acid 18S-HEPE: 18S-hydroxy-5Z,8Z,11Z,14Z,16E-eicosapentaenoic acid 18R-HEPE: 18R-hydroxy-5Z,8Z,11Z,14Z,16E-eicosapentaenoic acid 4S-HDHA: 4S-hydroxy-5E,7Z,10Z,13Z,16Z,19Z-docosahexaenoic acid 7S-HDHA: 7S-hydroxy-4Z,8E,10Z,13Z,16Z,19Z-docosahexaenoic acid 10S-HDHA: 10S-hydroxy-4Z,7Z,11E,13Z,16Z,19Z-docosahexaenoic acid 11S-HDHA: 11S-hydroxy-4Z,7Z,9E,13Z,16Z,19Z-docosahexaenoic acid 14S-HDHA: 14S-hydroxy-4Z,7Z,10Z,12E,16Z,19Z-docosahexaenoic acid 14R-HDHA: 14R-hydroxy-4Z,7Z,10Z,12E,16Z,19Z-docosahexaenoic acid 17S-HDHA: 17S-hydroxy-4Z,7Z,10Z,13Z,15E,19Z-docosahexaenoic acid 17R-HDHA: 17R-hydroxy-4Z,7Z,10Z,13Z,15E,19Z-docosahexaenoic acid 20S-HDHA: 20S-hydroxy-4Z,7Z,10Z,13Z,16Z,19Z-docosahexaenoic acid 17S-HDPAn-6: 17S-hydroxy-4Z,7Z,10Z,13Z,15E-docosapentaenoic acid 14S-HDPAn-6: 14S-hydroxy-4Z,7Z,10Z,12E,16Z-dcosapentaenoic acid 10S-HDPAn-6: 10S-hydroxy-4Z,7Z,11E,13Z,16Z-docosapentaenoic acid 17S-HDPAn-3: 17S-hydroxy-7Z,10Z,13Z,15E,19Z-docosapentaenoic acid 14S-HDPAn-3: 17S-hydroxy-7Z,10Z,12E,16Z,19Z-docosapentaenoic acid 10S-HDPAn-6: 10S-hydroxy-7Z,11E,13Z,16Z,19Z-docosapentaenoic acid 17-HpDPAn-3: 17-hydroperoxy-8Z,10Z,13Z,15E,19Z-docosapentaenoic acid RvD1n-3DPA: 7,8,17-trihydroxy-9,11,13,15E,19Z-docosapentaenoic acid RvD2n-3DPA: 7,16,17-trihydroxy-8,10,12,14E,19Z-docosapentaenoic acid RvD5n-3DPA: 7,17-trihydroxy-8E,10,13,15E,19Z-docosapentaenoic acid PD1n-3DPA: 10,17-dihydroxy-7Z,11,13,15,19Z-docosapentaenoic acid PD2n-3DPA: 16,17-dihydroxy-7Z,10,13,14,19Z-docosapentaenoic acid 14-HpDHA: 14-hydroperoxy-7Z,10Z,12E,16Z,19Z-docosapentaenoic acid MaR1n-3DPA: 7,14-dihydroxy-8,10,12,16Z,19Z-docosapentaenoic acid MaR2n-3DPA: 13,14-dihydroxy-7Z,9,11,16Z,19Z-docosapentaenoic acid MaR3n-3DPA: 14,21-dihydroxy-7Z,10Z,12E,16Z,19Z-docosapentaenoic acid Compositions of the present disclosure comprise Omega-3 (e.g., EPA and/or DHA), 17-HDHA and 18-HEPE. In some embodiments, 17-HDHA and 18-HEPE are present in a total amount of about 0.0005% to about 1% by weight in the composition. In some embodiments, the 17-HDHA is present in an amount of about 0.0002 wt. % to about 1 wt. %, for example about 0.0002 wt. %, 0.0004 wt. %, 0.0006 wt. %, 0.0008 wt. %, 0.001 wt. %, 0.002 wt. %, 0.003 wt. %, 0.004 wt. %, 0.005 wt. %, 0.006 wt. %, 0.007 wt. %, 0.008 wt. %, 0.009 wt. %, 0.01 wt. %, 0.02 wt. %, 0.03 wt. %, 0.04 wt. %, 0.05 wt. %, 0.06 wt. %, 0.07 wt. %, 0.08 wt. %, 0.09 wt. %, 0.1 wt. %, 0.12 wt. %, 0.14 wt. %, 0.16 wt. %, 0.18 wt. %, 0.2 wt. %, about 0.22 wt. %, about 0.24 wt. %, about 0.26 wt. %, about 0.28 wt. %, about 0.3 wt. %, about 0.32 wt. %, about 0.34 wt. %, about 0.36 wt. %, about 0.38 wt. %, about 0.4 wt. %, about 0.42 wt. %, about 0.44 wt. %, about 0.46 wt. %, about 0.48 wt. %, about 0.5 wt. %, about 0.52 wt. %, about 0.54 wt. %, about 0.56 wt. %, about 0.58 wt. %, about 0.6 wt. %, about 0.62 wt. %, about 0.64 wt. %, about 0.66 wt. %, about 0.68 wt. %, about 0.7 wt. %, about 0.72 wt. %, about 0.74 wt. %, about 0.76 wt. %, about 0.78 wt. %, about 0.8 wt. %, about 0.82 wt. %, about 0.84 wt. %, about 0.86 wt. %, about 0.88 wt. %, about 0.9 wt. %, about 0.92 wt. %, about 0.94 wt. %, about 0.96 wt. %, about 0.98 wt. %, or about 1 wt. %. In some embodiments, the 18-HEPE is present in an amount of about for example about 0.0002 wt. %, 0.0004 wt. %, 0.0006 wt. %, 0.0008 wt. %, 0.001 wt. %, 0.002 wt. %, 0.003 wt. %, 0.004 wt. %, 0.005 wt. %, 0.006 wt. %, 0.007 wt. %, 0.008 wt. %, 0.009 wt. %, 0.01 wt. %, 0.02 wt. %, 0.03 wt. %, 0.04 wt. %, 0.05 wt. %, 0.06 wt. %, 0.07 wt. %, 0.08 wt. %, 0.09 wt. %, 0.1 wt. %, 0.12 wt. %, 0.14 wt. %, 0.16 wt. %, 0.18 wt. %, 0.2 wt. %, about 0.22 wt. %, about 0.24 wt. %, about 0.26 wt. %, about 0.28 wt. %, about 0.3 wt. %, about 0.32 wt. %, about 0.34 wt. %, about 0.36 wt. %, about 0.38 wt. %, about 0.4 wt. %, about 0.42 wt. %, about 0.44 wt. %, about 0.46 wt. %, about 0.48 wt. %, about 0.5 wt. %, about 0.52 wt. %, about 0.54 wt. %, about 0.56 wt. %, about 0.58 wt. %, about 0.6 wt. %, about 0.62 wt. %, about 0.64 wt. %, about 0.66 wt. %, about 0.68 wt. %, about 0.7 wt. %, about 0.72 wt. %, about 0.74 wt. %, about 0.76 wt. %, about 0.78 wt. %, about 0.8 wt. %, about 0.82 wt. %, about 0.84 wt. %, about 0.86 wt. %, about 0.88 wt. %, about 0.9 wt. %, about 0.92 wt. %, about 0.94 wt. %, about 0.96 wt. %, about 0.98 wt. %, or about 1 wt. %. In some embodiments, the composition further comprises DPA. In some embodiments, the DPA is present in an amount of about 1 wt. % to about 10 wt. %, for example about 1 wt. %, about 2 wt. %, about 3 wt. %, about 4 wt. %, about 5 wt. %, about 6 wt. %, about 7 wt. %, about 8 wt. %, about 9 wt. %, or about 10 wt. %. In some embodiments, the composition further comprises 14-HDHA. In some embodiments, the 14-HDHA is present in an amount of about 0.001 wt. % to about 0.1 wt. %, for example about 0.001 wt. %, about 0.002 wt. %, about 0.003 wt. %, about 0.004 wt. %, about 0.005 wt. %, about 0.006 wt. %, about 0.007 wt. %, about 0.008 wt. %, about 0.009 wt. %, about 0.01 wt. %, about 0.02 wt. %, about 0.03 wt. %, about 0.04 wt. %, about 0.05 wt. %, about 0.06 wt. %, about 0.07 wt. %, about 0.08 wt. %, about 0.09 wt. %, or about 0.1 wt. %. In some embodiments, the composition further comprises 15-HETE. In some embodiments, the 15-HETE is present in an amount of about 0.0001 wt. % to about 0.01 wt. %, for example about 0.0001 wt. %, about 0.0002 wt. %, about 0.0003 wt. %, about 0.0004 wt. %, about 0.0005 wt. %, about 0.0006 wt. %, about 0.0007 wt. %, about 0.0008 wt. %, about 0.0009 wt. %, about 0.001 wt. %, about 0.0015 wt. %, about 0.002 wt. %, about 0.0025 wt. %, about 0.003 wt. %, about 0.0035 wt. %, about 0.004 wt. %, about 0.0045 wt. %, about 0.005 wt. %, about 0.0055 wt. %, about 0.006 wt. %, about 0.0065 wt. %, about 0.007 wt. %, about 0.0075 wt. %, about 0.008 wt. %, about 0.0085 wt. %, about 0.009 wt. %, about 0.0095 wt. %, or about 0.01 wt. %. In some embodiments, the composition further comprises 5-HETE. In some embodiments, the 5-HETE is present in an amount of about 0.0001 wt. % to about 0.01 wt. %, for example about 0.0001 wt. %, about 0.0002 wt. %, about 0.0003 wt. %, about 0.0004 wt. %, about 0.0005 wt. %, about 0.0006 wt. %, about 0.0007 wt. %, about 0.0008 wt. %, about 0.0009 wt. %, about 0.001 wt. %, about 0.0015 wt. %, about 0.002 wt. %, about 0.0025 wt. %, about 0.003 wt. %, about 0.0035 wt. %, about 0.004 wt. %, about 0.0045 wt. %, about 0.005 wt. %, about 0.0055 wt. %, about 0.006 wt. %, about 0.0065 wt. %, about 0.007 wt. %, about 0.0075 wt. %, about 0.008 wt. %, about 0.0085 wt. %, about 0.009 wt. %, about 0.0095 wt. %, or about 0.01 wt. %. In some embodiments, the composition further comprises MaR-1. In some embodiments, the MaR-1 is present in an amount of about 0.0001 wt. % to about 0.01 wt. %, for example about 0.0001 wt. %, about 0.0002 wt. %, about 0.0003 wt. %, about 0.0004 wt. %, about 0.0005 wt. %, about 0.0006 wt. %, about 0.0007 wt. %, about 0.0008 wt. %, about 0.0009 wt. %, about 0.001 wt. %, about 0.0015 wt. %, about 0.002 wt. %, about 0.0025 wt. %, about 0.003 wt. %, about 0.0035 wt. %, about 0.004 wt. %, about 0.0045 wt. %, about 0.005 wt. %, about 0.0055 wt. %, about 0.006 wt. %, about 0.0065 wt. %, about 0.007 wt. %, about 0.0075 wt. %, about 0.008 wt. %, about 0.0085 wt. %, about 0.009 wt. %, about 0.0095 wt. %, or about 0.01 wt. %. In some embodiments, the composition comprises pro-inflammatory compounds in a combined (e.g., total) amount of not more than about 0.005 wt. %, for example no more than about 0.005 wt. %, about 0.004 wt. %, about 0.003 wt. %, about 0.002 wt. %, about 0.001 wt. %, about 0.0005 wt. %, or no more than about 0.0001 wt. %. In some embodiments, the composition comprises 12-HETE, LTB4, Prostaglandin E2, Prostaglandin D2, Thromboxane B2, Prostaglandin F2α, 20-000H TLB4, 20-Hydoxy-LTB4, 11-HETE, 6-keto PGF1α, and 15-keto PGE2 in a combined (e.g., total) amount of not more than about 0.005 wt. %, for example no more than about 0.005 wt. %, about 0.004 wt. %, about 0.003 wt. %, about 0.002 wt. %, about 0.001 wt. %, about 0.0005 wt. %, or no more than about 0.0001 wt. %. In some embodiments, the composition comprises a total amount of SPMs and SPM Precursors of about 0.01 wt. % to about 1 wt. %, for example about 0.01 wt. %, about 0.015 wt. %, about 0.02 wt. %, about 0.025 wt. %, about 0.03 wt. %, about 0.035 wt. %, about 0.04 wt. %, about 0.045 wt. %, about 0.05 wt. %, about 0.055 wt. %, about 0.06 wt. %, about 0.065 wt. %, about 0.07 wt. %, about 0.075 wt. %, about 0.08 wt. %, about 0.085 wt. %, about 0.09 wt. %, about 0.095 wt. %, about 0.1 wt. %, about 0.15 wt. %, about 0.2 wt. %, about 0.25 wt. %, about 0.3 wt. %, about 0.35 wt. %, about 0.4 wt. %, about 0.45 wt. %, about 0.5 wt. %, about 0.55 wt. %, about 0.6 wt. %, about 0.65 wt. %, about 0.7 wt. %, about 0.75 wt. %, about 0.8 wt. %, about 0.85 wt. %, about 0.9 wt. %, about 0.95 wt. %, or about 1 wt. % In some embodiments, the composition comprises Omega-3 fatty acids or derivatives thereof (e.g., an ester such as an ethyl ester) in a total amount of about 20 wt. % to about 99 wt. %, for example about 20 wt. %, about 21 wt. %, about 22 wt. %, about 23 wt. %, about 24 wt. %, about 25 wt. %, about 26 wt. %, about 27 wt. %, about 28 wt. %, about 29 wt. %, about 30 wt. %, about 31 wt. %, about 32 wt. %, about 33 wt. %, about 34 wt. %, about 35 wt. %, about 36 wt. %, about 37 wt. %, about 38 wt. %, about 39 wt. %, about 40 wt. %, about 41 wt. %, about 42 wt. %, about 43 wt. %, about 44 wt. %, about 45 wt. %, about 46 wt. %, about 47 wt. %, about 48 wt. %, about 49 wt. %, about 50 wt. %, about 51 wt. %, about 52 wt. %, about 53 wt. %, about 54 wt. %, about 55 wt. %, about 56 wt. %, about 57 wt. %, about 58 wt. %, about 59 wt. %, about 60 wt. %, about 61 wt. %, about 62 wt. %, about 63 wt. %, about 64 wt. %, about 65 wt. %, about 66 wt. %, about 67 wt. %, about 68 wt. %, about 69 wt. %, about 70 wt. %, about 71 wt. %, about 72 wt. %, about 73 wt. %, about 74 wt. %, about 75 wt. %, about 76 wt. %, about 77 wt. %, about 78 wt. %, about 79 wt. %, about 80 wt. %, about 81 wt. %, about 82 wt. %, about 83 wt. %, about 84 wt. %, about 85 wt. %, about 86 wt. %, about 87 wt. %, about 88 wt. %, about 89 wt. %, about 90 wt. %, about 91 wt. %, about 92 wt. %, about 93 wt. %, about 94 wt. %, about 95 wt. %, about 96 wt. %, about 97 wt. %, about 98 wt. %, about 99 wt. %, or greater than about 99 wt. %. The Omega-3 fatty acids of the composition in a preferred embodiment are EPA and/or DHA, and in a more preferred embodiment, DHA is present in an amount of about 30% to about 45% and EPA is present in an amount of about 10% to about 26% by weight and 17-HDHA is present in an amount of about 0.0004% to about 0.04%, and 18-HEPE is present in an amount of about 0.0003% to about 0.04% by weight of the composition. Omega-3 fatty acids, 17-HDHA and 18-HEPE can be obtained from different sources including vegetables, microbial, animal or combinations of these sources, including different oils as, for example, fish oil, krill oil, vegetable oil, microbial oil or combinations among other. In one embodiment, the Omega-3, 17-HDHA and 18-HEPE are obtained from fish oil, Krill oil and/or algae oil. The chemical form of the Omega-3, 17-HDHA and 18-HEPE is selected from free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and combinations thereof. In one embodiment, the Omega-3 compounds are in ethyl ester form. The composition is useful for a pharmaceutical composition, a dietary supplement, a nutraceutical product, a medical food composition, a nutritional composition for infant formulae and/or prenatal formulae that increases tissue levels of SPM in vivo. In one embodiment, the composition is present in a capsule or other suitable dosage unit. The composition can be obtained using a method selected from chromatography, extraction, distillation and/or vacuum rectification from several sources as, for example, fish oil and krill oil. In one embodiment, the distillation is a short path molecular distillation process. In several embodiments, the composition can be obtained from a crude oil using a process comprising several steps. The first step is a chemically esterification of the crude oil with ethanol and a basic catalyst at a temperature of about 55° C. to about 85° C. to produce an esterified oil. This esterified oil is distilled to separate fatty acids shorter than 20 carbon atoms. This distillation is under vacuum of about 0.01 mbar to about 0.6 mbar and temperature of about 130° C. to about 190° C. for about 10 seconds to about 5 minutes to obtain a polyunsaturated fatty acid composition comprising about 20% to about 95% by weight EPA and/or DHA, and about 0.0005% to about 1% 17-HDHA and 18-HEPE by weight. This process can be covered in several stages in series. In one embodiment, if necessary, after elimination of fatty acids shorter than 20 carbon atoms, the esterified oil can be distilled to eliminate fatty acids higher than 23 carbon atoms. Before the step of distillation, to improve the quality of the composition and to remove oxidation, decomposition and/or degradation products, the polyunsaturated fatty acid composition is subjected to a supercritical fluid extraction (SFE) with CO2 as supercritical fluid, pressure of about 80 bar to about 115 bar, and temperature of about 39° C. to about 46° C. The oxidation, degradation and/or decomposition products eliminated by SFE can be selected from oligomers, dimers, polymers and conjugated dienes among others. In various embodiments, the polyunsaturated composition is subjected to a step of bleaching under vacuum with bleaching earths and diatomaceous earths. In an embodiment, the polyunsaturated oil composition is subjected to a transesterification step to obtain a composition containing a mixture of tri-glycerides and partial glycerides (mono-glycerides and di-glycerides). In one embodiment, the transesterification reaction can be catalyzed by lipases. In various embodiments, polyunsaturated oil composition is subjected to a deodorization step under vacuum and a countercurrent flow of nitrogen or water steam. In one embodiment, the composition is obtained from a starting material consisting of esterified concentrated oil; in these embodiments it is not necessary to make an esterification step. The concentrated esterified oil is distilled to separate fatty acids shorter than 20 carbon atoms. This distillation is under vacuum of about 0.01 mbar to about 0.6 mbar and temperature of about 130° C. to about 190° C. for about 10 seconds to about 5 minutes to obtain a polyunsaturated fatty acid composition comprising about 20% to about 95% by weight EPA and/or DHA, and about 0.0005% to about 1% 17-HDHA and 18-HEPE by weight. This process can be covered in several stages in series. In one embodiment, if necessary, after elimination of fatty acids shorter than 20 carbon atoms, the esterified oil can be distilled to eliminate fatty acids higher than 23 carbon atoms. Before the step of distillation, to improve the quality of the composition and to remove oxidation, decomposition and/or degradation products, the polyunsaturated fatty acid composition is subjected to a supercritical fluid extraction (SFE) with CO2 as supercritical fluid, pressure of about 80 bar to about 115 bar, and temperature of about 39° C. to about 46° C. In one embodiment, the oxidation, degradation and/or decomposition products eliminated by SFE can be selected from oligomers, dimers, polymers and conjugated dienes, among others. In one embodiment, the polyunsaturated oil composition, if necessary, can be subjected to a step of bleaching under vacuum with bleaching earths and diatomaceous earths. In one embodiment, the polyunsaturated oil composition, if necessary, can be subjected to a transesterification to obtain a composition containing a mixture of tri-glycerides and partial glycerides (mono-glycerides and di-glycerides). In one embodiment, the transesterification can be made by lipases, such as lipase from Candida antarctica. In one embodiment, if necessary, the polyunsaturated oil composition can be subjected to a deodorization step under vacuum and a countercurrent flow of nitrogen or water steam. In various embodiments, the composition is useful in a method to increase phagocytic activity, comprising administering to a subject a phagocytic activity enhancing amount of the composition. In a preferred embodiment, the composition is useful in a method to enhance macrophage polarization toward an M2-like phenotype in a subject, comprising administering to the subject a macrophage polarization enhancing amount of the composition. In one embodiment, the composition is useful for resolving inflammation associated with a disease in a subject, administering to the subject an inflammation-resolving amount of the composition. The diseases can be selected from Crohn's disease, irritable bowel disease (IBD), fatty liver, wound healing, arterial inflammation, sickle-cell disease, arthritis, psoriasis, urticaria, vasculitis, asthma, ocular inflammation, pulmonary inflammation, dermatitis, cardiovascular diseases, AIDS, Alzheimer's disease, atherosclerosis, cancer, type 2 diabetes, hypertension, infectious diseases, leukemia/lymphoma, metabolic syndrome, neonatology, neuromuscular disorders, obesity, perinatal disorders, rheumatic diseases, stroke, surgical transplantation, vascular disorders, periodontal diseases, and brain injury. In other embodiments, the composition can be used as a vaccine coadjuvant and/or as a chemotherapeutic coadjuvant. In various embodiments, the composition comprises EPA in an amount between about 10% to about 26% by weight and DHA in an amount of about 30% to about 45% by weight, and 17-HDHA and 18-HEPE in a collective amount of about 0.0005% to about 1% by weight of the composition. In one embodiment, the composition comprises EPA in an amount between about 10% to about 26% by weight and DHA in an amount of about 30% to about 45% by weight, 17-HDHA in an amount of about 0.0004% to about 0.04% by weight of the composition, and 18-HEPE in an amount of about 0.0003% to about 0.04% by weight of the composition. The composition can further comprise DPA. In one embodiment, the composition comprises EPA and/or DHA and DPA in an amount between about 20% to about 95%, and 17-HDHA and 18-HEPE in an amount of about 0.0005% to about 1% by weight of the composition. In some embodiments, the composition comprises EPA, DHA and DPA in an amount between about 20% to about 95%, and 17-HDHA and 18-HEPE in a collective amount of about 0.0005% to about 1% by weight of the composition. In various embodiments, the composition also contains at least one additional SPM, such as 18R/S-HEPE, 17R/S-HDHA, 5S-HEPE, 15R/S-HEPE, 4R/S-HDHA, 7R/S-HDHA, 10R/S-HDHA, 14R/S-HDHA, and/or RvE1. The Omega-3 fatty acid content in the composition is determined on a weight/weight percent basis relative to all fatty acids present in the composition as determined by methods such as those disclosed in the European Pharmacopeia monograph for Omega-3 fatty acids, European Pharmacopeia monograph method 2.49.29 or any equivalent method using gas chromatography, HPLC, FPLC, or other chromatographic method, and such content is expressed as a percentage in FFA content. 17-HDHA and 18-HEPE content of the composition is determined on a weight/weight basis relative to all fatty acids present in the composition using liquid chromatography-tandem mass spectrometry employing diagnostic transitions and co-elution with synthesized deuterated standards of 17-HDHA and 18-HEPE. In some embodiments, the composition further comprises an acceptable carrier or excipient that may be administered by a variety of routes, for example, oral, topical, transdermal, parenteral, intravenous, intramuscular, rectal, sublingual, epidural, intracerebral, intraocular, subcutaneous, vaginal, transmucosal, intrathecal or intraarticular, among other acceptable carriers or excipients known to those of skill in the art. The composition might also include one or more active ingredients, such as aspirin, curcumin, polyphenols, lutein, astaxanthin, and several vitamins (including vitamin C and vitamin E), among others. In some embodiments, the composition can contain an antioxidant to improve stability of the composition. In some embodiments, 17-HDHA and 18-HEPE can act as antioxidants in the composition. The composition can be delivered in a variety of forms, such as capsules, pills, tablets, a powder, sachets, emulsions, suspensions, solutions, sprays for intranasal administration, aerosols, gels, soft and hard gelatin capsules, liposomes, chewable tablets, microsphere delivery systems, creams, sterile injectable solutions, an osmotic delivery system, dry powder inhalers, orally disintegrating tablets, oral sprays, hydrogels, dermal patches, transdermal patches, lotions, or syrups, among other delivery forms known in the art. In some embodiments, the composition can be present in a capsule or other suitable dosage unit to be taken orally by a subject. In some embodiments, the composition can be present in a soft or hard gelatin capsule with different sizes, shapes, colors and forms to address bioavailability enhancement, composition stability and other composition challenges. In some embodiments, the composition can be delivered in an emulsion suitable for oral and/or parenteral administration to a subject. Such an emulsion can simplify the daily intake to just one sachet or spoon serving in oral administration and can also ensure minimal oxidation and good bioavailability of EPA, DHA, 17-HDHA and 18-HEPE in the composition, as well as increase the shelf life of the composition. Furthermore, parenteral nutrition can improve nutrient delivery to critically ill subjects. EPA, DHA and DPA are commonly found in marine oils, including fish, algae and krill oil, among other oils; in contrast, ALA is commonly found in seeds, such as flax seeds, camelina seeds, and chia seeds, among others. These are not the exclusive sources of Omega-3, however: it can also be obtained from sources as vegetable, microbial, and animal, or combinations thereof. In some embodiments, the Omega-3 fatty acids are obtained from an animal, vegetable and/or microbial source, alongside combinations of Omega-3 fatty acids obtained from different sources. In some embodiments, the Omega-3 fatty acids are obtained from fish oil, krill oil, vegetable oil, microbial oil and/or combinations thereof. In one embodiment, Omega-3 fatty acids are obtained from fish oil. In one embodiment, Omega-3 fatty acids are obtained from krill oil. In one embodiment, Omega-3 fatty acids are obtained from algae. As described in WO 2013/170006, which is incorporated herein by reference in its entirety, SPMs, including 17-HDHA and 18-HEPE, can be found in different natural sources as fish, krill, algae or other organisms containing Omega-3 fatty acids. In some embodiments, 17-HDHA and 18-HEPE are obtained from animal, vegetable and microbial sources. In some embodiments, 17-HDHA and 18-HEPE are obtained from fish oil, krill oil, vegetable oil, microbial oil and combinations thereof. In one embodiment, the 17-HDHA and 18-HEPE are obtained from fish oil. In one embodiment, the 17-HDHA and 18-HEPE are obtained from krill oil. In one embodiment, the 17-HDHA and 18-HEPE are obtained from algae. Omega-3 fatty acids, 17-HDHA and 18-HEPE can be present in the composition in different chemical forms, including free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides, and combinations thereof. In an embodiment, Omega-3 fatty acids are in ethyl ester form in the composition. In an embodiment, the 17-HDHA and 18-HEPE are in ethyl ester form in an amount of at least 80% by weight, and in a mixture of partial glycerides (tri-glycerides, mono-glycerides and di-glycerides). In one embodiment, EPA, DHA, 17-HDHA and 18-HEPE are in ethyl ester form. The composition can be obtained using a variety of methods, for example, chromatography, extraction, supercritical extraction, distillation and vacuum rectification, and/or any other method generally known to those skilled in the art of isolating and purifying Omega-3 polyunsaturated fatty acids. The composition can be obtained from two different starting materials consisting in a crude oil or an esterified concentrated oil. In various embodiments, the crude oil or the esterified concentrated oil is obtained from marine oil, vegetable oil, microbial oil, and mixtures of these oils. In various embodiments, the crude oil or the esterified concentrated marine oil is fish oil and/or krill oil. In one embodiment, the crude oil or the esterified concentrated oil is obtained from fish oil. In one embodiment, the oils can be obtained from anchovy, sardine, Jack mackerel, mackerel, tuna, salmon, Pollock, krill and/or algae. In one embodiment, the crude oil or the esterified concentrated oil is obtained from krill oil. In one embodiment, the crude oil or the esterified concentrated oil is obtained from algae oil. In various embodiments, when a crude oil is used as a starting material, the first step is a chemical esterification of the oil with ethanol and a basic catalyst, at a temperature of about 55° C. to about 85° C., to produce an esterified oil. In an embodiment, the basic catalyst used in the chemical esterification is sodium ethoxide (EtONa). In an embodiment, the basic catalyst used in the chemical esterification is potassium hydroxide (KOH). This esterified oil is distilled to separate fatty acids shorter than 20 carbon atoms. This distillation is under vacuum of about 0.01 mbar to about 0.6 mbar and temperature of about 130° C. to about 190° C. for about 10 seconds to about 5 minutes to obtain a polyunsaturated fatty acid composition comprising about 20% to about 95% by weight EPA and/or DHA, and about 0.0005% to about 1% 17-HDHA and 18-HEPE by weight. In one embodiment, if necessary, after elimination of fatty acids shorter than 20 carbon atoms, the esterified oil can be distilled to eliminate fatty acids higher than 23 carbon atoms. In one embodiment, the distillation is a short path molecular distillation process. These distillation steps to eliminate fatty acids shorter than 20 carbon atoms can be covered in several stages in series, until a polyunsaturated fatty acid composition comprising the desired composition is obtained. Before the step of distillation, to improve the quality of the composition and to remove oxidation, decomposition and/or degradation products, the polyunsaturated fatty acid composition is subjected to a supercritical fluid extraction (SFE) with CO2 as supercritical fluid, pressure of about 80 bar to about 115 bar, and temperature of about 39° C. to about 46° C. In an embodiment, the oxidation, decomposition and/or degradation products eliminated by SFE comprise one or more of oligomers, dimers, polymers and conjugated dienes. In an embodiment, the process, if necessary, can further comprise a step of bleaching the polyunsaturated fatty acid composition under vacuum with bleaching earths and diatomaceous earths. In an embodiment, the process further comprises a step of transesterification of the polyunsaturated fatty acid composition to obtain a composition containing a mixture of tri-glycerides and partial glycerides (mono-glycerides and di-glycerides). This transesterification yields a composition comprising a mixture of tri-glycerides and partial glycerides (mono-glycerides and di-glycerides). In an embodiment, this transesterification is catalyzed by lipases. In a preferred embodiment, lipases are active as of about 25° C., with an optimum temperature of about 50° C. to about 70° C. In one embodiment, the reaction of transesterification is carried out under vacuum. In an embodiment, the polyunsaturated oil composition, if necessary, can be subjected to a deodorization step under vacuum and a countercurrent flow of nitrogen or water steam. In a preferred embodiment, the deodorization step under vacuum is performed at a temperature of about 130° C. to about 200° C. When the starting material is esterified concentrated oil, the process is the same as that described above, but without the first step of esterification of the starting material. In various embodiments, this concentrated oil is distilled to separate fatty acids shorter than 20 carbon atoms. This distillation is under vacuum of about 0.01 mbar to about 0.6 mbar and temperature of about 130° C. to about 190° C. for about 10 seconds to about 5 minutes to obtain a polyunsaturated fatty acid composition comprising about 20% to about 95% by weight EPA and/or DHA, and about 0.0005% to about 1% 17-HDHA and 18-HEPE by weight. These distillation steps to eliminate fatty acids shorter than 20 carbon atoms can be covered in several stages in series, until a polyunsaturated fatty acid composition comprising the desired composition is obtained. In one embodiment, if necessary, after elimination of fatty acids shorter than 20 carbon atoms, the concentrated oil can be distilled to eliminate fatty acids higher than 23 carbon atoms. In one embodiment, the distillation is a short path molecular distillation process. Before the step of distillation, to improve the quality of the composition and to remove oxidation, decomposition and/or degradation products, the polyunsaturated fatty acid composition is subjected to a supercritical fluid extraction (SFE) with CO2 as supercritical fluid, pressure of about 80 bar to about 115 bar, and temperature of about 39° C. to about 46° C. In an embodiment, the process, if necessary, can further comprise a step of bleaching the polyunsaturated fatty acid composition under vacuum with bleaching earths and diatomaceous earths. In an embodiment, the process further comprises a step of transesterification of the polyunsaturated fatty acid composition to obtain a composition containing a mixture of tri-glycerides and partial glycerides (mono-glycerides and di-glycerides). This transesterification yields a mixture of tri-glycerides and partial glycerides (mono-glycerides and di-glycerides). In an embodiment, this transesterification is catalyzed by lipases. In one embodiment, lipases are active as of about 25° C., with an optimum temperature of about 50° C. to about 70° C. In one embodiment, the reaction of transesterification is carried out under vacuum. In an embodiment, the polyunsaturated oil composition, if necessary, can be subjected to a deodorization step under vacuum and a countercurrent flow of nitrogen or water steam. In a preferred embodiment, the deodorization step under vacuum is performed at a temperature of about 130° C. to about 200° C. Phagocytosis is an important physiological process characterized by the ingestion of foreign particles and killing of microorganisms by phagocytic leukocytes (granulocytes, monocytes and macrophages). Phagocytosis involves a complex series of events including, for example, production of pro- and anti-inflammatory cytokines and chemokines. Deficiencies in phagocytosis cause several pathological conditions (i.e., chronic inflammatory diseases) and cause severe and recurrent microbial (bacterial and fungal) infections. The activation of non-phlogistic (non-fever causing) phagocytosis and polarization of macrophages toward an M2-like phenotype is an essential step for the resolution of the inflammatory response and complete homeostasis of adipose tissue. Several SPMs, including RvD1, RvD2, Protectin D1, and Mar-1 (maresin 1), have been established as mediators that stimulate macrophage switching to the M2 phenotype. In some embodiments, the composition is useful to increase phagocytic activity of macrophages in a subject, administering to the subject a phagocytic activity enhancing amount of a composition. When comparing the activation of macrophages through this application with Omacor and a 3624 EE, the results show that Omacor and 3624 EE reduce the activation of macrophages; instead, the composition of interest produces an increase of phagocytic activity and polarization of macrophages toward a pro-resolution state (i.e., M2) (shown in example 2). In one embodiment, the increase of the phagocytic activity of the composition is at least 55% of the maximum value obtained for Mar-1 at concentration 1 nM. In some embodiments, the present disclosure provides methods for stimulating macrophage activation and polarization toward a pro-resolution state (i.e., M2) in a subject by enhancing the amount of SPMs and/or SPM Precursor species present in a naturally occurring oil composition. In one embodiment, the polyunsaturated fatty acid composition features methods to elevate SPM levels in plasma in a subject by administering to the subject an effective amount of the composition effective to elevate SPM levels in a subject. RvD1 has been established as an activator of non-phlogistic phagocytosis in macrophages, which is an essential step for the resolution of the inflammatory response. In some embodiments, the composition features methods to elevate RvD1 levels in plasma in a subject by administering to the subject an effective amount of the composition to elevate RvD1 level in a subject. In one embodiment, subjects who were administered 4 capsules of a composition containing 250 mg per capsule, as shown in FIG. 3, experienced a 53% greater elevation in plasma levels of RvD1 than subjects who were administered a placebo. In one preferred embodiment, the plasma elevation is produced one hour after the administration of the capsules. In one embodiment, the effective amount to elevate RvD1 in plasma levels in a subject is a daily dose of at least 300 mg DHA, approximately 100 mg EPA, ˜12.5 μg of 17-HDHA, and ˜10 μg of 18-HEPE. In another preferred embodiment, the effective amount to elevate RvD1 in plasma levels in a subject is a daily dose of at least ˜1200 mg DHA, ˜400 mg EPA, ˜50 μg of 17-HDHA and ˜40 μg of 18-HEPE. In some embodiments, the polyunsaturated fatty acid composition features methods for treating and resolving inflammation in a subject (e.g., a human being, dog, cat, horse and other animals) having a disease with an inflammatory component by administering to the subject an effective amount of the composition in an amount effective to activate resolution mechanisms and thus resolve local inflammation. In several embodiments, the diseases with an inflammatory component can be selected from Crohn's disease, IBD, ulcerative colitis, fatty liver, wound healing, arterial inflammation, sickle-cell disease, arthritis, psoriasis, urticaria, vasculitis, asthma, ocular inflammation, pulmonary inflammation, dermatitis, cardiovascular diseases, AIDS, Alzheimer's disease, atherosclerosis, cancer, type 2 diabetes, hypertension, infectious diseases, leukemia/lymphoma, metabolic syndrome, neonatology, neuromuscular disorders, obesity, perinatal disorders, rheumatic diseases, stroke, surgical transplantation, vascular disorders, periodontal diseases, brain injury, trauma and neuronal inflammation, among others. In some embodiments, the composition can be manufactured as a pharmaceutical composition, a dietary supplement, a nutraceutical product, a medical food composition, and a nutritional composition for infant formulae and/or prenatal formulae. In other embodiments, the composition can be used as a vaccine coadjuvant to potentiate the immune response to an antigen and/or modulate it towards the desired immune response. The tumour microenvironment, orchestrated largely by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival and migration of the tumour cells. Now it is well known that inflammation is a critical component of tumour progression. In another embodiment, due to the inflammatory component associated with cancer and the inflammation-resolving character of the composition, the composition can be useful as a chemotherapeutic coadjuvant. In some embodiments, the present disclosure provides a polyunsaturated fatty acid composition comprising about 20% to about 95%, by weight, Omega-3 fatty acids and 17-HDHA and 18-HEPE in a total amount of about 0.0005% to about 1%, by weight. In some embodiments, the composition further comprises an acceptable carrier. In some embodiments, the composition is present in a capsule or other suitable dosage unit. In some embodiments, the Omega-3 fatty acids comprise DHA and/or EPA. In some embodiments, the DHA is present in an amount of about 30% to about 45% by weight of the composition; the EPA is present in an amount of about 10% to about 26% by weight of the composition; the 17-HDHA is present in an amount of about 0.0004% to about 0.04% by weight of the composition; and the 18-HEPE is present in an amount of about 0.0003% to about 0.04% by weight of the composition. In some embodiments, the composition further comprises DPA. In some embodiments, the composition further comprises 14-HDHA, optionally 5-HETE, and optionally 7R,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoic acid (“MaR1”). In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from a vegetable, a microbe, an animal, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil, krill oil, vegetable oil, microbial oil, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil. In some embodiments, the Omega-3 fatty acids are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the Omega-3 fatty acids are in ethyl ester form. In some embodiments, the 17-HDHA and 18-HEPE are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the 17-HDHA and 18-HEPE are in the form of mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the present disclosure provides a dietary supplement, nutraceutical product, or medical food composition comprising a composition comprising about 20% to about 95%, by weight, Omega-3 fatty acids and 17-HDHA and 18-HEPE in a total amount of about 0.0005% to about 1%, by weight. In some embodiments, the composition further comprises an acceptable carrier. In some embodiments, the composition is present in a capsule or other suitable dosage unit. In some embodiments, the Omega-3 fatty acids comprise DHA and/or EPA. In some embodiments, the DHA is present in an amount of about 30% to about 45% by weight of the composition; the EPA is present in an amount of about 10% to about 26% by weight of the composition; the 17-HDHA is present in an amount of about 0.0004% to about 0.04% by weight of the composition; and the 18-HEPE is present in an amount of about 0.0003% to about 0.04% by weight of the composition. In some embodiments, the composition further comprises DPA. In some embodiments, the composition further comprises 14-HDHA, optionally 5-HETE, and optionally 7R,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoic acid (“MaR1”). In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from a vegetable, a microbe, an animal, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil, krill oil, vegetable oil, microbial oil, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil. In some embodiments, the Omega-3 fatty acids are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the Omega-3 fatty acids are in ethyl ester form. In some embodiments, the 17-HDHA and 18-HEPE are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the 17-HDHA and 18-HEPE are in the form of mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the present disclosure provides a nutritional composition for infant formulae and/or prenatal formulae comprising a composition comprising about 20% to about 95%, by weight, Omega-3 fatty acids and 17-HDHA and 18-HEPE in a total amount of about 0.0005% to about 1%, by weight. In some embodiments, the composition further comprises an acceptable carrier. In some embodiments, the composition is present in a capsule or other suitable dosage unit. In some embodiments, the Omega-3 fatty acids comprise DHA and/or EPA. In some embodiments, the DHA is present in an amount of about 30% to about 45% by weight of the composition; the EPA is present in an amount of about 10% to about 26% by weight of the composition; the 17-HDHA is present in an amount of about 0.0004% to about 0.04% by weight of the composition; and the 18-HEPE is present in an amount of about 0.0003% to about 0.04% by weight of the composition. In some embodiments, the composition further comprises DPA. In some embodiments, the composition further comprises 14-HDHA, optionally 5-HETE, and optionally 7R,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoic acid (“MaR1”). In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from a vegetable, a microbe, an animal, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil, krill oil, vegetable oil, microbial oil, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil. In some embodiments, the Omega-3 fatty acids are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the Omega-3 fatty acids are in ethyl ester form. In some embodiments, the 17-HDHA and 18-HEPE are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the 17-HDHA and 18-HEPE are in the form of mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a composition comprising about 20% to about 95%, by weight, Omega-3 fatty acids and 17-HDHA and 18-HEPE in a total amount of about 0.0005% to about 1%, by weight. In some embodiments, the composition further comprises an acceptable carrier. In some embodiments, the composition is present in a capsule or other suitable dosage unit. In some embodiments, the Omega-3 fatty acids comprise DHA and/or EPA. In some embodiments, the DHA is present in an amount of about 30% to about 45% by weight of the composition; the EPA is present in an amount of about 10% to about 26% by weight of the composition; the 17-HDHA is present in an amount of about 0.0004% to about 0.04% by weight of the composition; and the 18-HEPE is present in an amount of about 0.0003% to about 0.04% by weight of the composition. In some embodiments, the composition further comprises DPA. In some embodiments, the composition further comprises 14-HDHA, optionally 5-HETE, and optionally 7R,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoic acid (“MaR1”). In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from a vegetable, a microbe, an animal, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil, krill oil, vegetable oil, microbial oil, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil. In some embodiments, the Omega-3 fatty acids are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the Omega-3 fatty acids are in ethyl ester form. In some embodiments, the 17-HDHA and 18-HEPE are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the 17-HDHA and 18-HEPE are in the form of mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the present disclosure provides a process for obtaining a composition as disclosed herein from an oil using a method selected from chromatography, extraction, distillation and/or vacuum rectification. In some embodiments, the composition comprises about 20% to about 95%, by weight, Omega-3 fatty acids, and 17-H DHA and 18-HEPE in a total amount of about 0.0005% to about 1%, by weight. In some embodiments, the composition further comprises an acceptable carrier. In some embodiments, the composition is present in a capsule or other suitable dosage unit. In some embodiments, the Omega-3 fatty acids comprise DHA and/or EPA. In some embodiments, the DHA is present in an amount of about 30% to about 45% by weight of the composition; the EPA is present in an amount of about 10% to about 26% by weight of the composition; the 17-HDHA is present in an amount of about 0.0004% to about 0.04% by weight of the composition; and the 18-HEPE is present in an amount of about 0.0003% to about 0.04% by weight of the composition. In some embodiments, the composition further comprises DPA. In some embodiments, the composition further comprises 14-HDHA, optionally 5-HETE, and optionally 7R,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoic acid (“MaR1”). In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from a vegetable, a microbe, an animal, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil, krill oil, vegetable oil, microbial oil, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil. In some embodiments, the Omega-3 fatty acids are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the Omega-3 fatty acids are in ethyl ester form. In some embodiments, the 17-HDHA and 18-HEPE are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the 17-HDHA and 18-HEPE are in the form of mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the present disclosure provides a process for obtaining a composition as disclosed herein from a crude oil, the process comprising: (i) chemically esterifying crude oil with ethanol and a basic catalyst, at a temperature of about 55° C. to about 75° C. to produce esterified oil; (ii) distilling the esterified oil, under vacuum of about 0.01 mbar to about 0.6 mbar and at a temperature of about 130° C. to 190° C. for about 10 seconds to about 5 minutes to separate fatty acids shorter than 20 carbons to obtain a distilled esterified oil comprising about 20% to about 95% by weight EPA and/or DHA, and about 0.0005% to 1% by weight 17-HDHA and 18-HEPE; and (ii) subjecting the polyunsaturated fatty acid composition obtained in step (ii) to supercritical fluid extraction with CO2 as a supercritical fluid at a temperature of about 39° C. to 46° C. and pressure of about 80 bar to 115 bar to remove oxidation, decomposition and/or degradation products as oligomers, dimers, polymers and conjugated dienes from the composition. In some embodiments, step (ii) is made in several stages in series. In some embodiments, the process further comprises distilling the esterified oil obtained in step (ii) to remove fatty acids containing more than 23 carbon atoms in the corresponding fatty acid chains before step (iii). In some embodiments, the process further comprises bleaching the polyunsaturated fatty acid composition under vacuum with bleaching earths and diatomaceous earths. In some embodiments, the process further comprises transesterifying the polyunsaturated fatty acid composition in ethyl ester form to obtain a composition containing a mixture of tri-glycerides, mono-glycerides and di-glycerides. In some embodiments, the transesterifying comprises catalysis with one or more lipases. In some embodiments, the process further comprises deodorizing the composition of interest by applying a counterflow of nitrogen or water steam to the composition under vacuum. In some embodiments, the oil is obtained from fish, krill, vegetable, and/or microbes. In some embodiments, the composition comprises about 20% to about 95%, by weight, Omega-3 fatty acids and 17-HDHA and 18-HEPE in a total amount of about 0.0005% to about 1%, by weight. In some embodiments, the composition further comprises an acceptable carrier. In some embodiments, the composition is present in a capsule or other suitable dosage unit. In some embodiments, the Omega-3 fatty acids comprise DHA and/or EPA. In some embodiments, the DHA is present in an amount of about 30% to about 45% by weight of the composition; the EPA is present in an amount of about 10% to about 26% by weight of the composition; the 17-HDHA is present in an amount of about 0.0004% to about 0.04% by weight of the composition; and the 18-HEPE is present in an amount of about 0.0003% to about 0.04% by weight of the composition. In some embodiments, the composition further comprises DPA. In some embodiments, the composition further comprises 14-HDHA, optionally 5-HETE, and optionally 7R,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoic acid (“MaR1”). In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from a vegetable, a microbe, an animal, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil, krill oil, vegetable oil, microbial oil, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil. In some embodiments, the Omega-3 fatty acids are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the Omega-3 fatty acids are in ethyl ester form. In some embodiments, the 17-HDHA and 18-HEPE are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the 17-HDHA and 18-HEPE are in the form of mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the present disclosure provides a process for obtaining a polyunsaturated fatty acid composition from a concentrated esterified oil comprising: (i) distilling the concentrated esterified oil under vacuum of about 0.01 mbar to 0.6 mbar and at a temperature of about 130° C. to about 190° C. for about 10 seconds to about 5 minutes to separate fatty acids having fewer than 20 carbon atoms in the corresponding fatty acid chain to obtain a distilled esterified oil comprising about 20% to about 95% by weight EPA and/or DHA, and about 0.0005% to about 1% by weight 17-HDHA and 18-HEPE; (ii) subjecting the distilled esterified oil obtained in step (i) to supercritical fluid extraction with CO2 as a supercritical fluid at a temperature of about 20° C. to 40° C. and at a pressure of about 80 bar to about 115 bar to remove oxidation, decomposition and degradation products as oligomers, dimers, polymers and conjugated dienes from the composition. In some embodiments, step (i) is made in several stages in series. In some embodiments, the process further comprises distilling the distilled esterified oil obtained in step (i) to remove fatty acids having more than 23 carbon atoms in the corresponding fatty acid chain before step (ii). In some embodiments, the process further comprises bleaching the polyunsaturated fatty acid ethyl ester composition under vacuum with bleaching earths and diatomaceous earths. In some embodiments, the process further comprises transesterifying the polyunsaturated fatty acid ethyl ester composition to obtain a composition containing a mixture of tri-glycerides, mono-glycerides and di-glycerides. In some embodiments, the transesterifying comprises catalysis with one or more lipases. In some embodiments, the process further comprises deodorizing the polyunsaturated fatty acid ethyl ester composition of interest by applying a counterflow of nitrogen or water steam to the composition under vacuum. In some embodiments, the concentrated esterified oil is obtained from fish, krill, vegetable, and/or microbes. In some embodiments, the composition comprises about 20% to about 95%, by weight, Omega-3 fatty acids and 17-HDHA and 18-HEPE in a total amount of about 0.0005% to about 1%, by weight. In some embodiments, the composition further comprises an acceptable carrier. In some embodiments, the composition is present in a capsule or other suitable dosage unit. In some embodiments, the Omega-3 fatty acids comprise DHA and/or EPA. In some embodiments, the DHA is present in an amount of about 30% to about 45% by weight of the composition; the EPA is present in an amount of about 10% to about 26% by weight of the composition; the 17-HDHA is present in an amount of about 0.0004% to about 0.04% by weight of the composition; and the 18-HEPE is present in an amount of about 0.0003% to about 0.04% by weight of the composition. In some embodiments, the composition further comprises DPA. In some embodiments, the composition further comprises 14-HDHA, optionally 5-HETE, and optionally 7R,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoic acid (“MaR1”). In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from a vegetable, a microbe, an animal, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil, krill oil, vegetable oil, microbial oil, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil. In some embodiments, the Omega-3 fatty acids are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the Omega-3 fatty acids are in ethyl ester form. In some embodiments, the 17-HDHA and 18-HEPE are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the 17-HDHA and 18-HEPE are in the form of mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the present disclosure provides a method of increasing phagocytic activity of macrophages in a subject, comprising administering to the subject a phagocytic activity enhancing amount of a composition as disclosed herein. In some embodiments, the composition comprises about 20% to about 95%, by weight, Omega-3 fatty acids and 17-HDHA and 18-HEPE in a total amount of about 0.0005% to about 1%, by weight. In some embodiments, the composition further comprises an acceptable carrier. In some embodiments, the composition is present in a capsule or other suitable dosage unit. In some embodiments, the Omega-3 fatty acids comprise DHA and/or EPA. In some embodiments, the DHA is present in an amount of about 30% to about 45% by weight of the composition; the EPA is present in an amount of about 10% to about 26% by weight of the composition; the 17-HDHA is present in an amount of about 0.0004% to about 0.04% by weight of the composition; and the 18-HEPE is present in an amount of about 0.0003% to about 0.04% by weight of the composition. In some embodiments, the composition further comprises DPA. In some embodiments, the composition further comprises 14-HDHA, optionally 5-HETE, and optionally 7R,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoic acid (“MaR1”). In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from a vegetable, a microbe, an animal, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil, krill oil, vegetable oil, microbial oil, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil. In some embodiments, the Omega-3 fatty acids are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the Omega-3 fatty acids are in ethyl ester form. In some embodiments, the 17-HDHA and 18-HEPE are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the 17-HDHA and 18-HEPE are in the form of mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the present disclosure provides a method of enhancing macrophage polarization toward a pro-resolution phenotype in a subject, comprising administering to the subject a macrophage polarization enhancing amount of a composition as disclosed herein. In some embodiments, the composition comprises about 20% to about 95%, by weight, Omega-3 fatty acids and 17-HDHA and 18-HEPE in a total amount of about 0.0005% to about 1%, by weight. In some embodiments, the composition further comprises an acceptable carrier. In some embodiments, the composition is present in a capsule or other suitable dosage unit. In some embodiments, the Omega-3 fatty acids comprise DHA and/or EPA. In some embodiments, the DHA is present in an amount of about 30% to about 45% by weight of the composition; the EPA is present in an amount of about 10% to about 26% by weight of the composition; the 17-HDHA is present in an amount of about 0.0004% to about 0.04% by weight of the composition; and the 18-HEPE is present in an amount of about 0.0003% to about 0.04% by weight of the composition. In some embodiments, the composition further comprises DPA. In some embodiments, the composition further comprises 14-HDHA, optionally 5-HETE, and optionally 7R,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoic acid (“MaR1”). In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from a vegetable, a microbe, an animal, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil, krill oil, vegetable oil, microbial oil, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil. In some embodiments, the Omega-3 fatty acids are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the Omega-3 fatty acids are in ethyl ester form. In some embodiments, the 17-HDHA and 18-HEPE are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the 17-HDHA and 18-HEPE are in the form of mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the present disclosure provides a method of resolving inflammation associated with a disease in a subject in need thereof, comprising administering to the subject an inflammation-resolving amount of a composition as disclosed herein. In some embodiments, the composition comprises about 20% to about 95%, by weight, Omega-3 fatty acids and 17-HDHA and 18-HEPE in a total amount of about 0.0005% to about 1%, by weight. In some embodiments, the composition further comprises an acceptable carrier. In some embodiments, the composition is present in a capsule or other suitable dosage unit. In some embodiments, the Omega-3 fatty acids comprise DHA and/or EPA. In some embodiments, the DHA is present in an amount of about 30% to about 45% by weight of the composition; the EPA is present in an amount of about 10% to about 26% by weight of the composition; the 17-HDHA is present in an amount of about 0.0004% to about 0.04% by weight of the composition; and the 18-HEPE is present in an amount of about 0.0003% to about 0.04% by weight of the composition. In some embodiments, the composition further comprises DPA. In some embodiments, the composition further comprises 14-HDHA, optionally 5-HETE, and optionally 7R,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoic acid (“MaR1”). In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from a vegetable, a microbe, an animal, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil, krill oil, vegetable oil, microbial oil, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil. In some embodiments, the Omega-3 fatty acids are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the Omega-3 fatty acids are in ethyl ester form. In some embodiments, the 17-HDHA and 18-HEPE are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the 17-HDHA and 18-HEPE are in the form of mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the disease is selected from Crohn's disease, irritable bowel disease (“IBD”), fatty liver, wound healing, arterial inflammation, sickle-cell disease, arthritis, psoriasis, urticaria, vasculitis, asthma, ocular inflammation, pulmonary inflammation, dermatitis, cardiovascular diseases, AIDS, Alzheimer's disease, atherosclerosis, cancer, type 2 diabetes, hypertension, infectious diseases, leukemia/lymphoma, metabolic syndrome, neonatology, neuromuscular disorders, obesity, perinatal disorders, rheumatic diseases, stroke, surgical transplantation, vascular disorders, periodontal diseases, brain injury, trauma and neuronal inflammation. In some embodiments, the present disclosure provides a method for elevating SPM levels in plasma of a human subject, comprising administering to the human subject a composition as disclosed herein. In some embodiments, the composition comprises about 20% to about 95%, by weight, Omega-3 fatty acids and 17-HDHA and 18-HEPE in a total amount of about 0.0005% to about 1%, by weight. In some embodiments, the composition further comprises an acceptable carrier. In some embodiments, the composition is present in a capsule or other suitable dosage unit. In some embodiments, the Omega-3 fatty acids comprise DHA and/or EPA. In some embodiments, the DHA is present in an amount of about 30% to about 45% by weight of the composition; the EPA is present in an amount of about 10% to about 26% by weight of the composition; the 17-HDHA is present in an amount of about 0.0004% to about 0.04% by weight of the composition; and the 18-HEPE is present in an amount of about 0.0003% to about 0.04% by weight of the composition. In some embodiments, the composition further comprises DPA. In some embodiments, the composition further comprises 14-HDHA, optionally 5-HETE, and optionally 7R,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoic acid (“MaR1”). In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from a vegetable, a microbe, an animal, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil, krill oil, vegetable oil, microbial oil, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil. In some embodiments, the Omega-3 fatty acids are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the Omega-3 fatty acids are in ethyl ester form. In some embodiments, the 17-HDHA and 18-HEPE are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the 17-HDHA and 18-HEPE are in the form of mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the SPM comprises RvD1. In some embodiments, the present disclosure provides a use of a composition as disclosed herein as a vaccine coadjuvant. In some embodiments, the composition comprises about 20% to about 95%, by weight, Omega-3 fatty acids and 17-HDHA and 18-HEPE in a total amount of about 0.0005% to about 1%, by weight. In some embodiments, the composition further comprises an acceptable carrier. In some embodiments, the composition is present in a capsule or other suitable dosage unit. In some embodiments, the Omega-3 fatty acids comprise DHA and/or EPA. In some embodiments, the DHA is present in an amount of about 30% to about 45% by weight of the composition; the EPA is present in an amount of about 10% to about 26% by weight of the composition; the 17-HDHA is present in an amount of about 0.0004% to about 0.04% by weight of the composition; and the 18-HEPE is present in an amount of about 0.0003% to about 0.04% by weight of the composition. In some embodiments, the composition further comprises DPA. In some embodiments, the composition further comprises 14-HDHA, optionally 5-HETE, and optionally 7R,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoic acid (“MaR1”). In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from a vegetable, a microbe, an animal, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil, krill oil, vegetable oil, microbial oil, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil. In some embodiments, the Omega-3 fatty acids are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the Omega-3 fatty acids are in ethyl ester form. In some embodiments, the 17-HDHA and 18-HEPE are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the 17-HDHA and 18-HEPE are in the form of mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the present disclosure provides a use of a composition as disclosed herein as a chemotherapeutic coadjuvant. In some embodiments, the composition comprises about 20% to about 95%, by weight, Omega-3 fatty acids and 17-HDHA and 18-HEPE in a total amount of about 0.0005% to about 1%, by weight. In some embodiments, the composition further comprises an acceptable carrier. In some embodiments, the composition is present in a capsule or other suitable dosage unit. In some embodiments, the Omega-3 fatty acids comprise DHA and/or EPA. In some embodiments, the DHA is present in an amount of about 30% to about 45% by weight of the composition; the EPA is present in an amount of about 10% to about 26% by weight of the composition; the 17-HDHA is present in an amount of about 0.0004% to about 0.04% by weight of the composition; and the 18-HEPE is present in an amount of about 0.0003% to about 0.04% by weight of the composition. In some embodiments, the composition further comprises DPA. In some embodiments, the composition further comprises 14-HDHA, optionally 5-HETE, and optionally 7R,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoic acid (“MaR1”). In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from a vegetable, a microbe, an animal, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil, krill oil, vegetable oil, microbial oil, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil. In some embodiments, the Omega-3 fatty acids are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the Omega-3 fatty acids are in ethyl ester form. In some embodiments, the 17-HDHA and 18-HEPE are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the 17-HDHA and 18-HEPE are in the form of mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the present disclosure provides a composition as disclosed herein for increasing phagocytic activity of macrophages in a subject. In some embodiments, the composition comprises about 20% to about 95%, by weight, Omega-3 fatty acids and 17-HDHA and 18-HEPE in a total amount of about 0.0005% to about 1%, by weight. In some embodiments, the composition further comprises an acceptable carrier. In some embodiments, the composition is present in a capsule or other suitable dosage unit. In some embodiments, the Omega-3 fatty acids comprise DHA and/or EPA. In some embodiments, the DHA is present in an amount of about 30% to about 45% by weight of the composition; the EPA is present in an amount of about 10% to about 26% by weight of the composition; the 17-HDHA is present in an amount of about 0.0004% to about 0.04% by weight of the composition; and the 18-HEPE is present in an amount of about 0.0003% to about 0.04% by weight of the composition. In some embodiments, the composition further comprises DPA. In some embodiments, the composition further comprises 14-HDHA, optionally 5-HETE, and optionally 7R,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoic acid (“MaR1”). In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from a vegetable, a microbe, an animal, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil, krill oil, vegetable oil, microbial oil, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil. In some embodiments, the Omega-3 fatty acids are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the Omega-3 fatty acids are in ethyl ester form. In some embodiments, the 17-HDHA and 18-HEPE are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the 17-HDHA and 18-HEPE are in the form of mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the present disclosure provides a composition as disclosed herein for enhancing macrophage polarization toward a pro-resolution phenotype in a subject. In some embodiments, the composition comprises about 20% to about 95%, by weight, Omega-3 fatty acids and 17-HDHA and 18-HEPE in a total amount of about 0.0005% to about 1%, by weight. In some embodiments, the composition further comprises an acceptable carrier. In some embodiments, the composition is present in a capsule or other suitable dosage unit. In some embodiments, the Omega-3 fatty acids comprise DHA and/or EPA. In some embodiments, the DHA is present in an amount of about 30% to about 45% by weight of the composition; the EPA is present in an amount of about 10% to about 26% by weight of the composition; the 17-HDHA is present in an amount of about 0.0004% to about 0.04% by weight of the composition; and the 18-HEPE is present in an amount of about 0.0003% to about 0.04% by weight of the composition. In some embodiments, the composition further comprises DPA. In some embodiments, the composition further comprises 14-HDHA, optionally 5-HETE, and optionally 7R,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoic acid (“MaR1”). In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from a vegetable, a microbe, an animal, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil, krill oil, vegetable oil, microbial oil, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil. In some embodiments, the Omega-3 fatty acids are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the Omega-3 fatty acids are in ethyl ester form. In some embodiments, the 17-HDHA and 18-HEPE are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the 17-HDHA and 18-HEPE are in the form of mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the present disclosure provides a composition as disclosed herein for resolving inflammation associated with a disease in a subject in need thereof. In some embodiments, the composition comprises about 20% to about 95%, by weight, Omega-3 fatty acids and 17-HDHA and 18-HEPE in a total amount of about 0.0005% to about 1%, by weight. In some embodiments, the composition further comprises an acceptable carrier. In some embodiments, the composition is present in a capsule or other suitable dosage unit. In some embodiments, the Omega-3 fatty acids comprise DHA and/or EPA. In some embodiments, the DHA is present in an amount of about 30% to about 45% by weight of the composition; the EPA is present in an amount of about 10% to about 26% by weight of the composition; the 17-HDHA is present in an amount of about 0.0004% to about 0.04% by weight of the composition; and the 18-HEPE is present in an amount of about 0.0003% to about 0.04% by weight of the composition. In some embodiments, the composition further comprises DPA. In some embodiments, the composition further comprises 14-HDHA, optionally 5-HETE, and optionally 7R,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoic acid (“MaR1”). In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from a vegetable, a microbe, an animal, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil, krill oil, vegetable oil, microbial oil, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil. In some embodiments, the Omega-3 fatty acids are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the Omega-3 fatty acids are in ethyl ester form. In some embodiments, the 17-HDHA and 18-HEPE are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the 17-HDHA and 18-HEPE are in the form of mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the disease is selected from Crohn's disease, irritable bowel disease (IBD), fatty liver, ulcerative colitis, wound healing, arterial inflammation, sickle-cell disease, arthritis, psoriasis, urticaria, vasculitis, asthma, ocular inflammation, pulmonary inflammation, dermatitis, cardiovascular diseases, AIDS, Alzheimer's disease, atherosclerosis, cancer, type 2 diabetes, hypertension, infectious diseases, leukemia/lymphoma, metabolic syndrome, neonatology, neuromuscular disorders, obesity, perinatal disorders, rheumatic diseases, stroke, surgical transplantation, vascular disorders, periodontal diseases, brain injury, trauma and neuronal inflammation. In some embodiments, the present disclosure provides a composition as disclosed herein for elevating SPM levels in plasma of a human subject. In some embodiments, the composition comprises about 20% to about 95%, by weight, Omega-3 fatty acids and 17-HDHA and 18-HEPE in a total amount of about 0.0005% to about 1%, by weight. In some embodiments, the composition further comprises an acceptable carrier. In some embodiments, the composition is present in a capsule or other suitable dosage unit. In some embodiments, the Omega-3 fatty acids comprise DHA and/or EPA. In some embodiments, the DHA is present in an amount of about 30% to about 45% by weight of the composition; the EPA is present in an amount of about 10% to about 26% by weight of the composition; the 17-HDHA is present in an amount of about 0.0004% to about 0.04% by weight of the composition; and the 18-HEPE is present in an amount of about 0.0003% to about 0.04% by weight of the composition. In some embodiments, the composition further comprises DPA. In some embodiments, the composition further comprises 14-HDHA, optionally 5-HETE, and optionally 7R,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoic acid (“MaR1”). In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from a vegetable, a microbe, an animal, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil, krill oil, vegetable oil, microbial oil, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil. In some embodiments, the Omega-3 fatty acids are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the Omega-3 fatty acids are in ethyl ester form. In some embodiments, the 17-HDHA and 18-HEPE are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the 17-HDHA and 18-HEPE are in the form of mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the SPM comprises RvD1. In some embodiments, the present disclosure provides a use of a composition as disclosed herein in the manufacture of a medicament for increasing phagocytic activity of macrophages in a subject. In some embodiments, the composition comprises about 20% to about 95%, by weight, Omega-3 fatty acids and 17-HDHA and 18-HEPE in a total amount of about 0.0005% to about 1%, by weight. In some embodiments, the composition further comprises an acceptable carrier. In some embodiments, the composition is present in a capsule or other suitable dosage unit. In some embodiments, the Omega-3 fatty acids comprise DHA and/or EPA. In some embodiments, the DHA is present in an amount of about 30% to about 45% by weight of the composition; the EPA is present in an amount of about 10% to about 26% by weight of the composition; the 17-HDHA is present in an amount of about 0.0004% to about 0.04% by weight of the composition; and the 18-HEPE is present in an amount of about 0.0003% to about 0.04% by weight of the composition. In some embodiments, the composition further comprises DPA. In some embodiments, the composition further comprises 14-HDHA, optionally 5-HETE, and optionally 7R,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoic acid (“MaR1”). In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from a vegetable, a microbe, an animal, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil, krill oil, vegetable oil, microbial oil, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil. In some embodiments, the Omega-3 fatty acids are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the Omega-3 fatty acids are in ethyl ester form. In some embodiments, the 17-HDHA and 18-HEPE are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the 17-HDHA and 18-HEPE are in the form of mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the present disclosure provides a use of a composition as disclosed herein in the manufacture of a medicament for enhancing macrophage polarization toward a pro-resolution phenotype in a subject. In some embodiments, the composition comprises about 20% to about 95%, by weight, Omega-3 fatty acids and 17-HDHA and 18-HEPE in a total amount of about 0.0005% to about 1%, by weight. In some embodiments, the composition further comprises an acceptable carrier. In some embodiments, the composition is present in a capsule or other suitable dosage unit. In some embodiments, the Omega-3 fatty acids comprise DHA and/or EPA. In some embodiments, the DHA is present in an amount of about 30% to about 45% by weight of the composition; the EPA is present in an amount of about 10% to about 26% by weight of the composition; the 17-HDHA is present in an amount of about 0.0004% to about 0.04% by weight of the composition; and the 18-HEPE is present in an amount of about 0.0003% to about 0.04% by weight of the composition. In some embodiments, the composition further comprises DPA. In some embodiments, the composition further comprises 14-HDHA, optionally 5-HETE, and optionally 7R,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoic acid (“MaR1”). In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from a vegetable, a microbe, an animal, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil, krill oil, vegetable oil, microbial oil, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil. In some embodiments, the Omega-3 fatty acids are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the Omega-3 fatty acids are in ethyl ester form. In some embodiments, the 17-HDHA and 18-HEPE are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the 17-HDHA and 18-HEPE are in the form of mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the present disclosure provides a use of a composition as disclosed herein in the manufacture of a medicament for resolving inflammation associated with a disease in a subject in need thereof. In some embodiments, the composition comprises about 20% to about 95%, by weight, Omega-3 fatty acids and 17-HDHA and 18-HEPE in a total amount of about 0.0005% to about 1%, by weight. In some embodiments, the composition further comprises an acceptable carrier. In some embodiments, the composition is present in a capsule or other suitable dosage unit. In some embodiments, the Omega-3 fatty acids comprise DHA and/or EPA. In some embodiments, the DHA is present in an amount of about 30% to about 45% by weight of the composition; the EPA is present in an amount of about 10% to about 26% by weight of the composition; the 17-HDHA is present in an amount of about 0.0004% to about 0.04% by weight of the composition; and the 18-HEPE is present in an amount of about 0.0003% to about 0.04% by weight of the composition. In some embodiments, the composition further comprises DPA. In some embodiments, the composition further comprises 14-HDHA, optionally 5-HETE, and optionally 7R,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoic acid (“MaR1”). In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from a vegetable, a microbe, an animal, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil, krill oil, vegetable oil, microbial oil, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil. In some embodiments, the Omega-3 fatty acids are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the Omega-3 fatty acids are in ethyl ester form. In some embodiments, the 17-HDHA and 18-HEPE are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the 17-HDHA and 18-HEPE are in the form of mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the disease is selected from Crohn's disease, irritable bowel disease (“IBD”), fatty liver, ulcerative colitis, wound healing, arterial inflammation, sickle-cell disease, arthritis, psoriasis, urticaria, vasculitis, asthma, ocular inflammation, pulmonary inflammation, dermatitis, cardiovascular diseases, AIDS, Alzheimer's disease, atherosclerosis, cancer, type 2 diabetes, hypertension, infectious diseases, leukemia/lymphoma, metabolic syndrome, neonatology, neuromuscular disorders, obesity, perinatal disorders, rheumatic diseases, stroke, surgical transplantation, vascular disorders, periodontal diseases, brain injury, trauma and neuronal inflammation. In some embodiments, the present disclosure provides a use of a composition as disclosed herein in the manufacture of a medicament for elevating SPM levels in plasma of a human subject. In some embodiments, the composition comprises about 20% to about 95%, by weight, Omega-3 fatty acids and 17-HDHA and 18-HEPE in a total amount of about 0.0005% to about 1%, by weight. In some embodiments, the composition further comprises an acceptable carrier. In some embodiments, the composition is present in a capsule or other suitable dosage unit. In some embodiments, the Omega-3 fatty acids comprise DHA and/or EPA. In some embodiments, the DHA is present in an amount of about 30% to about 45% by weight of the composition; the EPA is present in an amount of about 10% to about 26% by weight of the composition; the 17-HDHA is present in an amount of about 0.0004% to about 0.04% by weight of the composition; and the 18-HEPE is present in an amount of about 0.0003% to about 0.04% by weight of the composition. In some embodiments, the composition further comprises DPA. In some embodiments, the composition further comprises 14-HDHA, optionally 5-HETE, and optionally 7R,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoic acid (“MaR1”). In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from a vegetable, a microbe, an animal, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil, krill oil, vegetable oil, microbial oil, or a combination thereof. In some embodiments, the Omega-3 fatty acids, 17-HDHA and 18-HEPE are obtained from fish oil. In some embodiments, the Omega-3 fatty acids are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the Omega-3 fatty acids are in ethyl ester form. In some embodiments, the 17-HDHA and 18-HEPE are in the form of free fatty acids, esters, phospholipids, mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the 17-HDHA and 18-HEPE are in the form of mono-glycerides, di-glycerides, tri-glycerides and/or combinations thereof. In some embodiments, the SPM comprises RvD1. EXAMPLES Example 1. Obtain an Oil Fraction Comprising DHA, EPA, 17-HDHA and 18-HEPE from Semi-Refined Marine Oil Six compositions of polyunsaturated fatty acids containing Omega-3 (20-95% by weight), 17-HDHA and 18-HEPE (about 0.0005-1% by weight) are included as examples of compositions of the present disclosure. The determination of the Omega-3 content was performed using European Pharmacopeia 2.4.29 method and determination of 17-HDHA and 18-HEPE was performed by liquid chromatography-tandem mass spectrometry employing diagnostic transition and co-elution with synthesized deuterated standards of 17-HDHA and 18-HEPE. 1.1 LM03-1. This composition was obtained from a starting material consisting on esterified concentrated marine oil. Esterified semirefined marine oil was then injected in a continuous flow rate in a vacuum distillation unit, composed mainly for an evaporator, that works at high vacuum in this example at 0.08-0.12 mbar and high temperature (140-144° C.), and within the time of exposure of the material at these conditions from 10 seconds to 5 minutes. In this stage an ethyl ester rich in fatty acids mainly shorter than C20 is distilled off. Then, the obtained marine oil was distilled to remove the higher components (with more than 23 carbon atoms), working at 0.09-0.12 mbar in pressure and 140-157° C. in temperature. These steps have been covered in two times in series. To improve the quality of the composition and remove oxidation, decomposition and degradation products as oligomers, dimers, polymers and conjugated dienes, the composition was subjected to a supercritical fluid extraction (SFE) by counter current extraction on a column with carbon dioxide at supercritical conditions, working at 44.5-45.5° C. in temperature and at a pressure of 80-86 bar. The composition obtained contained a total amount of Omega-3 of about 629.9 mg/g (as FFA), DHA in an amount of about 342.1 mg/g (as FFA), EPA in an amount of about 187.6 mg/g (as FFA), 17-HDHA in an amount of about 60.8 mg/kg and 18-HEPE in an amount of about 87.5 mg/kg with 1.4 mg/g of a mixed natural tocopherols to improve the oxidative stability of the product. The analytical data and content of this fraction is shown in Table 1. TABLE 1 Analysis of LM03-1 Determination Result Method SPM content 17 HDHA (mg/kg) 60.8 LC/MS 18 HEPE (mg/kg) 87.5 LC/MS 17 HDHA + 18 HEPE (mg/kg) 148.3 LC/MS Fatty acid profile EPA (mg/g as FFA) 187.6 Eur. Ph.2.4.29 DHA (mg/g as FFA) 342.1 Eur. Ph.2.4.29 Total Omega-3 (mg/g as FFA) 629.9 Eur. Ph.2.4.29 Sum of 18:3 ω-3, 18:4 ω-3, 20:4 ω-3, 20:5 ω-3, 21:5 ω-3, 22:5 ω-3, 22:6 ω-3 The analysis of the chemical status of 17-HDHA and 18-HEPE in fraction LM03.1 is shown in Table 2, where the percentages of each chemical form are expressed by weight. TABLE 2 Distribution of chemical forms of SPMs in LM03-1 % 17-HDHA (EE) in LM03-1 88.67 % 17-HDHA in other chemical form 11.33 (mono-glyceride, Di-glyceride, tri- glyceride and FFA) in LM03-1 % 18-HEPE (EE) in LM03-1 87.52 % 18-HEPE in other chemical form 12.48 (mono-glyceride, Di-glyceride, tri- glyceride and FFA) in LM03-1 1.2 LM03-2. This composition was obtained from a starting material consisting on esterified concentrated marine oil. Esterified semirefined marine oil was then injected in a continuous flow rate in a vacuum distillation unit, composed mainly for an evaporator, that works at high vacuum in this example at 0.08-0.12 mbar and high temperature (140-144° C.), and within the time of exposure of the material at these conditions from 10 seconds to 5 minutes. In this stage an ethyl ester rich in fatty acids mainly shorter than C20 was distilled off. Then, the obtained marine oil was redistilled to reduce once more time the shorter fatty acids working at 0.09-0.12 mbar in pressure and 140-157° C. in temperature. This final fraction and the obtained as distillate in the first stage were mixed and then distilled, in two stages in series: in the first stage working at 0.08-0.12 mbar of pressure and 140-144° C. of temperature and, in the second stage, working at 0.09-0.12 mbar in pressure and 140-157° C. in temperature. To improve the quality of the composition and remove oxidation, decomposition and degradation products as oligomers, dimers, polymers and conjugated dienes, the composition was subjected to a supercritical fluid extraction (SFE) by counter current extraction on a column with carbon dioxide at supercritical conditions, working at 44.5-45.5° C. in temperature and at a pressure of 80-86 bar. LM03-2 contained a total amount of Omega-3 of about 600 mg/g (as FFA), DHA in an amount of about 300.0 mg/g (as FFA), EPA in an amount of about 100.0 mg/g (as FFA), 17-HDHA in an amount of about 50.0 mg/kg and 18-HEPE in an amount of about 40.0 mg/kg with a maximum of 1.4 mg/g of a mixed natural tocopherols to improve the oxidative stability of the product. The analytical data and content of this fraction is shown in Table 3. TABLE 3 Analysis of LM03-2 Determination Result Method SPM content 17 HDHA (mg/kg) 50.0 LC/MS 18 HEPE (mg/kg) 40.0 LC/MS 17 HDHA + 18 HEPE (mg/kg) 90.0 LC/MS Fatty acid profile EPA (mg/g as FFA) 100.0 Eur. Ph.2.4.29 DHA (mg/g as FFA) 300.0 Eur. Ph.2.4.29 Total Omega-3 (mg/g as FFA) 600.0 Eur. Ph.2.4.29 Sum of 18:3 ω-3, 18:4 ω-3, 20:4 ω-3, 20:5 ω-3, 21:5 ω-3, 22:5 ω-3, 22:6 ω-3 1.3. LM03-3. This composition was obtained using the process described above from a starting material consisting on esterified concentrated marine oil. Esterified semirefined marine oil was then injected in a continuous flow rate in a vacuum distillation unit, composed mainly for an evaporator, that works at high vacuum in this example at 0.08-0.12 mbar and high temperature (150-154° C.), and within the time of exposure of the material at these conditions from 10 seconds to 5 minutes. In this stage an ethyl ester rich in fatty acids mainly shorter than twenty carbons was distilled off. Then, the obtained marine oil was redistilled to reduce once more time the shorter fatty acids working at 0.08-0.12 mbar in pressure and 155-165° C. in temperature. To improve the quality of the composition and remove oxidation, decomposition and degradation products as oligomers, dimers, polymers and conjugated dienes, the composition was subjected to a supercritical fluid extraction (SFE) by counter current extraction on a column with carbon dioxide at supercritical conditions, working at 44.5-45.5° C. in temperature and at a pressure of 80-86 bar. The composition LM03-3 obtained contained a total amount of Omega-3 of about 663.0 mg/g (as FFA), including DHA in an amount of about 441.7 mg/g (as FFA), and EPA in an amount of about 112.7 mg/g (as FFA). LM03-3 also contained significant amounts of 17-HDHA, 18-HEPE, 14-HDHA, 5-HETE and maresin 1 (MaR1), and no significant amounts of pro-inflammatory in an amount of about 65.2 mg/kg with a maximum of 1.1 mg/g of a mixed natural tocopherols to improve the oxidative stability of the product. The analytical data and content of this fraction is shown in Table 4. TABLE 4 Analysis of LM03-3 Component Abundance wt. % SPMs/ 18-HEPE 278550 μg/kg 0.02786 wt. % SPM 17-HDHA 146748 μg/kg 0.01467 wt. % Precursors 14-HDHA 97715 μg/kg 0.00977 wt. % maresin 1 7545 μg/kg 0.00075 wt. % 15-HETE 6970 μg/kg 0.00070 wt. % 5-HETE 5474 μg/kg 0.00055 wt. % RvE3 2617 μg/kg 0.00026 wt. % RvD5 1241 μg/kg 0.00012 wt. % MaR1 n-3DPA 827 μg/kg 0.00008 wt. % RvD6 440 μg/kg 0.00004 wt. % PD1 397 μg/kg 0.00004 wt. % RvD5m-3DPA 332 μg/kg 0.00003 wt. % RvD2n-3DPA 186 μg/kg 0.00002 wt. % RvE2 179 μg/kg 0.00002 wt. % RvD1 173 μg/kg 0.00002 wt. % RvE1 112 μg/kg 0.00001 wt. % lipoxin B4 126 μg/kg 0.00001 wt. % RvD4 97 μg/kg 0.00001 wt. % lipoxin A4 94 μg/kg 0.00001 wt. % RvD2 83 μg/kg 0.00001 wt. % RvD1n-3DPA 7 μg/kg 0.00000 wt. % RvD3 5 μg/kg 0.00000 wt. % TOTAL SPM/SPM 549917 μg/kg 0.05499 wt. % PRECURSORS: Pro- 12-HETE 2878 μg/kg 0.00029 wt. % Inflam- LTB4 669 μg/kg 0.00007 wt. % matories Prostaglandin E2 564 μg/kg 0.00006 wt. % Prostaglandin D2 300 μg/kg 0.00003 wt. % Thromboxane B2 56 μg/kg 0.00001 wt. % Prostaglandin F2α 34 μg/kg 0.00000 wt. % TOTAL PRO- 4501 μg/kg 0.00045 wt. % INFLAMMATORIES: ω-3 DHA (as free fatty acid) 441.7 mg/g 44.17 wt. % Fatty EPA (as free fatty acid) 112.7 mg/g 11.27 wt. % Acids Other Omega-3 Fatty 108.6 mg/g 10.86 wt. % Acids* TOTAL OMEGA-3 663.0 mg/g 66.30 wt. % FATTY ACIDS *18:3 ω-3, 18:4 ω-3, 20:4 ω-3, 21:5 ω-3, and 22:5 ω-3. 1.4. LM03-4. This composition was obtained from a starting material consisting on semirefined marine oil. Esterified semirefined marine oil was then injected in a continuous flow rate in a vacuum distillation unit, composed mainly for an evaporator, working at high vacuum (0.18 to 0.20 mbar) and high temperature (140° C. to 150° C.), and within the time of exposure of the material at these conditions from 10 seconds to 5 minutes. In this stage an ethyl ester rich in fatty acids mainly shorter than twenty carbons was distilled off. Then, the obtained marine oil was distilled to remove the higher components (with more than 23 carbon atoms), working at 155-172° C. and 0.18 to 0.20 mbar. The obtained fraction was distilled in a second stage, working in the first stage 0.08-0.12 mbar of pressure and 140-144° C. of temperature and, in the second stage, working at 0.09-0.12 mbar in pressure and 140-157° C. in temperature. Intermediate product was then processed in a urea complexation step to reduce the content of saturated and monounsaturated fatty acids. Urea was solved in ethanol and intermediate product is added. When, urea was precipitated from this solution, by forming adduct products with mainly saturated and monounsaturated ethyl esters. The urea adduct was removed by filtration, and ethanol was recovered by distillation. The resulting ethyl esters were washed with demineralized water. This step can be done in two stages in series. A bleaching step was performed then, to control and reduce urea traces. The composition obtained contained a total amount of Omega-3 of about 870.0 mg/g (as FFA), DHA in an amount of about 345.0 mg/g (as FFA), EPA in an amount of about 425.0 mg/g (as FFA), 17-HDHA in an amount of about 56.2 mg/kg and 18 HEPE in an amount of about 96.4 mg/kg with a maximum of 4.8 mg/g of a-tocopherol to improve the oxidative stability of the product. The analytical data and content of this fraction is shown in Table 5. TABLE 5 Analysis of LM03-4 Determination Result Method SPM content 17 HDHA (mg/kg) 56.2 LC/MS 18 HEPE (mg/kg) 96.4 LC/MS 17 HDHA + 18 HEPE (mg/kg) 152.6 LC/MS Fatty acid profile EPA (mg/g as FFA) 425.0 Eur. Ph.2.4.29 DHA (mg/g as FFA) 345.0 Eur. Ph.2.4.29 Total Omega-3 (mg/g as FFA) 870.0 Eur. Ph.2.4.29 Sum of 18:3 ω-3, 18:4 ω-3, 20:4 ω-3, 20:5 ω-3, 21:5 ω-3, 22:5 ω-3, 22:6 ω-3 1.5. LM03-5 This composition was obtained from a starting material consisting on semirefined marine oil. Semirefined marine oil was esterified to form ethyl esters, by contacting with ethanol and a basic catalyst (EtONa), at 55-65° C. a known quantity of ethanol and catalyst are added to the reactor. After the reaction time (2-4 hours) concluded, the excess of additives were evaporated. Then, a final washing step was included in order to neutralize the semirefined marine oil esterified. The composition obtained LM03-5 contained a total amount of Omega-3 of about 316.0 mg/g (as FFA), DHA in an amount of about 104.0 mg/g (as FFA), EPA in an amount of about 152.0 mg/g (as FFA), n-3 DPA in an amount of about 19.0 mg/g (as FFA) 17-HDHA in an amount of about 14.6 mg/kg and 18-HEPE in an amount of about 35.8 mg/kg. The analytical data and content of this fraction is shown in Table 6. TABLE 6 Analysis of LM03-5 Determination Result Method SPM content 17 HDHA (mg/kg) 14.6 LC/MS 18 HEPE (mg/kg) 35.8 LC/MS 17 HDHA + 18 HEPE (mg/kg) 50.4 LC/MS Fatty acid profile EPA (mg/g as FFA) 152.0 Eur. Ph.2.4.29 DHA (mg/g as FFA) 104.0 Eur. Ph.2.4.29 DPA (mg/g as FFA) 19.0 Eur. Ph.2.4.29 Total Omega-3 (mg/g as FFA) 316.0 Eur. Ph.2.4.29 Sum of 18:3 ω-3, 18:4 ω-3, 20:4 ω-3, 20:5 ω-3, 21:5 ω-3, 22:5 ω-3, 22:6 ω-3 1.6. LM03-6 This composition was obtained from a starting material consisting on esterified concentrated marine oil. Esterified semirefined marine oil was then injected in a continuous flow rate in a vacuum distillation unit, composed mainly for an evaporator, that works at high vacuum in this example at 0.08-0.12 mbar and high temperature (140-144° C.), and within the time of exposure of the material at these conditions from 10 seconds to 5 minutes. In this stage an ethyl ester rich in fatty acids mainly shorter than C20 was distilled off. Then, the obtained marine oil was distilled to remove the higher components (with more than 23 carbon atoms), working at 0.09-0.12 mbar in pressure and 140-157° C. in temperature. These steps have been covered in two times in series To improve the quality of the composition and remove oxidation, decomposition and degradation products as oligomers, dimers, polymers and conjugated dienes, the composition was subjected to a supercritical fluid extraction (SFE) by counter current extraction on a column with carbon dioxide at supercritical conditions, working at 44.5-45.5° C. in temperature and at a pressure of 80-86 bar. The composition obtained was subjected to a step of transesterification to obtain a composition containing a mixture of tri-glycerides and partial glycerides (mono-glycerides and di-glycerides). The reaction of transesterification was catalyzed by lipases at a temperature of about 50° C. to about 70° C. under vacuum. The obtained fraction was treated under vacuum with high temperatures and a countercurrent flow of steam (nitrogen) to remove the volatile components and improve the odour, if they are present. These volatile components were solved into the steam and flow out the deodorization equipment. The composition obtained LM03-6 contained a total amount of Omega-3 of about 635.0 mg/g (as FFA), DHA in an amount of about 189.0 mg/g (as FFA), EPA in an amount of about 342.0 mg/g (as FFA), 17-HDHA in an amount of about 126.8 mg/kg and 18-HEPE in an amount of about 95.2 mg/kg with a maximum of 4 mg/g of a mixed natural tocopherols to improve the oxidative stability of the product. The analytical data and content of this fraction is shown in Table 7. TABLE 7 Analysis of LM03-6 Determination Result Method SPM content 17 HDHA (mg/kg) 126.8 LC/MS 18 HEPE (mg/kg) 95.2 LC/MS 17 HDHA + 18 HEPE (mg/kg) 222.0 LC/MS Fatty acid profile EPA (mg/g as FFA) 342.0 Eur. Ph.2.4.29 DHA (mg/g as FFA) 189.0 Eur. Ph.2.4.29 Total Omega-3 (mg/g as FFA) 635.0 Eur. Ph.2.4.29 Sum of 18:3 ω-3, 18:4 ω-3, 20:4 ω-3, 20:5 ω-3, 21:5 ω-3, 22:5 ω-3, 22:6 ω-3 Example 2. Study of Regulation of Phagocytosis In Vitro Employing the Spectrophotometric Evaluation of Phagocytized Zymosan Bioparticles in PMA-stimulated THP-1 cells Macrophages play a central role in inflammation and host defense against microorganisms, and also participate actively in the resolution of inflammation after alternative activation from pro-inflammatory macrophages switched towards anti-inflammation (M2-like phenotype). To determine the capacity of promoting a macrophage pro-resolution phenotype (i.e. M2) and therefore to foster the resolution of inflammation, several oils were tested in a human macrophage model adapted by Lopez Vicario C from a method previously described (Titos et al., 2011) and compared with Mar-1 (the term Maresins is coined from Macrophage mediator in resolving inflammation), an established active compound in resolution of the inflammation. THP-1 cells were cultured in a 96-well black plate at a density of 3.5×104 cells/well in 200 μl RPMI 1640 medium (10% FBS). Cells were differentiated into macrophages with 50 ng/ml of phorbol 12-myristate 13-acetate (PMA) for 2 days and then, maintained with fresh RPMI medium (10% FBS) for 1 day. Then the macrophages were washed by aspiration×2 with sterile DPBS−/− and pretreated for 15 minutes with 150 μl of the compounds to be tested or vehicle (ethanol) using RPMI without phenol red (1% FBS). Each sample was tested in duplicate or triplicate. The compounds tested in this macrophage model were: Maresin 1 (from Cayman Chemicals) LM03-1 (a total amount of Omega-3 of about 629.9 mg/g (as FFA), DHA in an amount of about 342.1 mg/g (as FFA), EPA in an amount of about 187.6 mg/g (as FFA), 17-HDHA in an amount of about 60.8 mg/kg and 18-HEPE in an amount of about 87.5 mg/kg with 1.4 mg/g of a mixed natural tocopherols-3624 EE (about 33.0% EPA ethyl ester and about 22% DHA in ethyl ester form expressed as FFA) Omacor (about 42.5% EPA ethyl ester and about 34.5% DHA in ethyl ester form expressed as FFA) The concentration of Mar-1 used in the experiment was 1 nM, which has been determined the concentration with maximum activity in phagocytic activation for this compound in previous experiments using this model (data not shown). The oils tested, LM03-1, 3624 EE and Omacor, were diluted 1/103 for use in the experiment. After 15 minutes of pretreatment with the compounds to be tested, 50 μl of opsonized zymosan bioparticles (Molecular Probes; Z-2841; ratio cell/bioparticles=1/10) were added to each well of the plate (Final volume=200 μl) and mixed. The macrophages were incubated at 37° C. for 60 minutes and then the plate was centrifuged for 5 minutes at 400 g at room temperature and supernatant was discarded by aspiration. The macrophages were washed with sterile DPBS−/− before adding 100 μl of Trypan Blue Solution (diluted at 1:10 in sterile DPBS−/−) to quench fluorescence of bioparticles bound to the outside of the cell. Then, the macrophages were incubated for 2 minutes at room temperature and centrifuged for 5 minutes at 400 g at room temperature and the excess of Trypan Blue was aspirated. The fluorescent intensity of each sample was read in the fluorescence microplate reader FLUOstar OPTIMA (in a Costar 96 microplate) and average fluorescence intensity values were calculated to obtain phagocytosis response to the effector. Maresin-1, a very potent inducer of macrophage phagocytosis was used as a reference. 100% activity was assigned to compare the effect over phagocytic activity of the other compounds tested. The LM03-1 oil, as shown in FIG. 2, activated macrophage activation reaching more than 55% of the activity of Mar-1 (pure compound) in macrophage activation. LM03-1 oil fraction enhanced macrophage activity and polarization toward a pro-resolution phenotype (I.E. M2) due to its SPMs. The results obtained in this model indicate the resolution capacity of LM03-1 oil fraction. The other products tested in this model, 3624 EE and Omacor, did not activate phagocytosis activity much more; instead, these compounds diminished the phagocytic activity of macrophages in this model. Example 3. Study of Plasma Levels of RvD1 During a 1 Hour Period after Ingesting a Composition Containing DHA, EPA, 17-HDHA, and 18-HEPE To determine the variation in plasma levels of RvD1 after ingest a ethyl ester Omega-3 oil fraction containing EPA, DHA, 17-HDHA and 18-HEPE (LM03-2 oil fraction obtained in Example 1) compared with a placebo, a clinical study was designed over N=10 subjects administered LM03-2 composition and compared with N=5 subjects ingesting a placebo. The composition of LM03-2 used in this clinical trial contained a total amount of Omega-3 of about 600 mg/g (as FFA), DHA in an amount of about 300.0 mg/g (as FFA), EPA in an amount of about 100.0 mg/g (as FFA), 17-HDHA in an amount of about 50.0 mg/kg and 18-HEPE in an amount of about 40.0 mg/kg. The subject characteristics of the study appear in Table 8. TABLE 8 Subject characteristics of the study Variable LM03-2 (n = 10) Placebo (N = 5) P-value Age (y) 46.0 ± 2.4 51.4 ± 4.5 0.259 Height (m) 1.66 ± 0.01 1.69 ± 0.03 0.379 Weight (kg) 90.0 ± 5.6 88.5 ± 6.3 0.870 BMI 32.6 ± 1.9 31.2 ± 2.2 0.657 CRP (mg/l) 5.25 ± 1.2 5.84 ± 1.3 0.772 Subjects ingested 4 capsules (250 mg each capsule) of LM03-2 or placebo at 8:00 am; blood samples were collected before ingestion of the capsules and 15 min, 30 min and one hour post-ingestion. LM03-2 composition of each capsule is approximately 75 mg DHA, 25 mg EPA, and SPM precursors 17-HDHA (17.5 μg) and 18-HEPE (10 μg). RvD1 has been identified as an activator of non-phlogistic phagocytosis in macrophages, which is an essential step for the resolution of the inflammatory response. The blood samples were analyzed for plasma RvD1 levels and results are shown in FIG. 3. The increase of RvD1 levels in subjects one hour after the ingestion of 4 capsules of LM03-2 composition is 53% higher than the level just after the ingestion of the composition in these subjects, instead the levels of RvD1 one hour later in subjects that ingested a placebo raised a 5% over their initial value. This results show the capacity of the composition LM03-2 to elevate RvD1 levels in plasma. Example 4. Mice Subcutaneous Anti-Inflammatory Activity Trial To determine the anti-inflammatory activity of different oils, three oils were tested for their anti-inflammatory activity and compared with the activity of indomethacin (a nonsteroidal anti-inflammatory drug) in a subcutaneous in vivo model of inflammation using CD1 white male mice, adult (30-35 grams weight). N=5 mice were used in each group tested with an oil fraction group and N=4 mice were used in control and indomethacin groups. A prototypical inflammatory agent, LPS (lipopolysaccharide from the outer coat of bacteria) was injected subcutaneously as a single dose (5 mg per kg in a 200 μL volume) in the dorsal hind flank to create inflammation in mice. Thirty minutes prior to the administration of LPS, 100 μL of vehicle control (PBS phosphate buffer saline), indomethacin, or one of the oil fractions were administered by gavage. Neutrophil infiltration into the site of inflammation was measured non-invasively by bioluminescence emitted by conversion of luminol by the neutrophil enzyme myeloperoxidase. 150 μL of a suspension of luminol in PBS (50 mg/I) was administered to the mice and the image was taken after 15 minutes of the luminol injection. The bioluminescence was measured using an IVIS-lumina equipment (Perkin-Elmer, Tres Cantos, Madrid, Spain). The method used generates reproducible bioluminescence measurements of neutrophil activity in order to be able to measure statistically significant changes in neutrophil activity upon administration of different oil fractions and indomethacin. The oils fractions tested in the experiments are as follows: Krill: Tri-glyceride and phospholipids form (about 14.4% EPA and 7.4% DHA in weight expressed as FFA). LM03-3 containing a total amount of Omega-3 of about 663.0 mg/g (as FFA), DHA in an amount of about 441.7 mg/g (as FFA), EPA in an amount of about 112.7 mg/g (as FFA), and about 550 mg/kg of total SPMs/SPM Precursors, including 17-HDHA in an amount of about 146 mg/kg and 18-HEPE in an amount of about 279 mg/kg. Algae: Tri-glyceride form (about 0.2% EPA and 39.7% DHA in weight expressed as FFA). The results for the analysis of bioluminescence for each oil fraction compared with control and indomethacin are shown in two figures per compound tested, measure the total flux of the bioluminescence radiation (net radiance photons/sec) and the evolution of medium radiance (photons/sec/cm2/sr) along time. For krill oil, the response shown in FIGS. 4A and 4B was similar to the control and even over the control at 180 minutes. The response compared with the indomethacin was 37% higher, showing a significant value of p<0.02. As shown in FIGS. 4A and 4B, krill oil was not significantly anti-inflammatory in this model. The results detailed in FIGS. 5A and 5B, probe the anti-inflammatory character of fraction LM03-3. LM03-3 oil shows a clear anti-inflammatory effect at 90, 180 and 360 minutes with a quick response at 90 min and the effect is maintained during the 6 hours that last the experiment. This is the only tested oil that shows this quick and long effect. At time 180 minutes, the LM03-3 oil had the maximum difference compared to the control, with the total flux (photons/sec) 36% below the control (p<0.13). As shown in FIG. 6A, the total flux at time 180 min the value (photons/sec) for the Algae oil is 37% higher than the positive control indomethacin with a significant value of p<0.02. However this difference between algae oil and the indomethacin decrease being at 360 min close to the indomethacin. Example 5. Encapsulation of a Composition Containing EPA, DHA, 17-HDHA and 18-HEPE in a Capsule The oil fraction LM03-2 obtained in example 1 was encapsulated in an oval enteric soft gelatin shell. The specifications of encapsulated LM03-2 composition in a capsule are shown in Table 9. TABLE 9 Specifications of LM03-2 encapsulated Capsule weight 423 mg Contain weight 256 mg Weight variation 97-102% Specific gravity 0.75 g/mL Gastric disintegration Conform Intestinal disintegration <15 min Total acidity 1.51 mg KOH/g Cholesterol 0.33 mg/capsule Total Fat 256 mg/capsule Total Omega-3 169 mg/capsule EPA 75 mg/capsule DHA 25 mg/capsule 17-HDHA 12.5 mg/capsule 18-HEPE 10 mg/capsule Example 6. Emulsification of a Composition Containing EPA, DHA, 17-HDHA and 18-HEPE as Delivery Form The LM03-6 oil fraction obtained in Example 1 was mixed with demineralised water, emulsifiers, preservatives, stabilizers, natural flavours, pH controllers and sweeteners to provide an oral lipidic emulsion formed by a ordered network. This reaction is made at room temperature in absence of oxygen, by a previous blanketing step. At the end of the process, a pasteurization step is performed as microbiological control. The specification of the emulsified LM03-6 composition is shown in Table 10. The typical composition of the emulsified LM03-6 packed in a sachet is shown in Table 11. TABLE 10 Specifications of emulsified LM03-6. Total Omega-3 (as FFA) Min. 50 mg/g Min. 5 wt. % EPA (as FFA) Min. 10 mg/g Min. 1 wt. % DHA (as FFA) Min. 30 mg/g Min. 3 wt. % 17-HDHA Min. 5 mg/kg Min. 0.0005 wt. % 18-HEPE Min. 3 mg/kg Min. 0.0003 wt. % 17-HDHA + 18-HEPE Min. 8 mg/kg Min. 0.0008 wt. % TABLE 11 Specifications of emulsified LM03-6 packed in a sachet. Sachet 15 ml weight 14.97 g Total Omega-3 (as FFA) Min. 900 mg/sachet Min. 6.012 wt. % EPA (as FFA) Min. 150 mg/sachet Min. 1.002 wt. % DHA (as FFA) Min. 450 mg/sachet Min. 3.006 wt. % 17-HDHA Min. 75 μg/sachet Min. 0.0005 wt. % 18-HEPE Min. 60 μg/sachet Min. 0.0004 wt. % 17-HDHA + 18-HEPE Min. 135 μg/sachet Min. 0.0009 wt. % | <SOH> BACKGROUND <EOH>Inflammation is an unspecific response in defense of external pathogen agents to eliminate them and repair damaged tissues. Inflammation is a complex physiologic process that could be considered as acute or chronic depending on the duration of this process. Chronic inflammation is maintained over time, as a result of a lack of resolution of the acute initial phase of the inflammatory response or progressive initiation associated with diseases such as rheumatoid arthritis, atherosclerosis, tuberculosis, cancer, vascular diseases, metabolic syndrome, and neurological diseases as Alzheimer among others. Resolution of the inflammation is a different process from the anti-inflammatory process. Resolution of inflammation can be defined as the interval between maximum neutrophil infiltration to the point when they are lost from the tissue. Complete resolution is the ideal outcome of inflammation, although, if not properly regulated, it can lead to chronic inflammation, fibrosis, and loss of function. Pathologists divide the inflammatory response into initiation and resolution. The natural mechanism of the resolution of inflammation has acquired a high relevance during the last years due to the inflammation being recognized as an important characteristic of the above diseases. Resolution was considered to be a passive process before the discovery and identification of specialized pro-resolving mediators. Effective clearance of microbial infections and damaged tissue is self-limited and followed by resolution of inflammation. Resolution can be defined at the cellular level as the disappearance of accumulated polymorphonuclear leukocytes, and at the macroscopic level as reconstitution of tissue architecture and restoration of normal function. Complete restoration of tissue integrity after bacterial infection is directly related to the efficiency of microbe clearance and then to leukocyte clearance. Several mechanisms appear to drive the disappearance of inflammatory leukocytes. Apoptosis of leukocytes is one important route of elimination. Once phagocytosis is complete, leukocytes undergo programmed cell deaths in response to locally released mediators which regulate the rate of apoptosis. As polymorphonuclear leukocytes die, they simultaneously function as cytokine sinks and sequester earlier released pro-inflammatory cytokines. Apoptotic neutrophils are subsequently phagocytozed by macrophages (efferocytosis) in a so-called non-phlogistic fashion (i.e., in the absence of further generation of pro-inflammatory mediators), but with increased formation of anti-inflammatory mediators such as transforming growth factor-β (TGF-β), lipoxin A4 (LXA4) and interleukin-10. Another important route of elimination of leukocytes is egress from the inflamed tissue, as shown for eosinophils in pulmonary inflammation. Macrophages which have eliminated apoptotic neutrophils disappear in turn by either apoptosis or egress via the lymphatic system as inflammation resolves. Development of new products to facilitate the resolution of the inflammation, especially in chronic diseases associated with an important inflammatory component, such as Crohn's disease, irritable bowel disease (IBD), fatty liver, wound healing, arterial inflammation, sickle-cell disease, arthritis, psoriasis, urticaria, vasculitis, asthma, ocular inflammation, pulmonary inflammation, dermatitis, cardiovascular diseases, AIDS, Alzheimer's disease, atherosclerosis, cancer, type 2 diabetes, hypertension, infectious diseases, leukemia/lymphoma, metabolic syndrome, neonatology, neuromuscular disorders, obesity, perinatal disorders, rheumatic diseases, stroke, surgical transplantation, vascular disorders, periodontal diseases, brain injury, trauma and neuronal inflammation, among others, is greatly needed. | <SOH> SUMMARY <EOH>In several embodiments, the present disclosure provides a polyunsaturated fatty acid composition comprising about 20% to about 95%, by weight, Omega-3 fatty acids, and 17-HDHA and 18-HEPE in a total amount of about 0.0005% to about 1% by weight of the composition. In some embodiments, the composition can further comprise DPA and/or an acceptable carrier and can be present in a capsule or other suitable dosage unit. In one embodiment, the present disclosure provides a polyunsaturated fatty acid composition comprising about 20% to about 95%, by weight, Omega-3 fatty acids, and a collective amount of about 0.0005% to about 1% of 17-HDHA and 18-HEPE, by weight. In another embodiment, the present disclosure provides a dietary supplement, pharmaceutical product, nutraceutical product, medical food, infant formulae and/or prenatal formulae composition comprising a composition as disclosed herein. In another embodiment, the present disclosure provides a process for obtaining a composition as disclosed herein from an oil using a method selected from chromatography, extraction, distillation and/or vacuum rectification. In another embodiment, the present disclosure provides a process for obtaining a composition as disclosed herein from a crude oil, the process comprising: (i) chemically esterifying crude oil with ethanol and a basic catalyst, at a temperature of about 55° C. to about 75° C. to produce esterified oil; (ii) distilling the esterified oil under vacuum of about 0.01 mbar to 0.6 mbar and at a temperature of about 130° C. to 190° C. for about 10 seconds to about 5 minutes to separate fatty acids shorter than 20 carbon atoms to obtain a distilled esterified oil comprising about 20% to about 95% by weight EPA and/or DHA, and about 0.0005% to about 1% by weight 17-HDHA and 18-HEPE (collectively); and (iii) subjecting the polyunsaturated fatty acid composition obtained in step (ii) to supercritical fluid extraction with CO 2 as a supercritical fluid at a temperature of about 39° C. to about 46° C. and pressure of about 80 bar to about 115 bar to remove oxidation, decomposition and/or degradation products as oligomers, dimers, polymers and conjugated dienes from the composition. In another embodiment, the present disclosure provides a process for obtaining a composition as disclosed herein from a concentrated esterified oil, the process comprising: (i) distilling the concentrated esterified oil under vacuum of about 0.01 mbar to 0.6 mbar and at a temperature of about 130° C. to 190° C. for about 10 seconds to about 5 minutes to separate fatty acids having fewer than 20 carbon atoms in the corresponding fatty acid chain to obtain a distilled esterified oil comprising about 20% to about 95% by weight EPA and/or DHA, and about 0.0005% to about 1% by weight 17-HDHA and 18-HEPE (collectively); (ii) subjecting the distilled esterified oil obtained in step (i) to supercritical fluid extraction with CO 2 as a supercritical fluid at a temperature of about 20° C. to 40° C. and at a pressure of about 80 bar to about 115 bar to remove oxidation, decomposition and degradation products as oligomers, dimers, polymers and conjugated dienes from the composition. In another embodiment, the present disclosure provides a method of increasing phagocytic activity of macrophages in a subject comprising administering to the subject a phagocytic activity enhancing amount of a composition as disclosed herein. In another embodiment, the present disclosure provides a method of enhancing macrophage polarization toward a pro-resolution phenotype in a subject comprising administering to the subject a macrophage polarization-enhancing amount of a composition as disclosed herein. In another embodiment, the present disclosure provides a method of resolving inflammation associated with a disease in a subject in need thereof comprising administering to the subject an inflammation-resolving amount of a composition as disclosed herein. In another embodiment, the present disclosure provides a method of elevating SPM levels in plasma of a human subject comprising administering to the human subject an SPM-elevating amount of a composition as disclosed herein. In another embodiment, the present disclosure provides use of a composition as disclosed herein as a vaccine coadjuvant. In another embodiment, the present disclosure provides use of a composition as disclosed herein as a chemotherapeutic coadjuvant. In another embodiment, the present disclosure provides use of a composition as disclosed herein in the manufacture of a medicament for increasing phagocytic activity of macrophages in a subject. In another embodiment, the present disclosure provides use of a composition as disclosed herein in the manufacture of a medicament for enhancing macrophage polarization toward a pro-resolution phenotype in a subject. In another embodiment, the present disclosure provides use of a composition as disclosed herein in the manufacture of a medicament for resolving inflammation associated with a disease in a subject in need thereof. In another embodiment, the present disclosure provides use of a composition as disclosed herein in the manufacture of a medicament for elevating SPM levels in plasma of a human subject. | A61K31557 | 20180302 | 20180913 | A61K31557 | 1 | DRAPER, LESLIE A ROYDS | COMPOSITIONS COMPRISING OMEGA-3 FATTY ACIDS, 17-HDHA AND 18-HEPE AND METHODS OF USING SAME | SMALL | 0 | ACCEPTED | A61K | 2,018 |
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15,757,653 | PENDING | METHOD FOR TREATMENT PLANNING | A method for planning a treatment includes recording a first data record of three-dimensional image data of surfaces of an upper and lower jaw. A bite plate with cured impressions of the upper and lower jaw and markers is fitted to the patient. A second data record is recorded of three-dimensional image data of surface data of the bite plate without the patient. A movement recorder is fastened to the lower jaw while the patient bites on the bite plate. The bite plate is removed from the patient. Movements of the movement recorder during mastication movements are recorded and stored in a third data record as movement data. The three-dimensional image data of the first data record is combined with the movement data. A registration is performed using the second data record. The mastication movements of the lower jaw relative to the upper jaw are displayed for treatment planning. | 1-10 (canceled) 11. A method for planning a treatment on a set of teeth of a patient, the planning being based on a representation of mastication movements of the patient in which an upper row of teeth and a lower row of teeth move in relation to one another, the method comprising: recording a first data record with a camera system, the first data record comprising three-dimensional image data of surfaces of an upper jaw which is at least partly toothed and surfaces of a lower jaw which is at least partly toothed; fitting a bite plate to the patient, the bite plate comprising cured impressions of the upper jaw, cured impressions of the lower jaw, and identifiable markers arranged at least one of at and in the bite plate; recording a second data record comprising three-dimensional image data which comprises surface data of the bite plate without an involvement of the patient, the second data record allowing for an identification of the surfaces of the upper jaw, the surfaces of the lower jaw, and the identifiable markers of the bite plate therein; detachably fastening a movement recorder to the lower jaw of the patient while the patient bites on the bite plate fitted on the patient so as to register an orientation of the movement recorder in relation to the bite plate; removing the bite plate from the patient; recording movements of the movement recorder during the mastication movements using a detector detachably fastened to a head of the patient and storing the movements in a third data record as movement data; combining the three-dimensional image data of the first data record with the movement data of the third data record, wherein a registration is performed using the second data record; and presenting on a screen the mastication movements of the lower jaw in relation to the upper jaw for the purposes of planning the treatment. 12. The method as recited in claim 11, wherein only the bite plate is recorded in the second data record. 13. The method as recited in claim 11, wherein the second data record is recorded based on a model comprising the upper jaw and the lower jaw of the patient and the bite plate, the bite plate being inserted between the upper jaw and lower jaw of the model. 14. The method as recited in claim 13, wherein the model is a plaster cast model. 15. The method as recited in claim 13, wherein the bite plate or the model comprising the bite plate is recorded in the second data record via a three-dimensional x-ray scan. 16. The method as recited in claim 15, wherein the bite plate is surrounded by a metal sheet when recording the second data record via the three-dimensional x-ray scan. 17. The method as recited in claim 16, wherein the metal sheet comprises a varying thickness. 18. The method as recited in claim 11, wherein a holder is used to detachably fasten the movement recorder to the lower jaw of the patient, the holder being affixed to the lower jaw of the patient via an adhesive bonding. 19. The method as claimed in claim 18, wherein, the movement recorder is initially affixed to the holder of the bite plate in a first orientation, the first orientation of the movement recorder being recorded by the detector, the movement recorder is then affixed to the holder which is affixed to the lower jaw of the patient via the adhesive bonding in a second orientation, the second orientation of the movement recorder with the bite plate inserted being recorded by the detector, and the bite plate is then removed to facilitate the mastication movements which are undisturbed. 20. The method as recited in claim 11, wherein, the three-dimensional image data of the first data record is first combined with the movement data of the third data record so that a registration of the movement data and the data of the second data record initially occurs via the identifiable markers of the bite plate, and the registration of the three-dimensional image data of the first data record to the data of the second data record subsequently occurs. 21. A system for performing the method as recited in claim 11, the system comprising: a camera system for recording a first data record comprising three-dimensional image data of surfaces of an upper jaw which is at least partly toothed and surfaces of a lower jaw which is at least partly toothed of a patient; a bite plate fitted to the patient, the bite plate comprising cured impressions of the upper jaw, cured impressions of the lower jaw, and identifiable markers; a recording system for creating a second data record of three-dimensional x-ray data comprising surface data of the bite plate for identifying the surfaces of the upper jaw and the surfaces of the lower jaw, and data to identify the identifiable markers; a movement recorder configured to be detachably fastenable to the lower jaw of the patient; a device to register an orientation of the movement recorder in relation to the bite plate while the patient bites the bite plate; a detector detachably fastenable to a head of the patient, the detector being configured to record movements of the movement recorder during mastication movements and to store movement data recorded by the detector in a third data record; a computer for combining the three-dimensional image data of the first data record with the movement data of the third data record and for registration via the data of the second data record; and a screen for presenting the mastication movements of the lower jaw in relation to the upper jaw. 22. The system as claimed in claim 21, wherein the bite plate, when fitted to the patient, further comprises a plug-in adapter arranged in a front region of the bite plate, the plug-in adapter being configured to mechanically connect to the recording system for creating the second data record. 23. The system as recited in claim 22, wherein the recording system is an x-ray device. | CROSS REFERENCE TO PRIOR APPLICATIONS This application is a U.S. National Phase application under 35 U.S.C. § 371 of International Application No. PCT/EP2016/070965 filed on Sep. 6, 2016 and which claims benefit to German Patent Application No. 10 2015 115 034.4, filed on Sep. 8, 2015. The International Application was published in German on Mar. 16, 2017 as WO 2017/042156 A1 under PCT Article 21(2). FIELD The present invention relates to a method and to a system for planning a treatment on the set of teeth of a patient, wherein the planning is based on a representation of a mastication movement of the patient on a computer screen, the upper and the lower row of teeth moving in relation to one another during the mastication movement. BACKGROUND Imaging methods and electronic registrations are included among the most important methods for capturing the functional state of the stomatognathic system and for planning complex prosthetics restorations. Various methods for visualizing anatomical relationships in the living body are known in order to simplify the diagnosis for a treating medical practitioner and to facilitate an optimized therapy planning. DE 10 2012 104 912 A1, for example, describes the anatomical and in particular also the functional kinematic representation of jaw joints in volumetric and surface views in three dimensions. It is here possible to present a digital volumetric lower jaw image in different positions in relation to a digital volumetric upper jaw image. Condylography is used to record a movement and a multiplicity of position data records are stored (“condylogram”). Such a position data record describes the real spatial bearing of the lower jaw in relation to the upper jaw at a certain point of the movement. In the method, the data records are computationally “simulated” on the basis of a first data record that is recorded by a volume tomographic method, taking account of the ascertained movement data contained in the condylogram, and are presented to the observer on the screen. Such a method has also been described in the article “SICAT Function: Anatomical Real-Dynamic Articulation by Merging Cone Beam Computed Tomography and Jaw Motion Tracking Data”, International Journal of Computerized Dentistry 2014, 17(1); 65-74. A bite plate (“FusionBite”), which has dental impressions of the patient, and consequently impressions of the two rows of teeth in a cured compound plays a central role in the described procedure. The use of this bite plate makes it possible to have an exact spatial assignment between 3D x-ray data and the recorded (mastication) movement data. The bite plate is worn by the patient during an x-ray recording. After the data is assigned in a spatially exact manner with the aid of the bite plate, the movement of the jaw joints can be reproduced with a computer program. The simulated movement of the digital tooth impressions can in turn be presented on a screen and can be examined exactly on the basis of the moving representation. The volume tomographic data in the known methods are recorded by an x-ray scan on the patient who is subjected to corresponding x-ray exposure during the examination. The recording region in many x-ray devices is too small to be able to see the jaw joints in the recording. The recording region of such small x-ray devices suffices, however, for these to be used for the above-described procedure and for the patient-individual movement of the rows of teeth to be simulated on the basis of the digital tooth impressions. The patient in such x-ray devices is also exposed to ionizing radiation in order to establish the spatial assignment via the bite plate. DE 10 2013 204 207 A1 describes a bite fork via which it is possible to establish a relationship between the measurement data of an intraoral 3D surface scanner and the data of a 3D positioning system and capture the dental arch in order to be able to represent the surfaces statically and in motion. DE 10 2010 021 934 A1 describes a similar dental tool for obtaining correlation data, the tool interacting with a sensor system held on a frontal arch in order to be able to carry out movement measurements. SUMMARY An aspect of the present invention is to develop a method, implementable by simple devices, for representing the mastication movement, the method minimizing radiation exposure of the patient, allowing for anatomical peculiarities to be easily determined, and allowing the planning of prosthetic restorations to be undertaken while taking into account individual mastication habits of a patient. In an embodiment, the present invention provides a method for planning a treatment on a set of teeth of a patient. The planning is based on a representation of mastication movements of the patient in which an upper row of teeth and a lower row of teeth move in relation to one another. The method includes recording a first data record with a camera system. The first data record comprises three-dimensional image data of surfaces of an upper jaw which is at least partly toothed and surfaces of a lower jaw which is at least partly toothed. A bite plate is fitted to the patient. The bite plate comprises cured impressions of the upper jaw, cured impressions of the lower jaw, and identifiable markers arranged at least one of at and in the bite plate. A second data record is recorded comprising three-dimensional image data which comprises surface data of the bite plate without an involvement of the patient. The second data record allows for an identification of the surfaces of the upper jaw, the surfaces of the lower jaw, and the identifiable markers of the bite plate therein. A movement recorder is detachably fastened to the lower jaw of the patient while the patient bites on the bite plate fitted on the patient so as to register an orientation of the movement recorder in relation to the bite plate. The bite plate is removed from the patient. Movements of the movement recorder during the mastication movements are recorded using a detector detachably fastened to a head of the patient. The movements are stored in a third data record as movement data. The three-dimensional image data of the first data record is combined with the movement data of the third data record. A registration is performed using the second data record. The mastication movements of the lower jaw in relation to the upper jaw are presented on a screen for the purposes of planning the treatment. BRIEF DESCRIPTION OF THE DRAWINGS The present invention is described in greater detail below on the basis of embodiments and of the drawings in which: FIG. 1 shows a bite plate which has not yet been equipped with an impression compound; FIG. 2 shows a bite plate which has not yet been equipped with an impression compound surrounded by a cylinder made of a thin sheet which partly absorbs x-ray radiation during an x-ray scan; FIG. 3 shows the system for recording movement data detachably fastened to the lower jaw of a patient via a holder; FIG. 4 shows a detailed view of the system for recording movement data; FIG. 5 shows a simulation of the mastication movement using image data, namely the rows of teeth of upper jaw and lower jaw presented on a screen with the set of teeth being completely closed; FIG. 6 shows a simulation of the mastication movement using image data, namely the rows of teeth of upper jaw and lower jaw presented on a screen with the set of teeth being opened to a maximum extent; and FIG. 7 shows a simulation of the mastication movement using image data, namely the rows of teeth of upper jaw and lower jaw presented on a screen as a frontal view of the open set of teeth. DETAILED DESCRIPTION The essence of the present invention lies in completely dispensing with the x-ray scan on the patient and carrying out the x-ray scan, which is ultimately necessary for registering the data records, and consequently for the exact fusioning thereof, on a model representing the bite of the patient. According to the present invention, a known type of bite plate is fitted to the patient for this purpose, the bite plate having cured impressions of the at least partly toothed upper jaw and of the at least partly toothed lower jaw. The bite plate is provided with identifiable markers in order to be able to track the orientation of the bite plate in the second data record of the scanned data in an improved manner. The second data record containing three-dimensional image data of the bite plate is then recorded without patient involvement. This second data record should be recorded so that the surfaces of the toothed jaws and the markers of the bite plate can be identified. Two options exist for recording the second data record according to the present invention. It is firstly possible to record only the bite plate with the cured impression compound situated thereon, into which the tooth impressions have been dug. The “positive” surfaces of the toothed jaws can then be calculated retrospectively from the “negative” tooth impressions. If only the bite plate is scanned using a 3D x-ray method, it is advantageous to use a radiopaque impression compound in order to be able to identify the (negative) contour of the teeth in an improved manner. In an embodiment of the present invention, the bite plate can, for example, have a plug-in adapter (“flange”) in the front region via which a rigid mechanical connection to the recording system for creating a second data record, in particular to the x-ray device, is possible. It is secondly possible to make the second data record from a model of the set of teeth, in particular from a plaster cast model, with an upper and lower jaw of the patient. The surfaces of the toothed jaws are available as “positive” surfaces in the model. The plaster cast models lie in the impressions of the bite plate in an interlocking manner during the scan. The scan to be made of the bite plate is undertaken using a method allowing the negative and/or positive surfaces to be resolved. In certain circumstances, it is possible to record a three-dimensional data record using an optical camera scan. It is advantageous, however, if the scan is recorded using the x-ray radiation from a digital volume tomography (DVT) scanner. The use of the digital volume tomography (DVT) scanner makes it possible to exactly represent the surfaces of the bite plate and/or of the model. If use is made of x-ray radiation, it is advantageous to make the markers on the bite plate from a radiopaque material, for example, in the form of small, introduced spheres, so that they can be identified well in the three-dimensional data record. In detail, the method for planning a treatment on the set of teeth of a patient appears in the following steps on the basis of the representation of a mastication movement of the upper and lower row of teeth of the patient: Firstly, an intraoral camera system is used to record a first data record with three-dimensional image data of the surfaces of the upper jaw that is toothed to a greater or lesser extent and of the lower jaw that is toothed to a greater or lesser extent. The jaws can be visualized on a screen on the basis of the data both during and after the recording. The method also works with partly toothed jaws. There only need to be enough teeth present to allow a registration to be carried out. In the meantime, a bite plate (“FusionBite”) is fitted to the patient via the patient biting into the impression compound applied onto the bite plate. After curing, the bite plate has the cured impressions of the toothed upper jaw and of the toothed lower jaw. In order to be visible in the subsequent scan, identifiable markers with a defined form are provided at and/or in the bite plate, the markers consisting of a radiopaque material in order to be visible in the x-ray scan. The markers have a known spatial relationship to the plug-in adapter of the FusionBite in order to facilitate a spatially exact registration with the movement data. According to the present invention, the second data record with three-dimensional image data containing surface data of the bite plate and, optionally, of a model is then recorded without any patient involvement. The recording technique should be selected so that the surfaces of the toothed jaws and the markers of the bite plate can be identified in the data. For the purposes of recording the three-dimensional image data with surface data of the bite plate and of the model, it is advantageous if the bite plate is surrounded by a metal sheet, in particular a cylindrical metal sheet, for example, a cylindrical metal sheet made of copper or aluminum, with a varying thickness. The metal sheet can be connected to the bite plate via the adapter. The metal sheet brings about an x-ray attenuation similar to that of the soft tissue of the (missing) patient. The x-ray recordings therefore have similar grayscale value characteristics to a real patient scan. A movement recorder is fastened in a detachable manner to the lower jaw of the patient to record movement data. Fastening takes place while the patient bites into the fitted bite plate in order to be able to undertake a registration of the orientation of the movement recorder in relation to the bite plate. After the registration, the bite plate is removed from the mouth of the patient. A (movement) detector which is fastened at a fixed position to the head of the patient and which registers the movements of the movement recorder from this position serves as a counterpiece to the movement recorder. With the detachably fixed movement recorder and the detachably fixed detector, the patient then carries out a sequence of a plurality of mastication movements, where possible along different trajectories to the extent that this is permitted by the anatomy of their jaw. These mastication movements are recorded by the detector and stored in a third data record as movement data. The movement data represents movement lines of, in each case, individual points that are related to the lower jaw in a three-dimensional coordinate system that has been fixed by the upper jaw. Finally, the movement data are brought into a common coordinate system (“registered”) with the three-dimensional image data of the first data record so that, on the three-dimensional image data of the upper and lower row of teeth, the movement thereof can be simulated. The three-dimensional image data of the first data record are married to the individual movement data of the patient of the third data record via the registration by way of the second data record. The mastication movements of the toothed lower jaw in relation to the toothed upper jaw can then be presented on a screen for the purposes of treatment planning. Within the scope of treatment planning, the treating medical practitioner can virtually insert an implant into one of the jaws and observe how the implant fits into the anatomy of the simulated mastication movement. Via the direct fusion of digital tooth models and movement recordings, the method according to the present invention and the apparatus according to the present invention provide a solution that is suitable in practice and which is at the same time precise. It is thereby possible to present the real individual positions of the rows of teeth of the patient and the movement of the rows of teeth in the 3D volume in a manner that is anatomically precise. It is thereby possible to superimpose the DVT data onto digital models of the upper and lower jaw, which were obtained by intraoral or laboratory-based scanning methods, as a result of which the precondition was created for producing therapeutic edge-to-edge bite aids or tooth replacements with an optimized jaw relation and subjecting the design thereof to the individual movement patterns of the patient. An advantage of the procedure according to the present invention, which relates to the simulating representation of the mastication movements of upper and lower jaw, is that the patient is spared from radiation exposure by ionizing radiation. The present invention provides that the spatial assignment between the first data record and the third data record is effectuated via the second data record that is recorded on the model and not on the patient. For the purposes of measuring the movement and registering the movement, use is advantageously made of a system comprising a movement recorder and a detector, the system operating, for example, on an ultrasound time-of-flight basis, i.e., a conversion of times-of-flight of a plurality of acoustic signals into spatial information. A holder (“attachment”) for the movement recorder is detachably fastened to the patient in a para-occlusal manner therefor, the movement recorder in this case being a measurement sensor arc equipped with sound transmitters. The movement recorder has a magnetic coupling via which it can be stably fastened to the lower jaw attachment and to the bite plate. Four ultrasound transmitters are advantageously arranged on the lower jaw in an arcuate manner over a wide area, in front of the mouth and to the sides, via the movement recorder. The detector fastened above consists of three collinearly positioned microphones, which are respectively arranged to the left and to the right, so that, overall, a measurement field which is simultaneously close to the occlusion and close to the joints is defined. As a counterpart to the measurement sensor arc that moves with the lower jaw, the system comprises a microphone sensor unit affixed to the head, the microphone sensor unit resting against the glabella and the postauricular mastoid on both sides and being affixed by way of a rubber band over the back of the head. A movement measurement is thereby effectuated only via the mastication movement of the lower jaw relative to the head in a very natural fashion during the mastication movements. For the referencing with the second data record, the bite plate is interposed, the measurement sensor arc is placed on the bite plate, and a measurement is triggered for a few seconds. The bite plate is subsequently removed, the measurement sensor arc is fastened to the attachment, and the actual functional examination is carried out. The user has all available measured jaw movements and positions after fusioning the second data record and the movement data. On the basis of a selection list, a selection can be made between various jaw bearings. If a movement is selected from the list, a movement track with an anatomical reference is displayed automatically. The present invention will be described in more detail below on the basis of the drawings. FIG. 1 shows a bite plate 1 which has not yet been equipped with an impression compound at this stage. The impression compound is applied on both sides of the respective bearing face 2 before the patient leaves their bite in the impression compound to be cured. The impression compound is held by teeth 3 which are introduced into the bearing face 2. Markers 4 made of a radiopaque material are attached to the bite plate 1, it being possible to identify the markers 4 in the subsequent x-ray scan. The bite plate 1 also has a plug-in adapter 5 via which the bite plate 1 can be affixed to the recording device. In FIG. 2, the bite plate 1 is surrounded by a cylinder made of a thin sheet 6 which partly absorbs the x-ray radiation during the x-ray scan similar to the tissue of a real patient that surrounds the jaw. FIG. 3 shows a movement recorder 7 in an arcuate form which, as can be seen from the detailed view according to FIG. 4, is detachably fastened to the lower jaw of a patient 9 by way of a holder 8 (“attachment”). Four ultrasound transmitters 10 are arranged on the movement recorder 7 on both sides. The detector 11 fastened above the forehead of the patient 9 has three collinearly positioned microphones, respectively arranged to the left and to the right, which thereby define the measurement field. In the present case, the patient 9 additionally wears the bite plate 12. In this state, the measurement for registering the movement recorder 7 that has been attached by way of the holder 8 is effectuated, the movement recorder 7 having been fastened, just before this, to the bite plate 12 via an adapter. FIGS. 5-7 now show the result of the procedure according to the present invention, namely the rows of teeth of upper jaw 13 and lower jaw 14, presented on a screen, in different simulated movement stages and from different perspectives. In FIG. 5, the set of teeth are completely closed and they are opened to the maximum extent in FIG. 6. FIG. 7 is a frontal view of the open set of teeth. The movement tracks 15 from and during various mastication movements are plotted in the open oral cavity. The treating medical practitioner is now able to plan prosthetics restorations, for example, on the virtual set of teeth. The individual steps up to this simulation are summarized once again below with the sequence of steps not being restricted to this sequence: Step 1: recording the digital tooth impressions (first data record); Step 2: loading the bite plate with the curing impression compound; Step 3: creating a two-part plaster cast model on the basis of the impression; Step 4: creating the 3D x-ray scan (second data record) with the bite plate, which is held by the jaws of the plaster cast model; Step 5: reinserting the bite plate into the mouth of the patient for calibrating the movement-recording device; Step 6: performing an attachment of the T-attachment to the lower jaw teeth of the patient. The actual movement measurement, after the calibration of the device has been carried out, is effectuated using the T-attachment; Step 7: performing an initial calibration of the device for the movement measurement with the bite plate; Step 8: performing a barrier-free movement measurement (third data record) with the movement-recording device without a bite plate; Step 9: performing a registration of the 3D x-ray data (second data record) and the movement data (third data record) with the aid of the radiopaque spherical markers of the bite plate; Step 10: performing a registration of the digital tooth impressions (first data record) with the 3D x-ray data (second data record); and Step 11: performing a movement of the digital tooth impressions (first data record) and of the lower jaw on the basis of the individual movements of the patient (third data record). According to the present invention, the data of the second data record is only required to indirectly spatially reconcile the data of the first data record and the data of the third data record by way of the data of the second data record. The present invention is not limited to embodiments described herein; reference should be had to the appended claims. | <SOH> BACKGROUND <EOH>Imaging methods and electronic registrations are included among the most important methods for capturing the functional state of the stomatognathic system and for planning complex prosthetics restorations. Various methods for visualizing anatomical relationships in the living body are known in order to simplify the diagnosis for a treating medical practitioner and to facilitate an optimized therapy planning. DE 10 2012 104 912 A1, for example, describes the anatomical and in particular also the functional kinematic representation of jaw joints in volumetric and surface views in three dimensions. It is here possible to present a digital volumetric lower jaw image in different positions in relation to a digital volumetric upper jaw image. Condylography is used to record a movement and a multiplicity of position data records are stored (“condylogram”). Such a position data record describes the real spatial bearing of the lower jaw in relation to the upper jaw at a certain point of the movement. In the method, the data records are computationally “simulated” on the basis of a first data record that is recorded by a volume tomographic method, taking account of the ascertained movement data contained in the condylogram, and are presented to the observer on the screen. Such a method has also been described in the article “SICAT Function: Anatomical Real-Dynamic Articulation by Merging Cone Beam Computed Tomography and Jaw Motion Tracking Data”, International Journal of Computerized Dentistry 2014, 17(1); 65-74. A bite plate (“FusionBite”), which has dental impressions of the patient, and consequently impressions of the two rows of teeth in a cured compound plays a central role in the described procedure. The use of this bite plate makes it possible to have an exact spatial assignment between 3D x-ray data and the recorded (mastication) movement data. The bite plate is worn by the patient during an x-ray recording. After the data is assigned in a spatially exact manner with the aid of the bite plate, the movement of the jaw joints can be reproduced with a computer program. The simulated movement of the digital tooth impressions can in turn be presented on a screen and can be examined exactly on the basis of the moving representation. The volume tomographic data in the known methods are recorded by an x-ray scan on the patient who is subjected to corresponding x-ray exposure during the examination. The recording region in many x-ray devices is too small to be able to see the jaw joints in the recording. The recording region of such small x-ray devices suffices, however, for these to be used for the above-described procedure and for the patient-individual movement of the rows of teeth to be simulated on the basis of the digital tooth impressions. The patient in such x-ray devices is also exposed to ionizing radiation in order to establish the spatial assignment via the bite plate. DE 10 2013 204 207 A1 describes a bite fork via which it is possible to establish a relationship between the measurement data of an intraoral 3D surface scanner and the data of a 3D positioning system and capture the dental arch in order to be able to represent the surfaces statically and in motion. DE 10 2010 021 934 A1 describes a similar dental tool for obtaining correlation data, the tool interacting with a sensor system held on a frontal arch in order to be able to carry out movement measurements. | <SOH> SUMMARY <EOH>An aspect of the present invention is to develop a method, implementable by simple devices, for representing the mastication movement, the method minimizing radiation exposure of the patient, allowing for anatomical peculiarities to be easily determined, and allowing the planning of prosthetic restorations to be undertaken while taking into account individual mastication habits of a patient. In an embodiment, the present invention provides a method for planning a treatment on a set of teeth of a patient. The planning is based on a representation of mastication movements of the patient in which an upper row of teeth and a lower row of teeth move in relation to one another. The method includes recording a first data record with a camera system. The first data record comprises three-dimensional image data of surfaces of an upper jaw which is at least partly toothed and surfaces of a lower jaw which is at least partly toothed. A bite plate is fitted to the patient. The bite plate comprises cured impressions of the upper jaw, cured impressions of the lower jaw, and identifiable markers arranged at least one of at and in the bite plate. A second data record is recorded comprising three-dimensional image data which comprises surface data of the bite plate without an involvement of the patient. The second data record allows for an identification of the surfaces of the upper jaw, the surfaces of the lower jaw, and the identifiable markers of the bite plate therein. A movement recorder is detachably fastened to the lower jaw of the patient while the patient bites on the bite plate fitted on the patient so as to register an orientation of the movement recorder in relation to the bite plate. The bite plate is removed from the patient. Movements of the movement recorder during the mastication movements are recorded using a detector detachably fastened to a head of the patient. The movements are stored in a third data record as movement data. The three-dimensional image data of the first data record is combined with the movement data of the third data record. A registration is performed using the second data record. The mastication movements of the lower jaw in relation to the upper jaw are presented on a screen for the purposes of planning the treatment. | A61C19045 | 20180306 | 20180830 | A61C19045 | 0 | FOLGMANN, DREW S | METHOD FOR TREATMENT PLANNING | UNDISCOUNTED | 0 | PENDING | A61C | 2,018 |
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15,758,046 | PENDING | VACUUM NOZZLE | A method of and an apparatus for picking up cut gemstones which have been orientated table down is provided. A vacuum wand has a generally cylindrical body with a central bore culminating in a nozzle through which a vacuum may be applied. The wand comprises a retractable outer sleeve configured to slide axially over the nozzle, and a biasing mechanism for biasing the sleeve towards a position in which it extends beyond the nozzle. | 1. A vacuum wand for picking up cut gemstones which have been orientated table down, having a generally cylindrical body with a central bore culminating in a nozzle through which a vacuum may be applied, said wand comprising a retractable outer sleeve configured to slide axially over the nozzle, and a biasing mechanism for biasing the sleeve towards a position in which it extends beyond the nozzle. 2. A vacuum wand as claimed in claim 1, configured so that the sleeve cannot rotate relative to the nozzle. 3. A vacuum wand as claimed in claim 2, wherein the sleeve is provided with a flat surface which co-operates with a flat surface of the cylindrical body to prevent the rotation of the sleeve relative to the nozzle. 4. A vacuum wand as claimed in claim 1, wherein the nozzle is provided with a contact surface at a lower end thereof, said surface configured to retain a relatively small cut gemstone when vacuum is applied to the bore. 5. A vacuum wand as claimed in claim 4, wherein the contact surface of the nozzle is tapered inwards. 6. A vacuum wand as claimed in claim 4, wherein the contact surface of the nozzle is provided with a profiled groove extending transversely therethrough. 7. A vacuum wand as claimed in claim 1, wherein the sleeve is provided with a contact surface at a lower end thereof, said surface configured to retain a relatively large cut gemstone when vacuum is applied to the bore. 8. A vacuum wand as claimed in claim 7, wherein the contact surface of the sleeve is tapered inwards. 9. A vacuum wand as claimed in claim 7, wherein the contact surface of the sleeve is provided with a profiled groove extending transversely therethrough, said groove being circumferentially aligned with the groove of the nozzle. 10. A vacuum wand as claimed in claim 9, wherein an outer end of the profiled groove of the nozzle is of substantially the same width as an inner end of the profiled groove of the sleeve. 11. A vacuum wand as claimed in claim 1, wherein the sleeve is configured to retract axially over the nozzle when a gemstone being picked up has a smaller diameter than an internal diameter of the sleeve. 12. A vacuum wand as claimed in claim 1, wherein the sleeve is movable between an extended position, in which the contact surface of the sleeve is level with or below the contact surface of the nozzle, and a retracted position, in which the contact surface of the sleeve is above the contact surface of the nozzle. 13. A vacuum wand as claimed in claim 12, wherein the biasing mechanism comprises a spring. 14. A vacuum wand as claimed in claim 1, wherein retraction of the sleeve is limited by a shoulder of the wand body and co-operation between an upper flat surface of the sleeve and the wand body. 15. A vacuum wand as claimed in claim 1, wherein the sleeve is held in place on a distal end of the wand body by interlocking engagement with lugs. 16. A vacuum wand as claimed in claim 12, wherein a biasing force of the biasing mechanism is sufficient to return the sleeve from the retracted to the extended position, said biasing force being insufficient to dislodge a gemstone retained by the contact surface of the nozzle and/or the sleeve when the sleeve is returned to the extended position. 17. A transport mechanism for transporting cut gemstones, comprising a pivotable arm attached to a vacuum wand as claimed in claim 1. 18. A gemstone testing station comprising a device for orienting cut gemstones table down, a transport mechanism as claimed in claim 17, and an analysis instrument for carrying out analysis of the gemstones. 19. A screening device for determining whether a cut gemstone is natural or synthetic, including a testing station as claimed in claim 18. 20. A method of picking up a cut gemstone which has been orientated table down, comprising the steps of: providing a vacuum wand having a generally cylindrical body with a central bore culminating in a nozzle through which a vacuum may be applied, said wand comprising a retractable outer sleeve, configured to slide axially over the nozzle and a biasing mechanism for biasing the sleeve towards a position in which it extends beyond the nozzle; bringing the wand into contact with a pavilion of a gemstone; applying a vacuum through the bore to the nozzle; where the gemstone has a diameter greater than or equal to an internal diameter of the sleeve, retaining the gemstone by air pressure against the sleeve and/or the nozzle; or where the gemstone has a diameter smaller than the internal diameter of the sleeve, retracting the sleeve and retaining the gemstone by air pressure against the nozzle only. 21. A method of picking up a cut gemstone as claimed in claim 20, wherein the sleeve comprises a flat surface which co-operates with a flat surface of the cylindrical body to prevent rotation of the sleeve relative to the nozzle. 22. A method of picking up a cut gemstone as claimed in claim 20, wherein the nozzle comprises a tapered contact surface at a lower end thereof, said surface configured to retain a cut gemstone when vacuum is applied to the bore. 23. A method of picking up a cut gemstone as claimed in claim 20, wherein the sleeve comprises a generally conical contact surface at a lower end thereof, said surface configured to retain a cut gemstone when vacuum is applied to the bore. 24. A method of picking up a cut gemstone as claimed in claim 22, further comprising providing the contact surface of the nozzle with a profiled groove extending transversely therethrough. 25. A method of picking up a cut gemstone as claimed in claim 24, further comprising providing the contact surface of the sleeve with a profiled groove extending transversely therethrough, said groove being circumferentially aligned with the groove of the nozzle. 26. A method of picking up a cut gemstone as claimed in claim 23, wherein the sleeve is movable between an extended position, in which the contact surface of the sleeve is level with or below the contact surface of the nozzle, and a retracted position, in which the contact surface of the sleeve is above the contact surface of the nozzle. 27. A method of picking up a cut gemstone as claimed in claim 20, wherein the biasing mechanism comprises a spring. 28. A method of picking up a cut gemstone as claimed in claim 20, further comprising configuring a biasing force of the biasing mechanism to be sufficient to return the sleeve from the retracted to the extended position, but insufficient to dislodge a gemstone retained by the contact surface of the nozzle and/or the sleeve when the sleeve is returned to the extended position. 29. A method of picking up and transporting cut gemstones of a variety cuts and sizes which have been orientated table down, using the method of claim 20 and the same wand to pick up each gemstone. | TECHNICAL FIELD The present invention relates to a method and an apparatus for picking up cut gemstones which have been previously orientated. In particular, although not exclusively, the invention relates to a method and an apparatus for picking up cut diamonds. BACKGROUND Natural diamonds are stones from nature, consisting exclusively of diamond formed by geological processes over long periods of time. Synthetic diamonds are man-made stones manufactured by industrial processes, such as HPHT (high pressure high temperature) and CVD (chemical vapour deposition). Synthetic diamonds may be relatively easy to distinguish from natural diamonds when in an unpolished state, however, once polished and cut into a gemstone, identification that a stone is synthetic may be more difficult. Advanced screening instruments, such as the DiamondSure™ and DiamondView™ may be used to test whether a stone is natural or synthetic. Typically, such screening involves measuring the way in which light is absorbed by or emitted from a diamond. Before screening commences it is usually necessary for the stone being tested to be placed “table-down” in a precise location on the measurement surface or holder. In this context, the “table” is the largest central facet of the crown (the top half of the stone when mounted). In addition to screening larger, individual stones, it is also necessary to screen large numbers of smaller diamonds, including stones sometimes known as melee. Melee is a term of the trade that does not have a well defined size range, but can be considered in practice to refer to stones smaller than about 0.2 carats (20 points), and usually (but not necessarily) larger than about 0.01 or 0.02 carats. Due to their small size, melee stones are typically sold in parcels or lots. Since one parcel may contain hundreds of stones, it is possible for synthetic diamonds to be mixed in with natural stones. Screening of melee diamonds can potentially be extremely time consuming, since each stone must be tested individually and therefore placed in the correct orientation individually. WO 2012/146913 discloses an apparatus for orientating gemstones, in which discrete gemstones are provided on a travelling path which has a pair of opposed oscillating walls. These walls urge the gemstones into their most stable orientation—i.e. table-down—as they progress along the path. Once in this orientation, individual stones can be lifted from the travelling path by a vacuum wand and transported to a test station. FIG. 1 is a view of the apparatus 1 described in WO 2012/146913 for orientating gemstones. The melee stones are poured into a hopper 2 and pass through a pair of rollers 6. The speed of the rollers 6 is configured to separate out the stones so they pass through one at a time. The stones are then directed onto a rotating disc 10, as shown in FIG. 2. The disc 10 rotates clockwise and provides a circular travelling path, passing the stones through an agitator 13. The agitator 13 comprises a pair of opposed parallel vertical walls 11 which form a semi-circular channel 12. The walls 11 are connected to an oscillator 15 which oscillates the walls with sufficient magnitude and frequency that they collide with the stones on the travelling path. The centre of the pair of walls 14 oscillates along the radius of the rotating disc 10. The impact level of the walls 11 is chosen such that it is enough to knock a stone off its pavilion facet, but not to knock a stone off its most stable table facet. Eventually, the stones land table-down and are aligned by the time they reach a handling area 7. An orientation checking device 9 checks that each stone is table-down, by recording a side view silhouette image of the stone with a camera 16. If the stone is found to be correctly orientated, it is collected by the handler, comprising a swinging arm 3 and a vacuum wand 4, and transported to a synthetic detection device 17. If the stone is found to be incorrectly orientated, it will be transported back to the oscillating channel 12 to be re-orientated. This process continues until all stones in the melee have been orientated, tested and dispensed into an appropriate collection bin 5 via chutes 8. Diamonds which are to be sorted and tested using apparatus including the melee screener described above may comprise a wide range of sizes and cuts. Popular diamond cuts range from round brilliant to pear shaped to elongate baguette cuts. Stones which require screening may vary in size from small melee diamonds to much larger individual stones. In order to sort and process stones for testing quickly, it is desirable to be able to handle a wide variety of sizes and cuts using the same apparatus. Moreover, since each stone to be screened must be very precisely placed upon the measurement surface, it is desirable for the apparatus to be capable of precise positioning, regardless of variations in stone size or cut. FIG. 3a is a cross section of a stone held by a conventional nozzle. A 1 point cut stone (girdle 1.4 mm, depth 0.83 mm) has been picked up by the nozzle of a conventional vacuum wand. It will be noted that the stone is positioned centrally, with its culet in the centre of the nozzle. FIG. 3b shows the same stone, but in this case the nozzle has been lowered down onto the stone off centre, so that the stone is located on one side of the nozzle. Using this conventional nozzle, the stone may be as much as 0.3 mm off centre while still within nozzle, with the added potential for its position to move as it is transported. Furthermore, there is a significant danger in this situation that the stone will rotate as vacuum is applied to the nozzle so as to pick up the stone, meaning it is no longer table down, and is unlikely to be deposited table down when released from the nozzle onto the measurement instrument. Therefore, while the precise position of the nozzle can be guaranteed, the precise position of the stone within the nozzle cannot, and this may lead to incorrect positioning and/or orientation of the stone on the measurement surface and hence invalid test or measurement results. SUMMARY In accordance with one aspect of the present invention there is provided a vacuum wand for picking up cut gemstones which have been orientated table down, having a generally cylindrical body with a central bore culminating in a nozzle through which a vacuum may be applied, said wand comprising a retractable outer sleeve configured to slide axially over the nozzle, and a biasing mechanism for biasing the sleeve towards a position in which it extends beyond the nozzle. The vacuum wand may be configured so that the sleeve cannot rotate relative to the nozzle. The sleeve may be provided with a flat surface which co-operates with a flat surface of the cylindrical body to prevent the rotation of the sleeve relative to the nozzle. The nozzle may be provided with a contact surface at a lower end thereof configured to retain a relatively small cut gemstone when vacuum is applied to the bore. The contact surface of the nozzle may be tapered inwards. The contact surface of the nozzle may be provided with a profiled groove extending transversely therethrough. The sleeve may be provided with a contact surface at a lower end thereof, configured to retain a relatively large cut gemstone when vacuum is applied to the bore. The contact surface of the sleeve may be tapered inwards. The contact surface of the sleeve may be provided with a profiled groove extending transversely therethrough, circumferentially aligned with the groove of the nozzle An outer end of the profiled groove of the nozzle may be of substantially the same width as an inner end of the profiled groove of the sleeve. The sleeve may be configured to retract axially over the nozzle when a gemstone being picked up has a smaller diameter than an internal diameter of the sleeve. The sleeve may be movable between an extended position, in which the contact surface of the sleeve is level with or below the contact surface of the nozzle, and a retracted position, in which the contact surface of the sleeve is above the contact surface of the nozzle. The biasing mechanism may comprise a spring. Retraction of the sleeve may be limited by a shoulder of the wand body and co-operation between an upper flat surface of the sleeve and the wand body. The sleeve may be held in place on a distal end of the wand body by interlocking engagement with lugs A biasing force of the biasing mechanism may be sufficient to return the sleeve from the retracted to the extended position. The biasing force may be insufficient to dislodge a gemstone retained by the contact surface of the nozzle and/or the sleeve when the sleeve is returned to the extended position. A transport mechanism for transporting cut gemstones may comprise a pivotable arm attached to a vacuum wand according to the first aspect above. A gemstone testing station may comprise a device for orienting cut gemstones table down, the aforementioned transport mechanism, and an analysis instrument for carrying out analysis of the gemstones. A screening device for determining whether a cut gemstone is natural or synthetic may include the aforementioned testing station. In accordance with another aspect of the present invention there is provided a method of picking up a cut gemstone which has been orientated table down, comprising the steps of providing a vacuum wand having a generally cylindrical body with a central bore culminating in a nozzle through which a vacuum may be applied, the wand comprising a retractable outer sleeve, configured to slide axially over the nozzle and a biasing mechanism for biasing the sleeve towards a position in which it extends beyond the nozzle; bringing the wand into contact with a pavilion of a gemstone; applying a vacuum through the bore to the nozzle; where the gemstone has a diameter greater than or equal to an internal diameter of the sleeve, retaining the gemstone by air pressure against the sleeve and/or the nozzle; or where the gemstone has a diameter smaller than the internal diameter of the sleeve, retracting the sleeve and retaining the gemstone by air pressure against the nozzle only. The sleeve may comprise a flat surface which co-operates with a flat surface of the cylindrical body to prevent rotation of the sleeve relative to the nozzle. The nozzle may comprise a tapered contact surface at a lower end thereof, configured to retain a cut gemstone when vacuum is applied to the bore. The sleeve may comprise a generally conical contact surface at a lower end thereof, configured to retain a cut gemstone when vacuum is applied to the bore. The contact surface of the nozzle may be provided with a profiled groove extending transversely therethrough. The contact surface of the sleeve may be provided with a profiled groove extending transversely therethrough, being circumferentially aligned with the groove of the nozzle. The sleeve may be movable between an extended position, in which the contact surface of the sleeve is level with or below the contact surface of the nozzle, and a retracted position, in which the contact surface of the sleeve is above the contact surface of the nozzle. The biasing mechanism may comprise a spring. A biasing force of the biasing mechanism may be configured to be sufficient to return the sleeve from the retracted to the extended position, but insufficient to dislodge a gemstone retained by the contact surface of the nozzle and/or the sleeve when the sleeve is returned to the extended position. A method of picking up and transporting cut gemstones of a variety cuts and sizes which have been orientated table down may use the method of the second aspect above and the same vacuum wand to pick up each gemstone. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a perspective view of a known apparatus for orientating gemstones; FIG. 2 is a plan view of the apparatus of FIG. 1, with components removed for clarity; FIG. 3a is a cross section of a conventional vacuum nozzle holding a cut stone; FIG. 3b is a further cross section of the vacuum nozzle and stone of FIG. 3a; FIG. 4a is a perspective view of a vacuum wand for picking up cut stones; FIG. 4b is a cross section of the vacuum wand of FIG. 4a; FIG. 5a is an enlarged view of an end of the vacuum wand of FIG. 4a; FIG. 5b is an enlarged view of the end of the vacuum wand of FIG. 5a; FIG. 6 is a side view of the wand of FIG. 4 holding a 20 point brilliant cut stone; FIG. 7a is a side view of the vacuum wand of FIG. 4; FIG. 7b is a side view of the vacuum wand of FIG. 4, holding a 1 point brilliant cut stone in the pick up position; FIG. 7c is a side view of the vacuum wand of FIG. 4, holding a 1 point brilliant cut stone in the transport position; FIG. 8 is a perspective view of the wand holding a 1 point brilliant cut stone; FIG. 9a is a perspective view of the wand holding a large baguette cut stone; FIG. 9b is a perspective view of the wand holding a small baguette cut stone; and FIGS. 10a to 10h are perspective views of the wand holding a variety of different cut stones. DETAILED DESCRIPTION FIG. 4a is a perspective view of a vacuum wand 20 for picking up cut gemstones, such as diamonds. FIG. 4b is a cross-sectional view of the wand 20. FIGS. 5a and 5b are close up views of a nozzle 24 located at the end of the wand of FIG. 4a. The wand is designed to be used to pick up stones which have been previously orientated so that they are table down. This orientation may be performed by an automatic gemstone orientation apparatus, as discussed above. The wand 20 comprises an engagement portion 21, by which it may be fixed to a swinging arm similar to the arm 3 shown in FIG. 1. A cylindrical wand body 22 having a bore 18 therethrough is connected to the engagement portion 21. At a distal end of the wand body 22 the bore 18 ends in an inner fixed tapered nozzle 24 which is surrounded by a retractable outer sleeve 23, configured to slide axially over the body 22 and past the nozzle 24. When a vacuum is applied to the bore 18 (e.g. through port 19) a gemstone located in the nozzle 24 will be picked up and retained within the nozzle 24 and sleeve 23 by air pressure. In this example both the sleeve 23 and inner nozzle 24 are substantially circular in shape. The sleeve 23 and nozzle 24 both have contact surfaces 26, 27 respectively at lower ends thereof. The sleeve 23 is moveable between an extended position, in which the contact surface 26 of the sleeve 23 is level with or below the contact surface 27 of the nozzle 24, and a retracted position, in which the contact surface 26 of the sleeve 23 is above the contact surface 27 of the nozzle 24. The sleeve is biased towards the extended position, in this example by a spring 25 so that the sleeve is spring loaded. The sleeve 23 can therefore slide axially over the nozzle 24. The spring 25 is braced against a shoulder 34 of the wand body 22 at one end and against a flat upper surface 35 of the sleeve 23 at the other. The sleeve 23 is prevented from rotating relative to the nozzle 24 by flats 36 which abut the distal end of the wand body 22. Likewise, the flat upper surface 35 of the sleeve 23 abuts the wand body 21 when the sleeve 23 is in the retracted position, which prevents the sleeve 23 from retracting further. The sleeve 23 is held in place on the distal end of the wand body 21 by interlocking engagement with lugs 37. In this illustrated example, the inner nozzle 24 is provided with a tapered contact surface 26 against which a generally conical surface of a cut stone can be retained by air pressure when vacuum is applied through the bore. The sleeve 23 is similarly provided with a tapered contact surface 27 against which a portion of a surface of a cut stone can be retained when the nozzle is under vacuum. As can be seen from FIG. 5a, these contact surfaces 26, 27 are tapered from an outer diameter of the sleeve 23 to an inner diameter of the nozzle 24. As shown in FIG. 5b, both the sleeve 23 and inner nozzle 24 are provided with profiled grooves 28, 29. These grooves 28, 29 run radially through the contact surfaces 26, 27 of the nozzle 24 and sleeve 23, from an outer diameter of the sleeve 23 to an inner diameter of the nozzle 24. The grooves 28 of the sleeve 23 are circumferentially aligned with the grooves 29 of the nozzle 24. The profile of the grooves 28, 29 is generally tapered or v-shaped. It will be appreciated that this profile is particularly suited to accommodate a culet or keel of a cut stone. An outer end of the profiled groove 29 of the nozzle 24 is of substantially the same width as an inner end of the profiled groove 28 of the sleeve 23. The grooves 28, 29 therefore form a continuous channel across the contact surfaces 26, 27 of the nozzle 24 and sleeve 23. The operation of the vacuum wand 20 will now be described with reference to FIGS. 6 and 7, which show side views of the distal end of the wand. FIG. 6 shows the vacuum wand 20 holding a 20 point (0.2 carat) round brilliant cut stone. A round brilliant cut stone has a substantially round girdle, a generally conical pavilion and a crown with a flat facet (table) on an upper surface. In FIG. 6, the stone 30 is orientated table-down. Stones which have been subjected to an automated orientation process, as discussed above, may be roughly positioned under the nozzle 24. The nozzle 24 is lowered onto the stone 30 which is orientated table down on a handling surface (not shown here). The stone 30 is precisely centred by the sleeve 23, either by relative motion of the stone 30 or of the nozzle 24. In the example of FIG. 6, the diameter of stone 30 is larger than an internal diameter of the sleeve 23, and so the stone 30 may simultaneously come into contact with both the inner nozzle 24 and the sleeve 23. The stone 30 is retained by air pressure against both the contact surfaces 26, 27 of the nozzle 24 and the sleeve 23. Alternatively, the stone 30 may be in contact with the contact surface 26 of the sleeve 23 only, depending upon the stone's diameter and angular shape of the crown. The outer diameter of the sleeve 23 comes into contact with the stone 30, and not with the handling surface on which the stone 30 has been orientated table down. The sleeve 23 therefore remains biased by the spring 25 into an extended position, in which the contact surface 26 of the sleeve 23 is level with or below the contact surface 27 of the nozzle 24. The stone 30 is centred to the nozzle 24 upon pick up and can therefore be transported to one or more of: a testing station, a measurement station, a further processing system. The stone 30 may then be precisely placed thereon. In the example of FIGS. 7a to 7c, the stone 31 is a 1 point brilliant cut stone, having a diameter smaller than the internal diameter of the sleeve 23. In this case, the sleeve 23 will retract up over the nozzle 24, in the direction illustrated by the arrow shown in FIG. 7a. As the nozzle 24 is lowered over the stone 31, the retractable sleeve 23 makes contact with the handling surface H, as shown in FIG. 7b, and is pushed axially up over the nozzle. It will be appreciated that the axial movement of the sleeve 23 relative to the fixed nozzle 24 causes compression of the spring 25. The sleeve 23 makes contact with the handling surface H first, and retracts as the nozzle 24 descends until the nozzle contacts the stone 31. This is in contrast to the large stone 30 shown in FIG. 6 where the sleeve 23 and nozzle 24 simultaneously make contact with the stone 30. As illustrated in FIG. 7a, compression of the spring 25 and retraction of the sleeve 23 in the direction indicated by the arrow is limited by the shoulder 34 of the wand body 22 and co-operation between the upper flat surface 35 of the sleeve 23 and the wand body 21. This ensures that the spring 25 is not over-compressed and prevents damage to the nozzle 24. After pick up, the vacuum wand 20 is raised to prepare for transport. As the wand 20 is raised the spring 25 is no longer compressed by the handling surface and therefore the sleeve 23 is biased into an extended position once again, moving axially over body past the inner nozzle 24 in a direction indicated by the arrow shown in FIG. 7c. In other words, the sleeve 23 moves back down the wand 20 around the stone 31. It will be appreciated that as the wand is lowered onto a measurement surface (not shown here), the sleeve 23 will contact the surface and again retract around the stone 31. The vacuum is then released to place the stone 31 on the measurement surface. As the stone 31 has been precisely centred to the nozzle 24 and has been retained against the contact surface 27 of the nozzle 24 during transport, there has been no opportunity for the stone 31 to move around or to rotate within the nozzle 24 and therefore the stone 31 will be precisely placed table down by the vacuum wand 20 upon the measurement surface or holder. FIGS. 6 and 7 illustrate the operation of the wand 20 in relation to a stone 30 (hereinafter referred to as a medium-sized stone) which is larger than the external diameter of the sleeve 23 and to a stone 31 which has a diameter smaller than the internal diameter of the sleeve 23. In a case where a stone has a diameter just smaller than the external diameter of the sleeve 23 but larger than an external diameter of the nozzle 24, the stone may be in contact with the contact surfaces 26, 27 of both the nozzle 24 and the sleeve 23 at the point of pick up. However, when the stone is lifted off the handling surface and the sleeve 23 is biased back to an extended position, the stone may be retained against the contact surface 27 of the inner nozzle 24 only. The force at which the sleeve 23 is biased back into the extended position is therefore of great importance. If the biasing force is too weak, the sleeve 23 may not return to the extended position. If the biasing force is too strong, it may dislodge the medium-sized stone from its position against the contact surface 27. The strength of the biasing force provided by the spring 25 is therefore carefully configured to be just strong enough to return the sleeve 23 to the extended position. FIG. 8 is a perspective view of the 1 point stone 31 retained against the contact surface 27 of the inner nozzle 24. The stone 31 is precisely centred to the nozzle 24 but since its diameter is less than that of the inner diameter of the sleeve 23, the stone 31 is not in contact with the contact surface 26 of the sleeve 23. The stone 31 will not come into contact with the sleeve 23 either on pick-up, during transport or when the stone 31 is placed upon the measurement surface or holder. The operation of the profiled grooves 28, 29 will now be described with reference to FIGS. 9a and 9b. Stones 32, 33 shown in FIGS. 9a and 9b are elongate baguette cut stones, 20 points and 1 point respectively in size, being substantially rectangular in cross section and having one axis longer than the other. As discussed with reference to FIG. 5b, the sleeve 23 and inner nozzle 24 are provided with profiled grooves 28, 29, which run transversely across the contact surfaces 26, 27 of the nozzle 24 and sleeve 23. The grooves 28 of the sleeve 23 are circumferentially aligned with the grooves 29 of the nozzle 24. This alignment provides substantially continuous channels from an inner diameter of the nozzle 24 to the outer diameter of the sleeve 23. The grooves 28, 29 can therefore accommodate the long axis of a fancy cut stone, such as the 20 point baguette cut stone 32 shown in FIG. 9a. The tapered profile of the grooves 28, 29 is also suitable for stones which may have a flat keel rather than a pointed culet. Prior to pick up by the vacuum wand 20, the stone 32 is orientated table down by an automatic orientation device, such as the one discussed above. In addition to orientating cut stones table down, the device will also orient stones axially, i.e. a stone with one longer axis, such as a baguette cut stone, will generally be longitudinally orientated in the same way by the orientation device. The longitudinal orientation of the stone 32 when it reaches the handling area is therefore known, and the vacuum wand 20 may be installed such that the orientation of the long axis of the stone 32 and the orientation of the grooves 28, 29 are aligned. The operation of the vacuum wand 20 is substantially as described above with reference to FIG. 6. Where the stone to be picked up has a length L longer than or equal to the outer diameter of the sleeve 23, the stone 32 is retained by air pressure against both the contact surfaces 26, 27 of the nozzle 24 and the sleeve 23. The outer diameter of the sleeve 23 does not come into contact with the handling surface and therefore remains biased by the spring 25 into an extended position. The stone 32 is centred to the nozzle 24 by the grooves 28, 29 upon pick up and can therefore be transported to one or more of: a testing station, a measurement station, a further processing system. The stone 32 can then be precisely placed thereon. FIG. 9b illustrates the operation of the wand 20 with a 1 point baguette cut stone 33. In this case and as described with reference to FIGS. 7a to 7c, the length M of the stone 33 is less than the internal diameter of the sleeve 23 and therefore the retractable sleeve 23 makes contact with the handling surface (not shown here) and is pushed axially up over the nozzle 24 as the nozzle continues to descend until it makes contact with e stone 33. The stone 33 may be precisely centred to the nozzle 24 and within the profiled grooves 29. As can be seen in FIG. 9b, the stone 33 once retained by the wand 20 is centrally held against the contact surface 27 of the nozzle 24 only, and not against the contact surface 26 of the sleeve 23. Hence the stone 33 will not move around or rotate during transport and can be precisely positioned table down on a measurement surface or holder. It will be appreciated that the vacuum wand 20 described herein may be to pick up and transport cut gemstones of many different cuts and sizes. For example, the same wand 20 may be used to pick up both brilliant round and fancy cut stones, as shown in FIGS. 10a to 10h, including but not limited to: baguette (as shown in FIG. 10a), marquise (as shown in FIG. 10b), radiant (as shown in FIG. 10c), emerald (as shown in FIG. 10d), oval (as shown in FIG. 10e), princess (as shown in FIG. 10f), heart (as shown in FIG. 10g), pear (as shown in FIG. 10h), and carre cuts. The sprung mechanism of the wand 20 permits handling and placement of an extensive range of stone sizes, for example (but not limited to) 1 to 35 point round cut stones, and 1 to 20 point fancy cut stones. The configuration of the wand 20 ensures that even small stones do not rotate as vacuum is applied to the nozzle 24 so as to pick up the stone, meaning it will remain orientated in a table down position when released from the nozzle 24 onto the measurement instrument. The ability to use the same wand 20 for a wide range of stone cuts and sizes, whilst still ensuring precise placement of the stone for measuring or test purposes, may be advantageous in speeding up or streamlining existing apparatus for sorting, testing and/or measuring cut stones. It will be appreciated by the person skilled in the art that various modifications may be made to the above described embodiments, without departing from the scope of the present invention. The retractable sleeve may be biased by means other than a spring, for example, by magnetic means. The size and profile of the grooves in the sleeve and nozzle contact surfaces may vary according to the requirements of the application. The configuration of the sleeve and nozzle contact surfaces may vary, for example, the contact surfaces may be flat, or they may be treated or configured to provide additional grip. The inner and outer diameters of the sleeve and nozzle may vary in size as required. The sleeve and/or the nozzle may not be substantially circular; they may have an oval or irregular profile. The nozzle, sleeve, wand body and spring may comprise a metal, or may comprise a plastic material. While it is envisaged that the wand as herein described may be used with conventional sorting and measuring equipment, the wand may have uses with other types of equipment. | <SOH> BACKGROUND <EOH>Natural diamonds are stones from nature, consisting exclusively of diamond formed by geological processes over long periods of time. Synthetic diamonds are man-made stones manufactured by industrial processes, such as HPHT (high pressure high temperature) and CVD (chemical vapour deposition). Synthetic diamonds may be relatively easy to distinguish from natural diamonds when in an unpolished state, however, once polished and cut into a gemstone, identification that a stone is synthetic may be more difficult. Advanced screening instruments, such as the DiamondSure™ and DiamondView™ may be used to test whether a stone is natural or synthetic. Typically, such screening involves measuring the way in which light is absorbed by or emitted from a diamond. Before screening commences it is usually necessary for the stone being tested to be placed “table-down” in a precise location on the measurement surface or holder. In this context, the “table” is the largest central facet of the crown (the top half of the stone when mounted). In addition to screening larger, individual stones, it is also necessary to screen large numbers of smaller diamonds, including stones sometimes known as melee. Melee is a term of the trade that does not have a well defined size range, but can be considered in practice to refer to stones smaller than about 0.2 carats (20 points), and usually (but not necessarily) larger than about 0.01 or 0.02 carats. Due to their small size, melee stones are typically sold in parcels or lots. Since one parcel may contain hundreds of stones, it is possible for synthetic diamonds to be mixed in with natural stones. Screening of melee diamonds can potentially be extremely time consuming, since each stone must be tested individually and therefore placed in the correct orientation individually. WO 2012/146913 discloses an apparatus for orientating gemstones, in which discrete gemstones are provided on a travelling path which has a pair of opposed oscillating walls. These walls urge the gemstones into their most stable orientation—i.e. table-down—as they progress along the path. Once in this orientation, individual stones can be lifted from the travelling path by a vacuum wand and transported to a test station. FIG. 1 is a view of the apparatus 1 described in WO 2012/146913 for orientating gemstones. The melee stones are poured into a hopper 2 and pass through a pair of rollers 6 . The speed of the rollers 6 is configured to separate out the stones so they pass through one at a time. The stones are then directed onto a rotating disc 10 , as shown in FIG. 2 . The disc 10 rotates clockwise and provides a circular travelling path, passing the stones through an agitator 13 . The agitator 13 comprises a pair of opposed parallel vertical walls 11 which form a semi-circular channel 12 . The walls 11 are connected to an oscillator 15 which oscillates the walls with sufficient magnitude and frequency that they collide with the stones on the travelling path. The centre of the pair of walls 14 oscillates along the radius of the rotating disc 10 . The impact level of the walls 11 is chosen such that it is enough to knock a stone off its pavilion facet, but not to knock a stone off its most stable table facet. Eventually, the stones land table-down and are aligned by the time they reach a handling area 7 . An orientation checking device 9 checks that each stone is table-down, by recording a side view silhouette image of the stone with a camera 16 . If the stone is found to be correctly orientated, it is collected by the handler, comprising a swinging arm 3 and a vacuum wand 4 , and transported to a synthetic detection device 17 . If the stone is found to be incorrectly orientated, it will be transported back to the oscillating channel 12 to be re-orientated. This process continues until all stones in the melee have been orientated, tested and dispensed into an appropriate collection bin 5 via chutes 8 . Diamonds which are to be sorted and tested using apparatus including the melee screener described above may comprise a wide range of sizes and cuts. Popular diamond cuts range from round brilliant to pear shaped to elongate baguette cuts. Stones which require screening may vary in size from small melee diamonds to much larger individual stones. In order to sort and process stones for testing quickly, it is desirable to be able to handle a wide variety of sizes and cuts using the same apparatus. Moreover, since each stone to be screened must be very precisely placed upon the measurement surface, it is desirable for the apparatus to be capable of precise positioning, regardless of variations in stone size or cut. FIG. 3 a is a cross section of a stone held by a conventional nozzle. A 1 point cut stone (girdle 1.4 mm, depth 0.83 mm) has been picked up by the nozzle of a conventional vacuum wand. It will be noted that the stone is positioned centrally, with its culet in the centre of the nozzle. FIG. 3 b shows the same stone, but in this case the nozzle has been lowered down onto the stone off centre, so that the stone is located on one side of the nozzle. Using this conventional nozzle, the stone may be as much as 0.3 mm off centre while still within nozzle, with the added potential for its position to move as it is transported. Furthermore, there is a significant danger in this situation that the stone will rotate as vacuum is applied to the nozzle so as to pick up the stone, meaning it is no longer table down, and is unlikely to be deposited table down when released from the nozzle onto the measurement instrument. Therefore, while the precise position of the nozzle can be guaranteed, the precise position of the stone within the nozzle cannot, and this may lead to incorrect positioning and/or orientation of the stone on the measurement surface and hence invalid test or measurement results. | <SOH> SUMMARY <EOH>In accordance with one aspect of the present invention there is provided a vacuum wand for picking up cut gemstones which have been orientated table down, having a generally cylindrical body with a central bore culminating in a nozzle through which a vacuum may be applied, said wand comprising a retractable outer sleeve configured to slide axially over the nozzle, and a biasing mechanism for biasing the sleeve towards a position in which it extends beyond the nozzle. The vacuum wand may be configured so that the sleeve cannot rotate relative to the nozzle. The sleeve may be provided with a flat surface which co-operates with a flat surface of the cylindrical body to prevent the rotation of the sleeve relative to the nozzle. The nozzle may be provided with a contact surface at a lower end thereof configured to retain a relatively small cut gemstone when vacuum is applied to the bore. The contact surface of the nozzle may be tapered inwards. The contact surface of the nozzle may be provided with a profiled groove extending transversely therethrough. The sleeve may be provided with a contact surface at a lower end thereof, configured to retain a relatively large cut gemstone when vacuum is applied to the bore. The contact surface of the sleeve may be tapered inwards. The contact surface of the sleeve may be provided with a profiled groove extending transversely therethrough, circumferentially aligned with the groove of the nozzle An outer end of the profiled groove of the nozzle may be of substantially the same width as an inner end of the profiled groove of the sleeve. The sleeve may be configured to retract axially over the nozzle when a gemstone being picked up has a smaller diameter than an internal diameter of the sleeve. The sleeve may be movable between an extended position, in which the contact surface of the sleeve is level with or below the contact surface of the nozzle, and a retracted position, in which the contact surface of the sleeve is above the contact surface of the nozzle. The biasing mechanism may comprise a spring. Retraction of the sleeve may be limited by a shoulder of the wand body and co-operation between an upper flat surface of the sleeve and the wand body. The sleeve may be held in place on a distal end of the wand body by interlocking engagement with lugs A biasing force of the biasing mechanism may be sufficient to return the sleeve from the retracted to the extended position. The biasing force may be insufficient to dislodge a gemstone retained by the contact surface of the nozzle and/or the sleeve when the sleeve is returned to the extended position. A transport mechanism for transporting cut gemstones may comprise a pivotable arm attached to a vacuum wand according to the first aspect above. A gemstone testing station may comprise a device for orienting cut gemstones table down, the aforementioned transport mechanism, and an analysis instrument for carrying out analysis of the gemstones. A screening device for determining whether a cut gemstone is natural or synthetic may include the aforementioned testing station. In accordance with another aspect of the present invention there is provided a method of picking up a cut gemstone which has been orientated table down, comprising the steps of providing a vacuum wand having a generally cylindrical body with a central bore culminating in a nozzle through which a vacuum may be applied, the wand comprising a retractable outer sleeve, configured to slide axially over the nozzle and a biasing mechanism for biasing the sleeve towards a position in which it extends beyond the nozzle; bringing the wand into contact with a pavilion of a gemstone; applying a vacuum through the bore to the nozzle; where the gemstone has a diameter greater than or equal to an internal diameter of the sleeve, retaining the gemstone by air pressure against the sleeve and/or the nozzle; or where the gemstone has a diameter smaller than the internal diameter of the sleeve, retracting the sleeve and retaining the gemstone by air pressure against the nozzle only. The sleeve may comprise a flat surface which co-operates with a flat surface of the cylindrical body to prevent rotation of the sleeve relative to the nozzle. The nozzle may comprise a tapered contact surface at a lower end thereof, configured to retain a cut gemstone when vacuum is applied to the bore. The sleeve may comprise a generally conical contact surface at a lower end thereof, configured to retain a cut gemstone when vacuum is applied to the bore. The contact surface of the nozzle may be provided with a profiled groove extending transversely therethrough. The contact surface of the sleeve may be provided with a profiled groove extending transversely therethrough, being circumferentially aligned with the groove of the nozzle. The sleeve may be movable between an extended position, in which the contact surface of the sleeve is level with or below the contact surface of the nozzle, and a retracted position, in which the contact surface of the sleeve is above the contact surface of the nozzle. The biasing mechanism may comprise a spring. A biasing force of the biasing mechanism may be configured to be sufficient to return the sleeve from the retracted to the extended position, but insufficient to dislodge a gemstone retained by the contact surface of the nozzle and/or the sleeve when the sleeve is returned to the extended position. A method of picking up and transporting cut gemstones of a variety cuts and sizes which have been orientated table down may use the method of the second aspect above and the same vacuum wand to pick up each gemstone. | B07C5365 | 20180307 | 20180906 | B07C536 | 0 | CHIN, PAUL T | VACUUM NOZZLE | UNDISCOUNTED | 0 | REJECTED | B07C | 2,018 |
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15,758,578 | PENDING | METHOD FOR OPERATING AN INDUSTRIAL NETWORK AND INDUSTRIAL NETWORK | The invention relates to a method (300) for operating an industrial network (100). The industrial network (100) has at least one network device (101), which can be actuated by a central control device (103), and a local interface (102) for locally accessing (A) the network device (101). The method has the following steps: transmitting (301) an access request (Q) for locally accessing (A) the network device (101) via the local interface (A) to the central control device (103); authenticating (302) the access request (Q) by means of the central control device (103); and setting up (304) the local interface (102) by means of the central control device in order to locally access (A) the network device (101) on the basis of the access request (Q). The invention further relates to a corresponding industrial network. By using the proposed method and the proposed industrial network, access to the network device can be configured more efficiently and without loss. Furthermore, the security of the industrial network is increased. | 1. A method for operating an industrial network, the industrial network comprising at least one network device that is drivable by a central control device, and a local interface for a local access to the at least one network device, the method comprising: communicating an access request for the local access to a network device of the at least one network device via the local interface to the central control device; authenticating, by the central control device, the access request; and setting up, by the central control device, the local interface for the local access to the network device depending on the access request. 2. The method of claim 1, wherein the local access to the network device is temporally limited. 3. The method as claimed in of claim 1, further comprising deactivating the local interface after the local access to the network device has ended. 4. The method of claim 1, wherein the local access to the network device is effected with the aid of an access device, which that is coupled to the local interface, and wherein an access data set for enabling the local access to the network device via the local interface is provided at the access device if when the access request is authenticated. 5. The method of claim 1, further comprising generating a virtual network, that is part of the industrial network, the virtual network comprising at least the network device, to which the access request is directed, wherein the central control device is not part of the virtual network. 6. The method of claim 1, further comprising communicating access specifications of the access request to the central control device, wherein the access specifications comprise an identifier of an access device, an identity of service personnel, a connection type of the local access, connection requirements of the local access, an access duration, resources provided for the local access, or any combination thereof, and wherein setting up the local interface for the local access to the network device comprises setting up the local interface for the local access to the network device in accordance with the access specifications. 7. The method of claim 1, wherein setting up the local interface for the local access to the network device comprises instantiating applications at the local interface. 8. The method of claim 1, wherein setting up the local interface is effected with the aid of templates stored at the central control device. 9. The method of claim 1, wherein communicating the access request to the central control device, setting up the local interface by the central control device, or a combination thereof effected in an encrypted manner. 10. The method of claim 1, wherein the local access to the network device is effected for the purpose of maintaining, checking, monitoring, modifying, operating, repairing, switching on, switching off, driving the network device, for the purpose of locally retrieving data from the network device, or any combination thereof. 11. The method of claim 1, wherein the local access to the network device -is effected via a local area network, with the aid of Wireless LAN, Bluetooth, mobile radio technologies, LTE-based connections, in a wired manner, or any combination thereof, or via the local area network and with the aid of Wireless LAN, Bluetooth, mobile radio technologies, LTE-based connections, in a wired manner, or the combination thereof. 12. The method of claim 1, wherein the industrial network comprises a plurality of network devices, and the access request comprises a local access to a subnetwork of a plurality of network devices via the respective local interface. 13. The method of claim 1, wherein the local access to the network device has a smaller data transmission path than a data transmission path for driving the network device by the central control device. 14. An industrial network comprising: at least one network device that is drivable by a central control device; and a local interface for the local access to the at least one network device, an access request for the local access to a network device of the at least one network device being communicatable via the local interface to the central control device, wherein the central control device is configured to: authenticate the access request; and set up the local interface for the local access to the network device depending on the access request. 15. The industrial network of claim 14, wherein the industrial network is provided at least partly in the form of a virtual network in a network. | This application is the National Stage of International Application No. PCT/EP2015/070506, filed Sep. 8, 2015. The entire contents of this document is hereby incorporated herein by reference. BACKGROUND The present embodiments relate to a method for operating an industrial network, and to an industrial network. For maintenance work in industrial installations (e.g., wind farms), a remote service solution is usually employed. Accordingly, a maintenance engineer logs into an industrial network (e.g., industrial control network) of the installation to be maintained. The access rights to the industrial network are granted and monitored by a central control station. The logging into the industrial network by the engineer, the authentication of the engineer's access, and the monitoring of the engineer in the industrial network are effected by the central control station that is associated with high technical complexity. SUMMARY AND DESCRIPTION The scope of the present invention is defined solely by the appended claims and is not affected to any degree by the statements within this summary. The present embodiments may obviate one or more of the drawbacks or limitations in the related art. For example, an improved method for operating a network is provided. A method for operating an industrial network is provided. The industrial network includes at least one network device that is drivable by a central control device. The industrial network also includes a local interface for a local access to the network device. The local access to the network device may be realized via the local interface. The method includes communicating an access request for the local access to the network device via the local interface to the central control device. The method also includes authenticating the access request by the central control device, and using the central control device, setting up the local interface for the local access to the network device depending on the access request. The industrial network concerns, for example, any type of industrial communication networks (e.g., a production installation having production cells, a wind farm, or a part thereof). By way of example, the industrial network is an operator network of a power supply grid, and the network devices are individual generators (e.g., wind turbines) in this network. The industrial network may also include a traffic network and/or a supply network of resources (e.g., electricity, oil, water, natural gas, foodstuffs, or heat). For example, the industrial network includes a plurality of network devices. The network devices of the industrial network may concern individual modules (e.g., production modules, control units or field devices) in road traffic and/or in a supply network. For example, the network devices may operate at least partly in an automated manner (e.g., the network devices require no or only a reduced human intervention for their operation). In one embodiment, the network devices are at least partly coupled to one another, such that transport of data, material, products, and/or resources (e.g., electricity or energy) from and to one another is possible. The industrial network includes at least one central control device that may centrally control the network devices of the industrial network. For example, the central control device is configured to communicate and/or to interact with the network devices (e.g., to interrogate data from the network devices and/or to input data or commands into the network devices). For example, the industrial network may extend over a region that is dimensioned such that geographical distances between the individual network devices are up to tens of thousands of kilometers. The industrial network may include a backbone line, from which a plurality of branch connections proceed to the individual network devices and couple the network devices to the industrial network. Other network topologies, such as bus, ring or star topologies, may also be provided. Alternatively or additionally, the network may be coupled to a wide area network (WAN) and/or the Internet. For maintenance work on one or more network devices, access to the corresponding network device may be allowed for service personnel (e.g., engineer, operator, administrator or mechanic) The industrial network may be protected from access by unauthorized persons. In one embodiment, the industrial network is a closed, private communication network. For this purpose, the industrial network may be configured at least partly as a corporate network that internetworks spatially remote individual networks of a corporation and links the networks to the Internet, for example, via a common firewall. The access to the industrial network may be encrypted and/or require authentication. The central control device may also be configured for monitoring accesses to the network devices. The service personnel may request a local access to the network device, for example, from the central control device. For example, the local access to the network device is effected via and/or with the aid of the local interface assigned and connected to one or more network devices. The local interface may be connected to the assigned network device via a local area network (LAN), wireless LAN, mobile radio, and/or cable connections. The local interface may include a physical and/or virtual interface (e.g., a machine interface, a hardware interface, a network interface, a data interface, a software interface, or a combination thereof). The physical interface provides a physical connection to which an access device (e.g., a computer, a laptop or some other device capable of computation) may be connected in order to access the network device. In one embodiment, the local interface may provide an access device, or the access device may be present in a manner integrated into the local interface. The physical interface may include a network connection, via which components of the industrial network may be connected to the network device. For example, the physical interface may also be configured for converting between different communication protocols in order to enable a communication between the network device and different network components and/or the access device. A virtual interface may be an interface between programs, applications, and/or operating systems in order to enable an interaction between the programs, applications, and/or operating systems of the network device, the access device, and/or network components. For example, the local interface enables a data interrogation of the assigned network device and/or an input of data or commands into the assigned network device. The local interface may be equipped with a computing power in order, for example, to process data and to operate the assigned network device. The local interface may have a storage capacity in order, for example, to store access configurations, applications, or user specifications. The local interface may be regarded as an access point. The access request for the local access to the network device indicates, for example, the network device that is intended to be accessed, and/or an identity of the service personnel requesting the local access to the network device. The access request may be communicated to the central control device, for example, via the line of the industrial network, via a VPN connection, or via mobile radio. The central control device receives the access request and evaluates the access request. The authentication of the access request may be dependent on the results of the evaluation of the access request by the central control device. If the access request is authenticated, the central control device may set up the local interface such that the local access to the network device is enabled in accordance with the access request. In one embodiment, a trust level of the access request (e.g., of service personnel issuing the access request) is determined. Accordingly, the local interface may be set up in accordance with the trust level of the access request that is determined by the central control device. As a result of setting up the local interface for the local access, the local interface is activated and provided for the local access to the network device by the service personnel. The corresponding access rights, for example, are taken into account. Setting up the local interface may include activating physical connections, starting an access device, or producing a connection between the local interface and/or the network device. Setting up the local interface may include configuring a virtual interface at the local interface. In this case, an access configuration created by the central control device (e.g., an operating system or a set of applications) may be instantiated at the local interface. Virtual sensors (e.g., for data evaluation or data aggregation) may be instantiated at the network device. Instantiating operating systems, applications, or virtual sensors may include implementing, installing, starting, rolling out, and/or activating same. In one embodiment, the local interface is set up in an isolated manner and in a manner encapsulated such that the interface may be decomposed without residues. The instantiating includes, for example, the respectively required configurations, applications, and communication connections that are realized by virtual components. Consequently, such an access is intrinsically encapsulated. If a plurality of different accesses are active simultaneously, the different accesses therefore do not influence one another. The applications may be used, for example, for data interrogation and data input or for controlling the network device. The applications may include a terminal or a maintenance program for interaction with the network device. In one embodiment, data (e.g., applications, programs, or operating systems) for setting up the local interface may be present in a manner stored or installed at the local interface or at the access device. Setting up the local interface may involve generating a virtual network and/or instantiating virtual network functions for the virtual network. Various network configuration technologies (e.g., VPN, forming tunnels between network components or software defined networking (SDN)) may be employed here. The virtual network may be adapted to the access request. The virtual network is, for example, a virtual overlay network based on an existing network (e.g., industrial network, a WAN, or the Internet). The existing network, for example, uses parts of structures of the existing network in order to transport data. The virtual network functions may include, for example, control of the data traffic (e.g., traffic shaping), a firewall, switching, data traffic routing, or ports monitoring. For example, a virtual firewall may be instantiated at the local interface in order to restrict and/or filter the local access. In one embodiment, the virtual firewall is an industrial firewall specifically for protecting industrial networks. The local interface may be set up, for example, such that the local access to the network device satisfies specific connection requirements (e.g., specifications in accordance with quality of service (QoS) for the industrial network). The QoS may stipulate minimum requirements with respect to a quality and/or a grade of the connection and data transmission in an industrial network. By way of example, the QoS concerns a speed, latencies, a jitter, or a reliability of the connection and/or data transmission. The QoS may concern a frequency of disturbances, transmission errors, connection errors, and/or connection problems. In accordance with one embodiment, the local access to the network device is temporally limited. The access request may include an expected duration of the local access to the network device. The access duration may be defined by the central control device, requested with the access request, or defined in a general manner A predefined access duration may be stored at the central control device or at the local interface, and the access duration may be defined automatically. An indication of the access duration may include a start time, an end time, and/or a time interval of the local access to the network device. Temporally limiting the local access makes it possible to preclude an undesired access to the industrial network after the access duration has elapsed. The security of the industrial network may thus be increased. In accordance with a further embodiment, the method furthermore includes deactivating the local interface after the local access to the network device has ended. As a result, an unnecessary continuance of a possibility of access to the network device and/or the industrial network after the end of the local access is prevented and a security risk is eliminated. Deactivating the local interface may include, for example, deactivating components that are instantiated or generated at the local interface. The components concern, for example, the virtual network, the virtual network functions, the applications, and/or the operating systems. Deactivating may include closing, deleting, uninstalling, stopping, terminating, canceling, removing, or eliminating the corresponding component. In accordance with a further embodiment, the local access to the network device is effected with the aid of an access device that is coupled to the local interface. An access data set for enabling the local access to the network device via the local interface is provided at the access device if the access request is authenticated by the central control device. In one embodiment, the access data set contains information about the trust level of the local access and/or of the service personnel to which/whom the access data set is assigned. The access data set may be personalized (e.g., adapted to service personnel issuing the access request) and/or be valid only for the service personnel. The local access to the network device may be provided, for example, by creating an account (e.g., access account) that the service personnel may use to log into the industrial network. Accordingly, the access data set may contain account data (e.g., a user identification and a key) for logging into the network device and/or the industrial network. The access data set may be created by the central control device depending on results of the evaluation of the access request. The access data set may be present in a manner prestored at the central control device and may be output after an authentication of the access request. The access data set may include a time duration within which the access to the network device is granted. The access data set may be transmitted in an encrypted manner In one embodiment, the local interface may be set up for the local access to the network device if the service personnel input the access data set into the local interface or into an access device connected to the local interface. In accordance with a further embodiment, the method also includes generating a virtual network. The virtual network of the industrial network is then part of the industrial network and includes at least the network device to which the access request is directed. In this case, the central control device is segregated from the virtual network (e.g., is not part of the virtual network used by the access device for the local access to the at least one network device). By way of example, overlay networks are appropriate as a virtual network. Protocol-based networks such as VLANs, VPN, VPLS or the like and software-defined networks (SDN) may be provided. As a result, an encapsulated network, in which access to the local interface and to the assigned network device is limited, may be generated. A security risk for the industrial network may thus be lowered. Data transport between the service personnel and the network device is not effected via the central control device with the result that it is possible to achieve an improved connection quality on account of shorter latencies or smaller fluctuations. In accordance with a further embodiment, the method also includes communicating access specifications of the access request to the central control device. In this case, the access specifications include an identifier of an access device, an identity of service personnel, a connection type of the local access, connection requirements of the local access, an access duration, and/or resources provided for the local access. The method also includes setting up the interface for the local access to the network device in accordance with the access specifications. For example, the access specifications may define a bandwidth and/or a computing power for the local access to the network device. For the case where a plurality of local accesses to the network device take place simultaneously, a division of resources (e.g., of the bandwidth and of the computing power at the local interface and network device; with the aid of prioritization of connections) may be defined and managed The connection requirements may be determined, for example, by standards (e.g., quality of service of a communication service). The connection requirements may correspond to predefined standards (e.g., IEEE 802.1p). In accordance with a further embodiment, setting up the local interface includes instantiating applications at the local interface. The applications include, for example, applications that are used during the local access to the network device. The applications may include virtual sensors that are instantiated at the network device. The applications may be instantiated at the access device connected to the local interface. In accordance with a further embodiment, setting up the local interface is effected with the aid of templates that are present in a manner stored at the central control device. The templates may include components or parts of data or information relevant to setting up the local interface for the access to the network device. By way of example, the templates include information about the trust level, access type, access duration, connection requirements, access device, and/or resource distribution. For example, the templates may at least partly contain access specifications for the access to the network device. In accordance with a further embodiment, communicating the access request to the central control device is effected in an encrypted manner Additionally or alternatively, setting up the local interface by the central control device is effected in an encrypted manner As a result, the security of the industrial network may be increased further. For example, an attack from outside may be better repelled. In accordance with a further embodiment, the local access to the network device is effected for the purpose of maintaining, checking, monitoring, modifying, operating, repairing, switching on, switching off, driving the network device, and/or for the purpose of locally retrieving data from the network device. The service personnel may carry out the local access for one of the purposes mentioned above. For example, technical work is carried out on the assigned network device. In accordance with a further embodiment, the local access to the network device is effected via a local area network (LAN) and/or with the aid of Wireless LAN, Bluetooth, mobile radio technologies, LTE-based connections and/or in a wired manner As a result, a connection quality during the local access to the network device may be improved. In addition, a short data transmission path may further improve the connection quality. In accordance with a further embodiment, the industrial network includes a plurality of network devices. In this case, the access request includes a local access to a subnetwork of a plurality of network devices of the industrial network, where the local access is effected via the local interface. The above-described features of the method may also be applied to a local access to a subnetwork of the industrial network. The subnetwork of network devices may be a grouping of network devices that are geographically close together. For example, the subnetwork may correspond to one location of a plurality of locations of the industrial network. A subnetwork may be defined, for example, by the functionalities of the network devices (e.g., controllers for field devices in automation networks). The subnetwork may include a defined subset of network devices of the industrial network. The subnetwork may be embodied in the form of a virtual network. A local interface of a subnetwork may be connected to each of the network devices of the subnetwork and enable a local access to each of the network devices. In accordance with a further embodiment, the local access to the network device has a smaller data transmission path than a data transmission path for driving the network device by the central control device. For example, a geographical distance between the network device and the central control device is greater than a geographical distance between the network device and the local interface. A shorter data transmission path may reduce latencies during the data transmission and/or reduce undesired fluctuations (e.g., jitter). By way of example, the connection quality may be improved in this way. The method makes it possible, for example, that the guarantees concerning the connection quality that are required for a respective application mayn be realized. In one embodiment, a local interface is allocated in a planned manner and corresponding resources, for example of an underlying network infrastructure, are provided. As a result, specific connection qualities over the period for which the local interface exists may be guarantted. In accordance with a second aspect, an industrial network is provided. The industrial network includes at least one network device that is drivable by a central control device. The industrial network includes a local interface for the local access to the network device. The industrial network is suitable for performing the method described above. For example, the industrial network includes a plurality of network devices. All of the features proposed above for the method for operating an industrial network may also be correspondingly applied to the proposed industrial network. In accordance with one embodiment, the industrial network is provided at least partly in the form of a virtual personal network (VPN) in a network. For example, data transport in the industrial network is effected at least partly via a wide area network (WAN) or the Internet, which are used as a transmission path for the industrial network. Additionally or alternatively, the industrial network may include a backbone line or radio connection for transmitting data. The method and the industrial network of the present embodiments enable, for example, a local access to the network device with support of industrial quality of service requirements. Complex routing of connections over long geographical distances is not required. The local access may be provided temporarily. By deactivating the local access, connections, and/or functions that are possibly defective or beset by security risks may be eliminated. As a result, an increased security for the industrial network may be achieved. Network resources (e.g., bandwidth or computational capacities) may be organized and requested in a demand-oriented manner A monitoring complexity with respect to accesses to the network devices of the industrial network may likewise be reduced. The respective unit (e.g., the access device, the local interface, or the central control device) may be implemented in terms of hardware and/or in terms of software. In the case of an implementation in terms of hardware, the respective unit may be embodied as an apparatus or as part of an apparatus (e.g., as a computer or as a microprocessor or as a control computer of a vehicle). In the case of an implementation in terms of software, the respective unit may be embodied as a computer program product, as a function, as a routine, as part of a program code, or as an executable object. A computer program product that causes the method explained above to be carried out on a program-controlled device, such as elements of the network, for example, is provided. A respective program-controlled device may be either software- or hardware-based. In one embodiment, the access device may, for example, be implemented as a downloadable or short-time installable or activatable access application on a smart phone. A computer program product such as, for example, a computer program device may be provided or supplied, for example, as a storage medium, such as, for example, a memory card, USB stick, CD-ROM, DVD, or else in the form of a downloadable file from a server in a network. This may be effected, for example, in a wireless communication network by the transmission of a corresponding file with the computer program product or the computer program device. The embodiments and features described for the method are correspondingly applicable to the industrial network. Further possible implementations also include combinations, not explicitly mentioned, of features or embodiments described above or below with regard to the exemplary embodiments. In this case, the person skilled in the art will also add individual aspects as improvements or supplementations to the respective basic form of the invention. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows a schematic view of a first embodiment of an industrial network with an access device; FIG. 2 shows a schematic view of a second embodiment of an industrial network with the access device; FIG. 3 shows a sequence diagram of one embodiment of a method for operating an industrial network; FIG. 4 shows a schematic view of a third embodiment of an industrial network with the access device; FIG. 5 shows a schematic view of a fourth embodiment of an industrial network with the access device; and FIG. 6 shows a schematic view of a fifth embodiment of an industrial network with the access device. DETAILED DESCRIPTION In the figures, same or functionally same elements have been provided by the same reference sign, unless indicated otherwise. FIG. 1 shows a schematic view of a first embodiment of an industrial network 100 with an access device 104. The industrial network 100 includes a network device 101 and a local interface 102. The local interface 102 is connected to the network device 101 via a line 105. The network device 101 and the local interface 102 are connected to a central control device 103 via a respective line 106, 107. The local interface 102 allows service personnel U, being an engineer, an operator, a mechanic, or a system administrator, to have a local access A to the network device 101. The local interface 102 is connected to an access device 104. The access device 104 is equipped with a computing power and a storage capacity. The access device 104 is a computer, a mobile computer, or a terminal in the industrial network 100. With the aid of the access device 104, the network device 101 may be accessed via the local interface 102. The access device 104 is connected to the local interface 102 via a physical line (e.g., an Ethernet cable) or in a wireless manner (e.g., via W-LAN, or by mobile radio; via an LTE-Advanced connection). An access request Q is sent to the central control device 103 by the service personnel U via the access device 104. The control device 103 evaluates the access request Q, authenticates the access request Q, and defines a trust level of the service personnel U. The central control device 103 creates an access configuration K, in accordance with which the local interface 102 is set up for the local access A to the network device 101 by the service personnel U. The local interface 102 is equipped, for example, with a computing power and a storage capacity in order to store and/or implement the access configuration K. The access configuration K is communicated to the local interface 102 and instantiated at the local interface 102. This involves installing and starting a set of applications at the local interface 102 and virtual sensors for detecting and processing data at the network device 101. Consequently, the local interface 102 is set up for the local access A to the network device 101. With the aid of the applications and virtual sensors, the service personnel U may interact with the network device 101 and interrogate data from the network device 101. The local access A to the network device 101 may be effected for the purpose of maintaining, controlling, operating, operationally controlling, repairing, modifying the network device 101 or interrogating data from the network device 101. FIG. 2 shows a schematic view of a second embodiment of an industrial network 200 with the access device 104 in FIG. 1. The industrial network 200 has all of the features and elements and also devices of the industrial network 100 in FIG. 1. In addition, the central control device 103 is equipped with a database device 201, at which templates for setting up the local interface 102 for the local access A to the network device 101 are present in a prestored manner The templates include both prefabricated access configurations and components for an access configuration. The templates include, for example, access specifications (e.g., connection requirements), an identifier of an access device, an identity or trust level of the service personnel U, a connection type of the local access A, an access duration, and/or resources that characterize the local access A to the network device 101. By way of example, the industrial network is a power supply grid with a wind power installation as network device 101. From the central control device 103, which is a central server computer of the operator of the wind power installation 101, access to the control unit of the wind power installation 101 for 8 hours is requested by the service personnel U, being an engineer of the manufacturer of the wind power installation 101, in order to carry out a planned examination. The examination concerns, inter alia, a running power, wear, fluctuations of characteristic variables (e.g., voltage, frequency and amplitude), and correct drivability. In a further example, from the central server computer, access to the wind power installation 101 is requested by the service personnel in order to acquire statistical data (e.g., generated electrical power in the last 2 weeks). The central control device 103 creates the access configuration K for the local access A to the network device based on the templates stored at the database device 201. Afterward, the access configuration K is communicated to the local interface 102 and instantiated at the local interface 102. After successful authentication of the access request Q, the central control device 103 creates an access data set T in the form of an access token in accordance with the trust level of the service personnel U. The access token T contains a user identifier and a password for logging into the industrial network 200 and also an access duration (e.g., 24 hours or 7 days), within which the local access A is allowed. The access request Q and the access token T are communicated in an encrypted (e.g., private) connection (e.g., via the Internet as a VPN connection). FIG. 3 shows a sequence diagram of one embodiment of a method 300 for operating an industrial network. For example, the method 300 in FIG. 3 is suitable for operating the industrial networks 100, 200 in FIGS. 1 and 2. The method 300 shown in FIG. 3 is suitable for operating industrial networks that are illustrated in FIGS. 4 to 6 and are explained below. In FIG. 3, the central control device 103, the access device 104, and the local interface 102 are illustrated symbolically in a horizontal series alongside one another. A vertical time axis 310 shows a temporal progression of the method 300. In a first act 301, the access request Q is communicated by the access device 104 or the service personnel U to the central control device 103. In this case, the access request Q may contain the requested access specifications S. In a next act 302, the access request Q is authenticated by the central control device 103. For example, the access specifications S are evaluated. If appropriate, prestored templates (e.g., at the database 201 in FIG. 2) that correspond to the access request or to the access specifications are ascertained. Optionally, a trust level of the service personnel U is also defined. After a successful authentication of the access request Q, in a next act 303, the central control device 103 creates the access configuration K for setting up the local interface 102 for the local access A to the network device 101. Optionally, the central control device 103 also creates the access data set T for the service personnel U. The central control device 103 also optionally creates an access account at the local interface 102 or at the access device 104, using which access account the service personnel U may log into the network device 101 or the industrial network 100, 200. The access device is a computer or a terminal connected to or integrated into the local interface 102. In a next act 304, the access configuration K is communicated by the central control device 103 to the local interface 102 and instantiated at the central control device 103. In this way, the local interface 102 is set up for a local access A to the network device 101. The access configuration K is communicated in an encrypted manner and via a private connection (e.g., via the Internet as a VPN connection). In a further act 305, the access token T is provided to the service personnel U. The access token T may be conveyed to the service personnel directly (e.g., via mobile radio or a VPN connection) or may be provided at the local interface 102 and/or at the access device 104. In this case, the access token T is communicated in an encrypted manner The access token T also optionally contains access account data (e.g., a user identifier and a password) for logging into the network device 101 or the industrial network 100, 200 using the access account. In a further act 306, the local access A to the network device 101 is effected from the access device 104 via the local interface 102. The local access A enables, for example, maintenance work, service services, or data interrogations at the network device 101. In act 307, the local interface 102 is closed and blocked for the local access A. Optionally, the access data set T is also deleted and deactivated, such that the access data set T is no longer valid. The industrial network and the method are illustrated below based on examples of wind power installations and wind farms. The examples shown in FIGS. 4 to 6 have all of the features of the industrial network 100 shown in FIG. 1 and of the method for operating the industrial network 100 explained with the aid of FIG. 1. FIG. 4 shows a schematic view of a third embodiment of an industrial network 400 with the access device 104. The industrial network 400 includes a wind farm including wind power installations 101a to 101c. The wind power installations 101a-101c are connected to a respective local interface 102a-102b that enables a local access to the assigned wind power installation 101a-101c. The central control device 103 is embodied as a server computer having a computing power and storage capacity. The access device 104 is a mobile computer that may be connected to the local interfaces 102a-102c. FIG. 4 shows a local access A to the network device 101c from the mobile computer 104 via the local interface 102c. From the mobile computer 104, an access request Q is communicated to the server computer 103. The server computer 103 evaluates the access request Q. After successful authentication of the access request Q, an access data set T is created and communicated to the mobile computer 104. The server computer 103 defines the access configuration K, which is communicated to the local interface 102c and instantiated at the local interface 102c. The mobile computer 104 is connected to the local interface 102c by the service personnel U. The service personnel U use the access data set T on the mobile computer 104 to log into the industrial network 400. An operating system and various applications that are predefined by the access configuration K and are required for the local access are started on the mobile computer. A virtual sensor for detecting power characteristic curves at the wind power installation 101c is instantiated. The access configuration K is embodied, for example, such that the local access using the access data set T is limited to the local interface 102c and the assigned wind power installation 101c. For this purpose, a virtual network 401 is generated, which includes only part of the industrial network 400 and prevents access to further network devices 101a, 101b by the service personnel. Virtual network functions for the virtual network 401 are instantiated at the local interface. Network configuration technologies such as VPN, forming tunnels between network components and SDN, are employed for setting up the virtual network 401. A VPN-based connection is effected via a WAN or the Internet, without being accessible to unauthorized persons. The tunnel allows two or more subscribers of the industrial network to communicate with one another via a connection (e.g., Internet) that uses a different communication protocol than the industrial network. SDN technology enables a software-based configuration and structuring of the industrial network (e.g., of virtual networks within the industrial network) by the central control device. The virtual network functions include a targeted control of the data traffic between the mobile computer 104 and the wind power installation 101a, a limitation of the data traffic between the mobile computer 104 and other wind power installations 101b, 101c of the industrial network 400, and a blocking of the other connections in order to prevent unauthorized accesses to the network devices 101a-101c or to the industrial network 400. A virtual industrial firewall between the Internet and the industrial network 400 and also the virtual network 401 is instantiated in order to prevent an unauthorized access from the Internet. FIG. 5 shows a schematic view of a fourth embodiment of an industrial network 500 with the mobile computer 104 as access device. The industrial network 500 includes a plurality of wind power installations 101 as network devices. FIG. 5 shows the wind power installations 101 at two locations 501, 502. The wind power installations 101 at a first location 501 are combined to form a first subnetwork 503. The first subnetwork 503 is connected to a first interface 504 that enables access to the first subnetwork 503 and also to the network devices 101 of the first subnetwork 503. The wind power installations 101 at a second location 502 are analogously combined to form a second subnetwork 505, where the second subnetwork 505 is connected to a second interface 506, via which access to the wind power installations 101 of the subnetwork 506 is possible. The network configuration technologies VPN, tunnel, and SDN, for example, are employed for setting up the subnetworks 503, 505 within the industrial network 500. FIG. 6 shows a schematic view of a fifth embodiment of an industrial network 600 with the mobile computer 104 as access device. For example, the industrial network 600 includes the wind power installations 101 of the first subnetwork 503 in FIG. 5. FIG. 6 shows a local access A to the second subnetwork 503 of network devices 101 via the local interface 504. A geographical distance DA between the first subnetwork 503 and the mobile computer 104 is from a few centimeters to hundreds of meters. A geographical distance DC between the first subnetwork 503 and the server computer 103 is from a few kilometers to a few thousand kilometers. The access A to the first subnetwork 503 is effected without routing via the server computer 103, such that latencies during data transmission are shortened and a packet loss and fluctuations (e.g., jitter) are reduced. Overall, the connection quality is thus improved. The server computer is connected to the mobile computer 104 via a connection 601 and to the first subnetwork 503 via a connection 602. In this case, the connections 601, 602 are partly produced via the Internet. For example, the connection 601 constitutes a coupling formed by an authentication, and the connection 602 may be a protected connection (e.g., in the manner of a dedicated line). Alternatively or additionally, the connections 601, 602 may at least partly include an electrical, optical, or electromagnetic line. In one embodiment, the connection via the interface 504 may be a VPN connection. The central server computer 103 is linked into the network such that it is possible for the interface 504 to be set up. The industrial networks 100, 200, 400, 500, 600 described above may be set up such that a connection and data transmission within the industrial network satisfy predefined requirements (e.g., a quality of service or standards such as IEEE 802.1p). By the direct and local access to the network devices, the connection quality may be improved by comparison with routing via the central control device of the industrial network). The encapsulation of the local access by the service personnel U increases the security of the respective industrial network. The local access may be temporally limited in order to preclude unnecessary access possibilities with respect to the industrial network. Although the present invention has been described based on wind farms, the present invention is applicable in diverse ways (e.g., to production installations, other supply networks such as electricity, heat, water, oil or gas supply networks, traffic networks or communication networks). The elements and features recited in the appended claims may be combined in different ways to produce new claims that likewise fall within the scope of the present invention. Thus, whereas the dependent claims appended below depend from only a single independent or dependent claim, it is to be understood that these dependent claims may, alternatively, be made to depend in the alternative from any preceding or following claim, whether independent or dependent. Such new combinations are to be understood as forming a part of the present specification. While the present invention has been described above by reference to various embodiments, it should be understood that many changes and modifications can be made to the described embodiments. It is therefore intended that the foregoing description be regarded as illustrative rather than limiting, and that it be understood that all equivalents and/or combinations of embodiments are intended to be included in this description. | <SOH> BACKGROUND <EOH>The present embodiments relate to a method for operating an industrial network, and to an industrial network. For maintenance work in industrial installations (e.g., wind farms), a remote service solution is usually employed. Accordingly, a maintenance engineer logs into an industrial network (e.g., industrial control network) of the installation to be maintained. The access rights to the industrial network are granted and monitored by a central control station. The logging into the industrial network by the engineer, the authentication of the engineer's access, and the monitoring of the engineer in the industrial network are effected by the central control station that is associated with high technical complexity. | <SOH> SUMMARY AND DESCRIPTION <EOH>The scope of the present invention is defined solely by the appended claims and is not affected to any degree by the statements within this summary. The present embodiments may obviate one or more of the drawbacks or limitations in the related art. For example, an improved method for operating a network is provided. A method for operating an industrial network is provided. The industrial network includes at least one network device that is drivable by a central control device. The industrial network also includes a local interface for a local access to the network device. The local access to the network device may be realized via the local interface. The method includes communicating an access request for the local access to the network device via the local interface to the central control device. The method also includes authenticating the access request by the central control device, and using the central control device, setting up the local interface for the local access to the network device depending on the access request. The industrial network concerns, for example, any type of industrial communication networks (e.g., a production installation having production cells, a wind farm, or a part thereof). By way of example, the industrial network is an operator network of a power supply grid, and the network devices are individual generators (e.g., wind turbines) in this network. The industrial network may also include a traffic network and/or a supply network of resources (e.g., electricity, oil, water, natural gas, foodstuffs, or heat). For example, the industrial network includes a plurality of network devices. The network devices of the industrial network may concern individual modules (e.g., production modules, control units or field devices) in road traffic and/or in a supply network. For example, the network devices may operate at least partly in an automated manner (e.g., the network devices require no or only a reduced human intervention for their operation). In one embodiment, the network devices are at least partly coupled to one another, such that transport of data, material, products, and/or resources (e.g., electricity or energy) from and to one another is possible. The industrial network includes at least one central control device that may centrally control the network devices of the industrial network. For example, the central control device is configured to communicate and/or to interact with the network devices (e.g., to interrogate data from the network devices and/or to input data or commands into the network devices). For example, the industrial network may extend over a region that is dimensioned such that geographical distances between the individual network devices are up to tens of thousands of kilometers. The industrial network may include a backbone line, from which a plurality of branch connections proceed to the individual network devices and couple the network devices to the industrial network. Other network topologies, such as bus, ring or star topologies, may also be provided. Alternatively or additionally, the network may be coupled to a wide area network (WAN) and/or the Internet. For maintenance work on one or more network devices, access to the corresponding network device may be allowed for service personnel (e.g., engineer, operator, administrator or mechanic) The industrial network may be protected from access by unauthorized persons. In one embodiment, the industrial network is a closed, private communication network. For this purpose, the industrial network may be configured at least partly as a corporate network that internetworks spatially remote individual networks of a corporation and links the networks to the Internet, for example, via a common firewall. The access to the industrial network may be encrypted and/or require authentication. The central control device may also be configured for monitoring accesses to the network devices. The service personnel may request a local access to the network device, for example, from the central control device. For example, the local access to the network device is effected via and/or with the aid of the local interface assigned and connected to one or more network devices. The local interface may be connected to the assigned network device via a local area network (LAN), wireless LAN, mobile radio, and/or cable connections. The local interface may include a physical and/or virtual interface (e.g., a machine interface, a hardware interface, a network interface, a data interface, a software interface, or a combination thereof). The physical interface provides a physical connection to which an access device (e.g., a computer, a laptop or some other device capable of computation) may be connected in order to access the network device. In one embodiment, the local interface may provide an access device, or the access device may be present in a manner integrated into the local interface. The physical interface may include a network connection, via which components of the industrial network may be connected to the network device. For example, the physical interface may also be configured for converting between different communication protocols in order to enable a communication between the network device and different network components and/or the access device. A virtual interface may be an interface between programs, applications, and/or operating systems in order to enable an interaction between the programs, applications, and/or operating systems of the network device, the access device, and/or network components. For example, the local interface enables a data interrogation of the assigned network device and/or an input of data or commands into the assigned network device. The local interface may be equipped with a computing power in order, for example, to process data and to operate the assigned network device. The local interface may have a storage capacity in order, for example, to store access configurations, applications, or user specifications. The local interface may be regarded as an access point. The access request for the local access to the network device indicates, for example, the network device that is intended to be accessed, and/or an identity of the service personnel requesting the local access to the network device. The access request may be communicated to the central control device, for example, via the line of the industrial network, via a VPN connection, or via mobile radio. The central control device receives the access request and evaluates the access request. The authentication of the access request may be dependent on the results of the evaluation of the access request by the central control device. If the access request is authenticated, the central control device may set up the local interface such that the local access to the network device is enabled in accordance with the access request. In one embodiment, a trust level of the access request (e.g., of service personnel issuing the access request) is determined. Accordingly, the local interface may be set up in accordance with the trust level of the access request that is determined by the central control device. As a result of setting up the local interface for the local access, the local interface is activated and provided for the local access to the network device by the service personnel. The corresponding access rights, for example, are taken into account. Setting up the local interface may include activating physical connections, starting an access device, or producing a connection between the local interface and/or the network device. Setting up the local interface may include configuring a virtual interface at the local interface. In this case, an access configuration created by the central control device (e.g., an operating system or a set of applications) may be instantiated at the local interface. Virtual sensors (e.g., for data evaluation or data aggregation) may be instantiated at the network device. Instantiating operating systems, applications, or virtual sensors may include implementing, installing, starting, rolling out, and/or activating same. In one embodiment, the local interface is set up in an isolated manner and in a manner encapsulated such that the interface may be decomposed without residues. The instantiating includes, for example, the respectively required configurations, applications, and communication connections that are realized by virtual components. Consequently, such an access is intrinsically encapsulated. If a plurality of different accesses are active simultaneously, the different accesses therefore do not influence one another. The applications may be used, for example, for data interrogation and data input or for controlling the network device. The applications may include a terminal or a maintenance program for interaction with the network device. In one embodiment, data (e.g., applications, programs, or operating systems) for setting up the local interface may be present in a manner stored or installed at the local interface or at the access device. Setting up the local interface may involve generating a virtual network and/or instantiating virtual network functions for the virtual network. Various network configuration technologies (e.g., VPN, forming tunnels between network components or software defined networking (SDN)) may be employed here. The virtual network may be adapted to the access request. The virtual network is, for example, a virtual overlay network based on an existing network (e.g., industrial network, a WAN, or the Internet). The existing network, for example, uses parts of structures of the existing network in order to transport data. The virtual network functions may include, for example, control of the data traffic (e.g., traffic shaping), a firewall, switching, data traffic routing, or ports monitoring. For example, a virtual firewall may be instantiated at the local interface in order to restrict and/or filter the local access. In one embodiment, the virtual firewall is an industrial firewall specifically for protecting industrial networks. The local interface may be set up, for example, such that the local access to the network device satisfies specific connection requirements (e.g., specifications in accordance with quality of service (QoS) for the industrial network). The QoS may stipulate minimum requirements with respect to a quality and/or a grade of the connection and data transmission in an industrial network. By way of example, the QoS concerns a speed, latencies, a jitter, or a reliability of the connection and/or data transmission. The QoS may concern a frequency of disturbances, transmission errors, connection errors, and/or connection problems. In accordance with one embodiment, the local access to the network device is temporally limited. The access request may include an expected duration of the local access to the network device. The access duration may be defined by the central control device, requested with the access request, or defined in a general manner A predefined access duration may be stored at the central control device or at the local interface, and the access duration may be defined automatically. An indication of the access duration may include a start time, an end time, and/or a time interval of the local access to the network device. Temporally limiting the local access makes it possible to preclude an undesired access to the industrial network after the access duration has elapsed. The security of the industrial network may thus be increased. In accordance with a further embodiment, the method furthermore includes deactivating the local interface after the local access to the network device has ended. As a result, an unnecessary continuance of a possibility of access to the network device and/or the industrial network after the end of the local access is prevented and a security risk is eliminated. Deactivating the local interface may include, for example, deactivating components that are instantiated or generated at the local interface. The components concern, for example, the virtual network, the virtual network functions, the applications, and/or the operating systems. Deactivating may include closing, deleting, uninstalling, stopping, terminating, canceling, removing, or eliminating the corresponding component. In accordance with a further embodiment, the local access to the network device is effected with the aid of an access device that is coupled to the local interface. An access data set for enabling the local access to the network device via the local interface is provided at the access device if the access request is authenticated by the central control device. In one embodiment, the access data set contains information about the trust level of the local access and/or of the service personnel to which/whom the access data set is assigned. The access data set may be personalized (e.g., adapted to service personnel issuing the access request) and/or be valid only for the service personnel. The local access to the network device may be provided, for example, by creating an account (e.g., access account) that the service personnel may use to log into the industrial network. Accordingly, the access data set may contain account data (e.g., a user identification and a key) for logging into the network device and/or the industrial network. The access data set may be created by the central control device depending on results of the evaluation of the access request. The access data set may be present in a manner prestored at the central control device and may be output after an authentication of the access request. The access data set may include a time duration within which the access to the network device is granted. The access data set may be transmitted in an encrypted manner In one embodiment, the local interface may be set up for the local access to the network device if the service personnel input the access data set into the local interface or into an access device connected to the local interface. In accordance with a further embodiment, the method also includes generating a virtual network. The virtual network of the industrial network is then part of the industrial network and includes at least the network device to which the access request is directed. In this case, the central control device is segregated from the virtual network (e.g., is not part of the virtual network used by the access device for the local access to the at least one network device). By way of example, overlay networks are appropriate as a virtual network. Protocol-based networks such as VLANs, VPN, VPLS or the like and software-defined networks (SDN) may be provided. As a result, an encapsulated network, in which access to the local interface and to the assigned network device is limited, may be generated. A security risk for the industrial network may thus be lowered. Data transport between the service personnel and the network device is not effected via the central control device with the result that it is possible to achieve an improved connection quality on account of shorter latencies or smaller fluctuations. In accordance with a further embodiment, the method also includes communicating access specifications of the access request to the central control device. In this case, the access specifications include an identifier of an access device, an identity of service personnel, a connection type of the local access, connection requirements of the local access, an access duration, and/or resources provided for the local access. The method also includes setting up the interface for the local access to the network device in accordance with the access specifications. For example, the access specifications may define a bandwidth and/or a computing power for the local access to the network device. For the case where a plurality of local accesses to the network device take place simultaneously, a division of resources (e.g., of the bandwidth and of the computing power at the local interface and network device; with the aid of prioritization of connections) may be defined and managed The connection requirements may be determined, for example, by standards (e.g., quality of service of a communication service). The connection requirements may correspond to predefined standards (e.g., IEEE 802.1p). In accordance with a further embodiment, setting up the local interface includes instantiating applications at the local interface. The applications include, for example, applications that are used during the local access to the network device. The applications may include virtual sensors that are instantiated at the network device. The applications may be instantiated at the access device connected to the local interface. In accordance with a further embodiment, setting up the local interface is effected with the aid of templates that are present in a manner stored at the central control device. The templates may include components or parts of data or information relevant to setting up the local interface for the access to the network device. By way of example, the templates include information about the trust level, access type, access duration, connection requirements, access device, and/or resource distribution. For example, the templates may at least partly contain access specifications for the access to the network device. In accordance with a further embodiment, communicating the access request to the central control device is effected in an encrypted manner Additionally or alternatively, setting up the local interface by the central control device is effected in an encrypted manner As a result, the security of the industrial network may be increased further. For example, an attack from outside may be better repelled. In accordance with a further embodiment, the local access to the network device is effected for the purpose of maintaining, checking, monitoring, modifying, operating, repairing, switching on, switching off, driving the network device, and/or for the purpose of locally retrieving data from the network device. The service personnel may carry out the local access for one of the purposes mentioned above. For example, technical work is carried out on the assigned network device. In accordance with a further embodiment, the local access to the network device is effected via a local area network (LAN) and/or with the aid of Wireless LAN, Bluetooth, mobile radio technologies, LTE-based connections and/or in a wired manner As a result, a connection quality during the local access to the network device may be improved. In addition, a short data transmission path may further improve the connection quality. In accordance with a further embodiment, the industrial network includes a plurality of network devices. In this case, the access request includes a local access to a subnetwork of a plurality of network devices of the industrial network, where the local access is effected via the local interface. The above-described features of the method may also be applied to a local access to a subnetwork of the industrial network. The subnetwork of network devices may be a grouping of network devices that are geographically close together. For example, the subnetwork may correspond to one location of a plurality of locations of the industrial network. A subnetwork may be defined, for example, by the functionalities of the network devices (e.g., controllers for field devices in automation networks). The subnetwork may include a defined subset of network devices of the industrial network. The subnetwork may be embodied in the form of a virtual network. A local interface of a subnetwork may be connected to each of the network devices of the subnetwork and enable a local access to each of the network devices. In accordance with a further embodiment, the local access to the network device has a smaller data transmission path than a data transmission path for driving the network device by the central control device. For example, a geographical distance between the network device and the central control device is greater than a geographical distance between the network device and the local interface. A shorter data transmission path may reduce latencies during the data transmission and/or reduce undesired fluctuations (e.g., jitter). By way of example, the connection quality may be improved in this way. The method makes it possible, for example, that the guarantees concerning the connection quality that are required for a respective application mayn be realized. In one embodiment, a local interface is allocated in a planned manner and corresponding resources, for example of an underlying network infrastructure, are provided. As a result, specific connection qualities over the period for which the local interface exists may be guarantted. In accordance with a second aspect, an industrial network is provided. The industrial network includes at least one network device that is drivable by a central control device. The industrial network includes a local interface for the local access to the network device. The industrial network is suitable for performing the method described above. For example, the industrial network includes a plurality of network devices. All of the features proposed above for the method for operating an industrial network may also be correspondingly applied to the proposed industrial network. In accordance with one embodiment, the industrial network is provided at least partly in the form of a virtual personal network (VPN) in a network. For example, data transport in the industrial network is effected at least partly via a wide area network (WAN) or the Internet, which are used as a transmission path for the industrial network. Additionally or alternatively, the industrial network may include a backbone line or radio connection for transmitting data. The method and the industrial network of the present embodiments enable, for example, a local access to the network device with support of industrial quality of service requirements. Complex routing of connections over long geographical distances is not required. The local access may be provided temporarily. By deactivating the local access, connections, and/or functions that are possibly defective or beset by security risks may be eliminated. As a result, an increased security for the industrial network may be achieved. Network resources (e.g., bandwidth or computational capacities) may be organized and requested in a demand-oriented manner A monitoring complexity with respect to accesses to the network devices of the industrial network may likewise be reduced. The respective unit (e.g., the access device, the local interface, or the central control device) may be implemented in terms of hardware and/or in terms of software. In the case of an implementation in terms of hardware, the respective unit may be embodied as an apparatus or as part of an apparatus (e.g., as a computer or as a microprocessor or as a control computer of a vehicle). In the case of an implementation in terms of software, the respective unit may be embodied as a computer program product, as a function, as a routine, as part of a program code, or as an executable object. A computer program product that causes the method explained above to be carried out on a program-controlled device, such as elements of the network, for example, is provided. A respective program-controlled device may be either software- or hardware-based. In one embodiment, the access device may, for example, be implemented as a downloadable or short-time installable or activatable access application on a smart phone. A computer program product such as, for example, a computer program device may be provided or supplied, for example, as a storage medium, such as, for example, a memory card, USB stick, CD-ROM, DVD, or else in the form of a downloadable file from a server in a network. This may be effected, for example, in a wireless communication network by the transmission of a corresponding file with the computer program product or the computer program device. The embodiments and features described for the method are correspondingly applicable to the industrial network. Further possible implementations also include combinations, not explicitly mentioned, of features or embodiments described above or below with regard to the exemplary embodiments. In this case, the person skilled in the art will also add individual aspects as improvements or supplementations to the respective basic form of the invention. | H04L630884 | 20180308 | 20180913 | 57644.0 | H04L2906 | 0 | ANDERSON, MICHAEL D | METHOD FOR OPERATING AN INDUSTRIAL NETWORK AND INDUSTRIAL NETWORK | UNDISCOUNTED | 0 | REJECTED | H04L | 2,018 |
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15,758,973 | PENDING | COHERENCE-GATED WAVEFRONT-SENSORLESS ADAPTIVE-OPTICS MULTI-PHOTON MICROSCOPY, AND ASSOCIATED SYSTEMS AND METHODS | In one embodiment, a sensorless adaptive optics imaging system includes a source of light, an optical delivery unit having a wavefront modifying element, and an optical coherence tomography (OCT) sensor configured to acquire OCT images based on light emitted by the source of light and transmitted through the optical delivery unit. The system also includes a processing unit that can: process the OCT images, and determine an adjustment of parameters of the wavefront modifying element. In some embodiments, the system includes a multi-photon microscopy (MPM) sensor that acquires MPM images based on the light transmitted through the optical delivery unit. | 1. A sensorless adaptive optics imaging system, comprising: a source of light; an optical delivery unit having at least one wavefront modifying element; an optical coherence tomography (OCT) sensor configured to acquire OCT images based on a light emitted by the source of light and transmitted through the optical delivery unit; and a processing unit configured to: process the OCT images, and determine an adjustment of parameters of the wavefront modifying element. 2. The system of claim 1, further comprising a multi-photon microscopy (MPM) sensor configured to acquire MPM images based on the light emitted by the source of light and transmitted through the optical delivery unit, wherein the processing unit is further configured to process the MPM images. 3. The system of claim 2, wherein the acquisition of the OCT A-scans is synchronized to acquisition of the MPM sensor. 4. The system of claim 2, wherein the OCT images and the MPM images are co-registered. 5. The system of claim 2, further comprising a dichroic mirror (DcM) in the optical delivery unit, wherein the DcM is configured to split the light such that an MPM signal goes to one sensor and an OCT signal goes to a different sensor. 6. The system of claim 1, wherein the wavefront modifying element is transmissive and is located adjacent to an objective lens defining a pupil. 7. The system of claim 1, wherein an axial motion of a target is compensated using tracking during acquisition. 8. The system of claim 1, wherein the adjustment of the parameters of the wavefront modifying element minimizes a focal spot size. 9. The system of claim 1, wherein the adjustment of the parameters of the wavefront modifying element reduces system aberrations. 10. The system of claim 1, wherein the adjustment of the parameters of the wavefront modifying element is based on Zernike modes. 11. The system of claim 10, wherein the Zernike modes include defocus, astigmatism and coma. 12. The system of claim 1, wherein the adjustment of the parameters of the wavefront modifying element is based on Lukosz polynomials. 13. The system of claim 1, wherein the adjustment of the parameters of the wavefront modifying element is based on modes natural to the wavefront modifying element. 14. The system of claim 1, wherein the wavefront modifying element is deformable. 15. The system of claim 1, wherein at least one wavefront modifying element is a multi-actuator adaptive lens (MAL). 16. The system of claim 15, wherein the optical delivery unit further comprises a deformable variable focus lens (VL). 17. The system of claim 16, wherein one wavefront modifying element is a woofer, and other wavefront modifying element is a tweeter. 18. The system of claim 1, wherein at least one wavefront modifying element is transmissive. 19. The system of claim 1, wherein the wavefront modifying element is selected from a group consisting of a spatial light modulator, a deformable mirror, a liquid crystal, and a digital micro-mirror display. 20. The system of claim 1, wherein the wavefront modifying element is a spatial light modulator affecting the phase. 21. The system of claim 1, wherein the processing unit is further configured to correct a wavefront using pupil segmentation. 22. The system of claim 2, wherein different light sources are used for the MPM images and the OCT images. 23. The system of claim 22, wherein the light source for the MPM images is turned off while the light source for the OCT images is turned on and vice versa. 24. The system of claim 22, wherein a wavefront correction is performed with an OCT light source ON and an MPM light source OFF. 25. The system of claim 24, wherein the MPM light source is turned ON after a wavefront correction is performed. 26. The system of claim 1, wherein the optical delivery unit further comprises a scanning mirror configured to deliver a scanning beam. 27. The system of claim 25, wherein the scanning beam is delivered to a pupil of an eye. 28. The system of claim 1, wherein the source of light is a wavelength-swept laser. 29. The system of claim 2, wherein the source of light is a broad-band source of light. 30. The system of claim 1, wherein the OCT sensor is a high speed detector. 31. The system of claim 1, wherein the OCT images are retina images. 32. The system of claim 2, wherein the OCT images are 3-D OCT volume images that comprise 2-D B-scan images, and wherein the 2-D B-scan images comprise 1-D A-scan images. 33. The system of claim 32, wherein the MPM images are 2-D C-scans based on en face images generated by extracting and mapping intensities from user-selected depth region within the 3-D OCT volume images. 34. The system of claim 1, wherein the system further comprises a reference arm with a reference mirror, and wherein a location of the reference mirror adjusted for a coherence gating. 35. A method for acquiring images using sensorless adaptive optics, comprising: sending light through an optical delivery unit to a target, the optical delivery unit having at least one wavefront modifying element; acquiring OCT A-scans of a target by an OCT sensor; assembling the OCT A-scan images into 2-D OCT B-scan images; assembling the OCT B-scan images into 3-D OCT volume; selecting at least one OCT 2-D C-scan image within the 3-D OCT volume; determining merit functions of the OCT 2-D C-scan image; and adjusting the wavefront modifying element. 36. The method of claim 35, wherein the wavefront is represented by Zernike modes. 37. The method of claim 35, where coefficients of Zernike modes are selected based on the merit functions of the OCT 2-D C-scan images. 38. The method of claim 37, wherein the merit functions are processed using a hill climbing algorithm to obtain optimal coefficients of Zernike modes. 39. The method of claim 35, further comprising: acquiring multi-photon microscopy (MPM) 2-D C-scan images. 40. The method of claim 39, further comprising: averaging MPM 2-D C-scan images. 41. The method of claim 39, further comprising: co-registering the OCT images and the MPM images. 42. The method of claim 39, wherein the OCT 1-D A-scans are acquired by a high speed detector and the MPM 2-D C-scan images are acquired by a photo-multiplier tube (MPM) detector. 43. The method of claim 39, wherein the MPM 2-D C-scan images are based on en face generated by extracting and mapping intensities from the user-selected depth region within OCT volume. 44. The method of claim 39, wherein the MPM 2-D C-scan images are based on en face images generated by extracting and mapping intensities from the user-selected depth region within 3-D OCT volume. 45. The method of claim 35, wherein the wavefront modifying element is a multi-actuator adaptive lens (MAL). 46. The method of claim 35, further comprising a variable focus lens (VL). 47. The method of claim 35, wherein the wavefront modifying element is transmissive. 48. The method of claim 35, wherein the optical delivery unit includes a scanning mirror configured to deliver a scanning beam. 49. The method of claim 35, further comprising generating light by a wavelength-swept laser. 50. The method of claim 35, further comprising generating light by a broad-band source of light. 51. The method of claim 48, wherein the scanning mirror is configured to deliver a scanning beam to a pupil of an eye. 52. The method of claim 39, wherein the MPM 2-D C-scan images require a different energy of light than an energy of light for the OCT 2-D C-scan images. 53. A non-transitory computer-readable medium whose contents cause a computer to acquire and process images using sensorless adaptive optics, the images being acquired and processed by a method comprising: sending light through a n to a target, the optical delivery unit comprising at least one wavefront modifying element; acquiring OCT A-scans of 1-D depth profile of a target by an OCT sensor; assembling the OCT A-scans into 2-D OCT B-scan images; assembling the OCT B-scan images into 3-D OCT volume; selecting at least one OCT 2-D C-scan image within the 3-D OCT volume; determining merit functions of the OCT 2-D C-scan image; and adjusting the wavefront modifying element based on merit functions. | CROSS-REFERENCE(S) TO RELATED APPLICATION(S) This application claims priority to U.S. Application No. 62/217,508, filed Sep. 11, 2015, expressly incorporated herein by reference in its entirety. FIELD OF THE INVENTION The present invention relates generally to image acquisition and processing, and more particularly relates to methods and apparatus for image-based diagnostics of the eye. BACKGROUND Multi-photon microscopy (MPM) is an imaging technology that is used to obtain 3-D images from biological specimens with molecule specific contrast. The use of MPM for in vivo microscopy has multiple potential benefits over single photon microscopy, including applications such as non-invasive diagnostic imaging of the retina (the light sensitive tissue at the back of the eye). Compared to conventional microscopy with single photon excitation fluorescence, MPM uses light at longer wavelengths, in the near infrared (NIR), where tissue scattering and absorption is lower. The use of NIR light is particularly attractive for imaging the retina, which contains phototransduction pigments sensitive to the visible wavelengths. Unlike single photon processes, MPM techniques, such as two-photon excited fluorescence (TPEF), only occur at a narrow axial range around the focal point where the irradiance is the highest, providing an optical sectioning effect. However, a disadvantage of MPM imaging in ocular tissues is the high pulse energy required to elicit the non-linear effects. Minimizing the incident exposure energy is therefore important for non-invasive imaging, in particular for the delicate tissues of the retina. Although MPM is relatively unaffected by low levels of out-of-focus scattering, wavefront aberrations from the sample and optical path cause blurring of the focal spot. Since the MPM signal is quadratically proportional to the focused spot size, significant improvements in the signal-to-noise ratio can be achieved through wavefront shaping to approach the diffraction-limited focus with a large numerical aperture. Some conventional technologies apply adaptive optics (AO) to MPM to correct for refractive errors and promote diffraction-limited focusing in tissue. These conventional AO systems use a Hartmann-Shack Wavefront Sensor (HS-WFS) to detect the wavefront aberrations and, in a closed feedback loop control, guide the shape of an adaptive element, such as a deformable mirror, to correct the detected wavefront aberrations. Since the HS-WFS is sensitive to back-reflections, the conventional AO systems use curved mirrors instead of lenses, and long focal lengths to minimize the off-axis aberrations. Furthermore, the use of a wavefront sensor places significant design constraints on the system, requiring optical conjugation of the deformable element, WFS, and the pupil plane of the system. Additionally, the HS-WFS is generally only useful when there is a single scattering plane in the sample, because thick tissue samples or multi-layered samples negatively affect the ability to measure the wavefront. Furthermore, conventional MPM techniques may require relatively long time, e.g., 6-7 minutes for image acquisition using high power laser excitation energy. Therefore, these conventional technologies subject the patient's eye to a relatively long period of high stress. Accordingly, there remains a need for the eye imaging methods, systems and apparatuses that are relatively fast and do not cause high light-induced stress on the retina. DESCRIPTION OF THE DRAWINGS The foregoing aspects and the attendant advantages of this invention will become more readily appreciated as the same become better understood by reference to the following detailed description, when taken in conjunction with the accompanying drawings, wherein: FIGS. 1-3 are schematic views of image acquisition systems in accordance with embodiments of the presently disclosed technology. FIG. 4 is a sample cross-sectional view of the eye acquired in accordance with an embodiment of the presently disclosed technology. FIGS. 5A and 5B are flow charts of the image acquisition and analysis in accordance with an embodiment of the presently disclosed technology. FIGS. 6A-6F are sample images of the structures of an imaging eye phantom acquired in accordance with an embodiment of the presently disclosed technology. FIGS. 7A-7C are sample images of the retina of the eye acquired in accordance with an embodiment of the presently disclosed technology. FIG. 7D is a graph of the image intensity versus steps in accordance with an embodiment of the presently disclosed technology. FIGS. 8A-8D are sample images of the retina of the eye acquired in accordance with an embodiment of the presently disclosed technology. DETAILED DESCRIPTION Specific details of several embodiments of representative image acquisition and processing system, and associated methods are described below. The system and methods can be used for the imaging and diagnostics of the eye. A person skilled in the relevant art will also understand that the technology may have additional embodiments, and that the technology may be practiced without several of the details of the embodiments described below with reference to FIGS. 1-8G. In order to be effective, the combination of adaptive optics (AO) with multi-photon microscopy (MPM) for retinal imaging should be fast (on the order of seconds), and should minimize the high-energy laser exposure on the retina. A person of ordinary skill would know that adaptive optics or wavefront modifying elements (e.g., adaptive lenses, adaptive mirrors, adaptive liquid crystals) can act on light to modify the phase front, aberrations, etc. in order to change/adjust the optical properties of an optical system, such as the focal length, size and distortions of the focal point, etc. In some embodiments of the inventive technology, MPM imaging is combined with depth-resolved wavefront sensorless AO (WSAO) using the same light source, but separate detection systems. The WSAO typically can change its own optical properties without having to rely on the optical sensors that are part-of or are associated-with to the AO itself. The light used for MPM microscopy typically comprises of a train of pulses that are on the order of femtoseconds in duration. The femtosecond-pulsed laser can be selected to have adequate bandwidth (tens of nanometers) for optical coherence tomography (OCT) with coherence length on the order of microns. Coherent detection of the excitation light that is back-scattered from the sample enables OCT-like cross-sectional visualization of the sample. In at least some embodiments, due to the high sensitivity of OCT detection, a cross-sectional profile of the sample can be visualized that is much larger than the Rayleigh range of the focused beam. The OCT images can be used for image-guided WSAO aberration correction of the excitation beam in the sample. The OCT images can be acquired at low power since the back-scattered light used for the OCT detection is a single photon process. Following the aberration correction, the intensity of the excitation laser can be increased to perform the MPM imaging, which is acquired using a dedicated highly sensitive detector. Both the MPM and the OCT image acquisition sub-systems can share the same source and optical delivery unit delivery optics (including the WSAO) to ensure exact co-registration of the images during acquisition. FIG. 1 is a schematic view of an image acquisition system 100 in accordance with embodiments of the presently disclosed technology. Briefly stated, FIG. 1 shows a spectral domain OCT system comprising a light source 10a in the source arm, a mirror 14r in a reference arm REF, optical delivery unit directing light on a sample 30 in a optical delivery unit 86, a spectrometer (i.e., an OCT sensor or detector) 22a in detection arm, and a beam splitter 18. The beam splitter splits the source-light into the reference arm and optical delivery unit. The reference mirror is typically installed on a translation stage so that it can be moved back and forth to increase or decrease the path-length in the reference arm. The light-beams returning from the reference mirror and the sample return to the beam-splitter, and are further split into the source and detector arms. The light source can be a broad-band light source. For example, the full-width-half-max (FWHM) spectral width of the light source may range from 10 nm to 150 nm. Spectral domain OCT systems use spectroscopic detection method for measuring the interference generated from the light returned from the sample and reference arms. Generally, the interferometric light exiting the detector arm is dispersed via a grating. The spectra are acquired using a line-scan camera. The resulting spectra can be transferred to a processor for inverse Fourier transforming and relevant signal processing (such as obtaining the complex envelope of the interferometric signal) for obtaining depth dependent (i.e., axial) reflectivity profiles (A-scans). The axial resolution is governed by the source coherence length, typically about 3-10 μm. Two dimensional tomographic images (B-scans) are created from a sequence of axial reflectance profiles acquired while scanning the probe beam laterally across the specimen or biological tissue. Details of the system illustrated in FIG. 1 are described below. The source light 10a can include a laser (e.g., a 1560 nm femtosecond laser by Menlo Systems, Germany). In some embodiments, the laser can have a 120 nm (or other) bandwidth and 47 fs (or other) pulse duration at the laser output. The source of light 10a can also include a second-harmonic-generating (SHG) module (not shown) to frequency-double the light source from, e.g., 1560 nm to 780 nm. The wavelength of 780 nm can be used as the MPM excitation source as well as OCT light source, as explained in more detail below. In the illustrated embodiment, the 780 nm light was directed through a dispersion-pre-compression (DPC) 16 to compensate for the group delay dispersion from the optical elements and to provide approximately transform-limited pulse duration at the sample in order to maximize the MPM signal (generally, shorter pulses provide a larger MPM signal). In some embodiments, the dispersion pre-compression can be adjustable to accommodate different samples, for example a mouse eye. After pulse dispersion pre-compensation, the light can be split by the pellicle beam splitter (PBS) 18. In some embodiments, 95% (or other fraction) of the power in a beam 50 can be directed towards the sample through the optical delivery unit as a beam 53, and 5% (or other fraction) of the power towards a reference arm REF as a beam 51, which reflects back toward the PBS 18 as a beam 52, and further to mirrors 14a-14c as a beam 57. The terms “beam” and “light” are used interchangeably in this application to denote electromagnetic radiation either in a visible or in an invisible (e.g., infrared) spectrum. In some embodiments, the optical delivery unit 86 can one or more scanning mirrors 20, e.g., galvanometer-scanning mirrors (GM) or MEMS scanning mirrors, to scan the light across the surface of the sample within an eye 30. Two lenses f1 and f2, having the focal lengths of, e.g., 60 mm and 200 mm, respectively, can relay the conjugate plane from the GM to the objective lens fobj having a focal length of, e.g., 8 mm. A mirror 14d also directs the light coming from the scanning mirrors 20 to the PBS 18. A wavefront modifier such as an adaptive optics (AO) lens or a deformable mirror 21, e.g., a Multi-actuator Adaptive Lens (MAL), can be placed adjacent to the objective lens fobj. A person of ordinary skill would know other suitable types of wavefront modifiers or adaptive elements or adaptive optics elements or adaptive optics, e.g., a liquid crystal spatial light modulator, deformable mirror, or any other spatial light modulator, e.g. digital micromirror display, affecting the phase and/or intensity, can be used to modify the wavefront for aberration corrections and wavefront optimization. In at least some embodiments, a transmissive deformable component or wavefront modifier (e.g., an adaptive optics 21 that is a lens) enables a compact optical configuration, which may be important when using the technology in the vision science laboratories or clinical settings. A benefit of using transmissive elements for adaptive optics is that the wavefront modifying (or correcting) element can be placed adjacent to a pre-defined pupil plane without the need for an extra optical relay, thus further reducing the footprint of the optical system 100. A back-scattered excitation light 54 can be transmitted back as the light 56 by a dichroic mirror DcM and gets de-scanned at the scanning mirror 20. The de-scanned beam is recombined with the reference arm light 52 at the beam splitter 18, and directed to a spectrometer 22a (also referred to as an OCT sensor) as the light 57, 58. The sample light 56 and reference light 52 can generate an interference pattern on the spectrometer detector 22a. In some embodiments, the interference pattern can be processed into cross-sectional images using a graphical processing unit (GPU) 24 with associated software. In some embodiments, a central processing unit (CPU) or a GPU/CPU combination can be used with associated software. In some other embodiments, an embedded processor or Field Programmable Gate Array (FPGA) processor or an application specific integrated circuit (ASIC) with associated software can be used. A back-scattered excitation light 54 includes a two-photon excited fluorescence emission from the sample 30 that gets reflected as light 55 by the dichroic mirror DcM to a MPM sensor or detector such as a photo-multiplier tube (PMT) 26 without being de-scanned by the scanning mirror 20. In some embodiments, the two-photon excited fluorescence (or multi-photon signal) may be de-scanned by the scanning mirrors. One can use any other photodetector instead of the PMT as a MPM sensor. In some embodiments, a short-pass filter SPF and a focusing lens f3 are placed prior to the PMT (i.e., MPM sensor) to reject residual excitation light. In many embodiments, the back-scattered excitation light 54 includes both the excitation light and the two-photon excited fluorescence light. The excited light could include multi-photon light such as second or third harmonic generation light, etc. Furthermore, the excitation light may carry many times more energy than the two-photon excited fluorescence light. Therefore, the SPF can be used to let only the two-photon excited fluorescence light or multi-photon light into the PMT detector (i.e., the MPM sensor). In some embodiments, acquisition of the OCT A-scans is synchronized to the acquisition of the MPM sensor, which ensured that both OCT and MPM images are properly registered. The optical system described using dual wavefront modifying elements for light delivery to the human eye could be readily adapted for MPM imaging with aberration correction using the OCT images for WSAO. The importance of aberration correction is emphasized in order to maintain the smallest possible focal spot on the retina (diffraction limited with full pupil illumination) in order to minimize the optical energy required to generate the MPM signal from the retina. In order to excite non-linear processes, a short duration pulsed light source would be preferred. A highly sensitive MPM sensor such as a photomultiplier tube would be placed between the final lens and the subject's eye, using a dichroic mirror to reflect the two-photon excited fluorescence (TPEF) from the eye but passing the excitation beam. The laser power could be reduced during the aberration correction steps. Alternatively, since criteria for maintaining the minimum power exposure levels for humans is even more important than that for preclinical imaging, a second low power continuous wave (CW) broadband light source at the same wavelength could be co-aligned with the femtosecond laser input; the low power source could be used for optimization with the femtosecond laser off, and then after aberration correction is achieved, the low power laser can be turned OFF and the femtosecond laser turned ON for MPM imaging. FIG. 2 is a schematic view of the image acquisition system 200 in accordance with an embodiment of the presently disclosed technology. Briefly stated, in the OCT system 200, the broad-band light source (e.g., the light source 10a in FIG. 1) is replaced by a tunable frequency light source 10b. The detector array (e.g., the spectrometer 22a in FIG. 1) is replaced by a single detector 22b (or dual detectors for balanced detection). In some embodiments, the grating may not be needed in the system of FIG. 2. The wavelength of the source 10b can be tuned relatively rapidly (e.g., at a rate of 10 kHz-1 MHz) within a spectral range of typically 10 nm to 100 nm around the center wavelength. The instantaneous line width (spectral range of the tunable filter) is commonly better than 0.1 nm. In some embodiments, the average power of such a source generally ranges from 0.1 mW to 40 mW depending upon the applications. The source 10b may be electrically operated. Analog to digital converter (ADC) can be added to digitize the detector current for subsequent digital processing. Details of the system illustrated in FIG. 2 are described below. The detector 22b (also referred to as an OCT detector or a high speed detector or an OCT sensor) can be a photo-diode that converts light into electricity. The OCT sensor or detector may be a high-speed detector with the bandwidth of up to few hundred MHz. The OCT sensor or detector may be coupled with a high-speed A/D (analog to digital) converter, e.g., 8-bit or 12-bit converter, with a conversion rate of 0.1-2 GSamples/second. The relatively high conversion rate assists in achieving typical line-rates (rate of acquisition of A-scans) of 10,000 lines/s to 1 million lines/s. The light source 10b for imaging the retina in the eye 30 can be a wavelength-swept laser (e.g., a wavelength-swept laser by Axsun Inc. with an 80 nm full-width half-maximum (FWHM) spectrum centered at 1060 nm). In general, the wavelength of the light produced by the wavelength-swept laser is in a narrow band, but is also a function of time, i.e., the wavelength sweeps in a given period of time. In some embodiments, the line rate of the light source can be 100 kHz, with approximately 50% duty cycle. In order to increase the imaging speed, a ‘double buffered’ approach can be implemented in some embodiments in conjunction with a Fiber Bragg Grating (FBG) to align A-scans in real time. The OCT system 200 includes the optical delivery unit 86 and the reference path REF. The optical delivery path 86b can include wavefront modifying elements 21a and 21b (e.g., deformable lenses MAL and VL), relay lenses f1-f6, and the scanning mirrors 20 (e.g., galvanometer mounted mirrors GM) to deliver a scanning beam 71 to the pupil of the eye of the subject being imaged (e.g., to the eye 30). The wavefront modifying element 21a can be placed at the location of a collimating lens LC2, which collimates a light 70 from the fiber. This optical plane is conjugated to the adaptive optics element or wavefront modifier 21b (e.g., a deformable variable focus lens VL by ARCTIC 316-AR850, Lyon, France) via an optical relay. In some embodiments, the dual wavefront modifying elements 21a and 21b can create a ‘woofer-tweeter’ adaptive optics system. For example, the wavefront modifying element 21b (VL or “woofer”) can correct low order aberrations, while the wavefront modifying element 21a can correct higher order aberrations (MAL or “tweeter”). Two additional relays are used to conjugate the optical plane to the scanning mirrors 20 (e.g., an XY galvanometer mounted mirror GM, or MEMS scanning mirrors or other ways of scanning the beams), and then to the subject's eye's pupil. In some embodiments, the 1/e2 beam diameter at the pupil is approximately 5 mm. A returning light 72 propagates back through the optical elements, and can be acquired by an OCT sensor or detector 22b, together with a reference beam from a reference path REF. In some embodiments, the fiber optics couplers FC1 and FC2 can be replaced by fiber-optic circulators. In some embodiments, the wavefront modifying element 21b (e.g., the variable focus lens) can accommodate for the variation in subject's eyes up to approximately −6 diopters without mechanically moving lenses or the pupil plane. In some embodiments, due to the non-linearity and comparatively slow response time of the variable focus lens 21b, the focus can be adjusted manually to the retinal layer of interest using the cross-sectional OCT images as guidance. The position of the focus within the retina is readily observed as the brightness of the layers changed dynamically as the shape of the lens is changed. In some embodiments, the lenses can be standard achromatic doublets by Thorlabs Inc. and Edmund Optics, Inc. The total length of the optical delivery unit can be 1.5 m, and can be folded to fit on an optical breadboard mounted to a slit lamp base, therefore providing three dimensional translation of the imaging system relative to the subject's eye. The optical delivery unit can also be mechanically designed and assembled to have a chin-rest and 3-dimensional degrees of freedom. In some embodiments, the field of view limited by the diameter of the last optical relay is 4°×4°. The field of view can be expanded or shrunk as desired using appropriate lenses. If used for multi-photon microscopy (MPM), the OCT engine could be modified with a pulsed femtosecond laser and a spectrometer based OCT sensor/detection system, as shown with reference to FIG. 1. In the embodiments illustrated in FIG. 2 and FIG. 1, the OCT data can be processed and displayed in real time using a Graphics Processing Unit (GPU) platform and/or a CPU platform. In some embodiments, the GPU processing can be integrated with controls for the wavefront modifiers, merit function calculation, and real-time axial tracking of the retinal position in software. In the above implementations of OCT, Fourier Domain (FD) is often used interchangeably with Spectrometer Based (SD) OCT. Furthermore, FD is sometimes used to describe both SD and Wavelength Tunable Swept Source (SS) OCT. Another term of art for the SS OCT is Optical Frequency Domain Imaging (OFDI). In some embodiments, these techniques may be complementary to the Time Domain (TD) OCT described below. In time-domain OCT, the light source is typically a broad-band source. The axial (or depth) ranging can be achieved by continuously moving the reference mirror back and forth (typically using a motorized translation stage) while simultaneously monitoring the interferometric signal using an OCT sensor such as a single detector (or dual detectors for balanced detection). The interferometric signal is demodulated (either outside or inside the processor) to generate A-scans. Two dimensional tomographic images (B-scans) are created from a sequence of axial reflectance profiles acquired while scanning the probe beam laterally across the specimen or biological tissue. Therefore, in some embodiments, the OCT systems in FIGS. 1-3 may be replaceable with the time-domain OCT by, for example, making the reference mirror moveable and using an OCT sensor such as a single detector (or dual balanced detectors) like in FIG. 2 or replacing the spectrometer in FIGS. 1 and 3. The light source can be a broad-band source. Thus, the reference arm has a reference mirror and the reference mirror location is adjusted for coherence gating and generating OCT A-scans as well as B-scans and 3-D volumes. FIG. 3 is a schematic view of the image acquisition system 300 in accordance with an embodiment of the presently disclosed technology. The illustrated embodiment is generally similar to the one shown in FIG. 2. The system 300 includes two wavefront modifying elements 21a and 21b in the path of light emitted by a light source 10c. In some embodiments, the wavefront modifying elements 21a and 21b can operate as a “tweeter-woofer” pair. For example, the wavefront modifying element 21b (VFL or “woofer”) can correct low order aberrations, while the wavefront modifying element 21a can correct high order aberrations (MAL or “tweeter”). In the illustrated embodiment, the adaptive optics (or wavefront modifying) element 21a (MAL) was used for fine tuning of the focus as well as higher order aberration correction. In some embodiments, the corrected modes can be defocus, two astigmatisms, two coma, sphere, and two trefoils, corresponding to Zernike modes 4, 3, 5, 7, 8, 12, 6, 9, respectively. Higher modes can also be corrected without limitation. We are mentioning Zernike modes, but the proposed invention is applicable to other ways of describing wavefronts as well. For example, an alternative to Zernike modes can be another orthogonal-basis set, e.g., Lukosz polynomials. In some other embodiments, a non-orthogonal basis can also be used. Every wavefront modifying element has its own natural modes. These modes can be orthogonal, but it is not strictly necessary. Sometimes these modes may not be orthogonal. The modes can be a linear combination of the actuator functions that influence the wavefront and the adaptive or wavefront modifying element. Sometimes it might be more convenient for the wavefront modifier to operate using these modes. In some embodiments, the relative positions of the “woofer” and “tweeter” may be interchanged with respect to their illustrated positions. FIG. 4 is a sample cross-sectional view 400 of the human eye acquired in accordance with an embodiment of the presently disclosed technology. Five research volunteers were imaged. The maximum power at the cornea was 750 μw. Retinal imaging was performed without mydriasis. Since the wavelength was outside the visible spectrum, the imaging beam did not cause constriction of the pupil, and subjects with a pupil larger than 5 mm could be readily imaged. Imaging was performed with the subjects seated at a table with forehead and chin rest; a bite bar was not used during imaging. The operator aligned the imaging beam to the subject's eye under the guidance of a pupil camera that permitted the position of the infrared beam to be observed. The cross-sectional view includes multiple A-scans in the direction that is generally perpendicular to the retina (Z-direction). In some embodiments, the A-scans can be obtained by OCT scanning. The systems 100, 200, and/or 300 can be used to acquire the A-scans. Multiple 1-D A-scans can be assembled into a cross-sectional 2-D B-scan. The cross-sectional B-scan image of the retina may be presented on a logarithmic intensity scale as is common for OCT data. Multiple 2-D B-scans can be assembled into a 3-D OCT volume by combining the 2-D B-scans in the C direction. For example, the 3-D OCT volume may include 80 B-scans, each including 150 A-scans. For the cross-sectional view 400, the operator adjusted the focus to a retinal layer of interest 310 (i.e., the photoreceptor layer) using the variable focus lens with the B-scan images as guidance. In the illustrated embodiment, a thickness t of the layer of interest 310 was about 10 μm, while a thickness T of the entire retinal layer of interest was about 250 μm. In the software tool, the operator may interactively select the retinal layer to focus on, and may activate axial tracking in the software, displaying the en face images that were used for the image quality metric also in real time. For the cross sectional image 400, the subject was instructed to blink and then focus on a fixation target, at which time the aberration correction was initiated using the WSAO algorithm as described below with reference to FIG. 5. The time required to optimize the first 5 modes was about 4 s, after which the subject was permitted to blink and refocus. The operator could either save images after the first optimization, or elect to continue the optimization of the last three modes, which required another about 2 s. During saving, the acquired data was streamed to disk for post processing. The wavefront aberrations are represented using a set of orthonormal Zernike polynomials (or modes), which permits optimization of each Zernike mode independently. In one embodiment, the method first optimizes for defocus (Z=4), followed by two astigmatisms (Z=3, 5) and then the two comas (Z=7, 8). For each Zernike mode, the optimization is performed by acquiring an OCT volume for 10 different coefficients of each Zernike mode applied to the actuators of wavefront modifying element (e.g., MAL). For each coefficient value, an en face image is extracted, and the coefficient that produced the brightest image is selected as the optimal value. The optimization of the next Zernike mode continues in a hill climbing fashion, using the combination of the previously optimize modes as a starting point. Based on the acquisition parameters of the spectrometer, the optimization can be completed in about 4 s. When imaging human eye, the optimization should be performed within about 4 s. It is desirable for the patient comfort. After about 4 s, the person cannot fixate, and needs to blink. On the other hand, when imaging anesthetized mice, the aberration correction may take longer, on the order of 30 s or a minute. In some embodiments, the required wavefront correction could be estimated using pupil segmentation, or other approaches well known to practitioner skilled in the art. Pupil segmentation is a method of wavefront sensorless adaptive optics in which the wavefront aberrations are estimated by dividing the input beam into segments along the cross-sectional profile of the beam at a plane that is typically conjugated to the pupil. The lateral shift of the images acquired from a particular beam segment relative to a reference image (i.e., from the central segment) can be used to infer the relative slope of the wavefront at that segment. After measuring the wavefront slope variations across the pupil, they can be assembled by a person of ordinary skill and combined to control the wavefront correcting element to remove or reduce the aberrations. FIG. 5A is a flow chart of a high level description of the proposed sensor-less adaptive optics OCT method 500A in accordance with an embodiment of the presently disclosed technology. In some embodiments, some steps illustrated in the method 500A may be omitted, and/or some steps not shown in FIG. 5A may be added. The illustrated method 500A starts at step 505A. At step 510A, light is sent to the specimen in the optical delivery unit of the interferometer and the mirror in the reference arm (e.g., as described in FIG. 2). At step 515a, the light backscattered from the specimen is interfered with the light returning from the reference mirror at the coupler as shown in, e.g., FIG. 2 or at the beam-splitter as shown in FIG. 1. At step 520A the interference is monitored using a detector (i.e., an OCT sensor) as shown in, e.g., FIG. 2 or another OCT sensor such as a spectrometer as shown in FIG. 1. The data are processed to generate 1-dimensional OCT A-scans. The beam is scanned across the sample to generate 3-D data-sets. At step 525A, a location is selected within the tissue volume using 3-D data-sets for optimizing wavefront coefficients of (wavefront modes). In some embodiments, in order to compensate for axial motion during the acquisition, a real time automated retinal tracking software can be used to extract the correct layer within the tissue throughout the optimization process. Next, at step 530A, a wavefront mode (e.g., Zernike term if wavefronts are represented using Zernike polynomials or modes) is selected for optimizing wavefront. At step 535A the wavefront (or Zernike) coefficients are optimized by processing the images at the selected location. At step 540A, the method applies the optimal coefficient to the appropriate actuator of the wavefront modifying surface. At step 545A the method checks if all wavefront (or Zernike) modes have been processed. If more modes need to be optimized, the method selects the next mode at step 550A and then repeats steps 535A-545A. At step 555A, the image is further analyzed (or displayed for an observation). At step 560A, if more wavefronts need to be optimized for the light backscattered from different locations, the method proceeds to step 530A and repeats steps from step 535A onward. Otherwise, in no more wavefronts need to be optimized, the method finishes at step 565A. FIG. 5B is a flow chart of an image acquisition and analysis method 500 in accordance with an embodiment of the presently disclosed technology. In some embodiments, some steps illustrated in the method 500B may be omitted, and/or some steps not shown in FIG. 5 may be added. The illustrated method 500B starts at step 505B. At step 510B, the operator (or the computer) selects the OCT-scans. In some embodiments, the OCT scans may be obtainable using light source including a femtosecond laser or a wavelength-swept laser or a broad-band superluminiscent diode or other broad-band light source. Generally, the OCT-scans use relatively low energy, therefore reducing the stress on the retina of the eye. At step 515B, 1-D A-scans are obtained. The A-scans may, for example, represent the retina and the surrounding tissue of the eye. At step 520B, a count of the A-scans is taken to verify whether all 1-D A-scans required for a 2-D B-scan have been acquired. If all A-scans have been acquired, the method proceeds to assemble 2-D B-scan from the A-scans at step 525B. Otherwise, the method returns to step 515B. At step 530B, a count of the B-scans is taken. If all 2-D B-scans required for a 3-D OCT volume have not been assembled yet, the method returns to step 515B. Otherwise, if the required 2-D B-scans have been acquired, the method proceeds to assemble a 3-D OCT volume from 2-D B-scans. At step 540B, a merit function can be run on the 3-D OCT volume. Some sample merit functions can be light intensity in a given plane of the 3-D OCT volume, contrast, number and sharpness of the boundary lines in the plane, etc. Some other merit functions could also include power in the certain spatial spectral region or some other spatial frequency characteristics. After the merit functions are determined, the optimal merit function can be selected by, for example, comparing the merit functions against those of other images acquired with different values of the Zernike (or wavefront mode) coefficients applied to the actuator(s) of the wavefront correcting element. In some embodiments, the merit function that provides, e.g., the highest image intensity or image sharpness can be selected for the adaptive optics (AO) or wavefront adjustment of step 545B. Furthermore, in some embodiments, image irregularities can be evaluated at step 540B. For example, if the subject blinked or significantly moved the eye, the 3-D OCT volume may become invalid, which would be reflected in the values of the merit functions, and would signify a need to repeat the measurements for the particular 3-D OCT volume starting from, for example, step 515B. At step 545B, the adaptive optics (AO) parameters are adjusted. For example, wavefront modifying elements 21, 21a, 21b (MAL, VL, VFL) may be adjusted to change/reduce aberrations. In some embodiments, Zernike or wavefront modes can be optimized by adjusting the wavefront modifying elements 21, 21a, 21b. For example, for each Zernike or wavefront mode, the MAL can be stepped through a range of coefficient values. After step 545B, the method returns to step 515B to continue with the acquisition of the A-scans. After computing the merit function, the method proceeds to step 550B where C-scans can be assembled and their merit functions can be determined. For example, sample C-scans may be generated from the 3-D OCT volume along the retinal layers 310 shown in FIG. 4. At step 550B, a merit function can be determined for the C-scans. For example, an en face image corresponding to the layer of interest can be extracted from the OCT volume to compute the merit function. In some embodiments, the 3-D OCT volume can include just one 2-D B-scan. At step 555B, the wavefront modifying elements can be adjusted using corresponding actuators. In some embodiments, in order to compensate for axial motion during the acquisition, a real time automated retinal tracking software can be used to extract the correct retinal layer throughout the optimization process. Using a hill climbing algorithm (or other extremum-seeking algorithms), the coefficient that resulted in the brightest image can be identified, applied to the actuators of the MAL, and the next Zernike mode can be searched. For example, wavefront modifying elements 21, 21a, 21b (MAL, VL, VFL) may be adjusted to change, e.g., a focal length of one or more adaptive optics elements. Any other optimization algorithm can be used to obtain optimal coefficients for correcting the wavefronts. At step 560B, the method verifies whether the adjustments of the wavefront correcting parameters have been completed. If the adjustments have been completed, at step 565 the method can apply the optimal parameters to the wavefront modifying elements. The optimal parameters may be based on the calculated merit functions from step 550B. In some embodiments, the OCT imaging is combined with multi-photon microscopy (MPM). At step 570B, the system switches to multi-photon microscopy (MPM) C-scans. In general, the MPM scans require higher energy, which, in turn, stresses the retina more than the OCT scans. However, at this step, the adaptive optics elements or wavefront modifying elements (e.g., MAL, VL, VFL) may already be properly adjusted to minimize aberrations, therefore tightly focusing the light source and facilitating relatively quick MPM scan on the order of, for example, 2-5 seconds using relatively lower power of the source. At step 575B, the method verifies whether the last MPM C-scan has been acquired. If more MPM C-scans are to be acquired, the method proceeds to step 580B to acquire additional C-scans. In some embodiments, in conjunction with acquiring the MPM C-scans at step 580B, the method may also acquire OCT scans at step 590B. These OCT scans may be used to align and register the patient eye to improve the registering of the MPM scans. For example, in at least some embodiments, the MPM scans result in a relatively low signal to noise (S/N) ratio. Therefore, multiple MPM C-scans can be summed up to improve the S/N ratio at least if the noise is random. To properly sum and average the MPM C-scan from step 580B, the corresponding OCT scans from step 590B can help to ascertain correct physical location of the MPM C-scans. The MPM C-scans can be averaged in step 585B. The method may terminate at step 595B. The inventive technology embodies several advantages over the conventional technologies. Some examples of the advantages are: 1. High energy MPM C-scans are executed after the adaptive optics optimization (e.g., aberration correction, focal depth choice, etc.) had already been performed based on the low energy OCT scans. As a result, the stress on the retina is reduced; 2. Sensor-less adaptive optics design (e.g., Wavefront modifying lenses MAL, VL) results in a smaller system size and system simplification (e.g., no issues with isolating the sensors from the back scattered light); 3. Same optical delivery path (e.g., the optical delivery path 86) is used for both for MPM and OCT scans (“coregistration”); 4. Adaptive optics optimization is based on merit function (e.g., contrast, intensity, etc.) and/or application of Zernike function (or other suitable functions) or other suitable wavefront modes; 5. A compact, sensor-less adaptive optics OCT system where wavefront aberrations are estimated using optimization algorithm(s); and 6. The use of OCT for the optimization provides coherence gated depth resolved images, permitting accurate layer-selective aberration correction even in the presence of multi-layered samples. Several representative applications of the inventive technology are described with reference to FIGS. 6A-8D. FIGS. 6A-6F are sample images of the structures of the imaging phantom acquired in accordance with an embodiment of the presently disclosed technology. The impact of OCT-image-guided WSAO (e.g., wavefront modifying elements 21, 21a, 21b) wavefront correction on the quality of the MPM images was demonstrated on an imaging phantom. Lens paper stained with a fluorescent dye (excitable by a two photon process at the 780 nm, but not by a single photon at the fundamental wavelength) was covered with a layer of clear epoxy and sealed with a microscope coverslip. The purpose of the epoxy and coverslip was to introduce distortions for the demonstration of aberration correction with the OCT-image-guided WSAO. The fibers in the lens paper provided a structural back-scattering image for the OCT, with the intention of improving the TPEF signal from the dye, which represents the signal of interest in the phantom. Using the OCT data for optimization, TPEF images from the same location are presented before and after aberration correction in FIGS. 6A-6F. In particular, FIGS. 6A and 6D represent OCT en face images. FIGS. 6B and 6E are MPM images (e.g., two-photon excited fluorescence images) without adaptive optics (AO) optimization. FIG. 6B is acquired without AO optimization and FIG. 6C is acquired with optimized coefficients using OCT images corresponding to FIG. 6A. Similarly, FIG. 6E is a MPM image acquired without adaptive optics (AO) optimization and FIG. 6F is a MPM image acquired with AO optimization corresponding to FIG. 6D. The OCT en face image represents the structural appearance of the sample, but is not necessarily of particularly high aesthetic quality due to the large speckle. The purpose of the OCT was to provide depth-resolved aberration correction and cross-sectional aiming of the focal plane in order to improve the MPM; therefore having exquisite structural images was not important for this demonstration. The MPM image (i.e., a two-photon excited fluorescence or TPEF image) acquired after optimization is brighter and contains more detail in comparison to the images acquired before aberration correction. The TPEF images presented are an average of 10-20 frames. An embodiment of the invention is to use a “woofer-tweeter” configuration if a single wavefront correcting element with large stroke and spatial frequency is not available. In one embodiment, the MAL was used for fine tuning of the focus as well as higher order aberration correction. Although the MAL is capable of correcting aberrations up to 4th order Zernike polynomials or modes, we may restrict the aberration correction to those with highest impacts for a 5 mm beam at the pupil, for applications such as human retinal imaging. The modes used were defocus, two astigmatisms, two coma, sphere, and two trefoils, corresponding to Zernike modes 4, 3, 5, 7, 8, 12, 6, 9, respectively. The generalized WSAO optimization algorithm includes, for each Zernike mode, stepping the MAL through a range of coefficient values. At each step, an OCT volume was acquired, and an en face image corresponding to the layer of interest was extracted. The systems and methods proposed here are not limited to the aberrations described above and are applicable to other wavefront-modifying or correcting elements and other orders of Zernike polynomials (or other orders of wavefront aberration modes). In order to compensate for axial motion during the acquisition, real time automated retinal tracking algorithm or method or software was used to extract the correct retinal layer throughout the optimization process. The image quality metric was calculated based on the intensity of the en face OCT image, although other parameters, including OCT image sharpness could also be used. Using a hill climbing algorithm, the coefficient that resulted in the brightest image was applied to the MAL, and the next Zernike mode was searched. A person of ordinary skill would know where to look for the details of the hill climbing algorithm (e.g., https://en.wikipedia.org/wiki/Hill_climbing). One could also use other optimization algorithms to find optimal coefficients. In this embodiment, we used 10 steps per mode, however this could be reduced to speed up the optimization time. During optimization, the OCT volume size comprised of 150×80 A-scans, which corresponded to an en face image acquisition and processing rate of 12.5 frames per second. In some scans, en face image was generated by extracting and mapping the intensities from the user-selected depth region within the OCT volume. The brightness of this 2-D en face image was calculated by summing the intensity of each pixel and used as the merit function for the WSAO optimization. FIGS. 7A-7C are sample images of the retina of the eye acquired in accordance with an embodiment of the presently disclosed technology. The impact of the adaptive optics is demonstrated on en face images with the field of view reduced. Images of human retina were acquired at a retinal eccentricity of about 3°. These images we acquired by first aligning the subject's fovea approximately with the central field of view of the OCT system (in widefield mode), and then instructing the subject to focus on an off axis fixation target. Aberration correction was performed on a small field of view, which was then increased for visualization. The change in appearance of the photoreceptor layer can be observed before and after optimization as brighter and better defined circular photoreceptor structures. FIG. 7A shows an en face image on a small field of view acquired after aberration correction through metric function optimization, and FIG. 7B shows an en face image before optimization. Therefore, spots 95a in FIG. 7A appear brighter and better defined than similarly situated spots 95b in FIG. 7B. The same region is presented in FIG. 7C after optimization with a larger field of view. FIG. 7D is a graph of the image intensity versus steps in accordance with an embodiment of the presently disclosed technology. The horizontal axis shows the number of steps undertaken at, for example, step 550B of FIG. 5. The vertical axis shows the results of the merit function. In particular, the image intensity is used, but other merit functions, for example the image contrast, may also be used. The particular aberration modes presented here are defocus (DEF), astigmatism (Ast1 and Ast2), and coma (Com1 and Com2). Black dots for each aberration mode represents a local image intensity maximum for that mode, generally indicating the best achievable aberration correction for a particular mode. The values of the merit function are presented for each mode during the hill climbing optimization, but other optimization schemes are also possible. The ‘hill climbing’ effect of the algorithm is clearly observed, where the coefficients corresponding to the maximal merit function were selected. FIGS. 8A-8D are sample images of the retina of the eye acquired in accordance with an embodiment of the presently disclosed technology. A series of photoreceptor images acquired from the same subject at different retinal eccentricities along the horizontal axis from the optic nerve head toward the fovea. At each retinal location, the system was re-optimized in order to acquire the best images possible. The cone photoreceptors at large eccentricity are larger than the closely packed cones near the fovea. The limits of the resolution are visible at the lower eccentricities, where the appearance of the tightly packed cones approaches the resolution of the system. Generally, the sample results demonstrate that the wavefront-sensorless adaptive optics (WSAO) inventive technology for high resolution imaging can be very flexible for different retinal features. In addition to aberration correction on the outer retina (photoreceptor mosaic), the technology can also correct aberrations on structures of the optic nerve head. Since the image information is used for aberration correction, the anatomical features on which the image-based optimization is performed is generally known, although the method can be applied on the anatomical features that are not known a-priori. Many embodiments of the technology described below may take the form of computer- or controller-executable instructions, including routines executed by a programmable computer or controller. Those skilled in the art will appreciate that the technology can be practiced on computer/controller systems other than those shown and described below. The technology can be embodied in a special-purpose computer, controller or data processor that is specifically programmed, configured or constructed to perform one or more of the computer-executable instructions described below. Accordingly, the terms “computer” and “controller” as generally used herein refer to any data processor and can include Internet appliances and hand-held devices (including palm-top computers, wearable computers, cellular or mobile phones, multi-processor systems, processor-based or programmable consumer electronics, network computers, mini computers and the like). Information handled by these computers can be presented by any suitable display medium, including a CRT display or LCD. The technology can also be practiced in distributed environments, where tasks or modules are performed by remote processing devices that are linked through a communications network. In a distributed computing environment, program modules or subroutines may be located in local and remote memory storage devices. Aspects of the technology described below may be stored or distributed on computer-readable media, including magnetic or optically readable or removable computer disks, as well as distributed electronically over networks. Data structures and transmissions of data particular to aspects of the technology are also encompassed within the scope of the embodiments of the technology. From the foregoing, it will be appreciated that specific embodiments of the technology have been described herein for purposes of illustration, but that various modifications may be made without deviating from the disclosure. Moreover, while various advantages and features associated with certain embodiments have been described above in the context of those embodiments, other embodiments may also exhibit such advantages and/or features, and not all embodiments need necessarily exhibit such advantages and/or features to fall within the scope of the technology. Accordingly, the disclosure can encompass other embodiments not expressly shown or described herein. | <SOH> BACKGROUND <EOH>Multi-photon microscopy (MPM) is an imaging technology that is used to obtain 3-D images from biological specimens with molecule specific contrast. The use of MPM for in vivo microscopy has multiple potential benefits over single photon microscopy, including applications such as non-invasive diagnostic imaging of the retina (the light sensitive tissue at the back of the eye). Compared to conventional microscopy with single photon excitation fluorescence, MPM uses light at longer wavelengths, in the near infrared (NIR), where tissue scattering and absorption is lower. The use of NIR light is particularly attractive for imaging the retina, which contains phototransduction pigments sensitive to the visible wavelengths. Unlike single photon processes, MPM techniques, such as two-photon excited fluorescence (TPEF), only occur at a narrow axial range around the focal point where the irradiance is the highest, providing an optical sectioning effect. However, a disadvantage of MPM imaging in ocular tissues is the high pulse energy required to elicit the non-linear effects. Minimizing the incident exposure energy is therefore important for non-invasive imaging, in particular for the delicate tissues of the retina. Although MPM is relatively unaffected by low levels of out-of-focus scattering, wavefront aberrations from the sample and optical path cause blurring of the focal spot. Since the MPM signal is quadratically proportional to the focused spot size, significant improvements in the signal-to-noise ratio can be achieved through wavefront shaping to approach the diffraction-limited focus with a large numerical aperture. Some conventional technologies apply adaptive optics (AO) to MPM to correct for refractive errors and promote diffraction-limited focusing in tissue. These conventional AO systems use a Hartmann-Shack Wavefront Sensor (HS-WFS) to detect the wavefront aberrations and, in a closed feedback loop control, guide the shape of an adaptive element, such as a deformable mirror, to correct the detected wavefront aberrations. Since the HS-WFS is sensitive to back-reflections, the conventional AO systems use curved mirrors instead of lenses, and long focal lengths to minimize the off-axis aberrations. Furthermore, the use of a wavefront sensor places significant design constraints on the system, requiring optical conjugation of the deformable element, WFS, and the pupil plane of the system. Additionally, the HS-WFS is generally only useful when there is a single scattering plane in the sample, because thick tissue samples or multi-layered samples negatively affect the ability to measure the wavefront. Furthermore, conventional MPM techniques may require relatively long time, e.g., 6-7 minutes for image acquisition using high power laser excitation energy. Therefore, these conventional technologies subject the patient's eye to a relatively long period of high stress. Accordingly, there remains a need for the eye imaging methods, systems and apparatuses that are relatively fast and do not cause high light-induced stress on the retina. | A61B3102 | 20180309 | 20180830 | A61B310 | 0 | TRA, TUYEN Q | COHERENCE-GATED WAVEFRONT-SENSORLESS ADAPTIVE-OPTICS MULTI-PHOTON MICROSCOPY, AND ASSOCIATED SYSTEMS AND METHODS | SMALL | 0 | ACCEPTED | A61B | 2,018 |
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15,759,193 | PENDING | Rotary Steerable Drilling Tool and Method | A directional drilling system includes a rotary steerable tool. The rotary steerable tool includes an extendable member configured to extend outwardly from the rotary steerable tool upon actuation, and a geolocation electronics device configured to track a position of the rotary steerable tool and the extendable member and control actuation of the extendable member. The geolocation electronics device and extendable member are configured to rotate with the rotary steerable tool. | 1. A directional drilling system for drilling a directional well, comprising: a rotary steerable tool having a tool body comprising a flowbore; an extendable member configured to extend outwardly from the tool body upon actuation and which rotates with the rotary steerable tool while drilling the well; an electronic device having sensors configured to measure a position or location of the rotary steerable tool and which rotates with the rotary steerable tool while drilling the well; and a processor configured to receive an input from the sensors and to control actuation of the extendable member to deviate the rotary steering tool while drilling the well. 2. The system of claim 1, wherein: the rotary steerable tool comprises an electrically actuated valve configured to control communication of hydraulic pressure to the extendable member from a hydraulic source; and communication of the hydraulic pressure causes the extendable member to extend outwardly from the rotary steerable tool. 3. The system of claim 2, wherein the hydraulic source is drilling fluid flowing through the flowbore. 4. The system of claim 2, wherein the hydraulic source is a hydraulic pump. 5. The system of claim 1, wherein the electronics device is configured to determine a position of the rotary steering tool and control actuation of the extendable member according to the position of the rotary steering tool and a target drilling direction. 6. The system of claim 1, further comprising a plurality of extendable members and wherein the electronics device is configured to control actuation of the each extendable member. 7. The system of claim 1, wherein the extendable member is retractable. 8. The system of claim 1, wherein the position of the rotary steerable tool comprises a rotational position, azimuth or toolface angle, an inclination angle, or any combination thereof. 9. A method of directionally drilling a borehole, comprising: rotating a tool within the borehole, wherein the tool comprises a geolocation electronics device and an extendable member, the geolocation electronics device and the extendable member rotating with the tool; tracking a position of the rotating tool via the geolocation electronics device; tracking a position of the rotating extendable member via the geolocation electronics device; extending the extendable member outwardly into contact with a wall of the borehole upon the extendable member coming into a designated position with respect to the borehole; and applying a force against the wall of the borehole to adjust the direction of the drilling of the borehole. 10. The method of claim 9, retracting the extendable member upon the extendable member rotating out of the designated position. 11. The method of claim 9, wherein the geo-locating electronics device comprises one or more directional sensors configured to rotate with the rotary steerable tool. 12. The method of claim 9, wherein extending the extendable member comprises actuating a valve, thereby putting the extendable member in fluid communication with a source of hydraulic pressure 13. The method of claim 12, wherein the source of hydraulic pressure is drilling fluid flowing through a flowbore in the rotary steerable tool or a hydraulic pump within the tool. 14. The method of claim 9, further comprising extending one or more extendable members of the tool individually or as a group. 15. A directional drilling system, comprising: a rotary steerable tool, comprising: an extendable member configured to extend outwardly from the rotary steerable tool upon actuation; and an electronics device configured to measure a position or location of the rotary steerable tool and the extendable member and control actuation of the extendable member; and wherein the electronics device and extendable member are configured to rotate with the rotary steerable tool. 16. The system of claim 15, comprising a plurality of extendable members, wherein the electronics device is configured to control actuation of the each extendable member. 17. The system of claim 15, wherein the extendable member is hydraulically actuated. 18. The system of claim 17, wherein the electronics device comprises a plurality of directional sensors configured to rotate in with the rotary steerable tool while measuring the position of the rotary steerable tool, and wherein the electronics device controls actuation of the extendable member according to the position of the rotary steering tool and a target drilling direction. 19. The system of claim 17, wherein the rotary steerable tool further comprises an electrically actuated valve, wherein the valve puts the extendable member in fluid communication with a source of hydraulic pressure in an actuated state. 20. The system of claim 19, wherein the source of hydraulic pressure is drilling fluid flowing through a flowbore within the rotary steerable tool or a hydraulic pump within the rotary steerable tool. 21. The system of claim 15, wherein the rotary steerable tool further comprises one or more sensors configured to collect well data, logging while drilling data, measurement while drilling data, formation evaluation data, or any combination thereof. | BACKGROUND This section is intended to introduce the reader to various aspects of art that may be related to various aspects of the presently described embodiments. This discussion is believed to be helpful in providing the reader with background information to facilitate a better understanding of the various aspects of the described embodiments. Accordingly, it should be understood that these statements are to be read in this light and not as admissions of prior art. Directional drilling is commonly used to drill any type of well profile where active control of the well bore trajectory is required to achieve the intended well profile. For example, a directional drilling operation may be conducted when the target pay zone cannot be reached from a land site vertically above it. Directional drilling operations involve varying or controlling the direction of a downhole tool (e.g., a drill bit) in a wellbore to direct the tool towards the desired target destination. Examples of directional drilling systems include point-the-bit rotary steerable drilling systems and push-the-bit rotary steerable drilling systems. In both systems, the drilling direction is changed by repositioning the bit position or angle with respect to the well bore. Push-the-bit tools use pads on the outside of the tool which press against the well bore thereby causing the bit to press on the opposite side causing a direction change. Point-the-bit technologies cause the direction of the bit to change relative to the rest of the tool. Many directional drilling systems and techniques are based on rotary steerable systems, which allow the drill string to rotate while changing the direction of the borehole. However, these systems typically require a physical geostationary component near the drill bit which does not rotate with the drill bit in order to keep track of the position of the system. BRIEF DESCRIPTION OF THE DRAWINGS For a detailed description of the embodiments of the invention, reference will now be made to the accompanying drawings in which: FIG. 1 depicts a schematic view of a directional drilling operation, in accordance with one or more embodiments; FIG. 2A depicts a cross-sectional schematic view of a rotary steerable system with a geolocation device, in accordance with one or more embodiments; FIG. 2B depicts an example hydraulic configuration of the rotary steerable system, in accordance with one or more embodiments; FIG. 2C depicts another example hydraulic configuration of the rotary steerable system, in accordance with one or more embodiments; FIG. 3A depicts a radial cross-sectional schematic view of the rotary steerable system with a geolocation device, in accordance with one or more embodiments; FIG. 3B depicts a radial cross-sectional schematic view of another example embodiment of the rotary steerable system with a geolocation device, in accordance with one or more embodiments; FIG. 4A depicts an example hydraulic circuit of the rotary steerable tool, in accordance with one or more embodiments; FIG. 4B depicts another example hydraulic circuit of the rotary steerable tool, in accordance with one or more embodiments; FIG. 5A depicts an example of an internal hydraulic system of the rotary steerable tool, in accordance with one or more embodiments; FIG. 5B depicts another example of an internal hydraulic system of the rotary steerable tool, in accordance with one or more embodiments; and FIG. 6 depicts a block diagram of a rotary steerable system with geolocation device, in accordance with one or more embodiments. DETAILED DESCRIPTION The present disclosure provides methods and systems for directional drilling. Specifically, the present disclosure provides a directional drilling system, such as a rotary steerable system (RSS), with a geolocation device. The geolocation device rotates with the drill shaft while the system tracks tool position and controls actuation of one or more extendable members to direct the drill bit. Thus, the entire system can rotate and stationary parts can be eliminated, resulting in a more reliable and simplistic tool. Specifically, there is no relative rotation between the parts of the system. Thus, bearings can be eliminated and load transfer across components is simplified. Turning now to the figures, FIG. 1 depicts a schematic view of a drilling operation utilizing a directional drilling system 100, in accordance with one or more embodiments. The system of the present disclosure will be specifically described below such that the system is used to direct a drill bit in drilling a wellbore, such as a subsea well or a land well. Further, it will be understood that the present disclosure is not limited to only drilling an oil well. The present disclosure also encompasses natural gas wellbores, other hydrocarbon wellbores, or wellbores in general. Further, the present disclosure may be used for the exploration and formation of geothermal wellbores intended to provide a source of heat energy instead of hydrocarbons. Accordingly, FIG. 1 shows a tool string 126 disposed in a directional borehole 116. The tool string 126 including a rotary steerable tool 128 in accordance with various embodiments. The rotary steerable tool 128 provides full 3D directional control of the drill bit 114. A drilling platform 102 supports a derrick 104 having a traveling block 106 for raising and lowering a drill string 108. A kelly 110 supports the drill string 108 as the drill string 108 is lowered through a rotary table 112. In one or more embodiments, a topdrive is used to rotate the drill string 108 in place of the kelly 110 and the rotary table 112. A drill bit 114 is positioned at the downhole end of the tool string 126, and, in one or more embodiments, may be driven by a downhole motor 129 positioned on the tool string 126 and/or by rotation of the entire drill string 108 from the surface. As the bit 114 rotates, the bit 114 creates the borehole 116 that passes through various formations 118. A pump 120 circulates drilling fluid through a feed pipe 122 and downhole through the interior of drill string 108, through orifices in drill bit 114, back to the surface via the annulus 136 around drill string 108, and into a retention pit 124. The drilling fluid transports cuttings from the borehole 116 into the pit 124 and aids in maintaining the integrity of the borehole 116. The drilling fluid may also drive the downhole motor 129. The tool string 126 may include one or more logging while drilling (LWD) or measurement-while-drilling (MWD) tools 132 that collect measurements relating to various borehole and formation properties as well as the position of the bit 114 and various other drilling conditions as the bit 114 extends the borehole 108 through the formations 118. The LWD/MWD tool 132 may include a device for measuring formation resistivity, a gamma ray device for measuring formation gamma ray intensity, devices for measuring the inclination and azimuth of the tool string 126, pressure sensors for measuring drilling fluid pressure, temperature sensors for measuring borehole temperature, etc. The tool string 126 may also include a telemetry module 134. The telemetry module 134 receives data provided by the various sensors of the tool string 126 (e.g., sensors of the LWD/MWD tool 132), and transmits the data to a surface unit 138. Data may also be provided by the surface unit 138, received by the telemetry module 134, and transmitted to the tools (e.g., LWD/MWD tool 132, rotary steering tool 128, etc.) of the tool string 126. In one or more embodiments, mud pulse telemetry, wired drill pipe, acoustic telemetry, or other telemetry technologies known in the art may be used to provide communication between the surface control unit 138 and the telemetry module 134. In one or more embodiments, the surface unit 138 may communicate directly with the LWD/MWD tool 132 and/or the rotary steering tool 128. The surface unit 138 may be a computer stationed at the well site, a portable electronic device, a remote computer, or distributed between multiple locations and devices. The unit 138 may also be a control unit that controls functions of the equipment of the tool string 126. The rotary steerable tool 128 is configured to change the direction of the tool string 126 and/or the drill bit 114, such as based on information indicative of tool 128 orientation and a desired drilling direction. In one or more embodiments, the rotary steerable tool 128 is coupled to the drill bit 114 and drives rotation of the drill bit 114. Specifically, the rotary steerable tool 128 rotates in tandem with the drill bit 114. In one or more embodiments, the rotary steerable tool 128 is a point-the-bit system or a push-the-bit system. FIG. 2A depicts a cross-sectional schematic view of the rotary steerable tool 128 in the borehole 116, in accordance with one or more embodiments. The rotary steerable tool 128 includes a tool body 203 and a flowbore 201 through which drilling fluid flows. The rotary steerable tool 128 further includes one or more pads 202 located near the outer surface 204 of the rotary steerable tool 128. The pads 202 are configured to extend outwardly from the rotary steerable tool 128 upon actuation to direct the drill bit 114 towards a desired direction. Thus, the pads 202 are actuated into the extended position only when they are in a certain rotational position. Specifically, for a push-the-bit system, the resultant force of all the actuated pads applied on the wall of the borehole 116 should be in the opposite direction as the desired driving direction of the drill bit 114. Specifically, for a point-the-bit system, a fulcrum stabilizer can be positioned between the rotary steerable tool and the bit. In the case of the point system, the resultant force of all the actuated pads applied on the wall of the borehole 116 should be in the same direction as the desired driving direction of the bit 114. As the pads 202 are only put into the extended position when in the appropriate position during rotation of the rotary steerable tool 128, the pads 202 are pulled back to the tool once they are no longer in the appropriate position. The pads 202 can each be controlled independently or in groups. In one or more embodiments, hydraulic pressure is directed to the desired pad 202 or an associated piston 212 to actuate the extension of the pad 202. However, any suitable means of actuation, including for example mechanical or electrical actuation, may be used. As an example of hydraulic actuation, in one or more embodiments, extension of the pads 202 is enabled by generating a pressure differential between the flowbore 201 of the tool string 126 and the annulus 136 surrounding the tool string 126 and inside the borehole 116. Specifically, the pads 202, or intermediate actuation devices such as pistons 212, are each coupled to the flowbore 201 via a supply path 214 and actuation path 208 formed in the tool body 203. The actuation path 208 is also coupled to a bleed path 210 formed in the tool body which hydraulically couples to the annulus 136. The supply path 214 is coupled to the actuation path 208 via an electrically actuated valve 206, such as a solenoid valve. The valve 206 can be controlled to hydraulically couple and decouple the actuation path 208 from the supply path 214. Valve and flow path configurations include but are not limited to the following configurations as depicted in FIGS. 2B and 2C. As depicted in FIG. 2B, when the valve 206 is actuated, the actuation path 208 and the supply path 214 are coupled to the flowbore 201. Due to the pumping of drilling fluid into the flowbore 201 and the pressure drop at the bit, the flowbore 201 is at a high pressure relative to the annulus 136. As a result drilling fluid flows into the actuation path 208 from the flowbore 201. The increase in pressure in the actuation path 208 actuates extension of the piston 212 and pad 202. During activation, the activation path 208 is closed to the bleed path 210 and thus full differential pressure, between the flowbore 201 and annulus 136, is applied to the piston 212. During deactivation of the valve 206, the activation path 208 is open to the bleed path 210 and piston 212 is allowed to push the fluid to the annulus 136 via the bleed path 210. As depicted in FIG. 2C, when the valve 206 is actuated, the actuation path 208, supply path 214, and bleed path 210 are coupled to the flowbore 201 and to each other. Due to the pumping of drilling fluid into the flowbore 201 and the pressure drop at the bit, the flowbore 201 is at a high pressure relative to the annulus 136. As a result, drilling fluid flows into the actuation path 208 and bleed path 210 from the flowbore 201. The increase in pressure in the actuation path 208 actuates extension of the piston 212 and pad 202. It should be noted that some volume of fluid is flowing to the annulus via the bleed path 210, and that sufficient restriction 215 is necessary to maintain sufficient pressure differential between the flowbore 201 and annulus 136 in order to extend the piston 212 and pad 202. During deactivation of the valve 206, the activation path 208 is open to the bleed path 210 and piston 212 is allowed to push the fluid to the annulus 136 via the bleed path 210. In one or more embodiments, the piston 212 is coupled to the actuation path and the increase in pressure actuates a piston 212. The piston 212 may extend outward upon actuation and push the pad 202 outward. In one or more embodiments, the pad 202 is absent and the piston 212 pushes against the borehole 116. Each pad 202 can be opened independently through actuation of the respective valve 206. Any subset or all of the pads 202 can be opened at the same time. The valves 206 are controlled by a central geolocation device 213 discussed in more detail below. In one or more embodiments, the amount of force by which piston 212 or pad 202 pushes against the borehole 116 or the amount of extension may be controlled by controlling the flow of drilling fluid into the actuation path 208, which can be controlled via the valve 206 or various other valves or orifices places along the actuations path 208 or the bleed path 210. This helps enable control over the degree of direction change of the drill bit 114. In addition to the aforementioned geostationary device, the rotary steerable tool 128 may contain one or more sensors 216 for making any measurement including measurement while drilling data, logging while drilling data, formation evaluation data, and other well data. FIG. 3A depicts a radial cross-sectional schematic view of the rotary steerable tool 128, showing the pads 202. As shown, the pads 202 are close to the tool body 203 in a closed position and configured to extend outward into an open or actuated position. In the illustrated example, the pads 202 are coupled to the tool body 203 and pivot between the closed and open positions via hinges 304. As mentioned above, the pads 202 can be pushed outward and into the open position by the pistons 212. In the illustrated embodiment, the tool body 203 includes recesses 306 which house the pads 202 when in the closed position, thereby allowing the pads 202 to be flush with the tool body 203. As shown, the rotary steerable tool 128 includes three pads spaced 120 degrees apart around the circumference of the tool 128. However, the rotary steerable tool 128 can have more or less than the three pads 202 shown. The rotary steerable tool 128 can even have as few as one pad 202. The pad 202 and piston 212 mechanism is just one configuration of an extendable mechanism designed to push against the wall of the borehole 116 to urge the drill bit 114 in a direction. The rotary steerable tool 128 may include various other types of extendable members or mechanisms, including but not limited to pistons configured to push against the borehole 116 directly or pads 202 configured to be acted on by drilling fluid direction without an intermediate piston. The pads 202, or alternative extendable members or mechanism, may also include a retraction mechanism that moves the pads 202 back into the closed position, such as when the pads 202 are out of the appropriate position. For example, the pads 202 may include a spring that pulls the pads 202 back into the closed position. In some other embodiments, the pads 202 may be configured to fall back into the closed position when pressure applied by the drill fluid at the pads drops. In some embodiments, the pads 202 are coupled to the piston 212 and thus travel with the piston 212. In one or more embodiments, the pads 202 may also function as centralizers, in which all the pads 202 remain in the extended position, keeping the rotary steerable tool 128 centralized in the borehole 116. In such embodiments, the retraction mechanism can be disabled or not included. One of the key benefits of being able to keep the pads retracted is reduced wear on the pads 202 and pistons 212. FIG. 3B depicts a radial cross-sectional schematic view of another example rotary steerable tool 300, with a different pad and piston configuration. Specifically, the tool 300 includes a plurality of pads 302 located around the tool 300 and a plurality of pistons 312 configured to push the pads 302 outwardly. In some embodiments, and as illustrated, each pad 302 is pushed by two pistons 312. The pistons 312 may also be coupled to the respective pads 302. Each piston 312 is coupled to a hydraulic line 316 which provides a source of hydraulic pressure. Additionally, in some embodiments, each piston 312 includes a wear sleeve 314 for protecting the parts from wear caused by movement of the piston 312. FIG. 4A depicts a hydraulic circuit 400 of the rotary steerable tool 128 using hydraulic actuation to move the pads 202, in accordance with one or more embodiments. FIG. 4A is the embodiment of multiple 3 way-2 position valves that utilize differential mud pressure between the bore 201 and annulus 136. The hydraulic circuit 400 utilizes a pressure differential between the drilling fluid pumped into the rotary steerable tool 128 and the annulus 136 around the rotary steerable tool 128. The hydraulic circuit 400 includes a high pressure line 402, which represents the inside of the tool into which fluid is pumped, and a low pressure line 404, which represents the annulus 136. The high pressure line 402 is coupled to the drill bit 114, which provides flow restriction and the resulting differential pressure. Additionally, a flow restrictor 414 can be added to increase pressure differential in the case that the bit, alone, does not provide a sufficient pressure differential. The high pressure line 402 is also coupled to one or more electrically actuated valves 408. Each electric valve 408 is also coupled to a hydraulic piston line 406, and the low pressure line 404. Generally, there are as many hydraulic piston lines 406 as there are pistons 410 or pads 202 on the rotary steerable tool 128. The electrically actuated valves 408 separate the high pressure line 402 from the hydraulic piston lines 406, thereby separating the high pressure line 402 from the pistons 410. The electrically actuated valves 408 also separate the hydraulic pad lines 406 from the low pressure line 404, thereby separating the pistons 410 from the low pressure line 404. The electrically actuated valves 408 can be individually controlled to couple or decouple the high pressure line 402 and each of the hydraulic pad lines 406. Specifically, in one or more embodiments, when an electrically actuated valve 408 is actuated, the high pressure line is in fluid communication with the respective hydraulic piston line 406 and the respective piston 410. The pressure differential between the low pressure line 404 and the high pressure line 402 pushes drilling fluid through the respective hydraulic piston line 406, thereby actuating the piston 410. Actuation of the piston 410 causes pad extension or another protrusion to extend outwardly from the rotary steerable tool 128, applying a force on the wellbore, thereby changing the drilling direction. When an electrically actuated valve 408 is deactivated, the respective piston 410 is isolated from the high pressure line 402, and the piston 410 is in fluid communication with the low pressure line 404, allowing the piston 410 to retract and drain fluid through the low pressure line 404 to the annulus 136. FIG. 4B depicts a hydraulic circuit 400 of the rotary steerable tool 128 using hydraulic actuation to move the pads 202, in accordance with one or more embodiments. FIG. 4B is the embodiment of multiple 2 way-2 position valves that utilize differential mud pressure between the bore 201 and annulus 136. The hydraulic circuit 400 utilizes a pressure differential between the drilling fluid pumped into the rotary steerable tool 128 and the annulus 136 around the tool 128. The hydraulic circuit 400 includes a high pressure line 402, which represents the inside of the tool into which fluid is pumped, and a low pressure line 404, which represents the annulus 136. The high pressure line 402 is coupled to the drill bit 114, which provides flow restriction and the resulting differential pressure. Additionally, if necessary, a flow restrictor 414 can be added to increase pressure differential in the case where the bit, alone, does not provide a sufficient pressure differential. The high pressure line 402 is also coupled to one or more electrically actuated valves 408. Each electric valve 408 is also coupled to a hydraulic piston line 406 and the low pressure line 404. Generally, there are as many hydraulic piston lines 406 as there are pistons 410 or pads 202 on the rotary steerable tool 128. The electrically actuated valves 408 separate the high pressure line 402 from the hydraulic pad lines 406, thereby separating the high pressure line 402 from the pistons 410 and the low pressure line 404. The electrically actuated valves 408 can be individually controlled to couple or decouple the high pressure line 402 and each of the hydraulic piston lines 406. Specifically, in one or more embodiments, when an electrically actuated valve 408 is actuated, the high pressure line is in fluid communication with the respective hydraulic piston line 406, its respective piston 410, and the low pressure line 404. The pressure differential between the low pressure line 404 and the high pressure line 402 pushes drilling fluid through the respective hydraulic piston line 406, thereby actuating the piston 410. Actuation of the piston 410 causes pad extension or another protrusion to extend outwardly from the rotary steerable tool 128, applying a force on the wellbore, thereby changing the drilling direction. It should be noted that some volume of fluid is flowing to the annulus via the low pressure line 404 and that sufficient restriction 415 is necessary to maintain sufficient pressure differential, between the flowbore 201 and annulus 136 in order to extend the piston 410 and pad 202. When an electrically actuated valve 408 is deactivated, the respective piston 410 is isolated from the high pressure line 402, and the piston 410 is in fluid communication with the low pressure line 404, allowing the piston 410 to retract and drain fluid through the low pressure line 404 to the annulus 136. FIG. 5A depicts an embodiment of an internal hydraulic system 500 that can be used with the rotary steerable tool 128 using hydraulic actuation to move the pads 202, in accordance with one or more embodiments. In one or more embodiments, the hydraulic system 500 is contained within the rotary steerable tool 128 (i.e., not open to the annulus) and may utilize a general hydraulic fluid. The hydraulic system 500 includes a high pressure line 502 and a low pressure line 504. FIG. 5A is the embodiment of multiple 3 way-2 position valves that utilize differential hydraulic pressure between the high pressure line 502 and low pressure line 504. The high pressure line 502 is coupled to one or more electrically actuated valves 518. Each electric valve 518 is also coupled to a hydraulic piston line 506, and the low pressure line 504. Generally, there are as many hydraulic piston lines 506 as there are pistons 516 or pads 202 on the rotary steerable tool 128. The electrically actuated valves 518 separate the high pressure line 502 from the hydraulic piston lines 506, thereby separating the high pressure line 502 from the pistons 516. The electrically actuated valves 518 also separate the hydraulic piston lines 506 from the low pressure line 504, thereby separating the pistons 516 from the low pressure line 504. The electrically actuated valves 518 can be individually controlled to couple or decouple the high pressure line 502 and each of the hydraulic piston lines 506. Specifically, in one or more embodiments, when an electrically actuated valve 518 is actuated, the high pressure line is in fluid communication with the respective hydraulic piston line 506 and the respective piston 516. The pressure differential between the low pressure line 504 and the high pressure line 502 pushes hydraulic fluid through the respective hydraulic piston line 506, thereby actuating the piston 516. Actuation of the piston 516 causes pad extension or another protrusion to extend outwardly from the rotary steerable tool 128, applying a force on the wellbore, thereby changing the drilling direction. When an electrically actuated valve 518 is deactivated, the respective piston 516 is isolated from the high pressure line 502, and the piston 516 is in fluid communication with the low pressure line 504, allowing the piston 516 to retract and drain fluid through the low pressure line 504 to the return line 514. FIG. 5B depicts an embodiment of an internal hydraulic system 500 that can be used with the rotary steerable tool 128 using hydraulic actuation to move the pads 202, in accordance with one or more embodiments. In one or more embodiments, the hydraulic system 500 is contained within the rotary steerable tool 128 (i.e., not open to the annulus) and may utilize a general hydraulic fluid. The hydraulic system 500 includes a high pressure line 502 and a low pressure line 504. FIG. 5B is the embodiment of multiple 2 way-2 position valves that utilize differential hydraulic pressure between the high pressure line 502 and low pressure line 504. The high pressure line 502 is also coupled to one or more electrically actuated valves 518. Each electric valve 518 is also coupled to a hydraulic piston line 506 and the low pressure line 504. Generally, there are as many hydraulic piston lines 506 as there are pistons 516 or pads 202 on the rotary steerable tool 128. The electrically actuated valves 518 separate the high pressure line 502 from the hydraulic pad lines 506, thereby separating the high pressure line 502 from the pistons 516 and the low pressure line 504. The electrically actuated valves 518 can be individually controlled to couple or decouple the high pressure line 502 and each of the hydraulic piston lines 506. Specifically, in one or more embodiments, when an electrically actuated valve 518 is actuated, the high pressure line is in fluid communication with the respective hydraulic piston line 506, its respective piston 516, and the low pressure line 504. The pressure differential between the low pressure line 504 and the high pressure line 502 pushes hydraulic fluid through the respective hydraulic piston line 506, thereby actuating the piston 516. Actuation of the piston 516 causes pad extension or another protrusion to extend outwardly from the rotary steerable tool 128, applying a force on the wellbore, thereby changing the drilling direction. It should be noted that some volume of fluid is flowing to the low pressure line 504 and that sufficient restriction 515 is necessary to maintain sufficient pressure differential, between the high pressure line 502 and low pressure line 504. When an electrically actuated valve 518 is deactivated, the respective piston 516 is isolated from the high pressure line 502, and the piston 516 is in fluid communication with the low pressure line 504, allowing the piston 516 to retract and drain fluid through the low pressure line 504 to the return line 514. The internal hydraulic system 500 further includes a pump 510 and a reservoir 520 for the hydraulic fluid. The pump 510 draws hydraulic fluid from the reservoir 520 and circulates the hydraulic fluid. In one or more embodiments, the internal hydraulic system 500 includes a return line 514 coupled to the low pressure line 504 through which hydraulic fluid is circulated back to the reservoir 520. High pressure line 502 may also be coupled to the return line such that the hydraulic fluid can continue to circulate when none of the electrically actuated valves 518 are actuated and the high pressure line 502 is not in communication with the low pressure line 504. In one or more embodiments, the high pressure line 502 and the return line 514 are separated by a flow restrictor 508 which restricts the flow between the high pressure line 502 and the return line, thereby maintaining a relatively higher pressure in the high pressure line 502. The high pressure line 502 may also include a check valve 512 configured to prevent back flow. FIG. 6 depicts a block diagram of the geolocation device 213, in accordance with one or more embodiments. The geolocation device 213 includes a processor 602 and a suite of sensors, including directional sensors such as accelerometers 604, magnetometers 606, and gyroscopes 608, and the like for determining an azimuth or toolface angle of the drill bit 114 to a reference direction (e.g., magnetic north). The geolocation device 213 may include any number of these sensors and in any combination. Based on the azimuth and a desired drilling direction or drilling path, the rotary steerable tool 128 determines a suitable control scheme to steer the tool string 126 and drill bit 114 in the desired direction, thereby creating a directional borehole. The geolocation device 213 utilizes the sensors to maintain a geostationary reference for steering control of the rotary steerable tool 128 while the geolocation device 213 is also in rotation with the rotary steerable tool 128, without the need for a physically geostationary component. The geolocation device 213 may also include various other sensors 610 such as temperature sensors, magnetic field sensors, and rpm sensors, among others. The sensors are coupled to the processor 602. The sensors may be embedded anywhere on the rotary steerable tool 128 and are programmed or controlled to take respective measurements and transmit the measurements to the processor 602 in real time. The processor 602 is configured to control the pads 202 through actuation of the valves 206 according to the measurements made by the sensors as well as a profile of the drilling operation, thereby controlling the drilling direction of the drill bit 114. The profile of the drilling operation may include information such as the location of the drilling target, type of formation, and other parameters regarding the specific drilling operation. As the tool 128 rotates, the sensors (e.g., accelerometers 604, magnetometers 606, and gyroscopes 608) continuously feed measurements to the processor 602 while rotating with the tool 128. The processor 602 uses the measurements to continuously track the position of the tool 128 with respect to the target drilling direction in real time. From this the processor 602 can determine which direction to direct the drill bit 114. Since the location of the pads 202 are fixed with respect to the tool 128, the location of the pads 202 can be easily derived from the location of the tool 128. The processor 602 can then determine when to actuate the pads 202 in order to direct the drill bit 114 in the desired direction. Each of the pads 202 on the tool 128 can be actuated independently, in any combination, and at any time interval, which allows for agile, fully three dimensional control of the direction of the drill bit 114. The directional control may be relative to gravity toolface, magnetic toolface, or gyro toolface. For example, if the drill bit 114 needs to be directed towards high side (0 degree toolface angle), then the pads 202 need to extend and apply force against the borehole at the 180 degree location of the tool 128. Thus, a pad 202 is actuated when it rotates into the 180 degree location and retracts when it rotates out of the 180 degree location. In one or more embodiments, actuation of a pad 202 includes sending a current through the valve 206 to which the pad 202 is coupled. The valve 206 then couples the pad 202 to a hydraulic pressure differential, which actuates the pad 202. In one or more embodiments, each pad 202 is actuated as it rotates into the 180 degree location. Frequency of pad 202 extensions may depend on the speed of rotation of the tool 128 and the desired rate of direction change. For example, if the tool 128 is rotating at a relatively high speed, a pad 202 may only be actuated every other rotation. Similarly, if the desired rate of direction change of the tool 128 is high, the pad 202 may be actuated at a higher frequency than if the desired rate of direction change were lower. Such parameters can be controlled by the processor according to the profile of the drilling operation. The processor 602 is in communication with a control center 612. The control center 612 may send instructions or information to the processor such as the information related to the profile of the drilling operation such as location of the drilling target, rate of direction change, and the like. In one or more embodiments, the control center 612 may receive spontaneous control commands from an operator which are relayed as processor-readable commands to the processor 602 of the geolocation device 213. In some other embodiments, the control center 612 sends preprogrammed commands to the processor 602 set according to the profile of the drilling operation. The geolocation device 213 receives power from a power source. Examples of power sources include batteries, mud generators, among others. The power supply actually used in a specific application can be chosen based on performance requirements and available resources. In addition to the embodiments described above, many examples of specific combinations are within the scope of the disclosure, some of which are detailed below: Example 1 A directional drilling system for drilling a directional well, comprising: a rotary steerable tool having a tool body comprising a flowbore; an extendable member configured to extend outwardly from the tool body upon actuation and which rotates with the rotary steerable tool while drilling the well; an electronic device having sensors configured to measure a position or location of the rotary steerable tool and which rotates with the rotary steerable tool while drilling the well; and a processor configured to receive an input from the sensors and to control actuation of the extendable member to deviate the rotary steering tool while drilling the well. Example 2 The system of example 1, wherein: the rotary steerable tool further comprises an electrically actuated valve configured to control communication of hydraulic pressure to the extendable member from a hydraulic source; and communication of the hydraulic pressure causes the extendable member to extend outwardly from the rotary steerable tool. Example 3 The system of example 2, wherein the hydraulic source is drilling fluid flowing through the flowbore. Example 4 The system of example 2, wherein the hydraulic source is a hydraulic pump. Example 5 The system of example 1, wherein the electronics device is configured to determine a position of the rotary steering tool and control actuation of the extendable member according to the position of the rotary steering tool and a target drilling direction. Example 6 The system of example 1, further comprising a plurality of extendable members and wherein the electronics device is configured to control actuation of the each extendable member. Example 7 The system of example 1, wherein the extendable member is retractable. Example 8 The system of example 1, wherein the position of the rotary steerable tool comprises a rotational position, azimuth or toolface angle, an inclination angle, or any combination thereof. Example 9 A method of directionally drilling a borehole, comprising: rotating a tool within the borehole, wherein the tool comprises a geolocation electronics device and an extendable member, the geolocation electronics device and the extendable member rotating with the tool; tracking a position of the rotating tool via the geolocation electronics device; tracking a position of the rotating extendable member via the geolocation electronics device; extending the extendable member outwardly into contact with a wall of the borehole upon the extendable member coming into a designated position with respect to the borehole; and applying a force against the wall of the borehole to adjust the direction of the drilling of the borehole. Example 10 The method of example 9, retracting the extendable member upon the extendable member rotating out of the designated position. Example 11 The method of example 9, wherein the geo-locating electronics device comprises one or more directional sensors configured to rotate with the rotary steerable tool. Example 12 The method of example 9, wherein extending the extendable member comprises actuating a valve, thereby putting the extendable member in fluid communication with a source of hydraulic pressure Example 13 The method of example 12, wherein the source of hydraulic pressure is drilling fluid flowing through a flowbore in the rotary steerable tool or a hydraulic pump within the tool. Example 14 The method of example 9, further comprising extending one or more extendable members of the tool individually or as a group. Example 15 A directional drilling system, comprising: a rotary steerable tool, comprising: an extendable member configured to extend outwardly from the rotary steerable tool upon actuation; and an electronics device configured to measure a position or location of the rotary steerable tool and the extendable member and control actuation of the extendable member; and wherein the electronics device and extendable member are configured to rotate with the rotary steerable tool. Example 16 The system of example 15, comprising a plurality of extendable members, wherein the electronics device is configured to control actuation of the each extendable member. Example 17 The system of example 15, wherein the extendable member is hydraulically actuated. Example 18 The system of example 17, wherein the electronics device comprises a plurality of directional sensors configured to rotate in with the rotary steerable tool while measuring the position of the rotary steerable tool, and wherein the electronics device controls actuation of the extendable member according to the position of the rotary steering tool and a target drilling direction. Example 19 The system of example 17, wherein the rotary steerable tool further comprises an electrically actuated valve, wherein the valve puts the extendable member in fluid communication with a source of hydraulic pressure in an actuated state. Example 20 The system of example 19, wherein the source of hydraulic pressure is drilling fluid flowing through a flowbore within the rotary steerable tool or a hydraulic pump within the rotary steerable tool. Example 21 The system of example 15, wherein the rotary steerable tool further comprises one or more sensors configured to collect well data, logging while drilling data, measurement while drilling data, formation evaluation data, or any combination thereof. This discussion is directed to various embodiments of the invention. The drawing figures are not necessarily to scale. Certain features of the embodiments may be shown exaggerated in scale or in somewhat schematic form and some details of conventional elements may not be shown in the interest of clarity and conciseness. Although one or more of these embodiments may be preferred, the embodiments disclosed should not be interpreted, or otherwise used, as limiting the scope of the disclosure, including the claims. It is to be fully recognized that the different teachings of the embodiments discussed may be employed separately or in any suitable combination to produce desired results. In addition, one skilled in the art will understand that the description has broad application, and the discussion of any embodiment is meant only to be exemplary of that embodiment, and not intended to intimate that the scope of the disclosure, including the claims, is limited to that embodiment. Certain terms are used throughout the description and claims to refer to particular features or components. As one skilled in the art will appreciate, different persons may refer to the same feature or component by different names. This document does not intend to distinguish between components or features that differ in name but not function, unless specifically stated. In the discussion and in the claims, the terms “including” and “comprising” are used in an open-ended fashion, and thus should be interpreted to mean “including, but not limited to . . . .” Also, the term “couple” or “couples” is intended to mean either an indirect or direct connection. In addition, the terms “axial” and “axially” generally mean along or parallel to a central axis (e.g., central axis of a body or a port), while the terms “radial” and “radially” generally mean perpendicular to the central axis. The use of “top,” “bottom,” “above,” “below,” and variations of these terms is made for convenience, but does not require any particular orientation of the components. Reference throughout this specification to “one embodiment,” “an embodiment,” or similar language means that a particular feature, structure, or characteristic described in connection with the embodiment may be included in at least one embodiment of the present disclosure. Thus, appearances of the phrases “in one embodiment,” “in an embodiment,” and similar language throughout this specification may, but do not necessarily, all refer to the same embodiment. Although the present invention has been described with respect to specific details, it is not intended that such details should be regarded as limitations on the scope of the invention, except to the extent that they are included in the accompanying claims. | <SOH> BACKGROUND <EOH>This section is intended to introduce the reader to various aspects of art that may be related to various aspects of the presently described embodiments. This discussion is believed to be helpful in providing the reader with background information to facilitate a better understanding of the various aspects of the described embodiments. Accordingly, it should be understood that these statements are to be read in this light and not as admissions of prior art. Directional drilling is commonly used to drill any type of well profile where active control of the well bore trajectory is required to achieve the intended well profile. For example, a directional drilling operation may be conducted when the target pay zone cannot be reached from a land site vertically above it. Directional drilling operations involve varying or controlling the direction of a downhole tool (e.g., a drill bit) in a wellbore to direct the tool towards the desired target destination. Examples of directional drilling systems include point-the-bit rotary steerable drilling systems and push-the-bit rotary steerable drilling systems. In both systems, the drilling direction is changed by repositioning the bit position or angle with respect to the well bore. Push-the-bit tools use pads on the outside of the tool which press against the well bore thereby causing the bit to press on the opposite side causing a direction change. Point-the-bit technologies cause the direction of the bit to change relative to the rest of the tool. Many directional drilling systems and techniques are based on rotary steerable systems, which allow the drill string to rotate while changing the direction of the borehole. However, these systems typically require a physical geostationary component near the drill bit which does not rotate with the drill bit in order to keep track of the position of the system. | <SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>For a detailed description of the embodiments of the invention, reference will now be made to the accompanying drawings in which: FIG. 1 depicts a schematic view of a directional drilling operation, in accordance with one or more embodiments; FIG. 2A depicts a cross-sectional schematic view of a rotary steerable system with a geolocation device, in accordance with one or more embodiments; FIG. 2B depicts an example hydraulic configuration of the rotary steerable system, in accordance with one or more embodiments; FIG. 2C depicts another example hydraulic configuration of the rotary steerable system, in accordance with one or more embodiments; FIG. 3A depicts a radial cross-sectional schematic view of the rotary steerable system with a geolocation device, in accordance with one or more embodiments; FIG. 3B depicts a radial cross-sectional schematic view of another example embodiment of the rotary steerable system with a geolocation device, in accordance with one or more embodiments; FIG. 4A depicts an example hydraulic circuit of the rotary steerable tool, in accordance with one or more embodiments; FIG. 4B depicts another example hydraulic circuit of the rotary steerable tool, in accordance with one or more embodiments; FIG. 5A depicts an example of an internal hydraulic system of the rotary steerable tool, in accordance with one or more embodiments; FIG. 5B depicts another example of an internal hydraulic system of the rotary steerable tool, in accordance with one or more embodiments; and FIG. 6 depicts a block diagram of a rotary steerable system with geolocation device, in accordance with one or more embodiments. detailed-description description="Detailed Description" end="lead"? | E21B44005 | 20180309 | 20180906 | E21B4400 | 0 | BEMKO, TARAS P | Rotary Steerable Drilling Tool and Method | UNDISCOUNTED | 0 | ACCEPTED | E21B | 2,018 |
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15,759,375 | PENDING | SELECTIVE PROPRIETARY PROTOCOL SUPPORT INDICATION REMOVAL | Various communication systems may benefit from appropriate indication of support for communication protocols. In particular, certain wireless systems that use handover may use selective proprietary protocol support indication removal. A method can include determining protocol support based on a first configuration received from the source access node. The method can also include determining whether to continue, after a handover, using a proprietary protocol based on whether a first configuration remains unchanged. The method can further include using or ceasing from using the proprietary protocol based on the determination. | 1. A method, comprising: configuring, by an access node, a user equipment with a first proprietary protocol support indication configuration; and when the access node receives an uplink proprietary protocol indication, removing the radio resource control configuration, wherein the removal is done without performing any radio resource control reconfiguration over the air. 2. The method of claim 1, further comprising: in response to the access node receiving the uplink proprietary protocol indication, replying, by the access node, with a downlink medium access control message in order to confirm to the user equipment that the proprietary protocol indication has been silently deleted. 3. A method, comprising: determining protocol support based on a first configuration received from a source access node; determining whether to continue, after a handover, using a proprietary protocol based on whether the first configuration remains unchanged; and using or ceasing from using the proprietary protocol based on the determination. 4. The method of claim 3, further comprising: ceasing from using the proprietary protocol when the first configuration remains unchanged by a handover command 5. The method of claim 4, further comprising: subsequently receiving a second configuration indicating the proprietary protocol support, and using the proprietary protocol again based on the received second configuration. 6. The method of claim 3, further comprising: using the proprietary protocol upon receiving a configuration after the handover indicating support of the proprietary protocol. 7. The method of claim 5, wherein the second configuration is the same as the first configuration. 8. The method of claims 3, further comprising: receiving a downlink proprietary medium access control message and deleting a radio resource control configuration. 9. The method of claim 5, wherein the second configuration is different from the first configuration. 10. The method of claim 9, wherein when the second configuration is different from the first configuration, the second configuration is considered valid if the Measeld is not activated. 11-16. (canceled) 17. An apparatus, comprising: at least one processor; and at least one memory including computer program code, wherein the at least one memory and the computer program code are configured to, with the at least one processor, cause the apparatus at least to configure, by an access node, a user equipment with a first proprietary protocol support indication configuration; and when the access node receives an uplink proprietary protocol indication, removing remove the radio resource control configuration, wherein the removal is done without performing any radio resource control reconfiguration over the air. 18. The apparatus of claim 17, further comprising: in response to the access node receiving the uplink proprietary protocol indication, replying, by the access node, with a downlink medium access control message in order to confirm to the user equipment that the proprietary protocol indication has been silently deleted. 19-36. (canceled) 37. A computer program product embodied on a non-transitory computer readable medium encoded with instructions that, when executed in hardware, perform the process according to claim 1. 38. A computer program product embodied on a non-transitory computer readable medium encoded with instructions that, when executed in hardware, perform the process according to claim 3. | CROSS-REFERENCE TO RELATED APPLICATION This application is related to and claims the benefit and priority of U.S. Provisional Patent Application No. 62/216,814, filed Sep. 10, 2015, the entirety of which is hereby incorporated herein by reference. BACKGROUND Field Various communication systems may benefit from appropriate indication of support for communication protocols. In particular, certain wireless systems that use handover may use selective proprietary protocol support indication removal. Description of the Related Art When supporting a proprietary wireless protocol between an evolved Node B (eNB) and a user equipment (UE), it may be possible to indicate this proprietary protocol support to the UE through one or more mechanisms where the UE is sent a special message, for example, over radio resource control (RRC) signaling. In one example, this mechanism may involve using a specific RRC configuration/indicated in L2 or L3 layer signaling, where the parameter settings are set in a particularly unique fashion that is not expected to be used by any normal eNB. The RRC configuration can refer to configuration for an RRC event. Other mechanisms for indicating the proprietary protocol support through a special configuration are possible. When a UE with such a proprietary configuration is handed off to a neighboring eNB, it may be unknown as to whether the neighboring eNB also supports this proprietary protocol. Upon handoff, the neighboring eNB may be notified through standardized existing signaling, of the existing UE configurations, such as an RRC configuration. SUMMARY According to a first embodiment, a method can include determining protocol support based on a first configuration received from the source access node. The method can also include determining whether to continue, after a handover, using a proprietary protocol based on whether a first configuration remains unchanged. The method can further include using or ceasing from using the proprietary protocol based on the determination. In variant, the method can include ceasing from using the proprietary protocol when the first configuration remains unchanged by a handoff command. In a variant, the method can include subsequently receiving a second configuration indicating the proprietary protocol support, and using the proprietary protocol again based on the received second configuration. In a variant, the method can include using the proprietary protocol upon receiving a configuration after the handoff indicating support of the proprietary protocol. In a variant, the second configuration can be the same as the first configuration. In a variant, the method can further comprise receiving a downlink proprietary medium access control message and deleting an RRC configuration. In a variant, the second configuration can be different from the first. In a variant, when the second configuration is different from the first configuration, the second configuration can be considered valid if the Measeld is not activated. According to a second embodiment, a method can include detecting that a first access node supports a proprietary protocol, that a user equipment is performing handoff the first access node, and the user equipment's existing RRC configuration contains a first proprietary protocol indication. The method can also include using a radio resource control reconfiguration to provide another proprietary protocol indication to the user equipment. In a variant, the providing another proprietary protocol indication can include replacing the first proprietary protocol indication. In a variant, the method can include refraining from activating another RRC configuration. In a variant, the second configuration can be the same as the first configuration. In a variant, the second configuration can be different from the first configuration. In a variant, the second configuration does not activate the Measld. According to a third embodiment, a method can include configuring, by an access node, a user equipment with a first proprietary protocol support indication configuration. The method can also include, when the access node receives an uplink proprietary protocol indication, removing the RRC configuration, wherein this removal is done without performing any radio resource control reconfiguration over the air. In a variant, in response to the access node receiving the uplink proprietary protocol indication, replying, by the access node, with a downlink medium access control message in order to confirm to the user equipment that the proprietary protocol indication has been silently deleted. According to fourth through sixth embodiments, an apparatus can include means for performing the method according to the first through third embodiments respectively, in any of their variants. According to seventh through ninth embodiments, an apparatus can include at least one processor and at least one memory and computer program code. The at least one memory and the computer program code can be configured to, with the at least one processor, cause the apparatus at least to perform the method according to the first through third embodiments respectively, in any of their variants. According to tenth through twelfth embodiments, a computer program product may encode instructions for performing a process including the method according to the first through third embodiments respectively, in any of their variants. According to thirteen through fifteenth embodiments, a non-transitory computer readable medium may encode instructions that, when executed in hardware, perform a process including the method according to the first through third embodiments respectively, in any of their variants. According to sixteenth and seventeenth embodiments, a system may include at least one apparatus according to the fourth or seventh embodiments in communication with at least one apparatus according to the fifth, sixth, eighth, or ninth embodiments, respectively in any of their variants. BRIEF DESCRIPTION OF THE DRAWINGS For proper understanding of the invention, reference should be made to the accompanying drawings, wherein: FIG. 1 illustrates a scenario in which a user equipment may incorrectly determine that a target access node supports an unsupported proprietary protocol. FIG. 2 illustrates an approach in which a user equipment ignores RRC received during handoff, according to certain embodiments. FIG. 3 illustrates an approach in which in which silent deletion is implemented, according to certain embodiments. FIG. 4 illustrates an approach in which silent deletion is implemented except when the target access node supports the proprietary protocol, according to certain embodiments. FIG. 5 illustrates toggling data loading control information signals after a handoff, according to certain embodiments. FIG. 6 illustrates toggling data loading control information signals in an opposite direction (to the direction in FIG. 5) after a handoff, in accordance with certain embodiments. FIG. 7 illustrates a method according to certain embodiments. FIG. 8 illustrates another method according to certain embodiments. FIG. 9 illustrates a further method according to certain embodiments. FIG. 10 illustrates a system according to certain embodiments. DETAILED DESCRIPTION Once the UE is in the new/neighboring eNB, the proprietary UE configuration may cause some specific issues. For example, in one potential scenario, the neighboring eNB may utilize the RRC configuration it received upon handoff, and then (re)configure the UE with that RRC configuration. This would confuse the UE as the UE would interpret that RRC configuration as indicating that the eNB is supporting the proprietary protocol. This can then be an issue as the UE could then potentially start transmitting proprietary signaling to a standard eNB, with unpredictable results when that standard eNB receives the proprietary/nonstandard signaling. FIG. 1 illustrates a scenario in which a user equipment may incorrectly determine that a target access node supports an unsupported proprietary protocol. As shown in FIG. 1, after handoff UE may believe a new eNB supports proprietary protocol, when in fact the new eNB does not. As shown in FIG. 1, a Data Loading Control UE can be configured with an RRC connection reconfiguration having an RRC Data Loading Control Information Signal (DLCIS). The UE may respond with an RRC connection reconfiguration complete. The UE may then store RRC DLCIS and the eNB may store RRC DLCIS in UE context. The UE can then use a proprietary medium access control (MAC) message. Data loading control information signals can broadly refer to the kinds of information signals, such as MAC, RRC, and other air interface signaling, described by way of example in U.S. Patent Application Publication No. 2013/0324075, titled, “Data Loading Control,” the entirety of which is hereby incorporated herein by reference. Any suitable information signal utilizing MAC/RRC may be employed as a data loading control information signal. Subsequently a handover (HO) can start to a Vendor X enB that does not support Data Loading Control. A handover request may be provided with information on RRC DLCIS and the target eNB may acknowledge this request. Meanwhile, the UE can receive a handover command with no changes to the RRC configuration and can signal that RRC connection reconfiguration is complete. When the target eNB sends its RRC connection reconfiguration message, the target eNB may adopt and use the source RRC DLCIS configuration. Thus, the UE may incorrectly conclude that the target eNB supports the proprietary protocol(s). Certain embodiments may address the above-described situation and avoid the issues described therein. For example, in certain embodiments, a user equipment may ignore the proprietary configuration (e.g. configuration indicated in L2 or L3 layer/RRC) received during handoff. Alternatively, an access node, such as an eNB, can silently delete the proprietary configuration (e.g. RRC configuration) from storage and not provide the proprietary configuration signal to a target node during a handover process. In a further alternative, the target node may switch to another or different proprietary configuration signal that also indicates use of the proprietary protocol. FIG. 2 illustrates an approach in which a user equipment ignores RRC received during handoff, according to certain embodiments. This approach may differ from the approach shown in FIG. 1, in that the UE may initially treat the RRC configuration as invalid at handover. Thus, the UE may wait until the target eNB sends a subsequent RRC DLCIS and then store the RRC DLCIS and treat the notification as valid. In summary, in this approach the UE may not consider an RRC received during handoff as a valid protocol indication RRC. The UE may only begin using the proprietary protocol if then later the UE receives a configuration for the proprietary protocol during a separate/subsequent RRC reconfiguration. For example, the UE and the eNB may not silently remove the RRC. Similarly, the eNB is not required to remove the RRC configuration from the UE. In certain embodiments, a Data Loading Control UE would require a second RRC reconfiguration (carrying a configuration) in the target cell, before the RRC configuration received is considered valid. Here, a Data Loading Control UE is used as an example of a UE running a proprietary protocol. There is no requirement that a user equipment be specifically Data Loading Control. When the Data Loading Control UE receives RRC configuration as a part of the handoff procedure, the UE may refrain from using the RRC configured by this message as evidence that the target eNB supports the Data Loading Control protocol. Instead, after handoff, the UE can require a second RRC reconfiguration in that target cell, before considering the RRC configuration received as valid evidence that the target eNB supports the Data Loading Control protocol. A UE that is not configured to identify Data Loading Control protocol support from the RRC configuration may not use this RRC handoff configuration. Thus, even if a neighboring cell provides that RRC configuration to the non-configured UE as a part of handoff, that will not cause any problems with the non-configured UE. As such, the eNB is also not required to use RRC reconfiguration to remove the proprietary configuration from the non-configured UEs. FIG. 3 illustrates an approach in which in which silent deletion is implemented, according to certain embodiments. Similarly, FIG. 4 illustrates one example approach in which silent deletion is implemented except when the target access node supports the proprietary protocol. The embodiments illustrated in FIGS. 3 and 4 are just examples of certain embodiments and their features should not be taken as being required in all cases. In these approaches, the first downlink proprietary MAC message can serve as a confirmation to the UE that the network has deleted the RRC configuration. If the UE does not receive this confirmation, then the network may still be using the RRC configuration. After the UE completes handoff, if the UE receives the RRC message, it may refrain from using the Data Loading Control protocol. Optionally, if the UE does not receive a proprietary downlink MAC message, then the UE may repeat the uplink proprietary MAC message up to a maximum number of repetitions. The Data Loading Control UE can be configured to transmit the uplink MAC message in response to receiving the RRC Data Loading Control Information Signal. This can help to avoid a scenario in which the UE is unable to use Data Loading Control after handing off into a new eNB where Data Loading Control is supported. If the eNB receives an uplink proprietary protocol indication, for example an uplink proprietary MAC message, the eNB can do various things. First, the eNB can silently remove the RRC configuration. This removal can be a removal from storage within the eNB and possibly provided during handoff. This removal can be done without performing any RRC reconfiguration over the air. The eNB can reply with a downlink MAC message in order to confirm to the UE that the proprietary protocol indication (e.g. indication in layer L2 or L3) has been silently deleted, such that the UE can use the proprietary protocol after handoff, if it receives another proprietary protocol indication at that time. In other words, the silent deletion can ensure that if the target access node sends a corresponding RRC DLCIS, this means that the target access node supports the proprietary protocol, rather than that the target access node is simply copying the stored information at the source access node. If the UE transmits the uplink MAC message, but the source eNB never receives it, then this may create an issue in a case where the UE is not waiting for confirmation from the eNB. Thus, a downlink MAC message can be used as a confirmation that the network has received the uplink MAC message and has silently deleted. If the UE has not received this confirmation, then the RRC may still be included in the handoff command. For this reason, if the UE does not receive a downlink proprietary MAC message then the UE can refrain from using the Data Loading Control protocol after the next handoff. The configured UE can send an uplink proprietary MAC message. A justification of this uplink communication can that if the UE is a configured UE, and the UE never transmits an uplink MAC message, then there may still be a need for special behavior on the part of the eNB with respect to the RRC. After all, a configured UE may potentially use the RRC received after handoff. If this RRC received after handoff is from a copying target access node rather than a configured access node, the configured UE may be confused. In particular, the configured UE may think that the target cell supports the Data Loading Control protocol, when actually the target cell does not. If the UE is not a configured UE, and the eNB does not receive a proprietary MAC message, then no special behavior is required on the part of the eNB with respect to the proprietary protocol configuration. In other words, the eNB is not required to remove a proprietary protocol configuration from the non-configured UE. Moreover, the eNB can assume that a UE which does not respond to the specific proprietary configuration with a proprietary MAC message is not a configured UE. In a general, a non-configured UE may not use this RRC handoff configuration. Thus, even if a neighboring cell provides that RRC configuration to the non-configured UE, that will not cause any problems with the non-configured UE. As such, the eNB is not required to use RRC reconfiguration to remove the proprietary configuration from the non-configured UE, or indeed from any UE which does not respond to the RRC with a proprietary MAC message. FIG. 5 illustrates toggling data loading control information signals after a handoff, according to certain embodiments, while FIG. 6 illustrates toggling data loading control information signals in an opposite direction after a handoff, also in accordance with certain embodiments. In these approaches, there can be changing from one flavor of the Data Loading Control Information Signal to a different one in the immediately subsequent cell after a handoff. With the toggling approaches, there can be a second flavor of the RRC announcement. At least one of the parameters within the RRC Data Loading Control Information Signal can have two different possible values, where both values would indicate Data Loading Control protocol support. If this was the case, then the target eNB could see the RRC configuration that was used in the source cell, as the target eNB would have received that RRC as a part of the handoff process. Then the target eNB could use a different/alternate RRC Data Loading Control Information Signal such that the UE can be confident that the RRC it was receiving was not a result of the RRC being transferred during handoff. Thus, these approaches can toggle between two identical RRC configurations upon HO, with some minor difference between the two. For example, one RRC can have one proprietary configuration, and the other RRC can have a different proprietary configuration. Neither RRC can have a Measld (see 3GPP TS 36.311, which is hereby incorporated herein by reference in its entirety) configured to activate the RRC configuration. FIG. 7 illustrates a method according to certain embodiments. This may be a method of enabling a UE to determine a level of eNB proprietary protocol support after handoff. The method can include, at 710, determining protocol support based on a first configuration received from the source access node. The source access node can be an eNB. The method can also include, at 720, determining whether to continue, after a handover, using a proprietary protocol based on whether a first configuration remains unchanged. The method can further include using, at 730, or ceasing from using, at 735, the proprietary protocol based on the determination. The ceasing from using the proprietary protocol can occur when the first configuration remains unchanged by a handoff command. This may correspond to the user equipment detecting that the target access node is simply copying the source access node. The method can include, at 740, subsequently receiving a second configuration indicating the proprietary protocol support. This may be received from the target eNB. The method can further include, at 745, using the proprietary protocol again based on the received second configuration. The method can include using the proprietary protocol upon receiving a configuration after the handoff indicating support of the proprietary protocol. This may be the first time after handoff or the second or subsequent time after handoff. The second configuration can be the same as the first configuration. In this approach, an additional RRC may be required after handoff, as described above. The method can further include, at 715, receiving by the UE a downlink proprietary medium access control message and, at 717, deleting the RRC configuration. In this case, because the RRC is deleted, the first configuration will no longer still be in place. The second configuration can be different from the first. When the second configuration is different from the first configuration, the second configuration can be considered valid if the Measld is not activated. In this case, the fact that this is not activated, is a further clue that this configuration is not being used in the normal fashion. Instead, it is being used to indicate the proprietary protocol support. FIG. 8 illustrates another method according to certain embodiments. This may be a method of enabling an eNB to indicate proprietary protocol support to a UE, with special handling for handoff. The method can include, at 810, detecting that a first access node (eNB) supports a proprietary protocol, that a user equipment is performing handoff the first access node, and the user equipment's existing DLCI contains a first proprietary protocol indication. The method can also include, at 820, using a radio resource control reconfiguration to provide another proprietary protocol indication to the user equipment. The providing another proprietary protocol indication can include, at 825, replacing the first proprietary protocol indication. The method can include refraining from activating another configuration. As mentioned above, this lack of activation can help to verify the purpose of the first proprietary protocol indication. The second configuration can be the same as the first configuration. This may be the case in an embodiment in which the same RRC signal is again provided after handoff, as described above. Alternatively, the second configuration can be different from the first configuration. This may corresponding to the toggling embodiments described above. The second configuration may not activate the Measld. Thus the RRC configuration may not be activated. This can provide an additional check, as mentioned above. FIG. 9 illustrates a further method according to certain embodiments. This may be a method of enabling the eNB to indicate proprietary protocol support to a UE, with special handling for handoff. The method can include, at 910, configuring, by an access node, such as an eNB, a user equipment with a first proprietary protocol support indication configuration. This configuration may be, for example, a special RRC configuration. The method can also include, when the access node receives an uplink proprietary protocol indication at 920, removing at 930 the RRC configuration, for example as stored within the eNB and possibly provided during handoff. The uplink proprietary protocol indication can be an uplink proprietary MAC message. The removal can be done without performing any radio resource control reconfiguration over the air. In response to the access node receiving the uplink proprietary protocol indication, the method can include at 927 replying, by the access node, with a downlink medium access control message. This replay may confirm to the user equipment that the proprietary protocol indication, such as the RRC configuration, has been silently deleted. Thus, the UE can use the data loading control/proprietary protocol after handoff if the UE receives another proprietary protocol indication at that time. This may then avoids the issues illustrated in FIG. 1 where the configured UE could use Data Loading Control Protocol in response to a first Data Loading Control Information Signal that resulted from the first Data Loading Control Information Signal provided during handoff to that neighboring cell. In other words, a copy of the data loading control information signal received during handoff may not be evidence that the target eNB supports the protocol, may not be sufficient indication to the UE that it should use the proprietary protocol in that new target cell. Instead with this approach, the UE does not use the data loading control protocol until it receives a separate data loading control information signal, subsequent to handoff completing. Thus, certain embodiments may include a variety of the above-described features as separate embodiments or in combination with one another. Moreover, other variations and combinations are also permitted. For example, in certain embodiments the eNB can use over the air messaging to explicitly remove the RRC configuration from the UE. This may help to avoid any potential for problems when the UE is later handed off to another cell, where that other cell is quite possibly from another vendor and consequently may not support the same protocols. Moreover, certain embodiments may automatically detect non-configured UEs. The non-configured UEs can be those UEs that are not configured to support the proprietary protocol. The system may use an explicit mechanism that can avoid problems for the non-configured UEs. If, after the RRC announcement is configured, a Data Loading Control MAC message is not received, then a Data Loading Control UE can automatically self delete this RRC configuration. Furthermore, the eNB can automatically self delete this RRC configuration and not use over the air messaging to explicitly remove the RRC configuration. This removal of the RRC prior to handoff can avoid the need to perform this removal during the handoff procedure. Either an implicit or explicit mechanism can be used to remove RRC well prior to handoff. Additional triggers can be used by the UE and/or eNB. For example, if the UE hands-off within a particularly short time interval after the first MAC message, the Data Loading Control UE may ignore the RRC received after the next handoff as it may be resulting from the configured source eNB providing it to a non-configured target eNB. The modified RRC Data Loading Control Information Signal criteria can have various characteristics. For example, reference signal received quality (RSRQ) can be selectively utilized instead of just reference signal received power (RSRP). After the Data Loading Control Information Signal the UE may be prohibited from transmitting additional proprietary MAC message if more than a threshold number of proprietary MAC message are transmitted by the UE but no acknowledgment was received. This may help to prevent the configured UE from flooding a non-configured UE with proprietary MAC messages. More generally, the protocol can begin with the network using a RRC configuration for proprietary connection/protocol with a very specific set of configuration parameters to indicate to the UE that the eNB supports the special proprietary protocol. Thus, this extra RRC configuration may not alter the UE performance. The special proprietary Data Loading Control UEs can know that this special RRC configuration indicates that the Data Loading Control protocol is supported by that eNB. FIG. 10 illustrates a system according to certain embodiments of the invention. It should be understood that each block of the flowchart of FIGS. 7 through 9 may be implemented by various means or their combinations, such as hardware, software, firmware, one or more processors and/or circuitry. In one embodiment, a system may include several devices, such as, for example, network element 1010 and user equipment (UE) or user device 1020. The system may include more than one UE 1020 and more than one network element 1010, although only one of each is shown for the purposes of illustration. A network element can be an access point, a base station, an eNode B (eNB), or any other network element, such as any other access node. Each of these devices may include at least one processor or control unit or module, respectively indicated as 1014 and 1024. At least one memory may be provided in each device, and indicated as 1015 and 1025, respectively. The memory may include computer program instructions or computer code contained therein, for example for carrying out the embodiments described above. One or more transceiver 1016 and 1026 may be provided, and each device may also include an antenna, respectively illustrated as 1017 and 1027. Although only one antenna each is shown, many antennas and multiple antenna elements may be provided to each of the devices. Other configurations of these devices, for example, may be provided. For example, network element 1010 and UE 1020 may be additionally configured for wired communication, in addition to wireless communication, and in such a case antennas 1017 and 1027 may illustrate any form of communication hardware, without being limited to merely an antenna. Transceivers 1016 and 1026 may each, independently, be a transmitter, a receiver, or both a transmitter and a receiver, or a unit or device that may be configured both for transmission and reception. The transmitter and/or receiver (as far as radio parts are concerned) may also be implemented as a remote radio head which is not located in the device itself, but in a mast, for example. It should also be appreciated that according to the “liquid” or flexible radio concept, the operations and functionalities may be performed in different entities, such as nodes, hosts or servers, in a flexible manner. In other words, division of labor may vary case by case. One possible use is to make a network element to deliver local content. One or more functionalities may also be implemented as a virtual application that is provided as software that can run on a server. A user device or user equipment 1020 may be a user equipment (UE) or a mobile station (MS) such as a mobile phone or smart phone or multimedia device, a computer, such as a tablet, provided with wireless communication capabilities, personal data or digital assistant (PDA) provided with wireless communication capabilities, portable media player, digital camera, pocket video camera, navigation unit provided with wireless communication capabilities or any combinations thereof. The user device or user equipment 1020 may be a sensor or smart meter, or other device that may usually be configured for a single location. In an exemplifying embodiment, an apparatus, such as a node or user device, may include means for carrying out embodiments described above in relation to FIGS. 7 through 9. Processors 1014 and 1024 may be embodied by any computational or data processing device, such as a central processing unit (CPU), digital signal processor (DSP), application specific integrated circuit (ASIC), programmable logic devices (PLDs), field programmable gate arrays (FPGAs), digitally enhanced circuits, or comparable device or a combination thereof. The processors may be implemented as a single controller, or a plurality of controllers or processors. Additionally, the processors may be implemented as a pool of processors in a local configuration, in a cloud configuration, or in a combination thereof. For firmware or software, the implementation may include modules or unit of at least one chip set (e.g., procedures, functions, and so on). Memories 1015 and 1025 may independently be any suitable storage device, such as a non-transitory computer-readable medium. A hard disk drive (HDD), random access memory (RAM), flash memory, or other suitable memory may be used. The memories may be combined on a single integrated circuit as the processor, or may be separate therefrom. Furthermore, the computer program instructions may be stored in the memory and which may be processed by the processors can be any suitable form of computer program code, for example, a compiled or interpreted computer program written in any suitable programming language. The memory or data storage entity is typically internal but may also be external or a combination thereof, such as in the case when additional memory capacity is obtained from a service provider. The memory may be fixed or removable. The memory and the computer program instructions may be configured, with the processor for the particular device, to cause a hardware apparatus such as network element 1010 and/or UE 1020, to perform any of the processes described above (see, for example, FIGS. 7 through 9). Therefore, in certain embodiments, a non-transitory computer-readable medium may be encoded with computer instructions or one or more computer program (such as added or updated software routine, applet or macro) that, when executed in hardware, may perform a process such as one of the processes described herein. Computer programs may be coded by a programming language, which may be a high-level programming language, such as objective-C, C, C++, C#, Java, etc., or a low-level programming language, such as a machine language, or assembler. Alternatively, certain embodiments of the invention may be performed entirely in hardware. Furthermore, although FIG. 10 illustrates a system including a network element 1010 and a UE 1020, embodiments of the invention may be applicable to other configurations, and configurations involving additional elements, as illustrated and discussed herein. For example, multiple user equipment devices and multiple network elements may be present, or other nodes providing similar functionality, such as nodes that combine the functionality of a user equipment and an access point, such as a relay node. Certain embodiments may have various benefits and/or advantages. For example, certain embodiments may be suitable for implementation as a part of a proprietary knowledge sharing protocol. This mechanism can serve to enable the overall proprietary protocol. In addition, the specific protocol can further enable benefits such as avoiding the need to perform an extra RRC reconfiguration in the case where the UE is a configured UE. However, some embodiments of the invention can ensure that in the case of a non-configured UE, problems can be avoided by selectively performing the needed RRC reconfiguration in that case. One having ordinary skill in the art will readily understand that the invention as discussed above may be practiced with steps in a different order, and/or with hardware elements in configurations which are different than those which are disclosed. Therefore, although the invention has been described based upon these preferred embodiments, it would be apparent to those of skill in the art that certain modifications, variations, and alternative constructions would be apparent, while remaining within the spirit and scope of the invention. | <SOH> BACKGROUND <EOH> | <SOH> SUMMARY <EOH>According to a first embodiment, a method can include determining protocol support based on a first configuration received from the source access node. The method can also include determining whether to continue, after a handover, using a proprietary protocol based on whether a first configuration remains unchanged. The method can further include using or ceasing from using the proprietary protocol based on the determination. In variant, the method can include ceasing from using the proprietary protocol when the first configuration remains unchanged by a handoff command. In a variant, the method can include subsequently receiving a second configuration indicating the proprietary protocol support, and using the proprietary protocol again based on the received second configuration. In a variant, the method can include using the proprietary protocol upon receiving a configuration after the handoff indicating support of the proprietary protocol. In a variant, the second configuration can be the same as the first configuration. In a variant, the method can further comprise receiving a downlink proprietary medium access control message and deleting an RRC configuration. In a variant, the second configuration can be different from the first. In a variant, when the second configuration is different from the first configuration, the second configuration can be considered valid if the Measeld is not activated. According to a second embodiment, a method can include detecting that a first access node supports a proprietary protocol, that a user equipment is performing handoff the first access node, and the user equipment's existing RRC configuration contains a first proprietary protocol indication. The method can also include using a radio resource control reconfiguration to provide another proprietary protocol indication to the user equipment. In a variant, the providing another proprietary protocol indication can include replacing the first proprietary protocol indication. In a variant, the method can include refraining from activating another RRC configuration. In a variant, the second configuration can be the same as the first configuration. In a variant, the second configuration can be different from the first configuration. In a variant, the second configuration does not activate the Measld. According to a third embodiment, a method can include configuring, by an access node, a user equipment with a first proprietary protocol support indication configuration. The method can also include, when the access node receives an uplink proprietary protocol indication, removing the RRC configuration, wherein this removal is done without performing any radio resource control reconfiguration over the air. In a variant, in response to the access node receiving the uplink proprietary protocol indication, replying, by the access node, with a downlink medium access control message in order to confirm to the user equipment that the proprietary protocol indication has been silently deleted. According to fourth through sixth embodiments, an apparatus can include means for performing the method according to the first through third embodiments respectively, in any of their variants. According to seventh through ninth embodiments, an apparatus can include at least one processor and at least one memory and computer program code. The at least one memory and the computer program code can be configured to, with the at least one processor, cause the apparatus at least to perform the method according to the first through third embodiments respectively, in any of their variants. According to tenth through twelfth embodiments, a computer program product may encode instructions for performing a process including the method according to the first through third embodiments respectively, in any of their variants. According to thirteen through fifteenth embodiments, a non-transitory computer readable medium may encode instructions that, when executed in hardware, perform a process including the method according to the first through third embodiments respectively, in any of their variants. According to sixteenth and seventeenth embodiments, a system may include at least one apparatus according to the fourth or seventh embodiments in communication with at least one apparatus according to the fifth, sixth, eighth, or ninth embodiments, respectively in any of their variants. | H04W7627 | 20180312 | 20180628 | 62307.0 | H04W7627 | 0 | HOUSHMAND, HOOMAN | SELECTIVE PROPRIETARY PROTOCOL SUPPORT INDICATION REMOVAL | UNDISCOUNTED | 0 | PENDING | H04W | 2,018 |
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15,760,690 | PENDING | ONLINE CERTIFICATION MARK PUBLICATION SYSTEM | Disclosed herein is an online certification mark publication system. The online certification mark publication system includes: a certification mark registration unit configured to register and store a certification mark; an object construction unit configured to accept a registration of an object from a publisher terminal, to also accept a registration of a certification mark assigned to the registered object, and to set hierarchy between registered objects; a module generation unit configured to generate a certification mark module; and a module request processing unit configured to, when a request for a certification mark is received from the certification mark module inserted into the online page, transmit the certification mark of the published object and information about an inheritable certification mark in response to the request, wherein the certification mark is inherited based on the hierarchy between the objects. | 1. An online certification mark publication system, the online certification mark publication system connecting to a publisher terminal over a network, the online certification mark publication system comprising: a certification mark registration unit configured to register and store a certification mark; an object construction unit configured to accept a registration of an object from the publisher terminal, to also accept a registration of a certification mark assigned to the registered object, and to set hierarchy between registered objects; a module generation unit configured to generate a certification mark module which can be inserted into an online page on which the object is published, wherein the certification mark module displays the certification mark, assigned to the published object, within the online page; and a module request processing unit configured to, when a request for a certification mark is received from the certification mark module inserted into the online page, transmit the certification mark of the published object and information about an inheritable certification mark in response to the request, wherein the certification mark is inherited based on the hierarchy between the objects. 2. The online certification mark publication system of claim 1, wherein relationships between all the objects for which the hierarchy is set are configured to have directionality in a single direction. 3. The online certification mark publication system of claim 1, wherein each of the objects for which the hierarchy is set inherits a certification mark from a higher object thereof, and also inherits a certification mark inherited by the higher object. 4. The online certification mark publication system of claim 1, wherein the certification mark module is inserted into the online page, a predetermined size display space of the online page is allocated, and details of the certification mark are displayed on the corresponding display space. 5. The online certification mark publication system of claim 1, wherein when a plurality of certification marks is received in response to the request, the certification mark module sequentially displays details of the plurality of certification mark on the online page. 6. The online certification mark publication system of claim 1, wherein the certification mark module displays the object published on the online page and information about a higher object of the published object, as well as details of the certification mark. 7. The online certification mark publication system of claim 1, further comprising a certification mark guide unit configured to provide an online page which provides a description of the certification mark; wherein the certification mark module provides a link from the online page on which it is published to the online page which is provided by the certification mark guide unit. 8. The online certification mark publication system of claim 7, wherein the certification mark guide unit publishes the description of the certification mark and a description of an issuance organization issuing the corresponding certification mark, and performs the publication by inserting a certification mark module for a certification mark assigned to the issuance organization. 9. The online certification mark publication system of claim 1, wherein the object is a target to which certification is assigned, and includes any one or more of a product, a service, an individual, a company, an organization, and a group thereof. 10. The online certification mark publication system of claim 1, wherein the online page is any one or more of a webpage, a social network system (SNS), a blog, a messenger, a mail, and a mobile app page. 11. The online certification mark publication system of claim 2, wherein the object is a target to which certification is assigned, and includes any one or more of a product, a service, an individual, a company, an organization, and a group thereof. 12. The online certification mark publication system of claim 3, wherein the object is a target to which certification is assigned, and includes any one or more of a product, a service, an individual, a company, an organization, and a group thereof. 13. The online certification mark publication system of claim 4, wherein the object is a target to which certification is assigned, and includes any one or more of a product, a service, an individual, a company, an organization, and a group thereof. 14. The online certification mark publication system of claim 5, wherein the object is a target to which certification is assigned, and includes any one or more of a product, a service, an individual, a company, an organization, and a group thereof. 15. The online certification mark publication system of claim 6, wherein the object is a target to which certification is assigned, and includes any one or more of a product, a service, an individual, a company, an organization, and a group thereof. 16. The online certification mark publication system of claim 7, wherein the object is a target to which certification is assigned, and includes any one or more of a product, a service, an individual, a company, an organization, and a group thereof. 17. The online certification mark publication system of claim 8, wherein the object is a target to which certification is assigned, and includes any one or more of a product, a service, an individual, a company, an organization, and a group thereof. 18. The online certification mark publication system of claim 2, wherein the online page is any one or more of a webpage, a social network system (SNS), a blog, a messenger, a mail, and a mobile app page. | TECHNICAL FIELD The present invention relates to an online certification mark publication system which publishes a certification mark issued by an issuance server on an online page, such as a webpage or the like, on which an object is published and which verifies that the published certification mark has been issued to the online object. Furthermore, the present invention relates to an online certification mark publication system which sets the hierarchy between a plurality of online objects published on an online page and which enables a certification mark to be inherited based on the set hierarchy and also enables the inherited certification mark to be published on the online page. BACKGROUND ART Generally, users obtain certification from external organizations for the purpose of use for external advertisement, for a legal reason, or for the like. Certification includes various types of certification, such as quality certification, qualification certification, membership certification, affiliation certification, etc. Additionally, certification is present in various forms, such as certification for a pass in a test of an organization, certification for permission, certification for a member of a specific group, certification for the winning of a prize in a contest, the recommendation of an authority, an examination result, an advertisement review result, etc. Furthermore, certification is issued to a product, a service, or a company or individual which provides a product or service. Furthermore, when products or services are different but are of the same type or of similar types and form a single group, the same certification is assigned to all the products or services within the corresponding group. In the same manner, when companies or individuals form a group or a detailed group is present within a single company, the corresponding group may be a single certification target. Meanwhile, a certification organization certifies a certification target, and issues a certificate or the like capable of indicating the certification. The certification organization may be an individual, a company, an organization, a government, or a group thereof. Furthermore, the certificate or the like is an official document which is an evidence for the obtainment of certification, such as a certificate, a warrant, a license, a membership card, or the like. The certificate or the like may be present in the form of a paper document, an electronic document, a certification mark, text, or the like. By receiving external certification, a user can verify the excellence of himself or herself or his or her product or service and can advertise it externally, and thus the user attempts to obtain credible certification. When certification is obtained from a certification organization, the user places the certificate in an office or the like, or posts it on a homepage, an advertisement, or a product description in text format, image file format, or the like. In particular, certification is displayed offline by attaching a certification mark to a product, goods, or a service space. However, in spite of many efforts to promote the advantages of certification, a problem arises in that many consumers do not fully understand the details of each certification due to the proliferation of various certification systems. For this purpose, an electronic certification mark technology for attaching an electronic tag to a certification mark is proposed offline [see Patent document 1]. Furthermore, a certification mark can be imitated, and thus a technology for protecting a certification mark for distribution by means of a protection medium is also proposed [see Patent document 2]. Furthermore, a third party who sells a user's product on the Internet, such as an online open market, promotes the product by means of an advertizing material made by the user by including a certificate or certification mark image or by means of a certificate or certification mark image [see Patent document 3]. However, the details, validity, and counterfeiting of online certification marks need to be verified, like those of offline certification marks. Generally, for this purpose, the validity and certification-related details of a certificate published online can be checked by referring to a certification organization having issued the certificate by reference to a published certificate image or description. Furthermore, in order to verify the credibility of a certificate, an issuance organization must be checked for credibility. It may be possible to directly check the issuance organization itself for credibility, or to check credibility based on the certification of a higher certification organization (a government or the like) or an external organization (a media organization, an international organization, a well-known person, or the like). There are cases where an issuance organization posts the logos and links of one or more higher or related organizations on a website. However, in order to verify this, a problem arises in that it is necessary to visit each of the higher or related organizations and verify it through a search or the like. Furthermore, when a result cannot be accurately determined, it is difficult to determine whether the issuance organization is trustworthy or not, and time and cost are required due to a phone call or visit to each of the organizations. For example, a seller may post a health function certification mark, obtained from a certification organization without credibility, on a product sales page. In other words, an issuance organization which issued the health function certification mark of a corresponding product may not be an organization certified by a higher organization, such as the government, or related organization. However, a consumer may be misled by the certification mark, may mistake a product as a product for which a health function has been officially certified, and may then purchase the product. Even when the organization is not an issuance organization certified by a credible organization, it appears to be credible, and thus damage may be caused. When a third party selling a product is promoting using a certificate at a shopping mall or other website, damage may be caused because official sales qualification, the certification of a corresponding product, or the certification of a corresponding company is not verified. Furthermore, a problem arises in that there are cases where it is impossible to verify certification due to the mismanagement, absence or closing of the website of an issuance organization. Furthermore, a change to a certificate (such as a change in validity, a change to a certification mark, a change in the name of an organization, or the like) is not immediately transferred, and thus confusion may be caused. PATENT DOCUMENTS (Patent document 1) [Patent document 1] Korean Patent Application Publication No. 10-2009-0122852 (published on Dec. 1, 2009) (Patent document 2) [Patent document 2] Korean Patent Application Publication No. 10-2009-0058473 (published on Jun. 9, 2009) (Patent document 3) [Patent document 3] Korean Patent Application Publication No. 10-2011-0012687 (published on Feb. 9, 2011) DISCLOSURE Technical Problem The present invention has been conceived to overcome the above-described problems, and an object of the present invention is to provide an online certification mark publication system which publishes a certification mark issued by an issuance server on an online page, such as a webpage or the like, on which an object is published and which verifies that the published certification mark has been issued to the online object. Another object of the present invention is to provide an online certification mark publication system which sets the hierarchy between a plurality of online objects published on an online page and which enables a certification mark to be inherited based on the set hierarchy and also enables the inherited certification mark to be published on the online page. Technical Solution In order to accomplish the above objects, the present invention provides an online certification mark publication system, the online certification mark publication system connecting to a publisher terminal over a network, the online certification mark publication system including: a certification mark registration unit configured to register and store a certification mark; an object construction unit configured to accept a registration of an object from the publisher terminal, to also accept a registration of a certification mark assigned to the registered object, and to set hierarchy between registered objects; a module generation unit configured to generate a certification mark module which can be inserted into an online page on which the object is published, wherein the certification mark module displays the certification mark, assigned to the published object, within the online page; and a module request processing unit configured to, when a request for a certification mark is received from the certification mark module inserted into the online page, transmit the certification mark of the published object and information about an inheritable certification mark in response to the request, wherein the certification mark is inherited based on the hierarchy between the objects. In the online certification mark publication system of the present invention, the relationships between all the objects for which the hierarchy is set may be configured to have directionality in a single direction. In the online certification mark publication system of the present invention, each of the objects for which the hierarchy is set may inherit a certification mark from the higher object thereof, and may also inherit a certification mark inherited by the higher object. In the online certification mark publication system of the present invention, the certification mark module may be inserted into the online page, a predetermined size display space of the online page may be allocated, and the details of the certification mark may be displayed on the corresponding display space. In the online certification mark publication system of the present invention, when a plurality of certification marks is received in response to the request, the certification mark module may sequentially display the details of the plurality of certification mark on the online page. In the online certification mark publication system of the present invention, the certification mark module may display the object published on the online page and information about a higher object of the published object, as well as the details of the certification mark. The online certification mark publication system of the present invention may further include a certification mark guide unit configured to provide an online page which provides a description of the certification mark; the certification mark module may provide a link from the online page on which it is published to the online page which is provided by the certification mark guide unit. In the online certification mark publication system of the present invention, the certification mark guide unit may publish the description of the certification mark and a description of an issuance organization issuing the corresponding certification mark, and may perform the publication by inserting a certification mark module for a certification mark assigned to the issuance organization. In the online certification mark publication system of the present invention, the object may be a target to which certification is assigned, and may include any one or more of a product, a service, an individual, a company, an organization, and a group thereof. In the online certification mark publication system of the present invention, the online page may be any one or more of a webpage, a social network system (SNS), a blog, a messenger, a mail, and a mobile app page. Advantageous Effects As described above, in accordance with the online certification mark publication system according to the present invention, a certification network is constructed around a certification mark, thereby achieving the effect of enabling a third party to immediately and reliably check the certification mark and the validity thereof and also enabling the third party to share the information, publish the information at an outside site in a re-distribution manner, and obtain the verification thereof according to the authority thereof. DESCRIPTION OF DRAWINGS FIG. 1 is a block diagram showing the configuration of an overall system for the practice of the present invention; FIGS. 2 and 3 are views illustrating examples of the configuration of objects according to an embodiment of the present invention; FIG. 4 a view illustrating an example of an online page on which a certification mark module according to an embodiment of the present invention is published; FIG. 5 is a block diagram showing the configuration of a certification mark module according to an embodiment of the present invention; FIG. 6 is a block diagram showing the configuration of an online certification mark publication system according to an embodiment of the present invention; and FIGS. 7 and 8 are views illustrating the guide pages of certification marks. MODE FOR INVENTION Details for the practice of the present invention will be described with reference to the accompanying drawings below. Furthermore, in the following description of the present invention, the same reference symbols will be assigned to the same portions, and redundant descriptions thereof will be omitted. First, an example of the configuration of an overall system for the practice of the present invention will be described with reference to FIG. 1. As shown in FIG. 1, the overall system for the practice of the present invention includes: a publisher terminal 11 configured to publish a certification mark as well as an online object on an online page; an issuance server 12 configured to issue a certification mark; a publication server 50 configured to provide an online page 60, such as a webpage or the like, online; and a management server 30 configured to manage a certification mark. Furthermore, a certification mark module 70 as well as the content 61 of an object is published on the online page 60. The terminal 11 and the servers 12, 30 and 50 are connected over a network 20. Furthermore, a database 40 configured to store required data may be further included. The publisher terminal 11 is a common computing terminal, such as a PC, a notebook, a netbook, a smartphone, a tablet PC, a mobile, or the like, which is used by a publisher. The publisher terminal 11 subscribes to the management server 30 for membership, and registers and manages an object and a certification mark for the corresponding object. Furthermore, the publisher terminal 11 connects to the publication server 50, publishes the content 61 of an object on the online page 60, and publishes a certification mark by inserting the certification mark module 70 of the corresponding object into the corresponding online page 60. Alternatively, the publisher terminal 11 publishes and inserts the content 61 of the object and the certification mark module 70 on and into the publication server 50 without registering or managing its own certification mark. In this case, the publisher is a third party who is neither the issuer of the certification mark nor an object to which the certification mark is assigned. In other words, the publisher terminal 11 is the terminal of a person to whom the certification mark is issued or the terminal of the third party. In the following description, a job performed by the publisher refers to a job performed via the publisher terminal 11. Furthermore, reference symbol 11 is assigned to the publisher as well as the publisher terminal. Meanwhile, in this case, the object refers to a target to which a certification mark can be issued, such as a publisher himself or herself, his or her company, his or her product, his or her service, or the like. Furthermore, the online page 60 is a page which enables content to be published online, and refers to a webpage, a social network system (SNS), a blog, a messenger, a mail, or the like which enables content to be published online. Next, the issuance server 12 refers to a server or terminal which issues a certification mark to an object. The issuance server 12 registers with the management server 30 for membership, and transmits detailed information about the certification mark, issued by it, to the management server 30. In particular, when the content of the certification mark is changed because an image of the certification mark is changed, a validity period has been terminated, or the like, the issuance server 12 updates the corresponding data by transmitting information about the change to the management server 30. Furthermore, inversely, when the management server 30 actively requests information about the certification mark, the issuance server 12 transmits information about the corresponding certification mark. Alternatively, the issuance server 12 may disclose the content of the certification mark, and the management server 30 may connect to the issuance server 12 and take the corresponding certification mark and the content of the corresponding certification mark. The management server 30 connects to the issuance server 12 at predetermined time intervals, and fetches update information. In this case, the issuance server 12 may not connect to or register with the management server 30. Furthermore, the publication server 50 is a server which publishes an online page, and refers to a server which provides a service adapted to publish content online, such as a web server, an SNS server, a blog server, a mail server, or the like. Furthermore, the publication server 50 may be a server adapted to provide an online page, published on a mobile app, in conjunction with the mobile app. Accordingly, the online page 60 is an online page displayed by the publication server 50, and refers to a page which may be published and displayed on the Internet or a mobile network. Furthermore, the management server 30 accepts a membership registration from a publisher, and also accepts the registration of an object, i.e., a certification target, and a certification mark issued to the corresponding object from the publisher. Furthermore, the management server 30 receives detailed information about the certification mark directly from the publisher, or collects or receives the corresponding information from the issuance server 12 which issues the certification mark. Furthermore, the management server 30 generates and provides the certification mark module 70 which will be inserted into and published on the online page 60. The certification mark module 70 is a module including an image, a link, a script, and/or like adapted to be inserted into the online page 60, and is also a module configured to display a certification mark or provide detailed information about a certification mark. Furthermore, the certification mark module 70 displays or provides required information in response to a user's touch, click or the like, and also requests and receives required data from the management server 30. The certification mark module 70 is a module which is configured in page form and which includes a link, a script, and/or the like so that the certification mark module 70 can be easily inserted into the online page 60. Accordingly, the publisher terminal 11 may download the certification mark module 70, and may insert the downloaded certification mark module 70 into the online page 60, thereby publishing the certification mark module 70 on the online page 60. The database 40 is common storage media adapted to store data required for the management server 30, and stores membership information, a certification mark, detailed data regarding the certification mark, an object, etc. More specifically, the database 40 includes: a membership DB 41 configured to store membership data; a certification mark DB 42 configured to store certification marks, a structure between the certification marks, the detailed content of the certification marks, etc.; and an object DB 43 configured to data about objects, i.e., certification targets. However, the above configuration of the database 40 is merely a preferred embodiment. When a specific apparatus is developed, the database 40 may be configured in a different structure based on a database construction theory by considering the ease of access and retrieval, efficiency, and/or the like. Next, the structure of an object, i.e., a certification target, and the inheritance of a certification mark according to an embodiment of the present invention will be described with reference to FIG. 2. As shown in FIG. 2, objects, i.e., certification targets, may have a hierarchy. In FIG. 2, arrows indicate the hierarchy. In this case, a graph of objects drawn according to the hierarchy needs to satisfy the condition of a directed graph. In other words, the graph of objects is constructed based on the hierarchy between objects, and needs to have directionality in a single direction. For example, when hierarchy is constructed in the direction of the dotted line arrow from object A22 to object C in FIG. 2, a cyclic relationship is established in the form of C→A2→A22→C. A graph which forms such a cyclic relationship is not a directed graph. In other words, a graph based on the hierarchy between objects is a directed graph which does not have a cyclic relationship but has single directionality. When objects have the hierarchy therebetween, a lower object (or a child object) inherits the certification mark of a higher object (or a parent object). In other words, each object in the hierarchy inherits the certification mark of its higher object, and also inherits a certification mark which has been inherited by the higher object. For example, object A11 has objects A1, A, B1 and B as its higher objects. Accordingly, object A11 may inherit the certification marks of those higher objects. Furthermore, object A22 inherit certification marks from objects A2, B2, B, and C. Referring to the example of FIG. 3, Samsung Electronics Co., Ltd. manufactures refrigerators and mobile phones, and electronics distributor A and electronics distributor B of Yongsan Electronics Market distribute the products in Auction Online Market. It is assumed that the mobile phone division of Samsung Electronics Co., Ltd. has obtained quality management certification, electronics distributor B has obtained best customer satisfaction certification, and Auction Online Market has obtained service grand prix certification. In this case, a Galaxy Note inherits a total of three certification marks, i.e., the quality management certification mark of the mobile phone of Samsung Electronics Co., Ltd., the best customer satisfaction certification mark of electronics distributor B, and the service grand prix certification mark of Auction Online Market. Next, the configuration of the certification mark module 70 according to an embodiment of the present invention will be described in greater detail with reference to FIGS. 4 and 5. The certification mark module 70 is a module written in a language which will be displayed on the online page 60. In other words, the certification mark module 70 is a module written in a language which is used to form an online page, such as a webpage, a social network system (SNS), a blog, a messenger, a mail, or the like. Preferably, the certification mark module 70 is a web format module or mobile application module. More preferably, the certification mark module 70 is a page format module written in HTML format, HTML 5.0 or the like, and is a page format module composed of text, a link, a script, and/or the like. Alternatively, the certification mark module 70 may be implemented as a program module which runs on a mobile app or the like. In particular, the certification mark module 70 is written to perform specific functions in a programming language, such as Script, or the like. The functions which will be described below are functions which are written in a page writing language, such as Script, or the like, and are performed. Furthermore, as shown in FIG. 4, the certification mark module 70 is inserted into the online page 60, is allocated a predetermined size display space of the online page 60, and displays the content of a certification mark, an image, text or the like of a certification mark, the information of a certification mark, object information, or the like on the corresponding display space. In other words, the content of a certification mark may be displayed in the form of an image, text, or the like. Basically, this uses a method, such as an advertisement or blog plug-in method. In other words, in the case of a webpage, the module is inserted using a script language, such as Java Script, jQuery, ajax, or the like, and communication with the server is performed and data is transmitted and received in the format of html, XML, json, or the like by using an open API technology, such as Representational State Transfer (REST). Connection and control may be performed via an API key issued in advance. Furthermore, as shown in FIG. 5, the certification mark module 70 according to the present invention includes: a storage unit 71 configured to store the address of the management server 30 and an object ID; a request unit 72 configured to request and receive information about the certification mark of an object from the management server 30; a display unit 73 configured to display the object or the information about the certification mark; and a control unit 74 configured to perform a designated function, such as display, linkage, or the like, in compliance with an input command. The storage unit 71 performs storage in the form of the text of the certification mark module 70, or stores the address of the management server, an object ID, a name, etc. in a storage space or the like. Furthermore, the request unit 72 connects to the management server 30 by reference to the stored address of the management server 30. Furthermore, the request unit 72 transmits the ID of the corresponding object or the object ID stored in the storage unit 71 to the management server 30. Furthermore, the request unit 72 receives information about the certification mark from the management server 30. The display unit 73 displays the received information about the certification mark on the display space screen of the online page 60. In this case, when a plurality of certification marks is received, the contents or images of the certification marks may be sequentially displayed, or may be displayed on a segmented screen. In the case of a dynamic image, the display unit 73 may construct the dynamic image, or may receive the corresponding dynamic image directly from the management server 30. Alternatively, the display unit 73 may receive a plurality of certification mark images from the management server 30, and may dynamically and sequentially display the plurality of received images, such as content, etc. Furthermore, the display unit 73 may continuously display information, such as the name or the like of an object, on part of an allocated display space, or may sequentially and alternately display the information and the certification mark image. In this case, the displayed information may further include information, such as the version, validity, network connection state, final update date, original publication location, and/or the like of the certification mark module itself. When a user generates a predetermined event on the online page 60 through touching, clicking, or the like, the control unit 74 performs a designated function for the corresponding event. For example, when a user makes a click on a display space, movement to a webpage provided by the management server 40 may be performed, and a link to a page including a detailed description of the certification mark of a corresponding object may be made. Alternatively, when the cursor of a mouse is not clicked but entry into a corresponding display space is made, the operation of sequentially replacing a certification mark image with a subsequent image or the operation of enlarging a certification mark image is performed. Furthermore, the control unit 74 may update information a predetermined period after the certification mark module has been executed, or information may be passively updated by a user. Next, an online certification mark publication system according to an embodiment of the present invention will be described with reference to FIG. 6. As shown in FIG. 6, the online certification mark publication system according to the present invention includes: a member management unit 31 configured to register and manage a member; a certification mark registration unit 32 configured to register a certification mark; an object construction unit 33 configured to construct an object, i.e., a certification target, by registering it; a module generation unit 34 configured to generate and download the certification mark module 70; and a module request processing unit 35 configured to receive a request from the certification mark module 70 inserted into an online page, and to respond to the request. Furthermore, the online certification mark publication system may further include a certification mark guide unit 36 configured to provide an online page adapted to provide a guide to a certification mark, an issuance organization, etc. First, the member management unit 31 registers a member as a user, such as a publisher, or the like, receives membership information, and performs user certification for login. Next, the certification mark registration unit 32 registers and stores a certification mark. The certification mark is an official document or mark certifying the obtainment of certification, such as a certificate, a warrant, a license, a membership card, or the like, and may be displayed in one of various forms, such as a paper document form, an electronic document form, a mark form, a text form, etc. Although the certification mark of the present invention includes all types of marks which can be displayed online, it will be referred to as a certification mark for ease of description. The certification mark registration unit 32 may receive detailed information about a certification mark via the publisher terminal 11. The certification mark may be registered by a publisher or a manager. In other words, the manager may search for the content of a certification mark or fetch related detailed information from a corresponding issuance organization, and may store the information in a database. The detailed information about the certification mark includes the image, name, issuance organization (certification organization), validity period, certification content, certification number, and/or the like of the certification mark. Furthermore, the detailed information about the certification mark may further include detailed information about the issuance organization of the certification mark. For example, the credibility of a corresponding issuance organization, the details of certification received from another organization, or the like may be included. For example, the Therapist Association may issue a certification mark for the quality of products. When the corresponding Therapist Association has been certified by the Ministry of Health and Welfare, corresponding details may be registered as detailed information. Furthermore, the certification mark registration unit may receive a credibility evaluation value for the issuance organization of a corresponding certification mark from a manager, and may store the credibility evaluation value as detailed information. Next, the object construction unit 33 accepts the registration of an object, i.e., a certification target, from the publisher terminal 11, and sets the relationships between registered objects. The object is a certification target, and may be registered as a product or service, an individual, a company (organization), a group thereof, or the like. In this case, the object is assigned an identifier, such as an ID, a code, or the like. A product is preferably identified by the model number (or product model) of the product. When a plurality of product models, such as similar products, related products, or the like, obtains the same certification mark, the corresponding product models are organized as a group. Such a group is generated and registered as a single object. A service is identified by a service model, a unique code, a name, or the like. Like a plurality of products, when a plurality of services obtains a certification mark, the corresponding services may be organized as a group. Online content, such as a webtoon, a magazine, a newspaper, a drama, a movie, or the like, may be a single service. An individual is identified by a name, a residence registration number, a unique ID, or the like. Individuals are not organized as a group. Instead, individuals are organized as an organization, a company, a department, or the like, form an object, such as an organization or the like, and are set to the generated object, such as an organization or the like, based on an affiliation relationship (or hierarchy). Individuals, such as a plurality of therapists, are made to belong to the organization object of the Therapist Association. A company or organization is identified by a name, a unique ID, or the like. Companies or organizations are not organized as a group, but a plurality of companies or organizations are set as members of an umbrella company or organization. For example, when a plurality of companies is organized as Yongsan Electronics Market for a common purpose, the objects of companies within Yongsan Electronics Market are made to belong to the organization object of a Yongsan Electronics Market association. As shown in FIG. 2 or 3, the relationship between objects are set to a hierarchy or inheritance relationship. In other words, when at least two objects have a relationship, one object is formed as a higher object, and the other is formed as a lower object. Furthermore, when objects A, B and C have successive hierarchy, object C and object A have hierarchy, and thus object A is a higher object of object C. As described above, the relationship between the objects is formed according to a directed graph method, and thus the relationship between the objects has single directionality and a direction is not cyclic. For example, the relationships between a product and a manufacturer, a product and a sales company, a service and a service company, an individual and an organization, a service and an individual, a product and an online market, a sales company and an online market, etc. may be set to the relationships between lower and higher objects. Furthermore, when products, services, or the like are set to a group, as described above, the group is generated as a single object, and the hierarchy between the group and the products or services belonging to the group is determined based on their affiliation relationship. In other words, the group is a higher object, and the products or services belonging to the group is a lower object. Furthermore, the object construction unit 33 receives objects and the relationships between the objects from the publisher terminals 11, sets detailed information about and the relationships between the objects, and stores the information in the database 40. When the objects and the relationships between the objects are displayed in the form of a graph, a structure, such as a directed graph, is obtained. As described above, the entirety of a plurality of objects and relationships between the plurality of objects is referred to as an object configuration or object configuration structure. The overall object configuration (configuration structure) may be constructed for each member, or may be constructed to be used by all members or some members in common. For example, when the configuration of objects related to the manufacturer of electronic products, such as mobile phones or the like, is provided, mobile phone companies may use the overall object configuration (configuration structure) of mobile phones or the like without change. Furthermore, the object construction unit 33 provides the function of searching for an object. When the configuration of objects already constructed is used, the function of searching for an object is used in order to identify an object. Furthermore, the object construction unit 33 receives and stores detailed information about an object, such as a name, a function, a field, and/or the like, and the stored detailed information may be used for search purposes. Furthermore, the object construction unit 33 sets a certification mark assigned to a corresponding object. The certification mark which is set is a certification mark registered by the certification mark registration unit 32. More specifically, the object construction unit 33 connects a single object of an object configuration to the certification mark. For example, a Green Mark, i.e., a certification mark, may be assigned to a plurality of environment-friendly product objects. Accordingly, objects, i.e., a plurality of environment-friendly products, may be connected (referred) to the single certification mark “Green Mark,” or the certification mark thereof is set to a Green Mark. In other words, when a Green Mark is assigned to humidifiers of a specific model, a Green Mark is set as a certification mark for the humidifiers of the corresponding model, or the humidifiers of the corresponding model are connected to the Green Mark. In this case, the certification mark is connected (set) only when it is assigned directly to a corresponding object. For example, when electronics distributor A obtains the certification of quality management ISO2000, this certification mark is assigned directly to the company of electronics distributor A. However, the quality management certification mark is not assigned directly to mobile phones distributed by electronics distributor A. Accordingly, the quality management certification mark is assigned to and set for only the object of electronics distributor A, but is not assigned to and set for the mobile phones distributed by electronics distributor A. Next, the module generation unit 34 generates a module configured to display a certification mark assigned to a specific object by inserting the certification mark into an online page. As described above, the certification mark module 70 is a module written in a language which will be displayed on the online page 60. In other words, the certification mark module 70 is a module written in a language which is used to form an online page, such as a webpage, a social network system (SNS), a blog, a messenger, a mail, or the like. Accordingly, the publisher terminal 11 may publish the certification mark module 70 on the online page 60 by downloading the certification mark module 70 from the module generation unit 34 and inserting the downloaded certification mark module 70 into the online page 60. The certification mark module 70 is separately generated for each object. In other words, the single certification mark module 70 is generated for a single object. For example, a Green Mark certification mark may be assigned to all environment-friendly product objects. When a Green Mark is assigned to humidifiers of a specific model, a single unique certification mark module 70 is separately generated as a certification mark for the humidifiers of the corresponding model. The certification mark module 70 includes: an object, i.e., a certification target, or an object ID; object information about the details (name, model name, and/or the like) of the object; and the reference information of a certification mark, such as the address, link information, or the like of the management server 30 or an object configuration structure. The certification mark module 70 retrieves the certification mark related to the corresponding object by using the reference information of the certification mark. In other words, the certification mark module 70 connects to the management server 30, transmits an object ID, and retrieves the certification mark information of the corresponding object by requesting it from the management server 30. In this case, the management server 30 retrieves a certification mark inherited from a higher object as well as the certification mark directly assigned to the corresponding object. The certification mark information fetched from the management server 30 includes an image, certification content, description and the like of the certification mark. The image of the certification mark is an image which can be displayed on the online page 60, and may correspond to a static image or dynamic image. Furthermore, the certification content includes the name, certification details, validity period, and/or the like of the certification mark. Furthermore, a description of the certification mark may be further included. Furthermore, the certification mark module 70 displays the fetched certification mark information and the information about the corresponding object on the online page 60. In this case, when the certification marks are plural in number, the certification mark module 70 may sequentially display the plurality of certification marks via a dynamic screen, or may display the certification marks via a segmented screen. Furthermore, the certification mark module 70 additionally displays object identification information, such as the name and/or the like of the object on the screen. The reason for this is to enable a user to directly check whether a certification mark in question is a certification mark for the corresponding object. For example, product A may be published on the online page 60, and the certification mark module 70 for product B may be inserted. In this case, a user may verify the certification mark for the object published on the online page by directly examining a product name, a model, and/or the like, displayed by the certification mark module 70 on the online page 60, with his or her own eyes. Next, the module request processing unit 35 receives a request from the certification mark module 70 inserted into the online page 60, and transmits data about the corresponding request. In this case, an object for which the request is intended is identified by receiving the ID of the object. In particular, in response to the certification mark request, the module request processing unit 35 transmits a certification mark assigned to the corresponding object and information about certification marks which can be inherited by the object to the certification mark module 70. Preferably, the module request processing unit 35 transmits certification mark information, including an image, certification content, certification mark, description and/or the like of the certification mark, to the certification mark module 70. In this case, when certification marks corresponding to the object are plural in number, the module request processing unit 35 may transmit images of the certification marks by generating a dynamic image via which a plurality of images is sequentially displayed. Next, the certification mark guide unit 36 provides the online page 60 which describes the certification mark in detail. Preferably, the online page 60 is constructed inside the management server 30, or is constructed by a content server, such as a web server operating in conjunction with the management server 30, or the like. The online page 60 which provides the details of the certification mark refers to a page which provides text-oriented content in a webpage, a social network system (SNS), a blog, a mobile app, or the like. The online page which provides a guide to the certification mark is published by the manager of the management server 30. FIGS. 7 and 8 are views illustrating the guide pages of certification marks. FIG. 7 shows a certification mark by which the Physical Therapist Association (hereinafter referred to as the Therapist Association) officially certifies a distributor which sells physical therapy-related products, such as functional pillows. FIG. 7 shows an image and description of the certification mark for the official distributor. Furthermore, when there is an official page of the certification mark, a link to the page is displayed, and thus direct movement to the corresponding page is provided. Furthermore, the manager or management server 30 may assign a grade to the certification mark, and may publish the corresponding grade. In this case, preferably, the grade is a grade which is determined by considering the credibility of the certification mark, the authority of an issuance organization, or the like. Furthermore, the issuance organization which has issued the corresponding certification mark and a description of the issuance organization are additionally published. A link to the description of the issuance organization, the homepage of the issuance organization, or the like may be provided. As shown in FIG. 7, when the issuance organization has obtained a certification mark, the corresponding certification mark may be inserted using the certification mark module 70. In other words, since a space which provides a guide to the certification mark is also the online page 60, the certification mark module 70 may be inserted and published. In FIG. 7, the Therapists Association, i.e., an issuance organization, has obtained permission certification from the Ministry of Health and Welfare, the certification mark module 70 for the permission certification of the Ministry of Health and Welfare may be inserted and published. Furthermore, movement to a certification guide page for the permission certification of the Ministry of Health and Welfare may be performed by clicking on the certification mark module 70. The online page 60 for the permission certification mark of the Ministry of Health and Welfare is shown in FIG. 8. Meanwhile, the certification mark module 70 for each certification mark may be directly inserted into and published on the homepage of each issuance organization, or the like. In other words, in order to prove that the Therapist Association has been officially certified by the Ministry of Health and Welfare, the Therapist Association may insert and publish the certification mark module 70 for the permission certification of the Ministry of Health and Welfare into and on the homepage thereof. Since the homepage, mobile app page or the like of the Therapist Association is the single online page 60, all the certification marks obtained by the Therapist Association may be published using the certification mark module 70. Accordingly, via the guide page of the certification mark, a user may directly visit the homepage of the corresponding issuance organization and/or the like, and may check a certification mark obtained by the corresponding issuance organization. Therefore, the user may conveniently check the credibility of the certification mark, the authority of the issuance organization, etc. Although the invention contrived by the present inventor has been described in detail based on the embodiments, the present invention is not limited to the embodiments, but various modifications may be made without departing from the gist of the present invention. | <SOH> BACKGROUND ART <EOH>Generally, users obtain certification from external organizations for the purpose of use for external advertisement, for a legal reason, or for the like. Certification includes various types of certification, such as quality certification, qualification certification, membership certification, affiliation certification, etc. Additionally, certification is present in various forms, such as certification for a pass in a test of an organization, certification for permission, certification for a member of a specific group, certification for the winning of a prize in a contest, the recommendation of an authority, an examination result, an advertisement review result, etc. Furthermore, certification is issued to a product, a service, or a company or individual which provides a product or service. Furthermore, when products or services are different but are of the same type or of similar types and form a single group, the same certification is assigned to all the products or services within the corresponding group. In the same manner, when companies or individuals form a group or a detailed group is present within a single company, the corresponding group may be a single certification target. Meanwhile, a certification organization certifies a certification target, and issues a certificate or the like capable of indicating the certification. The certification organization may be an individual, a company, an organization, a government, or a group thereof. Furthermore, the certificate or the like is an official document which is an evidence for the obtainment of certification, such as a certificate, a warrant, a license, a membership card, or the like. The certificate or the like may be present in the form of a paper document, an electronic document, a certification mark, text, or the like. By receiving external certification, a user can verify the excellence of himself or herself or his or her product or service and can advertise it externally, and thus the user attempts to obtain credible certification. When certification is obtained from a certification organization, the user places the certificate in an office or the like, or posts it on a homepage, an advertisement, or a product description in text format, image file format, or the like. In particular, certification is displayed offline by attaching a certification mark to a product, goods, or a service space. However, in spite of many efforts to promote the advantages of certification, a problem arises in that many consumers do not fully understand the details of each certification due to the proliferation of various certification systems. For this purpose, an electronic certification mark technology for attaching an electronic tag to a certification mark is proposed offline [see Patent document 1]. Furthermore, a certification mark can be imitated, and thus a technology for protecting a certification mark for distribution by means of a protection medium is also proposed [see Patent document 2]. Furthermore, a third party who sells a user's product on the Internet, such as an online open market, promotes the product by means of an advertizing material made by the user by including a certificate or certification mark image or by means of a certificate or certification mark image [see Patent document 3]. However, the details, validity, and counterfeiting of online certification marks need to be verified, like those of offline certification marks. Generally, for this purpose, the validity and certification-related details of a certificate published online can be checked by referring to a certification organization having issued the certificate by reference to a published certificate image or description. Furthermore, in order to verify the credibility of a certificate, an issuance organization must be checked for credibility. It may be possible to directly check the issuance organization itself for credibility, or to check credibility based on the certification of a higher certification organization (a government or the like) or an external organization (a media organization, an international organization, a well-known person, or the like). There are cases where an issuance organization posts the logos and links of one or more higher or related organizations on a website. However, in order to verify this, a problem arises in that it is necessary to visit each of the higher or related organizations and verify it through a search or the like. Furthermore, when a result cannot be accurately determined, it is difficult to determine whether the issuance organization is trustworthy or not, and time and cost are required due to a phone call or visit to each of the organizations. For example, a seller may post a health function certification mark, obtained from a certification organization without credibility, on a product sales page. In other words, an issuance organization which issued the health function certification mark of a corresponding product may not be an organization certified by a higher organization, such as the government, or related organization. However, a consumer may be misled by the certification mark, may mistake a product as a product for which a health function has been officially certified, and may then purchase the product. Even when the organization is not an issuance organization certified by a credible organization, it appears to be credible, and thus damage may be caused. When a third party selling a product is promoting using a certificate at a shopping mall or other website, damage may be caused because official sales qualification, the certification of a corresponding product, or the certification of a corresponding company is not verified. Furthermore, a problem arises in that there are cases where it is impossible to verify certification due to the mismanagement, absence or closing of the website of an issuance organization. Furthermore, a change to a certificate (such as a change in validity, a change to a certification mark, a change in the name of an organization, or the like) is not immediately transferred, and thus confusion may be caused. | G06Q30018 | 20180316 | 20180927 | G06Q3000 | 0 | O'SHEA, BRENDAN S | ONLINE CERTIFICATION MARK PUBLICATION SYSTEM | MICRO | 0 | REJECTED | G06Q | 2,018 |
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15,762,013 | PENDING | AEROSOL PROVISION SYSTEM WITH REMOTE AIR INLET | A vapor provision system includes an aerosol delivery section configured to generate aerosol from liquid in a reservoir, an airflow path through the aerosol delivery section extending from an air inlet to a mouthpiece, a battery section configured to join to the aerosol delivery section and house a battery to provide electrical power to one or more components in the aerosol delivery section, the battery section arranged laterally to at least a portion to the aerosol delivery section with respect to a direction of airflow through the mouthpiece, and an interface region in which a surface of the aerosol delivery section faces a surface of the battery section when the sections are joined, the air inlet being located on the aerosol delivery section in the interface region so as to take in air that has been channeled over part of the battery section. | 1. A vapor provision system comprising: an aerosol delivery section configured to generate aerosol from liquid in a reservoir; an airflow path through the aerosol delivery section extending from an air inlet to a mouthpiece; a battery section configured to join to the aerosol delivery section and house a battery to provide electrical power to one or more components in the aerosol delivery section, the battery section arranged laterally to at least a portion of the aerosol delivery section with respect to a direction of airflow through the mouthpiece; and an interface region in which a surface of the aerosol delivery section faces a surface of the battery section when the aerosol delivery section and the battery section are joined; wherein the air inlet is located on the aerosol delivery section in the interface region so as to take in air that has been channeled over part of the battery section. 2. The vapor provision system according to claim 1, wherein the battery section is arranged laterally to the aerosol delivery section with respect to a direction of airflow through the mouthpiece. 3. The vapor provision system according to claim 1, wherein the battery section has a connecting portion that extends laterally to receive a base part of the aerosol delivery section, and the air inlet is located in a base wall of the aerosol delivery section that faces the connecting portion when the battery section and the aerosol delivery section are joined. 4. The vapor provision system according to claim 3, comprising co-operating screw threads or engaging elements on the connecting portion and the aerosol delivery section base part by which the battery section and the aerosol delivery section can be joined, the screw threads or engaging elements being shaped such that when the screw threads or engaging elements are fully engaged, air can flow over at least part of the screw threads or engaging elements to be taken in by the air inlet. 5. The vapor provision system according to claim 3, wherein a surface of the connecting portion that faces the base part of the aerosol delivery section has formed therein at least one recess such that when the battery section and the aerosol delivery section are joined a cavity is formed in the interface region with at least one external opening to air at an edge of the interface region, the air inlet being in airflow communication with the cavity. 6. The vapor provision system according to claim 5, wherein the at least one recess comprises at least one groove in the surface of the connecting portion, the at least one groove extending radially with respect to a central axis of the aerosol delivery section when joined to the battery section to an end that forms one of the at least one external openings. 7. The vapor provision system according to claim 6, wherein the base part of the aerosol provision section and the surface of the connecting portion are shaped to form a central cavity in the interface region with which the at least one groove is in airflow communication at an end opposite to the external opening end, the air inlet being in airflow communication with the central cavity. 8. The vapor provision system according to claim 7, wherein the central cavity houses an electrical connection between the battery section and the aerosol delivery section. 9. The vapor provision system according to claim 1, wherein the aerosol delivery section and the battery section are externally shaped such that when the aerosol delivery section and the battery section are joined a cavity is formed in the interface region with at least one external opening to air at an edge of the interface region, the air inlet being in airflow communication with the cavity. 10. The vapor provision system according to claim 9, wherein the surface of the battery section in the interface region is a side wall of the battery section and the surface of the aerosol delivery section in the interface region is a side wall of the aerosol delivery section. 11. The vapor provision system according to claim 9, wherein the cavity is at least partially formed by at least one recess in the side wall of the battery section having at least one end that forms one of the at least one external openings to air. 12. The vapor provision system according to claim 11, wherein the at least one recess is a groove extending across the side wall of the battery section from a first end to a second end, each of the first end and the second end forming one of the at least one external openings to air. 13. The vapor provision system according to claim 11, wherein the at least one recess has an end forming one of the at least one external openings to air, the end located at an edge of the interface proximate the mouthpiece. 14. The vapor provision system according to claim 5, wherein the cavity has at least two external openings to air. 15. The vapor provision system according to claim 5, further comprising an adjustable element configured to enable an effective size of the air inlet to be altered, so as to vary a level of airflow along the airflow path. 16. An aerosol delivery section for a vapor provision system which is configured to generate aerosol from liquid in a reservoir when joined to a battery section housing a battery, the aerosol delivery section comprising: an air inlet; an airflow path through the aerosol delivery section from the air inlet to a mouthpiece; and an interface region comprising a surface of the aerosol delivery section configured to face a surface of a battery section when the aerosol delivery section is joined to the battery section; wherein the air inlet is located in the interface region so as to take in air that has been channeled over part of the battery section when the aerosol delivery section and the battery section are joined. 17. A battery section for a vapor provision system which is configured to house a battery to provide electrical power to an aerosol delivery section when the battery section is joined to an aerosol delivery section, the battery section comprising: an interface region comprising a surface of the battery section configured to face a surface of an aerosol delivery section when the battery section is joined to the aerosol delivery section; and at least one recess formed in the interface region positioned for alignment with an air inlet in the aerosol delivery section, the at least one recess having at least one end at an edge of the interface region to define an external opening to air. | PRIORITY CLAIM The present application is a National Phase entry of PCT Application No. PCT/GB2016/052808, filed Sep. 12, 2016, which claims priority from GB Patent Application No. 1516792.7, filed Sep. 22, 2015, each of which is hereby fully incorporated herein by reference. TECHNICAL FIELD The present disclosure relates to an aerosol or vapor provision system with an air inlet. BACKGROUND Aerosol provision systems such as e-cigarettes generally contain a reservoir of a source liquid containing a formulation, typically including nicotine, from which an aerosol is generated, such as through vaporization or other means. Thus an aerosol source for an aerosol provision system may comprise a heating element coupled to a portion of the source liquid from the reservoir. When the heating element is activated it causes vaporization of a small amount of the source liquid, which is thus converted to an aerosol for inhalation by the user. More particularly, such devices are usually provided with one or more air inlet holes which may or may not be located away from a mouthpiece of the system. When a user sucks on the mouthpiece, air is drawn through the inlet holes and past the aerosol source. There is an air flow path connecting the inlet holes to the aerosol source and on to an opening in the mouthpiece so that air drawn past the aerosol source continues along the flow path to the mouthpiece opening, carrying some of the aerosol from the aerosol source with it. The aerosol-carrying air exits the aerosol provision system through the mouthpiece opening for inhalation by the user. Some aerosol provision systems are configured in two sections. An aerosol provision section houses the reservoir of source liquid and one or more heating elements, and has the airflow path defined therethrough from the inlet hole(s) to the mouthpiece. A battery section houses a battery (which may be replicable or rechargable) for providing electrical power to the heating element. An electrical connection is provided between the two sections. The sections can be separable from one another, in which case there is also a mechanical connection between the sections; this typically also makes the electrical connection. The two sections can be arranged linearly so that the battery section is connected at the opposite end of the aerosol provision section to the mouthpiece. This gives a generally elongate device in which the battery is aligned substantially along the direction of airflow in the flow path, and when the mouthpiece points upwards, as it does in use, the battery section is underneath the aerosol provision section. The air inlet can be located in a side wall of the aerosol delivery section just below the base of the reservoir, that is, the part of the reservoir remote from the mouthpiece. This gives a short and simple air flow path to the heating element (which is generally in or near the reservoir). However, there is a risk that the user will cover this air inlet with his hand or fingers when using the device. As well as inhibiting or reducing aerosol delivery, this can be unsafe in devices in which the heating element is switch-operated under control of the user. A lack of airflow can then lead to overheating. SUMMARY According to a first aspect of certain embodiments described herein, there is provided a vapor provision system comprising: an aerosol delivery section configured to generate aerosol from liquid in a reservoir; an airflow path through the aerosol delivery section extending from an air inlet to a mouthpiece; a battery section configured to join to the aerosol delivery section and house a battery to provide electrical power to one or more components in the aerosol delivery section, the battery section arranged laterally to at least a portion to the aerosol delivery section with respect to a direction of airflow through the mouthpiece; an interface region in which a surface of the aerosol delivery section faces a surface of the battery section when the sections are joined; wherein the air inlet is located on the aerosol delivery section in the interface region so as to take in air that has been channeled over part of the battery section. The battery section may be arranged laterally to the aerosol delivery section with respect to a direction of airflow through the mouthpiece. The battery section may have a connecting portion that extends laterally to receive a base part of the aerosol delivery section, the air inlet being located in a base wall of the aerosol delivery section that faces the connecting portion when the sections are joined. The vapor provision system may then further comprise co-operating screw threads or engaging elements on the connecting portion and the aerosol delivery section base part by which the sections can be joined, the screw threads or engaging elements being shaped such that when they are fully engaged, air can flow over at least part of the screw threads or engaging elements to be taken in by the air inlet. Alternatively, a surface of the connecting portion that faces the base part of the aerosol delivery section has formed therein at least one recess such that when the sections are joined a cavity is formed in the interface region with at least one external opening to air at an edge of the interface region, the air inlet being in airflow communication with the cavity. The at least one recess may comprise at least one groove in the said surface of the connecting portion, the or each groove extending radially with respect to a central axis of the aerosol delivery section when joined to the battery section to an end that forms one of the said at least one external openings. The base part of the aerosol provision section and the said surface of the connecting portion may be shaped to form a central cavity in the interface region with which each groove is in airflow communication at an end opposite to the external opening end, the air inlet being in airflow communication with the central cavity. The central cavity may house an electrical connection between the battery section and the aerosol delivery section. In an alternative embodiment the aerosol delivery section and the battery section may be externally shaped such that when they are joined a cavity is formed in the interface region with at least one external opening to air at an edge of the interface region, the air inlet being in airflow communication with the cavity. Said surface of the battery section in the interface region may be a side wall of the battery section and the said surface of the aerosol delivery section in the interface region may be a side wall of the aerosol delivery section. The cavity is at least partially formed by at least one recess in the said side wall of the battery section having at least one end that forms one of said external openings to air. For example, each recess may be a groove extending across the said side wall of the battery section from a first end to a second end, each of the first and second ends forming one of said external openings to air. Alternatively, each recess may have an end forming one of said external openings to air, said end located at an edge of the interface proximate the mouthpiece. The cavity may have at least two external openings to air. The vapor provision system may further comprise an adjustable element configured to enable an effective size of the air inlet to the altered, so as to vary the level of airflow along the airflow path. According to a second aspect of certain embodiments described herein, there is provided an aerosol delivery section for a vapor provision system which is configured to generate aerosol from liquid in a reservoir when joined to a battery section housing a battery, the aerosol delivery section comprising: an air inlet; an airflow path through the aerosol delivery section from the air inlet to a mouthpiece; and an interface region comprising a surface of the aerosol delivery section configured to face a surface of a battery section when the aerosol delivery section is joined to said battery section; wherein the air inlet is located in the interface region so as to take in air that has been channeled over part of the battery section when the sections are joined. The air inlet may be concealed from a user when the aerosol delivery section is joined to a battery section. In some examples, the air inlet may be located in a base wall or a side wall of the aerosol delivery section. According to a third aspect of certain embodiments described herein, there is provided a battery section for a vapor provision system which is configured to house a battery to provide electrical power to an aerosol delivery section when the battery section is joined to an aerosol delivery section, the battery section comprising an interface region comprising a surface of the battery section configured to face a surface of an aerosol delivery section when the battery section is joined to said aerosol delivery section; and at least one recess formed in the interface region positioned for alignment with an air inlet in said aerosol delivery section, the recess having at least one end at an edge of the interface region to define an external opening to air. The battery section may be configured such that an aerosol delivery section may be joined to it in an arrangement in which the battery section is arranged laterally to at least a portion to the aerosol delivery section with respect to a direction of airflow through a mouthpiece of the aerosol delivery section. The battery section may have a base portion that extends laterally to which an aerosol delivery section may be joined. These and further aspects of certain embodiments are set out in the appended independent and dependent claims. It will be appreciated that features of the dependent claims may be combined with each other and features of the independent claims in combinations other than those explicitly set out in the claims. Furthermore, the approach described herein is not restricted to specific embodiments such as set out below, but includes and contemplates any appropriate combinations of features presented herein. BRIEF DESCRIPTION OF THE DRAWINGS Various embodiments will now be described in detail by way of example only with reference to the accompanying drawings in which: FIG. 1 shows a schematic side view representation of an electronic cigarette to which embodiments of the disclosure are applicable. FIG. 1A shows an enlarged view of a lower part of the electronic cigarette of FIG. 1. FIGS. 2A and 2B show simplified side and top views of an electronic cigarette with regions of particular interest to the present disclosure highlighted. FIG. 3 shows a schematic cross-sectional view of an example aerosol delivery section of an electronic cigarette in accordance with an embodiment of the disclosure. FIG. 4 shows a schematic cross-sectional view of a further example aerosol delivery section coupled to a battery section. FIGS. 5A, 5B and 5C show an enlarged partial cross-sectional view, a plan view and a side view of parts of an electronic cigarette in accordance with an embodiment. FIGS. 6A and 6B show an enlarged partial cross-sectional view and a plan view of parts of an electronic cigarette in accordance with another embodiment. FIGS. 7A and 7B show an enlarged partial cross-sectional view and a plan view of parts of an electronic cigarette in accordance with a further embodiment. FIG. 8 shows a perspective view of a battery section of an electronic cigarette in accordance with an embodiment. FIGS. 9A and 9B show side views of a battery section and an aerosol delivery section in accordance with a further embodiment. FIGS. 10, 11 and 12 show side views of three example battery sections configured in accordance with further embodiments. FIGS. 13A and 13B show a side view and a top view of a battery section in accordance with an alternative embodiment. FIG. 14 shows a side view of battery section in accordance with a different embodiment. FIG. 15 shows a cross-sectional side view of an electronic cigarette in accordance with a yet further embodiment. FIG. 16 shows a schematic side view of an aerosol delivery section according to various embodiments. DETAILED DESCRIPTION Aspects and features of certain examples and embodiments are discussed/described herein. Some aspects and features of certain examples and embodiments may be implemented conventionally and these are not discussed/described in detail in the interests of brevity. It will thus be appreciated that aspects and features of apparatus and methods discussed herein which are not described in detail may be implemented in accordance with any conventional techniques for implementing such aspects and features. As described above, the present disclosure relates to aerosol provision systems, such as e-cigarettes. Throughout the following description the terms “e-cigarette” or “electronic cigarette” may sometimes be used; however, it will be appreciated these terms may be used interchangeably with aerosol (vapor) provision system. Directional terms in the present application, such as upper, lower, top, bottom, side and the like, are not to be considered limiting and are used for convenience and brevity, and consistency with the Figures. The terms apply to the typical orientation of an e-cigarette in use, when the mouthpiece points upward (such as in FIG. 1), and should be interpreted accordingly if considering a different orientation of an e-cigarette. FIG. 1 is a schematic diagram of an example aerosol/vapor provision system such as an e-cigarette 10 to which some embodiments are applicable. The e-cigarette 10 is a modular device comprising a battery section 12 and an aerosol delivery section 14 which are mechanically and electrically connected together. The battery section 12 houses a battery 26 and has one or more buttons or switches 15 for a user to operate to deliver electrical power to one or more components in the aerosol delivery section 14. The battery section 12, in this example, has two supporting sections 28a, 28b which extend laterally to receive and support the aerosol delivery section 14. In particular, the lower supporting section 28b is a connecting portion which makes the necessary electrical connections to the battery 26, and also provides a mechanical connection which may be, for example, a screw thread connection between cooperating screw threads on the connection portion 28b and the base of the aerosol delivery section 14, or a friction “push fit” style of connection. The aerosol delivery section 14 is cylindrical in this example, and at its base has a grip portion 24 provided with vertical grooves or other surface features to facilitate grip, so that a user can hold this part and rotate the aerosol delivery section 14 to disengage the screw threads, or pull to overcome the friction fit. Alternatively the two sections may be shaped to slot or fit together, with a latch, clip, hinged portion or other retaining element provided to secure the two section together in the joined configuration. Other joining arrangements may also be used. Once the relevant parts are disengaged or separated, the aerosol delivery section 14 can be lifted free from the battery section 12. FIG. 1A shows a simplified schematic partial side view of the lower part of the system 10 according to an example. The aerosol delivery section 14 is shown separated from the battery section 12. The battery section has an upwardly protruding connector 32 extending from the upper face of the connecting portion 28b, where the upper face is a wall or surface that faces the aerosol delivery section when the two sections are joined. The connector 32 is an electrode in a suitable housing or cover, by which an electrical connection can be made between the battery in the battery section 12 and components such as a heating element in the aerosol delivery section 14. The aerosol delivery section has a corresponding socket 34 formed inwardly on its lower face or wall which fits over the connector 32 and houses one or more electrical contacts which are brought into contact with the electrode to form the electrical connection when the sections are joined together. The aerosol delivery section 14 comprises the aforementioned grip section 24 at its base, above which is a tank base section 20. A tank or reservoir 16 extends upwardly from this base section 20 and is formed by transparent walls so that a user can conveniently observe liquid solution contained in the tank 16. The walls need not be transparent, however. A tube or pipe 17 runs centrally up through the tank 16; this defines part of the airflow path that runs through the aerosol delivery section 14. Disposed within the pipe 17 are one or more wicks mounted within or around one or more heating elements that might be in the form of coils (not shown). The wicks absorb liquid from the tank, the heating coils are heated when electrical current is supplied to them from the battery 26, and the liquid in the wicks is vaporized, and carried away on air flowing through the pipe 17. A lid 18 is provided to close the upper end of the tank 16. The lid 18 can be removed to allow the tank 16 to be refilled when the aerosol delivery section 14 is disconnected from the battery section 12. The airflow path passes through the lid 18 to a mouthpiece 22 through which a user can inhale to generate the required airflow along the airflow path. The mouthpiece, also known as a “drip tip”, may or may not be removable and/or replaceable. The opposite end of the air flow path within the aerosol delivery section 14 to the mouthpiece 22 is defined by at least one air inlet (not shown in FIG. 1) in the outer surface of the aerosol delivery section 14 which connects to the pipe 17. When a user inhales through the mouthpiece 22, air is taken in through the air inlet to flow along the air flow path. Locating the air inlet in an area such as the exposed side of the tank base section 20 provides a conveniently short path to the heating coils and wick. However, an inlet in this location is vulnerable to being wholly or partially covered by the user's hands or fingers as they hold the e-cigarette to inhale through it. Embodiments of the present disclosure propose positioning the air inlet to address this issue. In particular, the air inlet can be positioned so that air reaching it is not drawn directly in through a wall of aerosol delivery section 14, but instead is caused to flow over a part of the battery section 12 before reaching the air inlet. This can be achieved by locating the air inlet in an interface region where part of the aerosol delivery section faces part of the battery section, and shaping and configuring parts of the battery section and/or the aerosol delivery section in this interface region to facilitate this air flow by providing air flow communication between the air inlet and an external opening to air formed at the edge of the interface region where the aerosol delivery section is adjacent to the battery section. Arrangements in accordance with this proposal can configure this external open end of the air flow path so that the risk of the path being blocked when holding the device is reduced or avoided. FIGS. 2A and 2B are highly schematic representations of an e-cigarette 10 having a battery section 12 and an aerosol delivery section 14, to illustrate example positions of the interface region. The sections may be differently shaped than shown, with a differently shaped interface; these representations are examples only. The interface region is considered to be any area in which an outer surface or wall of the aerosol delivery section 14 faces an outer surface or wall of the battery section 12 when the two sections are joined together. In the side view of FIG. 2A, an interface region of interest is shown by the heavy line I, and comprises the area in which the base part of the aerosol delivery section 14 is received on the upper face of the connecting portion 28b, and the area in which a side wall of the aerosol delivery section 14 faces an adjacent side wall of the battery section 12. Note that the interface region extends through the thickness of the e-cigarette over the whole extent of the facing surfaces, and is not limited to the edges only. FIG. 2B shows a plan view of the system 10 from above, from which it can be seen that the interface region I between the side walls of the sections 12, 14 extends up to the top surface of the e-cigarette 10. In accordance with embodiments of the disclosure, the air inlet for the airflow channel is located on a surface of the aerosol delivery section 14 that is within the interface region, and at least one external opening to air that delivers air to the air inlet is located at an edge of the interface region, such as is indicated by the lines I in FIGS. 2A and 2B. FIG. 3 shows a cross-sectional schematic view of an aerosol delivery section 14 configured according to some embodiments. In this example, the grip section 24 has a screw thread 25 on its inner surface for coupling with a corresponding thread on the battery section 12. Above this lies the tank base section 20, which in this example forms a base wall of the aerosol delivery section 14. Other configurations may be envisaged where parts other than the tank base form the base wall, for example if other components are installed below the tank 16, or if a connecting mechanism other than a screw thread is employed, such as a push or snap fit. The base wall faces the upper face of the connecting portion 28b of a battery section when a battery section is joined to the aerosol delivery section, giving an interface region. Regardless of the nature of the base wall, in this embodiment the air inlet 30 is formed in this base wall, and connects with the pipe 17 so that air taken in through the inlet 30 flows along the flow path and into the pipe 17 to the heating coil or element (not shown) and subsequently out through the mouth piece 22, as indicated by the arrows A. The air inlet 30 need not be centrally located as illustrated, and may also comprise two or more separate inlets which each connect with the pipe 17. The term “air inlet” is intended to cover arrangements with a single inlet and also with more than one inlet where these inlets each supply air to the airflow path. To enable air intake into the air inlet 30 when the aerosol delivery section 14 is joined to its battery section, embodiments of the disclosure propose various configurations for one or more external aperture or openings to air displaced from the air inlet 30 and located at the interface edge, but in airflow communication with the air inlet 30. This allows the initial air entry point for the airflow path to be situated so that the risk of accidental blockage is mitigated. In some examples, this is achieved by moving this initial intake to a relatively low position on the e-cigarette so that the risk of a user blocking the air flow with his hand is reduced. FIG. 4 shows a cross-sectional schematic view of a vapor provision system in accordance with such an embodiment. The aerosol delivery section 14 is largely as in FIG. 3, except that the air inlet 30 in this example comprises a plurality of individual inlets in an annular arrangement that connect by channels to the pipe 17 (or the air inlet might be a single annular aperture). The aerosol delivery section 14 is shown coupled to the battery section 12 via the screw thread 25 which is engaged with a corresponding screw thread 27 upstanding from the upper face of the connecting portion 28b of the battery section 12. Note that for simplicity the electrical connection is not shown. The screw threads are configured such that when they are fully tightened together there are one or more gaps extending through the threads that form an air flow pathway or channel by which air can enter from the external environment, traverse the screw thread into the volume of the interface region (under the base wall 20 of the tank 16) and so through the air inlet 30 to the pipe 17, as shown by the arrows A. This might be achieved by having breaks in the screw thread, or otherwise forming the screw threads so that when coupled they form a seal which is leaky or not airtight. By using the screw thread in this way, the external opening to air may be caused to extend around a large part of the lower edge (circumference) of the aerosol delivery section 14 so that it is very unlikely that a user would completely cover the air intake in use. Alternative engagement arrangements between the aerosol delivery section 14 and the battery section can be configured to enable air intake in a similar manner to a leaky screw thread. For example, the aerosol delivery section and the battery section may be provided with cooperating engaging elements that are shaped to provide a friction fit when the two sections are pushed together or to provide a mechanical attachment by means of protruding lugs, a collar or similar element on one section that fit over or into depressions or hollows in the other section when the two sections are pushed together. These elements can be shaped so that when the sections are coupled or joined the resulting attachment is not airtight, and allows air to pass through to reach the air inlet in the base of the aerosol delivery section. Other arrangements are possible in which the air inlet is located in the base wall of the aerosol delivery section, the interface region being between the aerosol delivery section base and the upper surface of the connecting portion. FIG. 5A shows a cross-sectional view through the interface region of an embodiment having a base wall air inlet. The aerosol delivery section 14 is joined to the connecting portion 28b of the battery section 16. It has a socket 34 which engages with a connector 32 on the connecting portion 28b (as in FIG. 1A) to make the required electrical connection (not shown). A central air inlet 30 is formed in the base wall, within the socket 34. The socket is shaped so as to be larger than the connector so that there is a cavity 35 between the walls of the socket 34 and the walls of the connector 32, which is in airflow communication with the air inlet 30. To enable air to enter this cavity and thence the air inlet 30, the upper face of the connecting portion 28b of the battery section 16 has formed in it a number of recesses or grooves 40. The grooves have one end at or near to the connector 32 so that this end opens into the cavity between the connector 32 and the socket 34. In this example, the aerosol delivery section 14 has the same outer profile as the connecting section 28b at the interface region edge, so the grooves 40 have opposite ends in the side walls of the connecting section 28b, to form an external opening to air 42 at the end of each groove 40. Thus, when the aerosol delivery section is connected, air can enter the external openings, flow along the grooves 40 (under the base wall of the aerosol delivery section 14 and over those parts of the surface of the connecting portion that form the grooves) to the cavity and into the air inlet 30. FIG. 5B shows a plan view (to a different scale) of the connecting portion 28b, extending laterally from the battery section 16. In this example, there are seven grooves 40 arranged radially so that they extend inwardly from the ends in the side walls of the connecting portion towards the central connector 32. In effect, they are radially arranged with respect to a central longitudinal axis of the aerosol delivery section 14 when it is joined to the battery section 16. However, other arrangements are possible, for example if the connector and socket are not centrally disposed, or if a different configuration is otherwise preferred. For example, there may be a plurality of parallel grooves arranged with one end at the outer edge and one end reaching to the cavity. Groups of parallel grooves might be spaced apart around the connecting portion. Any number of grooves, from one upwards, can be used as required to achieve a desired level of air intake and airflow in the airflow path. The grooves need not be straight, and they may have a width that changes along their length. However, a larger number of grooves gives a larger number of external openings to air, which decreases the risk of the air intake being blocked by a user holding the e-cigarette. The grooves together can be thought of as comprising part of the cavity 35, so that the outer ends 42 of the grooves or recesses are the external openings to air of the cavity. FIG. 5C shows a side view (to a different scale) of the connecting portion 28b, depicting how the grooves extend out to the side walls of the connecting portion 28b so that their ends 42 appear as notches. FIG. 6A shows an alternative embodiment comprising grooves or recesses in the connecting portion upper face. Many features are the same as in the example of FIGS. 5A to 5C, and the remarks made regarding that example apply also to this example. A difference from the FIG. 5A example is that the aerosol delivery section 14 has a smaller width (diameter in this cylindrical example) than the connecting portion 28b on which it sits, so that the edges of the connecting portion 28b extend beyond the base of the aerosol delivery section 14. This means that there is no need for the grooves to extend out into the side walls of the connecting portion 28b. Instead, they terminate in the upper face of the connecting portion 28b at a point beyond the outer edge of the aerosol delivery section, to form the external openings to air 42. FIG. 6B shows a corresponding plan view (to a different scale) of the connecting portion 28b, in which it can be seen that the grooves (six in this example) are again radially arranged, but have outer ends located inwardly from the edge (side wall) of the connecting portion 16. FIG. 7A shows a further alternative embodiment comprising grooves or recesses in the connecting portion upper face. Again, many features are the same as in the example of FIGS. 5A to 5C, and the remarks made regarding that example apply also to this example. A difference from the FIG. 5A example is that the socket 34 and the connector 32 have closely matched diameters (or other width dimensions if not circular) so that the cavity 35 is limited to only a space above the connector 32 and below the air inlet 30 in the base of the socket 34. To enable air to reach the cavity 35 to enter the air inlet 30, the grooves 40, again in the upper face of the connecting portion, extend also up the sides of the connector 32 and terminate in the upper face of the connector 32 to communicate with the cavity 35. The outer ends 42 of the grooves 40 defining the external openings to air are formed in the outer wall of the connecting portion 28b, as in FIG. 5A, but may instead be formed as in FIG. 6A. FIG. 7B shows a corresponding plan view (to a different scale) of the connecting portion 28b, in which it can be seen that the grooves (five in this example) are again radially arranged, have outer ends 42 in the side wall of the connecting portion 16, and inner ends 44 in the upper face of the connector 32 to give airflow communication into the cavity 35. In other embodiments, the air inlet can be located in the side wall of the aerosol delivery section, so as to take in air received via the interface region between the side wall of the aerosol delivery section and the facing side wall of the battery section. This arrangement moves the air inlet away from electrical connection. This can be beneficial in reducing the risk of any leakage of the source liquid from the tank to the electrical contacts via the airflow pathway. To achieve such an arrangement, the outer surface of the battery section can be shaped so as to include one or more recesses or grooves in the wall that faces and abuts the aerosol delivery section. The recesses extend out to the edge of the interface region. When the sections are placed together, this shaping defines one or more cavities (multiple cavities are considered still as one cavity for understanding of these embodiments) in the interface region, which have an external communication to air via ends of the recesses that reach to the edge of the interface region and form openings thereat. The air inlet (which might be one or more individual apertures that connect with the pipe 17 as described with regard to FIGS. 3 and 4) is created in the aerosol delivery section in a position that is aligned with the cavity. Thus, air can be taken into the airflow path by entering through the external opening(s) into the cavity and then into the air inlet. The aerosol delivery section and the battery section can be configured to ensure that the alignment of the air inlet with the cavity is achieved and maintained when the two sections are joined. For example, there may be shaped co-operating parts that allow the sections to be engaged only in the required orientation, or a screw thread coupling may be structured to that the air inlet and the cavity are brought into alignment when the screw thread is fully fastened. FIG. 8 shows a perspective view of an example battery section 12 such as that shown in FIG. 1. Supporting sections 28a, 28b including connecting portion 28b extend laterally from the battery section to receive, support and hold an aerosol delivery section, and make an electrical connection to the aerosol delivery section via a connector 32. The battery section 12 has a side wall 50 which will face a side wall of a joined aerosol delivery section. The interface region lies in the area of these side walls in the following embodiments. FIG. 9A shows a side view of a battery section 12 from the direction of arrow X in FIG. 8. In this example, the side wall 50 has a groove 52 defined in its surface, extending substantially horizontally across the wall 50 from one side to the other. The groove 52 terminates at the edges of the wall, in this example in the form of notches 54 in the edges. Hence, the groove ends 54, which form the external openings to air in this embodiment, will be externally visible in this example. Alternatively, certain shapes of battery section, particularly those like this example where the side wall 50 is concave, will allow the groove ends 54 to be formed so as to be less visible. FIG. 9B shows a schematic side view of an aerosol delivery section 14 suitable for use with the battery section 12 of FIG. 9A. An air inlet 30 is formed in the side wall 60. In this example, the air inlet 30 is near the base of the tank 16, but it may be disposed elsewhere in the interface region, with corresponding positioning of the groove 54 so that the air inlet 30 and the groove can be aligned. In use, the two sections are joined so that the side wall 60 of the aerosol delivery section faces the side wall 50 of the battery section 12, defining the interface region. The groove 52, when brought together with the side wall 60 of the aerosol delivery section 14, can be thought of as a cavity of a particular shape, having two external openings to air (one each side of the battery section). A groove or recess with only one external end might be provided instead, but the use of more than one external opening to air reduces the risk of accidental blockage of the air intake. Additionally, cavities of other shapes and configurations, with various numbers of external openings, may be used instead. FIG. 10 shows a second example of a battery section 12, in side view, configured with a shaped side wall. In this example, three substantially parallel horizontal grooves are provided, each extending to both edges of the side wall 50 to give a total of six external openings to air. To function with this cavity arrangement, the aerosol delivery section might have three individual air inlets each connected to the airflow path, one for each groove 52, or a single air inlet having a large vertical extent that traverses all three grooves 52. FIG. 11 shows another example of a battery section 12, in side view, configured with a shaped side wall. In this example, a total of six grooves 52 are provided to define with cavity, three of which create external openings to air on one edge of the side wall 50 and three of which create external openings to air on the opposite side of the side wall 50. The grooves are angled so as to all meet together at their ends opposite to the external opening ends, forming a star shape. An arrangement such as this, in which multiple external openings connect to a single central recess 56 to which the air inlet will be aligned, provide the advantage of multiple air intake positions while avoiding any need for a large air inlet or multiple air inlets. FIG. 12 shows a similar example to that of FIG. 11. In this example, again shown in side view, the six grooves 52 in the side wall 50 meet at a much larger central recess 56. This provides the advantages of the FIG. 11 example together with more flexibility in the positioning of the air inlet for proper alignment with the cavity. This can give improved design freedom, for example, or require a less precise fit or coupling when a user joins the aerosol delivery section to the battery section 12. Embodiments of this type in which recesses are formed in the battery section side wall are not limited to configurations in which the recesses define external openings to air at the sides of the e-cigarette. The recesses or grooves may alternatively or additionally be arranged to as to define one or more external openings at the top of the device. To achieve this, the recess(es) may be aligned more vertically. FIG. 13A shows a side view of an example battery section 12 configured in this way. The upper supporting portion 28a is shown cut away to reveal the top part of the side wall 50. A vertical groove 52 is shaped into the side wall 50 extending from the top edge where it defines an external opening to air 54, down to a larger recess 56 where the air inlet on the aerosol delivery section can be aligned. FIG. 13B shows a plan view of the top of the battery section 12, showing how the groove forms the external opening to air 54 at the top edge of the wall when the aerosol delivery system 14 is inserted into the battery section 12. More than one vertical groove might be provided, which may or may not terminate in a common recess. Also, one or more substantially vertical grooves may be combined with one or more substantially horizontal grooves, so provide external openings to air at both the top and sides of the device. The sides of the device offer more space to accommodate a larger number of air intakes, but since these are more vulnerable to being covered in use than an intake at the top of the device, a top intake can be provided as well to ensure that there is at least one intake that is highly unlikely to be accidentally blocked. FIG. 14 shows a side view of an example battery section configured in this manner. It has the same features as the battery section shown in FIG. 13A, but also includes two additional grooves 52 which extend between external openings to air 54 in opposite side edges of the interface region and the larger recess 56. More such grooves or just one such groove might be included if desired. A further alternative is to combine a groove or recess in the battery section side wall 50 with one or more grooves or recesses in the connecting portion such as in the examples of FIGS. 5, 6 and 7. A groove in the battery section side wall may commence at an external opening in an edge of the interface region, and extend to the lower part of the battery section side wall to connect to a groove in the connection portion upper surface, to provide an air pathway to an air inlet in the base wall of the aerosol delivery section. FIG. 15 shows a schematic cross-sectional view of an example vapor provision device 10 having these features. The battery section 12 has formed in its side wall 50 a vertical groove or recess 52 extending from an external opening to air 54 at its top edge adjacent the mouthpiece 22 of the aerosol delivery section 14 down to the bottom edge of the side wall 50, where it connects to a groove 52 in the upper face of the connecting portion 28b. This groove 52 is in airflow communication with a cavity 35 between the connector 32 of the connecting portion 28b and the socket 34 in the base of the aerosol delivery section 14. In this way, air taken in at the external opening 54 at the top of the system flows along the connected grooves 54 to the cavity 35 and into the air inlet 30, to enter the airflow path through the aerosol delivery section 14. Grooves and recesses of any size, shape, position and quantity can be provided to carry air from the edge of the interface region (the exterior junction between the aerosol delivery section and the battery section) to an air inlet located inside the interface region. The grooves need not be straight or of constant width, and may meet together or remain separate. Each groove, or the overall cavity defined by one or more grooves or recesses, may have one or more than one external opening to air. The examples and embodiments discussed above have utilized various shapings in the outer surface of the battery section to achieve the desired channeling of air from the external intake(s) to the interior air inlet on the aerosol delivery section. Equivalent effects can be readily achieved by using shaping of the outer surface of the aerosol delivery section instead, or combining shaping of the aerosol delivery section and the battery section. Consequently, all such combinations are considered to be within the scope of the claimed invention. Moreover, precise shapings such as those described herein may not be required. Instead the aerosol delivery section and the battery section may be configured such that when they are joined, the facing surfaces are spaced apart sufficiently to define an air gap in communication with the external air over part or all of the interface region. FIG. 16 shows a highly schematic and simplified side view of an aerosol delivery section with shapings in its outer surface to channel air into an air inlet in an interface region. Note that the air inlet or inlets are not shown in this illustration, but may be positioned where desired to be in airflow communication with air guided by the shapings. Three example positions for possible shapings are shown in phantom; an individual device may have one or some of these only. As a first example, the aerosol delivery section 14 has a vertical groove 52a in a side wall 60 which in use will face a battery section, with an external opening to air 54 at its upper end. This is functionally equivalent to the vertical groove 52 in the battery section shown in FIG. 15. One or more vertical grooves or recesses 54a might be formed, which may or may not extend the full height of the aerosol delivery section 14. As a second example, the aerosol delivery section 14 has a series of horizontal grooves 52b formed in a side wall 60 which in use will face a battery section. Any number of such grooves (which may have any shape, such as a corrugation or concertina shape if many grooves are desired) may be included, which may come together to feed a single air intake, or may each feed a separate air intake. A third example is a series of grooves or recesses 54c in the base wall 20 of the aerosol delivery section 54, which will face the upper surface of a connecting portion of a battery section when the two sections are joined. These grooves 54c are in airflow communication with an air inlet in the base wall 20, such as in FIGS. 3, 5A, 6A and 7A, such as via a cavity 35 as in FIG. 5A, 6A or 7A, and might be radially arranged similar to the grooves in the FIG. 5B example. Any of the embodiments and examples presented herein may further comprise an airflow adjuster by which a user can modify the level of airflow in the airflow path and hence control the amount of aerosol delivered per inhalation. Any suitable adjuster may be employed. For example, the adjuster may comprise a movable element such as a curved or flat plate or ring which is slidable over the air inlet so as to partially cover the air inlet and alter an area of the effective bore of the air inlet. The adjuster is preferably configured such that the air inlet cannot be completely covered by the movable element (which would block the airflow path), and may be configured for continuous adjustment or for stepped adjustment between two or more predetermined air inlet sizes and the corresponding air flow levels. The various embodiments described herein are presented only to assist in understanding and teaching the claimed features. These embodiments are provided as a representative sample of embodiments only, and are not exhaustive and/or exclusive. It is to be understood that advantages, embodiments, examples, functions, features, structures, and/or other aspects described herein are not to be considered limitations on the scope of the invention as defined by the claims or limitations on equivalents to the claims, and that other embodiments may be utilized and modifications may be made without departing from the scope of the claimed invention. Various embodiments of the invention may suitably comprise, consist of, or consist essentially of, appropriate combinations of the disclosed elements, components, features, parts, steps, means, etc., other than those specifically described herein. In addition, this disclosure may include other inventions not presently claimed, but which may be claimed in future. | <SOH> BACKGROUND <EOH>Aerosol provision systems such as e-cigarettes generally contain a reservoir of a source liquid containing a formulation, typically including nicotine, from which an aerosol is generated, such as through vaporization or other means. Thus an aerosol source for an aerosol provision system may comprise a heating element coupled to a portion of the source liquid from the reservoir. When the heating element is activated it causes vaporization of a small amount of the source liquid, which is thus converted to an aerosol for inhalation by the user. More particularly, such devices are usually provided with one or more air inlet holes which may or may not be located away from a mouthpiece of the system. When a user sucks on the mouthpiece, air is drawn through the inlet holes and past the aerosol source. There is an air flow path connecting the inlet holes to the aerosol source and on to an opening in the mouthpiece so that air drawn past the aerosol source continues along the flow path to the mouthpiece opening, carrying some of the aerosol from the aerosol source with it. The aerosol-carrying air exits the aerosol provision system through the mouthpiece opening for inhalation by the user. Some aerosol provision systems are configured in two sections. An aerosol provision section houses the reservoir of source liquid and one or more heating elements, and has the airflow path defined therethrough from the inlet hole(s) to the mouthpiece. A battery section houses a battery (which may be replicable or rechargable) for providing electrical power to the heating element. An electrical connection is provided between the two sections. The sections can be separable from one another, in which case there is also a mechanical connection between the sections; this typically also makes the electrical connection. The two sections can be arranged linearly so that the battery section is connected at the opposite end of the aerosol provision section to the mouthpiece. This gives a generally elongate device in which the battery is aligned substantially along the direction of airflow in the flow path, and when the mouthpiece points upwards, as it does in use, the battery section is underneath the aerosol provision section. The air inlet can be located in a side wall of the aerosol delivery section just below the base of the reservoir, that is, the part of the reservoir remote from the mouthpiece. This gives a short and simple air flow path to the heating element (which is generally in or near the reservoir). However, there is a risk that the user will cover this air inlet with his hand or fingers when using the device. As well as inhibiting or reducing aerosol delivery, this can be unsafe in devices in which the heating element is switch-operated under control of the user. A lack of airflow can then lead to overheating. | <SOH> SUMMARY <EOH>According to a first aspect of certain embodiments described herein, there is provided a vapor provision system comprising: an aerosol delivery section configured to generate aerosol from liquid in a reservoir; an airflow path through the aerosol delivery section extending from an air inlet to a mouthpiece; a battery section configured to join to the aerosol delivery section and house a battery to provide electrical power to one or more components in the aerosol delivery section, the battery section arranged laterally to at least a portion to the aerosol delivery section with respect to a direction of airflow through the mouthpiece; an interface region in which a surface of the aerosol delivery section faces a surface of the battery section when the sections are joined; wherein the air inlet is located on the aerosol delivery section in the interface region so as to take in air that has been channeled over part of the battery section. The battery section may be arranged laterally to the aerosol delivery section with respect to a direction of airflow through the mouthpiece. The battery section may have a connecting portion that extends laterally to receive a base part of the aerosol delivery section, the air inlet being located in a base wall of the aerosol delivery section that faces the connecting portion when the sections are joined. The vapor provision system may then further comprise co-operating screw threads or engaging elements on the connecting portion and the aerosol delivery section base part by which the sections can be joined, the screw threads or engaging elements being shaped such that when they are fully engaged, air can flow over at least part of the screw threads or engaging elements to be taken in by the air inlet. Alternatively, a surface of the connecting portion that faces the base part of the aerosol delivery section has formed therein at least one recess such that when the sections are joined a cavity is formed in the interface region with at least one external opening to air at an edge of the interface region, the air inlet being in airflow communication with the cavity. The at least one recess may comprise at least one groove in the said surface of the connecting portion, the or each groove extending radially with respect to a central axis of the aerosol delivery section when joined to the battery section to an end that forms one of the said at least one external openings. The base part of the aerosol provision section and the said surface of the connecting portion may be shaped to form a central cavity in the interface region with which each groove is in airflow communication at an end opposite to the external opening end, the air inlet being in airflow communication with the central cavity. The central cavity may house an electrical connection between the battery section and the aerosol delivery section. In an alternative embodiment the aerosol delivery section and the battery section may be externally shaped such that when they are joined a cavity is formed in the interface region with at least one external opening to air at an edge of the interface region, the air inlet being in airflow communication with the cavity. Said surface of the battery section in the interface region may be a side wall of the battery section and the said surface of the aerosol delivery section in the interface region may be a side wall of the aerosol delivery section. The cavity is at least partially formed by at least one recess in the said side wall of the battery section having at least one end that forms one of said external openings to air. For example, each recess may be a groove extending across the said side wall of the battery section from a first end to a second end, each of the first and second ends forming one of said external openings to air. Alternatively, each recess may have an end forming one of said external openings to air, said end located at an edge of the interface proximate the mouthpiece. The cavity may have at least two external openings to air. The vapor provision system may further comprise an adjustable element configured to enable an effective size of the air inlet to the altered, so as to vary the level of airflow along the airflow path. According to a second aspect of certain embodiments described herein, there is provided an aerosol delivery section for a vapor provision system which is configured to generate aerosol from liquid in a reservoir when joined to a battery section housing a battery, the aerosol delivery section comprising: an air inlet; an airflow path through the aerosol delivery section from the air inlet to a mouthpiece; and an interface region comprising a surface of the aerosol delivery section configured to face a surface of a battery section when the aerosol delivery section is joined to said battery section; wherein the air inlet is located in the interface region so as to take in air that has been channeled over part of the battery section when the sections are joined. The air inlet may be concealed from a user when the aerosol delivery section is joined to a battery section. In some examples, the air inlet may be located in a base wall or a side wall of the aerosol delivery section. According to a third aspect of certain embodiments described herein, there is provided a battery section for a vapor provision system which is configured to house a battery to provide electrical power to an aerosol delivery section when the battery section is joined to an aerosol delivery section, the battery section comprising an interface region comprising a surface of the battery section configured to face a surface of an aerosol delivery section when the battery section is joined to said aerosol delivery section; and at least one recess formed in the interface region positioned for alignment with an air inlet in said aerosol delivery section, the recess having at least one end at an edge of the interface region to define an external opening to air. The battery section may be configured such that an aerosol delivery section may be joined to it in an arrangement in which the battery section is arranged laterally to at least a portion to the aerosol delivery section with respect to a direction of airflow through a mouthpiece of the aerosol delivery section. The battery section may have a base portion that extends laterally to which an aerosol delivery section may be joined. These and further aspects of certain embodiments are set out in the appended independent and dependent claims. It will be appreciated that features of the dependent claims may be combined with each other and features of the independent claims in combinations other than those explicitly set out in the claims. Furthermore, the approach described herein is not restricted to specific embodiments such as set out below, but includes and contemplates any appropriate combinations of features presented herein. | A24F47008 | 20180321 | 20180927 | A24F4700 | 0 | HARVEY, JAMES R | AEROSOL PROVISION SYSTEM WITH REMOTE AIR INLET | UNDISCOUNTED | 0 | REJECTED | A24F | 2,018 |
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15,762,165 | PENDING | NOVEL OPHTHALMIC COMPOSITION COMPRISING REBAMIPIDE AND METHOD FOR PREPARING THE SAME | An ophthalmic composition is provided that includes rebamipide and a method for preparing the same. The ophthalmic composition of maintains its transparency for a long time even in a physiologically neutral to weakly basic pH range that does not injure the cornea and conjunctiva of a patient suffering from dry eye and has improved stability so as not to be re-dispersed. | 1. An ophthalmic composition comprising: (1) rebamipide; (2) an anti-recrystallizing agent selected from the group consisting of a cyclodextrin derivative, an amino acid, and mixtures thereof; and (3) a buffering agent. 2. The ophthalmic composition of claim 1, wherein the concentration of rebamipide is 0.1 to 1.5 w/v %. 3. The ophthalmic composition of claim 1, wherein the cyclodextrin derivative is hydroxypropylbetadex. 4. The ophthalmic composition of claim 1, wherein the concentration of the cyclodextrin derivative is 1.0 to 10.0 w/v %. 5. The ophthalmic composition of claim 1, wherein the amino acid is selected from the group consisting of arginine, lysine, histidine, glycine, alanine, valine, and mixtures thereof. 6. The ophthalmic composition of claim 1, wherein the concentration of the amino acid is 0.1 to 5.0 w/v %. 7. The ophthalmic composition of claim 1, wherein the buffering agent is selected from the group consisting of borate, phosphate, tromethamine, and mixtures thereof. 8. The ophthalmic composition of claim 1, wherein the concentration of the buffering agent is 0.05 to 2.0 w/v %. 9. The ophthalmic composition of claim 1, further comprising at least one additive selected from the group consisting of a thickener, a solubilizing agent, an isotonic agent, and a pH adjusting agent. 10. The ophthalmic composition of claim 1, wherein the pH range of the ophthalmic composition is 7 to 8. 11. The ophthalmic composition of claim 1, wherein the composition is a solution. 12. A method for preparing an ophthalmic composition, wherein the method comprises: a first step (S-1) of obtaining a solution by dissolving rebamipide in a buffer solution; a second step (S-2) of adding and dissolving an anti-recrystallizing agent selected from the group consisting of a cyclodextrin derivative, an amino acid, and mixtures thereof in the solution obtained in the first step; and a third step (S-3) of filtering the solution obtained in the second step through a sterile filter. 13. The method of claim 12, wherein the second step comprises, after dissolving the anti-recrystallizing agent, the step of adding and dissolving at least one additive selected from the group consisting of a thickener, a solubilizing agent, an isotonic agent, and a pH adjusting agent. | TECHNICAL FIELD The present disclosure relates to an ophthalmic composition comprising rebamipide, which maintains its transparency, has excellent stability, and is easy to prepare, and a method for preparing the same. BACKGROUND ART Rebamipide [2-(4-chlorobenzoylamino)-3-(2-quinolon-4-yl)propionic acid] is a quinolone derivative represented by the following formula I. Rebamipide is known to increase gastric mucin to have anti-inflammatory and antiulcer actions on the digestive tract and thus has been used as an oral therapeutic agent for gastric ulcer since 1990. Moreover, the effects of rebamipide on an increase of goblet cell density in eyes, an increase of mucin in eyes, and an increase of lacrimal fluid have been proven, and thus rebamipide has been developed and sold as a therapeutic agent for dry eye syndrome in the form of an ophthalmic solution in Japan. However, rebamipide has low solubility in a pH range where it is applicable to the eye, which makes it difficult to maintain a stable and transparent aqueous solution during long-term storage and to manufacture in the form of a transparent ophthalmic solution, and thus is available in the form of an ophthalmic suspension. Moreover, in the commercially available ophthalmic suspensions, the drug is dispersed as particles, which causes a feeling of irritation in the eye as well as local pain. Research aimed at developing a transparent ophthalmic solution comprising rebamipide has continued to progress; however, it is believed that it is difficult to develop an aqueous preparation comprising rebamipide so far, and the products developed so far are in the form of an ophthalmic suspension. International Patent Publication No. WO 97/013515 discloses an aqueous suspension containing rebamipide. However, this suspension may form a flocculated suspension when standing for a long time. Therefore, the suspension needs to be shaken well to disperse the flocculated suspension. Moreover, the above suspension is a white suspension and thus may obscure the view. International Patent Publication No. WO 2008/050896 discloses a rebamipide-containing aqueous suspension with improved suspensibility which can keep the dispersed fine-particle state of rebamipide stable without having the fine particle agglutinated, compared to the aqueous suspension of the above-mentioned International Patent Publication No. WO 97/013515. However, this suspension may also form a precipitate when standing for a long time and is a white suspension that obscures the view. International Patent Publication No. WO 2006/052018 discloses an aqueous suspension containing crystalline rebamipide which has improved transparency, compared to the above-mentioned two aqueous suspensions. However, this invention requires expensive equipment such as a high-pressure homogenizer, a colloid mill, an ultrasonic device, etc. during manufacturing, the manufacturing process is very difficult and complicated, and the manufacturing time is long, resulting in high manufacturing costs. Moreover, it also has the problem that it forms a precipitate when standing for a long time. International Patent Publication No. WO 2009/154304 and International Patent Publication No. WO 2014/051163 disclose transparent rebamipide ophthalmic compositions. However, these ophthalmic solutions have a high pH of 8 or higher and are not suitable for a patient suffering from an injury in cornea and conjunctiva such as dry eye. Moreover, International Patent Publication No. WO 2008/074853 discloses a composition which uses a viscosity enhancer and a buffer to maintain the stability of an aqueous solution comprising rebamipide. However, this composition also has the problem that it forms a precipitate when standing for a long time. Therefore, it is necessary to develop a pharmaceutical composition comprising rebamipide, which maintains its transparency for a long time even in a physiologically neutral to weakly basic pH range (below 8) that does not injure the cornea and conjunctiva of a patient suffering from dry eye, and which has improved stability so as not to be re-dispersed. DISCLOSURE OF INVENTION Technical Problem An object of the present disclosure is to provide an ophthalmic composition comprising rebamipide, which is transparent in a pH range of 7 to 8. More specifically, an object of the present disclosure is to provide an ophthalmic composition comprising rebamipide, which maintains its transparency for a long time even in a physiologically neutral to weakly basic pH range that does not injure the cornea and conjunctiva of a patient suffering from dry eye, and which has improved stability so as not to be re-dispersed. Moreover, another object of the present disclosure is to provide a method for preparing an ophthalmic composition of the present disclosure in a simple manner without any complicated process. Solution to Problem In order to accomplish the objects of the present disclosure, the present disclosure provides a novel ophthalmic composition comprising rebamipide and a method for preparing the same, which will be described in detail below. Ophthalmic Composition Comprising Rebamipide The ophthalmic composition of the present disclosure comprises (1) rebamipide, (2) an anti-recrystallizing agent selected from the group consisting of a cyclodextrin derivative, an amino acid, and mixtures thereof, and (3) a buffering agent. Rebamipide may be prepared directly by a conventionally known method or commercially available. In the present disclosure, the concentration of rebamipide may be 0.1 to 1.5 w/v %, preferably 0.2 to 1.0 w/v %. The anti-recrystallizing agent used in the present disclosure is an additive to prevent a solution, which is sufficiently transparent but is present in a supersaturated state, from failing to maintain a transparent appearance without any precipitate being formed during long-term storage. The anti-recrystallizing agent that can be used in the present disclosure includes a cyclodextrin derivative and/or an amino acid. Examples of the cyclodextrin derivative used as the anti-recrystallizing agent in the present disclosure include alpha-, beta-, and gamma-cyclodextrin, and substituted derivatives thereof such as dimethyl-, hydroxyethyl-, hydroxypropyl-, or sulfobutylether-beta-cyclodextrin. Hydroxypropylbetadex may preferably be used. Moreover, the concentration of the cyclodextrin derivative may preferably be 1.0 to 10.0 w/v %. The amino acid that is another anti-recrystallizing agent of the present disclosure may comprise at least one selected from the group consisting of basic amino acids such as arginine, lysine, histidine, etc. and neutral amino acids such as glycine, alanine, valine, etc. Moreover, the concentration of the amino acid may preferably be 0.1 to 5.0 w/v %. In the present disclosure, the buffering agent may comprise at least one selected from the group consisting of borate, phosphate, tromethamine, and mixtures thereof. Borate may preferably be used as the buffering agent. Moreover, the concentration of the buffering agent may preferably be 0.05 to 2.0 w/v %. Moreover, the ophthalmic composition of the present disclosure may further comprise at least one additive selected from the group consisting of a thickener, a solubilizing agent, an isotonic agent, and a pH adjusting agent. The thickener is an additive that extends the amount of time a drug stays in the body during clinical application and may comprise at least one selected from the group consisting of polyvinylpyrrolidone, hydroxypropylmethylcellulose, and polyvinyl alcohol, but not limited thereto. Polyvinylpyrrolidone may preferably be used. The solubilizing agent is an additive to increase the solubility of a drug and may comprise at least one selected from the group consisting of polyoxyl 35 hydrogenated castor oil, poloxamer, and polysorbate. The isotonic agent may be added in an amount that makes the osmotic pressure of the ophthalmic solution similar to that of tears and may comprise chlorides, saccharides, propylene glycol, and glycerin. The pH adjusting agent is an additive to adjust the pH in a range that is applicable to the body (eye) and does not injure the cornea and conjunctiva and may comprise inorganic acids or organic acids. An inorganic acid such as phosphoric acid or phosphate may preferably be used. The ophthalmic composition of the present disclosure may preferably have a pH of 7 to 8, which is in a physiologically neutral to weakly basic range that does not injure the cornea and conjunctiva of a patient suffering from dry eye. Moreover, the ophthalmic composition of the present disclosure has excellent transparency in the above pH range (pH 7 to 8), maintains its transparency even after standing for a long time, and has improved stability so as not to be re-dispersed. According to a preferred embodiment of the present disclosure, the ophthalmic composition of the present disclosure is a solution formulation, rather than the existing aqueous suspension. The ophthalmic composition of the present disclosure has solved the problem that it is difficult to manufacture in the form of a solution due to low solubility and, at the same time, has ensured the excellent transparency and stability. Therefore, the ophthalmic composition of the present disclosure may be very useful as an ophthalmic solution to patients suffering from dry eye. Method for Preparing Ophthalmic Composition Comprising Rebamipide The method for preparing an ophthalmic composition of the present disclosure comprises: a first step (S-1) of obtaining a solution by dissolving rebamipide in a buffer solution; a second step (S-2) of adding and dissolving an anti-recrystallizing agent selected from the group consisting of a cyclodextrin derivative, an amino acid, and mixtures thereof in the solution obtained in the first step; and a third step (S-3) of filtering the solution obtained in the second step through a sterile filter. Moreover, the second step may further comprise, after dissolving the anti-recrystallizing agent, the step of adding and dissolving at least one additive selected from the group consisting of a thickener, a solubilizing agent, an isotonic agent, and a pH adjusting agent. Specifically, a buffer solution of a suitable concentration is prepared by adding a buffering agent, and then rebamipide is added and dissolved in the buffer solution while stirring. The pH adjusting agent may be added as necessary, and the anti-recrystallizing agent is added and dissolved in the transparent rebamipide solution while stirring. The thickener, the solubilizing agent, the pH adjusting agent, and the isotonic agent may be added in appropriate concentrations according to circumstances. Moreover, all of these processes are achieved by simple stirring, and filtration is performed using a 0.22 μm sterile filter to achieve sterilization. The manufacturing method of the present disclosure uses the anti-recrystallizing agent of rebamipide, such as the cyclodextrin derivative and/or amino acid, and the buffering agent to sufficiently maintain the transparency and prevent the formation of a precipitate layer even during long-term storage and can manufacture the ophthalmic composition comprising rebamipide by simple stirring without the use of expensive equipment. Pharmaceutical Composition, and Method of Preventing or Treating Dry Eye Syndrome The present disclosure provides a pharmaceutical composition comprising the ophthalmic composition of the present disclosure. The present disclosure also provides a pharmaceutical composition for treating dry eye syndrome comprising the ophthalmic composition of the present disclosure. The present disclosure also provides a method of treating dry eye syndrome comprising an administration of the ophthalmic composition of the present disclosure to patients. Advantageous Effects of Invention The ophthalmic composition of the present disclosure is prepared by mixing an anti-recrystallizing agent with a composition comprising rebamipide and a buffer solution, and thus it is possible to improve the transparency of the ophthalmic composition and maintain its transparency without aggregation or precipitation of dissolved particles even during long-term storage. Moreover, according to the present disclosure, it is possible to manufacture a transparent rebamipide ophthalmic solution by simple stirring without requiring complicated manufacturing processes such as high-pressure homogenization, ultrasonic dispersion, etc. by selecting a buffering agent suitable for the composition and adjusting the concentration of the buffer solution. Furthermore, it is possible to remove bacteria only by filtration using a 0.22 μm sterile filter, resulting in reduced manufacturing costs. MODE FOR THE INVENTION Hereinafter, Examples and Experimental Examples of the present disclosure will be described below for better understanding of the present disclosure, but the scope of the present disclosure is not limited by the Examples and Experimental Examples. Examples 1 to 13 and Comparative Examples 1 to 5 According to the composition and ratio of components shown in the following tables 1 and 2, to purified water of appropriate volume, a buffering agent was added while stirring. To the buffer solution while stirring, rebamipide was added and dissolved, and then hydroxypropylbetadex was added thereto. After the rebamipide and hydroxypropylbetadex were completely dissolved, a pH adjusting agent and an isotonic agent were added to adjust the pH level and the osmotic pressure. The resulting rebamipide solution was filtered using a 0.22 μm sterile filter to prepare colorless transparent ophthalmic compositions of Examples 1 to 13. According to the composition and ratio of components shown in the following tables 1 and 2, compositions of Comparative Examples 1 to 5 were prepared by the same preparation method described in Examples 1 to 13, except for the process of adding hydroxypropylbetadex. TABLE 1 Compositions I according to the composition of the buffering agent and hydroxypropylbetadex Comparative Examples Examples Components 1 2 3 4 5 6 1 2 3 Rebamipide (mg) 500 500 500 500 500 500 500 500 500 Hydroxypropyl- 10 10 10 5 5 5 — — — betadex (g) Sodium borate (g) 0.95 — — 0.95 — — 0.95 — — Sodium phosphate (g) — 0.75 — — 0.75 — — 0.75 — Tromethamine (g) — — 0.75 — — 0.75 — — 0.75 Sodium chloride or q.s q.s q.s q.s q.s q.s q.s q.s q.s glycerin Phosphoric acid q.s q.s q.s q.s q.s q.s q.s q.s q.s Purified water q.s q.s q.s q.s q.s q.s q.s q.s q.s Total Volume (mL) 100 pH about 7.8 TABLE 2 Compositions II according to the composition of the buffering agent and hydroxypropylbetadex Comparative Examples Examples Components 7 8 9 10 11 12 13 4 5 Rebamipide (mg) 500 500 500 500 500 500 500 500 500 hydroxypropyl- 2 2 2 5 5 10 10 — — betadex (g) Sodium borate (g) 0.95 0.50 0.10 0.50 0.10 0.50 0.10 0.50 0.10 Sodium chloride or q.s q.s q.s q.s q.s q.s q.s q.s q.s glycerin Phosphoric acid q.s q.s q.s q.s q.s q.s q.s q.s q.s Purified water q.s q.s q.s q.s q.s q.s q.s q.s q.s Total Volume (mL) 100 pH about 7.8 Examples 14 to 21 Compositions of Examples 14 to 21 were prepared by the same preparation method described in Examples 1 to 13, except for varying the composition and ratio of amino acids as shown in the following table 3. TABLE 3 Composition according to the composition and ratio of amino acids Examples Components 14 15 16 17 18 19 20 21 Rebamipide 500 500 500 500 500 500 500 500 (mg) Arginine (g) 2.0 — 1.0 — — 0.2 — — Lysine (g) — 2.0 — 1.0 — — 0.2 — Glycine (g) — — — — 0.5 — 0.2 Sodium borate 0.50 0.5 0.50 0.50 0.50 0.75 0.75 0.75 (g) Sodium chloride q.s q.s q.s q.s q.s q.s q.s q.s or glycerin Phosphate q.s q.s q.s q.s — — — — Phosphoric acid — — — — q.s q.s q.s q.s Purified water q.s q.s q.s q.s q.s q.s q.s q.s Total volume 100 (mL) pH about 7.8 Examples 22 to 29 Compositions of Examples 22 to 29 were prepared by the same preparation method described in Examples 1 to 13, except for varying the ratio of the thickener that can be further added to the ophthalmic composition comprising the anti-recrystallizing agent and the buffering agent as shown in the following table 4. TABLE 4 Composition according to the ratio of thickeners Examples Components 22 23 24 25 26 27 28 29 Rebamipide (mg) 500 500 500 500 500 500 500 500 Hydroxypropyl- 5 — 5 5 5 5 — — betadex (g) Arginine (g) — 1 1 — 0.2 — 1 — Lysine (g) — — — 1 — 0.2 — 1 Sodium borate (g) 0.50 0.50 0.50 0.50 0.75 0.75 0.50 0.50 Polyvinyl- 5 5 5 5 5 5 — — pyrrolidone (g) Hydroxypropyl- — — — — — — 0.5 0.5 methyl cellulose Sodium chloride q.s q.s q.s q.s q.s q.s q.s q.s or glycerin Phosphoric acid q.s q.s q.s q.s q.s q.s q.s q.s Purified water q.s q.s q.s q.s q.s q.s q.s q.s Total volume (mL) 100 pH about 7.8 Examples 30 to 34 Compositions of Examples 30 to 34 were prepared by the same preparation method described in Examples 1 to 13, except for varying the ratio of the solubilizing agent that can be further added to the composition comprising the anti-recrystallizing agent and the buffering agent as shown in the following table 5. TABLE 5 Compositions according to the ratio of solubilizing agents Examples Components 30 31 32 33 34 Rebamipide (mg) 500 500 500 500 500 Hydroxypropylbetadex 2 2 2 2 2 (g) Arginine (g) — 0.2 — 0.2 — Lysine (g) — — 0.2 — 0.2 Polyvinylpyrrolidone 2 2 2 2 2 (g) Sodium borate (g) 0.95 0.95 0.95 0.95 0.95 Polyoxyl 35 0.5 0.5 0.5 — — hydrogenated castor oil (g) Poloxamer (g) — — — 0.1 0.1 Sodium chloride q.s q.s q.s q.s q.s Phosphoric acid q.s q.s q.s q.s q.s Purified water q.s q.s q.s q.s q.s Total volume (mL) 100 pH about 7.8 Experimental Example 1 In order to evaluate the transparency and stability depending on the presence or absence of the anti-recrystallizing agent, the compositions prepared in Examples 1 to 13 and Comparative Examples 1 to 5 were stored at room temperature and under refrigeration, and then the presence or absence of crystal precipitation over time was determined and shown in the following tables 6 to 9. The transparency of the compositions was observed with the naked eye using a tester for the Insoluble Particulate Matter Test for Ophthalmic Solutions of the Korean Pharmacopoeia. TABLE 6 Evaluation of Stability at Room Temperature of Examples 1 to 13 During Preparation 1 Week 2 Weeks Examples 1 Transparent Transparent Transparent liquid liquid liquid 2 Transparent Transparent Transparent liquid liquid liquid 3 Transparent Transparent Transparent liquid liquid liquid 4 Transparent Transparent Transparent liquid liquid liquid 5 Transparent Transparent Transparent liquid liquid liquid 6 Transparent Transparent Transparent liquid liquid liquid 7 Transparent Transparent Transparent liquid liquid liquid 8 Transparent Transparent Transparent liquid liquid liquid 9 Transparent Transparent Transparent liquid liquid liquid 10 Transparent Transparent Transparent liquid liquid liquid 11 Transparent Transparent Transparent liquid liquid liquid 12 Transparent Transparent Transparent liquid liquid liquid 13 Transparent Transparent Transparent liquid liquid liquid TABLE 7 Evaluation of Stability at Room Temperature of Comparative Examples 1 to 5 During preparation 1 Week 2 Weeks Comparative 1 Transparent Transparent Precipitate Examples liquid liquid formed 2 Transparent Transparent Precipitate liquid liquid formed 3 Transparent Transparent Precipitate liquid liquid formed 4 Transparent Transparent Precipitate liquid liquid formed 5 Transparent Transparent Precipitate liquid liquid formed TABLE 8 Evaluation of Stability under Refrigeration of Examples 1 to 13 During preparation 1 Week 2 Weeks Examples 1 Transparent Transparent Transparent liquid liquid liquid 2 Transparent Transparent Transparent liquid liquid liquid 3 Transparent Transparent Transparent liquid liquid liquid 4 Transparent Transparent Transparent liquid liquid liquid 5 Transparent Transparent Transparent liquid liquid liquid 6 Transparent Transparent Transparent liquid liquid liquid 7 Transparent Transparent Transparent liquid liquid liquid 8 Transparent Transparent Transparent liquid liquid liquid 9 Transparent Transparent Transparent liquid liquid liquid 10 Transparent Transparent Transparent liquid liquid liquid 11 Transparent Transparent Transparent liquid liquid liquid 12 Transparent Transparent Transparent liquid liquid liquid 13 Transparent Transparent Transparent liquid liquid liquid TABLE 9 Evaluation of Stability under Refrigeration of Comparative Examples 1 to 3 During preparation 1 Week 2 Weeks Comparative 1 Transparent Transparent Precipitate Examples liquid liquid formed 2 Transparent Transparent Precipitate liquid liquid formed 3 Transparent Transparent Precipitate liquid liquid formed As shown in tables 6 to 9, the ophthalmic compositions of Examples 1 to 13 comprising the cyclodextrin derivative (hydroxypropylbetadex) that is an anti-recrystallizing agent were colorless and transparent even after standing for a long time, while precipitates were formed that does not comprise the anti-recrystallizing agent in the compositions of Comparative Examples 1 to 5 after 2 weeks. Experimental Example 2 In order to determine the availability of amino acids as an anti-recrystallizing agent, the compositions prepared in Examples 14 to 21 were stored at room temperature and under refrigeration, and then the presence or absence of crystal precipitation over time was determined by the same method as Experimental Example 1 and shown in the following tables 10 and 11. TABLE 10 Evaluation of Stability at Room Temperature of Examples 14 to 21 Room During Temperature preparation 1 Day 2 Weeks 4 Weeks Examples 14 Transparent Transparent Transparent Transparent liquid liquid liquid liquid 15 Transparent Transparent Transparent Transparent liquid liquid liquid liquid 16 Transparent Transparent Transparent Transparent liquid liquid liquid liquid 17 Transparent Transparent Transparent Transparent liquid liquid liquid liquid 18 Transparent Transparent Transparent Transparent liquid liquid liquid liquid 19 Transparent Transparent Transparent Transparent liquid liquid liquid liquid 20 Transparent Transparent Transparent Transparent liquid liquid liquid liquid 21 Transparent Transparent Transparent Transparent liquid liquid liquid liquid TABLE 11 Evaluation of Stability under Refrigeration of Examples 14 to 21 Room During Temperature preparation 1 Week 2 Weeks 4 Weeks Examples 14 Transparent Transparent Transparent Transparent liquid liquid liquid liquid 15 Transparent Transparent Transparent Transparent liquid liquid liquid liquid 16 Transparent Transparent Transparent Transparent liquid liquid liquid liquid 17 Transparent Transparent Transparent Transparent liquid liquid liquid liquid 18 Transparent Transparent Transparent Transparent liquid liquid liquid liquid 19 Transparent Transparent Transparent Transparent liquid liquid liquid liquid 20 Transparent Transparent Transparent Transparent liquid liquid liquid liquid 21 Transparent Transparent Transparent Transparent liquid liquid liquid liquid As a result of the experiment, the ophthalmic compositions of Examples 14 to 21 further comprising the amino acid also maintained the transparency (colorlessness) without any precipitate being formed. Experimental Example 3 In order to determine the effect of the addition of thickener, the compositions prepared in Examples 22 to 29 were stored at room temperature and under refrigeration, and then the presence or absence of crystal precipitation over time was determined by the same method as Experimental Example 1 and shown in the following tables 12 and 13. TABLE 12 Evaluation of Stability at Room Temperature of Examples 22 to 29 During preparation 1 Week 2 Weeks 4 Weeks Examples 22 Transparent Transparent Transparent Transparent liquid liquid liquid liquid 23 Transparent Transparent Transparent Transparent liquid liquid liquid liquid 24 Transparent Transparent Transparent Transparent liquid liquid liquid liquid 25 Transparent Transparent Transparent Transparent liquid liquid liquid liquid 26 Transparent Transparent Transparent Transparent liquid liquid liquid liquid 27 Transparent Transparent Transparent Transparent liquid liquid liquid liquid 28 Transparent Transparent Transparent Transparent liquid liquid liquid liquid 29 Transparent Transparent Transparent Transparent liquid liquid liquid liquid TABLE 13 Evaluation of Stability under Refrigeration of Examples 22 to 29 During preparation 1 Week 2 Weeks 4 Weeks Examples 22 Transparent Transparent Transparent Transparent liquid liquid liquid liquid 23 Transparent Transparent Transparent Transparent liquid liquid liquid liquid 24 Transparent Transparent Transparent Transparent liquid liquid liquid liquid 25 Transparent Transparent Transparent Transparent liquid liquid liquid liquid 26 Transparent Transparent Transparent Transparent liquid liquid liquid liquid 27 Transparent Transparent Transparent Transparent liquid liquid liquid liquid 28 Transparent Transparent Transparent Transparent liquid liquid liquid liquid 29 Transparent Transparent Transparent Transparent liquid liquid liquid liquid As a result of the experiment, it was observed that the compositions further comprising the thickener also maintained the transparency (colorlessness) and stability during the observation period. Experimental Example 4 In order to determine the effect of the addition of solubilizing agent, the compositions prepared in Examples 30 to 34 were stored at room temperature and under refrigeration, and then the presence or absence of crystal precipitation over time was determined by the same method as Experimental Example 1 and shown in the following tables 14 and 15. TABLE 14 Evaluation of Stability at Room Temperature of Examples 30 to 34 During preparation 1 Week 2 Weeks Examples 30 Transparent Transparent Transparent liquid liquid liquid 31 Transparent Transparent Transparent liquid liquid liquid 32 Transparent Transparent Transparent liquid liquid liquid 33 Transparent Transparent Transparent liquid liquid liquid 34 Transparent Transparent Transparent liquid liquid liquid TABLE 15 Evaluation of Stability under Refrigeration of Examples 30 to 34 During preparation 1 Week 2 Weeks Examples 30 Transparent Transparent Transparent liquid liquid liquid 31 Transparent Transparent Transparent liquid liquid liquid 32 Transparent Transparent Transparent liquid liquid liquid 33 Transparent Transparent Transparent liquid liquid liquid 34 Transparent Transparent Transparent liquid liquid liquid As a result of the experiment, it was observed that the compositions further comprising the solubilizing agent also maintained the transparency (colorlessness) and stability during the observation period. | <SOH> BACKGROUND ART <EOH>Rebamipide [2-(4-chlorobenzoylamino)-3-(2-quinolon-4-yl)propionic acid] is a quinolone derivative represented by the following formula I. Rebamipide is known to increase gastric mucin to have anti-inflammatory and antiulcer actions on the digestive tract and thus has been used as an oral therapeutic agent for gastric ulcer since 1990. Moreover, the effects of rebamipide on an increase of goblet cell density in eyes, an increase of mucin in eyes, and an increase of lacrimal fluid have been proven, and thus rebamipide has been developed and sold as a therapeutic agent for dry eye syndrome in the form of an ophthalmic solution in Japan. However, rebamipide has low solubility in a pH range where it is applicable to the eye, which makes it difficult to maintain a stable and transparent aqueous solution during long-term storage and to manufacture in the form of a transparent ophthalmic solution, and thus is available in the form of an ophthalmic suspension. Moreover, in the commercially available ophthalmic suspensions, the drug is dispersed as particles, which causes a feeling of irritation in the eye as well as local pain. Research aimed at developing a transparent ophthalmic solution comprising rebamipide has continued to progress; however, it is believed that it is difficult to develop an aqueous preparation comprising rebamipide so far, and the products developed so far are in the form of an ophthalmic suspension. International Patent Publication No. WO 97/013515 discloses an aqueous suspension containing rebamipide. However, this suspension may form a flocculated suspension when standing for a long time. Therefore, the suspension needs to be shaken well to disperse the flocculated suspension. Moreover, the above suspension is a white suspension and thus may obscure the view. International Patent Publication No. WO 2008/050896 discloses a rebamipide-containing aqueous suspension with improved suspensibility which can keep the dispersed fine-particle state of rebamipide stable without having the fine particle agglutinated, compared to the aqueous suspension of the above-mentioned International Patent Publication No. WO 97/013515. However, this suspension may also form a precipitate when standing for a long time and is a white suspension that obscures the view. International Patent Publication No. WO 2006/052018 discloses an aqueous suspension containing crystalline rebamipide which has improved transparency, compared to the above-mentioned two aqueous suspensions. However, this invention requires expensive equipment such as a high-pressure homogenizer, a colloid mill, an ultrasonic device, etc. during manufacturing, the manufacturing process is very difficult and complicated, and the manufacturing time is long, resulting in high manufacturing costs. Moreover, it also has the problem that it forms a precipitate when standing for a long time. International Patent Publication No. WO 2009/154304 and International Patent Publication No. WO 2014/051163 disclose transparent rebamipide ophthalmic compositions. However, these ophthalmic solutions have a high pH of 8 or higher and are not suitable for a patient suffering from an injury in cornea and conjunctiva such as dry eye. Moreover, International Patent Publication No. WO 2008/074853 discloses a composition which uses a viscosity enhancer and a buffer to maintain the stability of an aqueous solution comprising rebamipide. However, this composition also has the problem that it forms a precipitate when standing for a long time. Therefore, it is necessary to develop a pharmaceutical composition comprising rebamipide, which maintains its transparency for a long time even in a physiologically neutral to weakly basic pH range (below 8) that does not injure the cornea and conjunctiva of a patient suffering from dry eye, and which has improved stability so as not to be re-dispersed. | A61K4740 | 20180322 | 20180920 | A61K4740 | 0 | BARSKY, JARED | NOVEL OPHTHALMIC COMPOSITION COMPRISING REBAMIPIDE AND METHOD FOR PREPARING THE SAME | UNDISCOUNTED | 0 | ACCEPTED | A61K | 2,018 |
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15,763,613 | PENDING | CAMERA CALIBRATION BOARD, CAMERA CALIBRATION DEVICE, CAMERA CALIBRATION METHOD, AND PROGRAM-RECORDING MEDIUM FOR CAMERA CALIBRATION | A camera calibration board, which is arranged three-dimensionally above a board, includes the board, a plurality of flat plates, and a plurality of support columns having the same length. The plurality of flat plates are spatially arranged in a plane different from a plane in which the board is arranged. The board and each of the plurality of flat plates have different reflectances with respect to visible light. With this configuration, it is possible to accurately measure extrinsic parameters between cameras, which are required for calibrating cameras that use different types of image sensors, in order to easily analyze a group of images acquired from a plurality of sensors. | 1. A camera calibration board, comprising: a board; and a plurality of flat plates, which are arranged above the board via a plurality of support columns having the same length, respectively, wherein the plurality of flat plates are spatially arranged in a plane that is different from a plane in which the board is arranged, and wherein the board and each of the plurality of flat plates have different reflectances with respect to visible light. 2. The camera calibration board according to claim 1, wherein each of the plurality of flat plates has a rectangular shape. 3. The camera calibration board according to claim 1, wherein the board and each of the plurality of flat plates are heated or cooled to have different temperatures, and are processed so that heat is prevented from being transferred between the board and the each of the plurality of flat plates. 4. The camera calibration board according to claim 3, wherein the board or each of the plurality of flat plates to be heated or cooled includes a material having a high thermal conductivity and a high thermal radiation property. 5. The camera calibration board according to claim 3, wherein the board or each of the plurality of flat plates to be heated or cooled includes: a material having a high thermal conductivity; and a material having a high thermal radiation property, which is layered on the material having a high thermal conductivity. 6. The camera calibration board according to claim 3, wherein the board or each of the plurality of flat plates to be heated or cooled has built therein or attached thereto an object for heating or cooling the board or the each of the plurality of flat plates to be heated or cooled. 7. The camera calibration board according to claim 3, wherein each of the plurality of support columns includes a material having a low thermal conductivity. 8. A camera calibration device, comprising: a calibration image capturing circuitry, which includes first and second cameras of different types, which are configured to capture first and second calibration images, respectively, through use of the camera calibration board of claim 1; first and second feature point detection circuitry, which are configured to calculate first and second feature points from the first and the second calibration images, respectively; first and second camera parameter estimation circuitry, which are configured to calculate first and second camera parameters for the first and the second cameras from the first and the second feature points, respectively; and a bundle adjustment circuitry, which is configured to calculate extrinsic parameters between the first and the second cameras through use of the first and the second camera parameters. 9. The camera calibration device according to claim 8, wherein the first camera comprises a visible light camera, and the first calibration image comprises a visible light image, and wherein the second camera comprises a depth camera, and the second calibration image comprises a depth image. 10. A camera calibration device, comprising: a calibration image capturing circuitry, which includes first through N-th cameras of different types, where N is an integer of 3 or more, which are configured to capture first through N-th calibration images, respectively, through use of the camera calibration board of claim 3; first through N-th feature point detection circuitry, which are configured to calculate first through N-th feature points from the first through the N-th calibration images, respectively; first through N-th camera parameter estimation circuitry, which are configured to calculate first through to N-th camera parameters for the first through the N-th cameras from the first through the N-th feature points, respectively; and a bundle adjustment circuitry, which is configured to calculate extrinsic parameters between the first through to the N-th cameras through use of the first through the N-th camera parameters. 11. The camera calibration device according to claim 10, wherein the integer N is equal to 3, wherein the first camera comprises a visible light camera, and the first calibration image comprises a visible light image, wherein the second camera comprises a depth camera, and the second calibration image comprises a depth image, and wherein the third camera comprises a far-infrared camera, and the third calibration image comprises a far-infrared image. 12. A camera calibration method, comprising: capturing, by first through M-th cameras of different types, where M is an integer of 2 or more, first through M-th calibration images, respectively, through use of the camera calibration board of claim 1; calculating first through M-th feature points from the first through the M-th calibration images, respectively; calculating first through M-th camera parameters for the first through the M-th cameras from the first through the M-th feature points, respectively; and calculating extrinsic parameters between the first through the M-th cameras through use of the first through the M-th camera parameters. 13. A camera calibration program recording medium having recorded thereon a camera calibration program for causing a computer to execute the procedures of: calculating first through M-th feature points from first through M-th calibration images, respectively, where M is an integer of 2 or more, which are captured by first through M-th cameras of different types, respectively, through use of the camera calibration board of claim 1; calculating first through M-th camera parameters for the first through the M-th cameras from the first through the M-th feature points, respectively; and calculating extrinsic parameters between the first through the M-th cameras through use of the first through the M-th camera parameters. | TECHNICAL FIELD This invention relates to a camera calibration board, a camera calibration device, a camera calibration method, and a camera calibration program recording medium. BACKGROUND ART In recent years, in order to photograph various objects to be photographed, cameras that use sensors suited to their respective purposes have become widespread. For example, in order to monitor a person or the like, a monitoring camera that uses a visible light sensor has become widespread. Meanwhile, an inexpensive depth image acquisition camera (hereinafter also referred to as “depth camera”) for acquiring a depth image has also become widespread. In addition, in order to monitor a person or the like in the nighttime, a camera that uses an invisible light sensor, such as a near-infrared camera or a far-infrared camera, has also become widespread. In order to easily analyze a group of images acquired from a plurality of sensors, it is required to calibrate cameras that use different types of image sensors. More specifically, it is required to accurately measure intrinsic parameters representing lens distortion, an image center, and the like of each camera, and extrinsic parameters representing a relative positional relationship between cameras. Against such a background, as the related art, in Non Patent Document 1, there is disclosed a method of simultaneously calibrating cameras through use of a depth image and a visible light image. Further, in Non Patent Document 2, there is disclosed a method of calculating camera's intrinsic parameters from feature points obtained by calculation from images. There is also known other related art (patent documents), which is related to this invention. For example, in Patent Document 1, there is disclosed a calibration table to be used for a stereo camera calibration device. The calibration table disclosed in Patent Document 1 comprises a perforated plate, which is arranged on an upper surface of a flat plate, and in which a large number of holes are formed, and a plurality of sticks (calibration poles), which are randomly fitted to freely-selected positions of the large number of holes of the perforated plate. The upper surface of the flat plate is painted in black, an upper surface of the perforated plate is painted in gray, and a top portion of each calibration pole is painted in white. The length of each calibration pole is randomly set. Two cameras (left camera and right camera) are arranged above the calibration table so that optical axes thereof are inclined toward each other. The optical axes of the left camera and the right camera are set so as to be approximately focused on a given point of the calibration table. Further, in Patent Document 2, there is disclosed a camera parameter estimation apparatus configured to estimate camera parameters of one camera. The camera parameter estimation apparatus disclosed in Patent Document 2 comprises a corresponding point searching device and camera parameter estimation means. The corresponding point searching device searches for a corresponding point between a plurality of images obtained by photographing the same object by one camera. The camera parameter estimation means uses information on the corresponding point, which is input from corresponding point searching means, to perform optimization through bundle adjustment with camera posture coefficients being set as unknown quantities, to thereby estimate the camera parameters. PRIOR ART DOCUMENTS Patent Document Patent Document 1: JP H08-086613 A Patent Document 2: JP 2014-032628 A Non Patent Document Non Patent Document 1: Herrera, C., Juho Kannala, and Janne Heikkilae. “Joint depth and color camera calibration with distortion correction.” Pattern Analysis and Machine Intelligence, IEEE Transactions on 34.10 (2012): 2058-2064. Non Patent Document 2: Zhang, Zhengyou. “A flexible new technique for camera calibration.” Pattern Analysis and Machine Intelligence, IEEE Transactions on 22.11 (2000): 1330-1334. SUMMARY OF THE INVENTION Problem to be Solved by the Invention However, the method of Non Patent Document 1 has a problem of reduced accuracy of bundle adjustment, which is processing of highly accurately measuring extrinsic parameters between cameras from the visible light image and the depth image. The reason is as follows. In general, “bundle adjustment” is processing of calculating camera parameters through total optimization from coordinates of a group of corresponding identical points. However, with the method of Non Patent Document 1, it is difficult to highly accurately obtain coordinate values of a group of corresponding identical points through simple processing from the visible light image and the depth image. In Non Patent Document 2, there is merely disclosed the method of calculating the camera's intrinsic parameters from the feature points. Moreover, Patent Documents 1 and 2 have respective problems described below. In Patent Document 1, there is merely disclosed the calibration table to be used to easily and accurately calibrate spatial positions of the two cameras when an object is photographed with the two cameras. In other words, the calibration table disclosed in Patent Document 1 is used to calibrate the spatial positions of the two cameras of the same type, and is not intended in any way to calibrate a plurality of cameras of different types. Therefore, Patent Document 1 has a different problem to be solved. In Patent Document 2, there is merely disclosed the camera parameter estimation apparatus configured to estimate the camera parameters of one camera through the bundle adjustment. Also in Patent Document 2, there is no intention of calibrating a plurality of cameras of different types. Therefore, Patent Document 2 has a different problem to be solved. It is an object of this invention to provide a camera calibration board, a camera calibration device, a camera calibration method, and a camera calibration program recording medium, which are capable of solving the above-mentioned problems. A mode of this invention is a camera calibration board, comprising: a board; and a plurality of flat plates, which are arranged above the board via a plurality of support columns having the same length, respectively, wherein the plurality of flat plates are spatially arranged in a plane that is different from a plane in which the board is arranged, and wherein the board and each of the plurality of flat plates have different reflectances with respect to visible light. A camera calibration device according to this invention comprises: a calibration image capturing unit, which includes first through M-th cameras of different types, where M is an integer of 2 or more, which are configured to capture first through M-th calibration images, respectively, through use of the above-mentioned camera calibration board; first through M-th feature point detection units, which are configured to calculate first through M-th feature points from the first through the M-th calibration images, respectively; first through M-th camera parameter estimation units, which are configured to calculate first through to M-th camera parameters for the first through the M-th cameras from the first through the M-th feature points, respectively; and a bundle adjustment unit, which is configured to calculate extrinsic parameters between the first through to the N-th cameras through use of the first through the N-th camera parameters. A camera calibration method according to this invention comprises: capturing, by first through M-th cameras of different types, where M is an integer of 2 or more, first through M-th calibration images, respectively, through use of the above-mentioned camera calibration board; calculating, by first through M-th feature point detection units, first through M-th feature points from the first through the M-th calibration images, respectively; calculating, by first through M-th camera parameter estimation units, first through M-th camera parameters for the first through the M-th cameras from the first through the M-th feature points, respectively; and calculating, by a bundle adjustment unit, extrinsic parameters between the first through the M-th cameras through use of the first through the M-th camera parameters. A camera calibration program recording medium according to this invention is a medium having recorded thereon a camera calibration program for causing a computer to execute the procedures of: calculating first through M-th feature points from first through M-th calibration images, respectively, where M is an integer of 2 or more, which are captured by first through M-th cameras of different types, respectively, through use of the above-mentioned camera calibration board; calculating first through M-th camera parameters for the first through the M-th cameras from the first through the M-th feature points, respectively; and calculating extrinsic parameters between the first through the M-th cameras through use of the first through the M-th camera parameters. Effect of the Invention According to this invention, it is possible to highly accurately measure the extrinsic parameters between cameras, which are required for calibrating a plurality of cameras of different types. BRIEF DESCRIPTION OF THE DRAWING FIG. 1 is a schematic diagram of a camera calibration board according to one example embodiment of this invention. FIG. 2 is a block diagram for illustrating a schematic configuration of a camera calibration device according to Example of this invention. FIG. 3 is a flowchart for illustrating an operation of the camera calibration device illustrated in FIG. 2. FIG. 4 is a drawing (photograph) for illustrating an example of a calibration image (visible light image) captured by a visible light camera of a calibration image capturing unit, which is to be used in the camera calibration device illustrated in FIG. 2. FIG. 5 is a drawing (photograph) for illustrating an example of a calibration image (far-infrared image) captured by a far-infrared camera of the calibration image capturing unit, which is to be used in the camera calibration device illustrated in FIG. 2. MODES FOR EMBODYING THE INVENTION First Example Embodiment Next, a first example embodiment of this invention will be described in detail with reference to the drawings. Referring to FIG. 1, a camera calibration board to be used in the first example embodiment of this invention comprises a board 1, a plurality of flat plates 2, and a plurality of support columns 3. The plurality of support columns 3 have the same length. The plurality of flat plates 2 are arranged three-dimensionally above the board 1 via the respective corresponding support columns 2. In this case, each of the plurality of flat plates 2 is formed of a rectangular plate, and the plurality of flat plates 2 are spatially arranged in a plane. In the following, a case in which the board 1 is flat is described, but this invention is not limited thereto. In other words, it is only required that the plurality of flat plates 2 be spatially arranged in a certain plane that is separated from the board 1 by a predetermined distance. Further, in the camera calibration board to be used in the first example embodiment of this invention, the board 1 and each of the plurality of flat plates 2 have different reflectances with respect to visible light. For example, for the board 1, a white material or a material that has a color other than white and has a surface thereof painted with, for example, white paint or resin is used. In this case, for each of the flat plates 2, a material having a color other than white or a material having a surface thereof painted with, for example, paint or resin having a color other than white is used. As another example, for each of the flat plates 2, a white material or a material that has a color other than white and has a surface thereof painted with, for example, white paint or resin is used. In this case, for the board 1, a material having a color other than white or a material having a surface thereof painted with, for example, paint or resin having a color other than white is used. More generally, in the camera calibration board to be used in the first example embodiment of this invention, for the board 1, a material having a given color (hereinafter referred to as “color A”) or a material that has a color other than the color A and has a surface thereof painted with, for example, paint or resin having the color A is used. In this case, for each of the flat plates 2, a material having a color other than the color A or a material having a surface thereof painted with, for example, paint or resin having a color other than the color A is used. In this invention, when each of the flat plates 2 comprises a flat plate having a certain thickness, a surface of each of the flat plates 2 that is opposed to the board 1 may be chamfered. In any case, it is only required that the board 1 and each of the plurality of flat plates 2 have different reflectances with respect to visible light, and this invention is not limited to the above-mentioned configuration. In the first example embodiment, a calibration image capturing unit of a camera calibration device to be described later captures first and second calibration images through use of the camera calibration board described above. The calibration image capturing unit comprises a visible light camera configured to capture a visible light image as the first calibration image through use of the camera calibration board, and a depth camera configured to capture a depth image as the second calibration image through use of the camera calibration board. Next, effects of the first example embodiment will be described. According to the first example embodiment of this invention, it is possible to provide the camera calibration device capable of highly accurately measuring extrinsic parameters between cameras, which are required for calibrating the depth camera and the visible light camera from the visible light image acquired from the visible light camera and the depth image acquired from the depth camera. The reason is that, through use of the camera calibration board described in the first example embodiment, the board 1 and the plurality of flat plates 2 are located in planes different from each other and have different reflectances with respect to visible light, and hence a group of points arranged in the plane existing on the plurality of flat plates 2 can be highly accurately extracted from the visible light image and the depth image. Second Example Embodiment Now, a second example embodiment of this invention will be described in detail with reference to the drawings. Referring to FIG. 1, in a camera calibration board to be used in the second example embodiment of this invention, in addition to the configurations described above in the first example embodiment, the board 1 and the plurality of flat plates 2 are caused to have different temperatures, and the board 1 and the plurality of flat plates 2 are processed so that heat is not transferred therebetween. For example, in the camera calibration board, the plurality of flat plates 2 may be heated (or cooled) so that the board 1 and the plurality of flat plates 2 have different temperatures. As another example, in the camera calibration board, the board 1 may be heated (or cooled) so that the board 1 and the plurality of flat plates 2 have different temperatures. Further, for the board 1 or each of the plurality of flat plates 2 to be heated (or cooled), a material having a high thermal conductivity and a high thermal radiation property may be used so that the material has a uniform temperature. As another example, in order to achieve both a high thermal conductivity and a high thermal radiation property, the board 1 or each of the plurality of flat plates 2 may have a structure in which a material having a high thermal radiation property is layered on a material having a high thermal conductivity. More specifically, aluminum or other such metal may be used as a material having a high thermal conductivity, and as a material having a high thermal radiation property, resin or the like may be painted as paint on the material having a high thermal conductivity. As another example, in order to increase the thermal radiation property of aluminum or the like, a surface of the metal may be subjected to, for example, anodizing treatment, and the resultant may be used as the board 1 or each of the plurality of flat plates 2. Further, as a method of heating the board 1 or each of the plurality of flat plates 2, for example, an electric heating wire or other such object may be brought into contact with or built into the board 1 or each of the plurality of flat plates 2 to be heated, and current may be caused to flow through the electric heating wire to heat the board 1 or each of the plurality of flat plates 2. As other examples of the method of heating the board 1 or each of the plurality of flat plates 2, an object having a high or low temperature may be placed around the board 1 or each of the plurality of flat plates 2 to heat or cool the board 1 or each of the plurality of flat plates 2, or, for example, hot air or cold air may be used to heat or cool the board 1 or each of the plurality of flat plates 2. Still further, the structure in which the plurality of support columns 3 support the board 1 and the plurality of flat plates 2 with space therebetween is formed such that the board 1 and the plurality of flat plates 2 do not transfer heat therebetween. For example, for each of the support columns 3, a material having a low thermal conductivity may be used to support the board 1 and one of the plurality of flat plates 2 with space therebetween. As a material having a low thermal conductivity, for example, resin, plastic, wood, glass, expanded polystyrene, phenolic foam, or rigid polyurethane foam may be used. This invention is not limited thereto, and any material having a low thermal conductivity can be used. The camera calibration board to be used in the example embodiments of this invention can be used in any environment. For example, the camera calibration board may be used indoors, or may be used outdoors. In the second example embodiment, a calibration image capturing unit of a camera calibration device to be described later captures first through third calibration images through use of the camera calibration board described above. The calibration image capturing unit comprises a visible light camera configured to capture a visible light image as the first calibration image through use of the camera calibration board, a depth camera configured to capture a depth image as the second calibration image through use of the camera calibration board, and a far-infrared camera configured to capture a far-infrared image as the third calibration image through use of the camera calibration board. Next, effects of the second example embodiment will be described. According to the second example embodiment of this invention, it is possible to provide the camera calibration device capable of highly accurately measuring extrinsic parameters between cameras, which are required for simultaneously calibrating the depth camera, the far-infrared camera, and the visible light camera. The reason is that, through use of the camera calibration board to be used in the second example embodiment of this invention, the board 1 and the plurality of flat plates 2 are positioned in different planes, have different reflectances with respect to visible light, and have different temperatures, and hence a group of points arranged in the plane existing on the plurality of flat plates 2 can be highly accurately extracted from the visible light image, the depth image, and the far-infrared image. Example Now, Example of this invention will be described. In the following, an example is described in which processing is configured through use of image processing using the camera calibration board described in the above-mentioned first and second example embodiments, but this invention is not limited thereto. Referring to FIG. 2, a camera calibration device according to one Example of this invention comprises a calibration image capturing unit 10 and a computer (central processing unit; processor; data processing unit) 20 configured to operate under program control. The computer (central processing unit; processor; data processing unit) 20 comprises a visible light camera calibration unit 21, a depth camera calibration unit 22, an infrared camera calibration unit 23, and a bundle adjustment unit 30. Further, the visible light camera calibration unit 21 comprises a visible light image feature point detection unit 211 and a visible light camera parameter estimation unit 212. Similarly, the depth camera calibration unit 22 comprises a depth image feature point detection unit 221 and a depth camera parameter estimation unit 222. Moreover, the infrared camera calibration unit 23 comprises an infrared image feature point detection unit 231 and an infrared camera parameter estimation unit 232. The visible light image feature point detection unit 211, the depth image feature point detection unit 221, and the infrared image feature point detection unit 231 are also referred to as “first feature point detection unit”, “second feature point detection unit”, and “third feature point detection unit”, respectively. Further, the visible light camera parameter estimation unit 212, the depth camera parameter estimation unit 222, and the infrared camera parameter estimation unit 232 are also referred to as “first camera parameter estimation unit”, “second camera parameter estimation unit”, and “third camera parameter estimation unit”, respectively. Now, details of the respective components will be described. In the following, a method is described in which all of the visible light camera, the depth camera, and the far-infrared camera are used to construct the calibration image capturing unit 10, but this invention is not limited thereto. For example, the calibration image capturing unit 10, which uses the camera calibration board according to the example embodiments of this invention, may comprise only the visible light camera and the depth camera, comprise only the visible light camera and the far-infrared camera, or comprise only the far-infrared camera and the depth camera. The visible light camera, the depth camera, and the far-infrared camera are also referred to as “first camera”, “second camera”, and “third camera”, respectively. The calibration image capturing unit 10 acquires a plurality of calibration images through use of the camera calibration board described in the above-mentioned example embodiments of this invention. More specifically, after the board 1 or the plurality of flat plates 2 are heated, the plurality of calibration images may be captured by the visible light camera, the depth camera, and the far-infrared camera simultaneously in a plurality of postures as illustrated in FIG. 4 and FIG. 5, for example. FIG. 4 is a drawing for illustrating an example of the first calibration image (visible light image) captured by the visible light camera. FIG. 5 is a drawing for illustrating an example of the third calibration image-(far-infrared image) captured by the far-infrared camera. When the images are captured in a plurality of postures, the camera calibration board illustrated in FIG. 1 may be inclined with respect to an optical axis of each camera. For example, regarding the number of images to be captured, each camera may capture about 20 images. The captured images are stored in a memory (not shown). In the above, the case in which the calibration image capturing unit 10 newly captures calibration images is described, but this invention is not limited thereto. For example, calibration images that have been captured in advance and stored in the memory (not shown) may be read out. As another example, calibration images that have been captured in advance and calibration images that are newly captured by the calibration image capturing unit 10 may be stored in the memory (not shown). Referring back to FIG. 2, next, the images (visible light image, depth image, and far-infrared image) captured by the respective cameras (visible light camera, depth camera, and far-infrared camera) are supplied to the visible light camera calibration unit 21, the depth camera calibration unit 22, and the infrared camera calibration unit 23, respectively. The visible light image feature point detection unit 211, the depth image feature point detection unit 221, and the infrared image feature point detection unit 231 detect first through third feature points from the visible light image, the depth image, and the far-infrared image, respectively, which are to be used in the visible light camera parameter estimation unit 212, the depth camera parameter estimation unit 222, and the infrared camera parameter estimation unit 232, respectively. More specifically, for example, the visible light image feature point detection unit 211 detects from the visible light image (first calibration image) an intersection point on a checkered pattern of the plurality of flat plates 2 as the first feature point. As a method of detecting the first feature point, the Harris corner detection algorithm may be used, for example. Further, in order to calculate coordinates of the first feature point more accurately, the visible light image feature point detection unit 211 may use, for example, parabola fitting to detect the first feature point with subpixel accuracy. Further, first, as pre-processing, the depth image feature point detection unit 221 calculates a plane of the board 1 from the depth image (second calibration image), and converts a pixel value of each image into a value of a distance from the calculated plane. After that, in the same manner as in the visible light image feature point detection unit 211, the depth image feature point detection unit 221 may use, for example, the Harris corner detection algorithm to calculate coordinates of the second feature point. Further, as pre-processing, the infrared image feature point detection unit 231 removes noise of the far-infrared image (third calibration image), for example. After that, in the same manner as in the visible light image feature point detection unit 211, the infrared image feature point detection unit 231 may use, for example, the Harris corner detection algorithm to calculate coordinates of the third feature point. The method of detecting a feature point in this invention is not limited to the above-mentioned methods. For example, template matching or other such method may be used to detect a corner. As another example of the method of detecting a feature point in this invention, edge detection processing may be performed to detect edges of the checkered pattern, and then an intersection point of the edges may be detected as a corner. Next, the visible light camera parameter estimation unit 212, the depth camera parameter estimation unit 222, and the infrared camera parameter estimation unit 232 calculate first through third camera parameters of the respective cameras from the calculated coordinates of the first through the third feature points of the images, respectively. A more specific description is given taking the visible light image as an example. The visible light camera parameter estimation unit 212 may calculate intrinsic parameters of the visible light camera as the first camera parameter from the calculated first feature point (coordinates of the intersection on the checkered pattern) through use of, for example, the method described in Non Patent Document 2. More specifically, the visible light camera parameter estimation unit 212 may use a camera model described in Non Patent Document 2 to calculate intrinsic parameters of the camera model as the first camera parameter so that a reprojection error obtained from the calculated coordinates of the first feature point is minimized. In the above-mentioned Example, the method of calculating only the intrinsic parameters of the camera as the first camera parameter is described, but this invention is not limited thereto. For example, the visible light camera parameter estimation unit 212 may calculate lens distortion of the visible light camera at the same time as well as the intrinsic parameters, and correct the camera distortion. As another example, the visible light camera parameter estimation unit 212 may perform bundle adjustment for each camera from the coordinates of the first feature point acquired from the visible light camera, to thereby more accurately calculate intrinsic parameters, lens distortion, and extrinsic parameters as the first camera parameter. More specifically, the visible light camera parameter estimation unit 212 may use the camera model described in Non Patent Document 2 to calculate the intrinsic parameters, lens distortion, and extrinsic parameters of the camera model as the first camera parameter so that a reprojection error obtained from the calculated coordinates of the first feature point is minimized. Further, the depth camera parameter estimation unit 222 and the infrared camera parameter estimation unit 232 may calculate the second and third camera parameters by the same method that is used in the visible light camera parameter estimation unit 212. As another example, the depth camera parameter estimation unit 222 and the infrared camera parameter estimation unit 232 may calculate the second and third camera parameters through use of a model obtained by modeling characteristics of each camera more finely. For example, when the depth camera is taken as an example for description, the depth camera parameter estimation unit 222 may use a camera model described in Non Patent Document 1 to calculate intrinsic parameters and lens distortion of the depth camera as the second camera parameter. The bundle adjustment unit 30 calculates extrinsic parameters between the cameras through use of the coordinates of the first through the third feature points extracted by the visible light image feature point detection unit 211, the depth image feature point detection unit 221, and the infrared image feature point detection unit 231, respectively, and the first through the third camera parameters (values of intrinsic parameters and lens distortion of each camera) calculated by the visible light camera parameter estimation unit 212, the depth camera parameter estimation unit 222, and the infrared camera parameter estimation unit 232, respectively. More specifically, the bundle adjustment unit 30 may calculate the extrinsic parameters between the cameras so that a reprojection error obtained from the coordinates of the first through the third feature points extracted by the visible light image feature point detection unit 211, the depth image feature point detection unit 221, and the infrared image feature point detection unit 231, respectively, is minimized. Next, with reference to a flowchart of FIG. 3, an overall operation of the camera calibration device according to this Example will be described in detail. First, the respective cameras (visible light camera, depth camera, and far-infrared camera) capture the first through the third calibration images through use of the calibration board (S100). Next, the visible light image feature point detection unit 211, the depth image feature point detection unit 221, and the infrared image feature point detection unit 231 detect the first through the third feature points in the respective cameras (S101). Next, the visible light camera parameter estimation unit 212, the depth camera parameter estimation unit 222, and the infrared camera parameter estimation unit 232 calculate the first through the third camera parameters (intrinsic parameters) of the respective cameras from the coordinates of the first through the third feature points of images calculated for the respective cameras, respectively (S102). Further, the bundle adjustment unit 30 uses the first through the third camera parameters (values of intrinsic parameters and lens distortion of respective cameras) calculated by the visible light camera parameter estimation unit 212, the depth camera parameter estimation unit 222, and the infrared camera parameter estimation unit 232, respectively, to optimize the extrinsic parameters so that a reprojection error obtained from the extracted coordinates of the first through the third feature points is minimized, to thereby calculate the extrinsic parameters between the cameras (S103). In the above-mentioned Example, the case in which the calibration image capturing unit 10 comprises the visible light camera, the depth camera, and the far-infrared camera is taken as an example for description, but the calibration image capturing unit 10 may comprise only the visible light camera and the depth camera. In this case, the computer (central processing unit; processor; data processing unit) 20 is not required to include the infrared camera calibration unit 23. That is, the computer (central processing unit; processor; data processing unit) 20 comprises the visible light camera calibration unit 21, the depth camera calibration unit 22, and the bundle adjustment unit 30. The respective units of the camera calibration device are only required to be implemented through use of a combination of hardware and software. In a mode in which hardware and software are combined, a camera calibration program is loaded onto a random access memory (RAM), and a control unit (central processing unit (CPU)) and other hardware are caused to operate based on the program, to thereby implement each unit as corresponding means. Further, the program may be recorded in a recording medium for distribution. The program recorded in the recording medium is read into a memory in a wired or wireless manner, or via the recording medium itself, to cause the control unit and the like to operate. Examples of the recording medium include an optical disc, a magnetic disk, a semiconductor memory device, and a hard disk. When the example embodiments described above are described in another expression, the example embodiments can be implemented by causing, based on the camera calibration program loaded onto the RAM, a computer that is caused to operate as the camera calibration device to operate as the visible light camera calibration unit 21, the depth camera calibration unit 22, the infrared camera calibration unit 23, and the bundle adjustment unit 30. As described above, according to the Example of this invention, it is possible to highly accurately measure the extrinsic parameters between cameras, which are required for calibrating cameras of different types. Further, specific configurations of this invention are not limited to those of the above-mentioned example embodiments (Example), and this invention encompasses modifications that do not depart from the gist of this invention. For example, in the above-mentioned Example, the case is described in which three types of cameras including the visible light camera, the depth camera, and the far-infrared camera are used as different types of cameras, but it should be understood that this invention is similarly applicable also to a case in which four or more types of cameras are used. In the above, the invention of this application is described with reference to the example embodiments (Example), but the invention of this application is not limited to the above-mentioned example embodiments (Example). Various modifications that may be understood by a person skilled in the art can be made to the configurations and details of the invention of this application within the scope of the invention of this application. This application is based upon and claims the benefit of priority from Japanese Patent Application No. 2015-191417, filed on Sep. 29, 2015, the disclosure of which is incorporated herein in its entirety by reference. REFERENCE SIGNS LIST 1 board 2 flat plate 3 support column 10 calibration image capturing unit 20 computer (central processing unit; processor; data processing unit) 21 visible light camera calibration unit 211 visible light image feature point detection unit 212 visible light camera parameter estimation unit 22 depth camera calibration unit 221 depth image feature point detection unit 222 depth camera parameter estimation unit 23 infrared camera calibration unit 231 infrared image feature point detection unit 232 infrared camera parameter estimation unit 30 bundle adjustment unit | <SOH> BACKGROUND ART <EOH>In recent years, in order to photograph various objects to be photographed, cameras that use sensors suited to their respective purposes have become widespread. For example, in order to monitor a person or the like, a monitoring camera that uses a visible light sensor has become widespread. Meanwhile, an inexpensive depth image acquisition camera (hereinafter also referred to as “depth camera”) for acquiring a depth image has also become widespread. In addition, in order to monitor a person or the like in the nighttime, a camera that uses an invisible light sensor, such as a near-infrared camera or a far-infrared camera, has also become widespread. In order to easily analyze a group of images acquired from a plurality of sensors, it is required to calibrate cameras that use different types of image sensors. More specifically, it is required to accurately measure intrinsic parameters representing lens distortion, an image center, and the like of each camera, and extrinsic parameters representing a relative positional relationship between cameras. Against such a background, as the related art, in Non Patent Document 1, there is disclosed a method of simultaneously calibrating cameras through use of a depth image and a visible light image. Further, in Non Patent Document 2, there is disclosed a method of calculating camera's intrinsic parameters from feature points obtained by calculation from images. There is also known other related art (patent documents), which is related to this invention. For example, in Patent Document 1, there is disclosed a calibration table to be used for a stereo camera calibration device. The calibration table disclosed in Patent Document 1 comprises a perforated plate, which is arranged on an upper surface of a flat plate, and in which a large number of holes are formed, and a plurality of sticks (calibration poles), which are randomly fitted to freely-selected positions of the large number of holes of the perforated plate. The upper surface of the flat plate is painted in black, an upper surface of the perforated plate is painted in gray, and a top portion of each calibration pole is painted in white. The length of each calibration pole is randomly set. Two cameras (left camera and right camera) are arranged above the calibration table so that optical axes thereof are inclined toward each other. The optical axes of the left camera and the right camera are set so as to be approximately focused on a given point of the calibration table. Further, in Patent Document 2, there is disclosed a camera parameter estimation apparatus configured to estimate camera parameters of one camera. The camera parameter estimation apparatus disclosed in Patent Document 2 comprises a corresponding point searching device and camera parameter estimation means. The corresponding point searching device searches for a corresponding point between a plurality of images obtained by photographing the same object by one camera. The camera parameter estimation means uses information on the corresponding point, which is input from corresponding point searching means, to perform optimization through bundle adjustment with camera posture coefficients being set as unknown quantities, to thereby estimate the camera parameters. | <SOH> SUMMARY OF THE INVENTION <EOH> | H04N13246 | 20180327 | 20180913 | H04N13246 | 0 | SCHNURR, JOHN R | CAMERA CALIBRATION BOARD, CAMERA CALIBRATION DEVICE, CAMERA CALIBRATION METHOD, AND PROGRAM-RECORDING MEDIUM FOR CAMERA CALIBRATION | UNDISCOUNTED | 0 | REJECTED | H04N | 2,018 |
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15,764,079 | PENDING | INSTRUMENT CONTROLLER FOR ROBOTICALLY ASSISTED MINIMALLY INVASIVE SURGERY | A robot control system includes a controller device (120) mountable on a medical instrument and including a housing with a trackpad configured to interact with a printed circuit board therein to create electronic signals corresponding with movement of the trackpad. The electronic signals include a point signal and a click signal. An adapter is formed on the housing and is configured to detachably connect the controller device to the medical instrument. A display (118) is responsive to the point signal of the controller device to permit a cursor to be moved on the display to indicate a position to be imaged or moved to. A robot system (144) is configured to respond to the click signal to move one of a robot directly or an instrument held by the robot in accordance with the position to be imaged or moved to. | 1. A robot control system, comprising: a controller device mountable on a medical instrument and including a housing with a trackpad configured to interact with a printed circuit board therein to create electronic signals corresponding with movement of the trackpad, the electronic signals including a point signal and a click signal, and an adapter formed on the housing and configured to detachably connect the controller device to the medical instrument; a display responsive to the point signal of the controller device to permit a cursor to be moved on the display to indicate a position to be imaged or moved to; and a robot system configured to respond to the click signal to move one of a robot directly or an instrument held by the robot in accordance with the position to be imaged or moved to. 2. The system as recited in claim 1, wherein the trackpad is centrally disposed on the controller device and faces distally along when attached to the medical instrument. 3. The system as recited in claim 1, wherein the trackpad is disposed sideways on the controller device and faces in a perpendicular direction to a longitudinal axis of the medical instrument, when attached to the medical instrument. 4. The system as recited in claim 1, wherein the trackpad includes a point and click mechanism such that the point mechanism moves the cursor on the display and the click mechanism activates the robot system to move one of the robot or the instrument held by the robot to the cursor location. 5. The system as recited in claim 1, wherein the instrument held by the robot includes an imaging device. 6. The system as recited in claim 1, wherein the adaptor includes one of a channel, a clip or a magnet to attach to the medical instrument. 7. The system as recited in claim 1, wherein the controller device communicates wirelessly with a workstation to move the cursor in accordance with the point signal and activate the robot system with the click signal. 8. The system as recited in claim 1, further comprising an interface adapter configured to provide a wired connection between the controller device and a workstation to move a cursor in accordance with the point signal and activate the robot system with the click signal. 9. The system as recited in claim 1, wherein the trackpad controls a cursor on a display and the cursor position is translated by a cursor tracking program to a position in a robot coordinate system. 10. A robot control system, comprising: a handheld medical instrument; a controller device mountable on the medical instrument and including a housing with a trackpad configured to interact with a printed circuit board therein to create electronic signals corresponding with movement of the trackpad, the electronic signals including a point signal and a click signal, and an adapter formed on the housing and configured to detachably connect the controller device to the medical instrument, the controller device being configured to permit access to the trackpad by a hand of a user while employing the medical instrument; a display responsive to the point signal of the controller device to permit a cursor to be moved on the display to indicate a position to be imaged or moved to by an imaging device providing viewing content on the display; and a robot system configured to respond to the click signal to move the imaging device held by the robot in accordance with the position to be imaged or moved to such that the robot system is controlled by the user with the hand employing the medical instrument. 11. The system as recited in claim 10, wherein the trackpad is centrally disposed on the controller device and faces distally along when attached to the medical instrument. 12. The system as recited in claim 10, wherein the trackpad is disposed sideways on the controller device and faces in a perpendicular direction to a longitudinal axis of the medical instrument, when attached to the medical instrument. 13. The system as recited in claim 10, wherein the trackpad includes a point and click mechanism such that the point mechanism moves the cursor on the display and the click mechanism activates the robot system to adjust in accordance with the cursor location. 14. The system as recited in claim 10, wherein the adaptor includes one of a channel, a clip or a magnet to attach to the medical instrument. 15. The system as recited in claim 10, wherein the controller device communicates wirelessly with a workstation to move the cursor in accordance with the point signal and activate the robot system with the click signal. 16. The system as recited in claim 10, further comprising an interface adapter configured to provide a wired connection between the controller device and a workstation to move a cursor in accordance with the point signal and activate the robot system with the click signal. 17. The system as recited in claim 10, wherein the trackpad controls a cursor on a display and the cursor position is translated by a cursor tracking program to a position in a robot coordinate system. 18. A method for remote control of a robot, comprising: connecting a controller device on a medical instrument, the controller device including a housing with a trackpad configured to interact with a printed circuit board therein to create electronic signals corresponding with movement of the trackpad, the electronic signals including a point signal and a click signal, and an adapter formed on the housing and configured to detachably connect the controller device to the medical instrument; and positioning a robot system in response to the click signal to move one of a robot or an instrument held by the robot to a position in accordance with the point signal. 19. The method as recited in claim 18, wherein the trackpad includes a point and click mechanism, the method further comprising pointing a cursor to a position on a display and clicking to activate the robot system to move one of the robot or the instrument held by the robot to the cursor location. 20. The method as recited in claim 19, wherein the instrument held by the robot includes an imaging device and the method further comprises centering a display image on the cursor by moving the robot with the imaging device. | BACKGROUND Technical Field This disclosure relates to medical instruments and more particularly to a robot control device mounted on a medical instrument to provide additional freedom to a surgeon. Description of the Related Art Minimally invasive surgery is performed using elongated instruments inserted into a patient's body through small ports. Visualization during these procedures may include the use of an endoscope. In robotic guided minimally invasive surgery, one or more of the instruments is held and controlled by a robotic device. A robotic arm holding an endoscope needs to be controlled and manipulated by a member of a surgery team. Often, a different member of the team, other than the surgeon, needs to perform the robotic manipulation, as the surgeon frequently has both hands occupied holding instruments. This can dramatically impact the surgical workflow, as the surgeon needs to describe to another team member how he/she wants the robot to move, and the other team member needs to implement the instructions received. Aside from the time delay this causes, miscommunications can also result further slowing down the surgery. SUMMARY In accordance with the present principles, a controller device includes a base configured to support a printed circuit board and a button support positioned over the printed circuit board. A trackpad is supported by the button support and is configured to interact with the printed circuit board to create electronic signals corresponding with movement of the trackpad. An adapter is configured to detachably connect to a medical instrument such that the controller device remotely controls operation of at least one other instrument using the trackpad when mounted on the medical instrument. A robot control system includes a controller device mountable on a medical instrument and including a housing with a trackpad configured to interact with a printed circuit board therein to create electronic signals corresponding with movement of the trackpad. The electronic signals include a point signal and a click signal. An adapter is formed on the housing and is configured to detachably connect the controller device to the medical instrument. A robot system is configured to respond to the click signal generated to move one of a robot or an instrument held by the robot in accordance with the point signal. Another robot control system includes a controller device mountable on a medical instrument and including a housing with a trackpad configured to interact with a printed circuit board therein to create electronic signals corresponding with movement of the trackpad. The electronic signals include a point signal and a click signal. An adapter is formed on the housing and is configured to detachably connect the controller device to the medical instrument. A display is responsive to the point signal of the controller device to permit a cursor to be moved on the display to indicate a position to be imaged or moved to. A robot system is configured to respond to the click signal to move one of a robot directly or an instrument held by the robot in accordance with the position to be imaged or moved to. Yet another robot control system includes a handheld medical instrument and a controller device mountable on the medical instrument and including a housing with a trackpad configured to interact with a printed circuit board therein to create electronic signals corresponding with movement of the trackpad. The electronic signals include a point signal and a click signal. An adapter is formed on the housing and configured to detachably connect the controller device to the medical instrument. The controller device is configured to permit access to the trackpad by a hand of a user while employing the medical instrument. A display is responsive to the point signal of the controller device to permit a cursor to be moved on the display to indicate a position to be imaged or moved to by an imaging device providing viewing content on the display. A robot system is configured to respond to the click signal to move the imaging device held by the robot in accordance with the position to be imaged or moved to such that the robot system is controlled by the user with the hand employing the medical instrument. A method for remote control of a robot includes connecting (502) a controller device on a medical instrument, the controller device including a housing with a trackpad configured to interact with a printed circuit board therein to create electronic signals corresponding with movement of the trackpad, the electronic signals including a point signal and a click signal, and an adapter formed on the housing and configured to detachably connect the controller device to the medical instrument; and positioning a robot system in response to the click signal to move one of a robot or an instrument held by the robot to a position in accordance with the point signal. These and other objects, features and advantages of the present disclosure will become apparent from the following detailed description of illustrative embodiments thereof, which is to be read in connection with the accompanying drawings. BRIEF DESCRIPTION OF DRAWINGS This disclosure will present in detail the following description of preferred embodiments with reference to the following figures wherein: FIG. 1 is a block/flow diagram showing a controller system, which employs a controller device to control robot position in accordance with one embodiment; FIG. 2 is a perspective view showing a forward-facing controller device attached to a medical instrument in accordance with one embodiment; FIG. 3 is a back view showing a back surface of the controller device for attaching to a medical instrument in accordance with one embodiment; FIG. 4 is a side perspective view showing an interface adapter on a side surface of the controller device in accordance with one embodiment; FIG. 5 is an exploded perspective view showing internal portions of the controller device in accordance with one embodiment; FIG. 6 is a perspective view showing a side-facing controller device attached to a medical instrument in accordance with one embodiment; and FIG. 7 is a flow diagram showing a method for remote control of a robot in accordance with illustrative embodiments. DETAILED DESCRIPTION OF EMBODIMENTS In accordance with the present principles, devices and methods are provided that permit a surgeon to retain personal control of a robotic arm while still maintaining full dexterity and full use of both hands. In one embodiment, the robotic arm may hold, e.g., an endoscope. A controller device is provided that attaches to an instrument (e.g., a laparoscopic instrument) that the surgeon holds. A trackpad or joystick is provided on the controller device to permit the surgeon to move a virtual pointer on an endoscopic video screen. When the pointer is highlighted on the screen, a button on the device can be pressed, and the robot moves towards the point. In one embodiment, the selected point moves towards the center of the endoscopic view. It should be understood that the present invention will be described in terms of medical instruments; however, the teachings of the present invention are much broader and are applicable to any devices medical or otherwise. In some embodiments, the present principles are employed in performing procedures or analyzing complex biological or mechanical systems. In particular, the present principles are applicable to procedures in biological systems in all areas of the body such as the lungs, gastro-intestinal tract, excretory organs, blood vessels, etc. The present principles are applicable to devices for training users for procedures or for other applications. The elements depicted in the FIGS. may be implemented in various combinations of hardware and software and provide functions which may be combined in a single element or multiple elements. The functions of the various elements shown in the FIGS. can be provided through the use of dedicated hardware as well as hardware capable of executing software in association with appropriate software. When provided by a processor, the functions can be provided by a single dedicated processor, by a single shared processor, or by a plurality of individual processors, some of which can be shared. Moreover, explicit use of the term “processor” or “controller” should not be construed to refer exclusively to hardware capable of executing software, and can implicitly include, without limitation, digital signal processor (“DSP”) hardware, read-only memory (“ROM”) for storing software, random access memory (“RAM”), non-volatile storage, etc. Moreover, all statements herein reciting principles, aspects, and embodiments of the invention, as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalents as well as equivalents developed in the future (i.e., any elements developed that perform the same function, regardless of structure). Thus, for example, it will be appreciated by those skilled in the art that the block diagrams presented herein represent conceptual views of illustrative system components and/or circuitry embodying the principles of the invention. Similarly, it will be appreciated that any flow charts, flow diagrams and the like represent various processes which may be substantially represented in computer readable storage media and so executed by a computer or processor, whether or not such computer or processor is explicitly shown. Furthermore, embodiments of the present invention can take the form of a computer program product accessible from a computer-usable or computer-readable storage medium providing program code for use by or in connection with a computer or any instruction execution system. For the purposes of this description, a computer-usable or computer readable storage medium can be any apparatus that may include, store, communicate, propagate, or transport the program for use by or in connection with the instruction execution system, apparatus, or device. The medium can be an electronic, magnetic, optical, electromagnetic, infrared, or semiconductor system (or apparatus or device) or a propagation medium. Examples of a computer-readable medium include a semiconductor or solid state memory, magnetic tape, a removable computer diskette, a random access memory (RAM), a read-only memory (ROM), a rigid magnetic disk and an optical disk. Current examples of optical disks include compact disk—read only memory (CD-ROM), compact disk—read/write (CD-R/W), Blu-Ray™ and DVD. Reference in the specification to “one embodiment” or “an embodiment” of the present principles, as well as other variations thereof, means that a particular feature, structure, characteristic, and so forth described in connection with the embodiment is included in at least one embodiment of the present principles. Thus, the appearances of the phrase “in one embodiment” or “in an embodiment”, as well any other variations, appearing in various places throughout the specification are not necessarily all referring to the same embodiment. It is to be appreciated that the use of any of the following “/”, “and/or”, and “at least one of”, for example, in the cases of “A/B”, “A and/or B” and “at least one of A and B”, is intended to encompass the selection of the first listed option (A) only, or the selection of the second listed option (B) only, or the selection of both options (A and B). As a further example, in the cases of “A, B, and/or C” and “at least one of A, B, and C”, such phrasing is intended to encompass the selection of the first listed option (A) only, or the selection of the second listed option (B) only, or the selection of the third listed option (C) only, or the selection of the first and the second listed options (A and B) only, or the selection of the first and third listed options (A and C) only, or the selection of the second and third listed options (B and C) only, or the selection of all three options (A and B and C). This may be extended, as readily apparent by one of ordinary skill in this and related arts, for as many items listed. It will also be understood that when an element is referred to as being “on” or “over” another element, it can be directly on the other element or intervening elements may also be present. In contrast, when an element is referred to as being “directly on” or “directly over” another element, there are no intervening elements present. It will also be understood that when an element is referred to as being “connected” or “coupled” to another element, it can be directly connected or coupled to the other element or intervening elements may be present. In contrast, when an element is referred to as being “directly connected” or “directly coupled” to another element, there are no intervening elements present. Referring now to the drawings in which like numerals represent the same or similar elements and initially to FIG. 1, a system 100 for controlling a robot using a controller attached to an instrument is illustratively shown in accordance with one embodiment. System 100 may include a workstation or console 112 from which a procedure is supervised and/or managed. Workstation 112 preferably includes one or more processors 114 and memory 116 for storing programs and applications. A medical instrument 102 may include a laparoscopic instrument or any other instrument useful during a procedure, e.g., forceps, clamps, ablation electrodes, catheters, etc. The medical instrument 102 may be employed in conjunction with an imaging system 136. The imaging system or device 136 may include an endoscope or other scope configured to provide images 152 of an area of interest or an operable area. The medical instrument 102 includes a controller or controller device 120 mounted thereon. The controller 120 functions as a point and click device to reset a cursor position or image perspective on a display 118. Memory 116 may store a cursor tracking program 115. The cursor tracking program 115 takes an input from the controller 120 to reset the cursor position on the display 118. In one embodiment, the cursor position can track the position of the controller 120 so that moving the controller 120 moves the cursor. In another embodiment, the cursor position is altered using the controller 120, and the imaging system 136 is moved in accordance with the cursor on the display 118. When a new cursor position is set using the controller 120, the cursor tracking program 115 identifies a new coordinate and relays this information to a robot 144 to correlate a position of the robot 144 holding the imaging device 136 (e.g., endoscope) with the cursor position on the display 118. The cursor position is preferably centrally maintained on the display 118 to facilitate workflow. The cursor position may be set to other locations (other than the center) on the display 118, as desired. Position and orientation information about every point of the robot 144 relative to a reference location is known and can be provided, e.g., using encoders or other measurement systems. The position and orientation information of the robot 144 may be defined in terms of a robot coordinate system 150. The robot 144 may interact with a robot guidance/control system 154 tied into the workstation 112 to permit coordination between the controller 120 and the robot 144. A relationship between the robot 144 and the display 118 is correlated. Movement of a trackpad or other control on the controller 120 moves the cursor. Once the cursor is positioned properly, the controller 120 is activated (click). The cursor position is provided to cursor tracking 115, which translates the coordinates for the robot control system 154. The robot control system 154 send commands to control the robot 144 to reposition the imaging system 136 in accordance with the cursor position. One or more transforms may be employed to convey the cursor position to robot control commands. Workstation 112 includes the display 118 for other purposes as well, e.g., viewing images (including preoperative images computed tomography (CT), magnetic resonance (MR), etc., real-time X-ray images, etc.) of a subject (patient) 132. The images may include images as overlays on other images (e.g., endoscope images on X-ray images, CT images, etc.). Display 118 may also permit a user to interact with the workstation 112 and its components and functions, or any other element within the system 100. This is further facilitated by an interface 130 which may include a keyboard, mouse, a joystick, a haptic device, or any other peripheral or control to permit user feedback from and interaction with the workstation 112. In accordance with the present principles, a user or surgeon has personal control of the robot 144 holding the imaging device 136 (e.g., endoscope) so that exact actions can be performed as desired. In addition, the motion of the various joints in the robot 144 directly and intuitively relates to the motion that the surgeon truly desires, e.g., the motion of the endoscopic camera view. The surgeon can simply select a point on the screen of display 118 using the controller 120 to the position where the imaging point of view is desired thereby removing any complicated kinematics from the conscious workflow of the surgeon. In another embodiment, the robot 144 is employed to hold another instrument 103 (e.g., a laparoscopic instrument) instead of the imaging device 136 endoscope. When the user selects a point on screen, instead of the robot 144 moving towards that point, the robot 144 moves the instrument 103 to that point. This would in effect give the surgeon a “third hand”, allowing him to manipulate three instruments at once. Referring to FIG. 2, an instrument 202, which permits a surgeon to retain personal control of a robotic arm that holds, e.g., an endoscope, while still maintaining full dexterity and full use of both hands, is illustratively shown. A controller device 220 (e.g., controller 120, in FIG. 1) mounts on the instrument 202, which may include a laparoscopic instrument in one embodiment. The surgeon holds the instrument 202 in one hand. A trackpad or joystick 206 is provided on the controller 220 to permit the surgeon to move a virtual pointer on an endoscopic video screen (e.g., display 118, FIG. 1). In one embodiment, the instrument 202 includes a front or forward-facing controller device 220. The central trackpad 206 allows the user to move a pointer (cursor) on the endoscopic video feed and select a point to move towards by pressing down (clicking) on the central trackpad 206. Two buttons 208 provide additional functionality, such as display controls or the like. When the point that the surgeon desires is highlighted on the screen, a control mechanism (e.g., a click button on or below track pad 206) on the controller 220 is activated and the robot (144) moves towards the point, such that the selected point moves, e.g., towards the center of the endoscopic view. The controller 220 includes trackpad 206 at a centrally disposed location. In one embodiment, the controller 220 faces along a length of the laparoscopic instrument (FIG. 2). This gives the controller an almost “trigger-like” feel, permitting the surgeon's index finger to wrap around the controller 220 and rest comfortably on the trackpad 206. The surgeon can still use other fingers normally to manipulate the laparoscopic instrument 202. In another embodiment, the controller 220 can toggle between two modes. For example, a first mode may include selecting points on the endoscopic video feed and a second mode may provide for the direct manipulation of robotic joints. A button (e.g., button 208) can be pressed to toggle between the two modes. In another embodiment, a miniature “thumb” joystick may be substituted for the trackpad 206. A joystick may be easier to use if direct manipulation of the robotic joints is desired instead of selection of points on screen. Referring to FIG. 3, a back view of the controller 220 is illustratively shown. The controller 220 includes an instrument interface 304. The instrument interface 304 may be removable so that it can be configured for different devices or instruments. In the embodiment shown, the interface 304 forms a channel 302 to provide a securing position to receive the instrument (e.g., a laparoscopic instrument). The channel 302 may include other materials or structures to assist in securing the instrument. The controller 220 can have interchangeable adapters/interfaces 304 to permit the attachment to different instruments including, but not limited to laparoscopic instruments. In other embodiments, a magnetic adapter 305 may be employed to further secure the controller 220 to the instrument. In one embodiment, the magnetic adapter 305 may include a neodymium magnet that attaches to the metallic laparoscopic instrument handle. This adapter 305 permits for quick placement onto and off of the handle while still remaining firmly attached to the handle. In another embodiment, the controller can be manufactured as part of the laparoscopic handle itself. Referring to FIG. 4, a side perspective view of the controller 220 shows illustrative functionality of the controller 220. The controller 220 may include an adapter interface 306 for connecting to a universal serial bus (USB) or other interface adapter port. The interface 306 may provide data from the trackpad 206 and/or buttons 208 to the workstation 112 to permit recording of commands, to transform the commands into robot motion or change of a display perspective as described above. In one embodiment, communication between the controller 220 and the workstation 112 is performed wirelessly. Each device may include an antenna or include a printed circuit board with an antenna and communicate using known communication protocols, e.g., BLUETOOTH™, etc. The trackpad 206 can be employed to manipulate a virtual pointer or cursor on the endoscopic video feed (by wireless or wired signaling). When the desired point is selected, the user presses down on the trackpad 206, which serves as a button press, thereby initiating robotic motion. The robot then moves to center the selected point in the endoscopic video feed. If the user wants to stop the robot at any time, the user can press the trackpad button (206) at any time after motion has started. The additional buttons 208 can add other functionality, for example, additional degrees of motion such as, e.g., roll or zoom can be controlled using buttons 208 (e.g., one button can be used as zoom in, and the another as zoom out). Referring to FIG. 5, an exploded perspective view of the controller 220 is shown. The exploded view shows a cover 408 removed to expose internal features of the controller 220. The cover 408 includes openings 412 to permit access to buttons 208, trackpad 206 and interface adapter 306. The controller 220 includes a base 402, which functions as a support for electronic components. The base 402 supports a printed circuit board (PCB) 404, and may be employed to store a battery or batteries for a wireless embodiment. A button support 406 is connected to the base 402 to provide support for buttons 208 and trackpad 206. The buttons 208 and trackpad 206 interface with the PCB 404 to create electronic signals corresponding to position commands from the trackpad 206, the depression of the trackpad as a button, and the depression of the buttons 208. A back cover 410 engages the base 402 and is secured to the cover 408 by screws 414 or other mechanical devices. The interchangeable adapter/interface 304 is coupled to the back cover 410. In particularly useful embodiments, the controller 220 communicates wirelessly with the controlling computer/workstation using BLUETOOTH™ (or other wireless protocol). This gives the user greater range of motion and overall freedom. Wireless communication employs a battery that is encased inside the controller 220, e.g., within the holder 402. If a wireless protocol is used, the controller 220 may provide charging of the battery through the interface adapter 306. In another embodiment, a powered wired connection is employed instead, reducing overall range of motion but insuring a constant reliable power source. Using a wired connection also reduces the overall size of the controller 220, as a battery is not needed. The controller 220 may include the capability for both wires and wireless operation. Referring to FIG. 6, in another embodiment, a controller 420 includes a sideways orientation, such that the trackpad 206 faces roughly perpendicular to a length of an instrument 422 (e.g., a laparoscopic instrument)). The embodiment shown is configured for a right handed user. While the front-facing controller is configured more universally for all users, the sideways orientation may be easier for some users to employ. A clip or clips 424 are employed to attach the controller 220 to the instrument 422. Other connection mechanisms including magnets are also contemplated. The present principles are useful for giving a surgeon direct personal control of the robotic arm while freeing up his/her hands. Eye-tracking or oral dictation systems are not yet robust enough to guide the robot reliably, and foot pedals require additional dexterity and shifting of body weight in the midst of the surgery. While the present principles are particularly useful for laparoscopic surgery, the present principles may be employed in any number of procedures. Applications for robotic guided minimally invasive procedures may include cardiac surgery (e.g., atrial septal defect closure, valve repair/replacement, etc.); laparoscopic surgery (e.g., hysterectomy, prostactomy, etc.); gall bladder surgery; Natural Orifice Transluminal Surgery (NOTES); Single Incision Laparoscopic Surgery (SILS); pulmonary/bronchoscopic surgery; minimally invasive diagnostic interventions (e.g., arthroscopy); etc. Referring to FIG. 7, a method for remote control of a robot is shown in accordance with illustrative embodiments. In block 502, a controller device is provided. The controller device includes a housing with a trackpad (or joystick) configured to interact with a printed circuit board to create electronic signals corresponding with movement of the track pad. The electronic signals include a point signal and a click signal. The controller device is configured to be mounted on a medical instrument and is installed or mounted on the medical instrument using an adapter that is configured to detachably connect the controller device to the medical instrument. The adapter may be configured to be detachably removed from the instrument using an attachment mechanism, such as, a magnet, clip, channel, or the like. In block 504, a robot system is positioned in response to the click signal to move one of a robot or an instrument held by the robot to a position in accordance with the point signal. In block 506, the trackpad may include a point and click mechanism (e.g., trackpad and button). A cursor position may be controlled by pointing the cursor with the trackpad. The cursor position is provided on a display. By clicking the button of the trackpad, the cursor position is translated into a robot coordinate, and the robot and/or the instrument the robot is holding is moved to the corresponding cursor location. In block 508, the instrument held by the robot may include an imaging device (e.g., an endoscope). A display image may be centered on the cursor (as the cursor is moved) by moving the robot with the imaging device with the movement of the cursor. In block 510, the robot may be controlled using the controller, and/or an instrument held by the robot may be controlled using the controller device. In interpreting the appended claims, it should be understood that: a) the word “comprising” does not exclude the presence of other elements or acts than those listed in a given claim; b) the word “a” or “an” preceding an element does not exclude the presence of a plurality of such elements; c) any reference signs in the claims do not limit their scope; d) several “means” may be represented by the same item or hardware or software implemented structure or function; and e) no specific sequence of acts is intended to be required unless specifically indicated. Having described preferred embodiments for instrument controller for robotically assisted minimally invasive surgery (which are intended to be illustrative and not limiting), it is noted that modifications and variations can be made by persons skilled in the art in light of the above teachings. It is therefore to be understood that changes may be made in the particular embodiments of the disclosure disclosed which are within the scope of the embodiments disclosed herein as outlined by the appended claims. Having thus described the details and particularity required by the patent laws, what is claimed and desired protected by Letters Patent is set forth in the appended claims. | <SOH> BACKGROUND <EOH> | <SOH> SUMMARY <EOH>In accordance with the present principles, a controller device includes a base configured to support a printed circuit board and a button support positioned over the printed circuit board. A trackpad is supported by the button support and is configured to interact with the printed circuit board to create electronic signals corresponding with movement of the trackpad. An adapter is configured to detachably connect to a medical instrument such that the controller device remotely controls operation of at least one other instrument using the trackpad when mounted on the medical instrument. A robot control system includes a controller device mountable on a medical instrument and including a housing with a trackpad configured to interact with a printed circuit board therein to create electronic signals corresponding with movement of the trackpad. The electronic signals include a point signal and a click signal. An adapter is formed on the housing and is configured to detachably connect the controller device to the medical instrument. A robot system is configured to respond to the click signal generated to move one of a robot or an instrument held by the robot in accordance with the point signal. Another robot control system includes a controller device mountable on a medical instrument and including a housing with a trackpad configured to interact with a printed circuit board therein to create electronic signals corresponding with movement of the trackpad. The electronic signals include a point signal and a click signal. An adapter is formed on the housing and is configured to detachably connect the controller device to the medical instrument. A display is responsive to the point signal of the controller device to permit a cursor to be moved on the display to indicate a position to be imaged or moved to. A robot system is configured to respond to the click signal to move one of a robot directly or an instrument held by the robot in accordance with the position to be imaged or moved to. Yet another robot control system includes a handheld medical instrument and a controller device mountable on the medical instrument and including a housing with a trackpad configured to interact with a printed circuit board therein to create electronic signals corresponding with movement of the trackpad. The electronic signals include a point signal and a click signal. An adapter is formed on the housing and configured to detachably connect the controller device to the medical instrument. The controller device is configured to permit access to the trackpad by a hand of a user while employing the medical instrument. A display is responsive to the point signal of the controller device to permit a cursor to be moved on the display to indicate a position to be imaged or moved to by an imaging device providing viewing content on the display. A robot system is configured to respond to the click signal to move the imaging device held by the robot in accordance with the position to be imaged or moved to such that the robot system is controlled by the user with the hand employing the medical instrument. A method for remote control of a robot includes connecting ( 502 ) a controller device on a medical instrument, the controller device including a housing with a trackpad configured to interact with a printed circuit board therein to create electronic signals corresponding with movement of the trackpad, the electronic signals including a point signal and a click signal, and an adapter formed on the housing and configured to detachably connect the controller device to the medical instrument; and positioning a robot system in response to the click signal to move one of a robot or an instrument held by the robot to a position in accordance with the point signal. These and other objects, features and advantages of the present disclosure will become apparent from the following detailed description of illustrative embodiments thereof, which is to be read in connection with the accompanying drawings. | A61B3474 | 20180328 | 20181004 | A61B3400 | 0 | GHIMIRE, SHANKAR RAJ | INSTRUMENT CONTROLLER FOR ROBOTICALLY ASSISTED MINIMALLY INVASIVE SURGERY | UNDISCOUNTED | 0 | PENDING | A61B | 2,018 |
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15,764,916 | PENDING | SURGICAL CONTROL APPARATUS, SURGICAL CONTROL METHOD, AND PROGRAM | The present invention relates to a surgical control apparatus, a surgical control method, and a program that can prevent erroneous operations of surgical apparatuses when the surgical apparatuses are controlled with contactless inputs. A state estimation block (64) estimates a state of an operator recognized by a recognition block (61) on the basis of at least one type of contactless input sent from the operator. In accordance with the state estimated by the state estimation block (64), a command block (62) restricts a control operation of a surgical camera (11), a camera arm (12), or an image processing block (66) based on at least one type of contactless input sent from the operator recognized by the recognition block (61). The present invention is applicable to a surgical system and the like that have a surgical camera (11), a camera arm (12), an action recognition camera (13), a display (14), a control apparatus (15), a pair of glasses (17), a microphone (18), a marker, a foot switch (20), etc., thereby enabling the treatment realized by referencing images. | 1. A surgical control apparatus comprising: a state estimation block configured to estimate, on the basis of at least one type of contactless input from a user recognized by a first contactless input recognition block, a state of the user; and a restriction block configured to restrict, in accordance with the state estimated by the state estimation block, a control operation of a surgical apparatus based on at least one type of contactless input from the user recognized by a second contactless input recognition block. 2. The surgical control apparatus according to claim 1, wherein the contactless input is a voice, a line of sight, a movement, or a gesture of the user. 3. The surgical control apparatus according to claim 1, wherein the control operation is executed on the basis of at least one type of contactless input from the user recognized by the second contactless input recognition block and an input by contact from the user recognized by a contact input recognition block. 4. The surgical control apparatus according to claim 1, wherein the state estimation block estimates a state of the user as an action-other-than-surgical-procedure state, a downward viewing state, a close watching state, or an observation state. 5. The surgical control apparatus according to claim 4, wherein a control operation of the surgical apparatus is a menu display control operation of a display control apparatus, an annotation display control operation of a display control apparatus, an imaging control operation of a surgical imaging apparatus for taking a surgical field image, or an arm driving control operation for holding the surgical imaging apparatus. 6. The surgical control apparatus according to claim 5, wherein if a state of the user is estimated by the state estimation block to be an action-other-than-surgical-procedure state, the restriction block restricts the control operation of the surgical apparatus to the menu display control operation of the display control apparatus. 7. The surgical control apparatus according to claim 5, wherein if a state of the user is estimated by the state estimation block to be a downward viewing state, the restriction block restricts the control operation of the surgical apparatus to the annotation display control operation of the display control apparatus. 8. The surgical control apparatus according to claim 5, wherein if a state of the user is estimated by the state estimation block to be a close watching state, the restriction block restricts the control operation of the surgical apparatus to the imaging control operation of the surgical imaging apparatus. 9. The surgical control apparatus according to claim 5, wherein if a state of the user is estimated by the state estimation block to be an observation state, the restriction block restricts the control operation of the surgical apparatus to the driving control operation of the arm. 10. The surgical control apparatus according to claim 1, further comprising: a mode setting block configured to set an operation mode of the surgical control apparatus on the basis of at least one type of contactless input from the user recognized by the second contactless input recognition block. 11. The surgical control apparatus according to claim 10, wherein the state estimation block estimates the state if the operation mode is a mode for controlling the surgical apparatus on the basis of at least one type of contactless input from the user. 12. A surgical control method comprising: a state estimation step of estimating, on the basis of at least one type of contactless input from a user recognized by a first contactless input recognition block, a state of the user; and a restriction step of restricting, in accordance with the state estimated by processing in the state estimation step, a control operation of a surgical apparatus based on at least one type of contactless input from the user recognized by a second contactless input recognition block; these steps being executed by a surgical control apparatus. 13. A program for having a computer function as: a state estimation block configured to estimate, on the basis of at least one type of contactless input from a user recognized by a first contactless input recognition block, a state of the user; and a restriction block configured to restrict, in accordance with the state estimated by the state estimation block, a control operation of a surgical apparatus based on at least one type of contactless input from the user recognized by a second contactless input recognition block. | TECHNICAL FIELD The present disclosure relates to a surgical control apparatus, a surgical control method, and a program and, more particularly, to a surgical control apparatus, a surgical control method, and a program that are configured to prevent an erroneous operation of a surgical apparatus from happening in the case where the surgical apparatus is controlled by contactless inputs. BACKGROUND ART A surgical system has been devised in which a surgical system controls a surgical apparatus by inputting such contactless information as voices, gestures, and lines of sight (refer to PTL 1, for example). With such a surgical system, an operator for whom the practicing of sterilization measures is essential is able to control a surgical apparatus without touching the manipulation buttons and other controls. However, as compared with inputs by touch, contactless inputs may cause the erroneous recognition of inputs, thereby making a surgical apparatus operate in an erroneous manner. With a surgical system, any erroneous operation of a surgical apparatus affects the life of a patient, so that it is essential to prevent any erroneous operation of the surgical apparatus. CITATION LIST Patent Literature [PTL 1] U.S. Patent Application Publication No. 2011/026678 SUMMARY Technical Problem Therefore, in controlling surgical apparatuses by contactless inputs, the realization of fail-safe is demanded so as to prevent erroneous operations of the surgical apparatuses. The present disclosure, executed in consideration of the above-mentioned situations, is intended to prevent erroneous operations of surgical apparatuses when surgical apparatuses are controlled by contactless inputs. Solution to Problem According to one aspect of the present disclosure, there is provided a surgical control apparatus. This surgical control apparatus has: a state estimation block configured to estimate, on the basis of at least one type of contactless input from a user recognized by a first contactless input recognition block, a state of the user; and a restriction block configured to restrict, in accordance with the state estimated by the state estimation block, a control operation of a surgical apparatus based on at least one type of contactless input from the user recognized by a second contactless input recognition block. A surgical control method and a program practiced as other aspects of the present disclosure correspond to the surgical control apparatus practiced as one aspect of the present disclosure. In one aspect of the present disclosure, on the basis of at least one type of contactless input from a user recognized by the first contactless input recognition block, a state of the user is estimated and, in accordance with the estimated state, a control operation of the surgical apparatus based on at least one type of contactless input from the user recognized by the second contactless input recognition block is restricted. Advantageous Effects of Invention According to one aspect of the present disclosure, a surgical apparatus can be controlled. In addition, according to another aspect of the present disclosure, an erroneous operation of a surgical apparatus can be prevented when the surgical apparatus is controlled with contactless inputs. It should be noted that the effects described here are not necessarily restricted; namely, any of the effects described in the present disclosure may be effects denoted here. BRIEF DESCRIPTION OF DRAWINGS FIG. 1 is a block diagram illustrating one example of a configuration of a surgical system practiced as a first embodiment to which the present disclosure is applied. FIG. 2 is a diagram illustrating a driving operation of a surgical camera by a camera arm depicted in FIG. 1. FIG. 3 is a block diagram illustrating one example of a configuration of a control apparatus depicted in FIG. 1. FIG. 4 is a diagram illustrating one example of a relation between input information and commands. FIG. 5 is a diagram illustrating the description of the execution of a pivot movement command by a control block depicted in FIG. 3. FIG. 6 is a diagram for the description of the execution of a slide movement command by a control block depicted in FIG. 3. FIG. 7 is a diagram illustrating one example of a state of an operator estimated by a state estimation block depicted in FIG. 3. FIG. 8 is a diagram for the description of a method of estimating an operator state in the state estimation block depicted in FIG. 3. FIG. 9 is a flowchart indicative of control processing to be executed by the control apparatus of the surgical system depicted in FIG. 1. FIG. 10 is a flowchart indicative of details of the state estimation processing depicted in FIG. 9. FIG. 11 is a block diagram illustrating one example of a configuration of a surgical system practiced as a second embodiment to which the present disclosure is applied. FIG. 12 is a block diagram illustrating one example of a configuration of hardware of a computer. DESCRIPTION OF EMBODIMENTS The following describes modes (hereafter referred to as embodiments) of executing the present disclosure. It should be noted that the description will be done in the following sequence. 1. First Embodiment: Surgical System (FIG. 1 through FIG. 10) 2. Second Embodiment: Surgical System (FIG. 11) 3. Third Embodiment: Computer (FIG. 12) First Embodiment (Example of Configuration of Surgical System Practiced as First Embodiment) FIG. 1 is a block diagram illustrating one example of a configuration of a surgical system practiced as a first embodiment to which the present disclosure is applied. A surgical system 10 has a surgical camera 11, a camera arm 12, an action recognition camera 13, a display 14, a control apparatus 15, an operating table 16, surgical glasses 17, a microphone 18, a marker 19, and a foot switch 20. The surgical system 10 is arranged in an operating room or the like and enables such treatments as surgical operations and the like that reference images taken with the surgical camera 11. To be more specific, the surgical camera 11 (a surgical imaging apparatus) of the surgical system 10 is a modality device such as a 3D camera or the like held by the camera arm 12. The surgical camera 11 takes an image of the surgical field of a patient 21 lying on the operating table 16 and transmits a resultant 3D image to the control apparatus 15 as a surgical field image. The camera arm 12 holds the surgical camera 11 so as to control the position and the angle of the surgical camera 11. The action recognition camera 13 is a 2D camera, for example, and arranged on top of the display 14. The action recognition camera 13 takes an image of an operator 22 who wears the surgical glasses 17, the microphone 18, and the marker 19 on the head 22A. The action recognition camera 13 transmits a 2D image obtained as a result of imaging to the control apparatus 15 as an operator image. The display 14 is a 3D display having a comparatively large screen and arranged at a position (in the example depicted in FIG. 1, a position directly opposite to the operator 22 with the operating table 16 in between) comparatively far from the operator 22. Surgical field images and the like sent from the control apparatus 15 are displayed. The control apparatus 15 sets an operation mode to a manual mode or a hands-free mode. In the manual mode, the surgical system 10 is controlled on the basis of the input (force application to the camera arm 12 and an operation of manipulation buttons and the other controls, not depicted, installed on each of the component blocks, for example) by the hands of the operator 22. In the hands-free mode, the surgical system 10 is controlled on the basis of the contactless input of voice, line of sight, movement and direction of the head 22A, and gesture that are independent of the hands of the operator 22 and on the basis of the input by the contact of a leg 22B onto the foot switch 20. The control apparatus 15 receives an operator image sent from the action recognition camera 13 and detects the position of the marker 19 worn on the head 22A of the operator 22 within the operator image, thereby detecting the movement of the head 22A (head tracking) and recognizing the direction of the head 22A. Further, the control apparatus 15 recognizes a gesture done by the operator 22 from the operator image. The control apparatus 15 receives the information indicative of the direction of the line of sight of the operator 22 sent from the surgical glasses 17 and, the basis of this information and the position and direction of the head 22A, recognizes the position of the line of sight on the screen of the display 14. The control apparatus 15 receives a voice sent from the microphone 18 so as to execute voice recognition on that voice. The control apparatus 15 receives, from the foot switch 20, a manipulation signal indicative of a manipulation done on the foot switch 20 and, on the basis of that manipulation signal, recognizes the contents of the manipulation done on the foot switch 20. Further, if the operation mode is the hands-free mode, the control apparatus 15 uses, as input information, the movement and direction of the head 22A, a gesture of the operator 22, the line-of-sight positional information indicative of the position of a line of sight on the screen of the display 14, voice recognition results, sound volume, and the manipulation information indicative of the contents of a manipulation done on the foot switch 20. On the basis of the input information, the control apparatus 15 recognizes a command from the operator 22 and a state of the operator 22. In accordance with a state of the operator 22, the control apparatus 15 permits a command from the operator 22. In accordance with the permitted command, the control apparatus 15 controls the imaging by the surgical camera 11, controls the driving of the camera arm 12, controls the displaying of the display 14, and changes operation modes. The surgical glasses 17 are worn around the head 22A of the operator 22 and include a 3D polarized glasses and a line-of-sight detection device. The operator 22 can look at the display 14 through the 3D polarized glasses of the surgical glasses 17, thereby recognizing a surgical field image displayed on the display 14 as a 3D image. Further, by seeing surroundings through the surgical glasses 17, the operator 22 enters the line of sight into the surgical glasses 17. A line-of-sight device of the surgical glasses 17 detects the line of sight of the operator 22 and transmits the information indicative of the direction of the line of sight to the control apparatus 15. The microphone 18 is worn on the head 22A of the operator 22. The microphone picks up a surrounding voice including a voice and so on of the operator 22 and transmits the picked-up voice to the control apparatus 15. The marker 19 is worn on the head 22A of the operator 22. The foot switch 20 is arranged around the operator 22 and manipulated by the contact of the leg 22B of the operator 22. The foot switch 20 transmits a manipulation signal indicative of a manipulation done by the leg 22B of the operator 22 to the control apparatus 15. With the surgical system 10 as described above, the operator 22 lays the patient 21 on the operating table 16 and executes treatment such as a surgical operation while looking through the surgical glasses 17 at a surgical field image and so on displayed on the display 14. In addition, when the operation modes, the imaging conditions of the surgical camera 11, the positions and angles of the surgical camera 11, the displays of the display 14 or the like are changed, the operator 22 executes a contactless input operation or contact foot input operation. Therefore, the operator 22 is able to executes an input operation with a surgical tool, not depicted, held in the hand. It should be noted that the operator 22 need not execute sterilization processing every time the operator 22 executes an input operation. It should also be noted that, for a line-of-sight detection method, a method of detecting the movement and direction of the head 22A and a gesture of the operator 22, and a method of obtaining voice, any method may be employed. For example, the line-of-sight detection device or the microphone 18 may be not a wearable device. In the present description, the horizontal direction of the display 14 is referred to as x direction, the vertical direction is referred to as y direction, and the direction perpendicular to the screen of the display 14 is referred to as z direction. (Description of Driving of Surgical Camera) FIG. 2 is a diagram illustrating the driving of the surgical camera 11 by the camera arm 12 of FIG. 1. As depicted in A of FIG. 2, the camera arm 12 can make the surgical camera 11 execute a pivot movement for changing the imaging angles without changing the imaging center. To be more specific, the camera arm 12 can move the surgical camera 11 so as to always keep constant the distance from center P of a surgical field that is a target of the imaging by the surgical camera 11. This setup allows the surgical camera 11 to take surgical field images that are same in center P of the surgical field but different in the imaging angle. Further, as depicted in B of FIG. 2, the camera arm 12 is capable of making the surgical camera 11 execute a slide movement in the x direction in which the imaging center is moved in the x direction. Specifically, the camera arm 12 is capable of moving the surgical camera 11 in the x direction. This setup allows the surgical camera 11 to move center P of the surgical field that is a target of imaging along the x direction. Further, although not depicted, the camera arm 12 is capable of making the surgical camera 11 execute a slide movement in the y direction or the z direction. If the surgical camera 11 executes a slide movement in the y direction, the surgical camera 11 can zoom in or zoom out an imaging range. In addition, if the surgical camera 11 executes a slide movement in the z direction, the surgical camera 11 can move center P of the surgical field along the z direction. It should be noted that, in the present description, it is assumed that a slide movement of the surgical camera 11 be executed by the movement of the surgical camera 11 by the camera arm 12; however, it is also practicable to execute a slide movement by changing the imaging angles of the surgical camera 11 by the camera arm 12. (Example of Configuration of Control Apparatus) FIG. 3 is a block diagram illustrating one example of the configuration of the control apparatus 15 depicted in FIG. 1. The control apparatus 15 depicted in FIG. 3 has a recognition block 61, a command block 62, a mode setting block 63, a state estimation block 64, a control block 65, and an image processing block 66. The recognition block 61 of the control apparatus 15 has a voice recognition block 71, a line-of-sight recognition block 72, a head recognition block 73, a gesture recognition block 74, and a manipulation recognition block 75. The voice recognition block 71 (a contactless input recognition block) executes voice recognition on a voice sent from the microphone 18 so as to recognize a speech as the contactless input by the operator 22 (the user). In addition, the voice recognition block 71 recognizes the volume of a voice sent from the microphone 18 as the contactless input by the operator 22. The voice recognition block 71 supplies the speech and volume that are results of the voice recognition to the command block 62 as input information. The line-of-sight recognition block 72 (a contactless input recognition block) recognizes the position of the line of sight on the screen of the display 14 as the contactless input by the operator 22 on the basis of the information indicative of the direction of line of sight sent from the surgical glasses 17 and the position and direction of the head 22A recognized by the head recognition block 73. The line-of-sight recognition block 72 supplies the line-of-sight positional information indicative of the position thereof to the command block 62, the state estimation block 64, and the image processing block 66 as input information. The head recognition block 73 (a contactless input recognition block) detects the position of the marker 19 inside an operator image from the operator image sent from the action recognition camera 13 so as to recognize the position, movement and direction of the head 22A of the operator 22 as the contactless input by the operator 22. The head recognition block 73 supplies the movement and direction of the head 22A to the command block 62 and the state estimation block 64 as input information. In addition, the head recognition block 73 supplies the position and direction of the head 22A to the line-of-sight recognition block 72. The gesture recognition block 74 (a contactless input recognition block) recognizes, as the contactless input from the operator 22, the input of a gesture done by the operator 22 from an operator image sent from the action recognition camera 13. The gesture recognition block 74 supplies the gesture done by the operator 22 to the command block 62 as input information. The manipulation recognition block 75 (a contact input recognition block) receives a manipulation signal sent from the foot switch 20 and recognizes the contents of the manipulation done on the foot switch 20 as the contact input from the operator 22. The manipulation recognition block 75 supplies the manipulation information indicative of the contents of that manipulation to the command block 62 as input information. On the basis of the input information supplied from the recognition block 61, the command block 62 recognizes a command issued from the operator 22. If the recognized command is a command for changing operation modes, then the command block 62 notifies the mode setting block 63 of that command. On the other hand, if the recognized command issued from the operator 22 is not a command for changing operation modes, then the command block 62 (a restriction block) restricts the command issued from the operator 22 in accordance with a state supplied from the state estimation block 64. That is, in accordance with the state supplied from the state estimation block 64, the command block 62 permits a predetermined command issued from the operator 22. The command block 62 supplies the permitted command to the control block 65. In accordance with a command supplied from the command block 62, the mode setting block 63 sets the operation mode to the manual mode or the hands-free mode. The mode setting block 63 supplies the set mode to the state estimation block 64. If the operation mode supplied from the mode setting block 63 is the hands-free mode, the state estimation block 64 estimates a state of the operator 22 on the basis of the input information supplied from the recognition block 61. The state estimation block 64 notifies the command block 62 of the estimated state. The control block 65 executes the command supplied from the command block 62. To be more specific, if the command supplied from the command block 62 is a command associated with the imaging control of the surgical camera 11, then the control block 65 executes imaging control of the surgical camera 11 (the surgical apparatus) in accordance with that command. If the command supplied from the command block 62 is a command associated with the driving control of the camera arm 12, then control block 65 executes driving control of the camera arm 12 (the surgical apparatus) in accordance with that command. Further, if the command supplied from the command block 62 is a command associated with the display control of the display 14, then the control block 65 controls the image processing block 66 (the surgical apparatus) by supplying that command to the image processing block 66. The image processing block 66 processes a surgical field image sent from the surgical camera 11. To be more specific, the image processing block 66 supplies a surgical field image sent from to the surgical camera 11 to the display 14 without change, thereby displaying that surgical field image. Further, if the command supplied from the control block 65 is an annotation display command, then the image processing block 66 superimposes a mark (a predetermined image) on the position corresponding to the line of sight of the operator 22 inside the surgical field image sent from the surgical camera 11 on the basis of the line-of-sight positional information supplied from the line-of-sight recognition block 72. Next, the image processing block 66 supplies the surgical field imaged superimposed with the mark to the display 14, thereby displaying that surgical field image. In addition, if the command supplied from the control block 65 is a menu display command for displaying GUI (Graphical User Interface) such as menu buttons onto the display 14, then the image processing block 66 superimposes a surgical field image sent from the surgical camera 11 with a GUI image. The image processing block 66 supplies the surgical field image superimposed with the GUI to the display 14, thereby displaying that surgical field image. (Example of Relation Between Input Information and Commands) FIG. 4 is a diagram illustrating one example of a relation between input information and commands. As depicted in FIG. 4, if the voice recognition result in the input information is “zoom-in” and the line-of-sight positional information is indicative of a position inside the screen of the display 14, then the command block 62 recognizes that the command from the operator 22 is a command (hereafter referred to as a zoom-in imaging command) for having the surgical camera 11 zoom in around a subject corresponding to the line-of-sight position indicated in the line-of-sight positional information. Likewise, if the voice recognition result in the input information is “zoom-out” and the line-of-sight positional information is indicative of a position inside the screen of the display 14, then the command block 62 recognizes that the command from the operator 22 is a command (hereafter referred to as a zoom-out imaging command) for having the surgical camera 11 zoom out around a subject corresponding to the line-of-sight position indicated in the line-of-sight positional information. If the voice recognition result in the input information is “focus” and the line-of-sight positional information is indicative of a position inside the screen of the display 14, then the command block 62 recognizes that the command from the operator 22 is a command (hereafter referred to as a focus control command) for executing focus control of the surgical camera 11 such that the subject corresponding to the line-of-sight position indicated by the line-of-sight positional information is focused. It should be noted that a zoom-in imaging command, a zoom-out imaging command, and a focus control command are commands associated with the imaging control of the surgical camera 11, so that these types of command are classified into “imaging control.” As described above, the operator 22 is able to enter the contents of imaging control with a voice suited for command input and enter a position necessary for imaging control with the line of sight suited for positional input. Therefore, the operator 22 can easily execute commands associated with imaging control. Further, if the voice recognition result in the input information is “pivot,” the line-of-sight positional information is indicative of a position inside the screen of the display 14, the line-of-sight positional information does not change with time, the movement of the head 22A is travel, and the manipulation information is indicative of the pressing of the foot switch 20, then the command block 62 recognizes that the command from the operator 22 is a command (hereafter referred to as a pivot movement command) for controlling the camera arm 12 such that the surgical camera 11 pivotally moves in accordance with the movement of the head 22A. If the voice recognition result in the input information is “slide,” the movement of the head 22A is rotation, the line-of-sight positional information is indicative of a position inside the screen of the display 14, the direction in the temporal change of the position indicated by the line-of-sight positional information is the same as the rotational direction of the head 22A, and the manipulation information is indicative of the pressing of the foot switch 20, then the command block 62 recognizes that the command from the operator 22 is a command (hereafter referred to as a slide movement command) for controlling the camera arm 12 such that the surgical camera 11 slides in accordance with the position of the line of sight. It should be noted that a pivot movement command and a slide movement command are commands associated with the driving control of the camera arm 12, so that these types of commands are classified into “camera arm control.” As described above, if a combination of two or more pieces of input information does not satisfy the conditions, then the command block 62 does not recognize any such commands that for changing surgical field images as of “imaging control” type or “camera arm control” type as commands issued from the operator 22. For example, even if the voice recognition result in the input information is “zoom-in” (“zoom-out” or “focus”), but the line-of-sight positional information is not indicative of a position inside the screen, the command block 62 determines that the recognition done is erroneous, thereby not recognizing that the command from the operator 22 is a zoom-in imaging command (a zoom-out imaging command or a focus control command). Conversely, even if the line-of-sight positional information in the input information is indicative of a position inside the screen, but the voice recognition result is not “zoom-in” (“zoom-out” or “focus”), the command block 62 determines the recognition done is erroneous, thereby not recognizing that the command from the operator 22 is a zoom-in imaging command (a zoom-out imaging command or a focus control command). Even if the voice recognition result in the input information is “focus,” the line-of-sight positional information is indicative of a position inside the screen, the movement of the head 22A is travel, and the manipulation information is indicative of the pressing of the foot switch 20, but the line-of-sight positional information is indicative of temporal change, then the command block 62 determines that the recognition done is erroneous, thereby not recognizing that the command from the operator 22 is a pivot movement command. Further, even if the voice recognition result in the input information is “focus,” the line-of-sight positional information is indicative of a position inside the screen, the movement of the head 22A is travel, and the line-of-sight positional information does not temporarily change, but the manipulation information does not indicate that the foot switch 20 is pressed, then the command block 62 determines that the recognition done is erroneous, thereby not recognizing that the command from the operator 22 is a pivot movement command. Therefore, a recognition hit ratio of commands that change surgical field images and therefore greatly affect surgical operations can be enhanced. Consequently, the safety of surgery can be enhanced. In addition, a command of which type is “camera arm control” that greatly changes the contents of a surgical field image affects the surgery more than a command of which type is “imaging control.” Therefore, in the example depicted in FIG. 4, the number of pieces of input information under recognition conditions of a command of which type is “camera arm control” is greater than the number of pieces of input information under recognition conditions of a command of which type is “imaging control” by 3 to 2. It should be noted that a condition that manipulation information is indicative of the pressing of the foot switch 20 may be added to the recognition conditions of a command of which type is “imaging control,” thereby increasing the number of pieces of input information under the recognition information to 3. If the voice recognition result in the input information is “menu” and the manipulation information is indicative of the pressing of the foot switch 20, then the command block 62 recognizes that the command from the operator 22 is a menu display command. It should be noted that a menu display command is a command associated with the display control of GUI such as menu buttons and other controls of the image processing block 66 (the display control apparatus), so that the type of a menu display command is classified into “menu display control.” Further, if the voice recognition result in the input information is “annotation” or “pointer” and the manipulation information is indicative of the pressing of the foot switch 20, then the command block 62 recognizes that the command from the operator 22 is an annotation display command for displaying, as an annotation, a mark at a position corresponding to the line of sight of the operator 22 inside the screen of the display 14. It should be noted that an annotation display command is a command associated with the display control of an annotation of the image processing block 66, so that the type of an annotation command is classified into “annotation display control.” In addition, if the voice recognition result in the input information is “hands-free” and the manipulation information is indicative of the pressing of the foot switch 20, then the command block 62 recognizes that the command from the operator 22 is a command (hereafter referred to as a hands-free mode command) for setting the operation mode to the hands-free mode. If the voice recognition result in the input information is “stop” and the manipulation information is indicative of the pressing of the foot switch 20, then the command block 62 recognizes that the command from the operator 22 is a command (hereafter referred to as a manual mode command) for setting the operation mode in a normal state to the manual mode. As described above, when the operator 22 enters a speech associated with a menu display command, an annotation display command, or a manual mode command into the microphone 18 and executes an enter manipulation by pressing the foot switch 20, the command block 62 recognizes the entered command. Further, if the manipulation information in the input information is indicative of the long pressing of the foot switch 20, then the command block 62 recognizes that the command from the operator 22 is a manual mode command in a normal state. If the position indicated by the line-of-sight positional information in the input information is outside the screen of the display 14 and the manipulation information is indicative of the pressing of the foot switch 20, then the command block 62 recognizes that the command from the operator 22 is a manual mode command in a normal state. In addition, if the gesture of the operator 22 in the input information is other than a registered gesture or the sound volume in the input information is greater than a predetermined value, then the command block 62 recognizes that the command is a manual mode command in an emergency state. An emergency state denotes a state in which the hands-free mode must be stopped in emergency due to an erroneous operation or the like. It should be noted that conditions of recognizing a manual mode command in an emergency state may be other than that the gesture of the operator 22 is a registered gesture or other than that the sound volume is greater than a predetermined value if these recognition conditions are other than the recognition conditions of the other commands. A hands-free mode command and a manual mode command are commands associated with the control of the operation mode of the control apparatus 15, so that the types of these commands are classified into “mode control.” It should be noted that the relation between input information and commands is not restricted to the above-mentioned example depicted in FIG. 4. That is, if the operator 22 can enter the input contents necessary for command recognition by use of a voice and a sound volume, a line of sight, a movement and direction of the head 22A, a gesture, or the manipulation of the foot switch 20 that are suited for the type of these input contents, the recognition conditions are not restricted to particular ones. In the example depicted in FIG. 4, for example, the number of types of input information for contactless input in the case of command recognition conditions that the types are “menu display control,” “annotation display control,” and “mode control” is one; however, the number of input information types may be more than one. Further, a command to be recognized by the command block 62 may be any command as far as the command is for controlling each block of the surgical system 10. For example, the command block 62 may recognize a command for setting a various types of parameters of the surgical camera 11. (Explanation of Execution of Pivot Movement Command) FIG. 5 is a diagram illustrating the execution of a pivot movement command by the control block 65 depicted in FIG. 3. It should be noted that A of FIG. 5 is a diagram illustrating the head 22A and the display 14 as viewed in the y direction. B of FIG. 5 is a diagram illustrating the surgical camera 11 as viewed in a direction between the z direction and the y direction. As depicted in A of FIG. 5, when the operator 22 utters a voice “pivot” and the line of sight of the operator 22 is positioned at position R inside the screen of the display 14, if the operator 22 shifts only the head 22A in the x direction without moving the line-of-sight position on the screen while pressing the foot switch 20, then the command block 62 recognizes a pivot movement command. If a pivot movement command is supplied from the command block 62, the control block 65 driving-controls the camera arm 12 to cause the surgical camera 11 to do a pivot movement in the x direction by an amount corresponding to a travel amount of the head 22A. Consequently, as depicted in B of FIG. 5, the surgical camera 11 travels by an amount corresponding to a travel amount of the head 22A in the x direction without changing a distance from center P. (Explanation of Execution of Slide Movement Command) FIG. 6 is a diagram illustrating the execution of a slide movement command by the control block 65 depicted in FIG. 3. It should be noted that A of FIG. 6 is a diagram illustrating the head 22A and the display 14 as viewed in the y direction while B of FIG. 6 is a diagram illustrating the surgical camera 11 as viewed from the z direction. As depicted in A of FIG. 6, when the operator 22 utters a voice “pivot” and the line of sight of the operator 22 is positioned at position R inside the screen of the display 14, if the operator 22 causes the head 22A to rotate by angle α in a right direction so as to move the line-of-sight position on the screen in the x direction while pressing the foot switch 20, then the command block 62 recognizes a slide movement command. If a slide movement command is supplied from the command block 62, the control block 65 driving-controls the camera arm 12 so as to cause the surgical camera 11 to slide in the x direction, thereby placing a subject corresponding to position R′ of the line of sight on the screen after the movement to the center of imaging. Consequently, center P of the surgical field that is an imaging target of the surgical camera 11 travels in the x direction. It should be noted that the control block 65 may control the speed of a slide movement in accordance with a rotational speed of the head 22A. (Example of Estimated Operator States) FIG. 7 is a diagram illustrating an example of states of the operator 22 that are estimated by the state estimation block 64 of FIG. 3. As depicted in FIG. 7, the state estimation block 64 estimates that the operator 22 is in an action-other-than-surgical-procedure state, a downward viewing state, a close watching state, or an observing state. The action-other-than-surgical-procedure state denotes a state in which the operator 22 is executing an action other than a surgical procedure (for example, checking the hand holding forceps or understanding a situation of assistants and staffs around). In the action-other-than-surgical-procedure state, it is assumed that the operator 22 be not directly opposite to the display 14. Therefore, there is no need for changing surgical field images. Consequently, if the state of the operator 22 is estimated to be the action-other-than-surgical-procedure state, the command block 62 restricts the command from the operator 22 other than a command of which type is “mode control” that changes operation modes to the command of which type is “menu display control” that does not change surgical field images. The downward viewing state denotes a state in which the operator 22 is overlooking the surgical field in order to check for a tissue damage or bleeding, for example. In the downward viewing state, it is assumed that the line of sight of the operator 22 be frequently moving inside the screen of the display 14. In addition, in the downward viewing state, it is possible for the operator 22 to indicate a predetermined position within the surgical field image to surrounding assistants or staffs. Therefore, if the state of the operator 22 is estimated to be the downward viewing state, the command from the operator 22 other than a command of which type is “mode control” to a command of which type is “menu display control” and a command of which type is “annotation display control” that superimposes an annotation on a surgical field image. The close watching state is a state in which the operator 22 is executing a surgical operation while closely watching a single point inside a surgical field image. In the close watching state, the line of sight of the operator 22 is inside the screen of the display 14 and the movement of the line of sight of the operator 22 is less frequent, but the operator 22 is assumed to be moving. In the close watching state, it is not necessary for the operator 22 to change the contents of a surgical field image but the operator 22 must look at the surgical field image taken under the imaging conditions suited for the surgical procedure. Therefore, if the state of the operator 22 is estimated to the close watching state, then the command block 62 restricts the command from the operator 22 other than a command of which type is “mode control” to the commands of which types are “menu display control” and “annotation display control” and a command of which type is “imaging control” that changes imaging conditions. The observation state is a state in which the operator 22 temporarily interrupts the surgical procedure so as to observe the patient 21 for an important treatment. In the observation state, it is assumed that the line of sight of the operator 22 be inside the screen of the display 14 and the movement of the line of sight of the operator 22 and the movement of the operator 22 be less frequent. In the observation state, it is necessary for the operator 22 to observe a surgical field from various directions, so that the contents of a surgical field image must be changed. Consequently, if the state of the operator 22 is assumed to be the observation state, the command block 62 permits all of the commands from the operator 22 other than the commands of which type is “mode control.” That is, the command block 62 permits only the commands of which types are “menu display control,” “annotation display control,” and “imaging control” but also the commands of which type is “camera arm control” that changes the positions of the surgical camera 11. As described above, the degree of the necessity for changing surgical field images increases from the action other than surgical procedure state to the downward viewing state to the close watching state to the observation state in this order. It should be noted here that it is assumed that, in a state higher in the necessity for changing surgical field images, all of the commands that are permitted in the lower states be permitted; however, it is also practicable to determine the commands to be permitted for each of these states. For example, if the state of the operator 22 is the action-other-than-surgical-procedure state, the downward viewing state, the close watching state, or the observation state, then only the commands of which type is “menu display control,” “annotation display control,” “imaging control,” or “camera arm control” may be permitted. (Explanation of Method of Estimating Operator State) FIG. 8 is a diagram illustrating a method of estimating a state of the operator 22 in the state estimation block 64 depicted in FIG. 3. On the basis of the direction of the head 22A or the line-of-sight positional information in the input information, the state estimation block 64 determines whether the operator 22 is directly opposite to the display 14. To be more specific, if the direction of the head 22A is in the direction of the display 14, the state estimation block 64 determines that the operator 22 is directly opposite to the display 14; if the direction of the head 22A is not in the direction of the display 14, the state estimation block 64 determines that the operator 22 is not directly opposite to the display 14. Alternatively, if the position indicated by the line-of-sight positional information is inside the screen of the display 14, the state estimation block 64 determines that the operator 22 is directly opposite to the display 14; if the position indicated by the line-of-sight positional information is outside the screen of the display 14, the state estimation block 64 determines that the operator 22 is not directly opposite to the display 14. If the travel amount is greater than a predetermined value on the basis of the travel amount within a predetermined time of a position indicated by the line-of-sight positional information, the state estimation block 64 determines the that travel amount of the line of sight is high; if the travel amount is less than the predetermined value, the state estimation block 64 determines that the travel amount of the line of sight is low. Further, if the amount of movement of the head 22A is greater than a predetermined value within a predetermined time on the basis of the movement of the head 22A, the state estimation block 64 determines that the operator 22 is moving; if the amount of movement of the head 22A is less than the predetermined value, the state estimation block 64 determines that the operator 22 is not moving. It should be noted that it is also practicable that the recognition block 61 recognizes the movement of a part other than the head 22A of the operator 22 and, on the basis of the movement of the part other than the head 22A of the operator 22, the state estimation block 64 determines whether the operator 22 is moving or not. In this case, if the amount of movement of the part other than the head 22A of the operator 22 within a predetermined time is greater than a predetermined value, then the recognition block 61 determines that the operator 22 is moving; if the amount of movement of the part other than the head 22A of the operator 22 is less than the predetermined value, the recognition block 61 determines that the operator 22 is not moving. As depicted in FIG. 8, if the operator 22 is found to be not directly opposite to the display 14, the state estimation block 64 estimates that the state of the operator 22 is the action-other-than-surgical-procedure state. In this case, the type other than “mode control” of commands from the operator 22 that are permitted is “menu display control.” Also, if the operator 22 is found to be directly opposite to the display 14 and the travel amount of the line of sight is high, then the state estimation block 64 estimates that the state of the operator 22 is the downward viewing state. In this case, the types of permitted commands other than “mode control” are “menu display control” and “annotation display control.” Further, if the operator 22 is found to be directly opposite to the display 14, the travel amount of the line of sight is found to be low, and the operator 22 is found to be moving, then the state estimation block 64 estimates that the state of the operator 22 is the close watching state. In this case, the types of permitted commands other than “mode control” are “menu display control,” “annotation display control,” and “imaging control.” In addition, if the operator 22 is found to be not directly opposite to the display 14, the travel amount of the line of sight is found to be low, and the operator 22 is found to be not moving, then the state estimation block 64 estimates that the state of the operator 22 is the observation state. In this case, the types of permitted commands other than “mode control” are “menu display control,” “annotation display control,” “imaging control,” and “camera arm control.” It should be noted that, since the operator 22 executes a surgical procedure by use of forceps and the like while looking at the display 14, the frequency of the movement of the head 22A of the operator 22 during a surgical procedure is very low, but the frequency of the movement of the hands is high. Therefore, if not in the case where the amount of the movement of the head 22A is greater than a predetermined value but the amount of the movement of the head 22A is less than the predetermined value and the amount of the movement of other than the head 22A is greater than the predetermined value, the state estimation block 64 may determine that the state of the operator 22 is the close watching state. (Explanation of Processing by Surgical System) FIG. 9 is a flowchart indicative of the control processing to be executed by the control apparatus 15 of the surgical system 10 depicted in FIG. 1. This control processing starts when the power to the control apparatus 15 is turned on, for example. In step S11 depicted in FIG. 9, the mode setting block 63 sets the processing mode to the manual mode and supplies this information to the state estimation block 64. In step S12, the recognition block 61 recognizes the input information. Of the input information, the recognition block 61 supplies voice recognition result information, sound volume information, gesture information, and manipulation information to the command block 62. In addition, the recognition block 61 supplies line-of-sight positional information to the command block 62, the state estimation block 64, and the image processing block 66. The recognition block 61 supplies the movement and direction of the head 22A to the command block 62 and the state estimation block 64 as the input information. In step S13, on the basis of the input information supplied from the recognition block 61, the command block 62 recognizes a command from the operator 22. In step S14, the command block 62 determines whether the type of the recognized command is “mode control” or not. If the type of the command recognized in step S14 is “mode control,” then the command block 62 notifies the mode setting block 63 of that command, upon which the processing goes to step S15. In step S15, in accordance with the command supplied from the command block 62, the mode setting block 63 changes operation modes. The mode setting block 63 supplies the changed mode to the state estimation block 64, upon which the processing goes to step S16. On the other hand, if the type of the command recognized in step S14 is not found to be “mode control,” then the processing goes to step S16. In step S16, the state estimation block 64 determines the operation mode supplied from the mode setting block 63 is the hands-free mode or not. If the operation mode is found to be the hands-free mode in step S16, then the processing goes to step S17. In step S17, the control apparatus 15 executes state estimation processing for estimating a state of the operator 22 on the basis of the input information supplied from the recognition block 61. Details of this state estimation processing will be described later with reference to FIG. 10. In step S18, the command block 62 determines whether the type of the command recognized in step S13 from the operator 22 other than commands of which type is “mode control” is permitted or not. If the type of that command is found to be permitted in step S18, then the command block 62 supplies that command to the control block 65. Then, in step S19, the control block 65 executes the command supplied from the command block 62, upon which the processing goes to step S20. On the other hand, if the operation mode is found to be not the hands-free mode in step S16 or if the type of the command from the operator 22 other than commands of which type is “mode control” is found to be not permitted in step S18, then the processing goes to step S20. In step S20, the control apparatus 15 determines whether or not to turn off the power to the control apparatus 15; for example, the control apparatus 15 determines whether or not a command of powering off the control apparatus 15 has been issued by the operator 22. If the power to the control apparatus 15 is found to be not turned off in step s20, then the processing returns to step S12 so as to repeat the processing of steps S12 through S20. On the other hand, if the power to the control apparatus 15 is found to be turned off in step S20, the processing is terminated. FIG. 10 is a flowchart indicative of details of the state estimation processing in step S17 depicted in FIG. 9. In step S41 depicted in FIG. 10, on the basis of the direction of the head 22A or the line-of-sight positional information in the input information, the state estimation block 64 determines whether the operator 22 is directly opposite to the display 14 or not. If the operator 22 is found to be not directly opposite to the display 14 in step S41, then the state estimation block 64 estimates that the state of the operator 22 is the action-other-than-surgical-procedure state in step S42, notifying the command block 62 thereof. In step S43, the command block 62 sets the type of the command from the operator 22 to be permitted other than “mode control” to “menu display control.” Then, the processing returns to step S17 depicted in FIG. 9, upon which the processing of step S18 is executed. On the other hand, if the operator 22 is found to be directly opposite to the display 14 in step S41, the state estimation block 64 determines whether the travel amount of the line of sight is high or not on the basis of the travel amount within a predetermined time of the position indicated by the line-of-sight positional information in step S44. If the travel amount of the line of sight is found high in step S44, then the state estimation block 64 estimates that the state of the operator 22 is the downward viewing state in step S45, thereby notifying the command block 62 thereof. In step S46, the command block 62 sets the types of the commands from the operator 22 to be permitted other than “mode control” to “menu display control” and “annotation display control.” Then, the processing returns to step S17 depicted in FIG. 9 to repeat the processing of step S18. Further, if the travel amount of the line of sight is found to be low in step S44, then the state estimation block 64 determines whether the operator 22 is moving or not on basis of the movement of the head 22A in step S47. If the operator 22 is found to be moving in step S47, then the state estimation block 64 estimates that the state of the operator 22 is the close watching state in step S48, thereby notifying the command block 62 thereof. In step S49, the command block 62 sets the types of the commands from the operator 22 to be permitted other than “mode control” to “menu display control,” “annotation display control,” and “imaging control.” Then, the processing returns to step S17 depicted in FIG. 9 to repeat the processing of step S18. On the other hand, if the operator 22 is found to be not moving in step S47, then the state estimation block 64 estimates that the state of the operator 22 is the observation state in step S50, thereby notifying the command block 62 thereof. In step S51, the command block 62 sets the types of the commands from the operator 22 to be permitted to “menu display control,” “annotation display control,” “imaging control,” and “camera arm control.” Then the processing returns to step S17 depicted in FIG. 9 to repeat the processing of step S18. A described above, on the basis of combinations of two or more types of contactless inputs, the surgical system 10 controls the surgical camera 11, the camera arm 12, or the image processing block 66. Therefore, by executing contactless input operations suited for the types of input contents, for example, the operator 22 is able to easily and intuitively control the surgical camera 11, the camera arm 12, and the image processing block 66. That is, the surgical system 10 can realize NUI (Natural User Interface). As a result, the load of the operator 22 is mitigated. Further, as compared with the case in which the surgical camera 11, the camera arm 12, or the image processing block 66 is controlled by the contactless input of one type, the above-mentioned two or more types of contactless inputs enhance the hit ratio of input recognition, which in turn enhancing the safety of surgical procedures. Since the surgical system 10 allows the execution of input operations in a contactless manner or by the contact by the leg 22B, the operator 22 himself can execute input operations even if both hands are occupied by the execution of surgical procedure. As a result, as compared with the case in which the operator 22 executes input operations, there is no need for interrupting surgical procedure because of input operations, thereby saving the surgical time. In addition, as compared with the case in which a person other than the operator 22 executes input operations, the surgical system 10 allows the operator 22 execute control as intended by the operator 22, thereby mitigating the load of the operator 22. Further, the surgical system 10 can restrict the execution of commands issued by the operator 22 in accordance with a state of the operator 22 so as to real failsafe, thereby preventing the control operations that are not intended by the operator 22 due to the erroneous recognition of a command from the operator 22. Consequently, the safety of surgical procedure is enhanced. Still further, since the surgical system 10 can change the operation mode from the hands-free mode to the manual mode, if a control operation that is not intended by the operator 22 is executed due to the erroneous recognition of a command from the operator 22, the unintended control operation can be stopped. Second Embodiment (Example of Configuration of Second Embodiment of Surgical System) FIG. 11 is a block diagram illustrating one example of a configuration of a second embodiment of a surgical system to which the present disclosure is applied. With the configuration depicted in FIG. 11, the configurational components same as those previously described with FIG. 1 are denoted by the same reference symbols. The duplicate description will appropriately skipped. In configuration, a surgical system 100 depicted in FIG. 11 differs from the surgical system 10 depicted in FIG. 1 in that the surgical system 100 has a display 101 and a control apparatus 102 instead of the display 14 and the control apparatus 15 and does not have the surgical glasses 17 and the marker 19. With the surgical system 100, the distance between the display 101 and the operator 22 is shorter than the distance between the display 14 and the operator 22, so that the operator 22 recognizes a surgical field image displayed on the display 101 as a 3D image with the naked eyes without using the surgical glasses 17. To be more specific, the display 101 of the surgical system 100 is a 3D display having a comparatively small screen and is arranged at a position comparatively near the operator 22 (in the example depicted in FIG. 11, a position on the operating table 16 and near the operator 22). The display 101 displays surgical field images and so on sent from the control apparatus 102. On top of the display 101, the action recognition camera 13 is arranged. Except for a method of recognizing the line of sight and the movement and direction of the head 22A, the control apparatus 102 operates in the similar manner to the control apparatus 15, so that the following describes only this recognition method. The control apparatus 102 detects the position of the head 22A inside an operator image sent from the action recognition camera 13 so as to recognize the movement and direction of the head 22A. Further, the control apparatus 102 detects the direction of the line of sight of the operator 22 from an operator image so as to recognize the position of the line of sight on the screen of the display 14 on the basis of the detected direction. It should be noted that, with the surgical system 100, the operator 22 does not use the surgical glasses 17, so that the detection of line of sight is executed by use of an operator image taken with the action recognition camera 13; however, it is also practicable to execute the detection of line of sight by a line-of-sight detection device by making the operator 22 wear the surgical glasses having the line-of-sight detection device. Further, with the surgical system 100, since the distance between the action recognition camera 13 and the operator 22 is short, the movement and direction of the head 22A are detected from an operator image; however, it is also practicable to for the operator 22 to wear the marker 19 so as to detect the movement and direction of the head 22A from a position of the marker 19 inside an operator image. Still further, the display 101 may be arranged at a position comparatively far from the operator 22. The display 101 is a 3D display with which the operator 22 can recognize 3D images through 3D polarized glasses, so that the operator 22 may use 3D polarized glasses. Third Embodiment (Explanation of Computer to which Present Disclosure is Applied) The above-mentioned sequence of processing operations by the control apparatus 15 (102) can be executed by hardware or software. In the execution of the sequence of processing operations by software, the programs constituting that software are installed on a computer. It should be noted that the computer includes a computer built in dedicated hardware and a general-purse personal computer, for example, in which various programs can be installed for the execution of various functions. FIG. 12 is a block diagram illustrating one example of the hardware of a computer for executing the above-mentioned sequence of processing operations by programs. In a computer 200, a CPU (Central Processing Unit) 201, a ROM (Read Only Memory) 202, and a RAM (Random Access Memory) 203 are interconnected by a bus 204. The bus 204 is further connected with an input/output interface 205. The input/output interface 205 is connected with an input block 206, an output block 207, a storage block 208, a communication block 209, and a drive 210. The input block 206 includes a keyboard, a mouse, a microphone, and so on. The output block 207 includes a display, a speaker, and so on. The storage block 208 includes a hard disk drive, a nonvolatile memory, and so on. The communication block 209 includes a network interface and so on. The drive 210 drives a removable medium 211 such as a magnetic disc, an optical disc, a magneto-optical disc, or a semiconductor memory. With the computer 200 configured as described above, the CPU 201 loads programs from the storage block 208 into the RAM 203 via the input/output interface 205 and the bus 204 and executes the loaded programs so as to execute the above-mentioned sequence of processing operations. Programs to be executed by the computer 200 (the CPU 201) may be provided as recorded to the removable medium 211 that is a package medium or the like. In addition, programs may be provided through a wired or wireless transmission medium, such as a local area network, the Internet, or digital satellite broadcasting. With the computer 200, programs can be installed in the storage block 208 via the input/output interface 205 by loading the removable medium 211 on the drive 210. In addition, programs can be installed in the storage block 208 by receiving by the communication block 209 the programs via a wired or wireless transmission medium. Otherwise, programs can be installed in the ROM 202 or the storage block 208 in advance. It should be noted that programs to be executed by the computer 200 may be programs in which processing is executed in a time sequence manner by following the sequence described in the present description or in a parallel manner or on an on-demand basis with required timings. In the present description, a system denotes an aggregation of two or more configurational components (apparatuses, modules (parts), etc.) regardless whether all the configurational components are within a same housing or not. Therefore, two or more apparatuses accommodated in separate housings and interconnected via a network are a system or one apparatus with two or more modules accommodated in one housing is also a system. It should be noted that the effects described here are not necessarily restricted; namely, any of the effects described in the present disclosure may be effects denoted here. While preferred embodiments of the present disclosure are not limited to the embodiments described above and variations may be made without departing from the gist of the present disclosure. For example, in the first embodiment through the third embodiment, the control apparatus 15 (102) executes control operations on the basis of two or more types of contactless input combinations and the control operations are restricted in accordance with states of the operator 22, both thereby enhancing the safety of surgical procedure; however, it is also practicable to use only one of the above-mentioned measures so as to enhance the safety of surgical procedure. Further, targets of the restriction by the control apparatus 15 (102) may be anything as far as the targets are surgical apparatuses. For example, the control apparatus 15 (102) can also control such surgical imaging apparatuses as endoscopes and video microscopes. Moreover, it is also practicable for zoom control to be realized not by the imaging control of the surgical camera 11 but by processing a surgical field image in the image processing block 66. In this case, in accordance with a zoom-in imaging command, the image processing block 66 enlarges a surgical field image sent from the surgical camera 11 so as to execute electronic zooming in which a zoom-in image taken in a zoom-in manner around a subject corresponding to the position of line of sight is generated from the surgical field image. Likewise, in accordance with a zoom-out imaging command, the image processing block 66 reduces a surgical field image sent from the surgical camera 11 so as to generate a zoom-out image taken in a zoom-out manner around a subject corresponding to the position of line of sight from the surgical field image. It should be noted that, at this moment, on the basis of the line-of-sight positional information, the image processing block 66 may superimpose a marker on the position corresponding to the line of sight inside the zoom-in image or the zoom-out image. Further, while a surgical field image is displayed on the display 14, annotation display may be always executed. The contactless inputs are not restricted to the voice and line of sight of the operator 22, the movement and direction of the head 22A, and the gesture of the operator 22. For example, the contactless inputs may include the movement and attitude of other than the head 22A of the operator 22. The means of accepting contactless inputs may be wearable like the surgical glasses 17 and the microphone 18 or may not be wearable. Even if the operation mode is the manual mode, the control apparatus 15 (102) may estimate a state of the operator 22 and, in accordance with the estimated state, restrict the control of the surgical camera 11, the camera arm 12, and the image processing block 66. It should be noted that the present disclosure can also take the following configurations. (1) A surgical control apparatus including: a state estimation block configured to estimate, on the basis of at least one type of contactless input from a user recognized by a first contactless input recognition block, a state of the user; and a restriction block configured to restrict, in accordance with the state estimated by the state estimation block, a control operation of a surgical apparatus based on at least one type of contactless input from the user recognized by a second contactless input recognition block. (2) The surgical control apparatus according to (1) above, in which the contactless input is a voice, a line of sight, a movement, or a gesture of the user. (3) The surgical control apparatus according to (1) or (2) above, in which the control operation is executed on the basis of at least one type of contactless input from the user recognized by the second contactless input recognition block and an input by contact from the user recognized by a contact input recognition block. (4) The surgical control apparatus according to any one of (1) through (3) above, in which the state estimation block estimates a state of the user as an action-other-than-surgical-procedure state, a downward viewing state, a close watching state, or an observation state. (5) The surgical control apparatus according to (4) above, in which a control operation of the surgical apparatus is a menu display control operation of a display control apparatus, an annotation display control operation of a display control apparatus, an imaging control operation of a surgical imaging apparatus for taking a surgical field image, or an arm driving control operation for holding the surgical imaging apparatus. (6) The surgical control apparatus according to (5) above, in which if a state of the user is estimated by the state estimation block to be an action-other-than-surgical-procedure state, the restriction block restricts the control operation of the surgical apparatus to the menu display control operation of the display control apparatus. (7) The surgical control apparatus according to (5) or (6) above, in which if a state of the user is estimated by the state estimation block to be a downward viewing state, the restriction block restricts the control operation of the surgical apparatus to the annotation display control operation of the display control apparatus. (8) The surgical control apparatus according to any one of (5) through (7) above, in which if a state of the user is estimated by the state estimation block to be a close watching state, the restriction block restricts the control operation of the surgical apparatus to the imaging control operation of the surgical imaging apparatus. (9) The surgical control apparatus according to any one of (5) through (8) above, in which if a state of the user is estimated by the state estimation block to be an observation state, the restriction block restricts the control operation of the surgical apparatus to the driving control operation of the arm. (10) The surgical control apparatus according to any one of (1) through (9) above, further including: a mode setting block configured to set an operation mode of the surgical control apparatus on the basis of at least one type of contactless input from the user recognized by the second contactless input recognition block. (11) The surgical control apparatus according to (10) above, in which the state estimation block estimates the state if the operation mode is a mode for controlling the surgical apparatus on the basis of at least one type of contactless input from the user. (12) A surgical control method including: a state estimation step of estimating, on the basis of at least one type of contactless input from a user recognized by a first contactless input recognition block, a state of the user; and a restriction step of restricting, in accordance with the state estimated by processing in the state estimation step, a control operation of a surgical apparatus based on at least one type of contactless input from the user recognized by a second contactless input recognition block; these steps being executed by a surgical control apparatus. (13) A program for having a computer function as: a state estimation block configured to estimate, on the basis of at least one type of contactless input from a user recognized by a first contactless input recognition block, a state of the user; and a restriction block configured to restrict, in accordance with the state estimated by the state estimation block, a control operation of a surgical apparatus based on at least one type of contactless input from the user recognized by a second contactless input recognition block. REFERENCE SIGNS LIST 11 . . . Surgical camera, 12 . . . Camera arm, 15 . . . Control apparatus, 62 . . . Command block, 63 . . . Mode setting block, 64 . . . State estimation block, 66 . . . Image processing block, 71 . . . Voice recognition block, 72 . . . Line-of-sight recognition block, 73 . . . Head recognition block, 74 . . . Gesture recognition block, 75 . . . Manipulation recognition block | <SOH> BACKGROUND ART <EOH>A surgical system has been devised in which a surgical system controls a surgical apparatus by inputting such contactless information as voices, gestures, and lines of sight (refer to PTL 1, for example). With such a surgical system, an operator for whom the practicing of sterilization measures is essential is able to control a surgical apparatus without touching the manipulation buttons and other controls. However, as compared with inputs by touch, contactless inputs may cause the erroneous recognition of inputs, thereby making a surgical apparatus operate in an erroneous manner. With a surgical system, any erroneous operation of a surgical apparatus affects the life of a patient, so that it is essential to prevent any erroneous operation of the surgical apparatus. | <SOH> SUMMARY <EOH> | A61B3470 | 20180330 | 20180913 | A61B3400 | 0 | PHAM, MINH DUC GIA | SURGICAL CONTROL APPARATUS, SURGICAL CONTROL METHOD, AND PROGRAM | UNDISCOUNTED | 0 | PENDING | A61B | 2,018 |
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15,765,293 | PENDING | METHOD AND APPARATUS FOR ESTIMATING THE AORTIC PULSE TRANSIT TIME FROM TIME INTERVALS MEASURED BETWEEN FIDUCIAL POINTS OF THE BALLISTOCARDIOGRAM | A method and apparatus is proposed to estimate the aortic pulse transit time (PTT) from only time intervals measured between fiducial points of the longitudinal balistocardiogram (BCG) without the need to apply any sensor to the area where the arrival of the arterial pulse waveform is to be detected. From the longitudinal BCG of a subject, which can be obtained by means of sensors integrated in a single element with which the subject's body comes into contact, two fiducial points of the BCG waveform are detected in which one of the points is associated with the arrival of the arterial pulse wave to a zone proximal to the heart and the other is associated with the arrival of said arterial pulse wave to a distal zone, respectively. From the time interval between the two points, an estimate of the aortic (carotid-femoral) PTT is provided either directly or through a process of previous calibration. | 1. A method for estimating the aortic pulse transit time (PTT) from a time interval measured between fiducial points of a ballistocardiogram (BCG), comprising: a) detecting, by a digital signal processing system, a first fiducial point in a BCG; b) detecting, by the digital signal processing system, a second fiducial point in the BCG that is latter to the first fiducial point and belongs to a same heartbeat; c) measuring, by a computing system, a time interval between said first and second fiducial points; and d) estimating an aortic PTT from said time interval measured between the two chosen fiducial points, wherein the estimated aortic PTT corresponds directly to the interval obtained between the detected fiducial points of the BCG, or wherein the estimated aortic PTT is obtained using a relationship between said aortic PTT and the time interval between two fiducial points of the BCG, said relationship being obtained through calibration of said time interval with respect to another method for obtaining the aortic PTT. 2. The method according to claim 1, wherein the first and second fiducial points of the BCG are detected by exclusively using the BCG. 3. The method according to claim 1, wherein the two fiducial points of the BCG are identified from an auxiliary cardiovascular signal. 4. The method according to claim 3, wherein: a heartbeat is detected from a R peak of an electrocardiogram and the two fiducial points of the BCG are detected within defined intervals from the R peak of the electrocardiogram, corresponding to the same heartbeat; or a heartbeat is detected from the foot of a pulse wave of a photoplethysmogram or a impedance plethysmogram and the two fiducial points of the BCG are detected within defined intervals from the foot of said pulse wave within the same heartbeat. 5. (canceled) 6. The method according to claim 1, wherein the detected fiducial points of the BCG belong to the I and J waves. 7. The method according to claim 1, wherein the detected fiducial points of the BCG belong to the I and K waves. 8. The method according to claim 1, wherein the detected fiducial points of the BCG belong to the J and K waves. 9. The method according to claim 6, wherein the interval between BCG fiducial points is measured between a minimum of the I wave and a maximum of the J wave. 10. The method according to claim 7, wherein the interval between BCG fiducial points is measured between a minimum of the I wave and a minimum of the K wave. 11. The method according to claim 8, wherein the interval between BCG fiducial points is measured between a maximum of the J wave and a minimum of the K wave. 12. (canceled) 13. (canceled) 14. The method according to claim 1, wherein said calibration comprises the performance of a linear regression between the time interval measured between BCG fiducial points and the aortic PTT obtained by said another method, obtained from a photoplethysmogram. 15. (canceled) 16. (canceled) 17. An apparatus to automatically estimate the aortic pulse transit time (PTT) from the time interval between fiducial points of a ballistocardiogram (BCG), comprises: a) a digital signal processing system configured to automatically detect two fiducial points in a single heartbeat of a BCG; b) a computing system configured to calculate a time interval between said two fiducial points and to estimate an aortic PTT from the calculated time interval, wherein the estimated aortic PTT corresponds directly to the interval obtained between the detected fiducial points of the BCG or the aortic PTT is obtained using a relationship between said aortic PTT and the time interval between two fiducial points of the BCG, said relationship being obtained through calibration of said time interval with respect to another method for obtaining the aortic PTT; and c) a communication system configured to communicate the estimated aortic PTT to an user or to another apparatus. 18. The apparatus according to claim 17, further comprising, additionally, a second computing system configured to obtain the aortic PTT from the said time interval. 19. The apparatus according to claim 17, comprising an input for an auxiliary cardiovascular signal and a unit to determine an extreme value in the BGC signal after a reference point in said auxiliary signal. 20. The apparatus according to claim 19, wherein the auxiliary cardiovascular signal is an impedance plethysmogram, a photoplethysmogram, or an electrocardiogram. | CROSS-REFERENCE TO RELATED APPLICATIONS This application is the entry into national phase of International Application No. PCT/ES2016/070692, filed on Sep. 30, 2016, the content of which is hereby incorporated by reference in its entirety, which claims the benefit of Spanish Patent Application No. P20153144, filed on Oct. 2, 2015, the entire disclosure of which is incorporated herein by reference. FIELD OF THE INVENTION The present invention relates in general to systems for measuring physiological parameters through physical methods and, in particular, to a method and apparatus for estimating the aortic pulse transit time from time intervals measured between fiducial points exclusively measured on the ballistocardiogram (BCG). BACKGROUND OF THE INVENTION Pulse Transit Time (PTT), generated by the ejection of blood from the heart to the arterial system, is a very important parameter for diagnosing the state of the cardiovascular system. It is defined as the time interval between the arrival of the pulse wave at a point proximal to the heart and the arrival at another distal point. Using PTT can be evaluated, for example, arterial elasticity, which is an increasingly accepted indicator for predicting the risk of cardiovascular disease. Arterial elasticity has been associated to the presence of cardiovascular risk factors and arteriosclerotic disease, and its suitability for predicting risk of future cardiovascular events such as myocardial infarction, stroke, revascularization or aortic syndromes, among others, has been widely corroborated, as described in the document by C. Vlachopoulos, K. Aznaouridis, and C. Stefanadis, “Prediction of Cardiovascular Events and All-cause Mortality With Arterial Stiffness: a Systematic Review and Meta-analysis,” Journal American College Cardiology, vol. 55, no. 13, pp. 1318-27, March 2010. The degree of elasticity of an artery is normally evaluated from the propagation speed of the blood pulse wave, the so-called pulse wave velocity (PWV), according to the Moens-Korteweg's formula, PWV = Eh 2 r ρ , where E is the elastic modulus of the artery, h is the width of the arterial wall, r is the arterial radius and ρ is the blood density. The measurement of PWV in the aorta is of the greatest clinical relevance because the aorta and its main branches are responsible for most of the pathophysiological effects derived from arterial stiffness, so that aortic PWV is a good indicator of the state of stiffness of the subject's arteries. Aortic PWV has shown high predictivity of cardiovascular events in several epidemiologic studies, as described in the document by L. M. Van Bortel, S. Laurent, P. Boutouyrie, P. Chowienczyk, J. K. Cruickshank, et al., “Expert Consensus Document on the Measurement of Aortic Stiffness in Daily Practice Using Carotid-femoral Pulse Wave Velocity,” Journal Hypertension, vol. 30, no. 3, pp. 445-448, March 2012. A common method to non-invasively measure the PWV in an artery is from the PTT in said artery, according to PWV = D PTT , where D is the distance between the proximal and distal sites considered. On the aorta, the PWV is usually measured between the carotidal site, located in the medial area of the anterior edge of the sternocleidomastoid muscle, and the femoral site, located at the medial area of the inguinal crease. Arteries in such sites are superficial and easily accessible by using a sensor in direct contact to the skin, and the PTT between them properly reflects the aortic PTT since it includes most of the aortic and aortic-iliac propagation. Another parameter that can be measured from the elasticity of an artery is blood pressure, as the modulus of elasticity is related to changes in mean blood pressure P according to E=E0ekP, where E0 is the elasticity modulus of the artery at a reference mean arterial pressure and k is a constant that depends on the artery and whose valor is comprised between 0.016 mmHg−1 y 0.018 mmHg−1. Changes in arterial blood pressure and absolute values of arterial blood pressure can be estimated from PTT measurements in the aorta or in other arteries by using different calibration methods, as described, for example, in the document by D. Buxi, J. M. Redouté, and M. R. Yuce, “A Survey on Signals and Systems in Ambulatory Blood Pressure Monitoring Using Pulse Transit Time,” Physiological Measurements, DOI 10.1088/0967-3334/36/3/R1. The common procedure for measuring aortic PTT requires preparation (to expose, clean, place the sensors and connect the cables) of the carotidal and femoral sites to detect in each of them the arrival of the blood pressure pulse by means of, for instance, a photoplethysmograph (PPG) or an impedance plethysmograph (IPG) that detect local volume changes due to the arrival of the pressure pulse, or by means of an arterial tonometer that measures the pressure that a superficial artery exerts to a force sensor in close contact to it. These and other sensors able to detect the arrival of a blood pulse wave to the area where they are placed require skill in their placement, entail slow procedures and become uncomfortable for the subject. In addition, prolonged application of the sensor may cause discomfort to the subject, which makes it inadvisable to take the measurement for long periods of time because of the possible physiological effects of the measurement action. An alternative method to obtain information about the cardiovascular mechanical activity at the aorta that requires less preparation of the subject is to determine the timing of fiducial points of the ballistocardiogram (BCG), which reflects variations of the gravity center of the human body, either in terms of displacement, speed or acceleration, as a result of the ejection of blood in each heartbeat and the consequent propagation of the blood pulse wave through the arterial tree. The BCG can be obtained from different systems, some of them implemented with sensors embedded in daily use objects such as bodyweight scales, chairs or beds, as it is described in the document by O. T. Inan, P. F. Migeotte, K.-S. Park, M. Etemadi, K. Tavakolian, et al., “Ballistocardiography and Seismocardiography: a Review of Recent Advances,” IEEE Journal of Biomedical Health and Informatics, DOI 10.1109/JBHI.2014.2361732, or embedded in clothing such as shoes or socks. In such systems, measurements become faster and more comfortable, and in some implementations can be performed for long periods without causing any trouble to the subject because, instead of placing sensors at specific sites to detect the arrival of the pressure wave, it is the body of the subject that naturally contacts an element (platform, bodyweight scale, chair, bed, garment) with the sensors integrated in it. For the time being, the timing of fiducial points of the BCG have been used to detect the arrival of the blood pulse wave to proximal sites respect to the heart due to the relationship between the BCG and the onset of blood ejection into the aorta. For instance, in patent US 20130310700 A1 it is proposed to use fiducial points of a BCG obtained from a system embedded into a weighing scale as a proximal timing reference to measure the aortic PTT. However, the method described in said patent requires an additional sensor to detect the arrival of the blood pressure wave to a distal site. Obtaining proximal and distal temporal information on the same BCG signal would allow the aortic PTT to be measured more quickly and comfortably even over long periods of time, which would be very useful for evaluating arterial elasticity and its derived parameters. The method would also be of great interest to calculate other health indicators that involve the aortic PTT, such as myocardial contractility evaluated from the pre-ejection period (PEP) calculated by subtracting the PTT from the pulse arrival time (PAT). SUMMARY OF THE INVENTION The present invention provides a method and apparatus for estimating the aortic pulse transit time (PTT), said method and apparatus being defined in the independent claims. Several preferred embodiments are described in the dependent claims. As used herein and in any appended claims, the term aortic PTT refers to the PTT between the carotidal site, located in the medial area of the anterior edge of the sternocleidomastoid muscle, and the femoral site, located at the medial area of the inguinal crease. The innovative solution proposed in the present invention is the estimation of aortic PTT from time intervals measured between fiducial points exclusively obtained from the BCG. As this signal is usually obtained by means of sensors integrated in a single element with which the subject's body comes into contact, the use of BCG avoids the need for additional pulse wave sensors and the inconvenience of having to place these sensors in the specific areas where the arrival of the arterial pulse wave is to be detected. This innovative solution is based on the fact that BCG waves reflect changes in the center of gravity of the human body resulting from the overlapping effects of cardiac ejection and the propagation of the arterial pulse wave. Therefore, it is expected that the earliest points of BCG with respect to cardiac systole are mostly related to events linked to cardiac ejection, while the fiducial points furthest from the start of the signal with respect to cardiac systole are expected to be more influenced by events related to the arrival of the pulse wave to distal areas. Since the aorta is comparatively the artery with the greatest volume of blood and its orientation is longitudinal (parallel to the head-feet axis), it is expected that the waves of longitudinal BCG will be especially influenced by the mechanical activity derived from the propagation of the pulse wave that occurs in this main artery. As a result, a method is proposed for estimating aortic PTT comprising, first, of detecting two fiducial points of a BCG: a first point plausibly related to the arrival of the pulse wave to areas closer to the heart and a second point later in time plausibly related to the arrival of the pulse wave to more distal areas. The time interval between these two fiducial points is then measured. This interval corresponds, in a first way of obtaining it, directly to the aortic PTT. A second alternative way to obtain this transit time from the time interval measured between the two fiducial points is to calibrate the BCG interval using the aortic PTT obtained simultaneously with one of the known state-of-the-art methods as a reference. Using the relationship obtained in the calibration; in subsequent measurements the aortic PTT can be calculated from the time interval obtained exclusively from the BCG, thus achieving greater accuracy than in the first way proposed, although with a slower and more complex initial procedure. Applying the proposed method, the inventors have found that, specifically, BCG waves I and J are systematically coincident with the arrival of the pulse wave at the carotid and femoral points, respectively, making the IJ interval particularly suitable for obtaining the aortic PTT directly from it, according to the first proposed method of obtaining it. The use of the second method, based on IJ interval calibration, is also suitable if a more accurate measurement of the aortic PTT is desired. On the other hand, measured intervals between other arbitrarily chosen longitudinal BCG fiducial points are expected to be equally sensitive to changes in PTT in the aorta, such as the interval between waves I and K, or the interval between waves J and K. However, the different duration of these intervals with respect to the aortic PTT will result in the use of the proposed second method of obtaining the aortic PTT, based on a previous calibration of the relationship between the interval considered and the aortic PTT measured with any of the conventional methods. Even though an expert using the temporal relationships between the waves of the BCG and the time arrival of the blood pressure pulse to those particular sites of the arterial tree proposed in this invention, could identify visually the fiducial points that belong to a given heartbeat on a BCG recording and manually measure the time interval between them, an optimal implementation of this invention is through an apparatus that contains the means to process a signal to automatically detect a first and a second fiducial point in a BCG signal, the means to calculate the time interval between said fiducial points and to obtain from it the aortic PTT, and the means to communicate said aortic PTT to a user via a display element or to another device. An algorithm that is able to detect and measure the time interval between the I and J waves from the BCG signal solely could be, for instance, that described in the document by A. Akhbardeh, B. Kaminska y K. Tavakolian, “BSeg++: A modified Blind Segmentation Method for Ballistocardiogram Cycle Extraction,” Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), 2007, pp. 1896-1899. Other algorithms that belong to the state of the art rely on an additional cardiovascular signal to provide a more robust timing reference to identify the I wave and the J wave instead of using the BCG solely. For instance, on the previously cited document by Inan et al. (DOI 10.1109/JBHI.2014.2361732) the J wave is identified as the maximum of the BCG signal in a certain time interval after the R wave of the electrocardiogram (ECG). This method is easily replicable from other cardiovascular signals that have better signal-to-noise ratio (SNR) than the BCG and can be unobtrusively obtained from distal sites of the body, such as the PPG, the IPG locally measured, i.e., placed on the target site, or the IPG measured between two limbs. A major advantage of the invention herein described is that the aortic PTT is obtained by using only fiducial points of the BCG. This makes the measurement easier, faster and more comfortable even for long term measurements than the existing systems that require different cardiovascular signals to obtain at least one of the two fiducial points needed to measure a time interval, or that involve the placement of one or more sensors in the areas between which the PTT is to be measured. BRIEF DESCRIPTION OF THE DRAWINGS To complement the description that is being made and in order to provide a better understanding of the features of the invention, a set of drawings is accompanied as an integral part of this description where, with illustrative and not restrictive character, the following has been represented: FIG. 1 is a diagram that represents a bodyweight scale able to obtain the BCG and that constitutes the element with which the subject's body contacts in one of the embodiments of the present invention. FIG. 2 shows a typical BCG waveform, measured in a standing subject, their main waves: I, J, K, L, and M, which appear at each heartbeat, and the IJ interval. The zero in the abscissa axis coincides with the peak of the ECG R wave, even though this ECG signal is not essential for measuring the IJ interval. FIG. 3 shows, from top to bottom, an ECG recording (represented in order to ease the interpretation of the present invention even though it is not essential for measuring intervals between fiducial points of the BCG), a BCG recording obtained from a bodyweight scale, a PPG obtained at the carotidal site, and a PPG obtained at the femoral site, all of them simultaneously measured from a same subject. FIG. 4 shows an IJ interval record of the BCG and a carotid-femoral PTT record simultaneously obtained from the same subject while he was performing a paced respiration maneuver in order to modulate arterial stiffness via respiratory-induced blood pressure variations. FIG. 5 shows a linear regression analysis and a Bland-Altman analysis of 407 measurements of simultaneous IJ interval and carotid-femoral PTT. FIG. 6 shows an IK interval record of the BCG and a carotid-femoral PTT record simultaneously obtained from the same subject while he was performing a paced respiration maneuver in order to modulate arterial stiffness via respiratory-induced blood pressure variations. DETAILED DESCRIPTION OF VARIOUS PREFERRED EMBODIMENTS In a preferred embodiment of the present invention that is depicted in FIG. 1, a system integrated into a bodyweight scale (1) obtains a longitudinal BCG that reveals the mechanical activity due to cardiac ejection into the aorta, said BCG being obtained from a sensor (2) that consists of the strain gauges already included in the bodyweight scale, where they are used to measure body weight, and an analog signal processing block (3). From the BCG obtained at the output of the described system, the method for estimating aortic pulse transit time is first to detect two fiducial points in the BCG by digital signal processing: a first point related to the arrival of the arterial pulse wave to more proximal areas, which in this case would correspond to the minimum of wave I, and a second point related to the arrival of the arterial pulse wave to more distal areas, which in this case would correspond to the maximum of wave J. Next, the digital signal processing system (4) being used in this preferred embodiment to detect these fiducial points measures the time interval between them, which in this preferred embodiment is the time interval between the minimum of wave I and the maximum of wave J, called the IJ interval, in each beat. This IJ interval would correspond, in a first way of obtaining it, to the aortic PTT. Finally, the communication module (5) is responsible for communicating the estimated aortic PTT value of the subject through an LCD monitor. FIG. 2 shows an example of a BCG record that belongs to a single heart beat and has been obtained from a system embedded in a bodyweight scale; the I wave, J wave, and the IJ interval are annotated. FIG. 3 shows the ECG and BCG tracings simultaneously obtained from the same subject, as well as two tracings obtained from respective PPG sensors placed on the carotidal and femoral sites; the aortic PTT can be measured from these two sensors by placing each on the specific site where the blood pressure pulse must be detected, as usual. This figure illustrates the correspondence between the minimum of the I wave and the foot of the arterial blood pulse at the carotidal site (6), the correspondence between the maximum of the J wave and the foot of the arterial blood pulse at the femoral site (7), and how, consequently, the aortic PTT can be obtained from said two fiducial points by following the method proposed in this preferred embodiment. FIG. 4 shows a simultaneous IJ interval tracing, obtained from this preferred embodiment, and aortic PTT tracing measured by using two PPG sensors placed at the carotidal and femoral sites. These two tracings show the correspondence between the IJ interval and the aortic PTT when the subject is performing a paced respiration in order to modulate arterial stiffness via respiration-induced blood pressure changes. FIG. 5 shows the linear regression analysis and Bland-Altman analysis of 407 pairs of IJ interval and aortic PTT measurements obtained from different subjects under paced respiration that further illustrate the correspondence between both parameters. Since the IJ interval duration is similar to the aortic PTT duration and the magnitude of the respiration-induced trends is equivalent, in this preferred embodiment the aortic PTT is estimated as the IJ interval. The difference between intervals (mean-5.2 ms and standard deviation 13.2 ms, as shown in FIG. 5) is attributable to the intrinsic uncertainty of the measurement. To improve the accuracy of the aortic PTT estimation, a second preferred embodiment of the present invention is proposed using the relationship between the IJ interval and the aortic PTT previously determined through calibration. In this preferred embodiment, a linear regression between the IJ interval and the aortic PTT is calculated, obtained from the simultaneous measurement of both intervals in a target group or a representative part of it, which allows a more accurate estimation of the aortic PTT from the IJ interval alone through the equation of the obtained line in subsequent measurements. FIG. 6 shows the data obtained in another preferred embodiment, in which the PTT is estimated from the interval between the minimum of wave I and the minimum of wave K, which is the so-called IK interval. The result is shown together with the carotid-femoral PTT measured simultaneously in the same subject during a paced respiration maneuver. As with the IJ interval in FIG. 4, the IK interval reflects the changes in the carotid-femoral PTT induced by the maneuver but are now increased because their duration is longer than that of the IJ interval, so that, in this embodiment, the carotid-femoral PTT is necessarily obtained from the calibration of the IK interval with respect to the carotid-femoral PTT measured with other means. Once the invention has been sufficiently described, as well as three preferred embodiments, it should only be added that it is possible to make modifications in its constitution, materials used, and in the choice of the sensors used to obtain the BCG and the methods to identify the fiducial points of this BCG, without deviating from the scope of the invention, defined in the following claims. | <SOH> BACKGROUND OF THE INVENTION <EOH>Pulse Transit Time (PTT), generated by the ejection of blood from the heart to the arterial system, is a very important parameter for diagnosing the state of the cardiovascular system. It is defined as the time interval between the arrival of the pulse wave at a point proximal to the heart and the arrival at another distal point. Using PTT can be evaluated, for example, arterial elasticity, which is an increasingly accepted indicator for predicting the risk of cardiovascular disease. Arterial elasticity has been associated to the presence of cardiovascular risk factors and arteriosclerotic disease, and its suitability for predicting risk of future cardiovascular events such as myocardial infarction, stroke, revascularization or aortic syndromes, among others, has been widely corroborated, as described in the document by C. Vlachopoulos, K. Aznaouridis, and C. Stefanadis, “Prediction of Cardiovascular Events and All-cause Mortality With Arterial Stiffness: a Systematic Review and Meta-analysis,” Journal American College Cardiology , vol. 55, no. 13, pp. 1318-27, March 2010. The degree of elasticity of an artery is normally evaluated from the propagation speed of the blood pulse wave, the so-called pulse wave velocity (PWV), according to the Moens-Korteweg's formula, PWV = Eh 2 r ρ , where E is the elastic modulus of the artery, h is the width of the arterial wall, r is the arterial radius and ρ is the blood density. The measurement of PWV in the aorta is of the greatest clinical relevance because the aorta and its main branches are responsible for most of the pathophysiological effects derived from arterial stiffness, so that aortic PWV is a good indicator of the state of stiffness of the subject's arteries. Aortic PWV has shown high predictivity of cardiovascular events in several epidemiologic studies, as described in the document by L. M. Van Bortel, S. Laurent, P. Boutouyrie, P. Chowienczyk, J. K. Cruickshank, et al., “Expert Consensus Document on the Measurement of Aortic Stiffness in Daily Practice Using Carotid-femoral Pulse Wave Velocity,” Journal Hypertension , vol. 30, no. 3, pp. 445-448, March 2012. A common method to non-invasively measure the PWV in an artery is from the PTT in said artery, according to PWV = D PTT , where D is the distance between the proximal and distal sites considered. On the aorta, the PWV is usually measured between the carotidal site, located in the medial area of the anterior edge of the sternocleidomastoid muscle, and the femoral site, located at the medial area of the inguinal crease. Arteries in such sites are superficial and easily accessible by using a sensor in direct contact to the skin, and the PTT between them properly reflects the aortic PTT since it includes most of the aortic and aortic-iliac propagation. Another parameter that can be measured from the elasticity of an artery is blood pressure, as the modulus of elasticity is related to changes in mean blood pressure P according to in-line-formulae description="In-line Formulae" end="lead"? E=E 0 e kP , in-line-formulae description="In-line Formulae" end="tail"? where E 0 is the elasticity modulus of the artery at a reference mean arterial pressure and k is a constant that depends on the artery and whose valor is comprised between 0.016 mmHg −1 y 0.018 mmHg −1 . Changes in arterial blood pressure and absolute values of arterial blood pressure can be estimated from PTT measurements in the aorta or in other arteries by using different calibration methods, as described, for example, in the document by D. Buxi, J. M. Redouté, and M. R. Yuce, “A Survey on Signals and Systems in Ambulatory Blood Pressure Monitoring Using Pulse Transit Time,” Physiological Measurements , DOI 10.1088/0967-3334/36/3/R1. The common procedure for measuring aortic PTT requires preparation (to expose, clean, place the sensors and connect the cables) of the carotidal and femoral sites to detect in each of them the arrival of the blood pressure pulse by means of, for instance, a photoplethysmograph (PPG) or an impedance plethysmograph (IPG) that detect local volume changes due to the arrival of the pressure pulse, or by means of an arterial tonometer that measures the pressure that a superficial artery exerts to a force sensor in close contact to it. These and other sensors able to detect the arrival of a blood pulse wave to the area where they are placed require skill in their placement, entail slow procedures and become uncomfortable for the subject. In addition, prolonged application of the sensor may cause discomfort to the subject, which makes it inadvisable to take the measurement for long periods of time because of the possible physiological effects of the measurement action. An alternative method to obtain information about the cardiovascular mechanical activity at the aorta that requires less preparation of the subject is to determine the timing of fiducial points of the ballistocardiogram (BCG), which reflects variations of the gravity center of the human body, either in terms of displacement, speed or acceleration, as a result of the ejection of blood in each heartbeat and the consequent propagation of the blood pulse wave through the arterial tree. The BCG can be obtained from different systems, some of them implemented with sensors embedded in daily use objects such as bodyweight scales, chairs or beds, as it is described in the document by O. T. Inan, P. F. Migeotte, K.-S. Park, M. Etemadi, K. Tavakolian, et al., “Ballistocardiography and Seismocardiography: a Review of Recent Advances,” IEEE Journal of Biomedical Health and Informatics , DOI 10.1109/JBHI.2014.2361732, or embedded in clothing such as shoes or socks. In such systems, measurements become faster and more comfortable, and in some implementations can be performed for long periods without causing any trouble to the subject because, instead of placing sensors at specific sites to detect the arrival of the pressure wave, it is the body of the subject that naturally contacts an element (platform, bodyweight scale, chair, bed, garment) with the sensors integrated in it. For the time being, the timing of fiducial points of the BCG have been used to detect the arrival of the blood pulse wave to proximal sites respect to the heart due to the relationship between the BCG and the onset of blood ejection into the aorta. For instance, in patent US 20130310700 A1 it is proposed to use fiducial points of a BCG obtained from a system embedded into a weighing scale as a proximal timing reference to measure the aortic PTT. However, the method described in said patent requires an additional sensor to detect the arrival of the blood pressure wave to a distal site. Obtaining proximal and distal temporal information on the same BCG signal would allow the aortic PTT to be measured more quickly and comfortably even over long periods of time, which would be very useful for evaluating arterial elasticity and its derived parameters. The method would also be of great interest to calculate other health indicators that involve the aortic PTT, such as myocardial contractility evaluated from the pre-ejection period (PEP) calculated by subtracting the PTT from the pulse arrival time (PAT). | <SOH> SUMMARY OF THE INVENTION <EOH>The present invention provides a method and apparatus for estimating the aortic pulse transit time (PTT), said method and apparatus being defined in the independent claims. Several preferred embodiments are described in the dependent claims. As used herein and in any appended claims, the term aortic PTT refers to the PTT between the carotidal site, located in the medial area of the anterior edge of the sternocleidomastoid muscle, and the femoral site, located at the medial area of the inguinal crease. The innovative solution proposed in the present invention is the estimation of aortic PTT from time intervals measured between fiducial points exclusively obtained from the BCG. As this signal is usually obtained by means of sensors integrated in a single element with which the subject's body comes into contact, the use of BCG avoids the need for additional pulse wave sensors and the inconvenience of having to place these sensors in the specific areas where the arrival of the arterial pulse wave is to be detected. This innovative solution is based on the fact that BCG waves reflect changes in the center of gravity of the human body resulting from the overlapping effects of cardiac ejection and the propagation of the arterial pulse wave. Therefore, it is expected that the earliest points of BCG with respect to cardiac systole are mostly related to events linked to cardiac ejection, while the fiducial points furthest from the start of the signal with respect to cardiac systole are expected to be more influenced by events related to the arrival of the pulse wave to distal areas. Since the aorta is comparatively the artery with the greatest volume of blood and its orientation is longitudinal (parallel to the head-feet axis), it is expected that the waves of longitudinal BCG will be especially influenced by the mechanical activity derived from the propagation of the pulse wave that occurs in this main artery. As a result, a method is proposed for estimating aortic PTT comprising, first, of detecting two fiducial points of a BCG: a first point plausibly related to the arrival of the pulse wave to areas closer to the heart and a second point later in time plausibly related to the arrival of the pulse wave to more distal areas. The time interval between these two fiducial points is then measured. This interval corresponds, in a first way of obtaining it, directly to the aortic PTT. A second alternative way to obtain this transit time from the time interval measured between the two fiducial points is to calibrate the BCG interval using the aortic PTT obtained simultaneously with one of the known state-of-the-art methods as a reference. Using the relationship obtained in the calibration; in subsequent measurements the aortic PTT can be calculated from the time interval obtained exclusively from the BCG, thus achieving greater accuracy than in the first way proposed, although with a slower and more complex initial procedure. Applying the proposed method, the inventors have found that, specifically, BCG waves I and J are systematically coincident with the arrival of the pulse wave at the carotid and femoral points, respectively, making the IJ interval particularly suitable for obtaining the aortic PTT directly from it, according to the first proposed method of obtaining it. The use of the second method, based on IJ interval calibration, is also suitable if a more accurate measurement of the aortic PTT is desired. On the other hand, measured intervals between other arbitrarily chosen longitudinal BCG fiducial points are expected to be equally sensitive to changes in PTT in the aorta, such as the interval between waves I and K, or the interval between waves J and K. However, the different duration of these intervals with respect to the aortic PTT will result in the use of the proposed second method of obtaining the aortic PTT, based on a previous calibration of the relationship between the interval considered and the aortic PTT measured with any of the conventional methods. Even though an expert using the temporal relationships between the waves of the BCG and the time arrival of the blood pressure pulse to those particular sites of the arterial tree proposed in this invention, could identify visually the fiducial points that belong to a given heartbeat on a BCG recording and manually measure the time interval between them, an optimal implementation of this invention is through an apparatus that contains the means to process a signal to automatically detect a first and a second fiducial point in a BCG signal, the means to calculate the time interval between said fiducial points and to obtain from it the aortic PTT, and the means to communicate said aortic PTT to a user via a display element or to another device. An algorithm that is able to detect and measure the time interval between the I and J waves from the BCG signal solely could be, for instance, that described in the document by A. Akhbardeh, B. Kaminska y K. Tavakolian, “BSeg++: A modified Blind Segmentation Method for Ballistocardiogram Cycle Extraction,” Annual International Conference of the IEEE Engineering in Medicine and Biology Society ( EMBC ), 2007, pp. 1896-1899. Other algorithms that belong to the state of the art rely on an additional cardiovascular signal to provide a more robust timing reference to identify the I wave and the J wave instead of using the BCG solely. For instance, on the previously cited document by Inan et al. (DOI 10.1109/JBHI.2014.2361732) the J wave is identified as the maximum of the BCG signal in a certain time interval after the R wave of the electrocardiogram (ECG). This method is easily replicable from other cardiovascular signals that have better signal-to-noise ratio (SNR) than the BCG and can be unobtrusively obtained from distal sites of the body, such as the PPG, the IPG locally measured, i.e., placed on the target site, or the IPG measured between two limbs. A major advantage of the invention herein described is that the aortic PTT is obtained by using only fiducial points of the BCG. This makes the measurement easier, faster and more comfortable even for long term measurements than the existing systems that require different cardiovascular signals to obtain at least one of the two fiducial points needed to measure a time interval, or that involve the placement of one or more sensors in the areas between which the PTT is to be measured. | A61B51102 | 20180402 | 20181004 | A61B511 | 0 | MESSERSMITH, ERIC J | METHOD AND APPARATUS FOR ESTIMATING THE AORTIC PULSE TRANSIT TIME FROM TIME INTERVALS MEASURED BETWEEN FIDUCIAL POINTS OF THE BALLISTOCARDIOGRAM | SMALL | 0 | ACCEPTED | A61B | 2,018 |
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15,768,301 | PENDING | CXCR6-TRANSDUCED T CELLS FOR TARGETED TUMOR THERAPY | The present invention relates to CXCR6-transduced (a) T cell(s) such as (a) CD8+ T cell(s), (a) CD4+ T cell(s), (a) CD3+ T cell(s), (a) γδ T cell(s) or (a) natural killer (NK) T cell(s) for targeted tumor therapy, nucleic acid sequences, vectors capable of transducing such (a) T cell(s), (a) transduced T cell(s) carrying the nucleic acid sequences or vectors of the present invention, methods and kits comprising the nucleic acid sequences or vectors of the present invention. The invention also provides the use of said transduced T cell(s) in a method for the treatment of diseases characterized by CXCL16 overexpression as well as a pharmaceutical composition/medicament comprising (a) transduced T cell(s) expressing the CXCR6 for use in methods of treating diseases characterized by CXCL16 overexpression. | 1. A vector comprising a nucleic acid sequence selected from the group consisting of: (a) a nucleic acid sequence of SEQ ID NO: 1, and (b) a nucleic acid sequence, which is at least 84% identical to the sequence of SEQ ID NO: 1 and which is characterized by having a chemokine receptor 6 (CXCR6) activity. 2. The vector of claim 1, wherein said vector is an expression vector. 3. The vector of claim 1, wherein said vector is a retroviral vector. 4. The vector of claim 1, wherein said vector further comprising a regulatory sequence, which is operably linked to said nucleic acid sequence. 5. A transduced T cell expressing a chemokine receptor 6 (CXCR6) encoded by a nucleic acid sequence selected from the group consisting of: (a) a nucleic acid sequence of SEQ ID NO: 1, and (b) a nucleic acid sequence, which is at least 84% identical to the sequence of SEQ ID NO: 1 and which is characterized by having a chemokine receptor 6 (CXCR6) activity. 6. A method for the production of a transduced T cell expressing a chemokine receptor 6 (CXCR6), comprising the following steps: (a) transducing a T cell with a vector of claim 1; (b) culturing the transduced T cell under conditions allowing the expression of the chemokine receptor 6 (CXCR6) in or on said T cell; and (c) recovering the transduced T cell from the culture. 7. The method of claim 6, further comprising transfecting the transduced T cell with anti-CD3 and anti-CD28 antibodies; and expanding the transfected transduced T cell. 8. The method of claim 7, wherein the expansion occurs in the presence of cytokines selected from the group consisting of: interleukin-2 (IL-2), interleukin-15 (IL-15), and IL-2 and IL-15. 9. A transduced T cell expressing a chemokine receptor 6 (CXCR6) of claim 5. 10. (canceled) 11. (canceled) 12. A pharmaceutical composition comprising the transduced T cell of claim 5. 13. The transduced T cell of claim 5, wherein the transduced T cell is a T cell originally obtained from the patient to be treated with. 14. A method of treating a disease characterized by CXCL16 overexpression in a patient in need thereof, comprising administering to the patient the transduced T cell of claim 5. 15. The method of claim 14, wherein said disease is selected from the group consisting of colorectal cancer, brain cancer, ovarian cancer, prostate cancer, pancreatic cancer, breast cancer, renal cancer, nasopharyngeal carcinoma, hepatocellular carcinoma, gastric cancer, cervical cancer, bladder cancer, lymphoma, sarcoma, and lung cancer. 16. A kit for incorporating a nucleic acid sequence into a T cell, comprising a vector of claim 1. 17. The vector of claim 1, wherein the T cell is a T cell selected from the group consisting of a CD8+ T cell, CD4+ T cell, a γδ T cell and natural killer (NK) T cells. 18. The transduced T cell of claim 5, wherein the T cell is a T cell selected from the group consisting of a CD8+ T cell, CD4+ T cell, a γδ T cell and natural killer (NK) T cells. 19. The method of claim 6, wherein the T cell is a T cell selected from the group consisting of a CD8+ T cell, CD4+ T cell, a γδ T cell and natural killer (NK) T cells. 20. A method of treating a disease characterized by CXCL16 overexpression in a patient in need thereof, comprising administering to the patient the pharmaceutical composition of claim 12. | The present invention relates to CXCR6-transduced (a) T cell(s) such as (a) CD8+ T cell(s), (a) CD4+ T cell(s), (a) CD3+ T cell(s), (a) γδ T cell(s) or (a) natural killer (NK) T cell(s) for targeted tumor therapy, nucleic acid sequences, vectors capable of transducing such (a) T cell(s), (a) transduced T cell(s) carrying the nucleic acid sequences or vectors of the present invention, methods and kits comprising the nucleic acid sequences or vectors of the present invention. The invention also provides the use of said transduced T cell(s) in a method for the treatment of diseases characterized by CXCL16 overexpression as well as a pharmaceutical composition/medicament comprising (a) transduced T cell(s) expressing the CXCR6 for use in methods of treating diseases characterized by CXCL16 overexpression. Adoptive T cell therapy (ACT) is a powerful treatment approach using cancer-specific T cells (Rosenberg and Restifo, Science 348(6230) (2015), 62-68). ACT may use naturally occurring tumor-specific cells or T cells rendered specific by genetic engineering using T cell or chimeric antigen receptors (Rosenberg and Restifo, Science 348(6230) (2015), 62-68). WO-A1 2015/028444 that is located in the field of adoptive T cell therapy (ACT) describes transduced T cells expressing an anti-CD30 chimeric antigen receptor (CAR) for use in treating CD30 positive cancer. Moreover, US-A1 2014/271635 discloses recombinant T cells expressing a chimeric antigen receptor specific for CD19 for use in the treatment of diseases associated with the expression of CD19. ACT can successfully treat and induce remission in patients suffering even from advanced and otherwise treatment refractory diseases such as acute lymphatic leukemia, non-hodgkins lymphoma or melanoma (Dudley et al., J Clin Oncol 26(32) (2008), 5233-5239; Grupp et al., N Engl J Med 368 (16) (2013), 1509-1518; Kochenderfer et al., J Clin Oncol. (2015) 33(6):540-9. doi: 10.1200/JCO.2014.56.2025. Epub 2014 Aug. 25). However, long term benefits are restricted to a small subset of patients while most will relapse and succumb to their refractory disease. Access of T cells to tumor cells or tissue has been deemed essential for the success of ACT. Thus strategies enabling T cell entry need to be developed and implemented (Gattinoni et al., Nat Rev Immunol 6(5) (2006), 383-393). The currently most effective method to achieve enhanced T cell infiltration is total body irradiation, which permeabilizes tumor tissue, remodels the vasculature and depletes suppressive cells (Dudley et al., J Clin Oncol 23(10) (2005), 2346-2357). While this strategy has shown efficacy in clinical trials, its unspecific nature induces severe side effects, limiting its applicability and calling for more specific strategies (Dudley et al., J Clin Oncol 23(10) (2005), 2346-2357). T cell entry and trafficking into tissues is a tightly regulated process where integrins and chemokines play a central role (Franciszkiewicz et al., Cancer Res 72(24) (2012), 6325-6332; Kalos and June, Immunity 39(1) (2013), 49-60). Chemokines are secreted by resident cells and form gradients, which attract cells bearing their corresponding receptor, regulating cellular entry (Franciszkiewicz et al., Cancer Res 72(24) (2012), 6325-6332). Tumors use this principle to attract immune suppressive cellular populations while excluding proinflammatory subsets (Curiel et al., Nat Med 10(9) (2004), 942-949). Wennerberg et al., Cancer Immunol Immunother 64 (2015), 225-235, located in the field of adoptive T cell therapy (ACT), discloses that ex vivo expansion of natural killer (NK) cells results in an increased expression of the CXCR3 receptor. Further, it is described in Wennerberg et al. that these expanded NK cells displayed an improved migration capacity toward solid tumors secreting CXCL10. However, the NK cells as described in Wennerberg et al. were not genetically engineered to express the chemokine receptor CXCR3. Introducing chemokine receptors (that are targeted by chemokines expressed within the tumor tissue) into T cells has been used to redirect antigen-specific T cells and to enhance their migration into the tumor tissue. CCR2, CCR4 and CXCR2 have been tested in preclinical models. They lead to enhanced therapeutic efficacy of ACT but generally fail to reject tumors, indicating insufficient infiltration and functionality of T cells at the tumor site (Di Stasi et al., Blood 113(25) (2009), 6392-6402; Peng et al., Clin Cancer Res 16(22) (2010), 5458-5468; Asai et al., PLoS One 8(2) (2013), e56820). Further, Sapoznik et al., Cancer Immunol Immunother 61 (2012), 1833-1847 discloses that tumor infiltrating lymphocyte (TIL) cells engineered to express CXCR1 showed enhanced migration towards melanoma cells secreting the chemokine CXCL8. Further, the transfection of the murine B cell line Baf-3 cells with a vector construct harbouring the mouse CXCR6 was described (Matsumura et al., J. Immunol. 181 (2013), 3099-3107). However, the sole purpose of the experimental procedure described in the Matsumura et al. publication was to prove that CXCL16 secreted by mouse tumor cells previously treated with radiation was functional, i.e. that such mouse tumor cells could induce the migration of CXCR6 positive cells. Thus the transfection of the murine B cell line Baf-3 cells with a vector construct harbouring the mouse CXCR6 was made in order to generate a functional cell line for CXCL16 effects and not vice versa for CXCR6 impact. As mentioned above, the transfected cell line described in the Matsumura et al. publication is a murine B cell line, i.e. a lineage totally independent of T cells functionality and development. Thus the herein demonstrated therapeutic efficacy of CXCR6 transduced T cells cannot be extrapolated from the murine B cell line described in the Matsumura et al. publication. Further, Xiao et al., Oncotarget, 6(16) (2015), 14165-14178 discloses the construction of a vector expressing the full-length human CXCR6 for the transduction of human breast cells. Moreover, Deng et al., Nature 388 (1997), 296-300 discloses vectors harboring the human CXCR6 sequence as deposited under the accession number AF007545. However, the vectors as described in Xiao et al. and Deng et al. have neither been completely structurally characterized nor have been deposited. Accordingly, the targeted tumor therapy, particularly the adoptive T cell therapy needs to be improved in order to suffice the needs of the cancer patients. Thus, there is still a need to provide improved means having the potential to improve safety and efficacy of the ACT and overcome the above disadvantages. This need is addressed by the present invention by providing the embodiments as defined in the claims. The present invention relates to a vector capable of transducing (a) T cell(s), preferably (a) CD8+ T cell(s), (a) CD4+ T cell(s), (a) CD3+ T cell(s), (a) γδ T cell(s) or (a) natural killer (NK) T cell(s), most preferably (a) CD8+ T cell(s), comprising/which comprise a nucleic acid encoding a chemokine receptor 6 (CXCR6) or a fragment thereof, which is characterized by having chemokine receptor 6 (CXCR6) activity. CXCR6 is the receptor for CXCL16, which is secreted by myeloid cells but also by malignant cells such as pancreatic cancer cells (Gaida et al., Clin Exp Immunol 154(2) (2008), 216-223; van der Voort et al., J Leukoc Biol 87(6) (2010), 1029-1039). The expression of CXCR6 is restricted to certain CD4+ T cell subsets, natural killer (NK) T cells and myeloid cells but is absent from cytotoxic CD8+ T cells (Matloubian et al, Nat Immunol 1(4) (2000), 298-304; van der Voort et al, J Leukoc Biol 87(6) (2010), 1029-1039). The ligand of CXCR6 exists in two forms: membrane bound CXL16 and a secreted soluble form of CXCL16. This explains the dual function of CXCR6. CXCR6 mediates migration towards soluble CXCL16 and mediates adhesion through the membrane bound form (Matloubian et al., Nat Immunol 1(4) (2000), 298-304; Gough et al., J Immunol 172(6) (2004), 3678-3685). These properties render CXCR6 unique among chemokine receptors. In the context of the present invention, it has surprisingly and unexpectedly been found that CXCR6 can be transduced into CD8+ T cells and thereby mediates their migration towards tumor cells. In addition, the data that have been obtained in context of the present invention indicate that CXCR6-transduced T cells, preferably CD8+ T cells, CD4+ T cells, CD3+ T cells, γδ T cells or natural killer (NK) T cells, most preferably CD8+ T cells, have the further advantage that they adhere to the target tumor cells in an antigen-independent manner, and thus support tumor cell recognition at the tumor site. Accordingly, the present invention relates to the transduction of (a) T cell(s), preferably (a) CD8+ T cell(s), (a) CD4+ T cell(s), (a) CD3+ T cell(s), (a) γδ T cell(s) or (a) natural killer (NK) T cell(s), most preferably (a) CD8+ T cell(s), with CXCR6 thereby mediating their migration towards (a) tumor cell(s) secreting CXCL16. As shown in the appended Examples, the treatment of (a) tumor(s) with (a) transduced T cell(s) expressing a chemokine receptor 6 (CXCR6) significantly reduces the tumor size compared to control experiments (see FIG. 17). Accordingly, it was surprisingly found that transduced T cell(s) expressing a chemokine receptor 6 (CXCR6) can be used for the treatment of diseases characterized by CXCL16 overexpression such as pancreatic cancer. Thus, transduction of (a) T cell(s), preferably (a) CD8+ T cell(s), (a) CD4+ T cell(s), (a) CD3+ T cell(s), (a) γδ T cell(s) or (a) natural killer (NK) T cell(s), most preferably (a) CD8+ T cell(s), with CXCR6 will advantageously result in an improved adoptive T cell therapy. Accordingly, the present invention relates to a vector capable of transducing (a) T cell(s), preferably (a) CD8+ T cell(s), (a) CD4+ T cell(s), (a) CD3+ T cell(s), (a) γδ T cell(s) or (a) natural killer (NK) T cell(s), most preferably (a) CD8+ T cell(s), comprising/which comprise a nucleic acid sequence encoding CXCR6 or a fragment thereof, which is characterized by having CXCR6 activity. In the context of the present invention the vector may comprise a nucleic acid sequence, which encodes a fragment/polypeptide part of the full length chemokine receptor 6 (CXCR6). Thus, the chemokine receptor 6 (CXCR6), which is comprised in the herein provided vector is a fragment/polypeptide part of the full length CXCR6. The nucleic acid sequence encoding the full length chemokine receptor 6 (CXCR6) is shown herein as SEQ ID NO: 1 (human) and 3 (murine/mouse). The amino acid sequences of murine/mouse and human full length CXCR6 are shown herein as SEQ ID NOs: 4 (murine/mouse) and 2 (human), respectively (the Uni Prot Entry number of the human full length CXCR6 is 000574 (accession number with the entry version number 139 and version 1 of the sequence. The Uni Prot Entry number of the mouse full length CXCR6 is Q9EQ16 (accession number with the entry version number 111 and version 1 of the sequence)). In the context of the present invention, the nucleic acid sequence encodes “a chemokine receptor 6 (CXCR6)”. The term “chemokine receptor 6 (CXCR6)” and its scientific meaning relating to structure and function are well known in the art and is used accordingly in the context of the present invention (Shimaoka et al., J Leukoc Biol. 75(2) (2004), 267-274; Alkhatib G. et al., Nature 388(6639) (1997), 238; Paust et al., Nat Immunol. 11(12) (2010), 1127-1135). The function of the chemokine receptor 6 (CXCR6) within the vector of the present invention is to act as an attractor and a connector between a cell, preferably a T cell such as a CD8+ T cell, a CD4+ T cell, a CD3+ T cell, a γδ T cell or a natural killer (NK) T cells, most preferably a CD8+ T cell, that is to be transduced by a nucleic acid sequence expressing said chemokine receptor 6 (CXCR6) and target cell that (over-) expresses the chemokine (C-X-C motif) ligand 16 (CXCL16). The nucleic acid sequences of the full length CXCL16 is shown herein as SEQ ID NO: 5 (human) and 7 (murine/mouse). The amino acid sequences of murine/mouse and human full length CXCL16 are shown herein as SEQ ID NOs: 8 (murine/mouse) and 6 (human), respectively (the Uni Prot Entry number of the human full length CXCL16 is Q9H2A7 (accession number with the entry version number 129 and version 4 of the sequence). The Uni Prot Entry number of the mouse full length CXCL16 is Q8BSU2 (accession number with the entry version number 103 and version 2 of the sequence)). Thus, the transduced T cell(s) expressing a chemokine receptor 6 (CXCR6) encoded by a nucleic acid sequence described herein is capable of migrating towards and binding to (a) target cell(s) that (over-) expresses CXCL16 such as, e.g., progenitor disease cells, primary cell lines, epithelial cells, neuronal cells, lymphoid lineage cells, stem cells or tumor cells. The term “migrating” in the context of the present invention, refers to the capability of (transduced) T cells, which are characterized by (over-) expressing the CXCR6 towards (transduced) cells that (over-) express CXCL16 such as, e.g., progenitor disease cells, primary cell lines, epithelial cells, neuronal cells, lymphoid lineage cells, stems or tumor cells. The migration capacity of the target cells can be measured by flow cytometry, ELISA, microscopy or any other suitable device or system (Justus et al., J. Vis. Exp. (88) (2014), e51046, doi:10.3791/51046). In brief, such cell migration assays work as follows: transduced T cells (e.g. CD8+ T cells) are labelled with a suitable fluorescent dye and seeded in serum free medium in the upper well of a transwell insert in a 96 well plate. Recombinant CXCL16 is added to the lower chamber. Migration of cells is allowed at 37° C. Thereafter, cells reaching the lower well are quantified. Methods to measure migration are extensively known in the literature (Valster A. et al., Methods 37(2) (2005), 208-215) and include transwell-assays, confocal microscopy and flow cytometry for in vitro analysis, while flow cytometry, bioluminescence imaging and immunohistochemistry are used for in vivo analysis (see also Example section 2.5, infra, for further details). The term “binding” in the context of the present invention, refers to the capability of the chemokine receptor 6 (CXCR6) to associate with the target cell, which is characterized by (over-) expressing CXCL16, for example via covalent or non-covalent interactions. A “covalent” interaction is a form of chemical bonding that is characterized by the sharing of pairs of electrons between atoms, or between atoms and other covalent bonds. Covalent bonding includes many kinds of interaction well-known in the art such as, e.g., σ-bonding, π-bonding, metal to non-metal bonding, agostic interactions and three-center two-electron bonds. A “non-covalent” bond is a chemical bond that does not involve the sharing of pairs of electrons. Non-covalent bonds are critical in maintaining the three-dimensional structure of large molecules, such as proteins and nucleic acids, and are involved in many biological processes in which molecules bind specifically but transiently to one another. There are several types of non-covalent bonds, such as hydrogen bonding, ionic interactions, Van-der-Waals interactions, charge-charge, charge-dipole, dipole-dipole bonds and hydrophobic bonds. Non-covalent interactions often involve several different types of non-covalent bonds working in concert, e.g., to keep a ligand in position on a target binding site on the cell membrane. An interaction may occur with a group such as a charge or a dipole, which may be present many times at the surface of the cell membrane. Preferably, the interaction (i.e. the binding) occurs at a defined site (involves a specific cell membrane constituent/epitope) of the cell membrane, and goes along with the formation of at least one interaction, preferably the formation of a network of several specific interactions. Even more preferably, the binding is specific for the target cell, i.e. the binding occurs at the cell membrane of the target cell but not, or not significantly, at the cell membrane of a non-target cell. In the context of the present invention, the vector capable of transducing cells, comprises a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 1 (human) and 3 (murine/mouse) or a nucleic acid sequence, which is at least 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the sequence of SEQ ID NOs: 1 (human) or 3 (murine/mouse) and which is characterized by having a chemokine receptor 6 (CXCR6) activity. Accordingly, also encompassed by the present invention are nucleic acid molecules, nucleic acid sequences or sequence segments having at least 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the nucleic acid molecule/nucleic acid sequence depicted in SEQ ID NOs: 1 (human) or 3 (murine/mouse). Such variant molecules may be splice forms or homologous molecules from other specifies. It will be appreciated that these variant nucleic acid molecule/nucleic acid sequences nonetheless have to encode an amino acid sequence having the indicated function, i.e. the sequence encoded by a variant of SEQ ID NOs: 1 (human) or 3 (murine/mouse) has to be characterized by having a chemokine receptor 6 (CXCR6) activity as defined herein below. Accordingly, in the context of the present invention the nucleic acid sequence may be SEQ ID NOs: 1 (human) and 3 (murine/mouse) or a nucleic acid sequence, which is at least 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the sequence of SEQ ID NOs: 1 (human) or 3 (murine/mouse). If the herein provided vector capable of transducing (a) T cell(s), preferably (a) CD8+ T cell(s), (a) CD4+ T cell(s), (a) CD3+ T cell(s), (a) γδ T cell(s) or (a) natural killer (NK) T cell(s), most preferably (a) CD8+ T cell(s), comprises a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 1 (human) and 3 (murine/mouse) or a nucleic acid sequence, which is at least 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the sequence of SEQ ID NOs: 1 (human) or 3 (murine/mouse), then said nucleic acid sequence is characterized by having a chemokine 6 receptor (CXCR6) activity. The chemokine 6 receptor (CXCR6) activity is defined by the ability to migrate towards a CXCL16 gradient orchestered by CXCL16-producing cells in vitro and in vivo and allowing the accumulation of CXCR6-positive T cells at the target site, i.e. tumor site and/or by the ability to mediate adhesion directly by CXCL16-binding or indirectly through integrine activation to CXCL16-producing tumor cells, thereby increasing tumor cell recognition. Methods to measure migration are extensively known in the literature (Valster A. et al., Methods 37(2) (2005), 208-215) and include transwell-assays, confocal microscopy and flow cytometry for in vitro analysis, while flow cytometry, bioluminescence imaging and immunohistochemistry are used for in vivo analysis. In accordance with the present invention, the term “at least % identical to” in connection with nucleic acid sequences/nucleic acid molecules describes the number of matches (“hits”) of identical nucleic acids of two or more aligned nucleic acid sequences as compared to the number of nucleic acid residues making up the overall length of the amino acid sequences (or the overall compared part thereof). In other terms, using an alignment, for two or more sequences or subsequences, the percentage of nucleic acid residues that are the same (e.g. at least 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity) may be determined, when the (sub)sequences are compared and aligned for maximum correspondence over a window of comparison, or over a designated region as measured using a sequence comparison algorithm as known in the art, or when manually aligned and visually inspected. Preferred nucleic acids in accordance with the invention are those where the described identity exists over a region that is at least 100 to 150 nucleotides in length, more preferably, over a region that is at least 200 to 400 nucleotides in length. More preferred nucleic acids in accordance with the present invention are those having the described sequence identity over the entire length of the nucleic acid sequence shown in SEQ ID NO: 1 (human) or 3 (murine/mouse). It is well known in the art how to determine percent sequence identity between/among sequences using, for example, algorithms such as those based on CLUSTALW computer program (Thompson Nucl. Acids Res. 2 (1994), 4673-4680) or FASTA (Pearson and Lipman, Proc. Natl. Acad. Sci., 1988, 85; 2444). Although the FASTA algorithm typically does not consider internal non-matching deletions or additions in sequences, i.e., gaps, in its calculation, this can be corrected manually to avoid an overestimation of the % sequence identity. CLUSTALW, however, does take sequence gaps into account in its identity calculations. Also available to those having skill in this art are the BLAST and BLAST 2.0 algorithms (Altschul, Nucl. Acids Res., 25 (1977), 3389). The BLASTN program for nucleic acid sequences uses as default a word length (W) of 11, an expectation (E) of 10, M=5, N=4, and a comparison of both strands. For amino acid sequences, the BLASTP program uses as default a word length (W) of 3, and an expectation (E) of 10. The BLOSUM62 scoring matrix (Henikoff, Proc. Natl. Acad. Sci., 89 (1989), 10915) uses alignments (B) of 50, expectation (E) of 10, M=5, N=4, and a comparison of both strands. All those programs may be used for the purposes of the present invention. However, preferably the BLAST program is used. Accordingly, all the nucleic acid molecules having the prescribed function and further having a sequence identity of at least 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% as determined with any of the above recited or further programs available to the skilled person and preferably with the BLAST program fall under the scope of the invention. In accordance with the present invention, nucleic acid sequences, which are also referred to herein as polynucleotides or nucleic acid molecules, include DNA, such as cDNA or genomic DNA, and RNA. It is understood that the term “RNA” as used herein comprises all forms of RNA including mRNA, tRNA and rRNA but also genomic RNA, such as in case of RNA of RNA viruses. Preferably, embodiments reciting “RNA” are directed to mRNA. Further included are nucleic acid mimicking molecules known in the art such as synthetic or semi-synthetic derivatives of DNA or RNA and mixed polymers, both sense and antisense strands. They may contain additional non-natural or derivatized nucleotide bases, as will be readily appreciated by those skilled in the art. Such nucleic acid mimicking molecules or nucleic acid derivatives according to the invention include peptide nucleic acid (PNA), phosphorothioate nucleic acid, phosphoramidate nucleic acid, 2′-O-methoxyethyl ribonucleic acid, morpholino nucleic acid, hexitol nucleic acid (HNA) and locked nucleic acid (LNA), an RNA derivative in which the ribose ring is constrained by a methylene linkage between the 2′-oxygen and the 4′-carbon (see, for example, Braasch and Corey, Chemistry & Biology 8 (2001), 1-7). PNA is a synthetic DNA-mimic with an amide backbone in place of the sugar-phosphate backbone of DNA or RNA, as described by Nielsen et al., Science 254 (1991):1497; and Egholm et al., Nature 365(1993), 666. The nucleic acid molecules/nucleic acid sequences of the invention may be of natural as well as of synthetic or semi-synthetic origin. Thus, the nucleic acid molecules may, for example, be nucleic acid molecules that have been synthesized according to conventional protocols of organic chemistry. The person skilled in the art is familiar with the preparation and the use of such nucleic acid molecules (see, e.g., Sambrook and Russel “Molecular Cloning, A Laboratory Manual”, Cold Spring Harbor Laboratory, N.Y. (2001)). The term comprising, as used herein, denotes that further sequences, components and/or method steps can be included in addition to the specifically recited sequences, components and/or method steps. However, this term also encompasses that the claimed subject-matter consists of exactly the recited sequences, components and/or method steps. In those embodiments where the nucleic acid molecule comprises (rather than consists of) the recited sequence, additional nucleotides extend over the specific sequence either on the 5′ end or the 3′ end, or both. Those additional nucleotides may be of heterologous or homologous nature. In the case of homologous sequences, these sequences may comprise up to 1500 nucleotides at the 5′ and/or the 3′ end, such as e.g. up to 1000 nucleotides, such as up to 900 nucleotides, more preferably up to 800 nucleotides, such as up to 700 nucleotides, such as e.g. up to 600 nucleotides, such as up to 500 nucleotides, even more preferably up to 400 nucleotides, such as up to 300 nucleotides, such as e.g. up to 200 nucleotides, such as up to 100 nucleotides, more preferably up to 50 nucleotides, such as up to 40 nucleotides such as e.g. up to 30 nucleotides, such as up to 20 nucleotides, more preferably up to 10 nucleotides and most preferably up to 5 nucleotides at the 5′ and/or the 3′ end. The term “up to [ . . . ] nucleotides”, as used herein, relates to a number of nucleotides that includes any integer below and including the specifically recited number. For example, the term “up to 5 nucleotides” refers to any of 1, 2, 3, 4 and 5 nucleotides. Furthermore, in the case of homologous sequences, those embodiments do not include complete genomes or complete chromosomes. Additional heterologous sequences may, for example, include heterologous promoters, which are operatively linked to the coding sequences of the invention, as well as further regulatory nucleic acid sequences well known in the art and described in more detail herein below. Thus, in the context of the present invention, the nucleic acid sequences may be under the control of regulatory sequences. Accordingly, in the context of the present invention, the vector of the present invention further comprises a regulatory sequence, which is operably linked to the nucleic acid sequences described herein. For example, promoters, transcriptional enhancers and/or sequences, which allow for induced expression of the CXCR6 described herein may be employed. In the context of the present invention, the nucleic acid molecules are expressed under the control of a constitutive or an inducible promoter. Suitable promoters are e.g. the CMV promoter (Qin et al., PLoS One 5(5) (2010), e10611), the UBC promoter (Qin et al., PLoS One 5(5) (2010), e10611), PGK (Qin et al., PLoS One 5(5) (2010), e10611), the EF1A promoter (Qin et al., PLoS One 5(5) (2010), e10611), the CAGG promoter (Qin et al., PLoS One 5(5) (2010), e10611), the SV40 promoter (Qin et al., PLoS One 5(5) (2010), e10611), the COPIA promoter (Qin et al., PLoS One 5(5) (2010), e10611), the ACT5C promoter (Qin et al., PLoS One 5(5) (2010), e10611), the TRE promoter (Qin et al., PLoS One. 5(5) (2010), e10611), the Oct3/4 promoter (Chang et al., Molecular Therapy 9 (2004), S367-S367 (doi: 10.1016/j.ymthe.2004.06.904)), or the Nanog promoter (Wu et al., Cell Res. 15(5) (2005), 317-24). The term “regulatory sequence” refers to DNA sequences, which are necessary to effect the expression of coding sequences to which they are ligated. The nature of such control sequences differs depending upon the host organism. In prokaryotes, control sequences generally include (a) promoter(s), (a) ribosomal binding site(s), and (a) terminator(s). In eukaryotes generally control sequences include (a) promoter(s), (a) terminator(s) and, in some instances, (an) enhancer(s), (a) transactivator(s) or (a) transcription factor(s). The term “control sequence” is intended to include, at a minimum, all components the presence of which are necessary for expression, and may also include additional advantageous components. Furthermore, it is envisaged for further purposes that nucleic acid molecules may contain, for example, thioester bonds and/or nucleotide analogues. Said modifications may be useful for the stabilization of the nucleic acid molecule against endo- and/or exonucleases in the transduced T cell. Said nucleic acid molecules may be transcribed by an appropriate vector containing a chimeric gene, which allows for the transcription of said nucleic acid molecule in the transduced T cell. In this respect, it is also to be understood that such polynucleotide can be used for “gene targeting” or “gene therapeutic” approaches. In another embodiment said nucleic acid sequences are labeled. Methods for the detection of nucleic acids are well known in the art, e.g., Southern and Northern blotting, PCR or primer extension. This embodiment may be useful for screening methods for verifying successful introduction of the nucleic acid sequences described above during gene therapy approaches. Said nucleic acid sequence(s) may be a recombinantly produced chimeric nucleic acid sequence comprising any of the aforementioned nucleic acid sequences either alone or in combination. In the context of the present invention, the nucleic acid molecule is part of a vector of the present invention. The present invention therefore also relates to (a) vector(s) comprising the nucleic acid molecule described in the present invention. Herein the term “vector” relates to a circular or linear nucleic acid molecule, which can autonomously replicate in a host cell (i.e. in a transduced T cell) into which it has been introduced. The “vector” as used herein particularly refers to a plasmid, a cosmid, a virus, a bacteriophage and other vectors commonly used in genetic engineering. In the context of the present invention, the vector of the invention is suitable for the transformation of (a) T cell(s), preferably of (a) CD8+ T cell(s), (a) CD4+ T cell(s), (a) CD3+ T cell(s), (a) γδ T cell(s) or (a) natural killer (NK) T cell(s), most preferably (a) CD8+ T cell(s). Accordingly, in one aspect of the invention, the vector as provided herein is an expression vector. Expression vectors have been widely described in the literature. In particular, the herein provided vector preferably comprises a recombinant polynucleotide (i.e. a nucleic acid sequence encoding the chemokine receptor 6 (CXCR6) or a fragment thereof, which is characterized by having a CXCR6 activity as described herein) as well as (an) expression control sequence(s) operably linked to the nucleotide sequence to be expressed. The vector as provided herein preferably further comprises (a) promoter(s). The herein described vector may also comprise a selection marker gene and a replication-origin ensuring replication in the host (i.e. the transduced T cell). Moreover, the herein provided vector may also comprise a termination signal for transcription. Between the promoter and the termination signal there is preferably at least one restriction site or a polylinker, which enables the insertion of a nucleic acid molecule (e.g. a nucleic acid sequence encoding the CXCR6 described herein) desired to be expressed. The skilled person knows how such insertion can be put into practice. Examples of vectors suitable to comprise a nucleic acid molecule of the present invention to form the vector of the present invention are known in the art. For example, in context of the invention suitable vectors include cosmids, plasmids (e.g., naked or contained in liposomes) and viruses (e.g., lentiviruses, retroviruses, adenoviruses, and adeno-associated viruses) that incorporate the nucleic acid molecule of the invention (i.e. the nucleic acid sequence encoding the chemokine receptor 6 (CXCR6) or a fragment thereof, which is characterized by having a CXCR6 activity as described herein). Preferably, the vector of the present invention is a viral vector. More preferably, the vector of the present invention is a lentiviral vector, and even more preferably, the vector of the present invention is a retroviral vector (e.g. the pMP71 vector). Accordingly, in the context of the present invention, the vector is a lentiviral vector or a retroviral vector. The vector of the present invention allows for constitutive or conditional expression of the nucleic acid sequence of the present invention encoding the chemokine receptor 6 (CXCR6). In this context, suitable retoviral vectors for the expression of the CXCR6 are known in the art such as SAMEN CMV/SRa (Clay et al., J. Immunol. 163 (1999), 507-513), LZRS-id3-IHRES (Heemskerk et al., J. Exp. Med. 186 (1997), 1597-1602), FeLV (Neil et al., Nature 308 (1984), 814-820), SAX (Kantoff et al., Proc. Natl. Acad. Sci. USA 83 (1986), 6563-6567), pDOL (Desiderio, J. Exp. Med. 167 (1988), 372-388), N2 (Kasid et al., Proc. Natl. Acad. Sci. USA 87 (1990), 473-477), LNL6 (Tiberghien et al., Blood 84 (1994), 1333-1341), pZipNEO (Chen et al., J. Immunol. 153 (1994), 3630-3638), LASN (Mullen et al., Hum. Gene Ther. 7 (1996), 1123-1129), pG1XsNa (Taylor et al., J. Exp. Med. 184 (1996), 2031-2036), LCNX (Sun et al., Hum. Gene Ther. 8 (1997), 1041-1048), SFG (Gallardo et al., Blood 90 (1997), LXSN (Sun et al., Hum. Gene Ther. 8 (1997), 1041-1048), SFG (Gallardo et al., Blood 90 (1997), 952-957), HMB-Hb-Hu (Vieillard et al., Proc. Natl. Acad. Sci. USA 94 (1997), 11595-11600), pMV7 (Cochlovius et al., Cancer Immunol. Immunother. 46 (1998), 61-66), pSTITCH (Weitjens et al., Gene Ther 5 (1998), 1195-1203), pLZR (Yang et al., Hum. Gene Ther. 10 (1999), 123-132), pBAG (Wu et al., Hum. Gene Ther. 10 (1999), 977-982), rKat.43.267bn (Gilham et al., J. Immunother. 25 (2002), 139-151), pLGSN (Engels et al., Hum. Gene Ther. 14 (2003), 1155-1168), pMP71 (Engels et al., Hum. Gene Ther. 14 (2003), 1155-1168), pGCSAM (Morgan et al., J. Immunol. 171 (2003), 3287-3295), pMSGV (Zhao et al., J. Immunol. 174 (2005), 4415-4423), or pMX (de Witte et al., J. Immunol. 181 (2008), 5128-5136). Further, in the context of the present invention suitable lentiviral vectors for the expression of the chemokine receptor 6 (CXCR6) as encoded by the nucleic acid sequence of the present invention are, e.g. PL-SIN lentiviral vector (Hotta et al., Nat Methods. 6(5) (2009), 370-376), p156RRL-sinPPT-CMV-GFP-PRE/Nhel (Campeau et al., PLoS One 4(8) (2009), e6529), pCMVR8.74 (Addgene Catalogoue No.:22036), FUGW (Lois et al., Science 295(5556) (2002), 868-872, pLVX-EF1 (Addgene Catalogue No.: 64368), pLVE (Brunger et al., Proc Natl Acad Sci USA 111(9) (2014), E798-806), pCDH1-MCS1-EF1 (Hu et al., Mol Cancer Res. 7(11) (2009), 1756-1770), pSLIK (Wang et al., Nat Cell Biol. 16(4) (2014), 345-356), pLJM1 (Solomon et al., Nat Genet. 45(12) (2013), 1428-30), pLX302 (Kang et al., Sci Signal. 6(287) (2013), rs13), pHR-IG (Xie et al., J Cereb Blood Flow Metab. 33(12) (2013), 1875-85), pRRLSIN (Addgene Catalogoue No.: 62053), pLS (Miyoshi et al., J Virol. 72(10) (1998), 8150-8157), pLL3.7 (Lazebnik et al., J Biol Chem. 283(7) (2008), 11078-82), FRIG (Raissi et al., Mol Cell Neurosci. 57 (2013), 23-32), pWPT (Ritz-Laser et al., Diabetologia. 46(6) (2003), 810-821), pBOB (Man et al., J Mol Neurosci. 22(1-2) (2004), 5-11), or pLEX (Addgene Catalogue No.: 27976). The invention also relates to (a) transduced T cell(s), preferably (a) CD8+ T cell(s), (a) CD4+ T cell(s), (a) CD3+ T cell(s), (a) γδ T cell(s) or (a) natural killer (NK) T cell(s), most preferably (a) CD8+ T cell(s), expressing a chemokine receptor 6 (CXCR6) encoded by a nucleic acid sequence of the present invention. Accordingly, the invention refers to (a) T cell(s), preferably (a) CD8+ T cell(s), (a) CD4+ T cell(s), (a) CD3+ T cell(s), (a) γδ T cell(s) or (a) natural killer (NK) T cell(s), most preferably (a) CD8+ T cell(s), transduced with a vector expressing a chemokine receptor (CXCR6) encoded by a nucleic acid sequence selected from the group consisting of (a) a nucleic acid sequence of SEQ ID NO: 1 (human) or 3 (murine/mouse); and (b) a nucleic acid sequence, which is at least 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the sequence of SEQ ID NO: 1 (human) or 3 (murine/mouse) and which is characterized by having a chemokine receptor 6 (CXCR6) activity. Accordingly, in the context of the present, the transduced T cell(s) may comprise a nucleic acid sequence of the present invention encoding the chemokine receptor 6 (CXCR6) or a vector of the present invention, which expresses a chemokine receptor 6 (CXCR6) as encoded by a nucleic acid sequence of the present invention. Thus, in the context of the present invention the transduced T cell relates to a transduced T cell, preferably a CD8+ T cell, CD4+ T cell, a CD3+ T cell, a γδ T cell or a natural killer (NK) T cell, most preferably a CD8+ T cell, expressing a chemokine receptor 6 (CXCR6) encoded by a nucleic acid sequence selected from the group consisting of: (a) a nucleic acid sequence of SEQ ID NO: 1 (human) or 3 (murine/mouse); and (b) a nucleic acid sequence, which is at least 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the sequence of SEQ ID NO: 1 (human) or 3 (murine/mouse) and which is characterized by having a chemokine receptor 6 (CXCR6) activity. In the context of the present, the term “transduced T cell” relates to a genetically modified T cell (i.e. a T cell wherein a nucleic acid molecule has been introduced deliberately). The herein provided transduced T cell may comprise the vector of the present invention. In the context of the present invention, the term “transduced T cell” refers to (a) T cell(s), preferably (a) CD8+ T cell(s), (a) CD4+ T cell(s), (a) CD3+ T cell(s), (a) γδ T cell(s) or (a) natural killer (NK) T cell(s), most preferably (a) CD8+ T cell(s), which is (are) characterized by not expressing a chemokine receptor 6 (CXCR6) encoded by a nucleic acid sequence selected from the group consisting of (a) a nucleic acid sequence of SEQ ID NO: 1 (human) or 3 (murine/mouse); and (b) a nucleic acid sequence, which is at least 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the sequence of SEQ ID NO: 1 (human) or 3 (murine/mouse) and which is characterized by having a chemokine receptor 6 (CXCR6) activity. Preferably, the herein provided transduced T cell comprises the nucleic acid sequence of the present invention encoding the chemokine receptor 6 (CXCR6) and/or the vector of the present invention. The transduced T cell of the invention may be a T cell, which transiently or stably expresses the foreign DNA (i.e. the nucleic acid molecule, which has been introduced into the T cell). In particular, the nucleic acid sequence of the present invention encoding the chemokine receptor 6 (CXCR6) can be stably integrated into the genome of the T cell by using a retroviral or lentiviral transduction. By using mRNA transfection, the nucleic acid molecule of the present invention encoding the CXCR6 described herein may be expressed transiently. Preferably, the herein provided transduced T cell has been genetically modified by introducing a nucleic acid molecule in the T cell via a viral vector (e.g. a retroviral vector or a lentiviral vector). The expression can be constitutive or constitutional, depending on the system used. The chemokine receptor 6 (CXCR6) is a seven transmembrane receptor thereby only a part of the receptor is accessible from the intracellular spaced. Once transduced in T cells, CXCR6 expression on the surface of the transduced T cell can be detected by flow cytometry or microscopy, using anti-CXCR6 antibodies. Antibodies for the detection of CXCR6 are extensively described in the literature and are commercially available. Exemplarily, anti-CXCR6 antibodies are available from R&D Systems, Inc., MN, USA under the catalogue number “MAB699”. A full list of all commercially available anti-CXCR6 antibodies can be found at the Biocompare homepage (see http://www.biocompare.com/pfu/110447/soids/321781/Antibodies/CXCR6). T cells are cells of the adaptive immune system recognizing their target in an antigen specific manner. These cells are characterized by surface expression of CD3 and a T cell receptor (TCR), recognizing a cognate antigen in the context of major histocompatibility complexes (MHC). T cells may be further subdivided in CD4+ or CD8+ T cells. CD4+ T cells recognize an antigen through their TCR in the context of MHC class II molecules which are predominantly expressed by antigen-presenting cells. CD8+ T cells recognize their antigen in the context of MHC class I molecules which are present on most cells of the human body. While the main function of CD4+ T cells is to provide “help”, i.e. costimulatory factors to other antigen-specific cells such CD8+ T cells, CD8+ are directly cytotoxic to the target cell after TCR engagement. Methods for detecting CD4+ and CD8+ T cells are well known to those skilled in the art and include flow cytometry, microscopy, immunohistochemistry, RT-PCR or western blot (Kobold, J Natl Cancer Inst (2015), 107; Kobold, J Natl Cancer Inst 107 (2015), 364). The transduced T cell(s) of the present invention may be, e.g., (a) CD8+ T cell, (a) CD4+ T cell(s), (a) γδ T cell(s) or (a) natural killer (NK) T cell(s). Preferably, the transduced T cell of the present invention is (are) (a) transduced CD8+ T cell(s), (a) transduced CD4+ T cell(s), (a) γδ T cell(s) or (a) natural killer (NK) T cell(s), more preferably the transduced T cell(s) of the present invention is (are) (a) transduced CD8+ T cell(s) or (a) transduced CD4+ T cell(s), most preferably the transduced T cell is (are) (a) CD8+ T cell(s). Accordingly, in the context of the present invention, the transduced T cell is (are) most preferably (a) CD8+ T cell(s). Further, in the context of the present invention, it is also preferred that the transduced T cell(s) is (are) (an) autologous T cell(s). Accordingly, in the context of the present invention, the transduced T cell is (are) preferably (a) transduced autologous CD8+ T cell(s), (a) transduced autologous CD4+ T cell(s), (a) transduced autologous γδ T cell or (a) transduced autologous natural killer (NK) T cell(s). In addition to the use of (an) autologous T cell(s) isolated from the subject, the present invention also comprehends the use of (an) allogeneic T cell(s). Accordingly, in the context of the present invention the transduced T cell may also be an allogeneic T cell, such as a transduced allogeneic CD8+ T cell. The use of allogeneic T cells is based on the fact that these cells can recognize a specific antigen epitope presented by foreign antigen-presenting cells (APC), provided that the APC express the MHC molecule, class I or class II, to which the specific responding cell population, i.e. T cell population is restricted, along with the antigen epitope recognized by the T cells. An “allogeneic T cell” is a T cell, of which the donor is of the same species as the recipient but genetically not identical with the recipient. Thus, the term allogeneic refers to cells coming from an unrelated donor individual/subject, which has human leukocyte antigen (HLA) compatible to the individual/subject, which will be treated by e.g. the herein described CXCR6 expressing transduced T cell. An “Autologous T cell” refers to (a) T cell(s), which is (are) isolated/obtained as described herein above from the subject to be treated with the transduced T cell described herein. Accordingly, (an) “autologous T cell(s)” is (are) (a) T cell(s), wherein donor and recipient is the same individual. As described above, the transduced T cell(s) of the present invention is (are) transduced with a nucleic acid sequence expressing the herein provided chemokine receptor 6 (CXCR6). In the case of (a) cell(s) bearing natural anti-tumoral specificity such as tumor-infiltrating lymphocyte cells (TIL, Dudley et al., J Clin Oncol. 31(17) (2013), 2152-2159 (doi: 10.1200/JCO.2012.46.6441)) or (an) antigen-specific cell(s) sorted from the peripheral blood of patients for their tumor-specificity by flow cytometry (Hunsucker et al., Cancer Immunol Res. 3(3) (2015), 228-235 (doi: 10.1158/2326-6066.CIR-14-0001)), the cell(s) described herein would only be transduced with the chimeric receptor 6 (CXCR6) of the present invention. However, the transduced T cell(s) of the invention may be co-transduced with further nucleic acid molecules, e.g. with a nucleic acid sequence encoding a T cell receptor or a chimeric antigen receptor. In accordance with this invention, the term “T cell receptor” is commonly known in the art. In particular, herein the term “T cell receptor” refers to any T cell receptor, provided that the following three criteria are fulfilled: (i) tumor specificity, (ii) recognition of (most) tumor cells, which means that an antigen or target should be expressed in (most) tumor cells and (iii) that the TCR matches to the HLA-type of the subject to be treated. In this context, suitable T cell receptors, which fulfill the above mentioned three criteria are known in the art such as receptors recognizing WT1 (Wilms tumor specific antigen 1; for sequence information(s) see, e.g., Sugiyama, Japanese Journal of Clinical Oncology 40 (2010), 377-87), MAGE (for sequence see, e.g., WO-A1 2007/032255 and PCT/US2011/57272), SSX (U.S. Provisional Application No. 61/388,983), NY-ESO-1 (for sequence information(s) see, e.g., PCT/GB2005/001924) and/or HER2neu (for sequence information(s) see WO-A1 2011/0280894). The term “chimeric antigen receptor” or “chimeric receptor” is known in the art and refers to a receptor constituted of an extracellular portion of a single chain antibody domain fused by a spacer sequence to the signal domains of CD3z and CD28. Again, this chimeric antigen receptor should provide tumor specify and allow for the recognition of most tumor cells. Suitable chimeric receptors include: anti-EGFRv3-CAR (for sequence see WO-A1 2012/138475), anti-CD22-CAR (see WO-A1 2013/059593), anti-BCMA-CAR (see WO-A1 2013/154760), anti-CD19-CAR (see WO-A1 2012/079000 or US-A1 2014/0271635), anti-CD123-CAR (see US-A1 2014/0271582), anti-CD30-CAR (see WO-A1 2015/028444) or anti-Mesothelin-CAR (see WO-A1 2013/142034). The present invention also relates to a method for the production of (a) transduced T cell(s) expressing a chemokine receptor 6 (CXCR6) encoded by a nucleic acid sequence of the present invention, comprising the steps of transducing (a) T cell(s), preferably (a) CD8+ T cell(s), (a) CD4+ T cell(s), (a) γδ T cell(s) or (a) natural killer (NK) T cell(s), most preferably (a) CD8+ T cell(s), with a vector of the present invention, culturing the transduced T cell(s) under conditions allowing the expressing of the CXCR6 in or on said transduced T cell(s) and recovering said transduced T cell(s). In the context of the present invention, the transduced T cell(s) of the present invention is (are) preferably produced by/obtainable by the following process: (a) T cell(s), preferably (a) CD8+ T cell(s), (a) CD4+ T cell(s), (a) γδ T cell(s) or (a) natural killer (NK) T cell(s), most preferably (a) CD8+ T cell(s) is (are) isolated/obtained from a subject, preferably a human patient. Methods for isolating/obtaining (a) T cell(s), preferably (a) CD8+ T cell(s), (a) CD4+ T cell(s), (a) γδ T cell(s) or (a) natural killer (NK) T cell(s), most preferably (a) CD8+ T cell(s) from (a) patient(s) or from (a) donor(s) is (are) well known in the art and in the context of the present invention the T cell(s), preferably CD8+ T cell(s), CD4+ T cell(s), γδ T cell(s) or natural killer (NK) T cell(s), most preferably CD8+ T cell(s) from (a) subject(s)/patient(s) or from (a) donor(s) may be isolated by blood draw or removal of bone marrow. After isolating/obtaining (a) T cell(s) as a sample of the subject(s)/patient(s) or donor(s), the T cell(s) is (are) separated from the other ingredients of the sample. Several methods for separating T cell(s) from the sample is (are) known and include, without being limiting, e.g. leukapheresis for obtaining (a) T cell(s) from the peripheral blood sample from a patient or from a donor, isolating/obtaining T cells by using a FACSort apparatus, picking living of dead T cell(s) from fresh biopsy specimens harboring (a) living T cell(s) by hand or by using a micromanipulator (see, e.g., Dudley, Immunother. 26 (2003), 332-342; Robbins, Clin. Oncol. 29 (201 1), 917-924 or Leisegang, J. Mol. Med. 86 (2008), 573-58). Herein the term “fresh patient biopsy” refers to tissue, preferably tumor tissue, removed from a subject by surgical or any other known means as well as (a) tumor cell line(s) or (an) (isolated) cell(s) from a tumor tissue/tumor cell. The isolated/obtained T cell(s), preferably CD8+ T cell(s), CD4+ T cell(s), γδ T cell(s) or natural killer (NK) T cell(s), most preferably CD8+ T cell(s), is (are) subsequently cultivated and expanded, e.g., by using an anti-CD3 antibody, by using anti-CD3 and anti-CD28 monoclonal antibodies and/or by using an anti-CD3 antibody, an anti-CD28 antibody and in the presence of cytokines, e.g. interleukin-2 (IL-2) and/or interleukin-15 (IL-15) (see, e.g., Dudley, Immunother. 26 (2003), 332-342 or Dudley, Clin. Oncol. 26 (2008), 5233-5239). In a subsequent step the T cell(s) is (are) artificially/genetically modified/transduced by methods known in the art (see, e.g., Lemoine, J Gene Med 6 (2004), 374-386). Methods for transducing (a) cell(s), particularly (a) T cell(s), is (are) known in the art and include, without being limited, in a case where nucleic acid or a recombinant nucleic acid is transduced, for example, an electroporation method, calcium phosphate method, cationic lipid method or liposome method. The nucleic acid to be transduced can be conventionally and highly efficiently transduced by using a commercially available transfection reagent, for example, Lipofectamine (manufactured by Invitrogen, catalogue no.: 11668027). In a case where a vector is used, the vector can be transduced in the same manner as the above-mentioned nucleic acid as long as the vector is a plasmid vector (i.e. a vector that is not a viral vector In the context of the present invention, the methods for transducing (a) T cell(s) include(s) retroviral or lentiviral T cell transduction as well as mRNA transfection. “mRNA transfection” refers to a method well known to those skilled in the art to transiently express a protein of interest, like in the present case the CXCR6, in (a) T cell(s) to be transduced. In brief (a) T cell(s) may be electroporated with the mRNA coding for the CXCR6 described herein by using an electroporation system (such as e.g. Gene Pulser, Bio-Rad) and thereafter cultured by standard cell (e.g. T cell) culture protocol as described above (see Zhao et al., Mol Ther. 13(1) (2006), 151-159.) Preferably, the transduced T cell(s) of the invention is (are) (a) CD8+ T cell(s), (a) CD4+ T cell(s), (a) γδ T cell(s) or (a) natural killer (NK) T cell(s), ormost preferably (a) CD8+ T cell(s), and is (are) generated by lentiviral, or most preferably retroviral T cell transduction. In this context, suitable retroviral vectors for transducing (a) T cell(s) is (are) known in the art such as SAMEN CMV/SRa (Clay et al., J. Immunol. 163 (1999), 507-513), LZRS-id3-IHRES (Heemskerk et al., J. Exp. Med. 186 (1997), 1597-1602), FeLV (Neil et al., Nature 308 (1984), 814-820), SAX (Kantoff et al., Proc. Natl. Acad. Sci. USA 83 (1986), 6563-6567), pDOL (Desiderio, J. Exp. Med. 167 (1988), 372-388), N2 (Kasid et al., Proc. Natl. Acad. Sci. USA 87 (1990), 473-477), LNL6 (Tiberghien et al., Blood 84 (1994), 1333-1341), pZipNEO (Chen et al., J. Immunol. 153 (1994), 3630-3638), LASN (Mullen et al., Hum. Gene Ther. 7 (1996), 1123-1129), pG1XsNa (Taylor et al., J. Exp. Med. 184 (1996), 2031-2036), LCNX (Sun et al., Hum. Gene Ther. 8 (1997), 1041-1048), SFG (Gallardo et al., Blood 90 (1997), LXSN (Sun et al., Hum. Gene Ther. 8 (1997), 1041-1048), SFG (Gallardo et al., Blood 90 (1997), 952-957), HMB-Hb-Hu (Vieillard et al., Proc. Natl. Acad. Sci. USA 94 (1997), 11595-11600), pMV7 (Cochlovius et al., Cancer Immunol. Immunother. 46 (1998), 61-66), pSTITCH (Weitjens et al., Gene Ther 5 (1998), 1195-1203), pLZR (Yang et al., Hum. Gene Ther. 10 (1999), 123-132), pBAG (Wu et al., Hum. Gene Ther. 10 (1999), 977-982), rKat.43.267bn (Gilham et al., J. Immunother. 25 (2002), 139-151), pLGSN (Engels et al., Hum. Gene Ther. 14 (2003), 1155-1168), pMP71 (Engels et al., Hum. Gene Ther. 14 (2003), 1155-1168), pGCSAM (Morgan et al., J. Immunol. 171 (2003), 3287-3295), pMSGV (Zhao et al., J. Immunol. 174 (2005), 4415-4423), or pMX (de Witte et al., J. Immunol. 181 (2008), 5128-5136). In the context of the present invention, suitable lentiviral vector for transducing T cells are, e.g. PL-SIN lentiviral vector (Hotta et al., Nat Methods. 6(5) (2009), 370-376), p156RRL-sinPPT-CMV-GFP-PRE/Nhel (Campeau et al., PLoS One 4(8) (2009), e6529), pCMVR8.74 (Addgene Catalogoue No.:22036), FUGW (Lois et al., Science 295(5556) (2002), 868-872, pLVX-EF1 (Addgene Catalogue No.: 64368), pLVE (Brunger et al., Proc Natl Acad Sci USA 111(9) (2014), E798-806), pCDH1-MCS1-EF1 (Hu et al., Mol Cancer Res. 7(11) (2009), 1756-1770), pSLIK (Wang et al., Nat Cell Biol. 16(4) (2014), 345-356), pLJM1 (Solomon et al., Nat Genet. 45(12) (2013), 1428-30), pLX302 (Kang et al., Sci Signal. 6(287) (2013), rs13), pHR-IG (Xie et al., J Cereb Blood Flow Metab. 33(12) (2013), 1875-85), pRRLSIN (Addgene Catalogoue No.: 62053), pLS (Miyoshi et al., J Virol. 72(10) (1998), 8150-8157), pLL3.7 (Lazebnik et al., J Biol Chem. 283(7) (2008), 11078-82), FRIG (Raissi et al., Mol Cell Neurosci. 57 (2013), 23-32), pWPT (Ritz-Laser et al., Diabetologia. 46(6) (2003), 810-821), pBOB (Man et al., J Mol Neurosci. 22(1-2) (2004), 5-11), or pLEX (Addgene Catalogue No.: 27976). The transduced T cell/T cells of the present invention is/are preferably grown under controlled conditions, outside of their natural environment. In particular, the term “culturing” means that cells (e.g. the transduced T cell(s) of the invention), which are derived from multi-cellular eukaryotes, preferably from a human patient, are grown in vitro. Culturing cells is a laboratory technique of keeping cells alive, which are separated from their original tissue source. Herein, the transduced T cell(s) of the present invention is (are) cultured under conditions allowing the expression of the CXCR6 described herein in or on said transduced T cell(s). Conditions that allow the expression or a transgene (i.e. of the CXCR6 described herein) are commonly known in the art and include, e.g., agonistic anti-CD3- and anti-CD28 antibodies and the addition of cytokines such as interleukin 2 (IL-2), interleukin 7 (IL-7), interleukin 12 (IL-12) and/or interleukin 15 (IL-15). After expression of the CXCR6 described herein in the cultured transduced T cell(s), the transduced T cell(s) is (are) recovered (i.e. re-extracted) from the culture (i.e. from the culture medium). Also encompassed by the invention is (are) (a) transduced T cell(s) expressing a chemokine receptor 6 (CXCR6) as encoded by a nucleic acid molecule of the invention produced by/obtainable by the method of the present invention. Furthermore, the invention provides a pharmaceutical composition/medicament comprising (a) transduced T cell(s) expressing a chemokine receptor 6 (CXCR6) encoded by a nucleic acid sequence of the present invention or a transduced T cell as obtained by/produced by the method disclosed above. In the context of the present invention, said composition is a pharmaceutical composition further comprising, optionally, suitable formulations of carrier, stabilizers and/or excipients. In accordance with the present invention, the term “medicament” is used interchangeably with the term “pharmaceutical composition” and relates to a composition for administration to a patient, preferably a human patient. Accordingly, the invention provides (a) transduced T cell(s), preferably (a) CD8+ T cell(s), (a) CD4+ T cell(s), (a) γδ T cell(s) or (a) natural killer (NK) T cell(s), most preferably (a) CD8+ T cell(s), expressing a chemokine receptor 6 (CXCR6) as encoded by a nucleic acid molecule of the invention, or produced/obtainable by the method of the present invention for use as a medicament. In the context of the present invention that medicament/pharmaceutical composition is to be administered to a patient from which the transduced T cell(s) was (were) isolated/obtained. In the context of the present invention, the patient refers to a human patient. Furthermore, in the context of the present invention that patient suffers from a disease characterized by CXCL16 overexpression. In the context of the present invention diseases that are characterized by CXCL16 overexpression are known in the art and include e.g. colorectal cancer (Wagsater et al., Int J Mol Med. 14(1) (2004), 65-69), brain cancer (Ludwig et al., J Neurochem. 93(5) (2005), 1293-1303), ovarian cancer (Son et al., Cancer Biol Ther. 6(8) (2007), 1302-1312), prostate cancer (Lu et al., Mol Cancer Res. 6(4) (2008), 546-554), pancreatic cancer (Wente et al., Int J Oncol. 33(2) (2008), 297-308), breast cancer (Matsumura et al., J Immunol. 181(5) (2008), 3099-3107), renal cancer (Gutwein et al., Eur J Cancer. 45(3) (2009), 478-89), nasopharyngeal carcinoma (Parsonage et al., Am J Pathol. 180(3) (2012), 1215-22), hepatocellular carcinoma (Gao et al., Cancer Res. 72(14) (2012), 3546-3556), gastric cancer (Xing et al., Hum Pathol. 43(12) (2012), 2299-2307), cervical cancer (Huang et al., Chin J Cancer. 32(5) (2013), 289-296), bladder cancer (Lee et al., Oncol Lett. 5(1) (2013), 229-235), lymphoma (Liu et al., Oncol Rep. 30(2) (2013), 783-792), sarcoma (Na et al., Hum Pathol. 45(4) (2014), 753-760), or lung cancer (Hu et al., PLoS One. 9(6) (2014), e990562014). Accordingly, in the context of the present invention, the disease characterized by CXCL16 overexpression refers in the context of the present invention to a disease selected from the group consisting of colorectal cancer, brain cancer, ovarian cancer, prostate cancer, pancreatic cancer, breast cancer, renal cancer, nasopharyngeal carcinoma, hepatocellular carcinoma, gastric cancer, cervical cancer, bladder cancer, lymphoma, sarcoma, and lung cancer. In the context of the present invention the pharmaceutical composition that comprises (a) transduced T cell(s) of the present invention or (a) transduced T cell(s) produced by/obtainable by the method of the present invention is (are) to be administered in combination intervening treatment protocols. Examples of such intervening treatment protocols include but are not limited to, administration of pain medications, administration of chemotherapeutics, surgical handling of the disease or a symptom thereof. Accordingly the treatment regimens as disclosed herein encompass the administration of the transduced T cell(s) expressing a CXCR6 as described herein together with none, one, or more than one treatment protocol suitable for the treatment or prevention of a disease, or a symptom thereof, as described herein or as known in the art. Accordingly, in the context of the present invention transduced T cell(s) expressing the chemokine receptor 6 (CXCR6) as encoded by a nucleic acid sequence of the present invention can be used for the treatment of a proliferative disease, preferably cancer. More preferably, the herein provided transduced T cell(s) expressing the chemokine receptor 6 (CXCR6) as described herein is (are) used for the treatment of a disease (preferably a cancer), which is characterized by CXCL16 overexpression. Cancer types that are preferably treated with the herein provided transduced T cell expressing the chemokine receptor 6 (CXCR6) are described herein above. Thus, the transduced T cell(s) expressing a chemokine receptor 6 (CXCR6) encoded by a nucleic acid sequence described herein can be used in a method of treating any disease where tumor cells over-express CXCL16. The treatment method preferably involves cell collection by a method described above like isolating/collection of the cells by blood draw or removal of bone marrow. Subsequently, the isolated cell(s) is (are) modified virally or by mRNA electroporation with the fusion receptor (and optionally co-transduced with further nucleic acid molecules, e.g. with a nucleic acid sequence encoding (a) T cell receptor(s) or (a) chimeric receptor(s)). After cell expansion, as outlined above, the transduced T cell(s), preferably CD8+ T cell(s), CD4+ T cell(s), γδ T cell(s) or natural killer (NK) T cell(s), most preferably CD8+ T cell(s), is (are) transferred intravenously back to the patient. Moreover, the present invention provides a method for the treatment of diseases comprising the steps of isolating (a) T cell(s), preferably (a) CD8+ T cell(s), (a) CD4+ T cell(s), (a) γδ T cells or (a) natural killer (NK) T cell(s), most preferably (a) CD8+ T cell(s), from a subject, transducing said isolated T cell(s) with a nucleic acid encoding the chemokine receptor 6 (CXCR6) as described herein above, co-transducing said isolated T cell(s) with further nucleic acid molecules, e.g. with a nucleic acid sequence encoding (a) T cell receptor or (a) chimeric receptor(s) as described above, expanding the transduced T cell(s), and administering the transduced T cell(s) back to said subject. This treatment method described herein may be repeated e.g. one or two times per week The invention also relates to a method for treatment of a disease characterized by CXCL16 overexpression in a subject comprising the steps of (a) isolating (a) T cell(s), preferably (a) CD8+ T cell(s), (a) CD4+ T cell(s), (a) γδ T cell(s) or (a) natural killer (NK) T cell(s), most preferably (a) CD8+ T cell(s), from a subject; (b) transducing said isolated (a) T cell(s), e.g., (a) CD8+ T cell(s), with a vector comprising a nucleic acid sequence selected from the group consisting of: (i) a nucleic acid sequence of SEQ ID NOs: 1 or 3, and (ii) a nucleic acid sequence, which is at least 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the sequence of SEQ ID NOs: 1 or 3 and which is characterized by having a chemokine receptor 6 (CXCR6) activity; and (c) administering said transduced T cell(s), e.g. CD8+ T cell(s), to said subject. In the context of the present invention, said transduced T cell(s), e.g., CD8+ T cell(s), is (are) administered to said subject by intravenous infusion. Moreover, the present invention provides a method for the treatment of a disease characterized by CXCL16 overexpression comprising the steps of (a) isolating (a) T cell(s), preferably (a) CD8+ T cell(s), (a) CD4+ T cell(s), (a) γδ T cell(s) or (a) natural killer (NK) T cell(s), most preferably (a) CD8+ T cell(s), from a subject; (b) transducing said isolated T cell(s), e.g., (a) CD8+ T cell(s), with a vector comprising a nucleic acid sequence selected from the group consisting of: (i) a nucleic acid sequence of SEQ ID NOs: 1 or 3, and (ii) a nucleic acid sequence, which is at least 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the sequence of SEQ ID NOs: 1 or 3 and which is characterized by having a chemokine receptor 6 (CXCR6) activity; and (c) co-transducing said isolated T cell(s), e.g., (a) CD8+ T cell(s), with (a) T cell receptor(s); (d) expanding the T cell(s), e.g., (a) CD8+ T cell(s), by, e.g., anti-CD3 and anti-CD28 antibodies; and (e) administering the transduced T cell(s), e.g. CD8+ T cell(s), to said subject. The terms “treatment”, “treating” and the like are used herein to generally mean obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of partially or completely curing a disease and/or adverse effect attributed to the disease. The term “treatment” as used herein covers any treatment of a disease in a subject and includes: (a) preventing and/or ameliorating a proliferative disease (preferably cancer) from occurring in a subject that may be predisposed to the disease; (b) inhibiting the disease, i.e. arresting its development, like the inhibition cancer progression; or (c) relieving the disease, i.e. causing regression of the disease, like the repression of cancer. Preferably, the term “treatment” as used herein relates to medical intervention of an already manifested disorder, like the treatment of a diagnosed cancer. For the purposes of the present invention the “subject” (or “patient”) may be a vertebrate. In context of the present invention, the term “subject” includes both humans and other animals, particularly mammals, and other organisms. Thus, the herein provided methods are applicable to both human therapy and veterinary applications. Accordingly, said subject may be an animal such as a mouse, rat, hamster, rabbit, guinea pig, ferret, cat, dog, chicken, sheep, bovine species, horse, camel, or primate. Preferably, the subject is a mammal. Most preferably the subject is a human being. As described above, the present invention relates to a “pharmaceutical composition” comprising the herein provided transduced T cell expressing the chemokine receptor 6 (CXCR6) described herein (encoded by the nucleic acid molecule of the present invention). Said pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, excipient and/or diluent. Examples of suitable pharmaceutical carriers are well known in the art and include phosphate buffered saline solutions, water, emulsions, such as oil/water emulsions, various types of wetting agents, sterile solutions etc. The carrier may be a solution that is isotonic with the blood of the recipient. Compositions comprising such carriers can be formulated by well known conventional methods. The dosage regimen will be determined by the attending physician and clinical factors. As is well known in the medical arts, dosages for any one patient depends upon many factors, including the patient's size, body surface area, age, the particular compound to be administered, sex, time and route of administration, general health, and other drugs being administered concurrently. For example, the pharmaceutical composition of the invention may be administered to the subject at a dose of 104 to 1010 T cells/kg body weight, preferably 105 to 106 T cells/kg body weight. In the context of the present invention the pharmaceutical composition may be administered in such a way that an upscaling of the T cells to be administered is performed by starting with a subject dose of about 105 to 106 T cells/kg body weight and then going up to dose of 1010 T cells/kg body weight. The pharmaceutical composition of the invention may be administered intravenously (i.e. by intravenous infusion) but also intraperitoneally, intrapleurally, intrathecally, subcutaneously or intranodally. Intravenous carriers include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like preservatives and other additives may also be present in the pharmaceutical composition of the present invention, such as, e.g., antimicrobials, anti-oxidants, chelating agents, inert gases and the like. The pharmaceutical composition of the present invention may be used in co-therapy in conjunction with, e.g., molecules capable of providing an activation signal for immune effector cells, for cell proliferation or for cell stimulation. Said molecule may be, e.g., a further primary activation signal for T cells (e.g. a further costimulatory molecule: molecules of B7 family, Ox40L, 4.1 BBL, CD40L, anti-CTLA-4, anti-PD-1), or a further cytokine interleukin (e.g., IL-2). In context of the present invention, the components of the pharmaceutical composition to be used for therapeutic administration are preferably sterile. Sterility may readily be accomplished by, e.g., filtration through sterile filtration membranes (e.g., 0.2 micron membranes). The pharmaceutical composition of the present invention may be prepared by contacting the components of the pharmaceutical composition uniformly with liquid carriers. After its production, the pharmaceutical composition of the invention may be placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle. The invention also relates to a method for the treatment of diseases that are characterized by overexpressing CXCL16 such as, e.g., colorectal cancer, brain cancer, ovarian cancer, prostate cancer, pancreatic cancer, breast cancer, renal cancer, nasopharyngeal carcinoma, hepatocellular carcinoma, gastric cancer, cervical cancer, bladder cancer, lymphoma, sarcoma, or lung cancer comprising the administration of a transduced T cell as described herein to a subject. In the context of the present invention, said subject is a human (as explained above). In the context of the present invention, a method for the treatment of a disease is described that comprises the steps of isolating (a) T cell(s), preferably (a) CD8+ T cell(s), (a) CD4+ T cell(s), (a) γδ T cell(s) or (a) natural killer (NK) T cell(s), most preferably (a) CD8+ T cell(s), from a subject, transducing said isolated T cell(s) with a nucleic acid encoding the chemokine receptor 6 (CXCR6) as described herein above or with a vector comprising a nucleic acid encoding the CXCR6 as described herein above, and administering the transduced T cells to said subject. In the context of the present invention, said transduced T cells are administered to said subject by intravenous infusion. Moreover, the present invention provides a method for the treatment of diseases comprising the steps of isolating T cells, preferably CD8+ T cells, CD4+ T cells, γδ T cells or natural killer (NK) T cells, most preferably CD8+ T cells, from a subject, transducing said isolated T cells with a nucleic acid encoding the chemokine receptor 6 (CXCR6) as described herein above, co-transducing said isolated T cell(s) with further nucleic acid molecules, e.g. with a nucleic acid sequence encoding (a) T cell receptor(s) or (a) chimeric receptor(s) as described above, expanding the transduced cells, and administering the transduced cells back to said subject. The above mentioned expanding step of the transduced T cell(s) may be performed in the presence of (stimulating) cytokines such as interleukin-2 (IL-2) and/or interleukin-15 (IL-15). In the context of the present invention, the expanding step may also be performed in the presence of interleukin-12 (IL-12), interleukin-7 (IL-7) and/or interleukin-21 (IL-21). In accordance with the present invention, the expanding step of the transduced T cell(s) may also be performed in the presence of anti-CD3 and/or anti-CD28 antibodies. As described herein, the present invention relates to a kit comprising the nucleic acid molecule of the invention, the vector of the invention and/or the transduced T cell(s) of the invention. In the context of the present invention, a kit for incorporating a nucleic acid sequence selected from the group consisting of (a) a nucleic acid sequence of SEQ ID NO: 1, and (b) a nucleic acid sequence, which is at least 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the sequence of SEQ ID NO: 1 and which is characterized by having a chemokine receptor 6 (CXCR6) activity into a CD8+ T cell comprising a vector of the present invention is provided. Thus, the herein provided treatment methods may be realized by using this kit. Advantageously, the kit of the present invention further comprises optionally (a) reaction buffer(s), storage solutions (i.e. preservatives), wash solutions and/or remaining reagents or materials required for the conduction of the assays as described herein. Furthermore, parts of the kit of the invention can be packaged individually in vials or bottles or in combination in containers or multicontainer units. In addition, the kit may contain instructions for use. The manufacture of the kit of the present invention follows preferably standard procedures, which are known to the person skilled in the art. As mentioned above, the kit provided herein is useful for treating a subject, preferably a human patient, which has a disease that is characterized by over-expression of CXCL16 such as, e.g., colorectal cancer, brain cancer, ovarian cancer, prostate cancer, pancreatic cancer, breast cancer, renal cancer, nasopharyngeal carcinoma, hepatocellular carcinoma, gastric cancer, cervical cancer, bladder cancer, lymphoma, sarcoma, or lung cancer. The Figures show FIG. 1: CXCL16 induction by pancreatic cancer cells Panc02-OVA and T110299 upon IFN-γ or TNF-α stimulation Tumor cells (i.e. pancreatic cancer cell lines Panc02-OVA and T110299) (0.01×106/well) were seeded in a 96-well plate (flat bottom) and stimulated with recombinant IFN-γ (20 ng/ml) or TNF-α (20 ng/ml) (Peprotech, Hamburg). Supernatants were harvested after 48 hours. CXCL16 secretion was measured with a CXCL16 ELISA kit (R&D Systems, Inc., MN, USA). As shown in the Figure, the pancreatic cancer cell lines Panc02-OVA and T110299 release CXCL16 in the presence and absence of IFN-γ and TNF-α in vitro. FIG. 2: Induction of CXCL16 from Panc02-OVA and T110299 pancreatic cancer cells upon co-culture with antigen-specific T cells The pancreatic cancer cell lines Panc02-OVA and T110299 (0.03×106/well) were co-cultured (0.03×106/well) with T cells (1:1-10:1 ratios) in 96-well plates (flat bottom). Supernatants were harvested after 48 hours. CXCL16 secretion was measured with a CXCL16 ELISA kit (R&D Systems, Inc., MN, USA). As shown in FIG. 2, the antigen recognition in the context of MHC by antigen-specific T cells (OVA-specific, OT-1 T cells) on the surface of pancreatic cancer cells Panc02-OVA and T110299 induces release of CXCL16 from the pancreatic cancer cells. FIG. 3: Expression of CXCL16 in Panc02-OVA and T110299 tumor bearing mice Expression of CXCL16 in tumor bearing mice was analyzed over time in different organs. Female C57BL/6J mice (4 per group) (Janvier, France (Cat. Number 2014-07-DE-RM-20)) were injected subcutaneously with Panc02-OVA (Jacobs et al. Int J Cancer 128 (2011), 128) or T110299 tumor cells (Düwell et al., Cell Death Differ 21(12) (2014), 1825-1837) at a concentration of 2×106 cells per mice. Organs and tumors were analyzed after one, two or three weeks of induction and frozen in liquid nitrogen. After determination of the protein content by the Bradford method (Bio Rad, München) CXCL16 expression was measured with a CXCL16 ELISA kit (R&D Systems, Inc., MN, USA). The tumor site was found to be the site with the highest CXCL16 expression both in Panc02-OVA and T110299 tumors. FIG. 4: Migration of CXCR6-transduced T cells towards a gradient of recombinant CXCL16 CXCR6 (SEQ ID NOs: 3 (cDNA); 4 (protein))-transduced CD8+ T cells and GFP-transduced CD8+ T cells were compared for their ability to migrate towards a CXCL16 gradient. Migration medium (0.5% BSA in RPMI medium) was used with or without recombinant CXCL16 (SEQ ID NO: 9; serial dilutions from 50 ng/ml to 3.125 ng/ml) (Peprotech, Hamburg) in the lower chamber and T cells in the upper chamber (1×106 cells/well) of a 96-transwell plate. After 3 hours migrated T cells were resuspended with counting beads (Life Techonologies, Carlsbad, Calif., USA) for quantification. Migratory capacity was analyzed as cell number and GFP expression by flow cytometry (BD FACS Canto II). As shown in FIG. 4, CXCR6 (SEQ ID NOs: 3 (cDNA); 4 (protein))-transduced T cells specifically and dose dependently migrate towards CXCL16, which is not seen in T cells which were only transduced with GFP (SEQ ID NOs: 11 (nucleic acid); 12 (protein)). FIG. 4B shows that the migration is specific as enrichment of GFP is only seen in CXCR6 transduced T cells. P-values are depicted in the Figure, ** indicates p<0.01 and *** p<0.001. FIG. 5: Migration of CXCR6- and GFP-transduced T cells towards pancreatic cancer cell supernatant Tumor cells (i.e. T110299 cells) were seeded in a 6 well plate (1×106 cells/well) and stimulated with recombinant IFN-γ and TNF-α (20 ng/ml) (Peprotech, Hamburg). After 48 hours, supernatants were incubated 30 min with or without anti-CXCL16 neutralizing antibody (2 μg/ml) (R&D Systems, Inc., MN, USA, polyclonal). CXCR6 (SEQ ID NOs: 3 (cDNA); 4 (protein))-transduced CD8+ T cells and CD8+ T cells which were only transduced with GFP (SEQ ID NOs: 11 (nucleic acid); 12 (protein)) were seeded at 1×106 cells/well. After 3 hours, migrated T cells were resuspended with counting beads (Life Techonologies, Carlsbad, Calif., USA) for quantification. Migration was quantified as cell number and GFP expression by flow cytometry. As shown in the FIG. 5A, CXCR6 (SEQ ID NOs: 3 (cDNA); 4 (protein))-transduced T cells migrate specifically towards supernatants of T110299 cells, which is not seen with GFP (SEQ ID NOs: 11 (nucleic acid/cDNA); 12 (protein))-transduced T cells. FIG. 5B shows that the migration is specific as enrichment of GFP is only seen in CXCR6 transduced T cells. P-values are depicted in the Figure, ** indicates p<0.01 and *** p<0.001. FIG. 6: Activation of CXCR6—in comparison to GFP-transduced T cells in co-culture with T110299 or Panc02-OVA tumor cells The pancreatic cancer cell lines Panc02-OVA and T110299 (1×104/well) were co-cultured with T cells (1:1 to 1:10 ratios) in 96-well plates (flat bottom). Supernatants were harvested after 3, 8, 12, 24, 30 and 36 hours of co-culture. Activation level was measured as IFN-γ secretion by ELISA (Becton Dickinson, Franklin Lakes, N.J., USA). As shown in FIGS. 6A and 6B, CXCR6 (SEQ ID NOs: 3 (cDNA); 4 (protein))-transduced T cells show enhanced recognition of T110299 and Panc02-OVA in comparison to GFP (SEQ ID NOs: 11 (nucleic acid/cDNA); 12 (protein))-transduced T cells. P-values are depicted in FIGS. 6A and 6B, * indicates p<0.05, ** p<0.01; *** p<0.001. FIG. 7: Lysis of Panc02-OVA tumor cells by CXCR6- versus GFP-transduced OT-1-T cells The pancreatic cancer cell line Panc02-OVA (3×105 cells/well) was co-cultured with CXCR6 (SEQ ID NOs: 3 (cDNA); 4 (protein))-transduced CD8+ T cells in 96-well plates (flat bottom). Supernatants were harvested after 5 hours of co-culture. Cytotoxicity was measured as LDH release (Promega Corporation, Madison, Wis., USA; see FIG. 7A), and activation level as IFN-γ secretion by ELISA (Becton Dickinson, Franklin Lakes, N.J., USA; see FIG. 7B). As shown in the Figure, CXCR6 (SEQ ID NOs: 3 (cDNA); 4 (protein))-transduced T cells have enhanced and T cell dose dependent lysis capacity of Panc02-OVA tumor cells in comparison to OT-1 T cells which were only transduced with GFP (SEQ ID NOs: 11 (nucleic acid/cDNA); 12 (protein)). The p-value is depicted in the Figure, ** indicates p<0.01. FIG. 8: Migration of CXCR6-transduced OT-1 T cells towards Panc02-OVA-CXCL16 cells and subsequent lysis of these tumor cells in comparison to GFP-transduced OT-1 T cells The pancreatic cancer cell line Panc02-OVA was transduced with CXCL16 (SEQ ID NOs: 7 (cDNA) and 8 (protein); the Uniprot entry number of murine/mouse CXCL16 is Q8BSU2 (accession number with the enzry number version 102 and version 2 of the sequence)). A 96-transwell plate was coated with polylysin (100 μg/ml/well) (Sigma Aldrich, Steinheim). Tumor cells (1×105/well) were seeded in the lower chamber and incubated for 12 hours. T cells (8×105 cells/well) were administered in the upper chamber. After 2 hours, migration was stopped by removing the upper chamber. After additional 2 hours tumor cell killing was stopped by measuring LDH and IFN-γ secretion by ELISA. For quantification of migration, T cells were stained with an APC labeled anti-CD8 antibody (Biolegend, San Diego, Calif., USA, clone 53-6.7) and resuspended with counting beads (Life Techonologies, Carlsbad, Calif., USA). Migration was analyzed as cell number and GFP expression by flow cytometry. As shown in FIG. 8A, CXCR6-transduced OT-1 T cells specifically migrate towards CXCL16 producing tumor cells. FIG. 8B demonstrates that the migration twords the CXCL16 tumor cells is specific. Subsequently, the migrated T cells lysed these tumor cells (as shown in FIG. 8C). Tumor lysis correlated with T cell activation as measured by IFNγ release (see FIG. 8D). Migration, killing and activation is superior to the activity of GFP-transduced T cells. P-values are depicted in the Figure, * indicates p<0.05, ** p<0.01; *** p<0.001 and ns non-significant. FIG. 9: Treatment of established Panc02-OVA tumors in mice with GFP- or CXCR6-transduced OT-1 T cells Female C57BL/6J Mice (5 per group) (Janvier, Frankreich, Cat. Number 2014-07-DE-RM-20) were injected with Panc02-OVA tumor cells (2×106/mice) subcutaneously. After 7 days, T cells were adoptively transferred through the tail vein (10×106 cells per mice). Therapeutic efficiency was measured as tumor growth every other day. As shown in the Figure, the treatment of established Panc02-OVA tumors with CXCR6-transduced OT-1 T cells leads to superior anti-tumoral activity compared to GFP-transduced OT-1 T cells. FIG. 10: CXCL16 production by BM-derived dendritic cells Bone marrow was isolated from a C57BL/6J mouse (Janvier, Frankreich, Cat. Number 2014-07-DE-RM-20) Bone marrow cells were cultured with recombinant GM-CSF (20 ng/ml) (Peprotech, Hamburg) for seven days. Bone marrow derived dendritic cells (BM-DC, 104 per well) were seeded in a 96-well plate (flat bottom) and stimulated with recombinant proteins (20 ng/ml) (TNF-α, IFN-γ or IL-4, Peprotech, Hamburg; or R848 Enzo Life Science, Lörrach). Supernatants were harvested after 48 hours. CXCL16 secretion was measured by ELISA (R&D Systems, Inc., MN, USA, polyclonal). As shown in the Figure, bone marrow-derived dendritic cells produce substantial amounts of CXCL16, which can be further enhanced by different stimuli. FIG. 11: Clustering of CXCR6- and pMX-transduced T cells to dendritic cells T cells were stained with two different PKH cell linker dyes (Sigma Aldrich, Steinheim). Staining efficiency was verified with flow cytometry. CXCR6 pos.T cells (3×104 cells per well) were diluted in a 1:1 ratio with control-transduced T cells. T cell numbers were equilibrated by resuspension of 1:1 diluted samples of T cells with counting beads (Life Techonologies, Carlsbad, Calif., USA) and quantification of stained viable cells by flow cytometry. BM-DC were stimulated with OVA257-264 peptide (SEQ ID NO: 10; 1 μg/ml) (Invivogen, San Diego, Calif., USA) and CpG (3 μg/ml) (Coley Pharmaceutical Group, Düsseldorf) in 96 well plates (3×103 per well) and co-cultured with T cells at a 1:10 ratio for 3 hours partly in the presence or absence of anti-ICAM1α antibody (0.5 mg/ml) (BioXCell, NH, USA, clone YNI.7.4) or anti-CXCL16 neutralizing antibody (10 μg/ml) (R&D Systems, Inc., MN, USA, polyclonal) for 3 hours. Cells were gently transferred to a glass-bottomed dish and used for confocal microscopy. Clusters were analyzed for the proportion of CXCR6GFP pos. T cells to control-transduced T cells. As shown in FIGS. 11A and 11B, CXCR6 (SEQ ID NOs: 3 (cDNA); 4 (protein))-transduced T cells show enhanced clustering ability to dendritic cells compared to pMX-transduced T cells. The pMX-vector is an empty retroviral vector, which does not hold any insert. This vector can be found at the Addgene homepage (see https://www.addgene.org/vector-database/3674/). The pMX-transduced T cells are published in Kitamura (2003) Tokyo Exp Hematol. 31(11):1007-14. Enhanced clustering capacity is CXCL16 but not ICAM-1 dependent. P-values are depicted in the Figure, * indicates p<0.05, ** p<0.01; *** p<0.001 and ns non-significant. FIG. 12: Activation of CXCR6- and GFP-transduced OT-1 T cells in the presence of dendritic cells Co-culture of BM-DC cells (5×103 per well) with CXCR6GFP-transduced T cells or with GFP-transduced T cells (1:1 to 1:10 ratios) were performed in 96 well plates (flat bottom) in the presence of OVA257-264 peptide (1 μg/ml) (Invivogen, San Diego, Calif., USA). Supernatants were harvested after 2, 4 and 6 hours. IFN-γ secretion was measured by ELISA (Becton Dickinson, Franklin Lakes, N.J., USA). As shown in the Figure, CXCR6 (SEQ ID NOs: 3 (cDNA); 4 (protein))-transduced T cells display enhanced activation capacity by dendritic cells compared to GFP (SEQ ID NOs: 11 (cDNA); 12 (protein))-transduced T cells. FIG. 13: Expression of CXCR6 in Panc02-OVA tumor bearing mice Expression of CXCR6 in tumor bearing mice was analyzed in different organs, i.e. spleen, tumor-contralateral lymph node (LNk), tumor, kidney, tumor-ipsilateral lymph node (LNi) and lung and blood to peripheral blood cells. Female C57BL/6J mice (3 per group) (Janvier, France (Cat. Number 2014-07-DE-RM-20)) were injected subcutaneously with Panc02-OVA tumor cells (Jacobs et al. Int J Cancer 128 (2011) at a concentration of 2×106 per mice. Organs and tumors were isolated and processed on day 20 of induction. The tested spleen, tumor-contralateral lymph node (LNk), tumor, kidney, tumor-ipsilateral lymph node (LNi) and lung organs refer to single cell suspensions as obtained from wild type C57BL/6J mice of the corresponding organ or blood to peripheral blood cells from the C57BL/6J mice. For flow cytometric analysis, cells were stained with the following antibodies: (1.) Lymphoid panel: FITC-conjugated anti-mouse CD3e (clone 17A2, BioLegend, San Diego, Calif., USA), PE-conjugated anti-mouse CD4 (clone GK1.5, BioLegend, San Diego, Calif., USA), Pacific Blue-conjugated CD8a (clone 53-6.7, BioLegend, San Diego, Calif., USA), PerCp-Cy5.5-conjugated CD19 (clone 6D5, BioLegend, San Diego, Calif., USA) and PE-Cy7-conjugated NKp46 (clone 29A1.4, BioLegend, San Diego, Calif., USA). (2.) Myeloid panel: PE-Cy7-conjugated NKp46, APC-Cy7-conjugated CD11b (clone Ml/70, BioLegend, San Diego, Calif., USA), PE-conjugated CD11c (clone N418, BioLegend, San Diego, Calif., USA), FITC-conjugated Gr1 (clone RB6-8C5, BioLegend, San Diego, Calif., USA), PerCp-Cy5.5-conjugated Ly-6C (clone HK1.4, BioLegend, San Diego, Calif., USA) and Pacific Blue-conjugated F4/80 (clone BM8, BioLegend, San Diego, Calif., USA). The expression level of CXCR6 was analyzed by using a APC-conjugated anti-mouse CXCR6 antibody (FAB2145A, R&D Systems, Inc., MN, USA) and the corresponding isotype (rat IgG2B, RTK4530, BioLegend, San Diego, Calif., USA). All flow cytometric data were acquired on a BD FACS CantoII and analyzed using the FlowJo software. As shown in FIG. 13, CXCR6 cannot be detected in significant levels on the surface of the analyzed immune cells (CD8 T cells, CD4 Tcells, NK T cells and CD19 B cells) by flow cytometry. FIG. 14: Migration of CXCR6- and GFP-transduced T cells towards pancreatic cancer cell supernatant (A): CXCR6 (SEQ ID NOs: 3 (cDNA); 4 (protein))-transduced CD8+ T cells and GFP-transduced CD8+ T cells were compared for their ability to migrate towards a CXCL16 gradient. Migration medium (0.5% BSA in RPMI medium) was used with or without recombinant CXCL16 (SEQ ID NO: 9; serial dilutions from 50 ng/ml to 3.125 ng/ml) (Peprotech, Hamburg) in the lower chamber and T cells in the upper chamber (1×106 cells/well) of a 96-transwell plate. After 3 hours migrated T cells were resuspended with counting beads (Life Techonologies, Carlsbad, Calif., USA) for quantification. Migratory capacity was analyzed as cell number and GFP expression by flow cytometry (BD FACS Canto II). As shown in FIG. 4, CXCR6 (SEQ ID NOs: 3 (cDNA); 4 (protein))-transduced T cells specifically and dose dependently migrate towards CXCL16, which is not seen in T cells which were only transduced with GFP (SEQ ID NOs: 11 (nucleic acid); 12 (protein)). (B): Tumor cells (i.e. Panc02-OVA or T110299 cells) were seeded in a 6 well plate (1×106 cells/well) and stimulated with recombinant IFN-γ and TNF-α (20 ng/ml) (Peprotech, Hamburg). After 48 hours, supernatants were incubated 30 min with or without an anti-CXCL16 neutralizing antibody (2 μg/ml) (R&D Systems, Inc., MN, USA, polyclonal). CXCR6 (SEQ ID NOs: 3 (cDNA); 4 (protein))-transduced CD8+ T cells and GFP (SEQ ID NOs: 11 (cDNA); 12 (protein))-transduced CD8+ T cells were seeded at a concentration of 1×106 cells/well. After 3 hours, migrated T cells were resuspended with counting beads (Life Techonologies, Carlsbad, Calif., USA) for quantification. Migration was quantified as cell number and GFP expression by flow cytometry. As shown in FIG. 14B, CXCR6 (SEQ ID NOs: 3 (cDNA); 4 (protein))-transduced T cells migrate specifically towards supernatants of T110299 cells, which is not seen with GFP (SEQ ID NOs: 11 (cDNA); 12 (protein))-transduced T cells. P-values are depicted in the Figure, *** p<0.001. FIG. 15: Internalisation and recycling of CXCR6 due to CXCL16 binding CXCR6 (SEQ ID NOs: 3 (cDNA); 4 (protein))-transduced CD8+ T cells (5×105 cells) were treated with 200 ng recombinant CXCL16 (Peprotech, Hamburg) and analyzed by live fluorescence microscopy at time intervals of 5 minutes over a period of 1 hour. Confocal imaging was performed with a Leica SP2 AOBS confocal microscope. As shown in FIG. 15, CXCL16 stimulation resulted in a CXCR6 internalisation and re-expression within a time span of 30 minutes. FIG. 16: Adhesion of CXCR6-transduced T cells to recombinant CXCL16 CXCR6 (SEQ ID NOs: 3 (cDNA); 4 (protein))-transduced CD8+ T cells and GFP (SEQ ID NOs: 11 (cDNA); 12 (protein))-transduced CD8+ T cells were compared for their ability to adhere to immobilised recombinant CXCL16. First, T cells were stained with Calcein (Life Technologies, Carlsbad, Calif., USA) and pre-incubated with or without 2 μg/ml anti-mouse CXCL16 neutralizing antibody (R&D Systems, Inc., MN, USA, polyclonal). Nickel-coated 96-well plates (Cat. Number 15442, ThermoScientific, Darmstadt) were pre-incubated with 9 pmol His-tagged CXCL16 (Cat. Number 50142-M08H, SinoBiological, Peking, China) or 9 pmol BSA. The pre-stimulated T cells were transferred to the CXCL16 or BSA coated Nickel plate. After 25-minute incubation and a washing step, attached cells were lysed using RIPA buffer. Calcein was detected with the Mithras LB 940 Multimode Microplate Reader (Berthold Technologies, Bad Wildbad), where the fluorescent signal intensity is proportional to the quantity of adherent cells. As shown in FIG. 16, CXCR6 (SEQ ID NOs: 3 (cDNA); 4 (protein))-transduced T cells attach specifically to CXCL16. P-values are depicted in the Figure, ** p<0.01; *** p<0.001. FIG. 17: Treatment of established Panc02-OVA tumors in mice with GFP- or CXCR6-transduced OT-1 T cells Female C57BL/6J Mice (5 per group) (Janvier, Frankreich (Cat. Number 2014-07-DE-RM-20)) were injected with Panc02-OVA tumor cells (2×106/mice) or T110299-OVA tumor cells (4×106/mice) subcutaneously. After 5 days, T cells were adoptively transferred through the tail vein (10×106 cells per mice). Therapeutic efficiency was measured as tumor growth every other day. As shown in FIGS. 17A and 17B, the treatment of established Panc02-OVA tumors or T110299-OVA tumor cells with CXCR6 (SEQ ID NOs: 3 (cDNA); 4 (protein))-transduced OT-1 T cells leads to superior anti-tumoral activity compared to GFP (SEQ ID NOs: 11 (cDNA); 12 (protein))-transduced OT-1 T cells. P-values are depicted in the Figure, *** p<0.001. FIG. 18: Quantification of tumor-infiltrating iRFP (Red Fluorescent Protein)—or CXCR6-transduced OT-1 T cells Female C57BL/6J Mice (Janvier, Frankreich (Cat. Number 2014-07-DE-RM-20)) were injected with Panc02-OVA tumor cells (2×106/mice) subcutaneously. After 5 days, T cells were adoptively transferred through the tail vein (10×106 cells per mice). Organs and tumors were isolated and processed on day 10 of induction (five days after T cell transfer). 15 minutes before organ removal, eFluor® 450-conjugated anti-mouse CD31 (4 μg/mice, clone 390, eBioscience, Frankfurt) was injected intravenously through the tail vein. For flow cytometric analysis, cells were stained with Pacific Blue-conjugated anti-mouse CD8a (clone 53-6.7, BioLegend, San Diego, Calif., USA) and analyzed with counting beads (Life Techonologies, Carlsbad, Calif., USA) for quantification. For 2 Photon microscopy, tumors were embedded in 1.5% agarose and 2 Photon imaging was performed with the Leica “SP5II MP” system equipped with a “Spectra Physics MaiTai DeepSee” Ti:Sa pulsed laser. As shown in FIG. 20, CXCR6 (SEQ ID NOs: 3 (cDNA); 4 (protein transduced T cells are not only specifically enriched in tumor tissue, but also have the ability to migrate towards tumor areas with few blood vessels. FIG. 19: Quantification of tumor-infiltrating iRFP (Red Fluorescent Protein)—or CXCR6-transduced OT-1 T cells by flow cytometry. Female C57BL/6J Mice (Janvier, Frankreich (Cat. Number 2014-07-DE-RM-20) were injected with Panc02-OVA tumor cells (2×106/mice) subcutaneously. After 5 days, T cells were adoptively transferred through the tail vein (10×106 cells per mice). Organs and tumors were isolated and processed on day 10 of induction (five days after T cell transfer). For flow cytometric analysis, cells were stained with Pacific Blue-conjugated anti-mouse CD8a (clone 53-6.7, BioLegend, San Diego, Calif., USA) and analyzed with counting beads (Life Techonologies, Carlsbad, Calif., USA) for quantification. FIG. 19 demonstrates a specific enrichment of CXCR6 transduced T cells over iRFP transduced T cells. FIG. 20: CXCL16 secretion by human pancreatic cancer cells Tumor cells, i.e. human pancreatic cancer cell lines PA-TU-8988T (DSM ACC 162), SUIT-2 clone? (Iwamura et al., Jpn J Cancer Res 78(1) (1987), 54-62), MIA PaCa-2 (ATCC® CRM-CRL-1420™), and PANC-1 (ATCC® CRM-CRL-1420™) were seeded in a 6-well plate (flat bottom) at a concentration of 0.2×106/well. Supernatants were harvested after 72 hours. Human CXCL16 secretion was measured with a hCXCL16 ELISA kit (R&D Systems, Inc., MN, USA). As shown in FIG. 19, the human pancreatic cancer cell lines PA-TU-8988T (DSM ACC 162), SUIT-2 clone7 (Iwamura et al., Jpn J Cancer Res 78(1) (1987), 54-62), MIA PaCa-2 (ATCC® CRM-CRL-1420™), and PANC-1 (ATCC® CRM-CRL-1420™) release hCXCL16. FIG. 21: Sphere formation by human pancreatic cancer cells 96-well plates (flat bottom) were coated with 1.5% agarose. Human pancreatic cancer cell lines PaTu8988T, Suit-2 clone7, MiaPaCa2 and Panc1 (100 and 500 cells/well) were seeded in the agarose-coated 96-well plate (flat bottom). The formation of spheres was observed by PaTu8988T, Suit-2 clone7, MiaPaCa2 and Panc1 tumor cells. Supernatants were harvested after nine days and human CXCL16 production was measured with an hCXCL16 ELISA kit (R&D Systems, Inc., MN, USA). FIG. 22: Migration of CXCR6-transduced human T cells towards recombinant hCXCL16 CXCR6-transduced CD8+ human T cells and GFP-transduced CD8+ human T cells were compared for their ability to migrate towards hCXCL16. Migration medium (0.5% BSA in RPMI medium) was used with or without recombinant hCXCL16 (50 ng/ml) (Peprotech, Hamburg) in the lower chamber and T cells in the upper chamber (1×106 cells/well) of a 96-transwell plate. After 3 hours migrated T cells were resuspended with counting beads (Life Techonologies, Carlsbad, Calif., USA) for quantification. Migratory capacity was analyzed as cell number and GFP expression by flow cytometry (BD FACS Canto II). As shown in Figure X, CXCR6-transduced human T cells specifically migrate towards hCXCL16, which is not seen with GFP-transduced T cells. P-values are depicted in the Figure, * indicates p<0.05. The following Examples illustrate the invention Illustratively, as proof of the concept, in the following Examples, the experiments were carried by vector constructs harbouring the mouse/murine sequences of CXCR6 (SEQ ID NO: 3 (cDNA sequence encoding the protein sequence as shown in SEQ ID NO: 4)) and CXCL16 (SEQ ID NO: 7 (cDNA sequence encoding the protein sequence as shown in SEQ ID NO: 8)). Further, in the experiments as exemplified in FIGS. 20 and 21 vector constructs encoding the human sequences of CXCR6 (SEQ ID NO: 1 encoding the protein sequence as shown in SEQ ID NO: 2) was used. Example 1: Generation of the CXCR6 Vector Construct and the GFP Control Vector Construct The CXCR6 vector capable of transducing CD8+ T cells was generated by amplification of the full length murine CXCR6 sequence (SEQ ID NO: 3) and cloned into the pMP71-vector (Schambach et al., Mol Ther 2(5) (2000), 435-45; EP-B1 0 955 374) after EcoRI and NotI double digestion and ligation. The GFP vector capable of transducing CD8+ T cells was generated by amplification of the full length GFP sequence (SEQ ID NO: 11 (cDNA) and SEQ ID NO: 12 (protein)) and cloned into the pMP71-vector after EcoRI and NotI double digestion and ligation. Cloning was done using polymerase chain reaction from splenocyte cDNA and amplification of CXCR6 corresponding to the above mentioned sequence and the following primers: 5-ATTAGCGGCCGCATGGATGATGGCCATCAGG-3′ (SEQ ID NO: 13) and 5′-GGAAACCACCAGCATGTTTCAGGAATTC-3′ (SEQ ID NO: 14). The vector CXCR6GFP was generated in the same way as described above with regard to the CXCR6 and the GFP vector. In brief, the murine full length murine CXCR6 sequence (SEQ ID NO: 3) and the full length GFP sequence (SEQ ID NO: 11 (cDNA) and SEQ ID NO: 12 (protein)) was cloned into the pMP71-vector. The construction of the CXCR6 vector capable of transducing human CD8+ T cells was done in the same way as described above with regard to the CXCR6 vector harbouring the full length murine CXCR6 sequence. In brief length human CXCR6 sequence (SEQ ID NO: 1) was cloned into the pMP71-vector. Example 2: Transduction of T Cells and Assay Systems for the CXCL16 Secretion, T Cell Proliferation and Killing Assays 2.1 Cell Lines The murine pancreatic cancer cell line Panc02 and its ovalbumin-transfected counterpart Panc02-OVA have been previously described (Jacobs et al., Int J Cancer 128(4) (2011), 897-907). The Panc02-cell line was generated through injection of the carcinogen Methycholantren A into the pancreas of wild type C57Bl/6 mice to induce carcinogenesis. The tumor cell line T110299 was developed from a primary pancreatic tumor of a Ptf1aCre; KrasG12D; p53fl/R172H mouse 25 and is described in Duewell et al., Cell Death Differ 21(12) (2014), 1825-1837 (Erratum in: Cell Death Differ. 21(12) (2014), 161). The packaging cell line Plat-E has been previously described by Morita et al., Gene Ther 7 (2000), 1063-6). All cells were cultured in DMEM with 10% fetal bovine serum (FBS, Life Technologies, USA), 1% penicillin and streptomycin (PS) and 1% L-glutamine (all from PAA, Germany). 10 μg/ml puromycin and 1 μg/ml blasticidin (Sigma, Germany) were added to the Plat-E medium. Bone marrow derived dendritic cells were isolated from a C57BL/6J mouse (Janvier, France (Cat. Number 2014-07-DE-RM-20)). Bone marrow cells were cultured with recombinant GM-CSF (20 ng/ml) (Peprotech, Hamburg) for seven days. Bone marrow derived dendritic cells (BM-DC, 104 per well) were seeded in a 96-well plate (flat bottom) and stimulated with recombinant proteins (20 ng/ml) (TNF-α, IFN-γ or IL-4, Peprotech, Hamburg; or R848 Enzo Life Science, Lörrach). OT-1 T cells are T cells from OT-1 mice Stock number 003831. These OT-1 T cells were produced as follows. Primary splenocytes were harvested from OT-1-mice. Single cell suspensions of splenocytes were stimulated with anti-CD3 (clone 145-2c11 BD Pharmingen, USA), anti-CD28 (clone 37.51, BD Pharmingen, USA) and recombinant murine IL-2 (Peprotech, Germany) in T cell medium over night. The human pancreatic cancer cell line PA-TU-8988T is obtainable from the cell line depository Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures under the accession number DSM ACC 162. The origin of the deposited cell line PA-TU-89988T is human (Homo sapiens). The cell type is pancreas adenocarcinoma. More precisely, the cell line PA-TU-8988T was established in 1985 from the liver metastasis of a primary pancreatic adenocarcinoma from a 64-year-old woman; sister cell line of PA-TU-8988S (DSM ACC 204). The human pancreatic cancer cell line MIA PaCa-2 is obtainable from the American Type Culture Collection (ATCC) under the accession number CRM-CRL-1420™. The organism of the deposited cell line MIA PaCa-2 is human (Homo sapiens). The cell type is epithelial cell (Kras Crm). The human pancreatic cancer cell line PANC-1 is obtainable from the American Type Culture Collection (ATCC) under the accession number CRL-1469™. The organism of the deposited cell line PANC-1 is human (Homo sapiens). The tissue is pancreas/duct. The human pancreatic cancer cell line SUIT-2 has been previously described in Iwamura et al., Jpn J Cancer Res. 78(1) (1987), 54-62. The pancreatic cancer cell line SUIT-2 is characterized by producing carcinoembyronic antigen and carbohydrate antigen 19-9. 2.2 Animals Wild type C57Bl/6 mice were bought from Harlan laboratories (The Netherlands). Mice transgenic for a T cell receptor specific for ovalbumine (OT-1) were obtained from the Jackson laboratory, USA (Stock number 003831) and were bred in our animal facility under specific-pathogen free (SPF) conditions. OT-1 mice were crossed to CD45.1 congenic marker mice (obtained from the Jackson laboratory, stock number 002014) and to CD90.1 congeneic marker mice (Stock number: 000406) to generate CD45.1-OT-1 and CD90.1-OT-1 mice, respectively. Wild type C57Bl/6 mice were purchased from Janvier, France. Tumors were induced by subcutaneous injection of 2×106 tumor cells and mice were treated by i.v. injection of T cells as indicated. All experiments were randomized and blinded. For neutralization experiments, anti-IFN-γ antibody R4-6A2 (BioXcell, USA) or isotype control (BioXcell, USA) was applied i.p. at a dose of 200 μg per animal every three days for four doses. Tumor growth and condition of mice were monitored every other day. 2.3 T Cell Transduction 2.3.1 T Cell Transduction of Murine/Mouse T Cells The retroviral vector pMP71 (Schambach et al., Mol Ther 2(5) (2000), 435-45; EP-B1 0 955 374) was used for transfection of the ecotrophic packaging cell line Plat-E. Transduction was performed according to the method described by Leisegang et al. J Mol Med 86 (2008), 573; Mueller et al. J Virol 86 (2012), 10866-10869; Kobold et al., J Natl Cancer Inst 107 (2015), 364. In brief, packaging cell line Plat E (as described by Morita et al. Gene Ther 7 (2000), 1063) was seeded in 6-well plates and grown over night to 70-80% confluence. On day one, 16 μg of DNA were mixed together with 100 mM CaCl2 (Merck, Germany) and 126.7 μM Chloroquin (Sigma, USA). Plat-E cells were starved for 30 min in low serum medium (3%) and then incubated for 6 h with the precipitated DNA. Medium was then removed and exchanged with culture medium. On day two, primary splenocytes were harvested from C57Bl/6 mice (Janvier). Single cell suspensions of splenocytes were stimulated with anti-CD3 (clone 145-2c11 BD Pharmingen, USA), anti-CD28 (clone 37.51, BD Pharmingen, USA) and recombinant murine IL-2 (Peprotech, Germany) in T cell medium over night. On day 3, 24-well plates were coated with 12.5 μg/ml recombinant retronectin (Takara Biotech, Japan) for 2 h at room temperature, blocked with 2% bovine serum albumin (Roth, Germany) for 30 min at 37° C. and washed with PBS. Supernatant of Plat-E was harvested and passed through a filter (40 μm, Milipore, USA). Fresh T cell medium was then added to Plat E cells. 1 ml of filtered supernatant was distributed in each well and spinoculated for 2 hours at 4° C. Supernatant was then removed from the 24-well plate. 106 T cells were seeded in one ml T cell medium supplemented with 10 U IL-2 and 400,000 anti-CD3 and anti-CD28 beads (Invitrogen, Germany) per well and spinoculated at 800 g for 30 min at 32° C. On day four, Plat E supernatant was again harvested and filtered. 1 ml was added to each well of the 24-well plate and spinoculated at 800 g for 90 min at 32° C. Cells were subsequently incubated for 6 additional hours at 37° C. 1 ml supernatant was replaced by T cell medium with IL-2. On day five, cells were harvested, counted and reseeded at 106 cells/ml density in T cell medium supplemented with 10 ng IL-15 per ml (Peprotech, Germany). T cells were kept at this density until day 10 when cell analysis or functional assays were performed. Transduction with the retroviral vector pMX (de Witte et al., J. Immunol. 181 (2008), 5128-5136) was performed in the same way as transduction with the vector pMP71 as described above. 2.3.2 Human T Cell Transduction The retroviral vector pMP71 (Schambach et al., Mol Ther 2(5) (2000), 435-45; EP-Bl 0 955 374) was used for transfection of the amphotrophic packaging cell line Plat-A. Transduction was performed according to the method described by Leisegang et al. J Mol Med 86 (2008), 573; Mueller et al. J Virol 86 (2012), 10866-10869; Kobold et al., J Natl Cancer Inst 107 (2015), 364. In brief, packaging cell line Plat A (as described by Morita et al. Gene Ther 7 (2000), 1063) was seeded in 6-well plates and grown over night to 70-80% confluence. On day two, Plat A cells were transfected with the calcium phosphate precipitation method with 18 μg of retroviral vector plasmid pMP71 and then incubated for 6 h. Medium was then removed and exchanged with culture medium. Furthermore, primary PBMCs were isolated and CD3+ T cells were separated by MACS sorting (Miltenyi Biotec, Bergisch Gladbach). CD3+ human T cells were stimulated with anti-human CD3 (clone UCHT1 BD Pharmingen, USA), anti-human CD28 (clone CD28,2, BD Pharmingen, USA), recombinant IL-15 (Peprotech, Germany) and recombinant murine IL-2 (Peprotech, Germany) in T cell medium over night. On day four, 24-well plates were coated with 12.5 μg/ml recombinant retronectin (Takara Biotech, Japan) for 2 h at room temperature, blocked with 2% bovine serum albumin (Roth, Germany) for 30 min at 37° C. and washed with PBS. Supernatant of Plat-A was harvested and passed through a filter (0.45 μm, Milipore, USA). Fresh T cell medium was then added to Plat A cells. 1 ml of filtered supernatant was distributed in each well and spinoculated for 2 hours at 4° C. Supernatant was then removed from the 24-well plate. 106 human T cells were seeded in one ml T cell medium supplemented with IL-2, IL-15 and anti-human CD3 and anti-human CD28 Dynabeads (Invitrogen, Germany) per well and spinoculated at 800 g for 30 min at 32° C. On day five, Plat A supernatant was again harvested and filtered. 1 ml was distributed in each well and spinoculated for 2 hours at 4° C. Supernatant was removed and the infected T cells from the previous day were transferred in the 24-well plate and spinoculated at 800 g for 90 min at 32° C. Cells were subsequently incubated for 6 additional hours at 37° C. After incubation, cells were harvested, counted and reseeded at 106 cells/ml density in T cell medium supplemented with IL-15 and IL-2 (Peprotech, Germany). T cells were kept at this density until day 10 when cell analysis or functional assays were performed. 2.4 Co-Culture of Tumor Cells with T Cells T cells and tumor cells were co-cultured for 48 h at a ratio of 1:1 or 10:1 in the culture conditions described above. Supernatants were analyzed for IFN-γ by ELISA (BD) as described in section 2.5, infra. 2.5 Lytic Activity of CXCR6-Transduced T Cells in the Presence of CXCL16-Producing Tumor Cells LDH release was measured by a commercial kit (Promega). In brief, LDH catalizes the reduction of NAD+ to NADH and H+by oxidation of lactate to pyruvate. Next, diaphorase reacts with NADH and H+ to catalyze the reduction of a tetrazolium salt (INT) to formazan which absorbs at 490 nm. IFN-γ is measured by ELISA using complementary IFN-γ binding antibodies as capture and as detection antibodies and Horse Radish Peroxidase coupled secondary system. Cells expressing GFP are analyzed by a flow cytometer and GFP is excited by the 488 nm and detected in the 530 nm filter using a BD FACS Canto II Migration towards CXCL16 was performed using a standard transwell migration where the upper and lower part of the well are separated by commercial porous membranes, which can be passed by T cells. CXCL16 was added to the lower part of the well and the cells in the upper part. If the cells express CXCR6, they will migrate through the pores and can be measured by flow cytometry thereafter. 2.6 Statistical Analysis For statistics, GraphPad Prism software version 5.0b was used. All variables reported are continuous. Differences between experimental conditions were analyzed using the unpaired two-sided Student's t-test. For comparison of experimental conditions of individual mice, the Mann-Whitney test was used. p-values <0.05 were considered significant. For in vivo experiments, differences between groups were analyzed using two-way ANOVA with correction for multiple testing by the Bonferroni method. Differences in Panc02-OVA tumor growth in mice were analyzed by comparing tumor surface (defined as the width times the height of a tumor as measured by an analogue caliper) at each time point using two-way ANOVA with correction for multiple testing. 3. Examples of Particular Embodiments Examples of certain non-limiting embodiments of the disclosure are listed hereafter. In particular, the present invention relates to the following items: 1. A vector capable of transducing T cells comprising a nucleic acid sequence selected from the group consisting of: (a) a nucleic acid sequence of SEQ ID NO: 1 or SEQ ID NO: 3, and (b) a nucleic acid sequence which is at least 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the sequence of SEQ ID NO: 1 or SEQ ID NO: 3 and which is characterized by having a chemokine receptor 6 (CXCR6) activity. 2. The vector of item 1, wherein said vector is an expression vector. 3. The vector of item 1 or item 2, wherein said vector is a retroviral vector. 4. The vector of any one of item 1 to 3, wherein said vector further comprises a regulatory sequence which is operably linked to said nucleic acid sequence of item 1. 5. A transduced T cell expressing a chemokine receptor 6 (CXCR6) encoded by a nucleic acid sequence selected from the group consisting of: (a) a nucleic acid sequence of SEQ ID NO: 1 or SEQ ID NO: 3, and (b) a nucleic acid sequence which is at least 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the sequence of SEQ ID NO: 1 or SEQ ID NO: 3 and which is characterized by having a chemokine receptor 6 (CXCR6) activity. 6. The transduced T cell of item 5, wherein the chemokine receptor 6 (CXCR6) is stably integrated into the genome of the T cell. 7. The transduced T cell of item 5 or item 6, wherein the chemokine receptor 6 (CXCR6) or a fragment thereof is expressed on the surface of the T cell. 8. The transduced T cell of any one of items 5 to 7, wherein the transduced T cell is co-transduced with a T cell receptor. 9. A method for the production of a transduced T cell expressing a chemokine receptor 6 (CXCR6) comprising the following steps: (a) transducing a T cell with a vector comprising a nucleic acid sequence selected from the group consisting of: (i) a nucleic acid sequence of SEQ ID NO: 1 or SEQ ID NO: 3, and (ii) a nucleic acid sequence which is at least 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the sequence of SEQ ID NO: 1 or SEQ ID NO: 3 and which is characterized by having a chemokine receptor 6 (CXCR6) activity; (b) culturing the transduced T cell under conditions allowing the expression of the chemokine receptor 6 (CXCR6) in or on said T cell; and (c) recovering the transduced T cell from the culture. 10. The method of item 9, wherein the transduced T cell is expanded after the transfection by anti-CD3 and anti-CD28 antibodies. 11. The method of item 9 or item 10, wherein the expansion of the transduced T cells is performed in the presence of cytokines, preferably interleukin-2 (IL-2) and/or interleukin-15 (IL-15). 12. A transduced T cell expressing a chemokine receptor 6 (CXCR6) as obtainable by the method of any one of items 9 to 11. 13. The transduced T cell of any one of items 5 to 8 or 12, or obtainable by the method of any one of items 9 to 11 for use as a medicament. 14. The transduced T cell of any one of items 5 to 8, 12 or 13, or obtainable by the method of any one of items 9 to 11 for use in a method of treating a disease characterized by CXCL16 overexpression. 15. A pharmaceutical composition comprising a transduced T cell expressing a chemokine receptor 6 (CXCR6) encoded by a nucleic acid sequence selected from the group consisting of: (a) a nucleic acid sequence of SEQ ID NO: 1 or SEQ ID NO: 3, and (b) a nucleic acid sequence which is at least 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the sequence of SEQ ID NO: 1 or SEQ ID NO: 3 and which is characterized by having a chemokine receptor 6 (CXCR6) activity. 16. The pharmaceutical composition of item 15, wherein the transduced T cell comprises the vector of any one of items 1 to 4. 17. The pharmaceutical composition of item 15 or item 16, wherein the transduced T cell is a T cell that has originally been obtained from the patient to be treated with. 18. The pharmaceutical composition of any one of items 15 to 17, wherein the transduced T cell are expanded after transfection by anti-CD3 and anti-CD28 antibodies. 19. The pharmaceutical composition of item 18, wherein the expansion of the transduced T cells is performed in the presence of cytokines, preferably interleukin-2 (IL-2) and/or interleukin-15 (IL-15). 20. The pharmaceutical composition of any one of items 15 to 19 for use in a method of treating a disease characterized by CXCL16 overexpression. 21. A method for the treating of a disease characterized by CXCL16 overexpression in a subject comprising the steps of (a) isolating T cells from a subject; (b) transducing said isolated T cells with a vector comprising a nucleic acid sequence selected from the group consisting of: (i) a nucleic acid sequence of SEQ ID NO: 1 or SEQ ID NO: 3, and (ii) a nucleic acid sequence which is at least 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the sequence of SEQ ID NO: 1 or SEQ ID NO: 3 and which is characterized by having a chemokine receptor 6 (CXCR6) activity; and (c) administering said transduced T cells to said subject. 22. The method of item 21, wherein said transduced T cells are administered to said subject by intravenous infusion. 23. The method of item 21 or item 22, wherein said transduced T cells are expanded by anti-CD3 and anti-CD28 antibodies. 24. The method of item 23, wherein the expansion of the transduced T cells is performed in the presence of cytokines, preferably interleukin-2 (IL-2) and/or interleukin-15 (IL-15). 25. The transduced T cell of item 14 for use according to item 14, the pharmaceutical composition of item 20 for use according to item 20, or the method of any one of items 21 to 24, wherein said disease is selected from the group consisting of colorectal cancer, brain cancer, ovarian cancer, prostate cancer, pancreatic cancer, breast cancer, renal cancer, nasopharyngeal carcinoma, hepatocellular carcinoma, gastric cancer, cervical cancer, bladder cancer, lymphoma, sarcoma, and lung cancer. 26. A kit for incorporating a nucleic acid sequence selected from the group consisting of: (a) a nucleic acid sequence of SEQ ID NO: 1 or SEQ ID NO: 3, and (b) a nucleic acid sequence which is at least 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the sequence of SEQ ID NO: 1 or SEQ ID NO: 3 and which is characterized by having a chemokine receptor 6 (CXCR6) activity into a T cell comprising a vector of any one of items 1 to 4. 27. The vector of any one of items 1 to 4, the transduced T cell of any one of items 5 to 8, 10, 12, or 13, the method of any one of items 9 to 11, the transduced cell for the use according to any one of items 13 or 14, the pharmaceutical composition of any one of items 15 to 20, the method of any one of items 21 to 25, or the kit of item 26, wherein the T cell is a T cell selected from the group consisting of a CD8+ T cell, CD4+ T cell, a γδ T cell and a natural killer (NK) T cells. 28. The vector, the transduced T cell, the method, the pharmaceutical composition, or the kit according to item 27, wherein the T cell is a CD8+ T cell. | A61K3517 | 20180413 | 20180913 | A61K3517 | 0 | PAK, MICHAEL D | CXCR6-TRANSDUCED T CELLS FOR TARGETED TUMOR THERAPY | SMALL | 0 | PENDING | A61K | 2,018 |
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15,776,337 | PENDING | INFORMATION PROCESSING METHOD, AND DISPLAY APPARATUS | An information processing method in a content viewing system that includes: a first display apparatus and a second display apparatus configured to communicate with each other via a home network, receive and reproduce contents of a content distribution service from a server on a network; and a mobile terminal configured to communicate with each of the display apparatus, includes: a first step of obtaining account information, which the mobile terminal has, from the mobile terminal by the first display apparatus, the account information being associated with the content distribution service; a second step of transferring the account information to the second display apparatus by the first display apparatus; and a third step of receiving the contents from the server by using the account information by the second display apparatus to reproduce the contents. | 1. An information processing method for a content viewing system, the content viewing system comprising: a first display apparatus and a second display apparatus configured to communicate with each other via a home network, each of the first display apparatus and the second display apparatus being configured to receive contents of a content distribution service from a server on a network and reproduce the contents; and a mobile terminal configured to communicate with each of the first display apparatus and the second display apparatus, the information processing method comprising: a first step of obtaining account information, which the mobile terminal has, from the mobile terminal by the first display apparatus, the account information being associated with the content distribution service; a second step of transferring the account information obtained at the first step to the second display apparatus connected to the home network by the first display apparatus; and a third step of receiving the contents from the server by the second display apparatus by using the account information transferred at the second step to reproduce the contents. 2. The information processing method according to claim 1, wherein the first step includes carrying out an account registering process via an account registering screen outputted by the first display apparatus to obtain the account information that the mobile terminal has, and wherein the third step includes receiving the contents by using the account information to reproduce the contents without carrying out the account registering process via the account registering screen. 3. A display apparatus in a content viewing system, the content viewing system comprising: the display apparatus configured to communicate with others via a home network, the display apparatus being configured to receive contents of a content distribution service from a server on a network and reproduce the contents; and a mobile terminal configured to communicate with the display apparatus, wherein the display apparatus is configured to communicate with the mobile terminal to obtain account information, which the mobile terminal has, from the mobile terminal, the account information being associated with the content distribution service, wherein the obtained account information is transferred to other display apparatus that is connected to the home network, and wherein the contents are received from the server by using the transferred account information to be reproduced when the contents are transferred. 4. The display apparatus according to claim 3, wherein an account registering screen is outputted when to communicate with the mobile terminal, and an account registering process is carried out via the account registering screen to obtain the account information that the mobile terminal has, and wherein the received by using the account information without carrying out the account registering process via the account registering screen to be reproduced when the contents are transferred. 5. A display apparatus configured to be connected to a home network of a user, the display apparatus comprising: a content reproducing unit configured to receive contents from an outside to reproduce the contents so as to be displayed; an authenticating unit configured to carry out a process related to authentication for viewing the contents by using account information associated with a content distribution service, the contents being to be distributed in the content distribution service; and an account information sharing unit configured to communicate with a mobile terminal of the user to obtain account information that the mobile terminal has and register the account information as account information that is shared by a plurality of display apparatus connected to the home network. 6. The display apparatus according to claim 5, wherein the account information sharing unit includes: a first processing unit configured to transfer the account information to other display apparatus of the home network in a case where inquiry of the account information is received from the other display apparatus; and a second processing unit configured to transmit inquiry of the account information to other display apparatus of the home network, receive the account information from the other display apparatus, and register the transferred account information in its own display apparatus. 7. The display apparatus according to claim 5, wherein the account information sharing unit includes: a first processing unit configured to obtain the account information from the mobile terminal, and immediately transfer the account information to other display apparatus of the home network; and a second processing unit configured to receive the account information immediately transferred from other display apparatus of the home network, and register the account information in its own display apparatus. 8. The display apparatus according to claim 5, wherein the account information sharing unit includes: a first processing unit configured to obtain the account information from the mobile terminal and register the account information in its own display apparatus, the first processing unit being configured to transmit, as a response, the account information to other display apparatus in a case where a reference request of the account information is received from the other display apparatus of the home network; and a second processing unit configured to transmit a reference request of the account information to other display apparatus of the home network in a case where the authentication occurs, and use the account information received from the other display apparatus for the authentication without registering the account information in its own display apparatus. 9. The display apparatus according to claim 5, wherein, in a case where the account information is registered, the account information sharing unit carries out whereabouts confirmation of the mobile terminal, and wherein, in a case where it is detected that the mobile terminal is not in home associated with the home network, the registered account information is deleted. 10. The display apparatus according to claim 5, wherein, in a case where the account information is registered and a result of the authentication is failure, the account information sharing unit deletes the registered account information. 11. The display apparatus according to claim 5, further comprising: a user setting unit configured to carry out user setting related to sharing of the account information in the plurality of display apparatus of the home network, wherein the user setting unit displays a setting screen on a basis of a user input operation, and wherein the setting screen includes an item for setting whether the account information is to be shared or not for each display apparatus of the plurality of display apparatus. 12. The display apparatus according to claim 11, wherein, in a case where a mobile terminal of a guest for home associated with the home network of the user exists, the setting screen includes an item for setting whether account information that the mobile terminal of the guest is registered as the shared account information or not. | TECHNICAL FIELD The present invention relates to information processing and display technique related to viewing of contents in a content distribution service. BACKGROUND ART There are various kinds of content distribution services for distributing contents such as videos on a communication network. In the content distribution service, it is required to control authorities, permission and the like with respect to usage of the service and viewing of contents by a user. In other words, such controls are required with respect to reception and reproduction of the contents by apparatus of the user. Conventionally, for the controls, account information associated with a user who uses the content distribution service has been used. A content distribution server carries out authentication by using the account information. In a case where a result of the authentication is success, the user is permitted to receive and reproduce the contents via the apparatus of the user. On the other hand, in recent years, the case where plural kinds of apparatuses including a TV receiver (hereinafter, referred to also as a “display apparatus” or the like) are connected to a home network of a user and a home system is thereby constructed is increased. As an example of prior art regarding restriction to view contents, Japanese Patent No. 5,248,180 (Patent Document 1) is cited. In Patent Document 1, as an “operation target apparatus”, it is described that “a permitter who has authority grants permission for an operator for whom execution of a predetermined operation is restricted by a simple operation, whereby the operator is allowed to carry out the restricted operation”. RELATED ART DOCUMENTS Patent Documents Patent document 1: Japanese Patent No. 5,248,180B SUMMARY OF THE INVENTION Problems to be Solved by the Invention According to the prior art like Patent Document 1, it is possible to restrict viewing of contents. However, the prior art fails to consider various usage environments and usage situations such as a home network of the user. For that reason, in a case of dealing with it, usability for the user is not sufficient, and there is a problem in view of convenience. The user utilizes a content distribution service by using apparatus such as a TV receiver, which is connected to a home network, as a content reproducing apparatus, and can view contents. In order to allow the user to view the contents via the apparatus, it is necessary to carry out a work to set account information of the content distribution service to the apparatus. For example, the user sets the account information that is associated with his or her mobile terminal and this mobile terminal has to the apparatus of the home network. However, in a case where a plurality of apparatuses is connected to the home network, it is necessary to carry out a work to set account information to each apparatus. Therefore, labor of the user becomes large. Further, in a case where plural pieces of account information to be registered exist and the like, the labor of the user becomes further larger. It is an object of the present invention to provide, with respect to techniques including a display apparatus for viewing contents, a technique by which it is possible to reduce labor for a user to set account information to his or her apparatus while securing control of authority to view contents by using the account information, and this makes it possible to user-friendly improve convenience in various environments and situations. Means for Solving the Problem A representative embodiment of the present invention is an information processing method and a display apparatus that are characterized by having a configuration shown below. An information processing method according to one embodiment is an information processing method for a content viewing system, the content viewing system including: a first display apparatus and a second display apparatus configured to communicate with each other via a home network, each of the first display apparatus and the second display apparatus being configured to receive contents of a content distribution service from a server on a network and reproduce the contents; and a mobile terminal configured to communicate with each of the first display apparatus and the second display apparatus, the information processing method comprising: a first step of obtaining account information, which the mobile terminal has, from the mobile terminal by the first display apparatus, the account information being associated with the content distribution service; a second step of transferring the account information obtained at the first step to the second display apparatus connected to the home network by the first display apparatus; and a third step of receiving the contents from the server by the second display apparatus by using the account information transferred at the second step to reproduce the contents. A display apparatus according to one embodiment is a display apparatus in a content viewing system, the content viewing system including: the display apparatus configured to communicate with others via a home network, the display apparatus being configured to receive contents of a content distribution service from a server on a network and reproduce the contents; and a mobile terminal configured to communicate with the display apparatus, wherein the display apparatus is configured to communicate with the mobile terminal to obtain account information, which the mobile terminal has, from the mobile terminal, the account information being associated with the content distribution service, wherein the obtained account information is transferred to other display apparatus that is connected to the home network, and wherein the contents are received from the server by using the transferred account information to be reproduced when the contents are transferred. Effects of the Invention According to a representative embodiment of the present invention, with respect to techniques including a display apparatus for viewing contents, it is possible to reduce labor for a user to set account information to his or her apparatus while securing control of authority to view contents by using the account information, and this makes it possible to user-friendly improve convenience in various environments and situations. BRIEF DESCRIPTIONS OF THE DRAWINGS FIG. 1 is a view showing a system including a display apparatus according to a first embodiment of the present invention; FIG. 2 is a view showing a configuration of a content distribution server according to the first embodiment; FIG. 3 is a view showing a hardware configuration of the display apparatus according to the first embodiment; FIG. 4 is a view showing a software configuration of the display apparatus according to the first embodiment; FIG. 5 is a view showing an example of an operating sequence at the time of initial setting according to the first embodiment; FIG. 6 is a view showing a processing flow of the display apparatus according to the first embodiment; FIG. 7 is a view showing an example of an operating sequence at the time of initial setting according to a first modification example of the first embodiment; FIG. 8 is a view showing a system including a display apparatus and an example of an operating sequence at the time of the initial setting according to a second embodiment of the present invention; FIG. 9 is a view showing a processing flow of the display apparatus according to the second embodiment; FIG. 10 is a view showing a system including a display apparatus and an example of an operating sequence at the time of initial setting according to a third embodiment of the present invention; FIG. 11 is a view showing a processing flow of the display apparatus according to the third embodiment; FIG. 12 is a view showing a processing flow of the display apparatus according to a first modification example of the third embodiment; FIG. 13 is a view showing a system including a display apparatus and an example of an operating sequence at the time of initial setting according to a fourth embodiment of the present invention; FIG. 14 is a view showing an example of an account registering screen according to the fourth embodiment; FIG. 15 is a view showing an example of a setting screen according to the fourth embodiment; and FIG. 16 is a view showing a table example of setting information according to the fourth embodiment. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS Hereinafter, embodiments of the present invention will be described in detail with reference to the drawings. First Embodiment An information processing method and a display apparatus according to a first embodiment of the present invention will be described with reference to FIG. 1 to FIG. 7. The information processing method according to the first embodiment is a method including steps carried out by a content viewing system including the display apparatus according to the first embodiment. [Content Distribution Service, User Authentication, and Account Information] A content distribution service, user authentication, account information, and the like, which are a presupposition and an application target according to the following embodiments, will first be described. As the content distribution service, there are an IPTV service and the like. The IPTV service is a service to distribute contents, such as a movie film and a video distribution program, which contain a video, an audio, character information and the like, to an apparatus of a user on the Internet. The apparatus of the user is a content reproducing apparatus, and is a display apparatus such as a mobile terminal and a TV receiver. The apparatus has account information for allowing the user to view contents by using the content distribution service. The user is registered as a regular user to a content distribution server of a service provider by registering the account information and the like. The content distribution server carries out authentication by using the account information in order to control authority of services and contents. The user and the apparatus are required to obtain certification by using the account information when to use a service and view contents. The control of authority using the authentication allows violation of laws, such as unapproved copy, movement, change and the like regarding the contents, to be prevented. The authentication may be requested at the time of log-in to the content distribution service, or may be requested when to reproduce each of contents. For example, the content distribution server carries out user authentication. The content distribution server compares and checks the registered account information with account information received from the apparatus of the user, thereby carrying out the user authentication. As the authentication, apparatus authentication may be carried out in addition to the user authentication. The apparatus authentication is authentication regarding the apparatus that the user uses to view contents. In the apparatus authentication, it is confirmed whether the apparatus is a permitted apparatus or recommended apparatus or not. The account information is information that is associated with an account set to the user for each content distribution service. The account information is information on a combination of a user ID and a password, for example. However, it is not limited to this. As the user authentication, biometrics authentication may be included. In that case, information for the biometrics authentication may be contained in the account information. Means for predetermined protection, for example, encryption or the like may be applied to the account information and contents to be distributed. For example, contents are encrypted in advance in a predetermined method, and key information for decoding is exchanged separately. The key information is managed together with a content reproducing condition. In the content distribution service, a usage fee is often charged by the service provider. The charging is carried out in a predetermined method, and charging information is recorded. For example, the usage fee is calculated on the basis of counts when to accumulate data and view contents in the apparatus of the user. The same user basically reproduces contents of the content distribution service by the same apparatus, but there is a service in which a plurality of users and a plurality of apparatuses are permitted to reproduce contents under a predetermined condition. As a content distribution method, there are streaming, download, progressive download, and the like. Contents may accompany a program such as application software. The program operates when to reproduce the contents by the apparatus of the user. [Mobile Terminal, Display Apparatus, and Account Setting Work] The account information may be provided so as to be associated with the mobile terminal that is the apparatus of the user, for example. Namely, its account information may be stored in storage means of the mobile terminal. For example, the user inputs the account information into the mobile terminal. Alternatively, the service provider or an apparatus on a network inputs the account information into the mobile terminal. The user can use the content distribution service, that is, view contents on the mobile terminal by using the account information. The embodiment is one in which it is considered the case where even a display apparatus of a home network can use the content distribution service by using account information associated with a mobile terminal and that the mobile terminal has. The embodiment premises a state where a mobile terminal has account information. It is shifted from the state to a state where even a display apparatus of a home network of the user can use the content distribution service by using the account information. At the time of the user authentication for viewing contents on the display apparatus, the account information that the mobile terminal has is used. In order to do so, conventionally, the user is required to carry out a work to set the account information that the mobile terminal has to each of display apparatus that are connected to the home network. In order to allow all of the display apparatus to view contents, it is necessary to separately set the account information to each of the display apparatus. Labor of the user becomes larger in the work including the settings. Thus, in the embodiment, a mechanism to automate a process to register account information that a mobile terminal has to a plurality of display apparatus in home, and a mechanism to share the account information of the mobile terminal with the plurality of display apparatus of a home network are provided. These mechanisms can improve convenience in a case where the account information of the mobile terminal can be used by the plurality of display apparatus in the home. In the embodiment, an account sharing function corresponding to these mechanisms is provided. [Content Viewing System] FIG. 1 shows a configuration of the content viewing system that is a system including the display apparatus according to the first embodiment. The content viewing system includes a display apparatus 1, a mobile terminal 2, a home network 5, an external network 6, a content distribution server 7, a broadcast station 8, and the like. The display apparatus 1 is a TV receiver, and is the content reproducing apparatus that can receive and reproduce contents. The display apparatus 1 is an apparatus that has, as a function to receive and reproduce a broadcast program and contents, a displaying function to display the contents and the like on a screen. As the display apparatus 1, a plurality of display apparatus 1 connected to the home network 5 of the user is provided. In FIG. 1, as the plurality (“n”) of display apparatus 1, a display apparatus 1a, a display apparatus 1b, . . . , and a display apparatus 1n are provided. In this regard, names assigned to the respective display apparatus 1 are indicated by “TV1” to “TVn”. As the display apparatus 1, various kinds of apparatuses, such as a liquid crystal display, a projection-type video display apparatus (projector), a PC, a monitoring device, a tablet device, a recorder, a set-top box, and a video game machine, can be applied. In the case of the recorder or the set-top box, the display apparatus 1 does not includes the displaying function. However, such a display apparatus 1 can be applied in form of connecting to other apparatus provided with a displaying function and working together. The home network 5 is constructed in a house, which is in home of the user, a store or the like. A plurality of TV receivers that is the plurality of display apparatus 1 is connected to the home network 5. The home network 5 is in the control of a certain user (referred to as a “user U1”), and is a network that the other users cannot use basically. The home network 5 is constructed by an apparatus such as a router and a switch, cables and the like, for example. The user uses these apparatuses by purchasing or leasing them. The home network 5 is a communication network compatible with a communication interface corresponding to a wireless LAN such as Wi-Fi. The home network 5 and the display apparatus 1 are connected to each other via the communication interface. Wi-Fi is standard specification of the wireless LAN, which is formulated by IEEE's standard “IEEE 802.11a/IEEE 802.11b”. The home network 5 may be a communication network compatible with a communication interface corresponding to a wired LAN. The home network 5 can be connected to the external network 6 such as the Internet. The home network 5 has a communication interface to the external network 6, for example, an optical communication interface. The content distribution server 7 is connected to the external network 6. The content distribution server 7 is managed by the service provider, and is a server apparatus that provides a predetermined content distribution service. The content distribution server 7 holds and manages the contents. The content distribution server 7 distributes the contents in accordance with a request from the display apparatus 1 that is connected via the external network 6. The contents are a movie film, a video distribute program, and the like, which contain a video, an audio, character information and the like. The contents contain content data and content information. The content data are data such as a video. The content information is information for management and control regarding the contents, metadata, and the like. The broadcast station 8 provides the broadcast program and the like by means of broadcast waves. The TV receiver that is the display apparatus 1 has a function to receive the broadcast waves, a function to reproduce the broadcast program and the like, and a function to display the broadcast program on the screen. Each of the plurality of display apparatus 1 of the home network 5 can give and receive information with an external server and the like including the content distribution server 7 through the home network 5 and the external network 6. Each device can use a content distribution service of the content distribution server 7 by carrying out authentication using the account information, and can receive and reproduce contents. The display apparatus 1 communicates with the content distribution server 7 via the home network 5 and the external network 6 on the basis of a user operation. The display apparatus 1 transmits, to the content distribution server 7, a content reproducing request and user authentication information containing the account information for the user authentication. The display apparatus 1 receives contents from the content distribution server 7 after success of the user authentication, and reproduces the contents. This makes it possible for the user to view the contents through the display apparatus 1. The plurality of display apparatus 1 in FIG. 1 has a similar configuration and the same functions. They are not limited to this. In the plurality of display apparatus 1, a display system, an auxiliary function and the like other than essential elements, for example, may be different from each other, or different types of devices may be mixed. In FIG. 1, the plurality (“n”) of display apparatus 1 has already been installed and connected in the home network 5 at an initial state. It is not limited to this, and addition, removal, exchange or the like may occur in the home network 5 appropriately. The mobile terminal 2 of the user can be applied to various kinds of apparatuses including a smartphone, a tablet and the like. The mobile terminal 2 has a known configuration including a wireless communication function and the like. Each of the mobile terminal 2 and the display apparatus 1 has a communication interface for connecting to and communicating with each other in home. This communication interface may be wireless one or wired one, and may be even a short-range communication interface. The mobile terminal 2 has account information 101. The account information 101 is at least temporarily stored in storage means of the mobile terminal 2. In the example of FIG. 1, the mobile terminal 2 has account information (which is indicated by “A1”) 101 of a user U1, which is associated with the content distribution service (which is indicated by “X1”) of the content distribution server 7. This account information 101 is a target to be set to the display apparatus 1. The mobile terminal 2 may include a program for working together with the display apparatus 1, and the like. The program may be an application for using the account sharing function of the display apparatus 1. The application may cause the mobile terminal 2 to display a screen provided by the account sharing function. Further, the program for working together with the display apparatus 1 may be an application for giving an instruction to the display apparatus 1 from the mobile terminal 2 to use a function of the display apparatus 1. Namely, the application may be an application for using the mobile terminal 2 as a remote controller of the display apparatus 1. In this case, the mobile terminal 2 may be used as input means against the display apparatus 1. The mobile terminal 2 transmits, on the basis of a user input operation, an instruction for a predetermined control operation to the display apparatus 1 in a communication connection state with the display apparatus 1. The display apparatus 1 receives the instruction from the mobile terminal 2, and carries out an operation corresponding to the predetermined control operation in accordance with the instruction. The display apparatus 1 includes, as processing units that are constituent elements, a content reproducing unit 42, a user authenticating unit 44, and an account information sharing unit 45. The content reproducing unit 42 carries out a process to receive and reproduce contents, and display the contents on a screen in the display apparatus 1. The user authenticating unit 44 carries out a process related to the user authentication from the content distribution server 7 in the display apparatus 1 by using the account information. The account information sharing unit 45 is an element that realizes the account sharing function. The account information sharing unit 45 works together with the user authenticating unit 44 to carry out a process to cause the plurality of display apparatus 1 of the home network 5 to share the account information of the mobile terminal 2. Details of each unit will be described later. [Content Distribution Server] FIG. 2 shows a functional block configuration of hardware and software of the content distribution server 7. The content distribution server 7 includes a communication interface unit 50, a control unit 51, a memory 52, a storage 53 and the like, which are connected to each other via a bus 57. Various kinds of data, programs such as an application program, various kinds of information generated by the application program, contents 54, user managing information 55, apparatus information 56, and the like are stored in the storage 53. The control unit 51 controls the content distribution server 7. The control unit 51 develops from the storage 53 to the memory 52 and carries out the developed programs, thereby configuring various kinds of program function units in the memory 52. Various kinds of functions of the content distribution server 7 are realized by the various kinds of program function units. The various kinds of program function units contain a user managing unit 31, a content managing unit 32, and a content distributing unit 33. The communication interface unit 50 has a communication interface with the external network 6 to connect to the external network 6 and carry out a communicating process. The communication interface unit 50 transmits and receives information to and from the display apparatus 1 via the external network 6 and the home network 5. The user managing unit 31 includes a function to carry out the user authentication and the apparatus authentication, and manages information for authentication in the user managing information 55 and/or the apparatus information 56 of the storage 53. The user managing unit 31 distinguishes the user of the display apparatus 1 by means of the user authentication using the account information. The user managing information 55 is information for the user authentication containing the account information of the user. The apparatus information 56 is information for the apparatus authentication. Information containing the account information and user basic information is managed in the user managing information 55 in a table form, for example. The user basic information is information such as a name, address, and contact address. Key information, resume information, charging information, and the like may be managed in the user managing information 55. The resume information is information such as a content reproduction stopping position in the apparatus of the user. The content managing unit 32 accumulates and manages contents as a distribution target in the storage 53 as the contents 54. The contents 54 contain the content data and the content information. The contents 54 may be stored in an external apparatus of the content distribution server 7, for example, a DB server or the like on the external network 6. The contents 54 may contain applications, accompanying information, and the like. This application is a program that is transmitted together with the content data and used when to reproduce the contents on the display apparatus 1, for example. As examples of the content information, there are a content ID, a format, explanatory information, a size, a target apparatus, charge information, a viewing period, and the like. The explanatory information contains a genre, a title, and the like. The target apparatus is information indicating an apparatus suitable for display of the contents and execution of the application. The charge information is information for managing a usage charge of the content distribution service. The content distributing unit 33 carries out a process to distribute contents based on the contents 54 to the display apparatus 1 and the mobile terminal 2, which is the apparatus of the user, through the communication interface unit 50. The content distributing unit 33 carries out a control to distribute contents in accordance with performance of the apparatus of the user, for example, a process to distribute the content data with suitable resolution. The content distribution server 7 carries out the user authentication by the user managing unit 31 from the apparatus of the user when to log in the content distribution service, or when to receive the content reproducing request. At that time, the user managing unit 31 receives user authentication information containing the account information from the apparatus of the user. Further, in a case where the apparatus authentication is to be carried out, the user managing unit 31 receives apparatus information, for example, an apparatus ID of the display apparatus 1 from the apparatus of the user. The user managing unit 31 refers to the account information in the user managing information 55 to compare and check it with the account information from the apparatus of the user and determine a result of the user authentication. In a case where information of the both coincides with each other, the user managing unit 31 determines a result as success. In a case where they do not coincide with each other, the user managing unit 31 determines the result as failure. Further, in a case where a predetermined condition according to the content distribution service is not satisfied, the user managing unit 31 determines the result as failure. The user managing unit 31 transmits a response expressing the result of the authentication to the apparatus of the user. In a case where the result of the user authentication is success, the content distribution server 7 permits to receive and reproduce the contents in the apparatus of the user. The contents specified by the contents 54 is distributed to the apparatus of the user by the content distributing unit 33. Although it complies with the content distribution service, a plurality of accounts can be assigned to one display apparatus 1 or a plurality of display apparatus 1 with respect to the account. Further, a dependency relation among the plurality of accounts can be set with respect to the account. [Hardware Configuration of Display Apparatus] FIG. 3 shows a hardware configuration of a TV receiver that is the display apparatus 1 according to the first embodiment. The display apparatus 1 is connected to an antenna 11, and includes a tuner demodulating unit 12, a channel selection control unit 13, a signal separating unit 14, an audio decoding unit 15, a speaker 16, an audio outputting unit 17, a video decoding unit 18, a superimposing unit 19, a display unit 20, a video outputting unit 21, a communication interface unit 22, input means 23, a control unit 24, a memory 25, a storage 26, a digital interface unit 27, and the like. The respective units are connected to each other via a bus 28. Various kinds of data, programs such as an application program, various kinds of information generated by the application program, contents received by distribution, and the like are stored in the storage 26. The control unit 24 controls the display apparatus 1. The control unit 24 develops a program from the storage 26 in the memory 25 and carries out the program. This causes the various kinds of program function units to be configured in the memory 25. Various kinds of functions of the display apparatus 1 are realized by the various kinds of program function units. The input means 23 is an input device, an input interface or the like that receives a user input operation for the display apparatus 1, such as an operation panel, a remote controller, a keyboard, a mouse, a touch panel, for example. The user can instruct and set the display apparatus 1 by using the input means 23. The control unit 24 receives the user input operation through the input means 23 to control each unit of the channel selection control unit 13, the signal separating unit 14, the superimposing unit 19, the various kinds of program function units, the storage 26, the communication interface unit 22, and the like. The tuner demodulating unit 12 is controlled by the channel selection control unit 13 to turn to a desired channel of the service. The tuner demodulating unit 12 selects, as a channel, a digital broadcasting signal received from the broadcast station 8 via the antenna 11, and demodulates it to generate a transport stream. The channel selection control unit 13 receives a service channel-selecting instruction via the input means 23 to control the tuner demodulating unit 12 so as to switch channels to be selected. The channel selection control unit 13 controls the tuner demodulating unit 12 so as to switch to a channel number of a service or the like that broadcasts a program while currently being broadcasted by an instruction from the various kinds of program function units. The communication interface unit 22 has a communication interface with the home network 5 and a communication interface with the mobile terminal 2 to carry out respective communicating processes. The communication interface unit 22 is connected to the home network 5 via a communication interface compatible with a wireless LAN and the like. The communication interface unit 22 carries out the communicating process with a device on the external network 6 via the home network 5. The communication interface unit 22 can receive a content stream, a video/audio stream, an application program and the like as contents of the IPTV service from the content distribution server 7. The communication interface unit 22 carries out the communicating process with the mobile terminal 2 directly or via the home network 5. Data and information received through the communication interface unit 22 are stored in the storage 26 or the like. The communication interface unit 22 may have a function to directly communicate with an external apparatus via a predetermined communication interface in addition to or in place of a communicating function with the home network 5. The communication interface may be a wireless LAN such as Wi-Fi, IrDA (registered trademark), Bluetooth (registered trademark), NFC (Near Field Communication) or the like. The signal separating unit 14 separates the transport stream obtained by the tuner demodulating unit 12 and a stream of contents obtained through the communication interface unit 22 into types such as video data, audio data, caption sentence data, program information and the like. The signal separating unit 14 has a function to obtain the program information and transmit it to the other processing unit. In a case where there is a data transmitting request from the other processing unit, the signal separating unit 14 transmits specified data to a requestor. The audio decoding unit 15 decodes the audio data separated by the signal separating unit 14. Audio information decoded by the audio decoding unit 15 is outputted from the speaker 16. The audio information decoded by the audio decoding unit 15 may be outputted from the audio outputting unit 17 to the external apparatus. The video decoding unit 18 decodes the video data separated by the signal separating unit 14. The video information decoded by the video decoding unit 18 is transmitted to the superimposing unit 19. The superimposing unit 19 superimposes an EPG image and an OSD image created by the various kinds of program function units, an image generated from various kinds of information separated by the signal separating unit 14 onto the decoded video information from the video decoding unit 18. The various kinds of information contain subtitle information and the like. The superimposing unit 19 carries out composition of a browser displaying screen created by a browser engine (will be described later) and a video signal, switching of its selection and the like. The video information through the superimposing unit 19 is transmitted to the display unit 20 and displayed on the display unit 20. The display unit 20 is configured by a liquid crystal panel, a projection optical system, or the like, for example. The display unit 20 displays the video information on a screen. The video information contains a video of a broadcast via the tuner demodulating unit 12, a video of distribution via the communication interface unit 22, user interface information, the browser displaying screen, an image in the storage 26, something generated by the application program, and the like. The video information through the superimposing unit 19 may be outputted from the video outputting unit 21 to the external apparatus. The digital interface unit 27 outputs the transport stream separated by the signal separating unit 14 to the outside as digital data without decoding of a video or an audio. In a case where the display apparatus 1 is an apparatus such as the recorder or the set-top box, the display apparatus 1 has a configuration in which elements such as the display unit 20 and the speaker 16 are omitted. Thus, the display apparatus 1 has apparatuses such as the TV receiver, the monitoring device and the speaker, which are connect to the outside of this apparatus such as the recorder. Videos, audios and the like are transferred from the apparatus such as the recorder to the external apparatus to cause the external apparatus to output them. In a case where the display apparatus 1 is a PC or the monitoring device, the display apparatus 1 has a configuration in which a function to receive broadcast waves, that is, the antenna 11, the tuner demodulating unit 12 and the like are omitted. [Software Configuration of Display Apparatus] FIG. 4 shows a configuration of the memory 25 and the storage 26 as a software configuration of the display apparatus 1 in FIG. 2. Various kinds of data 501, programs, contents 502, user authentication information 503 containing account information 504, setting information 505, and the like are stored in the storage 26. The programs include a browser program 401, a content reproducing program 402, various kinds of application programs 403, a user authenticating program 404, and an account information sharing program 405. By developing the respective programs to the memory 25, a browser engine 41, the content reproducing unit 42, a various application unit 43, the user authenticating unit 44, the account information sharing unit 45, a user setting unit 46, and the like are composed. The account information 504 is user input information inputted by the user through the input means 23 at the time of user authentication or shared account information (will be described later). The account information 504 is information on a combination of a user ID and a password, for example. The user authentication information 503 may be stored not only in the storage 26, but also in a nonvolatile memory or external storage means (not shown in the drawings). It may contain apparatus authentication information for carrying out apparatus authentication in the user authentication information 503 or in parallel to this. The apparatus authentication information contains an apparatus ID of the mobile terminal 2 and/or the display apparatus 1, for example. As the apparatus ID, there are a MAC address, and an inherent (or unique) ID at the time of manufacture, for example. The user authentication information 503 containing the account information 504 may be one in which the user can change a value thereof, or one in which the value is determined in advance by the service provider or the like. The browser engine 41 includes function blocks such as an HTML parser, a DB creating unit, a rendering unit, and an image processing unit. The HTML parser analyzes a logical structure of HTML data that is obtained via the control unit 24. The HTML parser can interpret the HTML data to change into internal data that is to be used in the TV receiver. The DB creating unit generates a database regarding a structure of the HTML data. The rendering unit generates, on the basis of the database, a layout structure containing information with an expression form determined in each tag. The rendering unit generates, on the basis of the layout structure, the browser displaying screen in accordance with data in which magnitude, a position, and an image are taken. The image processing unit converts an obtained image file into image data on the basis of image file information that is specified by an image tag in the HTML data. The content reproducing unit 42 receives contents from the content distribution server 7 through the communication interface unit 22, and stores them in the storage 26 as the contents 502. The content reproducing unit 42 carries out a process to reproduce the contents 502, that is, a process to display a video of the contents 502 on a screen of the display unit 20, and the like. When to carry out the user authentication from the content distribution server 7, the user authenticating unit 44 carries out a process related to the user authentication by using the user authentication information 503 containing the account information 504. When to carry out the user authentication, the user authenticating unit 44 transmits the user authentication information 503 to the content distribution server 7 via the home network 5 and the external network 6 through the communication interface unit 22. The user authenticating unit 44 receives a result of the user authentication from the content distribution server 7. The user authenticating unit 44 may display the user interface information such as the user authentication information and a message on the screen of the display unit 20 when to carry out the user authentication. Application of the various application unit 43 indicate applications that are downloaded from the content distribution server 7 or the like in accordance with user's taste. The various application unit 43 carries out processes according to the applications. The account information sharing unit 45 works together with the process related to the user authentication of the user authenticating unit 44. The account information sharing unit 45 carries out a process to share the account information with the plurality of display apparatus 1 of the home network 5. The account information sharing unit 45 gets the account information associated with the mobile terminal 2 and had by the mobile terminal 2 from the mobile terminal 2 directly or via the home network 5. The account information sharing unit 45 registers the account information into the user authentication information 503 as the account information 504. The account information sharing unit 45 sets the account information as the shared account information of the plurality of display apparatus 1 of the home network 5. The account information sharing unit 45 controls the account information among the display apparatus 1 so that the account information can be shared with the plurality of display apparatus 1 and used for the user authentication. The account information sharing unit 45 controls so as to use the account information as one of input means of the user authentication information 503 to the user authenticating unit 44. Namely, the account information sharing unit 45 provides alternate means to input the account information through the input means 23. The user normally inputs the account information through the input means 23 when to carry out the user authentication in the display apparatus 1. On the other hand, in the embodiment, the account information 504 registered as the shared account information is used for a process related to the user authentication of the user authenticating unit 44 by using the account sharing function by the account information sharing unit 45. This makes it possible for the user to omit an account information inputting operation. Otherwise, details of the account information sharing unit 45 will be described later. The user setting unit 46 realizes a user setting function of the display apparatus 1. The user setting unit 46 causes the display unit 20 to display a setting screen on the basis of a user input operation. The user can carry out overall settings for the display apparatus 1 on the setting screen on the basis of the user input operation. The user setting unit 46 manages the setting information 505 for managing a setting state in the storage 26, a nonvolatile memory or the like. The other processing unit carries out an operation in accordance with the setting state of the setting information 505. [User Authentication] Timing of the user authentication of the content distribution service and a procedure example for communication are as follows. In a case where user authentication is to be carried out when to log in the content distribution service, it is as follows. The display apparatus 1 of the user accesses the content distribution service in order to log therein on the basis of a user operation. The content distribution server 7 transmits a user authentication information request to the display apparatus 1 for user authentication at the time of log-in. When the user authentication information request is received, the display apparatus 1 transmits user authentication information containing account information to the content distribution server 7. When the user authentication information is received, the content distribution server 7 compares and checks it with registered user authentication information to carry out the user authentication. In a case where a result of the user authentication is success, the content distribution server 7 transmits a response that the log-in is permitted. In a case where the result is failure, the content distribution server 7 transmits a response that the log-in is not permitted. A portal screen to view contents may be provided to the apparatus of the user who is a regular user for whom the user authentication is succeeded. The display apparatus 1 displays the portal screen on the basis of communication with the content distribution server 7. The portal screen contains content list information and the like. The user is allowed to select or search target contents to be viewed on the portal screen. The user can view contents in a log-in state without requiring user authentication. The display apparatus 1 transmits a content reproducing request including a content ID of contents selected by the user to the content distribution server 7. When the content reproducing request is received, the content distribution server 7 distributes the specified contents. In a case where user authentication for each content is carried out, it is as follows. The display apparatus 1 of the user transmits the content reproducing request, which contains the content ID of the contents selected by the user via the portal screen or the like, to the content distribution server 7. The content distribution server 7 transmits the user authentication information request to the display apparatus 1 for user authentication for each of the contents. When the user authentication information request is received, the display apparatus 1 transmits the user authentication information containing the account information to the content distribution server 7. The content distribution server 7 carries out the user authentication similarly. In a case where a result of the user authentication is success, the content distribution server 7 transmits a response that reproduction of the contents is permitted, and distributes the specified contents. In a case where the result is failure, the content distribution server 7 transmits a response that reproduction of the contents is not permitted. The content reproducing request and the user authentication information may be transmitted together. [Initial Setting] An operation and processing at the time of initial setting regarding the account information according to the first embodiment will be described with reference to FIG. 5 and the like. Here, the initial setting is setting necessary to make a state where the user is allowed to view contents via the display apparatus 1 in the system of FIG. 1. [Operating Sequence] FIG. 5 shows an example of an operating sequence between apparatuses at the time of initial setting according to the first embodiment. In FIG. 5, each of the plurality of display apparatus 1 has the same functions including the account information sharing unit 45. In the example of FIG. 5, the mobile terminal 2 of the user U1 is connected to a certain display apparatus 1a of the home network 5 to transfer and register the account information 101. Then, the account information 101 is shared with the plurality of display apparatus 1a to 1n of the home network 5 so as to be available. The initial setting of FIG. 5 includes an operation in which the account information 101 that the mobile terminal 2 has is registered in the plurality of display apparatus 1 of the home network 5 as the shared account information. There are Steps S1 to S9 in FIG. 5. Hereinafter, the operating sequence will be described in the order of Steps. (S1) The mobile terminal 2 of the user U1 is connected to any display apparatus 1 of the home network 5, for example, the display apparatus 1a by wireless connection or the like. The display apparatus 1a to which the mobile terminal 2 is connected in this manner is also referred to as “first apparatus” for convenience of explanation. (S2) The account information sharing unit 45 of the display apparatus 1a that is the first apparatus communicates with the mobile terminal 2 to obtain the account information 101 that the mobile terminal 2 has therein by causing the display apparatus 1a to transfer it. At the time of this transfer, it may be transferred in response to a request from the first apparatus to the mobile terminal 2, or transferred in response to an instruction from the mobile terminal 2 to the first apparatus. Further, the user may carry out an input operation corresponding to the initial setting against the mobile terminal 2 or the display apparatus 1. The mobile terminal 2 or the display apparatus 1 may receive the input operation to carry out transfer of the account information. (S3) The account information sharing unit 45 of the display apparatus 1a, which is the first apparatus registers, as the shared account information, the account information 101 obtained from the mobile terminal 2 to the account information 504 of the user authentication information 503 in the storage 26 of the display apparatus 1a. (S4) On the other hand, other display apparatus 1 of the home network 5, for example, the display apparatus 1b does not hold account information therein at the time of the initial setting. The other display apparatus 1 such as the display apparatus 1b to 1n is also referred to as “second apparatus” for convenience of explanation. The account information sharing unit 45 of the display apparatus 1b that is the second apparatus make an inquiry regarding the account information to the other display apparatus 1 of the home network 5, for example, the display apparatus 1a. This inquiry is an inquiry of whether to hold the account information or not, and is an inquiry containing a transfer request in a case where the account information is held. (S5) The display apparatus 1a that is the first apparatus carries out a response when to receive the inquiry from the display apparatus 1b that is the second apparatus. The account information sharing unit 45 of the first apparatus reads out the account information, which has already been registered in its own storage 26 as the shared account information, to transfer information containing the account information to the display apparatus 1b as an inquiry source, which is the second apparatus. (S6) When the information containing the account information transferred from the display apparatus 1a as an inquiry destination is received as a response, the display apparatus 1b as the inquiry source registers the account information in the account information 504 of the user authentication information 503 in its own storage 26 as the shared account information. This causes a state where the account information is also held in the display apparatus 1b. The display apparatus 1n and the like that are the other display apparatus 1 carry out the above operation similarly, thereby becoming a state the same account information is held in each of the display apparatus 1. This causes a state where the initial setting has been finished. The above operation is similar even in a case where any of the plurality of display apparatus 1 become the first apparatus and the second apparatus. For example, in a case where the mobile terminal 2 is first connected to the display apparatus 1b, the display apparatus 1b becomes the first apparatus and the other display apparatus 1 becomes the second apparatus. (S7) Then, when user authentication with the content distribution server 7 is carried out, the display apparatus 1a that is the first apparatus can carry out a process related to the user authentication by using the account information, which has already been registered therein at S3, by means of the user authenticating unit 44. (S8) Further, the mobile terminal 2 of the user U1 is then connected to the display apparatus 1b that is the second apparatus. In this case, the account information has already been registered in the display apparatus 1b at S6. For this reason, there is no need to transfer the account information from the mobile terminal 2 to the display apparatus 1b, and there is also no need to carry out an account registering process. (S9) As well as the display apparatus 1a, when the user authentication with the content distribution server 7 is carried out, the display apparatus 1b that is the second apparatus can carry out the process related to the user authentication by using the account information, which has already been registered therein at S6, by means of the user authenticating unit 44. [Processing Flow (1)] FIG. 6 shows a processing flow at the time of the initial setting in the display apparatus 1 according to the first embodiment. (A) of FIG. 6 shows a flow of first processing corresponding to the “first apparatus” of FIG. 5. (B) of FIG. 6 shows a flow of second processing corresponding to the “second apparatus” of FIG. 5. There are Steps S101 to S105 in (A) of FIG. 6. Hereinafter, the processing flow will be described in the order of Steps. (S101) The first apparatus is connected to the mobile terminal 2. (S102) The account information sharing unit 45 requests the mobile terminal 2 to transfer account information that the mobile terminal 2 has. This causes the account information to be transferred from the mobile terminal 2 to the display apparatus 1. The account information sharing unit 45 receives and obtains the transferred account information. (S103) The account information sharing unit 45 registers the account information obtained at S102 in the account information 504 of the user authentication information 503 in the storage 26 as the shared account information. At this time, the account information may be transferred or delivered from the account information sharing unit 45 to the user authenticating unit 44 to register the account information by the user authenticating unit 44. (S104) The account information sharing unit 45 waits for inquiry from the second apparatus that is another display apparatus 1 of the home network 5. In a case where the second apparatus receives inquiry from the account information sharing unit 45 (S104—Y), the processing flow proceeds to S105. (S105) The account information sharing unit 45 determines whether there is a problem or not even when the account information is provided to the second apparatus in response to the inquiry from the second apparatus. After it is confirmed that there is no problem, the account information sharing unit 45 reads out the shared account information held in the account information 504 of the storage 26, and transfers information containing the account information to the second apparatus that carried out the inquiry via the home network 5. There are Steps S111 to S115 in (B) of FIG. 6. Hereinafter, the processing flow will be described in the order of Steps. (S111) The account information sharing unit 45 of the second apparatus confirms whether the account information is held in the account information 504 of its own storage 26 or not, that is, whether the shared account information has already been registered or not. In a case where it is held (S111—Y), the processing flow terminates the process for the initial setting. In a case where it is not held (S111—N), the processing flow proceeds to S112. (S112) The account information sharing unit 45 confirms whether the other display apparatus 1 is connected to the home network 5 or not. In this regard, this step may be omitted in a case where it is known in advance connection and the display apparatus 1 thereof. In a case where the other display apparatus 1 is connected (S112—Y), the processing flow proceeds to S113. In a case where no display apparatus 1 is connected (S112—N), the processing flow is terminated. (S113) The account information sharing unit 45 transmits information on the inquiry regarding the account information to the other display apparatus 1 in the home network 5 via the home network 5. The other display apparatus 1 as an inquiry destination may be the first apparatus, or may be the second apparatus. (S114) In a case where the account information is transferred to the account information sharing unit 45 as a response from the first apparatus (S114—Y), the processing flow proceeds to S115. In a case where it is not transferred, the other display apparatus 1 as the inquiry destination is the second apparatus in which the account information is not held. The account information sharing unit 45 similarly carries out an inquiry in a case where there is the other display apparatus 1. In a case where the account information is not transferred from any of the display apparatus 1 (S114—N), the processing flow is terminated. (S115) The account information sharing unit 45 registers the account information received from the first apparatus to the account information 504 of the user authentication information 503 in its own storage 26 as the shared account information. Herewith, the process for the initial setting is terminated. In this regard, as a modification example, the confirmation of whether the account information is held or not and a request of transfer in the inquiry at S113 may be separated as separate communicating steps. Further, the second apparatus may similarly make an inquiry to all of the other display apparatus 1 of the home network 5 at the time of the inquiry, or may make an inquiry to a specific display apparatus 1. For example, in a case where the first apparatus in the home network 5 is known in advance, the account information sharing unit 45 may transmit a request of transfer to only the first apparatus. Further, when to transfer the account information among the display apparatus 1, the account information may be subjected to encryption or the like. The account information sharing unit 45 may manage, as information, a state of holding and sharing of the account information in the plurality of display apparatus 1 of the home network 5 in a table. For example, information on an apparatus ID, whether the account information of each of the display apparatus 1 is held or not, a role thereof and the like may be managed in the table for each piece of account information. As the role, there are the first apparatus, the second apparatus and the like. [Effects and the Like] As described above, according to the content viewing system of the first embodiment, it is possible to reduce labor for the user to set the account information to the plurality of display apparatus 1 of the home network 5 while securing control of authority to view contents by using the account information as a premise, and this makes it possible to user-friendly improve convenience in various environments and situations. For example, the user may carry out a work to register the account information that the mobile terminal 2 has to the first apparatus that is one of the display apparatus 1 of the home network 5 during the initial setting. This causes a state where the account information is automatically registered to the plurality of display apparatus 1 of the home network 5 to become sharing available. There is no need to separately register the account information to each of the display apparatus 1 of the home network, and this makes labor of the user smaller. The prior art is not a technique in which it is not considered that a mobile terminal and a display apparatus work together. Even in a case where the mobile terminal has account information, it is not easy to share the account information with a plurality of display apparatus of a home network. On the other hand, according to the first embodiment, such sharing can be easily realized by a simple operation. The following is cited as a modification example of the first embodiment. First, for example, there is a first television and a second television as the plurality of display apparatus 1 of the home network 5. Account information of the mobile terminal 2 has already been registered to the first television. A third television is newly added to home. An account information sharing unit 45 of the third television makes an inquiry to the other display apparatus 1 of the home network 5, for example, the first television for its own initial setting when the third television is connected to the home network 5. The first television that receives the inquiry transfers the account information to the third television. The third television registers the account information thereto, and terminates the initial setting. Namely, an account sharing function according to the modification example realizes a function to carry out registration for sharing the account information when the display apparatus 1 is connected to the home network 5. As another modification example, it may be a form of a home system that allows communication between a plurality of display apparatus 1 and between each of the display apparatus 1 and an external apparatus without a home network 5. In that case, an account sharing function is a function to share account information in the home system. First Modification Example The following is possible as a first modification example of the first embodiment. A first apparatus that is a display apparatus 1 registers therein account information obtained from a mobile terminal 2, and immediately transfers it to second apparatuses that are the other display apparatus 1 in a home network 5. The second apparatus that receives the account information thus immediately transferred registers the account information thereto. FIG. 7 shows an example of an operating sequence between apparatuses at the time of initial setting according to the first modification example of the first embodiment. There are Steps S11 to S16 in FIG. 7. Hereinafter, the operating sequence will be described in the order of Steps. (S11 to S13) At S11, the mobile terminal 2 of the user U1 is connected to any display apparatus 1 of the home network 5, for example, the display apparatus 1a. At S12, the account information sharing unit 45 of the display apparatus 1a that is the first apparatus causes the mobile terminal 2 to transfer the account information 101 that the mobile terminal 2 has to the display apparatus 1a to obtain it. At S13, the account information sharing unit 45 registers the account information 101 obtained from the mobile terminal 2 to the user authentication information 503 therein as the shared account information. (S14) Moreover, the account information sharing unit 45 of the display apparatus 1a that is the first apparatus immediately transfers information containing the account information at S13 to each of the second apparatuses that are the other display apparatus 1 of the home network 5. This information thus immediately transferred is also a registering instruction to the second apparatus. This immediate transfer may be carried out by broadcast transmission to the other display apparatus 1 of the home network 5, for example, or may be carried out by sequential transmission to each of the other display apparatus 1 in a predetermined order. (S15) On the other hand, each of the second apparatuses that are the other display apparatus 1 of the home network 5, for example, the display apparatus 1b receives the information immediately transferred at S14 from the first apparatus. The second apparatus registers the account information to the user authentication information 503 therein as the shared account information. This causes a state where the account information is also held in the display apparatus 1b. Similarly, it becomes a state where the account information is held in each of the display apparatus 1. This causes a state where the initial setting has already been finished. The above operation is similar even in a case where any of the plurality of display apparatus 1 become the first apparatus and the second apparatus. (S16) Then, the display apparatus 1a or the display apparatus 1b can carry out the process related to the user authentication by using the account information that has already been registered thereto when the user authentication with the content distribution server 7 is carried out. According to the first modification example of the first embodiment, the inquiry described above is not required, and by carrying out immediate transfer, it is possible to shorten a time required for the initial setting. Second Embodiment A display apparatus 1 and the like according to a second embodiment of the present invention will be described with reference to FIG. 8 to FIG. 9. A basic configuration according to the second embodiment is similar to that according to the first embodiment. Hereinafter, component parts of the second embodiment different from those of the first embodiment will be described. In the second embodiment, sharing of account information is realized in a home network 5 as well as the first embodiment. However, a processing method therefor is partly different from that of the first embodiment. In the second embodiment, a first apparatus that is a display apparatus 1 to which account information of a mobile terminal 2 is registered among a plurality of display apparatus 1 of the home network 5 is set to an “account server”. The “account server” mentioned herein means an apparatus and a role that representatively manages account information in the home network 5. The account information is not registered to a second apparatus that is another display apparatus 1 in the home network 5. Whenever the account information is required for user authentication, the second apparatus accesses the account server that is the first apparatus, and refers to and uses the account information. [Operating Sequence] FIG. 8 shows an example of an operating sequence between apparatuses at the time of initial setting according to the second embodiment. There are Steps S21 to S28 in FIG. 8. Hereinafter, the operating sequence will be described in the order of Steps. (S21) A mobile terminal 2 of a user U1 is connected to any display apparatus 1 of the home network 5, for example, a display apparatus 1a. (S22) Account information sharing unit 45 of the display apparatus 1a that is the first apparatus causes the display apparatus 1a to transfer account information 101 that the mobile terminal 2 has thereto, and obtains it. (S23) The account information sharing unit 45 registers, as shared account information, the account information 101 obtained from the mobile terminal 2 in account information 504 of user authentication information 503 of its own storage 26. The display apparatus 1a that is the first apparatus becomes the account server that manages the shared account information. The initial setting is basically terminated up to this point. In this regard, after S23, a step of notifying, from the display apparatus 1a that is the first apparatus, each of second apparatuses that are the other display apparatus 1 that the display apparatus 1a becomes an account server may further be provided. (S24) On the other hand, the second apparatus that is the other display apparatus 1 of the home network 5 does not hold the account information. User authentication with a content distribution server 7 occurs in the second apparatus, for example, the display apparatus 1b. Namely, necessity of account information occurs for the user authentication. (S25) An account information sharing unit 45 of the second apparatus transmits a reference request of the account information to the account server that is the first apparatus of the home network 5. (S26) In a case where a reference request is received from the second apparatus, the account information sharing unit 45 of the first apparatus transmits, as a response, the account information, which has already been registered thereto at S23, to the second apparatus as a requestor. (S27) The account information sharing unit 45 of the second apparatus does not register the account information received from the first apparatus to the second apparatus, but uses it in a process related to the user authentication of the user authenticating unit 44. (S28) Further, then, when user authentication with the content distribution server 7 is carried out, the display apparatus 1a that is the account server can use the account information held therein to carry out a process related to the user authentication. The above operation is similar even in a case where any of the plurality of display apparatus 1 become the first apparatus and the second apparatus. Only one display apparatus 1a is set as the account server in the above example. However, it is not limited to this. Two or more display apparatus 1 may become the account server. In that case, the second apparatus may access any of the account servers. Moreover, only a specific display apparatus 1 of the plurality of display apparatus 1 of the home network 5 may be set so as to become the account server. For example, by using a user setting function of the display apparatus 1, only the display apparatus 1a is set so as to become the account server. In that case, even though the mobile terminal 2 is first connected to any of apparatuses other than the display apparatus 1a, it is controlled so as not to become an account server on the basis of setting. [Processing Flow] FIG. 9 shows a processing flow at the time of initial setting in the display apparatus 1 according to the second embodiment. (A) of FIG. 9 shows a flow of first processing corresponding to the account server that is the first apparatus. (B) of FIG. 9 shows a flow of second processing corresponding to the second apparatus. There are Steps S141 to S145 in (A) of FIG. 9. Hereinafter, the processing flow will be described in the order of Steps. (S141 to S143) Steps S141 to S143 are similar to Steps S101 to S103 in the first embodiment. (S144, S145) At S144, the account information sharing unit 45 of the first apparatus that is the account server waits for a reference request of the account information from the second apparatus that is another display apparatus 1 of the home network 5. In a case where the account information sharing unit 45 receives a reference request (S144—Y), the processing flow proceeds to S145. At S145, the account information sharing unit 45 transmits, as a response to the reference request, the account information that the first apparatus has to the second apparatus. There are Steps S151 to S155 in (B) of FIG. 9. Hereinafter, the processing flow will be described in the order of Steps. (S151 to S153) At S151, in a case where user authentication by the user authenticating unit 44, that is, necessity of the account information occurs (S151—Y), the account information sharing unit 45 of the second apparatus causes the processing flow to proceed to S152. At S152, the account information sharing unit 45 confirms whether the account server that is the first apparatus is connected to the home network 5 or not. In a case where they are connected to each other (S152—Y), the processing flow proceeds to S152. At S153, the account information sharing unit 45 transmits a reference request of the account information to the account server that is the first apparatus. (S154, S155) At S154, in a case where the account information sharing unit 45 receives the account information, which is transferred as the response, from the account server that is the first apparatus (S154), the processing flow proceeds to S155. At S155, the account information sharing unit 45 causes the user authenticating unit 44 to use the account information received at S154 for the user authentication, and terminates the processing flow without registering it in its own storage 26. [Effects and the Like] As described above, according to the second embodiment, it is possible to realize sharing of the account information of the home network 5 as well as the first embodiment. In the second embodiment, a step of referring to the first apparatus from the second apparatus becomes necessary at the time of the user authentication. However, there is an advantage that the account information may be held securely only in the first apparatus. Further, in a case where setting for releasing a sharing state is to be changed, deletion of the shared account information and the like may be carried out only in the first apparatus. Third Embodiment A display apparatus 1 and the like according to a third embodiment of the present invention will be described with reference to FIG. 10 to FIG. 12. A basic configuration according to the third embodiment is similar to that of the first embodiment. Hereinafter, component parts of the third embodiment different from those of the first embodiment will be described. In the third embodiment, a situation is assumed that may occur in a case where plural pieces of account information of a plurality of mobile terminals 2 are registered in the display apparatus 1 of a home network 5. In the third embodiment, the display apparatus 1 has, as a setting change, a function to delete account information registered to the display apparatus 1 in accordance with a situation. [Content Viewing System] FIG. 10 shows an example of a content viewing system and an operating sequence according to the third embodiment. In FIG. 10, as a different point from FIG. 1, a user U2 who is a friend or the like of the user U1 is invited to home of the user U1. The user U1 possesses a “smartphone A” that is his or her own mobile terminal 2a, and the user U2 possesses a “smartphone B” that is his or her own mobile terminal 2b. The mobile terminal 2a of the user U1 has account information 101 regarding a content distribution service X1 as well as the first embodiment. Further, the mobile terminal 2b of the user U2 has account information 102 (which is indicated by “A2”) regarding the content distribution service X1. The user U2 can normally use the content distribution service X1 in home or the like of the user U2 by using his or her own display apparatus, the mobile terminal 2b, and the account information 102. In the example of FIG. 10, the user U2 who visits home of the user U1 temporarily uses the display apparatus 1 possessed by the user U1, and uses the content distribution service X1 by using the account information 102 of the mobile terminal 2b to view contents. The user U2 then goes home from the home of the user U1. The user U2 uses the same content distribution service X1 from the display apparatus of his or her home, for example. In the third embodiment, a function to control shared account information of the display apparatus 1 in home of the user U1 in such a situation is shown. [Operating Sequence] An example of an operating sequence according to the third embodiment will be described with reference to FIG. 10. There are Steps S31 to S36 in FIG. 10. Hereinafter, the operating sequence will be described in the order of Steps. (S31) First, an operation in home of the user U1 is basically similar to the operation that has been explained in the first embodiment. Namely, the account information 101 that the mobile terminal 2a has is registered to the display apparatus 1a as the shared account information, for example. (S32) The mobile terminal 2b of the user U2 who is a guest visiting home of the user U1 is connected to the display apparatus 1a, for example. (S33) Account information sharing unit 45 of the display apparatus 1a that is the first apparatus obtains the account information 102 that the mobile terminal 2b has by means of transfer. The display apparatus 1a registers the account information 102 to the account information 504 of the user authentication information 503 in its own storage 26. The account information 504 becomes a state where two of the account information 101 of the user U1 and the account information 102 of the user U2 are contained. In the present embodiment, as sharing of the account information, the account information 102 of the guest is held in only one display apparatus 1a. It is not limited to this. As well as the first embodiment and the like, the account information 102 of the guest can be held in the plurality of display apparatus 1 of the home network 5 by means of the account sharing function. In that case, the account information sharing unit 45 carries out transfer of the account information among the display apparatus 1 and the like as well as the first embodiment. This makes it possible for the user U2 to view contents via each of the display apparatus 1. Further, the mobile terminal 2b of the guest can be connected to any of the display apparatus 1 of the home network 5 to register the account information 102. Although it will be described later, user setting about whether the account information of the guest can be registered to the display apparatus 1 or not is possible. (S34) It becomes a state where the account information 102 of the user U2 is registered to the display apparatus 1a. Therefore, the user U2 can view contents of the content distribution service X1 on the display apparatus 1a through the user authentication using the account information 102. (S35) Then, the user U2 terminates to view the contents, and goes out from the home of the user U1 to his or her home, for example. A state 1101 shows a state where the mobile terminal 2b of the user U2 exists outside the home of the user U1, for example, in the home of the user U2. The user U2 uses the content distribution service X1 from the content distribution server 7 via the external network 6 through the display apparatus in the home and the mobile terminal 2b. Thus, in a case where the mobile terminal 2b whose account information 102 is registered to the display apparatus 1a becomes a situation to first exist in the home of the user U1 and go to the outside of the home, the account information 102 of the user U2 exists at both the home of the user U1 and the outside of the home of the user U1. In the case of such a situation, in the conventional system, a request from the home of the user U1 and a request from the outside of the home of the user U1 may occur as requests for a content distribution server. In that case, in a case where the content distribution server does not permit to view contents at a different place depending upon a service design, for example, a result of the user authentication for one request is set to failure not to permit viewing. The third embodiment is a technique in which such a situation is supposed. (S35) The account information sharing unit 45 of the display apparatus 1a that is the first apparatus, for example, regularly carries out whereabouts confirmation for the mobile terminal 2 to which the account information is registered, for example, the mobile terminal 2b. The account information sharing unit 45 carries out, as the whereabouts confirmation, detection and determination of whether the mobile terminal 2 of a registration source is in home associated with the home network 5 of the user U1 or not through the home network 5. This whereabouts confirmation is realized as follows, for example. The display apparatus 1 may detect and determine whether the mobile terminal 2 is in or outside home by determining whether the mobile terminal 2 is connected to the home network 5 or not. This connection determination may be determined on the basis of presence or absence of wireless connection between the display apparatus 1 and the mobile terminal 2, or may be determined on the basis of presence or absence of connection between the display apparatus 1 and the mobile terminal 2 via the home network 5. Further, the display apparatus 1 may try wireless connection to the mobile terminal 2 on the basis of information when to first carry out wireless connection to the mobile terminal 2, and determine it on the basis of its result. Namely, in a case where the wireless connection to the mobile terminal 2 is possible or there is a response therefrom, the display apparatus 1 may determine that the mobile terminal 2 exists in the home. In a case where the wireless connection is impossible or there is no response therefrom, the display apparatus 1 may determine that the mobile terminal 2 exists outside the home. In a case where wireless connection to the mobile terminal 2 is first established and the wireless connection is then cut or a predetermined time elapses after cutting the wireless connection, the display apparatus 1 may determine that the mobile terminal 2 exists outside the home. The whereabouts confirmation may be realized by using short-range wireless communication between an apparatus constituting the display apparatus 1 or the home network 5 and the mobile terminal 2. The whereabouts confirmation may use a method to use a beacon emitted by the mobile terminal 2 or the like and detect the beacon or the like by the display apparatus 1. Namely, the display apparatus 1 may determine that the mobile terminal 2 exists outside the home in a case where the mobile terminal 2 goes out from within a predetermined radius distance range associated with the home. At S35, the display apparatus 1a detects that a specific mobile terminal 2b whose account information is registered of a plurality of mobile terminals 2 that exists in the home of the user U1 does not exist in the home, that is, exists outside the home. (S36) The account information sharing unit 45 of the display apparatus 1a deletes the account information 102 of the mobile terminal 2b, which is registered and held thereto on the basis of detection of outside home at S35. Herewith, a setting state of the display apparatus 1a is updated to be invalidated so that the account information 102 cannot be used for the user authentication. This causes the user U2 to be set so that the user U2 cannot continue to use viewing of contents via the display apparatus 1 in the home of the user U1. [Processing Flow] FIG. 11 shows a processing flow as the first apparatus of the display apparatus 1 according to the third embodiment. There are Steps S161 to S165 in FIG. 11. Hereinafter, the processing flow will be described in the order of Steps. (S161 to S163) At S161, the first apparatus is connected to the mobile terminal 2 of a guest, for example, the mobile terminal 2b of the user U2. At S162, the account information sharing unit 45 of the first apparatus obtains account information of the mobile terminal 2 of the guest by means of transfer. At S163, the account information sharing unit 45 registers the account information of the guest to the account information 504 of the user authentication information 503 in its own storage 26. (S164, S165) At S164, the account information sharing unit 45 regularly carries out whereabouts confirmation of the mobile terminal 2 of the guest, which is a registration source of the account information at S163. In a case where the account information sharing unit 45 detects and determines that the mobile terminal 2 of the guest does not exist in the home, that is, exists outside the home (S164—N), the processing flow proceeds to S165. At S165, the account information sharing unit 45 deletes the account information of the mobile terminal 2 of the guest, which is registered to the account information 504 of the user authentication information 503 in its own storage 26. [Effects and the Like] As described above, according to the third embodiment, even in a case where a person such as a friend who comes to the home of the user temporarily uses the display apparatus 1 of the home network 5 to view contents, it is possible to carry out its setting easily. Further, in that case, the account information of the guest, which is registered to the display apparatus 1 in the home is deleted in a case where the mobile terminal 2 of the guest goes out from the home. Herewith, there is no worry that the account information is kept being used. The user as the guest is prevented from using the display apparatus 1 from the outside to view contents and the like. First Modification Example The following is possible as a first modification example of the third embodiment. In this first modification example, whereabouts confirmation and account information deletion for a mobile terminal 2 are carried out in accordance with a result of user authentication. FIG. 12 shows a processing flow as a first apparatus of a display apparatus 1 according to the first modification example of the third embodiment. There are Steps S171 to S176 in FIG. 12. Hereinafter, the processing flow will be described in the order of Steps. (S171) As well as the third embodiment, account information of the mobile terminal 2 of a guest is registered in the display apparatus 1. (S172, S173) At S172, user authentication with a content distribution server 7 occurs. The display apparatus 1 transmits a content reproducing request and the like to the content distribution server 7 on the basis of an operation of the user as the guest in accordance with a normal content view operating sequence. At that time, the user authenticating unit 44 transmits user authentication information containing the account information to the content distribution server 7 by using the account information of the guest that has already been registered thereto. The user authenticating unit 44 receives a result of user authentication from the content distribution server 7. At S173, in a case where in the display apparatus 1 the result of the user authentication is failure (S173—Y), the processing flow proceeds to S174. (S174, S175) At S174, the account information sharing unit 45 of the display apparatus 1 carries out the whereabouts confirmation of the mobile terminal 2 of the guest, which is a registration source of the account information. In a case where the mobile terminal 2 of the guest is in home (S174—Y), the processing flow is terminated because there is no problem. In a case where it is not in home (S174—N), the processing flow proceeds to S175. At S175, the account information sharing unit 45 works together with the user authenticating unit 44 to delete the account information of the mobile terminal 2 of the guest, which is registered thereto. In this regard, in a case where the account information is held in a plurality of display apparatus 1 of a home network 5 when to delete the account information, the first apparatus similarly deletes plural pieces of account information held in the plurality of display apparatus 1. In this case, for example, the first apparatus transmits an instruction to delete the account information to a second apparatus that is another display apparatus 1 of the home network 5. The second apparatus that receives the instruction deletes the corresponding account information that has been registered thereto. In the first modification example of the third embodiment, in a case where the result of the user authentication becomes failure in a situation that there is the account information in and outside the home of the user U1 as described above, the account information is deleted. This makes it possible to obtain the similar effects to those of the third embodiment. In this regard, it may be a form in which the step of the whereabouts confirmation at S174 is omitted and the account information is immediately deleted in a case where the result of the user authentication is failure. Fourth Embodiment A display apparatus 1 and the like according to a fourth embodiment of the present invention will be described with reference to FIG. 13 to FIG. 16. A basic configuration according to the fourth embodiment is similar to that according to the first embodiment. Hereinafter, component parts of the fourth embodiment different from those of the first embodiment will be described. In the fourth embodiment, with respect to an account sharing function, a plurality of display apparatus 1 of the home network 5 does not have the same operation and the same setting, but may have a different operation and different setting for each of the display apparatus 1. In the fourth embodiment, the account sharing function is restricted for each of the display apparatus 1. In the fourth embodiment, whether the account sharing function is to be used or not, that is, whether the account information is to be shared or not and the like can be set for each of the display apparatus 1. In the display apparatus 1 according to the fourth embodiment, a user setting function of allowing setting regarding the account sharing function as user setting is provided. This user setting function is realized by using a user setting unit 46 of FIG. 4. The user setting unit 46 works together with the account information sharing unit 45. A state of the user setting is managed by using setting information 505. The account information sharing unit 45 controls, on the basis of the setting information 505 of the user setting unit 46, whether account information is shared or not for each of the display apparatus 1. In the display apparatus 1 according to the fourth embodiment, an account registering screen is provided at the time of initial setting of account information regarding the account sharing function, and an account registering process is carried out. A first apparatus registers the account information through the account registering screen. In the display apparatus 1 according to the fourth embodiment, a setting screen is displayed on the display apparatus 1 by using the user setting function. A user can set the account sharing function regarding the plurality of display apparatus 1 of the home network 5 while watching the setting screen. A method to be used can be selected from various kinds of methods shown in the first to third embodiments described above in accordance with setting using the user setting function. For example, setting in which a specific display apparatus 1 can become the first apparatus, but another specific display apparatus 1 cannot become the first apparatus is possible like the first embodiment. Further, setting in which a specific display apparatus 1 can become an account server, but the other display apparatus 1 cannot become the account server is possible like the second embodiment. Further, setting in which a specific display apparatus 1 can become the first apparatus that is allowed to register account information of a guest is possible like the third embodiment. In the fourth embodiment, the following is also possible as setting regarding the account sharing function. In a case where one mobile terminal 2 has plural pieces of account information, setting to select so that all of the plural pieces of account information is not registered to the display apparatus 1, but part of the plural pieces of account information is registered is possible. Further, in a case where a plurality of mobile terminals 2 each having account information exists, setting to select so that the account information of all of the plurality of the mobile terminal 2 is not registered to the display apparatus 1, but the account information of a part of the mobile terminals 2 is registered is possible. Further, setting in which specific content of a group of contents in a content distribution service associated with the account information can be viewed, and another specific content cannot be viewed is possible. Setting regarding sharing of account information is possible for every account information and each mobile terminal 2. For example, a first mobile terminal has first and second account information. By user setting, the first account information can be shared with all of the display apparatus of the home network 5, and the second account information can be held in only a specific display apparatus 1. The user setting unit 46 displays the setting screen on a display unit 20. The user can carry out the user setting by means of an input operation through input means 23 to the display apparatus 1 while viewing the setting screen. Further, as described above, the user may operate the display apparatus 1 from the mobile terminal 2, whereby the user setting is similarly possible. In that case, the user setting unit 46 may display the setting screen on a screen of the mobile terminal 2. The following is possible with respect to timing to carry out the user setting by using the user setting function. At arbitrary timing, the user can basically invoke and use the setting screen by the user setting function in response to an operation for the display apparatus 1 or the mobile terminal 2. For example, the user setting is in advance possible before the initial setting. Further, the user setting is also possible after the initial setting. The account registering screen is displayed at the time of the initial setting, and at that time, it can transit to the setting screen. [Content Viewing System] FIG. 13 shows a content viewing system and an example of an operating sequence according to the fourth embodiment. In FIG. 13, as a different point from FIG. 1, a mobile terminal 2A of a user U1 has account information 111 (which is indicated by “A001”) and another mobile terminal 2B has another account information 112 (which is indicated by “A002”). The account information 111 is one for a content distribution service X1 of a content distribution server 7a, and the account information 112 is one for a content distribution service X2 of a content distribution server 7b. A display apparatus 1a displays the account registering screen at the time of the initial setting by means of the user setting unit 46, and displays the setting screen at arbitrary timing. [Operating Sequence] An example of an operating sequence at the time of initial setting according to the fourth embodiment will be described with reference to FIG. 13. In the present embodiment, the account information 111 that the mobile terminal 2A has is registered to the display apparatus 1a, and it is shared with all of the display apparatus 1 of the home network 5. The account information 112 that the mobile terminal 2B has is registered to only a specific display apparatus 1 on the basis of user setting. There are Steps S41 to S48 in FIG. 13. Hereinafter, the operating sequence will be described in the order of Steps. (S41) Registration of the account information 111 will first be described. For example, the mobile terminal 2A is connected to the display apparatus 1a. (S42) The user setting unit 46 of the display apparatus 1a that is the first apparatus displays an account registering screen (FIG. 14, will be described later) on a screen of the display unit 20 of the display apparatus 1a at the time of the initial setting. The user watches the account registering screen to confirm whether the account information 111 that the mobile terminal 2A has is to be registered as shared account information of all of the display apparatus 1 including the display apparatus 1a or not. In a case where it is to be registered, the user carries out an input to register it. (S43) The user setting unit 46 carries out an account registering process through the account registering screen at S42 on the basis of a user confirming input to register the account information 111 into the display apparatus 1a. Specifically, this process includes S44 to S46. (S44 to S46) At S44, the account information sharing unit 45 obtains the account information 111 from the mobile terminal 2 by means of transfer. At S45, the account information sharing unit 45 registers, as the shared account information, the account information 111 to the account information 504 of the user authentication information 503 in the storage 26. At S46, the account information sharing unit 45 carries out transfer and the like so as to become a state where the account information 111 is shared among the plurality of display apparatus 1 of the home network 5 in the similar manner to those of the first embodiment and the like. For example, the account information sharing unit 45 of the display apparatus 1n registers the account information 111 transferred from the display apparatus 1a to its own display apparatus 1n. (S47) Then, for example, the user can connect the mobile terminal 2A to the display apparatus 1n to use the content distribution service X1 through the display apparatus 1n and the like. At this time, since the account information 111 has already been registered to the display apparatus 1n as the shared account information, the display apparatus 1n does not output the account registering screen. The display apparatus 1n carries out a request for contents C1 to the content distribution server 7a on the basis of a user operation, for example. The display apparatus 1n creates the user authentication information by using the account information 111 held therein when to carry out the user authentication, and transmits it to the content distribution server 7a. This makes it possible for the user to view the contents C1 on the display apparatus 1n from the content distribution server 7a without labor for registering account information. (S48) Registration of the account information 112 that the mobile terminal 2B has is as follows. The user U1 invokes a user setting function by an input operation to any of the display apparatus 1, for example, the display apparatus 1a. At this time, the user U1 may connect the mobile terminal 2B to the display apparatus 1a to carry out the input operation. The user setting unit 46 displays a setting screen (FIG. 15, will be described later) on the display apparatus 1a. In the setting screen, there is a setting item of whether account information for each display apparatus 1 is shared or not with respect to the plurality of display apparatus 1 of the home network 5. In a case where the user U1 wants to register the account information 112 to only the display apparatus 1a, for example, the user U1 selects and sets that it is to be registered to only the display apparatus 1a on the setting screen. The user setting unit 46 stores a setting state thereof in the setting information 505. Subsequently, in a case where the user U1 finishes registering the account information 112, the user U1 connects the mobile terminal 2B to the display apparatus 1a, for example. The account information sharing unit 45 of the display apparatus 1a registers the account information 112 into its own storage 26 on the basis of the setting information 505, but does not register it to the other display apparatus 1. [Account Registering Screen] FIG. 14 shows an example of an account registering screen that is outputted by the display apparatus 1 to which the mobile terminal 2 is connected at the time of initial setting. This account registering screen includes an item f1, an item f2, and an item f3. A message of registration confirmation and the like are displayed in the item f1. In the present embodiment, “Account information that a mobile terminal has is registered as shared account information of all TVs including ‘TV1’ ?” is displayed in the item f1. Further, the content of the account information is displayed in the item f1 for confirmation. Further, “Yes” and “No” buttons corresponding to whether to register it or not are displayed in the item f1. The user can select whether to register it or not through the item f1. In a case where “register (Yes)” is selected, it corresponds to setting in which the account sharing function is used in all of the display apparatus 1 of the home network 5. Then, the operating sequence that has been described in the first embodiment and the like is carried out automatically. Further, in a case where “not register (No)” is selected in the item f1, the item f2 may be displayed. As well as conventional one, the item f2 is an item corresponding to the case where the account information is registered to only one display apparatus 1. In the present embodiment, “Account information that a mobile terminal has is registered to only ‘TV1’ as account information?” is displayed in the item f2. In a case where “register (Yes)” is selected, the account sharing function is not applied thereto, and the account information is not registered to the other display apparatus 1 of the home network 5. Further, a button that allows user setting regarding the account sharing function is displayed in the item f3. In a case where this item f3 is selected, it transits to a setting screen as shown in FIG. 15. [Setting Screen] FIG. 15 shows an example of the setting screen that is displayed by the user setting function of the user setting unit 46. This setting screen includes items g1 to g5. In the present embodiment, a display example at the time of initial setting is shown. The item g1 is an item to set whether the account sharing function regarding the plurality of display apparatus 1 of the home network 5 is to be used or not. The user can select whether to use it or not. In a case where “use” is selected in this item g1, the account sharing function, which has been explained in the first embodiment and the like, is applied with an effective state, and details can be set in the item g2 and the following. In a case where “not use” is selected in this item g1, it is not applied, and becomes an operation similar to the conventional one. The item g2 is a setting item regarding whether separate setting is carried out for each apparatus or not. The user can select whether to carry out the separate setting or not. In a case where it is set to carry out the separate setting in this item g2, the content thereof can be set in the item g4. The item g3 is a setting item of application propriety of the account sharing function regarding the mobile terminal 2 of the guest like the third embodiment. In a case where it is set to carry out sharing in this item g3, the content thereof can similarly be set in another item (not shown in the drawings). The item g4 is an item of the separate setting for each apparatus. In the present embodiment, a table for the setting is displayed in the item g4. The user setting unit 46 displays a table having the content corresponding a current setting state on the basis of the setting information 505. In this table, a name of the display apparatus 1 that is the apparatus, an apparatus ID, an account sharing propriety, and a content propriety are provided as items. The “account sharing propriety” item can set whether the account sharing function is to be applied or not for each of the display apparatus 1 indicated by the apparatus IDs. The user can set a propriety of each of the display apparatus 1 through the “account sharing propriety” item by an operation of a check button, for example. The display apparatus 1 set to “available” in this item carries out an operation by the account sharing function. The display apparatus 1 set to “unavailable” in this item does not carry out the operation by the account sharing function. For example, the display apparatus 1n indicated by “TVn” in a fourth row is set to “unavailable”, does not become any of the first apparatus and the second apparatus described above, and the account information is not held. The item g4 is a display example at the time of the initial setting before registering the account information, and an item of individual account information and an item of information regarding the mobile terminal 2 are not displayed therein. An item allowing separate setting for each piece of account information and an item allowing separate setting for each of the mobile terminals 2 can be realized similarly. Further, the “content propriety” item is a setting item regarding viewing propriety for each of contents in the display apparatus 1 indicated by the apparatus ID. The content of “content propriety” item can be set in the item g5. The item g5 is a setting item of propriety for each of contents. An ID of a content distribution service associated with the account information can be selected in the item g5. A list of the contents for every account information and every content distribution service is displayed in the item g5. The display apparatus 1 obtains content list information on the basis of communication with the content distribution server 7. In the present embodiment, a list of contents corresponding to certain account information is displayed in the item g5 as a table. It is not limited to this, but may be a form in which icons for respective contents are arranged therein, or the like. Items of explanatory information (not shown in the drawings), viewing propriety and the like are provided for each of the contents in the list. The user can set propriety for each of the contents in the “viewing propriety” item, for example, by an operation of the check button. In this regard, it may be a form in which all of the contents are basically shared and the user is caused to select non-sharing content, or a form in which all of the contents is basically not shared and the user is caused to select sharing content. [Setting Information] FIG. 16 shows a configuration example of a table of the setting information 505 that is managed by the user setting unit 46. The table of FIG. 16 includes, as columns, account information, a mobile terminal apparatus ID, a display apparatus apparatus ID, a sharing propriety, and a content propriety. A first column “account information” indicates account information that the mobile terminal 2 has. The “mobile terminal apparatus ID” in a second column indicates an apparatus ID of the mobile terminal 2. A third column “display apparatus apparatus ID” indicates an apparatus ID of the display apparatus 1, for example, a MAC address. A fourth column “sharing propriety” is a flag that indicates the account information in the first column is held in the display apparatus 1 in the third column and is shared or not. A fifth column “content propriety” indicates a setting value regarding the viewing propriety for each of contents. For example, “ALL” indicates a setting value to allow the user to view all contents of a content distribution service associated with account information. Further, an individual content ID can be described in this column, and contents that the user is allowed to view and contents that the user is not allowed to view can be set. First to third rows indicate setting for account information “A001” to be shared with three display apparatus 1 by using the account sharing function. Fourth to sixth rows indicate setting for account information “A002” to be registered to only the display apparatus 1a of the three display apparatus 1. Account information “B001” is held in the display apparatus 1a, but indicates setting in which the user is allowed to view only specific content “C00003”. [Effects and the Like] As described above, according to the fourth embodiment, the user setting function regarding the account sharing function and the like are provided. This makes it possible for the user to easily carry out account registration and user setting while watching the screen. A setting operation can directly be carried out by the display apparatus 1 alone, or can be carried out from the mobile terminal 2. The user can carry out, by using the user setting function, all the settings regarding the account sharing function for the plurality of display apparatus 1 of the home network 5 on the screen of the display apparatus 1 or the mobile terminal 2 in an easily understood manner. For that reason, it is possible to make labor of the user smaller and to prevent a setting error compared with the case where account information is separately set to a plurality of apparatuses like prior art. As described above, the present invention has been described specifically on the basis of the embodiments. However, the present invention is not limited to the embodiments, and the present invention may be modified into various forms without departing from the substance thereof. A combination of the plurality of embodiments described above, and replacement, addition or deletion of any constituent element are also possible. Each of the constituent elements and means can be realized by software program processing, a hardware circuit or the like. Various kinds of data, information, and programs in the apparatus may be a form to use those stored in an external storage medium or a form to use those stored in an apparatus on an external network. REFERENCE SINGS LIST 1, 1a, 1b, 1n . . . display apparatus, 2 . . . mobile terminal, 5 . . . home network, 6 . . . external network, 7 . . . content distribution server, 8 . . . broadcast station, 42 . . . content reproducing unit, 44 . . . user authenticating unit, 45 . . . account information sharing unit, 46 . . . user setting unit, 101 . . . account information. | <SOH> BACKGROUND ART <EOH>There are various kinds of content distribution services for distributing contents such as videos on a communication network. In the content distribution service, it is required to control authorities, permission and the like with respect to usage of the service and viewing of contents by a user. In other words, such controls are required with respect to reception and reproduction of the contents by apparatus of the user. Conventionally, for the controls, account information associated with a user who uses the content distribution service has been used. A content distribution server carries out authentication by using the account information. In a case where a result of the authentication is success, the user is permitted to receive and reproduce the contents via the apparatus of the user. On the other hand, in recent years, the case where plural kinds of apparatuses including a TV receiver (hereinafter, referred to also as a “display apparatus” or the like) are connected to a home network of a user and a home system is thereby constructed is increased. As an example of prior art regarding restriction to view contents, Japanese Patent No. 5,248,180 (Patent Document 1) is cited. In Patent Document 1, as an “operation target apparatus”, it is described that “a permitter who has authority grants permission for an operator for whom execution of a predetermined operation is restricted by a simple operation, whereby the operator is allowed to carry out the restricted operation”. | <SOH> SUMMARY OF THE INVENTION <EOH> | H04N21436 | 20180515 | 20180906 | H04N21436 | 0 | PENG, HSIUNGFEI | INFORMATION PROCESSING METHOD, AND DISPLAY APPARATUS | UNDISCOUNTED | 0 | ACCEPTED | H04N | 2,018 |
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15,782,128 | PENDING | PRODRUGS OF FUMARATES AND THEIR USE IN TREATING VARIOUS DISEASES | The present invention provides compounds of formula (I), and pharmaceutical compositions thereof. | 1. (canceled) 2. A crystalline form of a compound having the formula: having an X-ray powder diffraction pattern comprising peaks, in terms of degrees 2-theta±0.2 degrees, at 11.6, 21.0, 24.3, 27.4, and 27.9; preferably having additional peaks at 13.4, 16.6, 17.9, 23.0, and 26.9; preferably having additional peaks at 7.0, 16.1, 22.0, 23.7, 25.4, 28.5, 30.8, 31.0, 31.8, 32.2, 33.7, 34.2, 34.9, 35.0, 36.2, 36.6, and 38.2 when using a Cu X-ray source. 3. A pharmaceutical composition comprising a crystalline form of claim 2 and a pharmaceutically acceptable carrier. 4. A method of treating multiple sclerosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form of claim 2. 5. A method of treating multiple sclerosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition of claim 3. | RELATED APPLICATIONS This application is a continuation of U.S. application Ser. No. 15/704,219, filed Sep. 14, 2017, which is a continuation of U.S. application Ser. No. 15/295,370, filed Oct. 17, 2016, now U.S. Pat. No. 9,775,823, issued Oct. 3, 2017, which is a continuation of U.S. application Ser. No. 14/212,745, filed Mar. 14, 2014, now U.S. Pat. No. 9,505,776, issued Nov. 29, 2016, which claims the benefit of U.S. Provisional Application No. 61/934,365, filed Jan. 31, 2014 and U.S. Provisional Application No. 61/782,445, filed Mar. 14, 2013, the contents of which are incorporated herein by reference in their entireties. FIELD OF THE INVENTION The present invention relates to various prodrugs of monomethyl fumarate. In particular, the present invention relates to derivatives of monomethyl fumarate which offer improved properties relative to dimethyl fumarate. The invention also relates to methods of treating various diseases. BACKGROUND OF THE INVENTION Fumaric acid esters (FAEs) are approved in Germany for the treatment of psoriasis, are being evaluated in the United States for the treatment of psoriasis and multiple sclerosis, and have been proposed for use in treating a wide range of immunological, autoimmune, and inflammatory diseases and conditions. FAEs and other fumaric acid derivatives have been proposed for use in treating a wide-variety of diseases and conditions involving immunological, autoimmune, and/or inflammatory processes including psoriasis (Joshi and Strebel, WO 1999/49858; U.S. Pat. No. 6,277,882; Mrowietz and Asadullah, Trends Mol Med 2005, 111(1), 43-48; and Yazdi and Mrowietz, Clinics Dermatology 2008, 26, 522-526); asthma and chronic obstructive pulmonary diseases (Joshi et al., WO 2005/023241 and US 2007/0027076); cardiac insufficiency including left ventricular insufficiency, myocardial infarction and angina pectoris (Joshi et al., WO 2005/023241; Joshi et al., US 2007/0027076); mitochondrial and neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, retinopathia pigmentosa and mitochondrial encephalomyopathy (Joshi and Strebel, WO 2002/055063, US 2006/0205659, U.S. Pat. No. 6,509,376, U.S. Pat. No. 6,858,750, and U.S. Pat. No. 7,157,423); transplantation (Joshi and Strebel, WO 2002/055063, US 2006/0205659, U.S. Pat. No. 6,359,003, U.S. Pat. No. 6,509,376, and U.S. Pat. No. 7,157,423; and Lehmann et al., Arch Dermatol Res 2002, 294, 399-404); autoimmune diseases (Joshi and Strebel, WO 2002/055063, U.S. Pat. No. 6,509,376, U.S. Pat. No. 7,157,423, and US 2006/0205659) including multiple sclerosis (MS) (Joshi and Strebel, WO 1998/52549 and U.S. Pat. No. 6,436,992; Went and Lieberburg, US 2008/0089896; Schimrigk et al., Eur J Neurology 2006, 13, 604-610; and Schilling et al., Clin Experimental Immunology 2006, 145, 101-107); ischemia and reperfusion injury (Joshi et al., US 2007/0027076); AGE-induced genome damage (Heidland, WO 2005/027899); inflammatory bowel diseases such as Crohn's disease and ulcerative colitis; arthritis; and others (Nilsson et al., WO 2006/037342 and Nilsson and Muller, WO 2007/042034). FUMADERM®, an enteric coated tablet containing a salt mixture of monoethyl fumarate and dimethyl fumarate (DMF) which is rapidly hydrolyzed to monomethyl fumarate, regarded as the main bioactive metabolite, was approved in Germany in 1994 for the treatment of psoriasis. FUMADERM® is dosed TID with 1-2 grams/day administered for the treatment of psoriasis. FUMADERM® exhibits a high degree of interpatient variability with respect to drug absorption and food strongly reduces bioavailability. Absorption is thought to occur in the small intestine with peak levels achieved 5-6 hours after oral administration. Significant side effects occur in 70-90% of patients (Brewer and Rogers, Clin Expt'l Dermatology 2007, 32, 246-49; and Hoefnagel et al., Br J Dermatology 2003, 149, 363-369). Side effects of current FAE therapy include gastrointestinal upset including nausea, vomiting, diarrhea and/or transient flushing of the skin. Multiple sclerosis (MS) is an autoimmune disease with the autoimmune activity directed against central nervous system (CNS) antigens. The disease is characterized by inflammation in parts of the CNS, leading to the loss of the myelin sheathing around neuronal axons (gradual demyelination), axonal loss, and the eventual death of neurons, oligodendrocytes and glial cells. Dimethyl fumarate (DMF) is the active component of the experimental therapeutic, BG-12, studied for the treatment of relapsing-remitting MS (RRMS). In a Phase IIb RRMS study, BG-12 significantly reduced gadolinium-enhancing brain lesions. In preclinical studies, DMF administration has been shown to inhibit CNS inflammation in murine and rat EAE. It has also been found that DMF can inhibit astrogliosis and microglial activations associated with EAE. See, e.g., US Published Application No. 2012/0165404. There are four major clinical types of MS: 1) relapsing-remitting MS (RRMS), characterized by clearly defined relapses with full recovery or with sequelae and residual deficit upon recovery; periods between disease relapses characterized by a lack of disease progression; 2) secondary progressive MS (SPMS), characterized by initial relapsing remitting course followed by progression with or without occasional relapses, minor remissions, and plateaus; 3) primary progressive MS (PPMS), characterized by disease progression from onset with occasional plateaus and temporary minor improvements allowed; and 4) progressive relapsing MS (PRMS), characterized by progressive disease onset, with clear acute relapses, with or without full recovery; periods between relapses characterized by continuing progression. Clinically, the illness most often presents as a relapsing-remitting disease and, to a lesser extent, as steady progression of neurological disability. Relapsing-remitting MS (RRMS) presents in the form of recurrent attacks of focal or multifocal neurologic dysfunction. Attacks may occur, remit, and recur, seemingly randomly over many years. Remission is often incomplete and as one attack follows another, a stepwise downward progression ensues with increasing permanent neurological deficit. The usual course of RRMS is characterized by repeated relapses associated, for the majority of patients, with the eventual onset of disease progression. The subsequent course of the disease is unpredictable, although most patients with a relapsing-remitting disease will eventually develop secondary progressive disease. In the relapsing-remitting phase, relapses alternate with periods of clinical inactivity and may or may not be marked by sequelae depending on the presence of neurological deficits between episodes. Periods between relapses during the relapsing-remitting phase are clinically stable. On the other hand, patients with progressive MS exhibit a steady increase in deficits, as defined above and either from onset or after a period of episodes, but this designation does not preclude the further occurrence of new relapses. Notwithstanding the above, dimethyl fumarate is also associated with significant drawbacks. For example, dimethyl fumarate is known to cause side effects upon oral administration, such as flushing and gastrointestinal events including, nausea, diarrhea, and/or upper abdominal pain in subjects. See, e.g., Gold et al., N. Eng. J. Med., 2012, 367(12), 1098-1107. Dimethyl fumarate is dosed BID or TID with a total daily dose of about 480 mg to about 1 gram or more. Further, in the use of a drug for long-term therapy it is desirable that the drug be formulated so that it is suitable for once- or twice-daily administration to aid patient compliance. A dosing frequency of once-daily or less is even more desirable. Another problem with long-term therapy is the requirement of determining an optimum dose which can be tolerated by the patient. If such a dose is not determined this can lead to a diminution in the effectiveness of the drug being administered. Accordingly, it is an object of the present invention to provide compounds and/or compositions which are suitable for long-term administration. It is a further object of the present invention to provide the use of a pharmaceutical active agent in a manner which enables one to achieve a tolerable steady state level for the drug in a subject being treated therewith. Because of the disadvantages of dimethyl fumarate described above, there continues to be a need to decrease the dosing frequency, reduce side-effects and/or improve the physicochemical properties associated with DMF. There remains, therefore, a real need in the treatment of neurological diseases, such as MS, for a product which retains the pharmacological advantages of DMF but overcomes its flaws in formulation and/or adverse effects upon administration. The present invention addresses these needs. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 depicts the hydrolysis of Compound 16 at pH 7.9, 25° C., showing vinylic region, as observed by NMR over 90 minutes. FIG. 2 depicts the hydrolysis of Compound 16 at pH 7.9, 25° C., showing vinylic region, as observed by NMR over 19 hours. FIG. 3 depicts the hydrolysis of Compound 16 at pH 7.9, 25° C., showing aliphatic region, as observed by NMR over 19 hours. FIG. 4 depicts the hydrolysis of Reference Compound A at pH 7.9, 37° C., showing vinylic region, as observed by NMR over 15 hours. FIG. 5 depicts the hydrolysis of Reference Compound A at pH 7.9, 37° C., showing aliphatic region, as observed by NMR over 15 hours. FIG. 6 depicts a plot of weight loss vs time for Compound 14 and DMF. FIG. 7 depicts the unit cell for crystalline Compound 14. SUMMARY OF THE INVENTION This invention is directed to the surprising and unexpected discovery of novel prodrugs and related methods useful in the treatment of neurological diseases. The methods and compositions described herein comprise one or more prodrugs (e.g., aminoalkyl prodrugs) of monomethyl fumarate (MMF). The methods and compositions provide for a therapeutically effective amount of an active moiety in a subject for a time period of at least about 8 hours to at least about 24 hours. More specifically, the compounds of the invention can be converted in vivo, upon oral administration, to monomethyl fumarate. Upon conversion, the active moiety (i.e., monomethyl fumarate) is effective in treating subjects suffering from a neurological disease. The present invention provides, in part, a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof: wherein: R1 is unsubstituted C1-C6 alkyl; La is substituted or unsubstituted C1-C6 alkyl linker, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; and R2 and R3 are each, independently, H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; or alternatively, R2 and R3, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S or a substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S. The present invention also provides pharmaceutical compositions comprising one or more compounds of any of the formulae described herein and one or more pharmaceutically acceptable carriers. The present invention also provides methods of treating a neurological disease by administering to a subject in need thereof, a therapeutically effective amount of a compound of any of the formulae described herein, or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof, such that the disease is treated. The present invention also provides methods of treating multiple sclerosis by administering to a subject in need thereof, a therapeutically effective amount of a compound of any of the formulae described herein, or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof, such that the multiple sclerosis is treated. The present invention also provides methods of treating relapsing-remitting multiple sclerosis (RRMS) by administering to a subject in need thereof, a therapeutically effective amount of a compound of any of the formulae described herein, or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof, such that the multiple sclerosis is treated. The present invention also provides methods of treating secondary progressive multiple sclerosis (SPMS) by administering to a subject in need thereof, a therapeutically effective amount of a compound of any of the formulae described herein, or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof, such that the multiple sclerosis is treated. The present invention also provides methods of treating primary progressive multiple sclerosis (PPMS) by administering to a subject in need thereof, a therapeutically effective amount of a compound of any of the formulae described herein, or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof, such that the multiple sclerosis is treated. The present invention also provides methods of treating progressive relapsing multiple sclerosis (PRMS) by administering to a subject in need thereof, a therapeutically effective amount of a compound of any of the formulae described herein, or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof, such that the multiple sclerosis is treated. The present invention also provides methods of treating Alzheimer's disease by administering to a subject in need thereof, a therapeutically effective amount of a compound of any of the formulae described herein, or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof, such that the Alzheimer's disease is treated. The present invention also provides methods of treating cerebral palsy by administering to a subject in need thereof, a therapeutically effective amount of a compound of any of the formulae described herein, or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof, such that the cerebral palsy is treated. The present invention also provides compounds and compositions that enable improved oral, controlled- or sustained-release formulations. Specifically, dimethyl fumarate is administered twice or three times daily for the treatment of relapsing-remitting multiple sclerosis. In contrast, the compounds and compositions of the present invention may enable formulations with a modified duration of therapeutic efficacy for reducing relapse rates in subjects with multiple sclerosis. For example, the present compounds and compositions provide therapeutically effective amounts of monomethyl fumarate in subjects for at least about 8 hours, at least about 12 hours, at least about 16 hours, at least about 20 hours or at least about 24 hours. The present invention also provides compounds, compositions and methods which may result in decreased side effects upon administration to a subject relative to dimethyl fumarate. For example, gastric irritation and flushing are known side effects of oral administration of dimethyl fumarate in some subjects. The compounds, compositions and methods of the present invention can be utilized in subjects that have experienced or are at risk of developing such side effects. The present invention also provides for compounds and compositions which exhibit improved physical stability relative to dimethyl fumarate. Specifically, dimethyl fumarate is known in the art to undergo sublimation at ambient and elevated temperature conditions. The compounds of the invention possess greater physical stability than dimethyl fumarate under controlled conditions of temperature and relative humidity. Specifically, in one embodiment, the compounds of the formulae described herein exhibit decreased sublimation relative to dimethyl fumarate. Further, dimethyl fumarate is also known to be a contact irritant. See e.g., Material Safety Data Sheet for DMF. In one embodiment, the compounds of the present invention exhibit reduced contact irritation relative to dimethyl fumarate. For example, the compounds of the formulae described herein exhibit reduced contact irritation relative to dimethyl fumarate. The present invention also provides for compounds and compositions which exhibit decreased food effect relative to dimethyl fumarate. The bioavailability of dimethyl fumarate is known in the art to be reduced when administered with food. Specifically, in one embodiment, the compounds of the formulae described herein exhibit decreased food effect relative to dimethyl fumarate. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting. Other features and advantages of the invention will be apparent from the following detailed description and claims. DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel compounds and methods of treating a neurological disease by administering a compound of Formula (I), (Ia), (Ib), (II), (III), or (IV), synthetic methods for making a compound of Formula (I), (Ia), (Ib), (II), (III), or (IV), and pharmaceutical compositions containing a compound of Formula (I), (Ia), (Ib), (II), (III), or (IV). The present invention also provides compounds and methods for the treatment of psoriasis by administering to a subject in need thereof, a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (III), or (IV), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof. The present invention provides, in part, methods for the treatment of a neurological disease by administering to a subject in need thereof, a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (III), or (IV), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof. The neurological disease can be multiple sclerosis. The present invention further provides the use of a compound of Formula (I), (Ia), (Ib), (II), (III), or (IV), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof, for the preparation of a medicament useful for the treatment of a neurological disease. According to the present invention, a neurological disease is a disorder of the brain, spinal cord or nerves in a subject. In one embodiment, the neurological disease is characterized by demyelination, or degeneration of the myelin sheath, of the central nervous system. The myelin sheath facilitates the transmission of nerve impulses through a nerve fiber or axon. In another embodiment, the neurological disease is selected from the group consisting of multiple sclerosis, Alzheimer's disease, cerebral palsy, spinal cord injury, Amyotrophic lateral sclerosis (ALS), stroke, Huntington's disease, Parkinson's disease, optic neuritis, Devic disease, transverse myelitis, acute disseminated encephalomyelitis, adrenoleukodystrophy and adrenomyeloneuropathy, acute inflammatory demyelinating polyneuropathy (AIDP), chronic inflammatory demyelinating polyneuropathy (CIDP), acute transverse myelitis, progressive multifocal leucoencephalopathy (PML), acute disseminated encephalomyelitis (ADEM), and other hereditary disorders, such as leukodystrophies, Leber's optic atrophy, and Charcot-Marie-Tooth disease. In some embodiments, the neurological disorder is an auto-immune disease. In one embodiment, the neurological disease is multiple sclerosis. In another embodiment, the neurological disease is stroke. In another embodiment, the neurological disease is Alzheimer's disease. In another embodiment, the neurological disease is cerebral palsy. In another embodiment, the neurological disease is spinal cord injury. In another embodiment, the neurological disease is ALS. In another embodiment, the neurological disease is Huntington's disease. See, e.g., U.S. Pat. No. 8,007,826, WO2005/099701 and WO2004/082684, which are incorporated by reference in their entireties. In a further embodiment, the present invention provides methods for the treatment of a disease or a symptom of a disease described herein by administering to a subject in need thereof, a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (III), or (IV), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof. The present invention further provides the use of a compound of Formula (I), (Ia), (Ib), (II), (III), or (IV), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof, for the preparation of a medicament useful for the treatment of a disease or a symptom of a disease described herein. In another embodiment, the present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof, or a method for the treatment of a neurological disease by administering to a subject in need thereof, a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof: wherein: R1 is unsubstituted C1-C6 alkyl; La is substituted or unsubstituted C1-C6 alkyl linker, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; and R2 and R3 are each, independently, H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; or alternatively, R2 and R3, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S or a substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S. In one aspect of the compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof: R1 is unsubstituted C1-C6 alkyl; La is unsubstituted C1-C6 alkyl linker, unsubstituted C3-C10 carbocycle, unsubstituted C6-C10 aryl, unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; and R2 and R3 are each, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C6-C10 aryl, C3-C10 carbocycle, heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, wherein the alkyl, alkenyl, aryl, carbocycle, heterocycle, or heteroaryl groups may be optionally independently substituted one or more times with C1-C3-alkyl, OH, O(C1-C4 alkyl), carbonyl, halo, NH2, N(H)(C1-C6 alkyl), N(C1-C6 alkyl)2, SO2H, SO2(C1-C6 alkyl), CHO, CO2H, CO2(C1-C6 alkyl), or CN; or alternatively, R2 and R3, together with the nitrogen atom to which they are attached, form a heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; or a heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, wherein the heteroaryl or heterocycle may be optionally substituted one or more times with C1-C6 alkyl, CN, OH, halo, O(C1-C6 alkyl), CHO, carbonyl, thione, NO, or NH2. In one embodiment of this aspect, at least one of R1 and R2 is H. In another embodiment of this aspect, La is (CH2)2. In another embodiment of Formula (I), R2 and R3 together with the nitrogen to which they are attached form a heteroaryl, wherein the heteroaryl ring is a pyrrole ring, a pyrazole ring, an imidazole ring, a benzimidazole ring, a thiazole ring, a 1H-1,2,4-triazole ring, a 1H-1,2,3-triazole ring, a 1H-tetrazole ring, a pyrimidinone ring, an indole ring, or a benzoisothiazole ring, wherein all of the rings may be optionally substituted one or more times with C1-C6 alkyl, CN, OH, O(C1-C6 alkyl), CHO, NO2, or NH2. In still another embodiment of Formula (I), R2 and R3 together with the nitrogen to which they are attached form a heterocycle, wherein the heterocycle is a morpholine ring, a thiomorpholine ring, a pyrrolidine ring, a 2,5-dihydropyrrole ring, a 1,2-dihydropyridine ring, a piperazine ring, a succinimide ring, an isoindoline ring, a 2,5-dihydro-1H-tetrazole ring, an azetidine ring, a piperidine ring, a hexahydropyrimidine ring, a 2,3,3a,4,7,7a-hexahydro-1H-4,7-epoxyisoindole ring, a 3,4-dihydroquinazoline ring, a 1,2,3,4-tetrahydroquinazoline ring, an oxazolidine ring, an oxazolidinone ring, an imidazolidinone ring, a 1,3-dihydro-2H-imidazol-2-one ring, an imidizolidine thione ring, or an isothiazolidine ring, wherein all of the rings may be optionally substituted one or more times with C1-C6 alkyl, CO2(C1-C6 alkyl), OH, (CH2)1-4OH, O(C1-C6 alkyl), halo, NH2, (CH2)1-4NH2, (CH2)1-4NH(C1-C4 alkyl), (CH2)1-4N(C1-C4 alkyl)2, carbonyl, or thione. In one embodiment of Formula (I): R1 is unsubstituted C1-C3 alkyl; La is (CH2)1-6; and R2 and R3 are each, independently: H, methyl, ethyl, isopropyl, butyl, tert-butyl, cyclohexyl, cyclohexenyl, phenyl, benzyl, benzodioxole, pyridinyl, (CH2)2N(CH3)2, (CH2)3SO2H, (CH2)2SO2Me, CH2CO2H, or (CH2)2CN, or alternatively, R2 and R3, together with the nitrogen atom to which they are attached, form a morpholine ring optionally substituted one or more times with C1-C4 alkyl, carbonyl, or (CH2)1-3N(C1-C4 alkyl)2; an 8-oxa-3-azabicyclo[3.2.1]octane ring; a 1,4-dioxa-8-azaspiro[4.5]decane ring; a thiomorpholine ring substituted one or more times with carbonyl or thione; a piperazine ring optionally substituted with C1-C4 alkyl, halo, (CH2)2OH, C1-C4 alkyl ester; a pyrrolidine ring optionally substituted one or more times with C1-C4 alkyl or carbonyl; a 2,5-dihydropyrrole ring optionally substituted one or more times with C1-C4 alkyl or carbonyl; a succinimide ring optionally substituted one or more times with C1-C4 alkyl; a 3-azabicyclo[3.1.0]hexane-2,4-dione ring; a hexahydropyrimidine ring optionally substituted one or more times with C1-C4 alkyl or carbonyl; a pyrimidinone ring optionally substituted one or more times with C1-C4 alkyl; a pyrrole ring optionally substituted one or more times with C1-C4 alkyl, halo, C(O)NH2, or NO2; a pyrazole ring optionally substituted one or more times with C1-C4 alkyl, C(O)NH2, or NO2; an imidazole ring optionally substituted one or more times with C1-C4 alkyl or NO2; a 1,3-dihydro-2H-imidazol-2-one ring; a benzimidazole ring; a thiazole ring; an isoindoline ring substituted with carbonyl; a 1H-tetrazole ring; a 1H 2,5-dihydro-1H-tetrazole ring substituted with thione; a 1H-1,2,4-triazole ring; a 1H-1,2,3-triazole ring; an azetidine ring substituted with carbonyl; an piperidine ring optionally substituted one or more times with C1-C4 alkyl, carbonyl, halo, OH, or (CH2)1-4OH; a pyridinone ring optionally substituted one or more times with C1-C4 alkyl, OH, or CN; a 1,2-dihydropyridine ring substituted with carbonyl; a pyrimidinone ring optionally substituted one or more times with C1-C4 alkyl; an oxazolidine ring optionally substituted one or more times with C1-C4 alkyl; an oxazolidinone ring; an imidazolidinone ring optionally substituted one or more times with C1-C4 alkyl or carbonyl; an imidizolidine thione ring; an isothiazolidine ring optionally substituted one or more times with carbonyl; an indole ring; a 2,3,3a,4,7,7a-hexahydro-1H-4,7-epoxyisoindole ring optionally substituted one or more times with carbonyl; a 3,4-dihydroquinazoline ring substituted with carbonyl; 1,2,3,4-tetrahydroquinazoline ring substituted one or more times with carbonyl; or a benzoisothiazole ring optionally substituted one or more times with carbonyl. In another embodiment of Formula (I): R1 is unsubstituted C1-C3 alkyl; La is (CH2)1-6; and R2 and R3 are each, independently: H, methyl, ethyl, isopropyl, butyl, tert-butyl, cyclohexyl, phenyl, benzyl, benzodioxole, pyridinyl, (CH2)2N(CH3)2, (CH2)3SO2H, (CH2)2SO2Me, CH2CO2H, or (CH2)2CN; or alternatively, R2 and R3, together with the nitrogen atom to which they are attached, form a morpholine ring optionally substituted one or more times with C1-C4 alkyl, carbonyl, or (CH2)1-3N(C1-C4 alkyl)2; an 8-oxa-3-azabicyclo[3.2.1]octane ring; a thiomorpholine ring substituted one or more times with carbonyl or thione; a piperazine ring substituted with C1-C4 alkyl ester; a pyrrolidine ring optionally substituted one or more times with C1-C4 alkyl or carbonyl; a 2,5-dihydropyrrole ring optionally substituted one or more times with C1-C4 alkyl or carbonyl; a succinimide ring optionally substituted one or more times with C1-C4 alkyl; a 3-azabicyclo[3.1.0]hexane-2,4-dione ring; a hexahydropyrimidine ring optionally substituted one or more times with C1-C4 alkyl or carbonyl; a pyrimidinone ring optionally substituted one or more times with C1-C4 alkyl; an imidazole ring substituted with NO2; an isoindoline ring substituted with carbonyl; an azetidine ring substituted with carbonyl; an piperidine ring optionally substituted one or more times with C1-C4 alkyl, carbonyl, halo, OH, or (CH2)1-4OH; a pyridinone ring optionally substituted one or more times with C1-C4 alkyl, OH, or CN; a pyrimidinone ring optionally substituted one or more times with C1-C4 alkyl; an oxazolidine ring optionally substituted one or more times with C1-C4 alkyl; an oxazolidinone ring; an imidazolidinone ring optionally substituted one or more times with C1-C4 alkyl or carbonyl; an imidizolidine thione ring; an isothiazolidine ring optionally substituted one or more times with carbonyl; or a benzoisothiazole ring optionally substituted one or more times with carbonyl. In one aspect of the compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof: R1 is unsubstituted C1-C6 alkyl; La is unsubstituted C1-C6 alkyl linker, unsubstituted C3-C10 carbocycle, unsubstituted C6-C10 aryl, unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; and or R2 and R3, together with the nitrogen atom to which they are attached, form a heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; or a heterocycle comprising a 5-member ring and 1-3 heteroatoms selected from N, O and S, wherein the heteroaryl or heterocycle may be optionally substituted one or more times with C1-C6 alkyl, CN, OH, halo, O(C1-C6 alkyl), CHO, carbonyl, thione, NO, or NH2. In one embodiment of this aspect, at least one of R2 and R3 is H. In another embodiment of this aspect, La is (CH2)2. In still another embodiment of Formula (I), R2 and R3 together with the nitrogen to which they are attached form a heterocycle, wherein the heterocycle is, a thiomorpholine ring, a pyrrolidine ring, a 2,5-dihydropyrrole ring, a 1,2-dihydropyridine ring, a piperazine ring, a succinimide ring, an isoindoline ring, a 2,5-dihydro-1H-tetrazole ring, an azetidine ring, a piperidine ring, a hexahydropyrimidine ring, a 2,3,3a,4,7,7a-hexahydro-1H-4,7-epoxyisoindole ring, a 3,4-dihydroquinazoline ring, a 1,2,3,4-tetrahydroquinazoline ring, an oxazolidine ring, an oxazolidinone ring, an imidazolidinone ring, a 1,3-dihydro-2H-imidazol-2-one ring, an imidizolidine thione ring, or an isothiazolidine ring, wherein all of the rings may be optionally substituted one or more times with C1-C6 alkyl, CO2(C1-C6 alkyl), OH, (CH2)1-4OH, O(C1-C6 alkyl), halo, NH2, (CH2)1-4NH2, (CH2)1-4NH(C1-C4 alkyl), (CH2)1-4N(C1-C4 alkyl)2, carbonyl, or thione. In one embodiment of Formula (I): R1 is unsubstituted C1-C3 alkyl; La is (CH2)1-6; and R2 and R3, together with the nitrogen atom to which they are attached, form a morpholine ring substituted one or more times with C1-C4 alkyl, carbonyl, or (CH2)1-3N(C1-C4 alkyl)2; an 8-oxa-3-azabicyclo[3.2.1]octane ring; a 1,4-dioxa-8-azaspiro[4.5]decane ring; a thiomorpholine ring substituted one or more times with carbonyl or thione; a piperazine ring optionally substituted with C1-C4 alkyl, halo, (CH2)2OH, C1-C4 alkyl ester; a pyrrolidine ring optionally substituted one or more times with C1-C4 alkyl or carbonyl; a 2,5-dihydropyrrole ring optionally substituted one or more times with C1-C4 alkyl or carbonyl; a succinimide ring optionally substituted one or more times with C1-C4 alkyl; a 3-azabicyclo[3.1.0]hexane-2,4-dione ring; a hexahydropyrimidine ring optionally substituted one or more times with C1-C4 alkyl or carbonyl; a pyrimidinone ring optionally substituted one or more times with C1-C4 alkyl; a pyrrole ring optionally substituted one or more times with C1-C4 alkyl, halo, C(O)NH2, or NO2; a pyrazole ring optionally substituted one or more times with C1-C4 alkyl, C(O)NH2, or NO2; an imidazole ring optionally substituted one or more times with C1-C4 alkyl or NO2; a 1,3-dihydro-2H-imidazol-2-one ring; a benzimidazole ring; a thiazole ring; an isoindoline ring substituted with carbonyl; a 1H-tetrazole ring; a 1H 2,5-dihydro-1H-tetrazole ring substituted with thione; a 1H-1,2,4-triazole ring; a 1H-1,2,3-triazole ring; an azetidine ring substituted with carbonyl; an piperidine ring optionally substituted one or more times with C1-C4 alkyl, carbonyl, halo, OH, or (CH2)1-4OH; a pyridinone ring optionally substituted one or more times with C1-C4 alkyl, OH, or CN; a 1,2-dihydropyridine ring substituted with carbonyl; a pyrimidinone ring optionally substituted one or more times with C1-C4 alkyl; an oxazolidine ring optionally substituted one or more times with C1-C4 alkyl; an oxazolidinone ring; an imidazolidinone ring optionally substituted one or more times with C1-C4 alkyl or carbonyl; an imidizolidine thione ring; an isothiazolidine ring optionally substituted one or more times with carbonyl; an indole ring; a 2,3,3a,4,7,7a-hexahydro-1H-4,7-epoxyisoindole ring optionally substituted one or more times with carbonyl; a 3,4-dihydroquinazoline ring substituted with carbonyl; 1,2,3,4-tetrahydroquinazoline ring substituted one or more times with carbonyl; or a benzoisothiazole ring optionally substituted one or more times with carbonyl. In some embodiments of Formula (I), at least one of R1 and R2 is H. In other embodiments of Formula (I), La is (CH2)2. In a particular embodiment of Formula (I): R1 is methyl; La is (CH2)2; and R2 and R3, together with the nitrogen atom to which they are attached, form a succinimide ring. In another embodiment of Formula (I): R1 is methyl; La is (CH2)3; and R2 and R3, together with the nitrogen atom to which they are attached, form a succinimide ring. In still another embodiment of Formula (I): R1 is methyl; La is (CH2)4; and R2 and R3, together with the nitrogen atom to which they are attached, form a succinimide ring. For example, the neurological disease is multiple sclerosis. For example, the neurological disease is relapsing-remitting multiple sclerosis (RRMS). For example, the compound of Formula (I) is a compound listed in Table 1 herein. For example, in the compound of Formula (I), R1 is methyl. For example, in the compound of Formula (I), R1 is ethyl. For example, in the compound of Formula (I), La is substituted or unsubstituted C1-C6 alkyl linker. For example, in the compound of Formula (I), La is substituted or unsubstituted C1-C3 alkyl linker. For example, in the compound of Formula (I), La is substituted or unsubstituted C2 alkyl linker. For example, in the compound of Formula (I), La is methyl substituted or unsubstituted C2 alkyl linker. For example, in the compound of Formula (I), La is di-methyl substituted or unsubstituted C2 alkyl linker. For example, in the compound of Formula (I), La is methyl or di-methyl substituted C2 alkyl linker. For example, in the compound of Formula (I), La is unsubstituted C2 alkyl linker. For example, in the compound of Formula (I), R2 is substituted or unsubstituted C1-C6 alkyl. For example, in the compound of Formula (I), R2 is unsubstituted C1-C6 alkyl. For example, in the compound of Formula (I), R2 is unsubstituted C1-C3 alkyl. For example, in the compound of Formula (I), R2 is unsubstituted C1-C2 alkyl. For example, in the compound of Formula (I), R2 is C(O)ORa-substituted C1-C6 alkyl, wherein Ra is H or unsubstituted C1-C6 alkyl. For example, in the compound of Formula (I), R2 is S(O)(O)Rb-substituted C1-C6 alkyl, wherein Rb is unsubstituted C1-C6 alkyl. For example, in the compound of Formula (I), R3 is H. For example, in the compound of Formula (I), R3 is substituted or unsubstituted C1-C6 alkyl. For example, in the compound of Formula (I), R3 is unsubstituted C1-C6 alkyl. For example, in the compound of Formula (I), R2 and R3, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or a substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S. For example, in the compound of Formula (I), R2 and R3, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S. For example, in the compound of Formula (I), R2 and R3, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl ring. For example, in the compound of Formula (I), R2 and R3, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted piperidinyl ring. For example, in the compound of Formula (I), R2 and R3, together with the nitrogen atom to which they are attached, form an unsubstituted piperidinyl ring. For example, in the compound of Formula (I), R2 and R3, together with the nitrogen atom to which they are attached, form a halogen substituted piperidinyl ring. For example, in the compound of Formula (I), R2 and R3, together with the nitrogen atom to which they are attached, form a 4-halogen substituted piperidinyl ring. For example, in the compound of Formula (I), R2 and R3, together with the nitrogen atom to which they are attached, form an unsubstituted morpholinyl ring. For example, in the compound of Formula (I), R2 and R3, together with the nitrogen atom to which they are attached, form a morpholino N-oxide ring. For example, in the compound of Formula (I), R2 and R3, together with the nitrogen atom to which they are attached, form an unsubstituted pyrrolidinyl ring. For example, in the compound of Formula (I), R2 and R3, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S. For example, in the compound of Formula (I), R2 is substituted or unsubstituted C6-C10 aryl. For example, in the compound of Formula (I), R2 is unsubstituted C6-C10 aryl. For example, in the compound of Formula (I), R2 is unsubstituted phenyl. For example, in the compound of Formula (I), R2 is unsubstituted benzyl. In another embodiment, the present invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof, or a method for the treatment of a neurological disease by administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (Ia), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof: wherein: R1 is unsubstituted C1-C6 alkyl; La is substituted or unsubstituted C1-C6 alkyl linker, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; and R2 is H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S. For example, the neurological disease is multiple sclerosis. For example, the neurological disease is relapsing-remitting multiple sclerosis (RRMS). For example, in the compound of Formula (Ia), R1 is methyl. For example, in the compound of Formula (Ia), R1 is ethyl. For example, in the compound of Formula (Ia), La is substituted or unsubstituted C1-C6 alkyl linker. For example, in the compound of Formula (Ia), La is substituted or unsubstituted C1-C3 alkyl linker. For example, in the compound of Formula (Ia), La is substituted or unsubstituted C2 alkyl linker. For example, in the compound of Formula (Ia), La is methyl substituted or unsubstituted C2 alkyl linker. For example, in the compound of Formula (Ia), La is di-methyl substituted or unsubstituted C2 alkyl linker. For example, in the compound of Formula (Ia), La is methyl or di-methyl substituted C2 alkyl linker. For example, in the compound of Formula (Ia), La is unsubstituted C2 alkyl linker. For example, in the compound of Formula (Ia), R2 is substituted or unsubstituted C1-C6 alkyl. For example, in the compound of Formula (Ia), R2 is unsubstituted C1-C6 alkyl. For example, in the compound of Formula (Ia), R2 is methyl. For example, in the compound of Formula (Ia), R2 is unsubstituted C1-C3 alkyl. For example, in the compound of Formula (Ia), R2 is unsubstituted C1-C2 alkyl. For example, in the compound of Formula (Ia), R2 is C(O)ORa-substituted C1-C6 alkyl, wherein Ra is H or unsubstituted C1-C6 alkyl. For example, in the compound of Formula (Ia), R2 is S(O)(O)Rb-substituted C1-C6 alkyl, wherein Rb is unsubstituted C1-C6 alkyl. In another embodiment, the present invention provides a compound of Formula (Ib), or a pharmaceutically acceptable polymorph, hydrate, solvate or co-crystal thereof, or a method for the treatment of a neurological disease by administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (Ib), or a pharmaceutically acceptable polymorph, hydrate, solvate or co-crystal thereof: A− is a pharmaceutically acceptable anion; R1 is unsubstituted C1-C6 alkyl; La is substituted or unsubstituted C1-C6 alkyl linker, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; R3′ is substituted or unsubstituted C1-C6 alkyl; and R2 and R3 are each, independently, H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; or alternatively, R2 and R3, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or a substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S. For example, the neurological disease is multiple sclerosis. For example, the neurological disease is relapsing-remitting multiple sclerosis (RRMS). For example, in the compound of Formula (Ib), R1 is methyl. For example, in the compound of Formula (Ib), R1 is ethyl. For example, in the compound of Formula (Ib), La is substituted or unsubstituted C1-C6 alkyl linker. For example, in the compound of Formula (Ib), La is substituted or unsubstituted C1-C3 alkyl linker. For example, in the compound of Formula (Ib), La is substituted or unsubstituted C2 alkyl linker. For example, in the compound of Formula (Ib), La is methyl substituted or unsubstituted C2 alkyl linker. For example, in the compound of Formula (Ib), La is di-methyl substituted or unsubstituted C2 alkyl linker. For example, in the compound of Formula (Ib), La is methyl or di-methyl substituted C2 alkyl linker. For example, in the compound of Formula (Ib), La is unsubstituted C2 alkyl linker. For example, in the compound of Formula (Ib), R2 is substituted or unsubstituted C1-C6 alkyl. For example, in the compound of Formula (Ib), R2 is unsubstituted C1-C6 alkyl. For example, in the compound of Formula (Ib), R2 is unsubstituted C1-C3 alkyl. For example, in the compound of Formula (Ib), R2 is unsubstituted C1-C2 alkyl. For example, in the compound of Formula (Ib), R2 is C(O)ORa-substituted C1-C6 alkyl, wherein Ra is H or unsubstituted C1-C6 alkyl. For example, in the compound of Formula (Ib), R2 is S(O)(O)Rb-substituted C1-C6 alkyl, wherein Rb is unsubstituted C1-C6 alkyl. For example, in the compound of Formula (Ib), R3 is H. For example, in the compound of Formula (Ib), R3 is substituted or unsubstituted C1-C6 alkyl. For example, in the compound of Formula (Ib), R3 is unsubstituted C1-C6 alkyl. For example, in the compound of Formula (Ib), R2 and R3, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or a substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S. For example, in the compound of Formula (Ib), R2 and R3, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S. For example, in the compound of Formula (Ib), R2 and R3, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl ring. For example, in the compound of Formula (Ib), R2 and R3, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted piperidinyl ring. For example, in the compound of Formula (Ib), R2 and R3, together with the nitrogen atom to which they are attached, form an unsubstituted piperidinyl ring. For example, in the compound of Formula (Ib), R2 and R3, together with the nitrogen atom to which they are attached, form a halogen substituted piperidinyl ring. For example, in the compound of Formula (Ib), R2 and R3, together with the nitrogen atom to which they are attached, form a 4-halogen substituted piperidinyl ring. For example, in the compound of Formula (Ib), R2 and R3, together with the nitrogen atom to which they are attached, form an unsubstituted morpholinyl ring. For example, in the compound of Formula (Ib), R2 and R3, together with the nitrogen atom to which they are attached, form an unsubstituted pyrrolidinyl ring. For example, in the compound of Formula (Ib), R2 and R3, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S. For example, in the compound of Formula (Ib), R2 is substituted or unsubstituted C6-C10 aryl. For example, in the compound of Formula (Ib), R2 is unsubstituted C6-C10 aryl. For example, in the compound of Formula (Ib), R2 is unsubstituted phenyl. For example, in the compound of Formula (Ib), R2 is unsubstituted benzyl. For example, in the compound of Formula (Ib), R3′ is unsubstituted C1-C6 alkyl. For example, in the compound of Formula (Ib), R3′ is unsubstituted C1-C3 alkyl. For example, in the compound of Formula (Ib), R3′ is methyl. In one embodiment, the present invention provides a compound of Formula (II), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof, or a method for the treatment of a neurological disease by administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof: wherein: R1 is unsubstituted C1-C6 alkyl; R4 and R5 are each, independently, H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; R6, R7, R8 and R9 are each, independently, H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl or C(O)ORa; and Ra is H or substituted or unsubstituted C1-C6 alkyl. In one embodiment of Formula (II), R1 is methyl; R4 and R5 are each methyl; and R6, R7, R8 and R9 are each, independently, H or methyl. For example, the neurological disease is multiple sclerosis. For example, the neurological disease is relapsing-remitting multiple sclerosis (RRMS). For example, in the compound of Formula (II), R1 is methyl. For example, in the compound of Formula (II), R1 is ethyl. For example, in the compound of Formula (II), R4 is substituted or unsubstituted C1-C6 alkyl. For example, in the compound of Formula (II), R4 is unsubstituted C1-C6 alkyl. For example, in the compound of Formula (II), R4 is unsubstituted C1-C3 alkyl. For example, in the compound of Formula (II), R4 is unsubstituted C1-C2 alkyl. For example, in the compound of Formula (II), R4 is C(O)ORa-substituted C1-C6 alkyl, wherein Ra is H or unsubstituted C1-C6 alkyl. For example, in the compound of Formula (II), R4 is S(O)(O)Rb-substituted C1-C6 alkyl, wherein Rb is unsubstituted C1-C6 alkyl. For example, in the compound of Formula (II), R5 is H. For example, in the compound of Formula (II), R5 is substituted or unsubstituted C1-C6 alkyl. For example, in the compound of Formula (II), R5 is unsubstituted C1-C6 alkyl. For example, in the compound of Formula (II), R4 is substituted or unsubstituted C6-C10 aryl. For example, in the compound of Formula (II), R4 is unsubstituted C6-C10 aryl. For example, in the compound of Formula (II), R4 is unsubstituted phenyl. For example, in the compound of Formula (II), R4 is unsubstituted benzyl. For example, in the compound of Formula (II), R6, R7, R8 and R9 are each H. For example, in the compound of Formula (II), R6 is substituted or unsubstituted C1-C6 alkyl and R7, R8 and R9 are each H. For example, in the compound of Formula (II), R6 is unsubstituted C1-C6 alkyl and R7, R8 and R9 are each H. For example, in the compound of Formula (II), R8 is substituted or unsubstituted C1-C6 alkyl and R6, R7 and R9 are each H. For example, in the compound of Formula (II), R8 is unsubstituted C1-C6 alkyl and R6, R7 and R9 are each H. For example, in the compound of Formula (II), R6 and R8 are each, independently, substituted or unsubstituted C1-C6 alkyl and R7 and R9 are each H. For example, in the compound of Formula (II), R6 and R8 are each, independently, unsubstituted C1-C6 alkyl and R7 and R9 are each H. For example, in the compound of Formula (II), R6 and R7 are each, independently, substituted or unsubstituted C1-C6 alkyl and R8 and R9 are each H. For example, in the compound of Formula (II), R6 and R7 are each, independently, unsubstituted C1-C6 alkyl and R8 and R9 are each H. For example, in the compound of Formula (II), R8 and R9 are each, independently, substituted or unsubstituted C1-C6 alkyl and R6 and R7 are each H. For example, in the compound of Formula (II), R8 and R9 are each, independently, unsubstituted C1-C6 alkyl and R6 and R7 are each H. In one embodiment, the present invention provides a compound of Formula (III), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof, or a method for the treatment of a neurological disease by administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof: wherein: R1 is unsubstituted C1-C6 alkyl; is selected from the group consisting of: X is N, O, S, or SO2; Z is C or N; m is 0, 1, 2, or 3; n is 1 or 2; w is 0, 1, 2 or 3; t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; R6, R7, R8 and R9 are each, independently, H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl or C(O)ORa; and Ra is H or substituted or unsubstituted C1-C6 alkyl; and each R10 is, independently, H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; or, alternatively, two R10's attached to the same carbon atom, together with the carbon atom to which they are attached, form a carbonyl, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; or, alternatively, two R10's attached to different atoms, together with the atoms to which they are attached, form a substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S. For example, the neurological disease is multiple sclerosis. For example, the neurological disease is relapsing-remitting multiple sclerosis (RRMS). For example, in the compound of Formula (III), R1 is methyl. For example, in the compound of Formula (III), R1 is ethyl. For example, in the compound of Formula (III), is For example, in the compound of Formula (III), For example, in the compound of Formula (III), is For example, in the compound of Formula (III), is For example, in the compound of Formula (III), R6 is substituted or unsubstituted C1-C6 alkyl and R7, R8 and R9 are each H. For example, in the compound of Formula (III), R6 is unsubstituted C1-C6 alkyl and R7, R8 and R9 are each H. For example, in the compound of Formula (III), R8 is substituted or unsubstituted C1-C6 alkyl and R6, R7 and R9 are each H. For example, in the compound of Formula (III), R8 is unsubstituted C1-C6 alkyl and R6, R7 and R9 are each H. For example, in the compound of Formula (III), R6 and R8 are each, independently, substituted or unsubstituted C1-C6 alkyl and R7 and R9 are each H. For example, in the compound of Formula (III), R6 and R8 are each, independently, unsubstituted C1-C6 alkyl and R7 and R9 are each H. For example, in the compound of Formula (III), R6 and R7 are each, independently, substituted or unsubstituted C1-C6 alkyl and R8 and R9 are each H. For example, in the compound of Formula (III), R6 and R7 are each, independently, unsubstituted C1-C6 alkyl and R8 and R9 are each H. For example, in the compound of Formula (III), R8 and R9 are each, independently, substituted or unsubstituted C1-C6 alkyl, and R6 and R7 are each H. For example, in the compound of Formula (III), R8 and R9 are each, independently, unsubstituted C1-C6 alkyl, and R6 and R7 are each H. In one embodiment of Formula (III): R1 is unsubstituted C1-C6 alkyl; is selected from a group consisting of m is 0, 1, 2, or 3; t is 2, 4, or 6; R6, R7, R8 and R9 are each, independently, H, unsubstituted C1-C6 alkyl, or C(O)ORa, wherein Ra is H or unsubstituted C1-C6 alkyl; and two R10's attached to the same carbon atom, together with the carbon atom to which they are attached, form a carbonyl. In another embodiment, the present invention provides a compound of Formula (IV), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof, or a method for the treatment of a neurological disease by administering to a subject in need thereof, a therapeutically effective amount of a compound of Formula (IV), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof: wherein: R1 is unsubstituted C1-C6 alkyl; La is substituted or unsubstituted C1-C6 alkyl linker; R2 and R3 are each, independently, H, substituted or unsubstituted acyl, NR14R15, C(S)R11, C(S)SR11, C(S)NR11R12, C(S)NR11NR13R13R14, C(NR13)NR11R12, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; R11 and R12 are each, independently, H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; R13 is H or substituted or unsubstituted C1-C6 alkyl; and R14 and R15 are each, independently, H, substituted or unsubstituted acyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; wherein at least one of R2 and R3 is substituted or unsubstituted acyl, NR14R15, C(S)R11, C(S)SR11, C(S)NR11R12, C(S)NR11NR13R14, or C(NR13)NR11R12. In one embodiment of Formula (IV), R1 is C1-C6 alkyl; La is substituted or unsubstituted C1-C4 alkyl linker; and one of R2 and R3 is CO2(C1-C6 alkyl), CO2CH2Ph, CO2Ph, CO2Py, pyridinyl-N-oxide ester, C(O)CH2(imidazole), C(S)NHPh, or C(NH)NH2, wherein Ph or imidazole groups are optionally substituted with NO2. In another embodiment of Formula (IV), R1 is C1-C4 alkyl; La is substituted or unsubstituted C1-C4 alkyl linker; and R2 and R3 are each, independently, H, methyl, ethyl, isopropyl, butyl, tert-butyl, cyclohexyl, cyclohexenyl, phenyl, benzyl, benzodioxole, pyridinyl, (CH2)2N(CH3)2, (CH2)3SO2H, (CH2)2SO2Me, CHO, CH2CO2H, C(O)(CH2)2CO2H, NO, C(O)NH2, (CH2)2CN, tert-butyl ester, benzyl ester, pyridinyl ester, pyridinyl-N-oxide ester, C(O)CH2(2-nitro-1H-imidazol-1-yl), C(S)NHPh, C(NH)NH2—, ethyl substituted with carbonyl, propyl substituted with carbonyl, or phenyl ester substituted with NO2, wherein the phenyl and benzyl groups can be optionally substituted one or more times with methyl, NH2, NO2, OH, or CHO; wherein at least one of R2 and R3 is substituted or unsubstituted acyl, NR14R15, C(S)R11, C(S)SR11, C(S)NR11R12, C(S)NR11R13R14, or C(NR13)NR11R12. In one embodiment of Formula (IV), R1 is C1-C6 alkyl; La is (CH2)1-4; R2 is H or C(O)C1-C6 alkyl; and R3 is H or C(O)C1-C6 alkyl wherein at least one of R2 and R3 is C(O)C1-6 alkyl. For example, the compound is a compound listed in Table 1 herein. Representative compounds of the present invention include compounds listed in Table 1 and in Table 2. TABLE 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 A− is a pharmaceutically acceptable anion. TABLE 2 130 131 132 133 The present invention also provides pharmaceutical compositions comprising one or more compounds of Formula (I), (Ia), (Ib), (II), (III), or (IV) and one or more pharmaceutically acceptable carriers. In one embodiment, the pharmaceutical composition is a controlled release composition comprising a compound of Formula (I), (Ia), (Ib), (II), (III), or (IV) and one or more pharmaceutically acceptable carriers, wherein the controlled release composition provides a therapeutically effective amount of monomethyl fumarate to a subject. In another embodiment, the pharmaceutical composition is a controlled release composition comprising a compound of Formula (I), (Ia), (Ib), (II), (III), or (IV) and one or more pharmaceutically acceptable carriers, wherein the controlled release composition provides a therapeutically effective amount of monomethyl fumarate to a subject for at least about 8 hours to at least about 24 hours. In another embodiment, the pharmaceutical composition is a controlled release composition comprising a compound of Formula (I), (Ia), (Ib), (II), (III), or (IV) and one or more pharmaceutically acceptable carriers, wherein the controlled release composition provides a therapeutically effective amount of monomethyl fumarate to a subject for at least about 8 hours, at least about 10 hours, at least about 12 hours, at least about 13 hours, at least about 14 hours, at least about 15 hours, at least about 16 hours, at least about 17 hours, at least about 18 hours, at least about 19 hours, at least about 20 hours, at least about 21 hours, at least about 22 hours, at least about 23 hours or at least about 24 hours or longer. For example, at least about 18 hours. For example, at least about 12 hours. For example, greater than 12 hours. For example, at least about 16 hours. For example, at least about 20 hours. For example, at least about 24 hours. In another embodiment, a compound of Formula (I), (Ia), (Ib), (II), (III), or (IV) is efficiently converted to the active species, i.e., monomethyl fumarate, upon oral administration. For example, about 50 mole percent, about 55 mole percent, about 60 mole percent, about 65 mole percent, about 70 mole percent, about 75 mole percent, about 80 mole percent, about 85 mole percent, about 90 mole percent, or greater than 90 mole percent of the total dose of a compound of Formula (I), (Ia), (Ib), (II), (III), or (IV) administered is converted to monomethyl fumarate upon oral administration. In another embodiment, a compound of Formula (I), (Ia), (Ib), (II), (III), or (IV) is converted to the active species, i.e., monomethyl fumarate, upon oral administration more efficiently than dimethyl fumarate. In another embodiment, a compound of Formula (I), (Ia), (Ib), (II), (III), or (IV) is converted to the active species, i.e., monomethyl fumarate, upon oral administration more efficiently than one or more of the compounds described in U.S. Pat. No. 8,148,414. For example, a compound of Formula (I), (Ia), (Ib), (II), (III), or (IV) is essentially completely converted to the active species, i.e., monomethyl fumarate, upon oral administration. U.S. Pat. No. 8,148,414 is expressly incorporated by reference herein. In another embodiment, any one of Compounds 1-133 is efficiently converted to the active species, i.e., monomethyl fumarate, upon oral administration. For example, about 50 percent, about 55 percent, about 60 percent, about 65 percent, about 70 percent, about 75 percent, about 80 percent, about 85 percent, about 90 percent, or greater than 90 percent of the total dose of any one of Compounds 1-133 administered is converted to monomethyl fumarate upon oral administration. In another embodiment, any one of Compounds 1-133 is converted to the active species, i.e., monomethyl fumarate, upon oral administration more efficiently than dimethyl fumarate. In another embodiment, any one of Compounds 1-133 is converted to the active species, i.e., monomethyl fumarate, upon oral administration more efficiently than one or more of the compounds described in U.S. Pat. No. 8,148,414. For example, any one of Compounds 1-133 is completely converted to the active species, i.e., monomethyl fumarate, upon oral administration. For a drug to achieve its therapeutic effect, it is necessary to maintain the required level of blood or plasma concentration. Many drugs, including dimethyl fumarate, must be administered multiple times a day to maintain the required concentration. Furthermore, even with multiple administrations of such a drug per day, the blood or plasma concentrations of the active ingredient may still vary with time, i.e., at certain time points between administrations there are higher concentrations of the active ingredient than at other times. Thus, at certain time points of a 24-hour period, a patient may receive therapeutically effective amounts of the active ingredient, while at other time points the concentration of the active ingredient in the blood may fall below therapeutic levels. Additional problems with such drugs include that multiple dosing a day often adversely affects patient compliance with the treatment. Therefore, it is desirable to have a drug dosage form wherein the active ingredient is delivered in such a controlled manner that a constant or substantially constant level of blood or plasma concentration of the active ingredient can be achieved by one or at most two dosing per day. Accordingly, the present invention provides controlled-release formulations as described below. In general, such formulations are known to those skilled in the art or are available using conventional methods. As used herein, “controlled-release” means a dosage form in which the release of the active agent is controlled or modified over a period of time. Controlled can mean, for example, sustained, delayed or pulsed-release at a particular time. For example, controlled-release can mean that the release of the active ingredient is extended for longer than it would be in an immediate-release dosage form, i.e., at least over several hours. As used herein, “immediate-release” means a dosage form in which greater than or equal to about 75% of the active ingredient is released within two hours, or, more specifically, within one hour, of administration. Immediate-release or controlled-release may also be characterized by their dissolution profiles. Formulations may also be characterized by their pharmacokinetic parameters. As used herein, “pharmacokinetic parameters” describe the in vivo characteristics of the active ingredient over time, including for example plasma concentration of the active ingredient. As used herein, “Cmax” means the measured concentration of the active ingredient in the plasma at the point of maximum concentration. “Tmax” refers to the time at which the concentration of the active ingredient in the plasma is the highest. “AUC” is the area under the curve of a graph of the concentration of the active ingredient (typically plasma concentration) vs. time, measured from one time to another. The controlled-release formulations provided herein provide desirable properties and advantages. For example, the formulations can be administered once daily, which is particularly desirable for the subjects described herein. The formulation can provide many therapeutic benefits that are not achieved with corresponding shorter acting, or immediate-release preparations. For example, the formulation can maintain lower, more steady plasma peak values, for example, Cmax, so as to reduce the incidence and severity of possible side effects. Sustained-release dosage forms release their active ingredient into the gastro-intestinal tract of a patient over a sustained period of time following administration of the dosage form to the patient. Particular dosage forms include: (a) those in which the active ingredient is embedded in a matrix from which it is released by diffusion or erosion; (b) those in which the active ingredient is present in a core which is coated with a release rate-controlling membrane; (c) those in which the active ingredient is present in a core provided with an outer coating impermeable to the active ingredient, the outer coating having an aperture (which may be drilled) for release of the active ingredient; (d) those in which the active ingredient is released through a semi-permeable membrane, allowing the drug to diffuse across the membrane or through liquid filled pores within the membrane; and (e) those in which the active ingredient is present as an ion exchange complex. It will be apparent to those skilled in the art that some of the above means of achieving sustained-release may be combined, for example a matrix containing the active compound may be formed into a multiparticulate and/or coated with an impermeable coating provided with an aperture. Pulsed-release formulations release the active compound after a sustained period of time following administration of the dosage form to the patient. The release may then be in the form of immediate- or sustained-release. This delay may be achieved by releasing the drug at particular points in the gastro-intestinal tract or by releasing drug after a pre-determined time. Pulsed-release formulations may be in the form of tablets or multiparticulates or a combination of both. Particular dosage forms include: (a) osmotic potential triggered release (see U.S. Pat. No. 3,952,741); (b) compression coated two layer tablets (see U.S. Pat. No. 5,464,633); (c) capsules containing an erodible plug (see U.S. Pat. No. 5,474,784); sigmoidal releasing pellets (referred to in U.S. Pat. No. 5,112,621); and (d) formulations coated with or containing pH-dependent polymers including shellac, phthalate derivatives, polyacrylic acid derivatives and crotonic acid copolymers. Dual release formulations can combine the active ingredient in immediate release form with additional active ingredient in controlled-release form. For example, a bilayer tablet can be formed with one layer containing immediate release active ingredient and the other layer containing the active ingredient embedded in a matrix from which it is released by diffusion or erosion. Alternatively, one or more immediate release beads can be combined with one or more beads which are coated with a release rate-controlling membrane in a capsule to give a dual release formulation. Sustained release formulations in which the active ingredient is present in a core provided with an outer coating impermeable to the active ingredient, the outer coating having an aperture (which may be drilled) for release of the active ingredient, can be coated with drug in immediate release form to give a dual release formulation. Dual release formulations can also combine drug in immediate release form with additional drug in pulsed release form. For example, a capsule containing an erodible plug could liberate drug initially and, after a predetermined period of time, release additional drug in immediate- or sustained-release form. In some embodiments, the dosage forms to be used can be provided as controlled-release with respect to one or more active ingredients therein using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, or microspheres or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the pharmaceutical compositions of the invention. Thus, single unit dosage forms suitable for oral administration, such as tablets, capsules, gelcaps, and caplets that are adapted for controlled-release are encompassed by the present invention. Most controlled-release formulations are designed to initially release an amount of drug that promptly produces the desired therapeutic effect, and gradually and continually release of additional amounts of drug to maintain this level of therapeutic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled-release of an active ingredient can be stimulated by various inducers, for example pH, temperature, enzymes, concentration, or other physiological conditions or compounds. Powdered and granular formulations of a pharmaceutical preparation of the invention may be prepared using known methods. Such formulations may be administered directly to a subject, used, for example, to form tablets, to fill capsules, or to prepare an aqueous or oily suspension or solution by addition of an aqueous or oily vehicle thereto. Each of these formulations may further comprise one or more of a dispersing agent, wetting agent, suspending agent, and a preservative. Additional excipients, such as fillers, sweeteners, flavoring, or coloring agents, may also be included in these formulations. A formulation of a pharmaceutical composition of the invention suitable for oral administration may be prepared or packaged in the form of a discrete solid dose unit including, but not limited to, a tablet, a hard or soft capsule, a cachet, a troche, or a lozenge, each containing a predetermined amount of the active ingredient. In one embodiment, a formulation of a pharmaceutical composition of the invention suitable for oral administration is coated with an enteric coat. A tablet comprising the active ingredient may, for example, be made by compressing or molding the active ingredient, optionally with one or more additional ingredients. Compressed tablets may be prepared by compressing, in a suitable device, the active ingredient in a free flowing form such as a powder or granular preparation, optionally mixed with one or more of a binder, a lubricant, an excipient, a surface-active agent, and a dispersing agent. Molded tablets may be made by molding, in a suitable device, a mixture of the active ingredient, a pharmaceutically acceptable carrier, and at least sufficient liquid to moisten the mixture. Pharmaceutically acceptable excipients used in the manufacture of tablets include, but are not limited to, inert diluents, granulating and disintegrating agents, binding agents, and lubricating agents. Known dispersing agents include, but are not limited to, potato starch and sodium starch glycollate. Known surface-active agents include, but are not limited to, sodium lauryl sulphate and poloxamers. Known diluents include, but are not limited to, calcium carbonate, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, and sodium phosphate. Known granulating and disintegrating agents include, but are not limited to, corn starch and alginic acid. Known binding agents include, but are not limited to, gelatin, acacia, pre-gelatinized maize starch, polyvinylpyrrolidone, and hydroxypropyl methylcellulose. Known lubricating agents include, but are not limited to, magnesium stearate, stearic acid, silica, and talc. Tablets may be non-coated or they may be coated using known methods to achieve delayed disintegration in the gastrointestinal tract of a subject, thereby providing sustained release and absorption of the active ingredient. By way of example, a material such as glyceryl monostearate or glyceryl distearate may be used to coat tablets. Further by way of example, tablets may be coated using methods described in U.S. Pat. Nos. 4,256,108; 4,160,452; and U.S. Pat. No. 4,265,874 to form osmotically-controlled release tablets, optionally, with laser drilling. Tablets may further comprise a sweetener, a flavoring agent, a coloring agent, a preservative, or some combination of these in order to provide for pharmaceutically elegant and palatable formulations. Hard capsules comprising the active ingredient may be made using a physiologically degradable composition, such as gelatin or HPMC. Such hard capsules comprise the active ingredient, and may further comprise additional ingredients including, for example, an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin. Soft gelatin capsules comprising the active ingredient may be made using a physiologically degradable composition, such as gelatin. Such soft capsules comprise the active ingredient, which may be mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil. As used herein, “alkyl”, “C1, C2, C3, C4, C5 or C6 alkyl” or “C1-C6 alkyl” is intended to include C1, C2, C3, C4, C5 or C6 straight chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5 or C6 branched saturated aliphatic hydrocarbon groups. For example, C1-C6 alkyl is intended to include C1, C2, C3, C4, C5 and C6 alkyl groups. Examples of alkyl include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, or n-hexyl. In certain embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., C1-C6 for straight chain, C3-C6 for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms. As used herein, “alkyl linker” is intended to include C1, C2, C3, C4, C5, or C6 straight chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5, or C6 branched saturated aliphatic hydrocarbon groups. For example, C1-C6 alkyl linker is intended to include C1, C2, C3, C4, C5, and C6 alkyl linker groups. Examples of alkyl linker include, moieties having from one to six carbon atoms, such as, but not limited to, methyl (—CH2—), ethyl (—CH2CH2—), n-propyl (—CH2CH2CH2—), i-propyl (—CHCH3CH2—), n-butyl (—CH2CH2CH2CH2—), s-butyl (—CHCH3CH2CH2—), i-butyl (—C(CH3)2CH2—), n-pentyl (—CH2CH2CH2CH2CH2—), s-pentyl (—CHCH3CH2CH2CH2—) or n-hexyl (—CH2CH2CH2CH2CH2CH2—). The term “substituted alkyl linker” refers to alkyl linkers having substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents do not alter the sp3-hybridization of the carbon atom to which they are attached and include those listed below for “substituted alkyl.” “Heteroalkyl” groups are alkyl groups, as defined above, that have an oxygen, nitrogen, sulfur or phosphorous atom replacing one or more hydrocarbon backbone carbon atoms. As used herein, the term “cycloalkyl”, “C3, C4, C5, C6, C7 or C8 cycloalkyl” or “C3-C8 cycloalkyl” is intended to include hydrocarbon rings having from three to eight carbon atoms in their ring structure. In one embodiment, a cycloalkyl group has five or six carbons in the ring structure. The term “substituted alkyl” refers to alkyl moieties having substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Cycloalkyls can be further substituted, e.g., with the substituents described above. An “alkylaryl” or an “aralkyl” moiety is an alkyl substituted with an aryl (e.g., phenylmethyl(benzyl)). Unless the number of carbons is otherwise specified, “lower alkyl” includes an alkyl group, as defined above, having from one to six, or in another embodiment from one to four, carbon atoms in its backbone structure. “Lower alkenyl” and “lower alkynyl” have chain lengths of, for example, two to six or of two to four carbon atoms. “Aryl” includes groups with aromaticity, including “conjugated”, or multicyclic, systems with at least one aromatic ring. Examples include phenyl, benzyl, naphthyl, etc. “Heteroaryl” groups are aryl groups, as defined above, having from one to four heteroatoms in the ring structure, and may also be referred to as “aryl heterocycles” or “heteroaromatics”. As used herein, the term “heteroaryl” is intended to include a stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or other substituents, as defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O)p, where p=1 or 2). It is to be noted that total number of S and O atoms in the heteroaryl is not more than 1. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like. As used herein, “Ph” refers to phenyl, and “Py” refers to pyridinyl. Furthermore, the terms “aryl” and “heteroaryl” include multicyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, or indolizine. In the case of multicyclic aromatic rings, only one of the rings needs to be aromatic (e.g., 2,3-dihydroindole), although all of the rings may be aromatic (e.g., quinoline). The second ring can also be fused or bridged. The aryl or heteroaryl aromatic ring can be substituted at one or more ring positions with such substituents as described above, for example, alkyl, alkenyl, akynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl). As used herein, “carbocycle” or “carbocyclic ring” is intended to include any stable monocyclic, bicyclic or tricyclic ring having the specified number of carbons, any of which may be saturated, unsaturated, or aromatic. For example, a C3-C14 carbocycle is intended to include a monocyclic, bicyclic or tricyclic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms. Examples of carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl. Bridged rings are also included in the definition of carbocycle, including, for example, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane and [2.2.2]bicyclooctane. A bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms. In one embodiment, bridge rings are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge. Fused (e.g., naphthyl, tetrahydronaphthyl) and spiro rings are also included. As used herein, “heterocycle” includes any ring structure (saturated or partially unsaturated) which contains at least one ring heteroatom (e.g., N, O or S). Examples of heterocycles include, but are not limited to, morpholine, pyrrolidine, tetrahydrothiophene, piperidine, piperazine, and tetrahydrofuran. Examples of heterocyclic groups include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazol5(4H)-one, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. The term “substituted”, as used herein, means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C═C, C═N or N═N). “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The term “acyl”, as used herein, includes moieties that contain the acyl radical (—C(O)—) or a carbonyl group. “Substituted acyl” includes acyl groups where one or more of the hydrogen atoms are replaced by, for example, alkyl groups, alkynyl groups, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. The description of the disclosure herein should be construed in congruity with the laws and principals of chemical bonding. For example, it may be necessary to remove a hydrogen atom in order accommodate a substituent at any given location. Furthermore, it is to be understood that definitions of the variables (i.e., “R groups”), as well as the bond locations of the generic formulae of the invention (e.g., Formulas I, Ia, Ib, II III, and IV), will be consistent with the laws of chemical bonding known in the art. It is also to be understood that all of the compounds of the invention described above will further include bonds between adjacent atoms and/or hydrogens as required to satisfy the valence of each atom. That is, bonds and/or hydrogen atoms are added to provide the following number of total bonds to each of the following types of atoms: carbon: four bonds; nitrogen: three bonds; oxygen: two bonds; and sulfur: two-six bonds. As used herein, a “subject in need thereof” is a subject having a neurological disease. In one embodiment, a subject in need thereof has multiple sclerosis. A “subject” includes a mammal. The mammal can be e.g., any mammal, e.g., a human, primate, bird, mouse, rat, fowl, dog, cat, cow, horse, goat, camel, sheep or a pig. In one embodiment, the mammal is a human. The present invention provides methods for the synthesis of the compounds of each of the formulae described herein. The present invention also provides detailed methods for the synthesis of various disclosed compounds of the present invention according to the following schemes and as shown in the Examples. Throughout the description, where compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously. The synthetic processes of the invention can tolerate a wide variety of functional groups; therefore various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof. Compounds of the present invention can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or which will be apparent to the skilled artisan in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J., March's Advanced Organic Chemistry Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; and Greene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999, incorporated by reference herein, are useful and recognized reference textbooks of organic synthesis known to those in the art. The following descriptions of synthetic methods are designed to illustrate, but not to limit, general procedures for the preparation of compounds of the present invention. Compounds of the present invention can be conveniently prepared by a variety of methods familiar to those skilled in the art. The compounds of this invention with each of the formulae described herein may be prepared according to the following procedures from commercially available starting materials or starting materials which can be prepared using literature procedures. These procedures show the preparation of representative compounds of this invention. EXPERIMENTAL General Procedure 1 To a mixture of monomethyl fumarate (MMF) (1.0 equivalent) and HBTU (1.5 equivalents) in DMF (25 ml per g of MMF) was added Hünigs base (2.0 equivalents). The dark brown solution was stirred for 10 minutes, where turned into a brown suspension, before addition of the alcohol (1.0-1.5 equivalents). The reaction was stirred for 18 hours at room temperature. Water was added and the product extracted into ethyl acetate three times. The combined organic layers were washed with water three times, dried with magnesium sulphate, filtered and concentrated in vacuo at 45° C. to give the crude product. The crude product was purified by silica chromatography and in some cases further purified by trituration with diethyl ether to give the clean desired ester product. All alcohols were either commercially available or made following known literature procedures. As an alternative to HBTU (N,N,N′,N′-Tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate), any one of the following coupling reagents can be used: EDCI/HOBt (N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride/hydroxybenzotriazole hydrate); COMU ((1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate); TBTU (O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate); TATU (O-(7-azabenzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate); Oxyma (ethyl (hydroxyimino)cyanoacetate); PyBOP ((benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate); HOTT (S-(1-oxido-2-pyridyl)-N,N,N′,N′-tetramethylthiuronium hexafluorophosphate); FDPP (pentafluorophenyl diphenylphosphinate); T3P (propylphosphonic anhydride); DMTMM (4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium tetrafluoroborate); PyOxim ([ethyl cyano(hydroxyimino)acetato-O2]tri-1-pyrrolidinylphosphonium hexafluorophosphate); TSTU (N,N,N,N-tetramethyl-O—(N-succinimidyl)uronium tetrafluoroborate); TDBTU (O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate); TPTU (O-(2-oxo-1 (2H)pyridyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate); TOTU (O-[(ethoxycarbonyl)cyanomethylenamino]-N,N,N′,N′-tetramethyluronium tetrafluoroborate); IIDQ (isobutyl 1,2-dihydro-2-isobutoxy-1-quinolinecarboxylate); or PyCIU (chlorodipyrrolidinocarbenium hexafluorophosphate), As an alternative to Hünig's base (diisopropylethylamine), any one of the following amine bases can be used: triethylamine; tributylamine; triphenylamine; pyridine; lutidine (2,6-dimethylpyridine); collidine (2,4,6-trimethylpyridine); imidazole; DMAP (4-(dimethylamino)pyridine); DABCO (1,4-diazabicyclo[2.2.2]octane); DBU (1,8-diazabicyclo[5.4.0]undec-7-ene); DBN (1,5-diazabicyclo[4.3.0]non-5-ene); or Protonq Sponge® (N,N,N′,N′-tetramethyl-1,8-naphthalenediamine). General Procedure 2—Conversion of the Ester Product into the Hydrochloride Salt To a mixture of the ester product in diethyl ether (25 ml per g) was added 2M HCl in diethyl ether (1.5 equivalents). The mixture was stirred at room temperature for two hours. The solvent was decanted, more diethyl ether added and the solvent decanted again. The remaining mixture was then concentrated in vacuo at 45° C. and further dried in a vacuum oven at 55° C. for 18 hours to give the solid HCl salt. General Procedure 3 To a 100 mL, one-necked, round-bottomed flask, fitted with a magnetic stirrer and nitrogen inlet/outlet, were added 11 mL of an MTBE solution containing freshly prepared monomethyl fumaryl chloride (4.9 g, 33 mmol) and 50 mL of additional MTBE at 20° C. The resulting yellow solution was cooled to <20° C. with an ice water bath. Then, the alcohol, (33 mmol, 1 eq) was added dropwise, via syringe, over approximately 10 minutes. The reaction mixture was allowed to stir at <20° C. for 10 minutes after which time the cooling bath was removed and the reaction was allowed to warm to 20° C. and stir at 20° C. temperature for 16 hours. The reaction was deemed complete by TLC after 16 hours at RT. The reaction mixture was filtered through a medium glass fritted funnel to collect the off-white solids. The solids were dried in a vacuum oven at 25° C. overnight to afford the final product as an HCl salt. All alcohols were either commercially available or made following known literature procedures. General Procedure 4—Alkylation with an Appropriate Alkyl Mesylate A mixture of monomethyl fumarate (MMF) (1.3 equivalent), the alkyl mesylate (1 equivalent), and potassium carbonate (1.5 equivalent) in acetonitrile (50 ml per g of MMF) was heated at reflux overnight. The mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate, and the organic phase dried (MgSO4). Filtration and removal of the solvent under reduced pressure gave the crude product which was purified in each case by silica chromatography. General Procedure 5—Alkylation with an Appropriate Alkyl Chloride A mixture of monomethyl fumarate (MMF) (1.3 equivalent), the alkyl chloride (1 equivalent), and potassium carbonate (1.5 equivalent) in acetonitrile or dimethylformamide (50 ml per g of MMF) was heated at 20 to 65° C. overnight. The mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate, and the organic phase dried (MgSO4). Filtration and removal of the solvent under reduced pressure gave the crude product which was further purified by silica chromatography. Chemical Analysis/Procedures The NMR spectra described herein were obtained with a Varian 400 MHz NMR spectrometer using standard techniques known in the art. EXAMPLES Example 1 (E)-2,2′-((2-((4-methoxy-4-oxobut-2-enol)oxy)ethyl)azanediyl)diacetic acid hydrochloride (1) To a solution of 2-(bis(2-(tert-butoxy)-2-oxoethyl)amino)ethyl methyl fumarate (2.52 g, 6.2 mmol) in dioxane (25 ml) was added 2M HCl in dioxane (30 ml) and the mixture stirred for 90 hours. The precipitate was filtered, washed with diethyl ether and dried in a vacuum oven at 55° C. for 18 hours to give (E)-2,2′-((2-((4-methoxy-4-oxobut-2-enoyl)oxy)ethyl)azanediyl)diacetic acid hydrochloride, a white solid (1.31 g, 65%). 1H NMR (300 MHz, MeOD): δ 6.87 (2H, dd, J=16.1 Hz); 4.46-4.53 (2H, m); 4.09 (4H, s); 3.79 (3H, s); 3.57-3.63 (2H, m). [M+H]+=290.12. Methyl (2-(methyl(2-(methylsulfonyl)ethyl)amino)ethyl) fumarate hydrochloride (2) Methyl (2-(N-methylmethylsulfonamido)ethyl) fumarate 2 was synthesized following general procedure 1 and was converted to the HCl salt methyl (2-(methyl(2-(methylsulfonyl)ethyl)amino)ethyl) fumarate hydrochloride (procedure 2) (1.39 g, 95%). 1H NMR (400 MHz, DMSO): δ 11.51 (1H, m); 6.83 (2H, dd, J=15.8 Hz); 4.48 (1H, bs); 3.24-3.90 (7H, m); 3.07 (3H, s); 2.78 (2H, bs). [M+H]+=294.09. 2-(dimethylamino)propyl methyl fumarate hydrochloride (3) 2-(dimethylamino)propyl methyl fumarate 3 was synthesized following general procedure 1 and was converted to the HCl salt: 2-(dimethylamino)propyl methyl fumarate hydrochloride (procedure 2) (329 mg, 92%). 1H NMR (300 MHz, DMSO): δ 10.40 (1H, bs); 6.86 (2H, dd, J=15.8 Hz); 4.25-4.46 (2H, m); 3.71 (3H, s); 3.34 (1H, s); 2.69 (6H, s); 1.24 (3H, s). [M+H]+=216.14. (E)-2-((4-methoxy-4-oxobut-2-enoyl)oxy)-N,N,N-trimethylethanaminium iodide (4) To a solution of 2-(dimethylamino)ethyl methyl fumarate 19 (760 mg, 3.7 mmol) in diethyl ether (20 ml) was added methyl iodide (246 μl, 3.9 mmol). The mixture was stirred at room temperature for 18 hours where a precipitate slowly formed. The mixture was filtered, washed with diethyl ether and dried in a vacuum oven at 55° C. for 18 hours to give (E)-2-((4-methoxy-4-oxobut-2-enoyl)oxy)-N,N,N-trimethylethanaminium iodide, a white solid (1.15 g, 90%). 1H NMR (300 MHz, DMSO): δ 6.80 (2H, dd, J=16.1 Hz); 4.56 (2H, bs); 3.66-3.75 (5H, m); 3.11 (9H, s). [M+H]+=216.14. 2-(4,4-difluoropiperidin-1-yl)ethyl methyl fumarate hydrochloride (5) 2-(4,4-difluoropiperidin-1-yl)ethyl methyl fumarate 5 was synthesized following general procedure 1 and was converted to the HCl salt: 2-(4,4-difluoropiperidin-1-yl)ethyl methyl fumarate hydrochloride (procedure 2) (780 mg, 87%). 1H NMR (300 MHz, DMSO): δ 11.25 (1H, bs); 6.84 (2H, dd, J=16.1 Hz); 4.50 (2H, bs); 3.35-4.00 (8H, m); 3.05-3.30 (2H, m); 2.20-2.45 (3H, s). [M+H]+=278.16. 1-(dimethylamino)propan-2-yl methyl fumarate hydrochloride (6) 1-(dimethylamino)propan-2-yl methyl fumarate 6 was synthesized following general procedure 1 and was converted to the HCl salt 1-(dimethylamino)propan-2-yl methyl fumarate hydrochloride (procedure 2) (690 mg, 72%). 1H NMR (300 MHz, DMSO): δ 10.41 (1H, bs); 6.80 (2H, dd, J=15.8 Hz); 5.18-5.33 (1H, m); 3.20-3.55 (2H, m); 3.72 (3H, s); 2.60-2.80 (7H, m); 1.18-1.28 (3H, m). [M+H]+=216.14. Methyl (2-thiomorpholinoethyl) fumarate hydrochloride (7) Methyl (2-thiomorpholinoethyl) fumarate 7 was synthesized following general procedure 1 and was converted to the HCl salt, methyl (2-thiomorpholinoethyl) fumarate hydrochloride (procedure 2) (623 mg, 93%). 1H NMR (300 MHz, DMSO): δ 11.03 (1H, bs); 6.83 (2H, dd, J=15.6 Hz); 4.50 (2H, s); 3.00-3.80 (11H, m); 2.70-2.80 (2H, m). [M+H]+=216.14. [M+H]+=260.11. Methyl (2-(phenylamino)ethyl) fumarate hydrochloride (8) Methyl (2-(phenylamino)ethyl) fumarate 8 was synthesized following general procedure 1 and was converted to the HCl salt methyl (2-(phenylamino)ethyl) fumarate hydrochloride (procedure 2) (1.80 g, quantitative). 1H NMR (300 MHz, DMSO): δ 6.50-6.80 (9H, m); 4.29 (2H, t, 4.4 Hz); 3.72 (3H, s); 3.45 (2H, t, J=4.5 Hz). [M+H]+=250.13. 2-(dimethylamino)-2-methylpropyl methyl fumarate hydrochloride (9) 2-(dimethylamino)-2-methylpropyl methyl fumarate 9 was synthesized following general procedure 1 and was converted to the HCl salt, 2-(dimethylamino)-2-methylpropyl methyl fumarate hydrochloride (procedure 2) (883 mg, 76%). 1H NMR (300 MHz, DMSO): δ 10.20 (1H, bs); 6.91 (2H, dd, J=15.6 Hz); 4.29 (2H, s); 3.73 (3H, s); 2.57-2.80 (6H, m); 1.32 (6H, s). [M+H]+=230.16. Methyl (2-(methylsulfonyl)ethyl) fumarate (10) Methyl (2-(methylsulfonyl)ethyl) fumarate 10 was synthesized following general procedure 1 and (1.01 g, 37%). 1H NMR (400 MHz, CDCl3): δ 6.88 (2H, dd, J=16.0 Hz); 4.66 (2H, t, J=5.8 Hz); 3.82 (3H, s); 3.38 (2H, t, J=6.0 Hz); 2.99 (3H, s). [M+H]+=236.97. 2-(1,1-dioxidothiomorpholin)ethyl methyl fumarate hydrochloride (11) 2-(1,1-dioxidothiomorpholino)ethyl methyl fumarate 11 was synthesized following general procedure 1 and was converted to the HCl salt 2-(1,1-dioxidothiomorpholino)ethyl methyl fumarate hydrochloride (procedure 2) (1.33 g, 87%). 1H NMR (400 MHz, DMSO): δ 6.79 (2H, dd, J=15.8 Hz); 4.34 (2H, bs); 3.72 (4H, s); 2.90-3.70 (11H, m). [M+H]+=292.11. Methyl (2-(methyl(phenyl)amino)ethyl) fumarate hydrochloride (12) Methyl (2-(methyl(phenyl)amino)ethyl) fumarate 12 was synthesized following general procedure 1 and was converted to the HCl salt methyl (2-(methyl(phenyl)amino)ethyl) fumarate hydrochloride (procedure 2) (1.76 g, 97%). 1H NMR (400 MHz, DMSO): δ 6.72-7.40 (5H, m); 6.64 (2H, dd, J=16.0 Hz); 4.27 (2H, s); 3.70 (5H, s); 2.97 (3H, s). [M+H]+=264.14. 2-(benzyl(methyl)amino)ethyl methyl fumarate hydrochloride (13) 2-(benzyl(methyl)amino)ethyl methyl fumarate 13 was synthesized following general procedure 1 and was converted to the HCl salt 2-(benzyl(methyl)amino)ethyl methyl fumarate hydrochloride (procedure 2) (2.70 g, 96%). 1H NMR (400 MHz, DMSO): δ 10.65 (1H, bs); 7.39-7.60 (5H, m); 6.82 (2H, dd, J=15.8 Hz); 4.20-4.60 (4H, m); 3.73 (3H, s); 3.27-3.50 (2H, m); 2.69 (3H, s). [M+H]+=278.16. 2-(2, 5-dioxopyrrolidin-1-yl)ethyl methyl fumarate (14) 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumarate 14 was synthesized following general procedure 1 (1.03 g, 35%). 1H NMR (400 MHz, DMSO): δ 6.81 (2H, dd, J=15.8 Hz); 4.36 (2H, t, J=5.3 Hz); 3.84 (2H, t, J=5.1 Hz); 3.80 (3H, s); 2.73 (4H, s). [M+H]+=256.07. Methyl (2-(piperidin-1-yl)ethyl) fumarate hydrochloride (15) Methyl (2-(piperidin-1-yl)ethyl) fumarate hydrochloride 15 was synthesized following general procedure 3. 1H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 6.94-6.77 (m, 2H), 4.58-4.51 (m, 2H), 3.76 (s, 3H), 3.48-3.36 (m, 4H), 2.94 (dddd, J=15.9, 12.1, 9.2, 4.4 Hz, 2H), 1.91-1.64 (m, 5H), 1.37 (dtt, J=16.4, 11.3, 4.9 Hz, 1H). [M+H]+=241.93. Methyl (2-morpholinoethyl) fumarate hydrochloride (16) Methyl (2-morpholinoethyl) fumarate hydrochloride 16 was synthesized following general procedure 3. 1H NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 6.92 (d, J=15.9 Hz, 1H), 6.82 (d, J=15.9 Hz, 1H), 4.60-4.52 (m, 2H), 4.00-3.77 (m, 6H), 3.76 (s, 3H), 3.22-3.04 (m, 4H). [M+H]+=244.00. 2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethyl methyl fumarate hydrochloride (17) 2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethyl methyl fumarate hydrochloride 17 was synthesized following general procedure 3. 1H NMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 6.91 (d, J=15.9 Hz, 1H), 6.82 (d, J=15.9 Hz, 1H), 4.58-4.51 (m, 2H), 3.93 (s, 4H), 3.76 (s, 3H), 3.57-3.43 (m, 4H), 3.22-3.03 (m, 2H), 2.20-2.02 (m, 2H), 1.89-1.79 (m, 2H). [M+H]+=300.00. Methyl (2-(pyrrolidin-1-yl)ethyl) fumarate hydrochloride (18) Methyl (2-(pyrrolidin-1-yl)ethyl) fumarate hydrochloride 18 was synthesized following general procedure 3. 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 6.94 (d, J=15.8 Hz, 1H), 6.82 (d, J=15.8 Hz, 1H), 4.53-4.46 (m, 2H), 3.76 (s, 3H), 3.61-3.45 (m, 4H), 3.11-2.94 (m, 2H), 2.06-1.79 (m, 4H). [M+H]+=228.46. 2-(dimethylamino)ethyl methyl fumarate hydrochloride (19) 2-(dimethylamino)ethyl methyl fumarate hydrochloride 19 was synthesized following general procedure 3. 1H NMR (500 MHz, DMSO-d6) δ 10.87 (s, 1H), 6.93 (d, J=15.9 Hz, 1H), 6.80 (d, J=15.9 Hz, 1H), 4.53-4.45 (m, 2H), 3.75 (s, 3H), 3.44-3.38 (m, 2H), 2.77 (s, 5H). [M+H]+=201.84. 2-(diethylamino)ethyl methyl fumarate hydrochloride (20) 2-(diethylamino)ethyl methyl fumarate hydrochloride 20 was synthesized following general procedure 3. 1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 6.90 (d, J=15.8 Hz, 1H), 6.81 (d, J=15.9 Hz, 1H), 4.56-4.48 (m, 2H), 3.76 (s, 3H), 3.48-3.38 (m, 2H), 3.15 (qq, J=9.7, 5.5, 4.9 Hz, 4H), 1.24 (t, J=7.3 Hz, 6H). [M+H]+=230.59. 2-(3,3-difluoropyrrolidin-1-yl)ethyl methyl fumarate hydrochloride (21) 2-(3,3-Difluoropyrrolidin-1-yl)ethyl methyl fumarate 21 was synthesised from 2-(3,3-difluoropyrrolidin-1-yl)ethanol following general procedure 1. 2-(3,3-difluoropyrrolidin-1-yl)ethyl methyl fumarate was converted to 2-(3,3-difluoropyrrolidin-1-yl)ethyl methyl fumarate hydrochloride following general procedure 2 (0.55 g, 69%). 1H NMR (300 MHz, DMSO); δ 6.79 (2H, d); 4.20-4.39 (2H, m), 3.81 (2H, t), 3.66 (3H, s), 3.53-3.65 (4H, m), 2.54 (2H, sep). m/z [M+H]+'2 264.14. 2-(bis(2-methoxyethyl)amino)ethyl methyl fumarate hydrochloride (24) 2-(Bis(2-methoxyethyl)amino)ethyl methyl fumarate 24 was synthesised from 2-(bis(2-methoxyethyl)amino)ethanol following general procedure 1. 2-(Bis(2-methoxyethyl)amino)ethyl methyl fumarate was converted to 2-(bis(2-methoxyethyl)amino)ethyl methyl fumarate hydrochloride following general procedure 2 (1.00 g, 27%). 1H NMR (300 MHz, DMSO); δ 12.84 (1H, br s), 6.90 (2H, d), 4.73 (2H, t), 3.92 (4H, t), 3.81 (3H, s), 3.62 (2H, br s), 3.51-3.36 (4H, m), 3.34 (6H, s). m/z [M+H]+=290.12. 2-(2,4-Dioxo-3-azabicyclo[3.1.0]hexan-3-yl)ethyl methyl fumarate (22) 3-oxabicyclo[3.1.0]hexane-2,4-dione (1.0 g, 8.9 mmol) and ethanolamine (545 mg, 8.9 mmol) were heated neat at 200° C. for 2 hours. The crude reaction mixture was purified by silica chromatography (EtOAc) giving 3-(2-Hydroxyethyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (1.06 g, 77%). 1H NMR (300 MHz, CDCl3): δ 3.71 (2H, t), 3.56 (2H, t), 2.51 (2H, dd), 1.95 (1H, br s), 1.59-1.43 (2H, m). 2-(2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)ethyl methyl fumarate 22 was synthesised from 3-(2-Hydroxyethyl)-3-azabicyclo[3.1.0]hexane-2,4-dione following general procedure 1 (452 mg, 53%). 1H NMR (300 MHz, CDCl3): δ 6.81 (2H, d), 4.28 (2H, t), 3.80 (3H, s), 3.69 (2H, t), 2.48 (2H, dd), 1.59-1.49 (1H, m), 1.44-1.38 (1H, m). m/z [M+H]+=268.11. 2-(2,2-Dimethyl-5-oxopyrrolidin-1-yl)ethyl methyl fumarate (24) Tert-butyl acrylate (19.7 mL, 134.8 mmol) was added dropwise over 10 minutes to a refluxing solution of 2-nitropropane and Triton B (40% in methanol) (440 μL) in ethanol (50 mL). The reaction was heated at reflux overnight. The reaction solvent was removed under reduced pressure giving a crude residue that was dissolved in ethanol (200 mL) and hydrogenated overnight (300 psi) using Raney nickel (approximately 15 g). The reaction was filtered through celite. The solvent was removed under reduced pressure giving tert-butyl 4-amino-4-methylpentanoate (15.82 g, 63% yield). 1H NMR (300 MHz, CDCl3): δ 2.26 (2H, t), 1.65 (2H, t), 1.43 (9H, s), 1.68 (6H, s). To a solution of tert-butyl 4-amino-4-methylpentanoate (3.0 g, 16.04 mmol) in methanol (100 mL) was added chloroacetaldehyde (45% in H2O) (6.7 mL, 38.4 mmol) followed by acetic acid (2 mL, 35.0 mmol). After 1.5 hours sodium cyanoborohydride (1.51 g, 24.0 mmol) was added and the mixture stirred at room temperature for 3 hours. The reaction was partitioned between saturated aqueous sodium hydrogen carbonate (100 mL) and dichloromethane (300 mL). The organic phase was dried (MgSO4). Filtration and removal of the solvent under reduced pressure gave tert-butyl 4-((2-chloroethyl)amino)-4-methylpentanoate (3.90 g, 98% yield). 1H NMR (300 MHz, CDCl3): δ 3.63 (2H, t), 2.85 (2H, t), 2.24 (2H, t), 1.67 (2H, t), 1.44 (9H, s), 1.07 (6H, s). A mixture of tert-butyl 4-((2-chloroethyl)amino)-4-methylpentanoate (3.9 g, 15.7 mmol) and trifluoroacetic acid (27 mL) in dichloromethane (80 mL) were stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in further dichloromethane and concentrated again. This was repeated a further 3 times until the majority of the excess trifluoroacetic acid had been removed. The residue was dissolved in dichloromethane (500 mL) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (4.61 g, 24.1 mmol), hydroxybenzotriazole hydrate (3.25 g, 24.1 mmol) and diisopropylethylamine (21 mL, 120 mmol) added. The mixture was stirred at room temperature overnight. The reaction was washed with water (300 mL) and dried (MgSO4). Filtration and removal of the solvent under reduced pressure gave a crude residue that was purified by silica chromatography (heptane to ethyl acetate) giving 1-(2-chloroethyl)-5,5-dimethylpyrrolidin-2-one (1.24 g, 44% yield). 1H NMR (300 MHz, CDCl3): δ 3.61 (2H, t), 3.41 (2H, t), 2.38 (2H, t), 1.88 (2H, t), 1.24 (6H, s). 2-(2,2-Dimethyl-5-oxopyrrolidin-1-yl)ethyl methyl fumarate 24 was synthesised from 1-(2-chloroethyl)-5,5-dimethylpyrrolidin-2-one following general procedure 5 (1.02 g, 41%). 1H NMR (300 MHz, CDCl3); 6.85 (2H, d), 4.33 (2H, t), 3.80 (3H, s), 3.41 (2H, t), 2.39 (2H, t), 1.88 (2H, t), 1.23 (6H, s). m/z [M+H]+=270.17. (E)-4-(2-((4-methoxy-4-oxobut-2-enoyl)oxy)ethyl)morpholine 4-oxide (26) To a solution of methyl (2-morpholinoethyl) fumarate (1.1 g, 4.5 mmol) [synthesised from 4-(2-chloroethyl)morpholine following general procedure 5] in dichloromethane was added m-chloroperbenzoic acid (1.87 g, 5.4 mmol) and the reaction mixture stirred for 1 h. The reaction mixture was diluted with water (25 mL) and washed with dichloromethane (3×50 mL). The aqueous phase was lyophilized giving (E)-4-(2-((4-methoxy-4-oxobut-2-enoyl)oxy)ethyl)morpholine 4-oxide 26 (0.19 g, 16%). 1H NMR (300 MHz, CDCl3); 6.87 (1H, d), 6.81 (1H, d), 4.92-4.88 (2H, M), 4.44 (2H, t), 3.78-3.73 (2H, m), 3.54-3.48 (2H, m), 3.34 (2H, t), 3.15 (2H, d). m/z [M+H]+=260.2. 2-(3,5-dioxomorpholino)ethyl methyl fumarate (27) To a solution of diglycolic anhydride (2.0 g, 17 mmol) in pyridine (10 mL) was added ethanolamine (2.1 g, 34 mmol) and heated at reflux for 2 h. The volatiles were removed in vacuo and the residue heated at 180° C. for 2 h and then 220° C. for 90 min. The reaction mixture was cooled and the residue purified on silica eluting with dichloromethane/ethyl acetate (4:1) giving 4-(2-hydroxyethyl)morpholine-3,5-dione (1.05 g, 38%). 1H NMR (300 MHz, CDCl3); 4.39 (4H, s), 4.02 (2H, t), 3.80 (2H, t). 2-(3,5-dioxomorpholino)ethyl methyl fumarate 27 was synthesised from 4-(2-hydroxyethyl)morpholine-3,5-dione following general procedure 1 (0.82 g, 96%). 1H NMR (300 MHz, CDCl3); 6.83 (1H, d), 6.75 (1H, d), 4.39-4.43 (6H, m), 4.12 (2H, t), 3.79 (3H, s). 2-(2,2-dimethylmorpholino)ethyl methyl fumarate hydrochloride (28) To a solution of 2,2-dimethylmorpholine (1.0 g, 8.7 mmol) in dichloromethane (35 mL) was added chloroacetaldehyde (50% in water, 1.65 mL, 13.0 mmol), followed by sodium triacetoxyborohydride (2.8 g, 13.0 mmol). The reaction mixture was stirred for 90 min, diluted with 1 M aqueous sodium hydroxide (40 mL) and the organic phase separated. The aqueous phase was extracted with dichloromethane (2×30 mL) and the organic phases combined. After being dried over MgSO4 the volatiles were removed in vacuo giving 4-(2-chloroethyl)-2,2-dimethylmorpholine (1.45 g, 94%). 1H NMR (300 MHz, CDCl3); 3.73 (2H, dd), 3.55 (2H, t), 2.64 (2H, t), 2.43 (2H, dd), 2.25 (2H, s), 1.24 (6H, s). 2-(2,2-Dimethylmorpholino)ethyl methyl fumarate 28 was synthesised from 4-(2-chloroethyl)-2,2-dimethylmorpholine following general procedure 5 (0.71 g, 93%). 4-(2-chloroethyl)-2,2-dimethylmorpholine was converted to 4-(2-chloroethyl)-2,2-dimethylmorpholine hydrochloride following general procedure 2 (0.69 g, 87%). 1H NMR (300 MHz, CDCl3); 6.85 (1H, d), 6.77 (1H, d), 4.52-4.47 (2H, m), 3.93-3.85 (2H, m), 3.70 (3H, s), 3.48-3.43 (2H, m), 3.32-3.00 (4H, m), 1.24 (6H, s). m/z [M+H]+=272.2. 2-(2,6-dimethylmorpholino)ethyl methyl fumarate hydrochloride (29) To a solution of 2,6-dimethylmorpholine (1.0 g, 9.0 mmol) in dichloromethane (40 mL) was added chloroacetaldehyde (50% in water, 1.02 mL, 13.5 mmol) and acetic acid (0.75 mL, 13.5 mmol) followed by sodium triacetoxyborohydride (2.8 g, 13.5 mmol). The reaction mixture was stirred for 4 h, diluted with dichloromethane (20 mL) and washed with saturated aqueous sodium hydrogen carbonate (30 mL). The organic phase separated, dried over MgSO4 the volatiles were removed in vacuo. The residue was further purified by silica chromatography eluting with heptanes/ethyl acetate (1:1) giving 4-(2-chloroethyl)-2,6-dimethylmorpholine (0.44 g, 30%). 1H NMR (300 MHz, CDCl3); 3.75-3.62 (2H, m), 3.58 (2H, t), 2.65-2.79 (4H, m), 1.83 (2H, t), 1.15 (6H, d). 2-(2,6-dimethylmorpholino)ethyl methyl fumarate 29 was synthesised from 4-(2-chloroethyl)-2,6-dimethylmorpholine following general procedure 5 (0.54 g, 71%). 2-(2,6-dimethylmorpholino)ethyl methyl fumarate was converted to 2-(2,6-dimethylmorpholino)ethyl methyl fumarate hydrochloride following general procedure 2 (0.19 g, 64%). 1H NMR (300 MHz, CDCl3); 6.83 (1H, d), 6.75 (1H, d), 4.47-4.43 (2H, m), 3.93-3.82 (2H, m), 3.67 (3H, s), 3.46-3.40 (2H, m), 2.72 (2H, t), 1.10 (6H, d). m/z [M+H]+=272.2. Methyl (2-(3-oxomorpholino)ethyl) fumarate (30) A mixture of potassium tert-butoxide (5.9 g, 52.3 mmol) and toluene (50 mL) was heated at 75° C. for 30 min and then diethanolamine (5.0 g, 47.6 mmol) added. The reaction mixture was heated a further 30 min and then methyl chloroacetate (4.4 mL, 50.0 mmol) added. After a further 2 h heating the reaction was diluted with methanol (21 mL) and cooled to room temperature. The reaction mixture was filtered, washed with toluene and the mother liquor evaporated. The residue was further purified by silica flash column chromatography giving 4-(2-hydroxyethyl)morpholin-3-one (0.65 g, 9%). 1H NMR (300 MHz, CDCl3); 4.19 (2H, s), 3.89 (2H, t), 3.81 (2H, t), 3.57 (2H, t), 3.48 (2H, t), 2.89 (1H, s). Methyl (2-(3-oxomorpholino)ethyl) fumarate 30 was synthesised from 4-(2-hydroxyethyl)morpholin-3-one following general procedure 1 (0.71 g, 62%). 1H NMR (300 MHz, DMSO); 6.72 (2H, s), 4.28 (2H, t), 3.98 (2H, s), 3.77 (2H, t), 3.71 (3H, t), 3.59 (2H, t), 3.38 (2H, t). m/z [M+H]+=258.1. Methyl (2-(2-oxomorpholino)ethyl) fumarate hydrochloride (31) Methyl (2-(2-oxomorpholino)ethyl) fumarate 31 was synthesised from 4-(2-hydroxyethyl)morpholin-2-one following general procedure 1 (0.53 g, 34%). Methyl (2-(2-oxomorpholino)ethyl) fumarate was converted to methyl (2-(2-oxomorpholino)ethyl) fumarate hydrochloride following general procedure 2 (0.20 g, 34%). 1H NMR (300 MHz, DMSO); 3.75 (2H, s), 4.29-4.23 (4H, m), 3.71 (3H, s), 3.34 (2H, s), 2.73 (2H, t), 2.68 (2H, t). m/z [M+H]+=258.15. 2-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)ethyl methyl fumarate hydrochloride (32) 2-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)ethyl methyl fumarate 32 was synthesised from 3-(2-chloroethyl)-8-oxa-3-azabicyclo[3.2.1]octane following general procedure 5 (0.25 g, 50%). 2-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)ethyl methyl fumarate was converted to 2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)ethyl methyl fumarate hydrochloride following general procedure 2 (0.20 g, 73%). 1H NMR (300 MHz, D2O); 6.82 (1H, d), 6.75 (1H, d), 4.52-4.42 (4H, m), 3.69 (3H, s), 3.45-3.37 (4H, m), 3.26-3.19 (2H, m), 2.10-1.85 (4H, m). m/z [M+H]+=270.0. 2-(2-((Dimethylamino)methyl)morpholino)ethyl methyl fumarate hydrochloride (33) 2-(2-((Dimethylamino)methyl)morpholino)ethyl methyl fumarate 33 was synthesised from 1-(4-(2-chloroethyl)morpholin-2-yl)-N,N-dimethylmethanamine following general procedure 5 (0.17 g, 16%). 2-(2-((Dimethylamino)methyl)morpholino)ethyl methyl fumarate was converted to 2-(2-((Dimethylamino)methyl)morpholino)ethyl methyl fumarate hydrochloride following general procedure 2 (0.17 g, 95%). 1H NMR (300 MHz, D2O); 6.84 (1H, d), 6.77 (1H, d), 4.50-4.45 (2H, m), 4.21-4.06 (2H, m), 3.87-3.77 (1H, m), 3.68 (3H, s), 3.56-3.47 (2H, m), 3.25-3.09 (3H, m), 2.94 (1H, dd), 2.81 (6H, bs). m/z [M+H]+=301.2. 2-((3 S,5S)-3,5-Dimethylmorpholino)ethyl methyl fumarate hydrochloride (34) 2-((3 S,5 S)-3,5-Dimethylmorpholino)ethyl methyl fumarate 34 was synthesised from (3S,5S)-4-(2-chloroethyl)-3,5-dimethylmorpholine following general procedure 5 (0.11 g, 25%). 2-((3S,5S)-3,5-Dimethylmorpholino)ethyl methyl fumarate was converted to 2-((3S,5S)-3,5-dimethylmorpholino)ethyl methyl fumarate hydrochloride following general procedure 2 (0.08 g, 68%). 1H NMR (300 MHz, D2O); 7.15-7.00 (2H, m), 4.77-4.70 (2H, m), 4.20-4.08 (2H, m), 4.01-3.85 (8H, m), 3.68-3.58 (1H, m). m/z [M+H]+=272.3. 2-(2,5-Dioxomorpholino)ethyl methyl fumarate (35) 2-(2,5-Dioxomorpholino)ethyl methyl fumarate 35 was synthesised from 4-(2-hydroxyethyl)morpholine-2,5-dione following general procedure 1 (0.27 g, 65%). 1H NMR (300 MHz, DMSO); 6.75 (1H, d), 6.71 (1H, d), 4.72 (2H, s), 4.30 (2H, s), 4.26 (2H, t), 3.72 (3H, s), 3.60 (2H, t). m/z [M+H]+=272.2. (E)-Methyl 3-(4-methyl-2,5,7-trioxabicyclo[2.2.2]octan-1-yl)acrylate (130) Methyl ((3-methyloxetan-3-yl)methyl) fumarate was synthesised from 3-methyl-3oxetane methanol following general procedure 1 (0.86 g, 89%). 1H NMR (300 MHz, CDCl3); 6.88 (2H, s), 4.52 (2H, d), 4.40 (2H, d), 4.30 (2H, s), 3.82 (3H, s), 1.35 (3H, s). To a solution of methyl ((3-methyloxetan-3-yl)methyl) fumarate 130 (0.20 g, 0.93 mmol) in dichloromethane (5 mL) at 5° C. was added borontrifluoride diethyletherate (0.058 mL, 0.47 mmol). After 1 h a further portion of borontrifluoride diethyletherate (0.058 mL, 0.47 mmol) was added and the reaction mixture warmed to 20° C. over 1 h. To the reaction mixture was added triethylamine (0.13 mL, 0.93 mmol) and then this was loaded directly onto a silica column. The desired product was eluted with heptane/ethyl acetate (6:4) containing triethylamine (2.5% v/v) giving (E)-methyl 3-(4-methyl-2,5,7-trioxabicyclo[2.2.2]octan-1-yl)acrylate (0.12 g, 60%). 1H NMR (300 MHz, CDCl3); 6.66 (1H, d), 6.25 (1H, d), 3.97 (6H, s), 3.73 (3H, s), 0.84 (3H, s). m/z [M+H]+=215.2. Methyl prop-2-yn-1-yl fumarate (131) Methyl prop-2-yn-1-yl fumarate 131 was synthesized from propargyl alcohol following general procedure 1 (0.51 g, 68%). 1H NMR (300 MHz, DMSO); 6.85-6.70 (2H, m), 4.81 (2H, d), 3.72 (3H, s), 3.60 (1H, t). 2-(1,3-Dioxoisoindolin-2-yl)ethyl methyl fumarate (36) 2-(1,3-Dioxoisoindolin-2-yl)ethyl methyl fumarate 36 was synthesised from 2-(2-hydroxyethyl)isoindoline-1,3-dione following general procedure 1 (0.63 g, 79%). 1H NMR (300 MHz, MeOD); 7.87-7.77 (4H, m), 6.74-6.73 (2H, m), 4.45-4.40 (2H, m), 4.01-3.96 (2H, m), 3.76 (3H, s). m/z [M+H]+=304.1. 4-(2,5-Dioxopyrrolidin-1-yl)butyl methyl fumarate (132) 4-(2,5-Dioxopyrrolidin-1-yl)butyl methyl fumarate 132 was synthesised from 1-(4-hydroxybutyl)pyrrolidine-2,5-dione following general procedure 1 (0.77 g, 79%). 1H NMR (300 MHz, MeOD); 6.81-6.79 (2H, m), 4.20 (2H, t), 3.78 (3H, s), 3.50 (2H, t), 2.67 (4H, s), 1.71-1.62 (4H, m). m/z [M+H]+=284.2. 2-(3,3-Dimethyl-2,5-dioxopyrrolidin-1-yl)ethyl methyl fumarate (36) 2-(3,3-Dimethyl-2,5-dioxopyrrolidin-1-yl)ethyl methyl fumarate 36 was synthesised from 1-(2-hydroxyethyl)-3,3-dimethylpyrrolidine-2,5-dione following general procedure 1 (0.72 g, 74%). 1H NMR (300 MHz, CDCl3); 6.83 (1H, d), 6.77 (1H, d), 4.38 (2H, t), 3.82 (1H, t), 3.80 (3H, s), 2.55 (2H, s), 1.31 (6H, s). m/z [M+H]+=284.1. 3-(2,5-Dioxopyrrolidin-1-yl)propyl methyl fumarate (133) 3-(2,5-Dioxopyrrolidin-1-yl)propyl methyl fumarate 133 was synthesised from 1-(3-hydroxypropyl)pyrrolidine-2,5-dione following general procedure 1 (0.64 g, 69%). 1H NMR (300 MHz, MeOD); 6.82 (2H, s), 4.17 (2H, t), 3.79 (3H, s), 3.59 (2H, t), 2.67 (4H, s), 1.95 (2H, dt). m/z [M+H]+=270.2. Methyl (2-(2-oxopyrrolidin-1-yl)ethyl) fumarate (38) Methyl (2-(2-oxopyrrolidin-1-yl)ethyl) fumarate 38 was synthesised from 1-(2-hydroxyethyl)pyrrolidin-2-one following general procedure 1 (0.68 g, 73%). 1H NMR (300 MHz, MeOD); 6.85 (2H, s), 4.33 (2H, t), 3.80 (3H, s), 3.59 (2H, t), 3.46 (2H, t), 2.37 (2H, t), 2.03 (2H, dt). [M+H]+=242.1. Methyl (2-(2-oxooxazolidin-3-yl)ethyl) fumarate (39) Methyl (2-(2-oxooxazolidin-3-yl)ethyl) fumarate 39 was synthesised from 3-(2-hydroxyethyl)oxazolidin-2-one following general procedure 1 (0.77 g, 92%). 1H NMR (300 MHz, MeOD); 6.82 (2H, s), 4.39-4.30 (4H, m), 3.78 (3H, s), 3.72-3.67 (2H, m), 3.58-3.54 (2H, m). m/z [M+H]+=244.2. 2-(4,4-Dimethyl-2,5-dioxoimidazolidin-1-yl)ethyl methyl fumarate (42) 2-(4,4-Dimethyl-2,5-dioxoimidazolidin-1-yl)ethyl methyl fumarate 42 was synthesised from 3-(2-hydroxyethyl)-5,5-dimethylimidazolidine-2,4-dione following general procedure 1 (0.33 g, 33%). 1H NMR (300 MHz, CDCl3); 6.82 (2H, s), 5.50 (NH), 4.40 (2H, t), 3.86-3.76 (5H, m), 1.43 (6H, s). m/z [M+H]+=285.2. Methyl (2-(N-propionylpropionamido)ethyl) fumarate (42) Methyl (2-propionamidoethyl) fumarate 41 was synthesised from N-(2-hydroxyethyl)propionamide following general procedure 1 (1.7 g, 96%). 1H NMR (300 MHz, CDCl3); 6.87 (2H, s), 4.29 (2H, t), 3.81 (3H, s), 3.58 (2H, q), 2.21 (2H, q), 1.15 (3H, t). A mixture of methyl (2-propionamidoethyl) fumarate (1.7 g, 7.4 mmol), propionic anhydride (36 mL) and sodium propionate (1.0 g, 10.4 mmol) was heated at 150° C. for 16 h. The reaction was cooled, concentrated to ⅓rd volume and then loaded onto a silica column and eluted with 0-20% ethyl acetate/dichloromethane. The product containing fractions were combined, evaporated and re-purified by silica flash chromatography eluting with 10-50% ethyl acetate/heptanes giving methyl (2-(N-propionylpropionamido)ethyl) fumarate 42 (0.18 g, 21%). 1H NMR (300 MHz, CDCl3); 6.83-6.82 (2H, m), 4.34 (2H, t), 4.01 (2H, t), 3.81 (3H, s), 2.75 (4H, q), 1.16 (6H, t). 2-((3R,4S)-3,4-Dimethyl-2,5-dioxopyrrolidin-1-yl)ethyl methyl fumarate (23) Racemic 2-((3R,4S)-3,4-dimethyl-2,5-dioxopyrrolidin-1-yl)ethyl methyl fumarate 23 was synthesised from racemic (3R,4S)-1-(2-hydroxyethyl)-3,4-dimethylpyrrolidine-2,5-dione following general procedure 1 (0.54 g, 44%). 1H NMR (300 MHz, CDCl3); 6.81-6.80 (2H, m), 4.37 (2H, t), 3.82 (2H, t), 3.80 (3H, s), 3.00-2.88 (2H, m), 1.25-1.18 (6H, m). m/z [M+H]+=284.2. 2-Acetamidoethyl methyl fumarate (43) 2-Acetamidoethyl methyl fumarate was synthesised from N-(2-hydroxyethyl)acetamide 43 following general procedure 1 (0.23 g, 70%). 1H NMR (300 MHz, CDCl3); 6.87 (2H, s), 5.80 (NH), 4.29 (2H, t), 3.81 (3H, s), 3.57 (2H, q), 2.00 (3H, s). m/z [M+H]+=216.14. 2-(N-Acetylacetamido)ethyl methyl fumarate (44) A mixture of 2-acetamidoethyl methyl fumarate (0.62 g, 2.9 mmol), acetic anhydride (15 mL) and sodium acetate (0.33 g, 4.0 mmol) was heated at reflux for 20 h. The reaction mixture was evaporated and the residue suspended in dichloromethane. The supernatant was loaded onto a silica column and eluted with 0-205 ethyl acetate/dichloromethane giving 2-(N-Acetylacetamido)ethyl methyl fumarate 44 (0.36 g, 48%). 1H NMR (300 MHz, CDCl3); 6.87 (1H, d), 6.82 (1H, d), 4.36 (2H, d), 4.00 (2H, d), 3.81 (3H, s), 2.44 (3H, s). 2-((tert-butoxycarbonyl)amino)ethyl methyl fumarate (48) To a suspension of monomethyl fumarate (MMF) (1.0 equivalent) in dichloromethane (11 mL per g of MMF) was added diisopropylethylamine (3 equivalents), 2-((tert-butoxylcarbonyl)amino)ethanol (1.02 equivalents) and N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium tetrafluoroborate (1.5 equivalents). The reaction was stirred for 1-18 hours at <10° C. The reaction was quenched with 1M hydrochloric acid (0.6 mL/mL of DCM). The organic layer was washed with 10% (w/w) aqueous sodium bicarbonate solution (0.6 mL/mL of DCM) followed by 37% (w/w) sodium chloride solution (0.6 mL/mL of DCM). The organic layer was dried over sodium sulfate, filtered to remove the drying agent, and the solution added to a silica plug (˜6 g of silica gel/g of MMF) and the plug flushed with DCM until no more product eluted. ˜80% of the DCM was removed under reduced pressure at 30° C. after which time 25 mL of MTBE/g of MMF were added and the solution further concentrated at 30° C. until −10 mL/g of MMF remained. The resulting suspension was cooled to 5° C. for at least 1 hour and then the resulting solids were collected by filtration to give the desired MMF ester prodrug. (3.8 g, 91%). 1H NMR (400 MHz, DMSO-d6) δ 7.08 (t, J=5.4 Hz, 1H), 6.89 (d, J=15.8 Hz, 1H), 6.79 (d, J=15.8 Hz, 1H), 4.18 (t, J=5.3 Hz, 2H), 3.81 (s, 3H), 3.28 (q, J=5.4 Hz, 2H), 1.43 (s, 9H). m/z [M+H]+=274.3. 2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl methyl fumarate (55) To a suspension of monomethyl fumarate (MMF) (1.0 equivalent) in dichloromethane (11 ml per g of MMF) was added diisopropylethylamine (3 equivalents), the desired alcohol (1.02 equivalents) and N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium tetrafluoroborate (1.5 equivalents). The reaction was stirred for 1-18 hours at <10° C. The reaction was quenched with 1M hydrochloric acid (0.6 mL/mL of DCM). The organic layer was washed with 10% (w/w) aqueous sodium bicarbonate solution (0.6 mL/mL of DCM) followed by 37% (w/w) sodium chloride solution (0.6 mL/mL of DCM). The organic layer was dried over sodium sulfate, filtered to remove the drying agent, and the solution added to a silica plug (˜6 g of silica gel/g of MMF) and the plug flushed with DCM until no more product eluted. ˜80% of the DCM was removed under reduced pressure at 30° C. after which time 25 mL of MTBE/g of MMF were added and the solution further concentrated at 30° C. until −10 mL/g of MMF remained. The resulting suspension was cooled to 5° C. for at least 1 hour and then the resulting solids were collected by filtration to give the desired MMF ester prodrug. (2.4 g, 67%). 1H NMR (400 MHz, Chloroform-d) δ 6.82 (d, J=2.8 Hz, 2H), 6.74 (s, 2H), 4.36 (t, J=5.3 Hz, 2H), 3.86 (t, J=5.3 Hz, 2H), 3.81 (s, 3H). m/z [M+H]+=254.2. Reference Compound A 2-(diethylamino)-2-oxoethyl methyl fumarate 2-(diethylamino)-2-oxoethyl methyl fumarate was synthesized following general procedure 3 and conformed to reported data in U.S. Pat. No. 8,148,414. Example 2—Aqueous Chemical Stability of Several Compounds Stock solutions of the compounds in acetonitrile or acetonitrile/methanol were prepared at 20 mg/mL and 20 μL, spiked into 3 mL of buffer phosphate (100 mM) and incubated at 37° C. Aliquots (50 μL) were sampled at different time points and diluted 20 fold with ammonium formate (pH 3.5)/acetonitrile. The diluted samples were analyzed by HPLC. The peak areas corresponding to the compounds were plotted against time and the data were fitted to a first-order mono-exponential decay where the rate constant and the half-life were determined (Table 3). In some cases, in which the half life is too long (>360 min), an estimated value of the half life is reported using the initial slope at low conversion (<10%). TABLE 3 Compound pH 8 (t ½, min) 1 15 4 45 5 24 6 2.0 7 26.0 8 36.0 9 7.0 10 67.0 11 >240 12 396 14 144 15 3.0 16 20.0 17 11.0 18 5.0 19 6.0 20 5.0 Reference 120 Compound A Stock solutions of the compounds in acetonitrile or acetonitrile/MeOH were prepared at 0.05M. A 0.010 mL aliquot of the stock was spiked into 1 mL of 50 mM buffer phosphate pH 8 and incubated at 37° C. Typically, aliquots (0.010 mL) were sampled at different time points and immediately injected in the HPLC with UV detection (211 nm). The peak areas corresponding to the compounds were plotted against time and the data were fitted to a first-order mono-exponential decay where the rate constant and the half-life were determined from the slope (Table 4). TABLE 4 Compound pH 8 (t ½, min) 1 15 4 30 5 24 6 2 19 117 22 144 23 186 26 129 27 37 28 <10 29 <10 30 229 31 26 32 13 33 115 35 37 182 38 201 39 183 40 203 42 158 43 177.5 44 145 48 220 130 1010 131 96 133 246 Example 3—Evaluation of Aqueous Chemical Stability with NMR The chemical hydrolysis was followed by dissolving the ester in phosphate buffered D2O (pH 7.9) in an NMR tube, heating the NMR tube to 37° C. and periodically recording the spectra. These various species produced by hydrolysis of the diesters were followed over time. See FIGS. 1-5. Example 4—Delivery of MMF in Rats Upon Oral Administration of Prodrugs Rats were obtained commercially and were pre-cannulated in the jugular vein. Animals were conscious at the time of the experiment. All animals were fasted overnight and until 4 hours post-dosing of a prodrug in the disclosure. Blood samples (0.25 mL/sample) were collected from all animals at different time-points up to 24 hours post-dose into tubes containing sodium fluoride/sodium EDTA. Samples were centrifuged to obtain plasma. Plasma samples were transferred to plain tubes and stored at or below −70° C. prior to analysis. To prepare analysis standards, 20 uL of rat plasma standard was quenched with 60 uL of internal standard. The sample tubes were vortexed for at least 1 min and then centrifuged at 3000 rpm for 10 min. 50 uL of supernatant was then transferred to 96-well plates containing 100 L water for analysis by LC-MS-MS. LC-MS/MS analysis was performed using an API 4000 equipped with HPLC and autosampler. The following HPLC column conditions were used: HPLC column: Waters Atlantis T3; flow rate 0.5 mL/min; run time 5 min; mobile phase A: 0.1% formic acid in water; mobile phase B: 0.1% formic acid in acetonitrile (ACN); gradient: 98% A/2% B at 0.0 min; 98% A/2% B at 1 min; 5% A/95% B at 3 min; 5% A/95% B at 3.75 min; 97% A/3% B at 4 min; and 98% A/2% B at 5.0 min. MMF was monitored in positive ion mode. MMF, DMF or MMF prodrug was administered by oral gavage to groups of two to six adult male Sprague-Dawley rats (about 250 g). Animals were conscious at the time of the experiment. MMF, DMF or MMF prodrug was orally administered in an aqueous solution of 0.5% hydroxypropyl methyl cellulose (HPMC), 0.02% polysorbate 80, and 20 mM citrate buffer (pH 5), at a dose of 10 mg-equivalents MMF per kg body weight. The percent absolute bioavailability (F %) of MMF was determined by comparing the area under the MMF concentration vs time curve (AUC) following oral administration of MMF, DMF or MMF prodrug with the AUC of the MMF concentration vs time curve following intravenous administration of MMF on a dose normalized basis. The MMF prodrugs, when administered orally to rats at a dose of 10 mg/kg MMF-equivalents in the aqueous vehicle, exhibited an absolute oral bioavailability (relative to IV) ranging from about 3% to about 96% (See Tables 5 and 6). Tables 5 and 6 show data from two independent studies. TABLE 5 Percent Absolute Compound No. Bioavailability (F %) MMF 43% DMF 53% 16 60-82% 4 3% 14 96% 10 73% TABLE 6 Percent Absolute Compound No. Bioavailability (F %) MMF 69.6 DMF 69.6 132 60.3 40 70.4 39 91.4 5 81.1 11 71.4 Example 5—Delivery of MMF in Dogs Upon Oral Administration of Prodrugs Male Beagle dogs were obtained from the test facility's colony of non-native animals. All animals were fasted overnight prior to dose administration. Oral doses were administered via oral gavage. The gavage tube was flushed with 10 mL of water prior to removal. All animals were observed at dosing and at each scheduled collection. All abnormalities were recorded. Blood samples were collected in Sodium Fluoride/Na2EDTA tubes and stored on wet ice until processed to plasma by centrifugation (300 rpm at 5° C.) within 30 minutes of collection. All plasma samples were transferred into separate 96-well plates (matrix tubes) and stored at −80° C. until concentration analysis was performed via LC/MS/MS using an RGA 3 assay. Extraction Procedure: Note: Thawed test samples at 4° C. (Kept in ice while on bench). 1. Aliquoted 20 uL of study sample, standard, and QC samples into labeled 96-well plate. 2. Added 120 uL of appropriate internal standard solution (125 ng/mL mouse embryo fibroblasts (MEF)) to each tube, except for the double blank to which 120 uL of appropriate acetonitrile:FA (100:1) was added. 3. Sealed and vortexed for one minute. 4. Centrifuged at 3000 rpm for 10 minutes. 5. Transferred 100 uL of supernatant to a clean 96-well plate containing 100 uL water. 6. Sealed and vortexed gently for 2 minutes. The percent absolute bioavailability (F %) of MMF was determined by comparing the area under the MMF concentration vs time curve (AUC) following oral administration of MMF prodrug with the AUC of the MMF concentration vs time curve following intravenous administration of MMF on a dose normalized basis. The MMF prodrugs, when administered orally to dogs at a dose of 10 mg/kg MMF-equivalents in the aqueous vehicle, exhibited an absolute oral bioavailability (relative to IV) ranging from about 31% to about 78% (See Table 7). TABLE 7 Percent Absolute Compound No. Bioavailability (F %) 16 54% 16 (capsule) 54% 14 78% 10 31% Example 6—Physical Stability of the Instant Prodrugs and DMF in Crystalline Form The physical stability of compounds of the present invention and DMF were measured via thermogravimetric analysis (TGA). FIG. 6 shows a plot of weight loss at 60° C. vs time for Compound 14 (12.15 mg), no change, and DMF (18.40 mg), ˜100% weight loss in less than 4 hours. These data indicate that DMF undergoes sublimation while Compound 14 is physically stable under similar conditions. Example 7—Single Crystal X-Ray Data for Compound 14 Compound 14 produced by the method described in Example 1 was analyzed. FIG. 7 depicts the unit cell. The single crystal x-ray data are included below: Single Crystal Data: Empirical formula: C11 H13 N O6 Formula weight: 255.22 Temperature: 173(2) K Wavelength: 1.54178 Å Space group: P-1 Unit cell dimensions: a = 6.07750(10) Å α = 84.9390(10)°. b = 7.96290(10) Å β = 80.0440(10)°. c = 12.7850(2) Å γ = 71.9690(10)°. Volume: 579.080(15) A3 Z: 2 Density (calculated): 1.464 Mg/m3 Absorption coefficient: 1.034 mm−1 F(000): 268 Crystal size: 0.37×0.15×0.15 mm3 Reflections collected: 8446 Independent reflections: 2229 [R(int)=0.0249] Refinement method: Full-matrix least-squares on F2 Goodness-of-fit on F2:1.049 Final R indices [I>2sigma(I)] R1=0.0317, wR2=0.0850 R indices (all data): R1=0.0334, wR2=0.0864. While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims. | <SOH> BACKGROUND OF THE INVENTION <EOH>Fumaric acid esters (FAEs) are approved in Germany for the treatment of psoriasis, are being evaluated in the United States for the treatment of psoriasis and multiple sclerosis, and have been proposed for use in treating a wide range of immunological, autoimmune, and inflammatory diseases and conditions. FAEs and other fumaric acid derivatives have been proposed for use in treating a wide-variety of diseases and conditions involving immunological, autoimmune, and/or inflammatory processes including psoriasis (Joshi and Strebel, WO 1999/49858; U.S. Pat. No. 6,277,882; Mrowietz and Asadullah, Trends Mol Med 2005, 111(1), 43-48; and Yazdi and Mrowietz, Clinics Dermatology 2008, 26, 522-526); asthma and chronic obstructive pulmonary diseases (Joshi et al., WO 2005/023241 and US 2007/0027076); cardiac insufficiency including left ventricular insufficiency, myocardial infarction and angina pectoris (Joshi et al., WO 2005/023241; Joshi et al., US 2007/0027076); mitochondrial and neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, retinopathia pigmentosa and mitochondrial encephalomyopathy (Joshi and Strebel, WO 2002/055063, US 2006/0205659, U.S. Pat. No. 6,509,376, U.S. Pat. No. 6,858,750, and U.S. Pat. No. 7,157,423); transplantation (Joshi and Strebel, WO 2002/055063, US 2006/0205659, U.S. Pat. No. 6,359,003, U.S. Pat. No. 6,509,376, and U.S. Pat. No. 7,157,423; and Lehmann et al., Arch Dermatol Res 2002, 294, 399-404); autoimmune diseases (Joshi and Strebel, WO 2002/055063, U.S. Pat. No. 6,509,376, U.S. Pat. No. 7,157,423, and US 2006/0205659) including multiple sclerosis (MS) (Joshi and Strebel, WO 1998/52549 and U.S. Pat. No. 6,436,992; Went and Lieberburg, US 2008/0089896; Schimrigk et al., Eur J Neurology 2006, 13, 604-610; and Schilling et al., Clin Experimental Immunology 2006, 145, 101-107); ischemia and reperfusion injury (Joshi et al., US 2007/0027076); AGE-induced genome damage (Heidland, WO 2005/027899); inflammatory bowel diseases such as Crohn's disease and ulcerative colitis; arthritis; and others (Nilsson et al., WO 2006/037342 and Nilsson and Muller, WO 2007/042034). FUMADERM®, an enteric coated tablet containing a salt mixture of monoethyl fumarate and dimethyl fumarate (DMF) which is rapidly hydrolyzed to monomethyl fumarate, regarded as the main bioactive metabolite, was approved in Germany in 1994 for the treatment of psoriasis. FUMADERM® is dosed TID with 1-2 grams/day administered for the treatment of psoriasis. FUMADERM® exhibits a high degree of interpatient variability with respect to drug absorption and food strongly reduces bioavailability. Absorption is thought to occur in the small intestine with peak levels achieved 5-6 hours after oral administration. Significant side effects occur in 70-90% of patients (Brewer and Rogers, Clin Expt'l Dermatology 2007, 32, 246-49; and Hoefnagel et al., Br J Dermatology 2003, 149, 363-369). Side effects of current FAE therapy include gastrointestinal upset including nausea, vomiting, diarrhea and/or transient flushing of the skin. Multiple sclerosis (MS) is an autoimmune disease with the autoimmune activity directed against central nervous system (CNS) antigens. The disease is characterized by inflammation in parts of the CNS, leading to the loss of the myelin sheathing around neuronal axons (gradual demyelination), axonal loss, and the eventual death of neurons, oligodendrocytes and glial cells. Dimethyl fumarate (DMF) is the active component of the experimental therapeutic, BG-12, studied for the treatment of relapsing-remitting MS (RRMS). In a Phase IIb RRMS study, BG-12 significantly reduced gadolinium-enhancing brain lesions. In preclinical studies, DMF administration has been shown to inhibit CNS inflammation in murine and rat EAE. It has also been found that DMF can inhibit astrogliosis and microglial activations associated with EAE. See, e.g., US Published Application No. 2012/0165404. There are four major clinical types of MS: 1) relapsing-remitting MS (RRMS), characterized by clearly defined relapses with full recovery or with sequelae and residual deficit upon recovery; periods between disease relapses characterized by a lack of disease progression; 2) secondary progressive MS (SPMS), characterized by initial relapsing remitting course followed by progression with or without occasional relapses, minor remissions, and plateaus; 3) primary progressive MS (PPMS), characterized by disease progression from onset with occasional plateaus and temporary minor improvements allowed; and 4) progressive relapsing MS (PRMS), characterized by progressive disease onset, with clear acute relapses, with or without full recovery; periods between relapses characterized by continuing progression. Clinically, the illness most often presents as a relapsing-remitting disease and, to a lesser extent, as steady progression of neurological disability. Relapsing-remitting MS (RRMS) presents in the form of recurrent attacks of focal or multifocal neurologic dysfunction. Attacks may occur, remit, and recur, seemingly randomly over many years. Remission is often incomplete and as one attack follows another, a stepwise downward progression ensues with increasing permanent neurological deficit. The usual course of RRMS is characterized by repeated relapses associated, for the majority of patients, with the eventual onset of disease progression. The subsequent course of the disease is unpredictable, although most patients with a relapsing-remitting disease will eventually develop secondary progressive disease. In the relapsing-remitting phase, relapses alternate with periods of clinical inactivity and may or may not be marked by sequelae depending on the presence of neurological deficits between episodes. Periods between relapses during the relapsing-remitting phase are clinically stable. On the other hand, patients with progressive MS exhibit a steady increase in deficits, as defined above and either from onset or after a period of episodes, but this designation does not preclude the further occurrence of new relapses. Notwithstanding the above, dimethyl fumarate is also associated with significant drawbacks. For example, dimethyl fumarate is known to cause side effects upon oral administration, such as flushing and gastrointestinal events including, nausea, diarrhea, and/or upper abdominal pain in subjects. See, e.g., Gold et al., N. Eng. J. Med., 2012, 367(12), 1098-1107. Dimethyl fumarate is dosed BID or TID with a total daily dose of about 480 mg to about 1 gram or more. Further, in the use of a drug for long-term therapy it is desirable that the drug be formulated so that it is suitable for once- or twice-daily administration to aid patient compliance. A dosing frequency of once-daily or less is even more desirable. Another problem with long-term therapy is the requirement of determining an optimum dose which can be tolerated by the patient. If such a dose is not determined this can lead to a diminution in the effectiveness of the drug being administered. Accordingly, it is an object of the present invention to provide compounds and/or compositions which are suitable for long-term administration. It is a further object of the present invention to provide the use of a pharmaceutical active agent in a manner which enables one to achieve a tolerable steady state level for the drug in a subject being treated therewith. Because of the disadvantages of dimethyl fumarate described above, there continues to be a need to decrease the dosing frequency, reduce side-effects and/or improve the physicochemical properties associated with DMF. There remains, therefore, a real need in the treatment of neurological diseases, such as MS, for a product which retains the pharmacological advantages of DMF but overcomes its flaws in formulation and/or adverse effects upon administration. The present invention addresses these needs. | <SOH> SUMMARY OF THE INVENTION <EOH>This invention is directed to the surprising and unexpected discovery of novel prodrugs and related methods useful in the treatment of neurological diseases. The methods and compositions described herein comprise one or more prodrugs (e.g., aminoalkyl prodrugs) of monomethyl fumarate (MMF). The methods and compositions provide for a therapeutically effective amount of an active moiety in a subject for a time period of at least about 8 hours to at least about 24 hours. More specifically, the compounds of the invention can be converted in vivo, upon oral administration, to monomethyl fumarate. Upon conversion, the active moiety (i.e., monomethyl fumarate) is effective in treating subjects suffering from a neurological disease. The present invention provides, in part, a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof: wherein: R 1 is unsubstituted C 1 -C 6 alkyl; L a is substituted or unsubstituted C 1 -C 6 alkyl linker, substituted or unsubstituted C 3 -C 10 carbocycle, substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; and R 2 and R 3 are each, independently, H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted C 3 -C 10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; or alternatively, R 2 and R 3 , together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S or a substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S. The present invention also provides pharmaceutical compositions comprising one or more compounds of any of the formulae described herein and one or more pharmaceutically acceptable carriers. The present invention also provides methods of treating a neurological disease by administering to a subject in need thereof, a therapeutically effective amount of a compound of any of the formulae described herein, or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof, such that the disease is treated. The present invention also provides methods of treating multiple sclerosis by administering to a subject in need thereof, a therapeutically effective amount of a compound of any of the formulae described herein, or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof, such that the multiple sclerosis is treated. The present invention also provides methods of treating relapsing-remitting multiple sclerosis (RRMS) by administering to a subject in need thereof, a therapeutically effective amount of a compound of any of the formulae described herein, or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof, such that the multiple sclerosis is treated. The present invention also provides methods of treating secondary progressive multiple sclerosis (SPMS) by administering to a subject in need thereof, a therapeutically effective amount of a compound of any of the formulae described herein, or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof, such that the multiple sclerosis is treated. The present invention also provides methods of treating primary progressive multiple sclerosis (PPMS) by administering to a subject in need thereof, a therapeutically effective amount of a compound of any of the formulae described herein, or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof, such that the multiple sclerosis is treated. The present invention also provides methods of treating progressive relapsing multiple sclerosis (PRMS) by administering to a subject in need thereof, a therapeutically effective amount of a compound of any of the formulae described herein, or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof, such that the multiple sclerosis is treated. The present invention also provides methods of treating Alzheimer's disease by administering to a subject in need thereof, a therapeutically effective amount of a compound of any of the formulae described herein, or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof, such that the Alzheimer's disease is treated. The present invention also provides methods of treating cerebral palsy by administering to a subject in need thereof, a therapeutically effective amount of a compound of any of the formulae described herein, or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof, such that the cerebral palsy is treated. The present invention also provides compounds and compositions that enable improved oral, controlled- or sustained-release formulations. Specifically, dimethyl fumarate is administered twice or three times daily for the treatment of relapsing-remitting multiple sclerosis. In contrast, the compounds and compositions of the present invention may enable formulations with a modified duration of therapeutic efficacy for reducing relapse rates in subjects with multiple sclerosis. For example, the present compounds and compositions provide therapeutically effective amounts of monomethyl fumarate in subjects for at least about 8 hours, at least about 12 hours, at least about 16 hours, at least about 20 hours or at least about 24 hours. The present invention also provides compounds, compositions and methods which may result in decreased side effects upon administration to a subject relative to dimethyl fumarate. For example, gastric irritation and flushing are known side effects of oral administration of dimethyl fumarate in some subjects. The compounds, compositions and methods of the present invention can be utilized in subjects that have experienced or are at risk of developing such side effects. The present invention also provides for compounds and compositions which exhibit improved physical stability relative to dimethyl fumarate. Specifically, dimethyl fumarate is known in the art to undergo sublimation at ambient and elevated temperature conditions. The compounds of the invention possess greater physical stability than dimethyl fumarate under controlled conditions of temperature and relative humidity. Specifically, in one embodiment, the compounds of the formulae described herein exhibit decreased sublimation relative to dimethyl fumarate. Further, dimethyl fumarate is also known to be a contact irritant. See e.g., Material Safety Data Sheet for DMF. In one embodiment, the compounds of the present invention exhibit reduced contact irritation relative to dimethyl fumarate. For example, the compounds of the formulae described herein exhibit reduced contact irritation relative to dimethyl fumarate. The present invention also provides for compounds and compositions which exhibit decreased food effect relative to dimethyl fumarate. The bioavailability of dimethyl fumarate is known in the art to be reduced when administered with food. Specifically, in one embodiment, the compounds of the formulae described herein exhibit decreased food effect relative to dimethyl fumarate. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting. Other features and advantages of the invention will be apparent from the following detailed description and claims. | A61K31225 | 20171012 | 20180215 | 95061.0 | A61K31225 | 1 | SPRINGER, STEPHANIE K | PRODRUGS OF FUMARATES AND THEIR USE IN TREATING VARIOUS DISEASES | UNDISCOUNTED | 1 | CONT-ACCEPTED | A61K | 2,017 |
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15,782,519 | ACCEPTED | Compositions for Fecal Floral Transplantation and Methods for Making and Using Them and Devices for Delivering Them | In alternative embodiments, the invention provides compositions, e.g., formulations, used for gastric, gastrointestinal and/or colonic treatments or lavage, e.g., orthostatic lavage, e.g., for inducing the purgation (e.g., cleansing) of a gastrointestinal (GI) tract, including a colon; and methods for making and using them. In alternative embodiments, compositions and methods of the invention are used for the stabilization, amelioration, treatment and/or prevention of constipation, for the treatment of abdominal pain, particularly non-specific abdominal pain, and diarrhea, including diarrhea caused by a drug side effect, a psychological condition, a disease or a condition such as Crohn's Disease, a poison, a toxin or an infection, e.g., a toxin-mediated traveler's diarrhea, or C. difficile or the pseudo-membranous colitis associated with this infection. In alternative embodiments, the invention provides pharmaceuticals and products (articles) of manufacture for delivering these compositions and formulations to an individual, e.g., a human or an animal. The invention also provides devices for delivering a fecal material to a patient. | 1-43. (canceled) 44. A method comprising: receiving a stool sample from a healthy donor at a central location, wherein the donor has been prescreened for infectious agents; placing the stool sample within a stool collection device; mixing the stool sample with a liquid to form a mixture, wherein the liquid comprises a buffer and a cryoprotectant, and wherein the cryoprotectant is selected from the group consisting of glycerol, polyethylene glycol, trehalose, skim milk, erythritol, arabitol, sorbitol, glucose, fructose, and a combination thereof; homogenizing and filtering the mixture to produce a filtrate comprising a substantially entire microbiota of the stool sample, wherein the filtrate is substantially free of fiber. 45. The method of claim 44, wherein the filtrate comprises less than 1% non-flora material from the stool sample. 46. The method of claim 44, wherein the liquid, the filtrate, or both further comprise an antioxidant. 47. The method of claim 44, wherein the liquid, the filtrate, or both further comprise cysteine. 48. The method of claim 44, wherein the method further comprises lyophilizing the filtrate. 49. The method of claim 48, wherein the method further comprises encapsulating the lyophilized filtrate into a carrier. 50. The method of claim 49, wherein the carrier is selected from the group consisting of a tablet, a geltab, a pill, and a capsule. 51. The method of claim 44, wherein the method further comprises freezing the filtrate. 52. The method of claim 44, wherein the method further comprises encapsulating the filtrate. 53. The method of claim 52, wherein the encapsulated filtrate is frozen for storage. 54. The method of claim 52, wherein the encapsulated filtrate is in an graded release capsule. 55. The method of claim 44, wherein the stool collection device is sterile and sealed. 56. The method of claim 44, wherein the mixture, the filtrate, or both are maintained in an substantially anaerobic environment. 57. The method of claim 44, wherein the method further comprises adding one or more cultured bacteria to the filtrate. 58. The method of claim 44, wherein the method comprises recurrent filtration with decreasing filter sizes. 59. A method comprising: receiving a stool sample from a healthy donor at a central location, wherein the donor has been prescreened for infectious agents; mixing the stool sample with a liquid to form a mixture, wherein the liquid comprises a buffer, a cryoprotectant, and an antioxidant; homogenizing and filtering the mixture to produce a filtrate comprising a substantially entire microbiota of the stool sample. 60. The method of claim 59, wherein the cryoprotectant comprises trehalose. 61. The method of claim 59, wherein the filtrate comprises cysteine. 62. The method of claim 59, wherein the filtrate comprises less than 1% non-flora material from the stool sample. 63. A method comprising: receiving a stool sample from a healthy donor at a central location, wherein the donor has been prescreened for infectious agents; mixing the stool sample with a liquid to form a mixture; homogenizing and filtering the mixture to produce a filtrate comprising a substantially entire microbiota of the stool sample, wherein the filtrate further comprises a cryoprotectant and an antioxidant. | TECHNICAL FIELD This invention generally relates to medicine and gastroenterology, pharmacology and microbiology. In alternative embodiments, the invention provides compositions, e.g., formulations or preparations, and devices, used for the transplantation of a treated or isolated fecal flora, and methods for making and using them. In alternative embodiments, compositions, devices and methods of the invention can be used for any gastric, gastrointestinal and or colonic treatment or lavage. In alternative embodiments, compositions, devices and methods of the invention are used for the amelioration, stabilization, treatment and/or prevention of a disease or a condition such as constipation, Crohn's Disease, exposure to a poison or a toxin or for an infection, e.g., a toxin-mediated traveller's diarrhea; or any bowel disease or condition having a bowel dysfunction component, for example, an inflammatory bowel disease (IBD), Crohn's disease, hepatic encephalopathy, enteritis, colitis, irritable bowel syndrome (IBS), fibromyalgia (FM), chronic fatigue syndrome (CFS), depression, attention deficit/hyperactivity disorder (ADHD), multiple sclerosis (MS), systemic lupus erythematosus (SLE), travellers' diarrhea, small intestinal bacterial overgrowth, chronic pancreatitis, or a pancreatic insufficiency. In alternative embodiments, the invention provides pharmaceuticals and products (articles) of manufacture for delivering these compositions and formulations to an individual, e.g., a human or an animal. The invention also provides devices for delivering a fecal material to an individual, e.g., a patient. BACKGROUND Bacterial flora of the bowel has recently gained importance from a therapeutic point of view. It is now realized that the human flora, rather than just being waste material resulting from digestion of food, is an important virtual organ containing large numbers of living microorganisms. There are in excess of one hundred thousand different subspecies—or more—arranged in families and subgroups of genetically different but often linearly related organisms. The waste “material” makes up a proportion of the flora. The bacterial content of the flora is actively breaking down or metabolizing the non-absorbed matter, largely fiber, on which the bacterial cells grow. Because the bacterial flora is contained within the human body and is made up of living components it constitutes in fact as a living organ or a virtual organ. This virtual organ can be healthy in that it doesn't contain any pathogenic organisms, or it can become infected or infested with parasite, bacteria or viruses. When infected with some pathogenic species, such infecting species can manufacture molecules that affect secretion, which can cause pain, or can paralyze the bowel causing constipation. Infection of the bowel flora or bowel flora organ can impact the health of the individual. Many of these infections can be acute, such as cholera, but some can be chronic and can really impact on the life of the individual carrying the infected flora. For example, after antibiotic therapy some of the families of the bacteria can be suppressed or eradicated and infectious agents such as Clostridium difficile and other pathogens can lodge and become passengers within the human flora. These ‘passengers’ are also pathogenic because they can produce toxins e.g. toxins A and B for C. difficile. DEFINITIONS The following are some definitions that may be helpful in understanding the description of the present invention. These are intended as general definitions and should in no way limit the scope of the present invention to those terms alone, but are put forth for a better understanding of the following description. Unless the context requires otherwise or specifically stated to the contrary, integers, steps or elements of the invention recited herein as singular integers, steps or elements clearly encompass both singular and plural forms of the recited integers, steps or elements. Throughout this specification, unless the context requires otherwise, the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated step or element or integer or group of steps or elements or integers, but not the exclusion of any other step or element or integer or group of elements or integers. Thus, in the context of this specification, the term “comprising” means “including principally, but not necessarily solely”. SUMMARY According to a first aspect of the present invention, there is provided a delivery vehicle, formulation, composition, pharmaceutical preparation, product of manufacture, container or device, comprising: an entire (or substantially entire) microbiota; a treated or untreated fecal flora; a complete or partial fecal flora, a fecal flora substantially or completely purified of non-fecal floral fecal material, or a partially, substantially or completely isolated or purified fecal flora, made by a process comprising: (i) providing an entire (or substantially entire) microbiota, a treated or untreated fecal flora sample, a complete or partial fecal flora sample, a fecal flora substantially or completely purified of non-fecal floral fecal material or a partially, substantially or completely isolated or purified fecal flora; and, a delivery vehicle, formulation, pharmaceutical preparation, composition, product of manufacture, container or device, and (ii) placing the entire (or substantially entire) microbiota, the treated or untreated fecal flora sample, the complete or partial fecal flora sample, the fecal flora substantially or completely purified of non-fecal floral fecal material, or the partially, substantially or completely isolated or purified fecal flora in the delivery vehicle, formulation, composition, pharmaceutical preparation, product of manufacture, container or device. According to a second aspect of the present invention, there is provided a product (article) of manufacture comprising a delivery vehicle, formulation, composition pharmaceutical preparation, container or device of the first aspect. According to a third aspect of the present invention, there is provided a method for making a delivery vehicle, formulation, composition pharmaceutical preparation, product of manufacture, container or device according to the first or second aspect comprising (i) providing: an entire (or substantially entire) microbiota; a treated or untreated fecal sample; a complete or partial fecal flora sample, a fecal flora substantially or completely purified of non-fecal floral fecal material or a partially, substantially or completely isolated or purified fecal flora; and, a delivery vehicle, formulation, pharmaceutical preparation, composition product of manufacture, container or device, and (ii) placing the entire (or substantially entire) microbiota, treated or untreated fecal sample, the complete or partial fecal flora, the fecal flora substantially or completely purified of non-fecal floral fecal material or the partially, substantially or completely isolated or purified fecal flora in the delivery vehicle, formulation, pharmaceutical preparation, composition, product of manufacture, container or device, and creating a substantially or completely oxygen-free environment in the container or device. According to a fourth aspect of the present invention there is provided a method for the amelioration, stabilization, treatment and/or prevention of an infection, disease, treatment, poisoning or a condition having a bowel dysfunction component or side-effect, or for the amelioration, treatment and/or prevention of a constipation, for the treatment of an abdominal pain, a non-specific abdominal pain or a diarrhea, a diarrhea caused by: a drug side effect or a psychological condition or Crohn's Disease, a poison, a toxin or an infection, a toxin-mediated travelers diarrhea, or a Clostridium or a C. perfringens welchii or a C. difficile infection or a pseudo-membranous colitis associated with a Clostridium infection, comprising: administering to an individual in need thereof via a delivery vehicle, formulation, composition, pharmaceutical preparation, product of manufacture, container or device of the first aspect, or a product (article) of manufacture of the second aspect the entire (or substantially entire) microbiota, the treated or untreated fecal flora sample, the complete or partial fecal flora sample, the fecal flora substantially or completely purified of non-fecal floral fecal material, or the partially, substantially or completely isolated or purified fecal flora. According to a fifth aspect of the present invention, there is provided a delivery vehicle, formulation, composition, pharmaceutical preparation, product of manufacture, container or device comprising: an entire (or substantially entire) microbiota; a partially, substantially or completely isolated or purified fecal flora; or, a composition comprising a fecal flora substantially or a completely purified of non-fecal floral fecal material. According to a sixth aspect of the present invention, there is provided a method for the amelioration, stabilization, treatment and/or prevention of an infection, disease, treatment, poisoning or a condition having a bowel dysfunction component or side-effect comprising administering to an individual in need thereof via a delivery vehicle, formulation, composition, pharmaceutical preparation, product of manufacture, container or device according to the fifth aspect the entire (or substantially entire) microbiota, the partially, substantially or completely isolated or purified fecal flora, or the composition comprising a fecal flora substantially or a completely purified of non-fecal floral fecal material. According to a seventh aspect of the present invention, there is provided a device for delivering a fecal material or a composition of the first aspect, comprising: (a) a device as illustrated in FIG. 1B or FIG. 2; or (b) a device comprising (i) a bag or container comprising an exit aperture operably connected to the proximal end of a flexible tube or equivalent, (ii) an open or close valve or equivalent or an obdurator screwtop at the distal end of the flexible tube or equivalent, and (iii) a pump, or a hand pump, for moving material in the bag or container through the flexible tube or equivalent and out the distal end or out the open or close valve or equivalent; or (c) the device of (a) or (b), further comprising a fecal material or a composition of the first aspect. According to an eighth aspect of the present invention, there is provided a bag or container comprising: an entire (or substantially entire) microbiota; a treated or untreated fecal flora; a complete or partial fecal flora, a fecal flora substantially or completely purified of non-fecal floral material or, a partially, substantially or completely isolated or purified fecal flora, or a composition thereof wherein the bag or container is structurally the same as or similar to a bag or container of a device of the seventh aspect. According to a ninth aspect of the present invention, there is provided a method for the amelioration, stabilization, treatment and/or prevention of, or decreasing or delaying the symptoms of, an infection, disease, treatment, poisoning or a condition having a bowel dysfunction component or side-effect, or for the amelioration, treatment and/or prevention of a constipation, for the treatment of an abdominal pain, a non-specific abdominal pain or a diarrhea, a diarrhea caused by: a drug side effect or a psychological condition or Crohn's Disease, a poison, a toxin or an infection, a toxin-mediated travellers diarrhea, or a Clostridium or a C. perfringens welchii or a C. difficile infection or a pseudo-membranous colitis associated with a Clostridium infection, or for preventing, or decreasing or delaying the symptoms of, or ameliorating or treating individuals with spondyloarthropathy, spondylarthritis or sacrolileitis (an inflammation of one or both sacroiliac joints); a nephritis syndrome; an inflammatory or an autoimmune condition having a gut or an intestinal component; lupus; irritable bowel syndrome (IBS or spastic colon); or a colitis; Ulcerative Colitis or Crohn's Colitis; constipation; autism; a degenerative neurological diseases; amyotrophic lateral sclerosis (ALS), Multiple Sclerosis (MS) or Parkinson's Disease (PD); a Myoclonus Dystonia;, Steinert's disease; proximal myotonic myopathy; an autoimmune disease; Rheumatoid Arthritis (RA) or juvenile idiopathic arthritis (JIA); Chronic Fatigue Syndrome; benign myalgic encephalomyelitis; chronic fatigue immune dysfunction syndrome; chronic infectious mononucleosis; epidemic myalgic encephalomyelitis; obesity; hypoglycemia, pre-diabetic syndrome, type I diabetes or type II diabetes; Idiopathic thrombocytopenic purpura (ITP); an acute or chronic allergic reaction; hives, a rash, a urticaria or a chronic urticaria; and/or insomnia or chronic insomnia, Grand mal seizures or petit mal seizures, comprising: administering to an individual in need thereof via a delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device of the first aspect or a product (article) of manufacture of the second aspect of the entire (or substantially entire) microbiota, the treated or untreated fecal flora sample, the complete or partial fecal flora sample, the fecal flora substantially or completely purified of non-fecal floral fecal material, or the partially, substantially or completely isolated or purified fecal flora, in single, repeat or multiple administrations, deliveries or infusions. According to a tenth aspect of the present invention, there is provided an entire (or substantially entire) microbiota, a treated or untreated fecal flora sample, a complete or partial fecal flora sample, a fecal flora substantially or completely purified of non-fecal floral fecal material, or a partially, substantially or completely isolated or purified fecal flora for use in the amelioration, stabilization, treatment and/or prevention of an infection, disease, treatment, poisoning or a condition having a bowel dysfunction component or side-effect, or for the amelioration, treatment and/or prevention of a constipation, for the treatment of an abdominal pain, a non-specific abdominal pain or a diarrhea, a diarrhea caused by: a drug side effect or a psychological condition or Crohn's Disease, a poison, a toxin or an infection, a toxin-mediated travelers diarrhea, or a Clostridium or a C. perfringens welchii or a C. difficile infection or a pseudo-membranous colitis associated with a Clostridium infection. According to an eleventh aspect of the present invention, there is provided use of an entire (or substantially entire) microbiota, a treated or untreated fecal flora sample, a complete or partial fecal flora sample, a fecal flora substantially or completely purified of non-fecal floral fecal material, or a partially, substantially or completely isolated or purified fecal flora in the preparation of a medicament for the amelioration, stabilization, treatment and/or prevention of an infection, disease, treatment, poisoning or a condition having a bowel dysfunction component or side-effect, or for the amelioration, treatment and/or prevention of a constipation, for the treatment of an abdominal pain, a non-specific abdominal pain or a diarrhea, a diarrhea caused by: a drug side effect or a psychological condition or Crohn's Disease, a poison, a toxin or an infection, a toxin-mediated travelers diarrhea, or a Clostridium or a C. perfringens welchii or a C. difficile infection or a pseudo-membranous colitis associated with a Clostridium infection. According to a twelfth aspect of the present invention, there is provided use of a device of the seventh aspect for delivering a fecal material or an entire (or substantially entire) microbiota, a treated or untreated fecal flora sample, a complete or partial fecal flora sample, a fecal flora substantially or completely purified of non-fecal floral fecal material, or a partially, substantially or completely isolated or purified fecal flora in the amelioration, stabilization, treatment and/or prevention of an infection, disease, treatment, poisoning or a condition having a bowel dysfunction component or side-effect, or for the amelioration, treatment and/or prevention of a constipation, for the treatment of an abdominal pain, a non-specific abdominal pain or a diarrhea, a diarrhea caused by: a drug side effect or a psychological condition or Crohn's Disease, a poison, a toxin or an infection, a toxin-mediated travelers diarrhea, or a Clostridium or a C. perfringens welchii or a C. difficile infection or a pseudo-membranous colitis associated with a Clostridium infection. In alternative embodiments, the invention provides compositions (including formulations, pharmaceutical compositions, foods, feeds, supplements, products of manufacture, and the like) comprising: delivery vehicle, formulation, container or device, comprising a treated or untreated fecal flora, or a partially, substantially or completely isolated fecal flora; and methods of making and using them. In alternative embodiments, the invention provides delivery vehicles, formulations, pharmaceutical preparations, products of manufacture, containers or devices, comprising: a treated or untreated fecal flora, an entire (or substantially entire) microbiota, and/or a partially, substantially or completely isolated fecal flora, made by a process comprising: (a) (i) providing a treated or untreated fecal sample, or a sample comprising an entire (or substantially entire) microbiota, or a composition comprising a complete or partial fecal flora, or a partially, substantially or completely isolated or purified fecal flora; and, a delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device, and (ii) placing the treated or untreated fecal sample, the partially, substantially or completely isolated or purified fecal flora, the entire (or substantially entire) microbiota, or a composition comprising a complete or partial fecal flora or partially, substantially or completely isolated or purified fecal flora, in the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device, and optionally creating a substantially or completely oxygen-free environment in the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device, and optionally the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device is sterile or bacteria-free before the placing of the treated or untreated fecal sample, or the partially, substantially or completely isolated or purified fecal flora; (b) the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device of (a), wherein the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device is made substantially or completely oxygen free (e.g., at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9% oxygen free) by: incorporating into the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device a built in or clipped-on oxygen-scavenging mechanism; and/or, the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device comprises or is coated with an oxygen scavenging material; and/or completely or substantially replacing the air in the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device with nitrogen and/or other inert non-reactive gas or gases; (c) the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device of (a) or (b), wherein the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device simulates (creates) partially, substantially or completely an anaerobic environment; (d) the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device of any, of (a) to (c), wherein the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device is manufactured, labelled or formulated for human or animal use; (e) the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device of (d), wherein the animal use is for a veterinary use; (f) the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device of any of (a) to (e), wherein a stabilizing agent or a glycerol is added to, or mixed into, the treated or untreated fecal sample, entire (or substantially entire) microbiota, or partially, substantially or completely isolated fecal flora, before storage or freezing, spray-drying, freeze-drying or lyophilizing; (g) the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device of any of (a) to (f), wherein the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device is initially manufactured or formulated as a liquid, a suspension, a gel, a geltab, a semisolid, a tablet, a sachet, a lozenge or a capsule, or as an enteral formulation, or re-formulated for final delivery as a liquid, a suspension, a gel, a geltab, a semisolid, a tablet, a sachet, a lozenge or a capsule, or as an enteral formulation; (h) the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device of any of (a) to (g), wherein the fecal sample is treated such that the fecal flora is separated from rough particulate matter in the fecal sample by: homogenizing, centrifuging and/or filtering a rough particulate matter or a non-floral matter of the fecal material, or by plasmapheresis, centrifugation, celltrifuge, column chromatography (e.g., affinity chromatography), immunoprecipitation (e.g., antibodies fixed to a solid surface, such as beads or a plate); (i) the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device of any of (a) to (h), wherein the treated or untreated fecal flora, entire (or substantially entire) microbiota, or partially, substantially or completely isolated or purified fecal flora, is lyophilized, freeze-dried or frozen, or processed into a powder; (j) the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device of any of (a) to (i), wherein the fecal flora (including e.g., the entire (or substantially entire) microbiota) is initially derived from an individual screened or tested for a disease or infection, and/or the fecal flora is initially derived from an individual screened to have a normal, healthy or wild type population of fecal flora; (k) the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device of any of (a) to (j), wherein a substantially isolated or a purified fecal flora or entire (or substantially entire) microbiota is (comprises) an isolate offecal flora that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9% isolated or pure, or having no more than about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% or 1.0% or more non-fecal floral material; or (l) the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device of any of (a) to (j), wherein the amount of the treated or untreated fecal sample, entire (or substantially entire) microbiota, or the partially, substantially or completely isolated or purified fecal flora is formulated for or calibrated for repeat or multiple delivery or infusions, wherein optionally the repeated or multiple administration, delivery, infusion or implantation protocol comprises infusions done daily for the first about 10 days, second daily for about 10 days, third daily then fourth daily possibly weekly and then optionally maintain second or more weekly infusions until the histology reverses towards normality. In alternative embodiments, the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device of the invention further comprises: a saline, a media, a defoaming agent, a surfactant agent, a lubricant, an acid neutralizer, a marker, a cell marker, a drug, an antibiotic, a contrast agent, a dispersal agent, a buffer or a buffering agent, a sweetening agent, a debittering agent, a flavouring agent, a pH stabilizer, an acidifying agent, a preservative, a desweetening agent and/or colouring agent; at least one vitamin, mineral and/or dietary supplement, wherein optionally the vitamin comprises a thiamine, riboflavin, nicotinic acid, pantothenic acid, pyridoxine, biotin, folic acid, vitamin B12, lipoic acid, ascorbic acid, vitamin A, vitamin D, vitamin E, vitamin K, a choline, a camitine, and/or an alpha, beta and/or gamma carotene; or a prebiotic nutrient, wherein optionally the prebiotic comprises any ingredient that stimulates the stability, growth and/or activity of the fecal flora or fecal bacteria, or optionally comprises polyols, fructooligosaccharides (FOSs), oligofructoses, inulins, galactooligosaccharides (GOSs), xylooligosaccharicles (XOSs), polydextroses, monosaccharides, tagatose, and/or mannooligosaccharides. In alternative embodiments, the invention provides products (articles) of manufacture comprising a delivery vehicle, formulation, pharmaceutical preparation, container or device of the invention. In alternative embodiments, the invention provides methods for making a delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device, comprising a treated or untreated fecal flora, entire (or substantially entire) microbiota, or a partially, substantially or completely isolated or purified fecal flora, comprising: (a) (i) providing a treated or untreated fecal sample, or a composition comprising a complete or partial fecal flora, an entire (or substantially entire) microbiota, or a partially, substantially or completely isolated or purified fecal flora; and, a delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device, and (ii) placing the treated or untreated fecal sample, the partially, substantially or completely isolated or purified fecal flora, the entire (or substantially entire) microbiota, or a composition comprising a complete or partial fecal flora or partially, substantially or completely isolated or purified fecal flora, in the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device, and creating a substantially or completely oxygen-free environment in the container or device; (b) the method of (a), wherein the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device is made substantially or completely oxygen free by: incorporating into the delivery vehicle, formulation, container or device a built in or clipped-on oxygen-scavenging mechanism; and/or, the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device comprises or is coated with an oxygen scavenging material; and/or completely or substantially replacing the air in the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device with nitrogen and/or other inert non-reactive gas or gases; (c) the method of (a) or (b), wherein the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device simulates (creates) partially, substantially or completely an anaerobic environment; (d) the method of any of (a) to (c), wherein the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device is manufactured, labelled or formulated for human or animal use; (e) the method of (d), wherein the animal use is for a veterinary use; (f) the method of any of (a) to (e), wherein a prebiotic, a stabilizing agent or a glycerol is added to, or mixed into, the treated or untreated fecal sample, or partially, substantially or completely isolated or purified fecal flora, before storage or freeze-drying, spray-drying, freezing or lyophilizing; (g) the method of any of (a) to (f), wherein the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device is initially manufactured or formulated as a liquid, a suspension, a gel, a geltab, a semisolid, a tablet, a sachet, a lozenge or a capsule, or as an enteral formulation, or re-formulated for final delivery as a liquid, a suspension, a gel, a geltab, a semisolid, a tablet, a sachet, a lozenge or a capsule, or as an enteral formulation; (h) the method of any of (a) to (g), wherein the fecal sample is treated such that the fecal flora is separated from rough particulate matter in the fecal sample by: homogenizing, centrifuging and/or filtering a rough particulate matter or a non-floral matter of the fecal material, or by plasmapheresis, centrifugation, centrifuge, column chromatography (e.g., affinity chromatography), immunoprecipitation (e.g., antibodies fixed to a solid surface, such as beads or a plate); (i) the method of any of (a) to (h), wherein the treated or untreated fecal flora, or partially, substantially or completely isolated or purified fecal flora, is lyophilized, freeze-dried or frozen, or processed into a powder; (j) the method of any of (a) to (i), wherein the fecal flora is initially derived from an individual screened or tested for a disease or infection, and/or the fecal flora is initially derived from an individual screened to have a normal, healthy or wild type population of fecal flora; or (k) the method of any of (a) to (j), further comprising adding to the treated or untreated fecal flora, or adding to a liquid or solution used to isolate or purify, store, freeze, freeze-dry, spray-dry, lyophilize, transport, reconstitute and/or deliver a treated or untreated fecal flora (optionally an entire (or substantially entire) microbiota, a partially, substantially or completely isolated or purified fecal flora, or a composition comprising a fecal flora substantially or completely purified of non-fecal floral fecal material of the invention): a saline, a media, a defoaming agent, a surfactant agent, a lubricant, an acid neutralizer, a marker, a cell marker, a drug, an antibiotic, a contrast agent, a dispersal agent, a buffer or a buffering agent, a sweetening agent, a debittering agent, a flavouring agent, a pH stabilizer, an acidifying agent, a preservative, a desweetening agent and/or colouring agent, and/or at least one vitamin, mineral and/or dietary supplement, wherein optionally the vitamin comprises a thiamine, riboflavin, nicotinic acid, pantothenic acid, pyridoxine, biotin, folic acid, vitamin B12, lipoic acid, ascorbic acid, vitamin A, vitamin D, vitamin E, vitamin K, a choline, a camitine, and/or an alpha, beta and/or gamma carotene, and/or a prebiotic nutrient, wherein optionally the prebiotic comprises any ingredient that stimulates the stability, growth and/or activity of the fecal flora or fecal bacteria, or optionally comprises polyols, fructooligosaccharides (FOSs), oligofructoses, inulins, galactooligosaccharides (GOSs), xylooligosaccharides (XOSs), polydextroses, monosaccharides, tagatose, and/or mannooligosaccharides; (l) the method of any of (a) to (k), wherein an entire (or substantially entire) microbiota, a substantially isolated or a purified fecal flora is (comprises) an isolate of fecal flora that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9% isolated or pure, or having no more than about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% or 1.0% or more non-fecal floral material; or (m) the method of any of (a) to (l), wherein the amount of the entire (or substantially entire) microbiota, the treated or untreated fecal sample, or the partially, substantially or completely isolated or purified fecal flora is formulated for or calibrated for repeat or multiple delivery or infusions, wherein optionally the repeated or multiple administration, delivery, infusion or implantation protocol comprises infusions done daily for the first about 10 days, second daily for about 10 days, third daily then fourth daily possibly weekly and then optionally maintain second or more weekly infusions until the histology reverses towards normality. In alternative embodiments, the invention provides methods for the amelioration, stabilization, treatment and/or prevention of an infection, disease, treatment, poisoning or a condition having a bowel dysfunction component or side-effect, or for the amelioration, stabilization, treatment and/or prevention of a constipation, for the treatment of an abdominal pain, a non-specific abdominal pain or a diarrhea, a diarrhea caused by: a drug side effect or a psychological condition or Crohn's Disease, a poison, a toxin or an infection, a toxin-mediated travellers diarrhea, or a Clostridium or a C. difficile or a pseudo-membranous colitis associated with a Clostridium infection, comprising administering to an individual in need thereof a delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device of the invention, or a product (article) of manufacture of the invention. In alternative embodiments, the invention provides methods for the amelioration, stabilization, treatment and/or prevention of an infection, disease, treatment, poisoning or a condition having a bowel dysfunction component or side-effect comprising administering to an individual in need thereof a delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device of the invention, or a product (article) of manufacture of the invention, or their contents (e.g., the bacterial flora contained therein). In alternative embodiments, the amount of the treated or untreated fecal sample, or the partially, substantially or completely isolated or purified fecal flora is formulated for or calibrated for repeat or multiple delivery or infusions; or the partially, substantially or completely isolated or purified fecal flora is delivered in repeated or multiple infusions, wherein optionally the repeated or multiple administration, delivery, infusion or implantation protocol comprises infusions done daily for the first about 10 days, second daily for about 10 days, third daily then fourth daily possibly weekly and then optionally maintain second or more weekly infusions until the histology reverses towards normality. In alternative embodiments, of the methods the infection, disease, treatment, poisoning or condition having a bowel dysfunction component or side-effect comprises an inflammatory bowel disease (IBD), Crohn's disease, hepatic encephalopathy, enteritis, colitis, Irritable Bowel Syndrome (IBS), fibromyalgia (FM), chronic fatigue syndrome (CFS), depression, attention deficit/hyperactivity disorder (ADHD), multiple sclerosis (MS), systemic lupus erythematosus (SLE), travellers' diarrhea, small intestinal bacterial overgrowth, chronic pancreatitis, a pancreatic insufficiency, exposure to a poison or a toxin or for an infection, a toxin-mediated travellers diarrhea, a poisoning, a pseudomembranous colitis, a Clostridium infection, a C. perfringens welchii or a Clostridium difficile infection, a neurological condition, Parkinson's disease, myoclonus dystonia, autism, amyotrophic lateral sclerosis, multiple sclerosis, Grand mal seizures or petit mal seizures. In alternative embodiments, the amount of the treated or untreated fecal sample, or the partially, substantially or completely isolated or purified fecal flora, is formulated for or calibrated for repeat or multiple delivery or infusions; or the treated or untreated fecal sample or the partially, substantially or completely isolated or purified fecal flora is delivered in repeated or multiple infusions, wherein optionally the repeated or multiple administration, delivery, infusion or implantation protocol comprises infusions done daily for the first about 10 days, second daily for about 10 days, third daily then fourth daily possibly weekly and then optionally maintain second or more weekly infusions until the histology reverses towards normality. In alternative embodiments, the invention provides delivery vehicles, formulations, pharmaceutical preparations, products of manufacture, containers or devices comprising: (a) an entire (or substantially entire) microbiota, a partially, substantially or completely isolated or purified fecal flora, or a composition comprising a fecal flora substantially or completely purified of non-fecal floral fecal material, and optionally further comprising an excipient, or a fluid, a saline, a buffer, a buffering agent or a media, or a fluid-glucose-cellobiose agar (RGCA) media; (b) the composition, container or device, formulation, or product of manufacture of (a), wherein the entire (or substantially entire) microbiota or the fecal flora is isolated or purified from a human or an animal fecal material; (c) the composition, container or device, formulation, or product of manufacture of (a) or (b), wherein the entire (or substantially entire) microbiota or the fecal flora is isolated or purified using a method or protocol comprising use of a centrifuge, a centrifuge, a column or an immuno-affinity column, or wherein the entire (or substantially entire) microbiota or the fecal flora is isolated or purified by a method comprising homogenizing, centrifuging and/or filtering a rough particulate matter or a non-floral matter of the fecal material, or by plasmapheresis, centrifugation, centrifuge, column chromatography (e.g., affinity chromatography), immunoprecipitation (e.g., antibodies fixed to a solid surface, such as beads or a plate); (d) the composition, container or device, formulation, or product of manufacture of any of (a) to (c), wherein the entire (or substantially entire) microbiota or the substantially or completely isolated or purified fecal flora, or the fecal flora substantially or completely purified of non-fecal floral fecal material, is in a substantially or completely oxygen-free environment in the composition, container or device, formulation, or product of manufacture; (e) the delivery vehicle, formulation, container or device of (d), wherein the composition, container or device, formulation, or product of manufacture is made substantially or completely oxygen free by: incorporating into the delivery vehicle, formulation, container or device a built in or clipped-on oxygen-scavenging mechanism; and/or, the delivery vehicle, formulation, container or device comprises or is coated with an oxygen scavenging material; and/or completely or substantially replacing the air in the delivery vehicle, formulation, container or device with nitrogen and/or other inert non-reactive gas or gases; (f) the composition, container or device, formulation, or product of manufacture of any of (a) to (c), wherein the entire (or substantially entire) microbiota, the substantially or completely isolated or purified fecal flora, or the fecal flora substantially or completely purified of non-fecal floral fecal material, is in a substantially or completely anaerobic environment; (g) the composition, container or device, formulation, or product of manufacture of any of (a) to (f), wherein the delivery vehicle, formulation, container or device is manufactured, labelled or formulated for human or animal use; (h) the composition, container or device, formulation, or product of manufacture of (g), wherein the animal use is for a veterinary use; (i) the composition, container or device, formulation, or product of manufacture of any of (a) to (h), wherein a stabilizing agent or a glycerol is added to, or mixed into, the entire (or substantially entire) microbiota, or the partially, substantially or completely isolated or purified fecal flora, or the composition comprising a fecal flora substantially or completely purified of non-fecal floral fecal material, before storage or freezing, freeze-drying, spray-drying or lyophilizing; (j) the composition, container or device, formulation, or product of manufacture of any of (a) to (f), wherein the composition, container or device, formulation, or product of manufacture is initially manufactured or formulated as a liquid, a suspension, a gel, a geltab, a semisolid, a tablet, a sachet, a lozenge or a capsule, or as an enteral formulation, or re-formulated for final delivery as a liquid, a suspension, a gel, a geltab, a semisolid, a tablet, a sachet, a lozenge or a capsule, or as an enteral formulation; (k) the composition, container or device, formulation, or product of manufacture of any of (a) to (j), wherein the entire (or substantially entire) microbiota, or the partially, substantially or completely isolated or purified fecal flora, or the composition comprising a fecal flora substantially or completely purified of non-fecal floral fecal material, is lyophilized, freeze-dried, in powder form, or frozen; (l) the composition, container or device, formulation, or product of manufacture of any of (a) to (k), wherein the entire (or substantially entire) microbiota or the fecal flora is initially derived from an individual screened or tested for a disease or infection, and/or the entire (or substantially entire) microbiota or the fecal flora is initially derived from an individual screened to have a normal, healthy or wild type population of fecal flora; or (m) the composition, container or device, formulation, or product of manufacture of any of (a) to (l), further comprising adding to the entire (or substantially entire) microbiota, the partially, substantially or completely isolated or purified fecal flora, or a composition comprising a fecal flora substantially or completely purified of non-fecal floral fecal material, or adding to a liquid or solution used to isolate or purity, store, freeze, freeze-dry, spray-dry, lyophilize, transport, reconstitute and/or deliver a treated or untreated fecal flora: a saline, a media, a defoaming agent, a surfactant agent, a lubricant, an acid neutralizer, a marker, a cell marker, a drug, an antibiotic, a contrast agent, a dispersal agent, a buffer or a buffering agent, a sweetening agent, a debittering agent, a flavouring agent, a pH stabilizer, an acidifying agent, a preservative, a desweetening agent and/or colouring agent, and/or at least one vitamin, mineral and/or dietary supplement, wherein optionally the vitamin comprises a thiamine, riboflavin, nicotinic acid, pantothenic acid, pyridoxine, biotin, folic acid, vitamin B12, lipoic acid, ascorbic acid, vitamin A, vitamin D, vitamin E, vitamin K, a choline, a camitine, and/or an alpha, beta and/or gamma carotene, and/or a prebiotic nutrient, wherein optionally the prebiotic comprises any ingredient that stimulates the stability, growth and/or activity of the entire (or substantially entire) microbiota or the fecal flora or fecal bacteria, or optionally comprises polyols, fructooligosaccharides (FOSs), oligofructoses, inulins, galactooligosaccharides (GOSs), xylooligosaccharides (XOSs), polydextroses, monosaccharides, tagatose, and/or mannooligosaccharides; (n) the composition, container or device, formulation, or product of manufacture of any of (a) to (m), wherein a substantially isolated or a purified fecal flora is (comprises) an isolate of the entire (or substantially entire) microbiota or fecal flora that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9% isolated or pure, or having no more than about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% or 1.0% or more non-fecal floral material; or (m) the composition, container or device, formulation, or product of manufacture of any of (a) to (l), wherein the amount of the entire (or substantially entire) microbiota or the treated or untreated fecal sample, or the partially, substantially or completely isolated or purified fecal flora is formulated for or calibrated for repeat or multiple delivery or infusions, wherein optionally the repeated or multiple administration, delivery, infusion or implantation protocol comprises infusions done daily for the first about 10 days, second daily for about 10 days, third daily then fourth daily possibly weekly and then optionally maintain second or more weekly infusions until the histology reverses towards normality. In alternative embodiments, the invention provides methods for the amelioration, stabilization, treatment and/or prevention of an infection, disease, treatment, poisoning or a condition having a bowel dysfunction component or side-effect comprising administering to an individual in need thereof a composition, container or device, formulation, or product of manufacture of the invention. In alternative embodiments, of the methods the infection, disease, treatment, poisoning or condition having a bowel dysfunction component or side-effect comprises an inflammatory bowel disease (IED), Crohn's disease, hepatic encephalopathy, enteritis, colitis, irritable bowel syndrome (IES), fibromyalgia (FM), chronic fatigue syndrome (CFS), depression, attention deficit/hyperactivity disorder (ADHD), multiple sclerosis (MS), systemic lupus erythematosus (SLE), travellers' diarrhea, small intestinal bacterial overgrowth, chronic pancreatitis, a pancreatic insufficiency, exposure to a poison or a toxin or for an infection, a toxin-mediated travellers diarrhea, a poisoning, a pseudomembranous colitis, a Clostridium infection, a C. perfringens welchii or a Clostridium difficile infection, a neurological condition, Parkinson's disease, myoclonus dystonia, autism, amyotrophic lateral sclerosis, multiple sclerosis, Grand mal seizures or petit mal seizures. In alternative embodiments, the invention provides methods for the amelioration, stabilization, treatment and/or prevention of, or decreasing or delaying the symptoms of, an infection, disease, treatment, poisoning or a condition having a bowel dysfunction component or side-effect, or for the amelioration, treatment and/or prevention of a constipation, for the treatment of an abdominal pain, a non-specific abdominal pain or a diarrhea, a diarrhea caused by: a drug side effect or a psychological condition or Crohn's Disease, a poison, a toxin or an infection, a toxin-mediated traveller's diarrhea, or a Clostridium or a C. perfringens welchii or a C. difficile infection or a pseudo-membranous colitis associated with a Clostridium infection, or for preventing, decreasing or delaying the symptoms of, ameliorating stabilizing, or treating individuals (e.g., patients or animals) with spondyloarthropathy, spondylarthritis or sacrolileitis (an inflammation of one or both sacroiliac joints); a nephritis syndrome; an inflammatory or an autoimmune condition having a gut or an intestinal component such as lupus, irritable bowel syndrome (IBS or spastic colon) or a colitis such as Ulcerative Colitis or Crohn's Colitis; constipation, autism; degenerative neurological diseases such as amyotrophic lateral sclerosis (ALS), Multiple Sclerosis (MS) or Parkinson's Disease (PD); a Myoclonus Dystonia (e.g., Steinert's disease or proximal myotonic myopathy); an autoimmune disease such as Rheumatoid Arthritis (RA) or juvenile idiopathic arthritis (JIA); Chronic Fatigue Syndrome (including benign myalgic encephalomyelitis, chronic fatigue immune dysfunction syndrome, chronic infectious mononucleosis, epidemic myalgic encephalomyelitis); obesity; hypoglycemia, pre-diabetic syndrome, type I diabetes or type II diabetes; Idiopathic thrombocytopenic purpura (ITP); an acute or chronic allergic reaction such as hives, a rash, a urticaria or a chronic urticaria; and/or insomnia or chronic insomnia, Grand mal seizures or petit mal seizures, comprising: administering to an individual in need thereof a delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device of the invention, or a product (article) of manufacture of the invention, in single, repeat or multiple administrations, deliveries or infusions. In alternative embodiments, the amount of the entire (or substantially entire) microbiota, the treated or untreated fecal sample, or the partially, substantially or completely isolated or purified fecal flora, is formulated for or calibrated for repeat or multiple delivery or infusions; or the entire (or substantially entire) microbiota, the treated or untreated fecal sample or the partially, substantially or completely isolated or purified fecal flora is delivered in repeated or multiple infusions, wherein optionally the repeated or multiple administration, delivery, infusion or implantation protocol comprises infusions done daily for the first about 10 days, second daily for about 10 days, third daily then fourth daily possibly weekly and then optionally maintain second or more weekly infusions until the histology reverses towards normality. In alternative embodiments, the invention provides devices for delivering a (bacterial flora-comprising) composition of the invention, or an entire (or substantially entire) microbiota or a fecal material comprising: (a) a device as illustrated in FIG. 1 or FIG. 2, or equivalent thereof; or (b) (1) a bag or container comprising an exit aperture operably connected to the proximal end of a flexible tube or equivalent, wherein the bag or container is optionally made of a material impervious to a gas or to oxygen, and optionally the bag or container is made of a flexible material, or a polyethylene terephthalate polyester film-comprising (or a MYLAR™-comprising) material, and optionally the bag or container is an (IV-like) intravenous-like bag, and optionally the bag or container has an attachment that will allow the bag to be hung on a stand, e.g., to be positioned/hung above an endoscope, and optionally the bag or container is operably connected via an open or close valve or equivalent to a negative pressure device that can remove all gas or air from the bag, and optionally the bag or container is operably connected via an open or close valve or equivalent to a fluid source or storage container for flushing out the bag through the exit aperture, and optionally the fluid source or storage container is under positive pressure, and optionally the flexible tube or equivalent comprises at least one clip or close valve or one way valve to prevent backwash of material from distal to proximal portions of the tube, or from the tube back to the bag or container; (2) an open or close valve or equivalent or an obdurator screwtop at the distal end of the flexible tube or equivalent, and optionally a Luer lock tip for attachment to a colonoscope or an endoscopic Luer lock port or equivalent, wherein optionally the Luer lock tip is built into the valve, or is separate from the valve, and optionally an enema tube tip for attachment to an enema tube or device or equivalent, wherein optionally the enema tube tip is built into the valve, or is separate from the valve, and optionally further comprising a safety device or safety clip to close the distal aperture in case the valve or Luer lock tip, or enema tip, is lost (flies off) under pressure; and (3) a pump, or a hand pump, for moving material in the bag or container through the flexible tube or equivalent and out the distal end or out the open or close valve or equivalent; or (c) the device of (a) or (b), further comprising a fecal material or a composition of the invention. In alternative embodiments, the invention provides bags or containers comprising an entire (or substantially entire) microbiota, or a treated or untreated fecal flora, or a partially, substantially or completely isolated fecal flora, or a composition of the invention (e.g., a formulation comprising an entire (or substantially entire) microbiota, a partially, substantially or completely isolated or purified fecal flora, or a composition comprising a fecal flora substantially or completely purified of non-fecal floral fecal material), and optionally further comprising an excipient, or a fluid, a saline, a buffer, a buffering agent or a media, or a fluid-glucose-cellobiose agar (RGCA) media, wherein the bag or container is structurally the same as or similar to a bag or container of a device of the invention (e.g., as illustrated in FIG. 1 or FIG. 2), wherein optionally the interior of the bag is substantially or completely an oxygen-free environment, or the interior of the bag is substantially or completely similar to an anaerobic environment. In alternative embodiments, specific anti C. difficile oral antibodies (for example avian) can be added to a solution (e.g., a saline, media, buffer) used to isolate or purify, store, freeze, freeze-dry, spray-dry lyophilize, transport, reconstitute and/or deliver a composition (e.g., a partially, substantially or completely isolated or purified fecal flora, or a composition comprising a fecal flora substantially or completely purified of non-fecal floral fecal material) of the invention. The combination of the product with these specific anti C. difficile oral antibodies enhances the eradication mechanism of the product. The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims. All publications, patents, patent applications cited herein are hereby expressly incorporated by reference for all purposes. BRIEF DESCRIPTION OF THE DRAWINGS The drawings set forth herein are illustrative of embodiments of the invention and are not meant to limit the scope of the invention as encompassed by the claims. FIG. 1A illustrates an exemplary storage device of the invention; and, FIG. 1B illustrates an exemplary delivery device of the invention, as described below. FIG. 2 illustrates an exemplary delivery device of the invention. Like reference symbols in the various drawings indicate like elements. Reference will now be made in detail to various exemplary embodiments of the invention, examples of which are illustrated in the accompanying drawings. The following detailed description is provided to give the reader a better understanding of certain details of aspects and embodiments of the invention, and should not be interpreted as a limitation on the scope of the invention. DETAILED DESCRIPTION In alternative embodiments, the invention provides compositions, e.g., formulations and pharmaceutical preparations, products of manufacture, and containers and delivery vehicles, and devices and delivery materials, comprising treated and/or isolated faecal (fecal) material for faecal floral transplantation. In one embodiment, the treated and/or isolated fecal material of the invention comprising faecal floral (e.g., bacteria) is transplanted between different individuals, e.g., human to human or between animals. In one embodiment, the treated fecal material of the invention is transplanted back into the same individual from which it was collected, e.g., to repopulate a colon after drug treatment (e.g., antibiotic treatment or chemotherapy) or after an orthostatic lavage, e.g., for inducing the purgation (e.g., cleansing) of a gastrointestinal (GI) tract, including a colon. The invention provides methods for the amelioration, stabilization, or treatment of a bowel disease or infection comprising use of a delivery vehicle, formulation, product of manufacture, or container or device of the invention; e.g., as a fecal bacteriotherapy, fecal transfusion, fecal transplant, or human probiotic infusion (HPI). In alternative embodiments, the invention provides methods for ameliorating, stabilizing, treating or preventing any infection, bowel disease or condition having a bowel dysfunction component, for example, a poisoning, a pseudomembranous colitis, a Clostridium difficile infection, an inflammatory bowel disease (IBD), Crohn's disease, hepatic encephalopathy, enteritis, colitis, irritable bowel syndrome (IBS), fibromyalgia (FM), chronic fatigue syndrome (CFS), depression, attention deficit/hyperactivity disorder (ADHD), multiple sclerosis (MS), systemic lupus erythematosus (SLE), travellers' diarrhea, small intestinal bacterial overgrowth, chronic pancreatitis, or a pancreatic insufficiency. For example, in one embodiment, as antibiotics do not eradicate C. difficile and its spore, a delivery vehicle, formulation, product of manufacture, or container or device of the invention comprising treated and/or isolated fecal flora can ameliorate, stabilize or eradicate C. difficile (or the pseudo-membranous colitis associated with this infection) when infused into a colon of the infected or ill individual, e.g., a patient or animal. In alternative embodiments the fecal flora obtained from a donor (which in treated or isolated form is in alternative embodiments in a delivery vehicle, formulation, product of manufacture, or container or device of the invention) comprises a part of, substantially all of, or all of the infected or ill recipient's missing or inadequate (e.g., in numbers or function) fecal flora, e.g., bacteria. While the invention is not limbed by any particular mechanism of action, in some embodiments it is the transfer of the equivalent of: a part of, substantially all of, or all of the fecal flora of the infected individual from the donor to the recipient (e.g., from human to human) that ameliorates or eradicates the infection or the pseudo-membranous colitis associated with this infection. In alternative embodiments, the compositions, e.g., formulations and pharmaceutical preparations, and devices, delivery materials, delivery vehicles, products of manufacture, containers and devices of the invention allow the safe transplantation of fecal flora (e.g., human flora) components to individuals in need thereof, e.g., to infected, sick and dying patients, thus providing a consistently safe yet, functioning flora for delivery to a recipient or patient. In alternative embodiments, the invention provides a reliable method for producing standardized fresh fecal flora which can have a long shelf life. For example, in one embodiment, the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device comprising the fecal flora comprises a substantially or completely oxygen-free environment. In another embodiment, nutrients such as “prebiotic nutrients” can be added (e.g., in dry or liquid forms) to a solution (e.g., a saline, media, buffer) used to isolate or purify, store, freeze, freeze-dry, spray-dry, lyophilize, transport, reconstitute and/or deliver a composition (e.g., a partially, substantially or completely isolated or purified fecal flora, or a composition comprising a fecal flora substantially or completely purified of non-fecal floral fecal material) of the invention. A prebiotic nutrient can be any ingredient that stimulates the stability, growth and/or activity of the fecal flora, e.g., bacteria; for example, in alternative embodiments, polyols, fructooligosaccharides (FOSs), oligofructoses, inulins, galactooligosaccharides (GOSs), xylooligosaccharides (XOSs), polydextroses, monosaccharides such as tagatose, and/or mannooligosaccharides are used as prebiotics to practice this invention. In one embodiment, the prebiotics are added to prevent “shock” to the fecal flora subsequent to their isolation or purification, freezing, freeze-drying, spray-drying, reconstitution in solution and the like. In alternative embodiments, components of the compositions, e.g., delivery vehicles, formulations and pharmaceutical preparations, products of manufacture, or containers or devices, of the invention comprise an entire (or substantially entire) microbiota, or a Bacteroides and/or Firmicutes in large numbers (e.g., a larger proportion of Bacteroides and/or Firmicutes is present that is normally found in situ), e.g., to be able to ameliorate and/or eradicate a C. difficile infection and/or the pseudo-membranous colitis associated with this infection. In alternative embodiments, the compositions, e.g., delivery vehicles, formulations and pharmaceutical preparations, products of manufacture, or containers or devices, of the invention can be available (e.g., formulated and/or dosaged for) for recurrent use in individuals, e.g., in patients or animals, with the more difficult to treat conditions such as colitis (e.g., the pseudo-membranous colitis of a C. difficile infection) and constipation. In alternative embodiments, components of the compositions e.g., delivery vehicles, formulations and pharmaceutical preparations, products of manufacture, or containers or devices, of the invention comprise a selection of bacterial species e.g. Bacteroides, Firmicutes, Bacillus thuringiensis (a bacterium capable of producing peptide antibiotics for C. difficile). The bacterial species may be separated by celftrifugation or plasmapharesis. In alternative embodiments the selection of bacterial species e.g. Bacteroides, Firmicutes, Bacillus thuringiensis may be added to components of the compositions e.g., delivery vehicles, formulations and pharmaceutical preparations, products of manufacture, or containers or devices as fortification of concentrations comprising the bacterial species to contain wild types of bacteria. In alternative embodiments, compositions of the invention can be formulated as fecal slurries, saline or buffered suspensions (e.g., for an enema, suspended in a buffer or a saline), in a drink (e.g., a milk, yoghurt, a shake, a flavoured drink or equivalent) for oral delivery, and the like. In alternative embodiments, compositions of the invention can be formulated as an enema product, a spray dried product, reconstituted enema, a small capsule product, a small capsule product suitable for administration to children, a bulb syringe, a bulb syringe suitable for a home enema with a saline addition, a powder product, a powder product in oxygen deprived sachets, a powder product in oxygen deprived sachets that can be added to, for example, a bulb syringe or enema, or a spray dried product in a device that can be attached to a container with an appropriate carrier medium such as yoghurt or milk and that can be directly incorporated and given as a dosing for example for children. In one embodiment, compositions of the invention can be delivered directly in a carrier medium via a screw-top lid wherein the fecal material is suspended in the lid and released on twisting the lid straight into the carrier medium. In alternative embodiments methods of delivery of compositions of the invention include use of fecal slurries into the bowel, via an enema suspended in saline or a buffer, orally in a drink (e.g., a milk, yoghurt, a flavoured drink and the like), via a small bowel infusion via a nasoduodenal tube, via a gastrostomy, or by using a colonoscope. In some embodiment, there may be advantages delivering via a colonoscope to infuse as proximally as possible, and to detect any colonic pathology. In alternative embodiments methods, fecal flora used in the composition and methods of the invention is initially derived (entirely or in part) from an individual screened or tested for a disease or infection, and/or the fecal flora is initially derived from an individual screened to have a normal, healthy or normal, representative “wild type” population of fecal flora; e.g., a normal complement of a Bacteroides and/or Firmicutes, and/or other fecal flora such as Bacillus Thuringiensis. In one embodiment, depending on a deficiency of a floral (e.g., bacterial) specie or species in a donor fecal material, or to achieve a desired effect, one or more additional (or “supplemental”) species, e.g., Bacteroides, Firmicutes and/or Bacillus Thuringiensis species, is added to (or is administered with) the delivered product either initially when the product is made, or at the time of delivery, e.g., the additional species is/are mixed in before application to the individual (e.g., patient or animal), e.g., when a powder, lyophilate, or freeze-dried composition is reconstituted for delivery; or the one or more additional (or “supplemental”) species can be co-administered. These additional floral species can be directly isolated or purified from a donor, or can be expanded (cultured) for a time in vitro before addition, or can come from (be derived from) a pure culture, e.g., from an ATTC stock. For example, in some applications, e.g., to achieve a desired effect or therapeutic outcome, a delivery of an enhanced amount of one or more fecal flora (e.g., bacterial) species is used, e.g., the delivered product (e.g., an entire (or substantially entire) microbiota, or a composition comprising a complete or partial fecal flora, or a partially, substantially or completely isolated or purified fecal flora) is enhanced with (is “spiked” with”) one or more additional (or “supplemental”) species, e.g., Bacteroides, Firmicutes and/or Bacillus Thuringiensis species, which can be directly isolated from a donor, or can come from a pure culture, and the like. In some embodiments, selection of the donor is of crucial importance, e.g., to avoid infecting the recipient with a separate infection or disease. In alternative embodiments the donor is tested (screened) at least for e.g., retrovirus (e.g., human immunodeficiency virus, HIV); hepatitis A, B, and/or C; cytomegalovirus; Epstein-Barr virus, detectable parasites and/or bacterial pathogens, depending on the specie of the donor and recipient, e.g., human or animal. In alternative embodiments, the invention provides a process for preparing fecal flora (e.g., an entire (or substantially entire) microbiota) for transplantation, first comprising a collection from one or more healthy (e.g., screened) donor(s). In alternative embodiments, a fresh stool is transported via a stool collection device of the invention, which in one embodiment comprises a suitably oxygen free (or substantially oxygen free) appropriate container. An exemplary suitable stool collection device 1 is shown in FIG. 1A. FIG. 1A shows an exemplary container of the invention for containing the stool and including a slot 2 for receiving the stool. The container may then be placed into a bag 3 suitably a disposable leak proof ziplock/sealing bag. In alternative embodiments, the container can be made oxygen free by e.g., incorporating into the container a built in or clipped-on oxygen-scavenging mechanism, e.g., oxygen scavenging pellets as described e.g., in U.S. Pat. No: 7,541,091. In another embodiment, the container itself is made of an oxygen scavenging material, e.g., oxygen scavenging iron, e.g., as described by O2BLOCK™, or equivalents, which uses a purified and modified layered clay as a performance-enhancing carrier of oxygen-scavenging iron; the active iron is dispersed directly in the polymer. In one embodiment, oxygen-scavenging polymers are used to make the container itself or to coat the container, or as pellets to be added; e.g., as described in U.S. Pat. App. Pub. 20110045222, describing polymer blends having one or more unsaturated olefinic homopolymers or copolymers; one or more polyamide homopolymers or copolymers; one or more polyethylene terephthalate homopolymers or copolymers; that exhibit oxygen-scavenging activity. In one embodiment, oxygen-scavenging polymers are used to make the container itself or to coat the container, or as pellets to be added; e.g., as described in U.S. Pat. App. Pub. 20110008554, describing compositions comprising a polyester, a copolyester ether and an oxidation catalyst, wherein the copolyester ether comprises a polyether segment comprising poly(tetramethylene-co-alkylene ether). In one embodiment, oxygen-scavenging polymers are used to make the container itself or to coat the container, or as pellets to be added; e.g., as described in U.S. Pat. App. Pub. 201000255231, describing a dispersed iron/salt particle in a polymer matrix, and an oxygen scavenging film with oxygen scavenging particulates. Alternatively, in addition to or in place of the oxygen-scavenging mechanism, the air in the container is replaced (completely or substantially) with nitrogen and/or other inert non-reactive gas or gases. In alternative embodiments, the container simulates (creates) partially, substantially or completely an anaerobic environment. In alternative embodiments, the stool (e.g., fecal sample) is held in an aesthetically acceptable container that will not leak nor smell yet maintain an anaerobic environment. In alternative embodiments, the container is sterile before receiving the fecal flora. In alternative embodiments, the container is maintained below room temperature, e.g., refrigerated, during most or all of its preparation, transportation and/or storage at e.g., a “stool bank” or at the site where the transplantation will take place. For example, once delivered to a “processing stool bank” it is stored in a cool room, cold container or ref ridgerator to minimize flora metabolism. In alternative embodiments, it is not to be frozen to prevent destruction of the bacterial cells of the stool. In alternative embodiments, stabilizing agents such as glycerol are added to the harvested and/or stored material. In one embodiment, the stool is frozen suddenly in liquid nitrogen or any similar coolant so e.g., it can be stored for prolonged periods of time while waiting processing. In alternative embodiments, the stool is tested for various pathogens, as noted above. In alternative embodiments, once cleared of infective agents, it is homogenized and filtered to remove large particles of matter. In alternative embodiments, it is subdivided into desired volumes, e.g., which can be between 5 cc and 3 or more liters. For example, in one embodiment, a container comprises a 50 gram (g) stool, which can be held in an appropriate oxygen resistant plastic, e.g., a metallized polyethylene terephthalate polyester film, or a metallized MYLAR™. In alternative embodiments, as shown in FIG. 1B, the exemplary therapeutic vehicle (delivery system) 10 and the equipment in which the stool material is held is an intravenous-like (IV-like) giving set 11, e.g., with a hand pump 12 attached to the set. Suitably the bag 11 is metallised MYLAR™ which is impervious to gases. The hand pump 12 can allow the contents of the liquefied stool residing in the upper part of the plastic device to be easily pumped forward when the entire equipment tubing is attached by Luer lock mechanism 13 to the colonoscope biopsy channel. In this way a colonoscope or even an enteroscope will become the delivery mechanism. For this embodiment, this would usually be into the colon at any distance, and alternatively into the caecum. In alternative embodiments, the material is passed into a terminal ileum or even higher, as desired. In alternative embodiments, it can be infused into the duodenum or below with an enteroscope. In alternative embodiments, C. difficile (or the pseudo-membranous colitis associated with this infection) is ameliorated or eradicated with the infused fecal sample, or treated stool. Another alternative embodiment is shown in FIG. 1. In this embodiment the therapeutic vehicle/delivery system 20 including an IV-like bag 21 including saline (NaCl) 22 and stool/cells 23 of the invention. In addition to the hand pump 24 and Luer lock 25, the delivery system is provided with a flushing port 26 (for flushing out the bag), a clip 27 (to prevent backwash) and an enema tip 28 with Luer lock attachment. In alternative embodiments, the transplant material is subject to homogenization and straining. In alternative embodiments, this treated material is placed into a container, e.g., a bag, that can be attached to a nasogastric or naso-duodenal tube to allow the contents to be infused e.g., into either a stomach, duodenum or the distal jejunum. Alternatively it can be kept in a container, e.g., a bag, which can be attached to an enema tip to be given as an enema. In alternative embodiments, to separate the non-bacterial components and produce a stable product that can be frozen or lyophilized and have a long shelf life, the stool can be homogenized and filtered from rough particulate matter. In alternative embodiments, the microscopic fiber/nonliving matter is then separated from the bacteria. Several methods can be used, including e.g., recurrent filtration with filter sizes, e.g., coming down to the size of the bacterium. In one embodiment different filters are used to isolate the bacterial spp. This differs from the technique used for example by Williams in WO 2011/033310A1 which uses a crude technique of filtration with a gauze and is inferior to that of the present invention which utilises different sized filtration membranes to obtain the purified bacteria. In one embodiment, a filtration procedure for filtering whole stool is suitably used to reach the highest concentration of almost 100% bacteria. In one embodiment, the filtering procedure is a two-step procedure suitably using glass fibre depth filters for initial clarification. In one embodiment, the stool is filtered under positive pressure. In one embodiment, this would be using a combination or sandwich configuration with a 30 micron PVDF filter. In one embodiment, this sandwich procedure will be filtering the product under positive pressure. Later, membrane concentration can, in one embodiment, be used as another step to reduce the volume of the filtrate. In one embodiment, this can be done prior to freeze drying or spray drying under nitrogen cover. Alternative membranes that can be used for filtration include, but not limited to, nylon filters, cellulose nitrate filters, PES filters, Teflon filters, mixed cellulose Ester filters, polycarbonate filters, polypropylene filters, PVC fillers or quartz filters. Various combinations of these can be used to achieve a high purity of bacteria with solids and liquid removed ready for freezing, spray-drying or lyophilisation. For freezing, in alternative embodiments, the bacteria is held in a liquid that will prevent bursting of cells on thawing. This can include various stabilizers, e.g., glycerol and appropriate buffers, and/or ethylene glycol. In alternative embodiments, cryo-protectance uses final concentrations of stabilizer(s) of between about 20% to 60%, depending in the stabilizer(s) used; this helps stabilize proteins by preventing formation of ice crystals that would otherwise destroy protein structures. In alternative embodiments, stabilizers that help reduce destruction of living bacteria include skim milk, erythritol, arabitol, sorbitol, glucose, fructose and other polyols. Polymers such as dextran and polyethylene glycol can also be used to stabilize the faecal bacterial cells. Mixing the appropriate amount of the bacterial flora with the stabilizer allows it to be snap frozen and kept frozen in the container that will be used to transport it to appropriate facility where the patient will have this infused after thawing. In alternative embodiments, an entire (or substantially entire) microbiota, or an isolated and/or treated (e.g., purified or isolated) fecal material and/or flora, can be lyophilized or freeze dried, or the product can be frozen. In alternative embodiments freeze-drying allows the majority of cells to remain viable, and produces a powdered form of the product that can be gently pulverized into a powder. The powder, or lyophilized or freeze-dried flora or isolate, then can be encapsulated into a carrier, e.g., a tablet, geltab, pill or capsule, e.g., an enteric-coated capsule, or placed into oil-filled capsules for ingestion. Alternatively, the freeze-dried or lyophilized product, or powder, can be reconstituted before delivery to an individual in e.g., a fluid, e.g., a sterile fluid, such as saline, a buffer or a media such as a fluid-glucose-cellobiose agar (RGCA) media. In alternative embodiments an entire (or substantially entire) microbiota, or an isolated and/or treated (e.g., purified or isolated) fecal material and/or flora can be spray-dried. In one embodiment spray-drying is preferred over freeze-drying or lyophilising., In alternative embodiments, the entire (or substantially entire) microbiota, or isolated and/or treated fecal material and/or flora, is supplemented with wild type bacteria which has been derived from normal animal (e.g., human) flora and/or recombinantly treated bacteria, e.g., recombinant microorganisms that can synthesize a protein, small molecule or carbohydrate that has a self-protective or ameliorative effect; or recombinant microorganisms that can self-destruct when provided with an appropriate signal, e.g., a chemical delivered by ingestion. In alternative embodiments, the transplantation product (e.g., a composition of the invention comprising an isolated or purified fecal flora or an entire (or substantially entire) microbiota) is delivered by an infusion, e.g., through the rectum, stoma or down the upper gastrointestinal (GI) tract, or it can be used in a suppository pill, tablet or encapsulated form, e.g., with an enteric-coated graded release capsule or a tablet, e.g., with the addition of excipients. In alternative embodiments the transplantation product is administered as a suppository to give the highest concentration in the rectum. In one embodiment, the transplantation product (e.g., a composition of the invention comprising an isolated or purified fecal flora or an entire (or substantially entire) microbiota) is stored before, during and/or after delivery to an individual, or for or during the delivery, in a fluid, e.g., a sterile fluid, such as saline, a buffer or a media such as a fluid-glucose-cellobiose agar (RGCA) media. In alternative embodiments, the compositions and methods of the invention are used to ameliorate, stabilize, prevent and/or treat: various gastrointestinal conditions, e.g., C. difficile infection, C. perfringens welchii and other Clostridium infections, irritable bowel syndrome, constipation, pouchitis, Crohn's disease and microscopic colitis; neurological conditions such as Parkinson's disease, myoclonus dystonia, autism, amyotrophic lateral sclerosis and multiple sclerosis, Grand mal seizures or petit mal seizures. In one embodiment, the neurological conditions are treated by encapsulated or frozen material. In alternative embodiments, for colitis patients, recurrent administration is required to suppress and reverse the inflammatory bowel disease and irritable bowel syndrome. In alternative embodiments, a crude collected stool is filtered and/or homogenized, and then its bacterial cells are separated (e.g., from the “crud” which contains the fiber) by plasmapheresis, centrifugation, celltrifuge, column chromatography (e.g., affinity chromatography), immunoprecipitation (e.g., antibodies fixed to a solid surface, such as beads or a plate). Centrifugation, including use of a “celltrifuge” (e.g., a Baxter model MEDIFUGE I2I5™) are processes that involve centrifugal force to separate mixtures. For “celltrifugation”, the densest components will then fly to the outside of the spinning plates while the rest of the components will migrate to the axis. The effect of the gravitational force will be increased by spinning the flattened product between rapidly moving glass plates. The centrifuge or centrifuge can be set up such that the stool will be diluted adequately and set on a spinning cycle and collection of cells will occur only peripherally on the centrifuge. In alternative embodiments, wild type bacterial cells (including e.g., an entire (or substantially entire) microbiota) separated or purified e.g., by centrifugation, celltrifugation, plasmapheresis and the like, are frozen using a cryoprotectant. In alternative embodiments, this material is frozen in a container, e.g., a bag, which can then be used to infuse through a colonoscope, naso-duodenal or nasogastric tube. In alternative embodiments, it can be delivered to a facility (e.g., a hospital pharmacy) to be kept frozen, e.g., at −20° C. or below. Alternatively the centrifuged material can be lyophilized; and can be used either in a solution, gels, geltabs, pills, capsules or tablets, or suppositories, e.g., to be reconstituted later as an enema or infuse set through a colonoscope. In one embodiment the cryoprotectant is trehalose. Trehalose may also function as a component upon reconstitution or as an additional agent prior to spray-drying or freeze-drying. In alternative embodiments, solutions, gels, geltabs, pills, capsules or tablets comprising compositions of the invention (e.g., isolated or purified fecal flora or an entire (or substantially entire) microbiota) can be taken long term, e.g., on a daily basis long term, e.g., for one, two, three or four weeks or months or more, to treat, stabilize, ameliorate or prevent a chronic and/or an immune condition such as e.g., persistent infection, rheumatoid arthritis, systemic lupus erythematosus, autoimmune renal diseases, e.g., nephritis, severe obstruction, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and other conditions set forth herein. Preparations or Cultures of Entire Microbiota In alternative embodiments, compositions (e.g., products of manufacture or formulations) of the invention, comprise preparations, formulations, cultures or culture extracts or isolates comprising an entire or substantially entire microbiota of an individual or specie, e.g., a human or other mammal. In alternative embodiments, the invention provides compositions and methods for preventing, decreasing the symptoms of, ameliorating stabilizing, or treating various infections, disease or conditions comprising administration of these “entire or substantially entire microbiota” preparations (e.g., cultures or culture isolates); for example, administering “entire or substantially entire microbiota” preparations for preventing, decreasing the symptoms of, ameliorating, stabilizing, or treating: spondyloarthropathy, spondylarthritis or sacrolileitis (an inflammation of one or both sacroiliac joints); a nephritis syndrome; an inflammatory or an autoimmune condition having a gut or an intestinal component such as lupus, irritable bowel syndrome (IBS or spastic colon) or a colitis such as Ulcerative Colitis or Crohn's Colitis; constipation, autism; a degenerative neurological diseases such as amyotrophic lateral sclerosis (ALS), Multiple Sclerosis (MS) or Parkinson's Disease (PD); a Myoclonus Dystonia (e.g., Steinert's disease or proximal myotonic myopathy); an autoimmune disease such as Rheumatoid Arthritis (RA) or juvenile idiopathic arthritis (JIA); Chronic Fatigue Syndrome (including benign myalgic encephalomyelitis, chronic fatigue immune dysfunction syndrome, chronic infectious mononucleosis, epidemic myalgic encephalomyelitis); obesity; hypoglycemia, pre-diabetic syndrome, type I diabetes or type II diabetes; Idiopathic thrombocytopenic purpura (ITP); an acute or chronic allergic reaction such as hives, a rash, a urticaria or a chronic urticaria; and/or insomnia or chronic insomnia, Grand mal seizures or petit mal seizures. In alternative embodiments, the invention provides compositions and methods for administration of these “entire or substantially entire microbiota” preparations to prevent, decrease the symptoms of, ameliorate or treat various infections, diseases or conditions comprising e.g., constipation, an inflammatory bowel disease (IBD), Crohn's disease, hepatic encephalopathy, enteritis, colitis, irritable bowel syndrome (IBS), fibromyalgia (FM), chronic fatigue syndrome (CFS), depression, attention deficit/hyperactivity disorder (ADHD), multiple sclerosis (MS), systemic lupus erythematosus (SLE), travelers' diarrhea, small intestinal bacterial overgrowth, chronic pancreatitis, a pancreatic insufficiency, exposure to a poison or a toxin or for an infection, a toxin-mediated travelers diarrhea, a poisoning, a pseudomembranous colitis, a Clostridium infection, a C. perfringens welchii or a Clostridium difficile infection, a neurological condition, Parkinson's disease, myoclonus dystonia, autism, amyotrophic lateral sclerosis or multiple sclerosis, Grand mal seizures or petit mal seizures. While the invention is not limited by any particular mechanism of action, a treated or untreated fecal sample of the invention, or a composition comprising a complete or partial fecal floral sample (e.g., an entire or substantially entire microbiota”) of the invention, or a partially, substantially or completely isolated or purified fecal flora of the invention, when infused into a recipient (e.g., a human or a mammal) colonize the gut. In one embodiment, these fecal floral preparations are made (e.g., isolated) by filtering human flora, and/or by spinning or centrifuging, plasmapheresis, celltrifuge, column chromatography (e.g., affinity chromatography), or immunoprecipitation and the like, to extract almost pure or substantially pure, or pure, fecal flora (e.g., “bacterial mass”). In an alternative embodiment, compositions of the invention are prepared by culturing an entire (or substantially entire) microbiota cultured simultaneously (e.g., all together without any pre-segregating out of any particular bacterial species). In one embodiment, an “entire (or substantially entire) microbiota culture” sample is formulated e.g., as a liquid, or as a freeze dried or frozen product. In one embodiment, these preparations do not contain any (or are substantially free of) non-floral material, e.g., non-absorbed components normally present in a fecal sample, e.g., a raw human stool. In one embodiment, a raw (e.g., human) stool is made into a therapeutic agent or formulation. In one embodiment, the invention provides methods of culturing an entire mammalian, e.g., a human, flora by taking a stool sample from a suitable donor. In one embodiment, a suitable donor is a pathogen free individual; e.g., in one aspect a sample is collected from a donor who has been classified as normal and free of any pathogens. In one embodiment, as a stand-alone therapeutic or in conjunction with other therapies, bacteria from lean donors may be used to treat obesity in obese patients. In alternative embodiments, a culture is carried out for about 2, 3, 4, 5, 6, 7 or 8 or more days under total or substantially total anaerobic conditions. Standard culturing procedures can be used using, e.g., a non-selective gut microbiota medium (GMM), and in one embodiment, incubated at (human) body temperature of about 36.8° C. An atmosphere devoid of (or substantially devoid of) oxygen and containing nitrogen, carbon dioxide and hydrogen can be used. Differing GMM can be is used with varying concentrations of the composition of the GMM. Colonies or the cultured flora are then harvested by e.g., scraping with a sterile scraper. Harvested colonies or cultured flora can be frozen e.g., in about minus 80° or below (e.g., in a freezer), using e.g., a cryoprecipitate such as e.g., a glycerol, a cysteine or a milk. Such cultures can then be aliquoted to be used only once (as re-culturing can cause a loss of adhesions). In one embodiment, methods can comprise re-culturing e.g., in a lipid culture medium resembling a GMM. This entire medium can be frozen again using e.g., a glycerol with a cysteine; and in one embodiment, can be kept frozen or freeze-dried. This can produce between about 108 to about 1010 CFUs. In alternative embodiments, powder, dried, frozen, freeze-dried or liquid or other forms of the cultured (e.g., human) bacteria (e.g., an entire or substantially entire microbiota”) can be formulated and/or used either as an enema, a food or food supplement or formulation (e.g., added to a yoghurt, milk, drink, flavoured drink or a food), or delivered as a capsule, tablet, geltab or the like (e.g., as an enteric coated capsule) to recolonise or alternatively or therapeutically “colonize” a gut flora. In alternative embodiments cultured bacteria is added to the culture or sample or formulation of “entire (or substantially entire) microbiota”. For example, in one embodiment the first administration or the initial daily formulations comprise only an “entire microbiota” formulation; while in other embodiments the first administration or the initial daily formulations comprise both “entire microbiota” and additional cultured bacteria, e.g., cultured probiotic bacteria. In alternative embodiments, the less frequent formulations or dosages (which can be stepwise in small or larger intervals, or periodic intervals, or intervals as determined by the physician or veterinarian according to rate of improvement, and the like) comprise only “entire microbiota”; while in other embodiments comprise both “entire microbiota” and the additional cultured bacteria, e.g., cultured probiotic bacteria. In alternative embodiments, to achieve a desired effect or therapeutic outcome, the additional cultured bacteria (e.g., added to the “entire microbiota”) is a Bacteroides, Firmicutes and/or Bacillus thuringiensis species, which be directly isolated from a donor, or can come from a pure culture, and the like. In alternative embodiments, a delivery of an enhanced amount of one or more fecal flora (e.g., bacterial) species is used, e.g., the delivered “entire microbiota” product is enhanced with (is “spiked” with”) one-or more additional species, e.g., a Bacteroides, Firmicutes and/or Bacillus thuringiensis species. Multiple or Repeated Infusions or Administrations In alternative embodiments, compositions (e.g., products of manufacture or formulations) of the invention, including a treated or untreated fecal sample, or a partially, substantially or completely isolated or purified fecal flora, or a “culture of entire human microbiota” of the invention, or an entire (or substantially entire) microbiota or combination thereof is formulated for or calibrated for repeat or multiple delivery or infusions. In alternative embodiments of methods of the invention, the partially, substantially or completely isolated or purified fecal flora, e.g., of entire human microbiota, or an entire (or substantively entire) microbiota, or combination thereof, are delivered or administered by repeat or multiple delivery or infusions. The invention thus provides compositions and methods for treating, stabilizing, or ameliorating gut flora infections or conditions which are difficult to permanently reverse, or for treating or ameliorating conditions characterised by gut flora infections which are difficult to permanently reverse. It has been discovered that multiple, repeated infusions can overcome gut flora infections or conditions that are difficult to permanently reverse. In alternative embodiments, in practicing the methods and/or compositions (e.g., products of manufacture or formulations) of the invention, multiple or repeated fecal flora implantations (administrations, infusions) can overcome an underlying tenacious ongoing flora infection in an individual (e.g., an animal or a patient) with e.g., pathogenic and/or foreign bacterial strains, or a chronic condition. With inadequate elimination of the infective (e.g., pathogenic and/or foreign) bacteria, the ongoing original symptoms can return. It is known that bacteria sometimes do not divide and may live in biofilms in many wet (e.g., interior) surfaces of the body. Secondly, bacteria have spores which can be more difficult to eradicate at intermittent times of sporulation. There are also dormant forms of bacteria that can be intra- and extra-cellular where they are much more difficult to eradicate—unless the dormant form is dividing. Finally, intracellular bacteria may wait until the gut wall cell in which they are housed is shed into the gut lumen re-infecting the flora. In alternative embodiments, the multiple or repeated bowel flora infusions of the methods of the invention can, and may be required, to kill or otherwise inactivate the viable (e.g., infective, pathogenic and/or foreign) bacteria which were protected inside the cell, biofilm and the like. In alternative embodiments, the multiple or repeated bowel flora infusions of the methods of the invention can, and may be required, to kill or otherwise inactivate bacterial cells that travel up crypts closer to lumen, where they are shed into the faecal stream and re-infect the individual or patient. Additionally, in alternative embodiments, the multiple (recurrent) or repeated fecal flora implantations (administrations, infusions) of methods and/or compositions (e.g., products of manufacture or formulations) of the invention are effective for preventing, stabilizing, decreasing the symptoms of, ameliorating or treating individuals (e.g., patients) with: spondyloarthropathy, spondylarthritis or sacrolileitis (an inflammation of one or both sacroiliac joints); a nephritis syndrome; an inflammatory or an autoimmune condition having a gut or an intestinal component such as lupus, Irritable Bowel Syndrome (IBS or spastic colon) or a colitis such as Ulcerative Colitis or Crohn's Colitis; constipation, autism; a degenerative neurological diseases such as amyotrophic lateral sclerosis (ALS), Multiple Sclerosis (MS) or Parkinson's Disease (PD); a Myoclonus Dystonia (e.g., Steinert's disease or proximal myotonic myopathy); an autoimmune disease such as Rheumatoid Arthritis (RA) or juvenile idiopathic arthritis (JIA); Chronic Fatigue Syndrome (including benign myalgic encephalomyelitis, chronic fatigue immune dysfunction syndrome, chronic infectious mononucleosis, epidemic myalgic encephalomyelitis); obesity; hypoglycemia, pre-diabetic syndrome, type I diabetes or type II diabetes; Idiopathic thrombocytopenic purpura (ITP); an acute or chronic allergic reaction such as hives, a rash, a urticaria or a chronic urticaria; and/or insomnia or chronic insomnia, Grand mal seizures or petit mal seizures. In alternative embodiments the invention is practiced (is carried out) either by use of methods or compositions of the invention, including recurrent enemas of human filtered stool, recurrent infusions through a naso-duodenal (ND) or a naso-gastric (NG) tube. In alternative embodiments, methods or compositions of the invention formulate or use various formulations, e.g., frozen extracted stool bacterial material can be suspended as a flavoured drink or put down an ND or an NG tube or inserted as an enema. In alternative embodiments, extracted bacteria—the ‘wild types’ are freeze-dried (optionally, after partial, substantial or complete purification and isolation) and formed into powder; they then can be ingested, e.g., as enteric-coated capsules, tablets, solutions and the like. In alternative embodiments, these ‘products’ of the invention are initially taken, infused or administered daily, then less and less frequently, and in some embodiments, ultimately once every few weeks or monthly. In alternative embodiments cultured bacteria can be used in addition to or with the partial, substantial or completely purified or isolated fecal flora. For example, in one embodiment the first administration or the initial daily formulations comprise only partial, substantial or completely purified or isolated fecal flora; while in other embodiments the first administration or the initial daily formulations comprise both partial, substantial or completely purified or isolated fecal flora and cultured bacteria, e.g., cultured probiotic bacteria. In alternative embodiments, the less frequent formulations or dosages (which can be stepwise in small or larger intervals, or periodic intervals, or intervals as determined by the physician or veterinarian according to rate of improvement, and the like) comprise only partial, substantial or completely purified or isolated fecal flora; while in other embodiments comprise both partial, substantial or completely purified or isolated fecal flora and cultured bacteria; or in other embodiments comprise only cultured bacteria, e.g., cultured probiotic bacteria. In alternative embodiments, to achieve a desired effect or therapeutic outcome, the cultured bacteria is a Bacteroides and/or Firmicutes species and/or Bacillus thuringiensis, which may be directly isolated from a donor, or can come from a pure culture, and the like. In alternative embodiments, a delivery of an enhanced amount of one or more fecal flora (e.g., bacterial) species is used, e.g., the delivered product is enhanced with (is “spiked” with”) one or more additional species, e.g., a Bacteroides and/or Firmicutes species and/or Bacillus thuringiensis. In alternative embodiments, for adequate efficacy as to be determined by the skilled artisan, the formulations are introduced daily, or not daily—but instead recurrently for prolonged periods of time, e.g., in much higher doses. In alternative embodiments, the repeated or multiple infusion, administration or implantation protocols comprise infusions done daily for about the first 10 days, and subsequently a second daily different dosage or formulation for about 10 days, and optionally a subsequent different third daily; then optionally a different fourth daily, weekly, or monthly dosage or formulation, and then optionally maintaining different dosages or formulations for a further daily, weekly or monthly delivery or infusion until the histology reverses towards normality or other treatment parameter or goal is achieved; e.g., for the treatment of Irritable Bowel Syndrome, colitis such as Ulcerative Colitis or Crohn's Colitis, constipation, autism, degenerative neurological diseases such as Multiple Sclerosis (MS), Parkinson's Disease (PD), Myoclonus Dystonia, Rheumatoid Arthritis, Chronic Fatigue Syndrome, obesity, diabetes, type II diabetes, Idiopathic thrombocytopenic purpura (ITP), autoimmune diseases, chronic urticaria and/or insomnia or chronic insomnia, Grand mal seizures or petit mal seizures. In alternative embodiments, the repeated or multiple infusion, administration or implantations are done with: a first formulation daily for the first 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days; a second dosage or formulation daily for a subsequent 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days or more; then optionally a third subsequent dosage or formulation daily (e.g., for a subsequent 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days or more); then optionally a fourth dosage or formulation daily or weekly (e.g., for a subsequent 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days, weeks, months or more); and optionally then maintaining weekly or monthly infusions until e.g., the histology reverses towards normality, or other appropriate parameter for treatment or recovery; e.g., for treatment of Irritable Bowel Syndrome, colitis such as Ulcerative Colitis or Crohn's Colitis, constipation, autism, degenerative neurological diseases such as Multiple Sclerosis (MS), Parkinson's Disease (PD), Myoclonus Dystonia, Rheumatoid Arthritis, Chronic Fatigue Syndrome, obesity, diabetes, type II diabetes, Idiopathic thrombocytopenic purpura (ITP), autoimmune diseases, chronic urticaria and/or insomnia or chronic insomnia, Grand mal seizures or petit mal seizures. One of skill in the art, e.g., a physician or veterinarian, can assess the individual's improvement and determine the exact, appropriate dosage or frequency of administration in this “repeat administration” embodiment of the invention. In alternative embodiments, these exemplary protocols also can be used for infusing or ingesting cultured probiotic bacteria that would be swept down the bowel in waves so as to address the issue of the biofilms spores, dormant forms and intracellular bacteria. In summary, in alternative embodiments, the invention provides compositions and methods for treating, stabilizing, or ameliorating gut flora infections that are difficult to permanently reverse, or for treating or ameliorating conditions characterised by or related to gut flora infections that are difficult to permanently reverse or control, by multiple, repeated infusions of fecal flora, as described herein. In alternative embodiments the fecal microbiota transplant compositions and methods of the invention are effective in the more difficult conditions listed above in addition to conditions where a Clostridium, e.g., C. difficile, is the infective agent. In alternative embodiments, repeated or recurrent infusions are the key to obtaining a cure, a stabilization or a prolonged remission. Devices for Delivering Compositions of the Invention The invention also provides devices for delivering compositions of the invention, e.g., an exemplary delivery device is illustrated in FIG. 1B. In alternative embodiments, a device of the invention also can comprise or consist of: (b) (I) a bag or container comprising an exit aperture operably connected to the proximal end of a flexible tube or equivalent, wherein the bag or container is optionally made of a material impervious to a gas or to oxygen, and optionally the bag or container is made of a flexible material, or a polyethylene terephthalate polyester film-comprising (or a MYLAR™-comprising) material, and optionally the bag or container is an (IV-like) intravenous-like bag, and optionally the bag or container has an attachment that will allow the bag to be hung on a stand, e.g., to be positioned/hung above an endoscope, and optionally the bag or container is operably connected via an open or close valve or equivalent to a negative pressure device that can remove all gas or air from the bag, and optionally the bag or container is operably connected via an open or close valve or equivalent to a fluid source or storage container for flushing out the bag through the exit aperture, and optionally the fluid source or storage container is under positive pressure, and optionally the flexible tube or equivalent comprises at least one clip or close 25 valve or one way valve to prevent backwash of material from distal to proximal portions of the tube, or from the tube back to the bag or container; (2) an open or close valve or equivalent or an obdurator screwtop at the distal end of the flexible tube or equivalent, and optionally a Luer lock tip for attachment to a colonoscope or an endoscopic Luer lock port or equivalent, wherein optionally the Luer lock tip is built into the valve, or is separate from the valve, and optionally an enema tube tip for attachment to an enema tube or device or equivalent, wherein optionally the enema tube tip is built into the valve, or is separate from the valve, and optionally further comprising a safety device or safety clip to close the distal 5 aperture in case the valve or Luer lock tip, or enema tip, is lost (flies off) under pressure; and (3) a pump, or a hand pump, for moving material in the bag or container through the flexible tube or equivalent and out the distal end or out the open or close valve or equivalent. In alternative embodiments, a device of the invention further comprises a treated or untreated fecal flora, or a partially, substantially or completely isolated fecal flora, or a composition of the invention, e.g., a partially, substantially or completely isolated or purified fecal flora, or a composition comprising a fecal flora substantially or completely purified of non-fecal floral fecal material, and optionally further comprising an excipient, or a fluid, a saline, a buffer, a buffering agent or a media, or a fluid-glucose-cellobiose agar (RGCA) media. In one embodiment, the invention provides a bag or container comprising a treated or untreated fecal flora, or a partially, substantially or completely isolated fecal flora, or a composition of the invention, e.g., a partially, substantially or completely isolated or purified fecal flora, or a composition comprising a fecal flora substantially or completely purified of non-fecal floral fecal material, and optionally further comprising an excipient, or a fluid, a saline, a buffer, a buffering agent or a media, or a fluid-glucose-cellobiose agar (RGCA) media, wherein the bag or container is structurally the same as or similar to a bag or container of a device of the invention, e.g., a bag or container comprising an exit aperture operably connected to the proximal end of a flexible tube or equivalent, etc., as described herein. The invention will be further described with reference to the following examples; however, it is to be understood that the invention is not limited to such examples. EXAMPLES Example 1 Exemplary Methods of the Invention One exemplary procedure of the invention involves a 5- to 10-day treatment with enemas comprising a treated or isolated fecal bacterial flora of the invention initially derived from a healthy donor. Alternatively, patients can recover after just one treatment. In one embodiment, the best choice for donor is a close relative who has been tested for a wide array of bacterial and parasitic agents. The enemas are prepared and administered in a hospital environment to ensure all necessary precautions. An exemplary probiotic infusion of the invention can also be administered through a nasogastric tube, delivering the bacteria directly to the small intestine. These two methods can be combined to achieve a desired result. Regular checkups should be required up to a year following the procedure. In one embodiment an autologous fecal sample is provided by a patient before a medical treatment, and it is stored in a refrigerator, lyophilized or freeze-dried or equivalent. Should the patient subsequently develop an infection, e.g., a C. difficile infection, the sample is prepared (extracted) with saline and filtered. The filtrate can be freeze-dried and the resulting solid enclosed in a capsule, e.g., an enteric coated capsule. Administration of the capsules can restore the patient's own colonic flora and combat the infection, e.g., the C. difficile. In one embodiment, samples are delivered into the duodenum via a nasal probe. In one embodiment, a method of the invention comprises the collection from healthy donors of fresh, human flora (stool), bringing it to a centralized institution, processing it in such a fashion that it will be given prolonged life, checking for pathogens, maintaining temperature control to reduce metabolic activity of the bacteria and controlling for oxygen-shock, developing a storage facility of the homogenized, standardized flora, and shipping the flora out to distant hospitals to treat patients with e.g. acute pseudo membranous colitis, severe C. difficile infection, septicaemia or other comparable conditions. In one embodiment, the product of the invention is a modified stool composition. The stool needs to be collected and promptly placed into an anaerobic container which extracts air, possibly with substances that adsorb and absorb oxygen or can be evacuated and filled with nitrogen or other gas which is either inert or will not damage anaerobic flora. It has to be held in an aesthetically acceptable container which will not leak the stool nor the gas which is producing the anaerobic situation. Once delivered to the central ‘bank’ the stool can be stored in a cold room to slow down metabolism but not be frozen to prevent the water expansion-destruction of the bacterial cells contained in stool. In one embodiment, either antioxidants and/or substances such as glycerol are added to help stabilize the bacteria in the cold and prevent them from becoming destroyed during storage and during transport. In one embodiment the product is stored/contained as (in) a volume of between about 10 cc and 3 liters of stool. In one embodiment it is stored in a (as a) 300 cc container (or amount) and held in appropriate oxygen-resistant material, e.g., a plastic, an oxygen-resistant or gas impervious polyethylene terephthalate polyester film (e.g., in metallized form), or a metallized MYLAR™, or an aluminized MYLAR™, which can be attached to a pump through a giving set that will be attached to the colonoscope and administered through a colonoscope into a distal small bowel or into the upper colon/terminal ileum, to overcome Clostridium difficile infection. Central Flora Supply Institution or “Bank” In one embodiment, an institution functions to supply the human flora in the following manner: 1. Stool will be collected in special containers and held cool anaerobically until it arrives at the central flora processing unit. 2. In a processing unit special additives will be added including glycerol, possibly antioxidants and other special preservatives and kept cool, homogenized and dispensed into appropriate intravenous-like bags but with somewhat thicker product such as a gas impervious polyethylene terephthalate polyester film, or an aluminized MYLAR™. This will prevent oxygen being transferred, nitrogen escaping and the smell being detected by administering staff. The bags will then be kept stored at a temperature that does not allow bacteria to freeze and be ready for transport in coolers to hospitals that will be carrying out the faecal transplantation. 3. The bag will be supplied with an attached giving set, so that it does not have to be handled by hospital staff. There will be attached to it a ‘blood type’ pump, with one way valve. On the (IV-like) intravenous-like bag there will be attachments that will be able to allow the bag to be hung on an IV fluids stand and be positioned/hung above the endoscope. The endoscopist will then take off the obdurator screwtop and attach to the Luer lock tip onto the endoscopic Luer lock port to be infused through the biopsy forceps channel at the tip of the colonoscope or endoscope. A safety device would be attached in case the tip flies off under pressure. The air will then be bled from the tube as the product is allowed to run down the ‘giving set’ with pressure mechanisms along the giving set, with air bled, and then stool only will be administered using the administering pump into the patient's colon and flushed, for example with some saline. 4. The endoscopist would then withdraw the colonoscope, turn the patient ‘head down/legs up’ to allow air and liquid to be absorbed and prevent the patient from undergoing defecation too early. This will allow the bacteria to re-gain temperature, start attaching themselves to the bowel wall as described e.g., by Grehan et al: J of Clinical Gastroenterology, September 2010. A number of embodiments of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims. | <SOH> BACKGROUND <EOH>Bacterial flora of the bowel has recently gained importance from a therapeutic point of view. It is now realized that the human flora, rather than just being waste material resulting from digestion of food, is an important virtual organ containing large numbers of living microorganisms. There are in excess of one hundred thousand different subspecies—or more—arranged in families and subgroups of genetically different but often linearly related organisms. The waste “material” makes up a proportion of the flora. The bacterial content of the flora is actively breaking down or metabolizing the non-absorbed matter, largely fiber, on which the bacterial cells grow. Because the bacterial flora is contained within the human body and is made up of living components it constitutes in fact as a living organ or a virtual organ. This virtual organ can be healthy in that it doesn't contain any pathogenic organisms, or it can become infected or infested with parasite, bacteria or viruses. When infected with some pathogenic species, such infecting species can manufacture molecules that affect secretion, which can cause pain, or can paralyze the bowel causing constipation. Infection of the bowel flora or bowel flora organ can impact the health of the individual. Many of these infections can be acute, such as cholera, but some can be chronic and can really impact on the life of the individual carrying the infected flora. For example, after antibiotic therapy some of the families of the bacteria can be suppressed or eradicated and infectious agents such as Clostridium difficile and other pathogens can lodge and become passengers within the human flora. These ‘passengers’ are also pathogenic because they can produce toxins e.g. toxins A and B for C. difficile. | <SOH> SUMMARY <EOH>According to a first aspect of the present invention, there is provided a delivery vehicle, formulation, composition, pharmaceutical preparation, product of manufacture, container or device, comprising: an entire (or substantially entire) microbiota; a treated or untreated fecal flora; a complete or partial fecal flora, a fecal flora substantially or completely purified of non-fecal floral fecal material, or a partially, substantially or completely isolated or purified fecal flora, made by a process comprising: (i) providing an entire (or substantially entire) microbiota, a treated or untreated fecal flora sample, a complete or partial fecal flora sample, a fecal flora substantially or completely purified of non-fecal floral fecal material or a partially, substantially or completely isolated or purified fecal flora; and, a delivery vehicle, formulation, pharmaceutical preparation, composition, product of manufacture, container or device, and (ii) placing the entire (or substantially entire) microbiota, the treated or untreated fecal flora sample, the complete or partial fecal flora sample, the fecal flora substantially or completely purified of non-fecal floral fecal material, or the partially, substantially or completely isolated or purified fecal flora in the delivery vehicle, formulation, composition, pharmaceutical preparation, product of manufacture, container or device. According to a second aspect of the present invention, there is provided a product (article) of manufacture comprising a delivery vehicle, formulation, composition pharmaceutical preparation, container or device of the first aspect. According to a third aspect of the present invention, there is provided a method for making a delivery vehicle, formulation, composition pharmaceutical preparation, product of manufacture, container or device according to the first or second aspect comprising (i) providing: an entire (or substantially entire) microbiota; a treated or untreated fecal sample; a complete or partial fecal flora sample, a fecal flora substantially or completely purified of non-fecal floral fecal material or a partially, substantially or completely isolated or purified fecal flora; and, a delivery vehicle, formulation, pharmaceutical preparation, composition product of manufacture, container or device, and (ii) placing the entire (or substantially entire) microbiota, treated or untreated fecal sample, the complete or partial fecal flora, the fecal flora substantially or completely purified of non-fecal floral fecal material or the partially, substantially or completely isolated or purified fecal flora in the delivery vehicle, formulation, pharmaceutical preparation, composition, product of manufacture, container or device, and creating a substantially or completely oxygen-free environment in the container or device. According to a fourth aspect of the present invention there is provided a method for the amelioration, stabilization, treatment and/or prevention of an infection, disease, treatment, poisoning or a condition having a bowel dysfunction component or side-effect, or for the amelioration, treatment and/or prevention of a constipation, for the treatment of an abdominal pain, a non-specific abdominal pain or a diarrhea, a diarrhea caused by: a drug side effect or a psychological condition or Crohn's Disease, a poison, a toxin or an infection, a toxin-mediated travelers diarrhea, or a Clostridium or a C. perfringens welchii or a C. difficile infection or a pseudo-membranous colitis associated with a Clostridium infection, comprising: administering to an individual in need thereof via a delivery vehicle, formulation, composition, pharmaceutical preparation, product of manufacture, container or device of the first aspect, or a product (article) of manufacture of the second aspect the entire (or substantially entire) microbiota, the treated or untreated fecal flora sample, the complete or partial fecal flora sample, the fecal flora substantially or completely purified of non-fecal floral fecal material, or the partially, substantially or completely isolated or purified fecal flora. According to a fifth aspect of the present invention, there is provided a delivery vehicle, formulation, composition, pharmaceutical preparation, product of manufacture, container or device comprising: an entire (or substantially entire) microbiota; a partially, substantially or completely isolated or purified fecal flora; or, a composition comprising a fecal flora substantially or a completely purified of non-fecal floral fecal material. According to a sixth aspect of the present invention, there is provided a method for the amelioration, stabilization, treatment and/or prevention of an infection, disease, treatment, poisoning or a condition having a bowel dysfunction component or side-effect comprising administering to an individual in need thereof via a delivery vehicle, formulation, composition, pharmaceutical preparation, product of manufacture, container or device according to the fifth aspect the entire (or substantially entire) microbiota, the partially, substantially or completely isolated or purified fecal flora, or the composition comprising a fecal flora substantially or a completely purified of non-fecal floral fecal material. According to a seventh aspect of the present invention, there is provided a device for delivering a fecal material or a composition of the first aspect, comprising: (a) a device as illustrated in FIG. 1B or FIG. 2 ; or (b) a device comprising (i) a bag or container comprising an exit aperture operably connected to the proximal end of a flexible tube or equivalent, (ii) an open or close valve or equivalent or an obdurator screwtop at the distal end of the flexible tube or equivalent, and (iii) a pump, or a hand pump, for moving material in the bag or container through the flexible tube or equivalent and out the distal end or out the open or close valve or equivalent; or (c) the device of (a) or (b), further comprising a fecal material or a composition of the first aspect. According to an eighth aspect of the present invention, there is provided a bag or container comprising: an entire (or substantially entire) microbiota; a treated or untreated fecal flora; a complete or partial fecal flora, a fecal flora substantially or completely purified of non-fecal floral material or, a partially, substantially or completely isolated or purified fecal flora, or a composition thereof wherein the bag or container is structurally the same as or similar to a bag or container of a device of the seventh aspect. According to a ninth aspect of the present invention, there is provided a method for the amelioration, stabilization, treatment and/or prevention of, or decreasing or delaying the symptoms of, an infection, disease, treatment, poisoning or a condition having a bowel dysfunction component or side-effect, or for the amelioration, treatment and/or prevention of a constipation, for the treatment of an abdominal pain, a non-specific abdominal pain or a diarrhea, a diarrhea caused by: a drug side effect or a psychological condition or Crohn's Disease, a poison, a toxin or an infection, a toxin-mediated travellers diarrhea, or a Clostridium or a C. perfringens welchii or a C. difficile infection or a pseudo-membranous colitis associated with a Clostridium infection, or for preventing, or decreasing or delaying the symptoms of, or ameliorating or treating individuals with spondyloarthropathy, spondylarthritis or sacrolileitis (an inflammation of one or both sacroiliac joints); a nephritis syndrome; an inflammatory or an autoimmune condition having a gut or an intestinal component; lupus; irritable bowel syndrome (IBS or spastic colon); or a colitis; Ulcerative Colitis or Crohn's Colitis; constipation; autism; a degenerative neurological diseases; amyotrophic lateral sclerosis (ALS), Multiple Sclerosis (MS) or Parkinson's Disease (PD); a Myoclonus Dystonia;, Steinert's disease; proximal myotonic myopathy; an autoimmune disease; Rheumatoid Arthritis (RA) or juvenile idiopathic arthritis (JIA); Chronic Fatigue Syndrome; benign myalgic encephalomyelitis; chronic fatigue immune dysfunction syndrome; chronic infectious mononucleosis; epidemic myalgic encephalomyelitis; obesity; hypoglycemia, pre-diabetic syndrome, type I diabetes or type II diabetes; Idiopathic thrombocytopenic purpura (ITP); an acute or chronic allergic reaction; hives, a rash, a urticaria or a chronic urticaria; and/or insomnia or chronic insomnia, Grand mal seizures or petit mal seizures, comprising: administering to an individual in need thereof via a delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device of the first aspect or a product (article) of manufacture of the second aspect of the entire (or substantially entire) microbiota, the treated or untreated fecal flora sample, the complete or partial fecal flora sample, the fecal flora substantially or completely purified of non-fecal floral fecal material, or the partially, substantially or completely isolated or purified fecal flora, in single, repeat or multiple administrations, deliveries or infusions. According to a tenth aspect of the present invention, there is provided an entire (or substantially entire) microbiota, a treated or untreated fecal flora sample, a complete or partial fecal flora sample, a fecal flora substantially or completely purified of non-fecal floral fecal material, or a partially, substantially or completely isolated or purified fecal flora for use in the amelioration, stabilization, treatment and/or prevention of an infection, disease, treatment, poisoning or a condition having a bowel dysfunction component or side-effect, or for the amelioration, treatment and/or prevention of a constipation, for the treatment of an abdominal pain, a non-specific abdominal pain or a diarrhea, a diarrhea caused by: a drug side effect or a psychological condition or Crohn's Disease, a poison, a toxin or an infection, a toxin-mediated travelers diarrhea, or a Clostridium or a C. perfringens welchii or a C. difficile infection or a pseudo-membranous colitis associated with a Clostridium infection. According to an eleventh aspect of the present invention, there is provided use of an entire (or substantially entire) microbiota, a treated or untreated fecal flora sample, a complete or partial fecal flora sample, a fecal flora substantially or completely purified of non-fecal floral fecal material, or a partially, substantially or completely isolated or purified fecal flora in the preparation of a medicament for the amelioration, stabilization, treatment and/or prevention of an infection, disease, treatment, poisoning or a condition having a bowel dysfunction component or side-effect, or for the amelioration, treatment and/or prevention of a constipation, for the treatment of an abdominal pain, a non-specific abdominal pain or a diarrhea, a diarrhea caused by: a drug side effect or a psychological condition or Crohn's Disease, a poison, a toxin or an infection, a toxin-mediated travelers diarrhea, or a Clostridium or a C. perfringens welchii or a C. difficile infection or a pseudo-membranous colitis associated with a Clostridium infection. According to a twelfth aspect of the present invention, there is provided use of a device of the seventh aspect for delivering a fecal material or an entire (or substantially entire) microbiota, a treated or untreated fecal flora sample, a complete or partial fecal flora sample, a fecal flora substantially or completely purified of non-fecal floral fecal material, or a partially, substantially or completely isolated or purified fecal flora in the amelioration, stabilization, treatment and/or prevention of an infection, disease, treatment, poisoning or a condition having a bowel dysfunction component or side-effect, or for the amelioration, treatment and/or prevention of a constipation, for the treatment of an abdominal pain, a non-specific abdominal pain or a diarrhea, a diarrhea caused by: a drug side effect or a psychological condition or Crohn's Disease, a poison, a toxin or an infection, a toxin-mediated travelers diarrhea, or a Clostridium or a C. perfringens welchii or a C. difficile infection or a pseudo-membranous colitis associated with a Clostridium infection. In alternative embodiments, the invention provides compositions (including formulations, pharmaceutical compositions, foods, feeds, supplements, products of manufacture, and the like) comprising: delivery vehicle, formulation, container or device, comprising a treated or untreated fecal flora, or a partially, substantially or completely isolated fecal flora; and methods of making and using them. In alternative embodiments, the invention provides delivery vehicles, formulations, pharmaceutical preparations, products of manufacture, containers or devices, comprising: a treated or untreated fecal flora, an entire (or substantially entire) microbiota, and/or a partially, substantially or completely isolated fecal flora, made by a process comprising: (a) (i) providing a treated or untreated fecal sample, or a sample comprising an entire (or substantially entire) microbiota, or a composition comprising a complete or partial fecal flora, or a partially, substantially or completely isolated or purified fecal flora; and, a delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device, and (ii) placing the treated or untreated fecal sample, the partially, substantially or completely isolated or purified fecal flora, the entire (or substantially entire) microbiota, or a composition comprising a complete or partial fecal flora or partially, substantially or completely isolated or purified fecal flora, in the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device, and optionally creating a substantially or completely oxygen-free environment in the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device, and optionally the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device is sterile or bacteria-free before the placing of the treated or untreated fecal sample, or the partially, substantially or completely isolated or purified fecal flora; (b) the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device of (a), wherein the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device is made substantially or completely oxygen free (e.g., at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9% oxygen free) by: incorporating into the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device a built in or clipped-on oxygen-scavenging mechanism; and/or, the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device comprises or is coated with an oxygen scavenging material; and/or completely or substantially replacing the air in the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device with nitrogen and/or other inert non-reactive gas or gases; (c) the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device of (a) or (b), wherein the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device simulates (creates) partially, substantially or completely an anaerobic environment; (d) the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device of any, of (a) to (c), wherein the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device is manufactured, labelled or formulated for human or animal use; (e) the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device of (d), wherein the animal use is for a veterinary use; (f) the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device of any of (a) to (e), wherein a stabilizing agent or a glycerol is added to, or mixed into, the treated or untreated fecal sample, entire (or substantially entire) microbiota, or partially, substantially or completely isolated fecal flora, before storage or freezing, spray-drying, freeze-drying or lyophilizing; (g) the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device of any of (a) to (f), wherein the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device is initially manufactured or formulated as a liquid, a suspension, a gel, a geltab, a semisolid, a tablet, a sachet, a lozenge or a capsule, or as an enteral formulation, or re-formulated for final delivery as a liquid, a suspension, a gel, a geltab, a semisolid, a tablet, a sachet, a lozenge or a capsule, or as an enteral formulation; (h) the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device of any of (a) to (g), wherein the fecal sample is treated such that the fecal flora is separated from rough particulate matter in the fecal sample by: homogenizing, centrifuging and/or filtering a rough particulate matter or a non-floral matter of the fecal material, or by plasmapheresis, centrifugation, celltrifuge, column chromatography (e.g., affinity chromatography), immunoprecipitation (e.g., antibodies fixed to a solid surface, such as beads or a plate); (i) the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device of any of (a) to (h), wherein the treated or untreated fecal flora, entire (or substantially entire) microbiota, or partially, substantially or completely isolated or purified fecal flora, is lyophilized, freeze-dried or frozen, or processed into a powder; (j) the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device of any of (a) to (i), wherein the fecal flora (including e.g., the entire (or substantially entire) microbiota) is initially derived from an individual screened or tested for a disease or infection, and/or the fecal flora is initially derived from an individual screened to have a normal, healthy or wild type population of fecal flora; (k) the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device of any of (a) to (j), wherein a substantially isolated or a purified fecal flora or entire (or substantially entire) microbiota is (comprises) an isolate offecal flora that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9% isolated or pure, or having no more than about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% or 1.0% or more non-fecal floral material; or (l) the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device of any of (a) to (j), wherein the amount of the treated or untreated fecal sample, entire (or substantially entire) microbiota, or the partially, substantially or completely isolated or purified fecal flora is formulated for or calibrated for repeat or multiple delivery or infusions, wherein optionally the repeated or multiple administration, delivery, infusion or implantation protocol comprises infusions done daily for the first about 10 days, second daily for about 10 days, third daily then fourth daily possibly weekly and then optionally maintain second or more weekly infusions until the histology reverses towards normality. In alternative embodiments, the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device of the invention further comprises: a saline, a media, a defoaming agent, a surfactant agent, a lubricant, an acid neutralizer, a marker, a cell marker, a drug, an antibiotic, a contrast agent, a dispersal agent, a buffer or a buffering agent, a sweetening agent, a debittering agent, a flavouring agent, a pH stabilizer, an acidifying agent, a preservative, a desweetening agent and/or colouring agent; at least one vitamin, mineral and/or dietary supplement, wherein optionally the vitamin comprises a thiamine, riboflavin, nicotinic acid, pantothenic acid, pyridoxine, biotin, folic acid, vitamin B 12 , lipoic acid, ascorbic acid, vitamin A, vitamin D, vitamin E, vitamin K, a choline, a camitine, and/or an alpha, beta and/or gamma carotene; or a prebiotic nutrient, wherein optionally the prebiotic comprises any ingredient that stimulates the stability, growth and/or activity of the fecal flora or fecal bacteria, or optionally comprises polyols, fructooligosaccharides (FOSs), oligofructoses, inulins, galactooligosaccharides (GOSs), xylooligosaccharicles (XOSs), polydextroses, monosaccharides, tagatose, and/or mannooligosaccharides. In alternative embodiments, the invention provides products (articles) of manufacture comprising a delivery vehicle, formulation, pharmaceutical preparation, container or device of the invention. In alternative embodiments, the invention provides methods for making a delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device, comprising a treated or untreated fecal flora, entire (or substantially entire) microbiota, or a partially, substantially or completely isolated or purified fecal flora, comprising: (a) (i) providing a treated or untreated fecal sample, or a composition comprising a complete or partial fecal flora, an entire (or substantially entire) microbiota, or a partially, substantially or completely isolated or purified fecal flora; and, a delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device, and (ii) placing the treated or untreated fecal sample, the partially, substantially or completely isolated or purified fecal flora, the entire (or substantially entire) microbiota, or a composition comprising a complete or partial fecal flora or partially, substantially or completely isolated or purified fecal flora, in the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device, and creating a substantially or completely oxygen-free environment in the container or device; (b) the method of (a), wherein the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device is made substantially or completely oxygen free by: incorporating into the delivery vehicle, formulation, container or device a built in or clipped-on oxygen-scavenging mechanism; and/or, the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device comprises or is coated with an oxygen scavenging material; and/or completely or substantially replacing the air in the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device with nitrogen and/or other inert non-reactive gas or gases; (c) the method of (a) or (b), wherein the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device simulates (creates) partially, substantially or completely an anaerobic environment; (d) the method of any of (a) to (c), wherein the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device is manufactured, labelled or formulated for human or animal use; (e) the method of (d), wherein the animal use is for a veterinary use; (f) the method of any of (a) to (e), wherein a prebiotic, a stabilizing agent or a glycerol is added to, or mixed into, the treated or untreated fecal sample, or partially, substantially or completely isolated or purified fecal flora, before storage or freeze-drying, spray-drying, freezing or lyophilizing; (g) the method of any of (a) to (f), wherein the delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device is initially manufactured or formulated as a liquid, a suspension, a gel, a geltab, a semisolid, a tablet, a sachet, a lozenge or a capsule, or as an enteral formulation, or re-formulated for final delivery as a liquid, a suspension, a gel, a geltab, a semisolid, a tablet, a sachet, a lozenge or a capsule, or as an enteral formulation; (h) the method of any of (a) to (g), wherein the fecal sample is treated such that the fecal flora is separated from rough particulate matter in the fecal sample by: homogenizing, centrifuging and/or filtering a rough particulate matter or a non-floral matter of the fecal material, or by plasmapheresis, centrifugation, centrifuge, column chromatography (e.g., affinity chromatography), immunoprecipitation (e.g., antibodies fixed to a solid surface, such as beads or a plate); (i) the method of any of (a) to (h), wherein the treated or untreated fecal flora, or partially, substantially or completely isolated or purified fecal flora, is lyophilized, freeze-dried or frozen, or processed into a powder; (j) the method of any of (a) to (i), wherein the fecal flora is initially derived from an individual screened or tested for a disease or infection, and/or the fecal flora is initially derived from an individual screened to have a normal, healthy or wild type population of fecal flora; or (k) the method of any of (a) to (j), further comprising adding to the treated or untreated fecal flora, or adding to a liquid or solution used to isolate or purify, store, freeze, freeze-dry, spray-dry, lyophilize, transport, reconstitute and/or deliver a treated or untreated fecal flora (optionally an entire (or substantially entire) microbiota, a partially, substantially or completely isolated or purified fecal flora, or a composition comprising a fecal flora substantially or completely purified of non-fecal floral fecal material of the invention): a saline, a media, a defoaming agent, a surfactant agent, a lubricant, an acid neutralizer, a marker, a cell marker, a drug, an antibiotic, a contrast agent, a dispersal agent, a buffer or a buffering agent, a sweetening agent, a debittering agent, a flavouring agent, a pH stabilizer, an acidifying agent, a preservative, a desweetening agent and/or colouring agent, and/or at least one vitamin, mineral and/or dietary supplement, wherein optionally the vitamin comprises a thiamine, riboflavin, nicotinic acid, pantothenic acid, pyridoxine, biotin, folic acid, vitamin B 12 , lipoic acid, ascorbic acid, vitamin A, vitamin D, vitamin E, vitamin K, a choline, a camitine, and/or an alpha, beta and/or gamma carotene, and/or a prebiotic nutrient, wherein optionally the prebiotic comprises any ingredient that stimulates the stability, growth and/or activity of the fecal flora or fecal bacteria, or optionally comprises polyols, fructooligosaccharides (FOSs), oligofructoses, inulins, galactooligosaccharides (GOSs), xylooligosaccharides (XOSs), polydextroses, monosaccharides, tagatose, and/or mannooligosaccharides; (l) the method of any of (a) to (k), wherein an entire (or substantially entire) microbiota, a substantially isolated or a purified fecal flora is (comprises) an isolate of fecal flora that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9% isolated or pure, or having no more than about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% or 1.0% or more non-fecal floral material; or (m) the method of any of (a) to (l), wherein the amount of the entire (or substantially entire) microbiota, the treated or untreated fecal sample, or the partially, substantially or completely isolated or purified fecal flora is formulated for or calibrated for repeat or multiple delivery or infusions, wherein optionally the repeated or multiple administration, delivery, infusion or implantation protocol comprises infusions done daily for the first about 10 days, second daily for about 10 days, third daily then fourth daily possibly weekly and then optionally maintain second or more weekly infusions until the histology reverses towards normality. In alternative embodiments, the invention provides methods for the amelioration, stabilization, treatment and/or prevention of an infection, disease, treatment, poisoning or a condition having a bowel dysfunction component or side-effect, or for the amelioration, stabilization, treatment and/or prevention of a constipation, for the treatment of an abdominal pain, a non-specific abdominal pain or a diarrhea, a diarrhea caused by: a drug side effect or a psychological condition or Crohn's Disease, a poison, a toxin or an infection, a toxin-mediated travellers diarrhea, or a Clostridium or a C. difficile or a pseudo-membranous colitis associated with a Clostridium infection, comprising administering to an individual in need thereof a delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device of the invention, or a product (article) of manufacture of the invention. In alternative embodiments, the invention provides methods for the amelioration, stabilization, treatment and/or prevention of an infection, disease, treatment, poisoning or a condition having a bowel dysfunction component or side-effect comprising administering to an individual in need thereof a delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device of the invention, or a product (article) of manufacture of the invention, or their contents (e.g., the bacterial flora contained therein). In alternative embodiments, the amount of the treated or untreated fecal sample, or the partially, substantially or completely isolated or purified fecal flora is formulated for or calibrated for repeat or multiple delivery or infusions; or the partially, substantially or completely isolated or purified fecal flora is delivered in repeated or multiple infusions, wherein optionally the repeated or multiple administration, delivery, infusion or implantation protocol comprises infusions done daily for the first about 10 days, second daily for about 10 days, third daily then fourth daily possibly weekly and then optionally maintain second or more weekly infusions until the histology reverses towards normality. In alternative embodiments, of the methods the infection, disease, treatment, poisoning or condition having a bowel dysfunction component or side-effect comprises an inflammatory bowel disease (IBD), Crohn's disease, hepatic encephalopathy, enteritis, colitis, Irritable Bowel Syndrome (IBS), fibromyalgia (FM), chronic fatigue syndrome (CFS), depression, attention deficit/hyperactivity disorder (ADHD), multiple sclerosis (MS), systemic lupus erythematosus (SLE), travellers' diarrhea, small intestinal bacterial overgrowth, chronic pancreatitis, a pancreatic insufficiency, exposure to a poison or a toxin or for an infection, a toxin-mediated travellers diarrhea, a poisoning, a pseudomembranous colitis, a Clostridium infection, a C. perfringens welchii or a Clostridium difficile infection, a neurological condition, Parkinson's disease, myoclonus dystonia, autism, amyotrophic lateral sclerosis, multiple sclerosis, Grand mal seizures or petit mal seizures. In alternative embodiments, the amount of the treated or untreated fecal sample, or the partially, substantially or completely isolated or purified fecal flora, is formulated for or calibrated for repeat or multiple delivery or infusions; or the treated or untreated fecal sample or the partially, substantially or completely isolated or purified fecal flora is delivered in repeated or multiple infusions, wherein optionally the repeated or multiple administration, delivery, infusion or implantation protocol comprises infusions done daily for the first about 10 days, second daily for about 10 days, third daily then fourth daily possibly weekly and then optionally maintain second or more weekly infusions until the histology reverses towards normality. In alternative embodiments, the invention provides delivery vehicles, formulations, pharmaceutical preparations, products of manufacture, containers or devices comprising: (a) an entire (or substantially entire) microbiota, a partially, substantially or completely isolated or purified fecal flora, or a composition comprising a fecal flora substantially or completely purified of non-fecal floral fecal material, and optionally further comprising an excipient, or a fluid, a saline, a buffer, a buffering agent or a media, or a fluid-glucose-cellobiose agar (RGCA) media; (b) the composition, container or device, formulation, or product of manufacture of (a), wherein the entire (or substantially entire) microbiota or the fecal flora is isolated or purified from a human or an animal fecal material; (c) the composition, container or device, formulation, or product of manufacture of (a) or (b), wherein the entire (or substantially entire) microbiota or the fecal flora is isolated or purified using a method or protocol comprising use of a centrifuge, a centrifuge, a column or an immuno-affinity column, or wherein the entire (or substantially entire) microbiota or the fecal flora is isolated or purified by a method comprising homogenizing, centrifuging and/or filtering a rough particulate matter or a non-floral matter of the fecal material, or by plasmapheresis, centrifugation, centrifuge, column chromatography (e.g., affinity chromatography), immunoprecipitation (e.g., antibodies fixed to a solid surface, such as beads or a plate); (d) the composition, container or device, formulation, or product of manufacture of any of (a) to (c), wherein the entire (or substantially entire) microbiota or the substantially or completely isolated or purified fecal flora, or the fecal flora substantially or completely purified of non-fecal floral fecal material, is in a substantially or completely oxygen-free environment in the composition, container or device, formulation, or product of manufacture; (e) the delivery vehicle, formulation, container or device of (d), wherein the composition, container or device, formulation, or product of manufacture is made substantially or completely oxygen free by: incorporating into the delivery vehicle, formulation, container or device a built in or clipped-on oxygen-scavenging mechanism; and/or, the delivery vehicle, formulation, container or device comprises or is coated with an oxygen scavenging material; and/or completely or substantially replacing the air in the delivery vehicle, formulation, container or device with nitrogen and/or other inert non-reactive gas or gases; (f) the composition, container or device, formulation, or product of manufacture of any of (a) to (c), wherein the entire (or substantially entire) microbiota, the substantially or completely isolated or purified fecal flora, or the fecal flora substantially or completely purified of non-fecal floral fecal material, is in a substantially or completely anaerobic environment; (g) the composition, container or device, formulation, or product of manufacture of any of (a) to (f), wherein the delivery vehicle, formulation, container or device is manufactured, labelled or formulated for human or animal use; (h) the composition, container or device, formulation, or product of manufacture of (g), wherein the animal use is for a veterinary use; (i) the composition, container or device, formulation, or product of manufacture of any of (a) to (h), wherein a stabilizing agent or a glycerol is added to, or mixed into, the entire (or substantially entire) microbiota, or the partially, substantially or completely isolated or purified fecal flora, or the composition comprising a fecal flora substantially or completely purified of non-fecal floral fecal material, before storage or freezing, freeze-drying, spray-drying or lyophilizing; (j) the composition, container or device, formulation, or product of manufacture of any of (a) to (f), wherein the composition, container or device, formulation, or product of manufacture is initially manufactured or formulated as a liquid, a suspension, a gel, a geltab, a semisolid, a tablet, a sachet, a lozenge or a capsule, or as an enteral formulation, or re-formulated for final delivery as a liquid, a suspension, a gel, a geltab, a semisolid, a tablet, a sachet, a lozenge or a capsule, or as an enteral formulation; (k) the composition, container or device, formulation, or product of manufacture of any of (a) to (j), wherein the entire (or substantially entire) microbiota, or the partially, substantially or completely isolated or purified fecal flora, or the composition comprising a fecal flora substantially or completely purified of non-fecal floral fecal material, is lyophilized, freeze-dried, in powder form, or frozen; (l) the composition, container or device, formulation, or product of manufacture of any of (a) to (k), wherein the entire (or substantially entire) microbiota or the fecal flora is initially derived from an individual screened or tested for a disease or infection, and/or the entire (or substantially entire) microbiota or the fecal flora is initially derived from an individual screened to have a normal, healthy or wild type population of fecal flora; or (m) the composition, container or device, formulation, or product of manufacture of any of (a) to (l), further comprising adding to the entire (or substantially entire) microbiota, the partially, substantially or completely isolated or purified fecal flora, or a composition comprising a fecal flora substantially or completely purified of non-fecal floral fecal material, or adding to a liquid or solution used to isolate or purity, store, freeze, freeze-dry, spray-dry, lyophilize, transport, reconstitute and/or deliver a treated or untreated fecal flora: a saline, a media, a defoaming agent, a surfactant agent, a lubricant, an acid neutralizer, a marker, a cell marker, a drug, an antibiotic, a contrast agent, a dispersal agent, a buffer or a buffering agent, a sweetening agent, a debittering agent, a flavouring agent, a pH stabilizer, an acidifying agent, a preservative, a desweetening agent and/or colouring agent, and/or at least one vitamin, mineral and/or dietary supplement, wherein optionally the vitamin comprises a thiamine, riboflavin, nicotinic acid, pantothenic acid, pyridoxine, biotin, folic acid, vitamin B 12 , lipoic acid, ascorbic acid, vitamin A, vitamin D, vitamin E, vitamin K, a choline, a camitine, and/or an alpha, beta and/or gamma carotene, and/or a prebiotic nutrient, wherein optionally the prebiotic comprises any ingredient that stimulates the stability, growth and/or activity of the entire (or substantially entire) microbiota or the fecal flora or fecal bacteria, or optionally comprises polyols, fructooligosaccharides (FOSs), oligofructoses, inulins, galactooligosaccharides (GOSs), xylooligosaccharides (XOSs), polydextroses, monosaccharides, tagatose, and/or mannooligosaccharides; (n) the composition, container or device, formulation, or product of manufacture of any of (a) to (m), wherein a substantially isolated or a purified fecal flora is (comprises) an isolate of the entire (or substantially entire) microbiota or fecal flora that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9% isolated or pure, or having no more than about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% or 1.0% or more non-fecal floral material; or (m) the composition, container or device, formulation, or product of manufacture of any of (a) to (l), wherein the amount of the entire (or substantially entire) microbiota or the treated or untreated fecal sample, or the partially, substantially or completely isolated or purified fecal flora is formulated for or calibrated for repeat or multiple delivery or infusions, wherein optionally the repeated or multiple administration, delivery, infusion or implantation protocol comprises infusions done daily for the first about 10 days, second daily for about 10 days, third daily then fourth daily possibly weekly and then optionally maintain second or more weekly infusions until the histology reverses towards normality. In alternative embodiments, the invention provides methods for the amelioration, stabilization, treatment and/or prevention of an infection, disease, treatment, poisoning or a condition having a bowel dysfunction component or side-effect comprising administering to an individual in need thereof a composition, container or device, formulation, or product of manufacture of the invention. In alternative embodiments, of the methods the infection, disease, treatment, poisoning or condition having a bowel dysfunction component or side-effect comprises an inflammatory bowel disease (IED), Crohn's disease, hepatic encephalopathy, enteritis, colitis, irritable bowel syndrome (IES), fibromyalgia (FM), chronic fatigue syndrome (CFS), depression, attention deficit/hyperactivity disorder (ADHD), multiple sclerosis (MS), systemic lupus erythematosus (SLE), travellers' diarrhea, small intestinal bacterial overgrowth, chronic pancreatitis, a pancreatic insufficiency, exposure to a poison or a toxin or for an infection, a toxin-mediated travellers diarrhea, a poisoning, a pseudomembranous colitis, a Clostridium infection, a C. perfringens welchii or a Clostridium difficile infection, a neurological condition, Parkinson's disease, myoclonus dystonia, autism, amyotrophic lateral sclerosis, multiple sclerosis, Grand mal seizures or petit mal seizures. In alternative embodiments, the invention provides methods for the amelioration, stabilization, treatment and/or prevention of, or decreasing or delaying the symptoms of, an infection, disease, treatment, poisoning or a condition having a bowel dysfunction component or side-effect, or for the amelioration, treatment and/or prevention of a constipation, for the treatment of an abdominal pain, a non-specific abdominal pain or a diarrhea, a diarrhea caused by: a drug side effect or a psychological condition or Crohn's Disease, a poison, a toxin or an infection, a toxin-mediated traveller's diarrhea, or a Clostridium or a C. perfringens welchii or a C. difficile infection or a pseudo-membranous colitis associated with a Clostridium infection, or for preventing, decreasing or delaying the symptoms of, ameliorating stabilizing, or treating individuals (e.g., patients or animals) with spondyloarthropathy, spondylarthritis or sacrolileitis (an inflammation of one or both sacroiliac joints); a nephritis syndrome; an inflammatory or an autoimmune condition having a gut or an intestinal component such as lupus, irritable bowel syndrome (IBS or spastic colon) or a colitis such as Ulcerative Colitis or Crohn's Colitis; constipation, autism; degenerative neurological diseases such as amyotrophic lateral sclerosis (ALS), Multiple Sclerosis (MS) or Parkinson's Disease (PD); a Myoclonus Dystonia (e.g., Steinert's disease or proximal myotonic myopathy); an autoimmune disease such as Rheumatoid Arthritis (RA) or juvenile idiopathic arthritis (JIA); Chronic Fatigue Syndrome (including benign myalgic encephalomyelitis, chronic fatigue immune dysfunction syndrome, chronic infectious mononucleosis, epidemic myalgic encephalomyelitis); obesity; hypoglycemia, pre-diabetic syndrome, type I diabetes or type II diabetes; Idiopathic thrombocytopenic purpura (ITP); an acute or chronic allergic reaction such as hives, a rash, a urticaria or a chronic urticaria; and/or insomnia or chronic insomnia, Grand mal seizures or petit mal seizures, comprising: administering to an individual in need thereof a delivery vehicle, formulation, pharmaceutical preparation, product of manufacture, container or device of the invention, or a product (article) of manufacture of the invention, in single, repeat or multiple administrations, deliveries or infusions. In alternative embodiments, the amount of the entire (or substantially entire) microbiota, the treated or untreated fecal sample, or the partially, substantially or completely isolated or purified fecal flora, is formulated for or calibrated for repeat or multiple delivery or infusions; or the entire (or substantially entire) microbiota, the treated or untreated fecal sample or the partially, substantially or completely isolated or purified fecal flora is delivered in repeated or multiple infusions, wherein optionally the repeated or multiple administration, delivery, infusion or implantation protocol comprises infusions done daily for the first about 10 days, second daily for about 10 days, third daily then fourth daily possibly weekly and then optionally maintain second or more weekly infusions until the histology reverses towards normality. In alternative embodiments, the invention provides devices for delivering a (bacterial flora-comprising) composition of the invention, or an entire (or substantially entire) microbiota or a fecal material comprising: (a) a device as illustrated in FIG. 1 or FIG. 2 , or equivalent thereof; or (b) (1) a bag or container comprising an exit aperture operably connected to the proximal end of a flexible tube or equivalent, wherein the bag or container is optionally made of a material impervious to a gas or to oxygen, and optionally the bag or container is made of a flexible material, or a polyethylene terephthalate polyester film-comprising (or a MYLAR™-comprising) material, and optionally the bag or container is an (IV-like) intravenous-like bag, and optionally the bag or container has an attachment that will allow the bag to be hung on a stand, e.g., to be positioned/hung above an endoscope, and optionally the bag or container is operably connected via an open or close valve or equivalent to a negative pressure device that can remove all gas or air from the bag, and optionally the bag or container is operably connected via an open or close valve or equivalent to a fluid source or storage container for flushing out the bag through the exit aperture, and optionally the fluid source or storage container is under positive pressure, and optionally the flexible tube or equivalent comprises at least one clip or close valve or one way valve to prevent backwash of material from distal to proximal portions of the tube, or from the tube back to the bag or container; (2) an open or close valve or equivalent or an obdurator screwtop at the distal end of the flexible tube or equivalent, and optionally a Luer lock tip for attachment to a colonoscope or an endoscopic Luer lock port or equivalent, wherein optionally the Luer lock tip is built into the valve, or is separate from the valve, and optionally an enema tube tip for attachment to an enema tube or device or equivalent, wherein optionally the enema tube tip is built into the valve, or is separate from the valve, and optionally further comprising a safety device or safety clip to close the distal aperture in case the valve or Luer lock tip, or enema tip, is lost (flies off) under pressure; and (3) a pump, or a hand pump, for moving material in the bag or container through the flexible tube or equivalent and out the distal end or out the open or close valve or equivalent; or (c) the device of (a) or (b), further comprising a fecal material or a composition of the invention. In alternative embodiments, the invention provides bags or containers comprising an entire (or substantially entire) microbiota, or a treated or untreated fecal flora, or a partially, substantially or completely isolated fecal flora, or a composition of the invention (e.g., a formulation comprising an entire (or substantially entire) microbiota, a partially, substantially or completely isolated or purified fecal flora, or a composition comprising a fecal flora substantially or completely purified of non-fecal floral fecal material), and optionally further comprising an excipient, or a fluid, a saline, a buffer, a buffering agent or a media, or a fluid-glucose-cellobiose agar (RGCA) media, wherein the bag or container is structurally the same as or similar to a bag or container of a device of the invention (e.g., as illustrated in FIG. 1 or FIG. 2 ), wherein optionally the interior of the bag is substantially or completely an oxygen-free environment, or the interior of the bag is substantially or completely similar to an anaerobic environment. In alternative embodiments, specific anti C. difficile oral antibodies (for example avian) can be added to a solution (e.g., a saline, media, buffer) used to isolate or purify, store, freeze, freeze-dry, spray-dry lyophilize, transport, reconstitute and/or deliver a composition (e.g., a partially, substantially or completely isolated or purified fecal flora, or a composition comprising a fecal flora substantially or completely purified of non-fecal floral fecal material) of the invention. The combination of the product with these specific anti C. difficile oral antibodies enhances the eradication mechanism of the product. The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims. All publications, patents, patent applications cited herein are hereby expressly incorporated by reference for all purposes. | A61K3574 | 20171012 | 20180508 | 20180208 | 99854.0 | A61K3574 | 1 | PAGUIO FRISING, MICHELLE F | Compositions for Fecal Floral Transplantation and Methods for Making and Using Them and Devices for Delivering Them | UNDISCOUNTED | 1 | CONT-ACCEPTED | A61K | 2,017 |
15,782,980 | PENDING | METHOD OF DETECTING AND/OR IDENTIFYING ADENO-ASSOCIATED VIRUS (AAV) SEQUENCES AND ISOLATING NOVEL SEQUENCES IDENTIFIED THEREBY | Adeno-associated virus rh.10 sequences, vectors containing same, and methods of use are provided. | 1. A method for delivering a transgene product to a subject, said method comprising administering an adeno-associated virus (AAV) comprising an AAV capsid comprising vp1, vp2 and vp3 proteins, said vp3 having the amino acid sequence of 204 to 738 of SEQ ID NO: 81 or an AAV vp3 protein having a sequence at least 95% identical to the full length amino acid sequence of 204 to 738 of SEQ ID NO: 81, said AAV having packaged in the capsid a nucleic acid molecule comprising at least one AAV inverted terminal repeat (ITR) and a non-AAV nucleic acid sequence which encodes a gene product operably linked to sequences which direct expression thereof in a host cell. 2. The method according to claim 1, wherein the AAVrh10 capsid comprises vp1 proteins having an amino acid sequence of about amino acids 1 to 738 of SEQ ID NO:81. 3. The method according to claim 1, wherein the sequence is at least 97% identical to the vp1 and/or vp3 of SEQ ID NO: 81 4. The method according to claim 1, wherein the sequence is at least 99% identical to the vp1 and/or vp3 of SEQ ID NO: 81. 5. The method according to claim 1, wherein the vp2 protein has an amino acid sequence of about amino acids 138 to 738 of SEQ ID NO:81. 6. The method according to claim 1, wherein the gene product is a vascular endothelial growth factor (VEGF). 7. The method according to claim 1, wherein the gene product is selected from β-glucuronidase (GUSB) and alpha-1 antitrypsin (A1AT). 8. The method according to claim 1, wherein the gene product is a factor IX protein. 9. The method according to claim 1, wherein the gene product is a factor VIII protein. 10. The method according to claim 1, wherein the gene product is erythropoietin. 11. An isolated capsid protein comprising an AAVrh10 protein selected from the group consisting of: vp1 capsid protein, amino acids (aa) 1 to 738 of SEQ ID NO: 81; vp2 capsid protein, aa 138 to 738 of SEQ ID NO: 81; and vp3 capsid protein, aa 203 to 738 of SEQ ID NO: 81. 12. An isolated or synthetic nucleic acid molecule encoding a protein according to claim 11. 13. An isolated or synthetic nucleic acid molecule encoding a fragment of an adeno-associated virus rh10 capsid protein, said nucleic acid molecule selected from the group consisting of: vp1, nt 845 to 3061 of SEQ ID NO:59; vp2, nt 1256 to 3061 of SEQ ID NO:59; and vp3, nt 1454 to 3061 of SEQ ID NO:59. 14. A molecule according to claim 12, wherein said molecule is a plasmid. 15. A molecule according to claim 12, wherein said molecule further comprises a functional AAV rep gene. 16. A method of generating a recombinant adeno-associated virus (AAV) comprising an AAV serotype rh10 capsid comprising the steps of culturing a host cell containing: (a) a molecule according to claim 12 which encodes an adeno-associated virus capsid; (b) a functional rep gene; (c) a minigene comprising AAV inverted terminal repeats (ITRs) and a transgene; and (d) sufficient helper functions to permit packaging of the minigene into the AAV capsid protein. 17. An in vitro host cell transfected with an adeno-associated virus according to claim 1. 18. A composition comprising an AAV according to claim 1, and a physiologically compatible carrier. 19. A composition comprising a molecule according to claim 12, and a physiologically compatible carrier. | CROSS-REFERENCE TO RELATED APPLICATIONS This is a divisional of U.S. patent application Ser. No. 13/633,971, filed Oct. 3, 2012, which is a divisional of U.S. patent application Ser. No. 12/962,793, filed Dec. 8, 2010, now U.S. Pat. No. 8,524,446, issued Sep. 3, 2013, which is a continuation of U.S. patent application Ser. No. 10/291,583, filed Nov. 12, 2002, now abandoned, which claims the benefit under 35 USC 119(e) of U.S. Provisional Patent Application No. 60/386,675, filed Jun. 5, 2002, U.S. Provisional Patent Application No. 60/377,066, filed May 1, 2002, U.S. Provisional Patent Application No. 60/341,117, filed Dec. 17, 2001, and U.S. Provisional Patent Application No. 60/350,607, filed Nov. 13, 2001. These applications are incorporated by reference herein. BACKGROUND OF THE INVENTION Adeno-associated virus (AAV), a member of the Parvovirus family, is a small nonenveloped, icosahedral virus with single-stranded linear DNA genomes of 4.7 kilobases (kb) to 6 kb. AAV is assigned to the genus, Dependovirus, because the virus was discovered as a contaminant in purified adenovirus stocks. AAV's life cycle includes a latent phase at which AAV genomes, after infection, are site specifically integrated into host chromosomes and an infectious phase in which, following either adenovirus or herpes simplex virus infection, the integrated genomes are subsequently rescued, replicated, and packaged into infectious viruses. The properties of non-pathogenicity, broad host range of infectivity, including non-dividing cells, and potential site-specific chromosomal integration make AAV an attractive tool for gene transfer. Recent studies suggest that AAV vectors may be the preferred vehicle for gene therapy. To date, there have been 6 different serotypes of AAVs isolated from human or non-human primates (NHP) and well characterized. Among them, human serotype 2 is the first AAV that was developed as a gene transfer vector; it has been widely used for efficient gene transfer experiments in different target tissues and animal models. Clinical trials of the experimental application of AAV2 based vectors to some human disease models are in progress, and include such diseases as cystic fibrosis and hemophilia B. What are desirable are AAV-based constructs for gene delivery. SUMMARY OF THE INVENTION In one aspect, the invention provides a novel method of detecting and identifying AAV sequences from cellular DNAs of various human and non-human primate (NHP) tissues using bioinformatics analysis, PCR based gene amplification and cloning technology, based on the nature of latency and integration of AAVs in the absence of helper virus co-infection. In another aspect, the invention provides method of isolating novel AAV sequences detected using the above described method of the invention. The invention further comprises methods of generating vectors based upon these novel AAV serotypes, for serology and gene transfer studies solely based on availability of capsid gene sequences and structure of rep/cap gene junctions. In still another aspect, the invention provides a novel method for performing studies of serology, epidemiology, biodistribution and mode of transmission, using reagents according to the invention, which include generic sets of primers/probes and quantitative real time PCR. In yet another aspect, the invention provides a method of isolating complete and infectious genomes of novel AAV serotypes from cellular DNA of different origins using RACE and other molecular techniques. In a further aspect, the invention provides a method of rescuing novel serotypes of AAV genomes from human and NHP cell lines using adenovirus helpers of different origins. In still a further aspect, the invention provides novel AAV serotypes, vectors containing same, and methods of using same. These and other aspects of the invention will be readily apparent from the following detailed description of the invention. BRIEF DESCRIPTION OF THE DRAWINGS FIGS. 1A through 1AAAR provide an alignment of the nucleic acid sequences encoding at least the cap proteins for the AAV serotypes. The full-length sequences including the ITRs, the rep region, and the capsid region are provided for novel AAV serotype 7 [SEQ ID NO: 1], and for previously published AAV1 [SEQ IN NO:6], AAV2 [SEQ ID NO:7]; and AAV3 [SEQ ID NO:8]. Novel AAV serotypes AAV8 [SEQ ID NO:4] and AAV9 [SEQ ID NO:5] are the subject of co-filed applications. The other novel clones of the invention provided in this alignment include: 42-2 [SEQ ID NO:9], 42-8 [SEQ ID NO:27], 42-15 [SEQ ID NO:28], 42-5b [SEQ ID NO: 29], 42-1b [SEQ ID NO:30]; 42-13 [SEQ ID NO: 31], 42-3a [SEQ ID NO: 32], 42-4 [SEQ ID NO:33], 42-5a [SEQ ID NO: 34], 42-10 [SEQ ID NO:35], 42-3b [SEQ ID NO: 36], 42-11 [SEQ ID NO: 37], 42-6b [SEQ ID NO:38], 43-1 [SEQ ID NO: 39], 43-5 [SEQ ID NO: 40], 43-12 [SEQ ID NO:41], 43-20 [SEQ ID NO:42], 43-21 [SEQ ID NO: 43], 43-23 [SEQ ID NO:44], 43-25 [SEQ ID NO: 45], 44.1 [SEQ ID NO:47], 44.5 [SEQ ID NO:47], 223.10 [SEQ ID NO:48], 223.2 [SEQ ID NO:49], 223.4 [SEQ ID NO:50], 223.5 [SEQ ID NO: 51], 223.6 [SEQ ID NO: 52], 223.7 [SEQ ID NO: 53], A3.4 [SEQ ID NO: 54], A3.5 [SEQ ID NO:55], A3.7 [SEQ ID NO: 56], A3.3 [SEQ ID NO:57], 42.12 [SEQ ID NO: 58], 44.2 [SEQ ID NO: 59]. The nucleotide sequences of the signature regions of AAV10 [SEQ ID NO: 117], AAV11 [SEQ ID NO: 118] and AAV12 [SEQ ID NO: 119] are provided in this figure. Critical landmarks in the structures of AAV genomes are shown. Gaps are demonstrated by dots. The 3′ ITR of AAV1 [SEQ ID NO:6] is shown in the same configuration as in the published sequences. TRS represents terminal resolution site. Notice that AAV7 is the only AAV reported that uses GTG as the initiation codon for VP3. FIGS. 2A through 2M are an alignment of the amino acid sequences of the proteins of the vp1 capsid proteins of previously published AAV serotypes 1 [SEQ ID NO:64], AAV2 [SEQ ID NO:70], AAV3 [SEQ ID NO: 71], AAV4 [SEQ ID NO:63], AAV5 [SEQ ID NO: 114], and AAV6 [SEQ ID NO:65] and novel AAV sequences of the invention, including: C1 [SEQ ID NO:60], C2 [SEQ ID NO:61], C5 [SEQ ID NO:62], A3-3 [SEQ ID NO:66], A3-7 [SEQ ID NO:67], A3-4 [SEQ ID NO:68], A3-5 [SEQ ID NO: 69], 3.3b [SEQ ID NO: 62], 223.4 [SEQ ID NO: 73], 223-5 [SEQ ID NO:74], 223-10 [SEQ ID NO:75], 223-2 [SEQ ID NO:76], 223-7 [SEQ ID NO: 77], 223-6 [SEQ ID NO: 78], 44-1 [SEQ ID NO: 79], 44-5 [SEQ ID NO:80], 44-2 [SEQ ID NO:81], 42-15 [SEQ ID NO: 84], 42-8 [SEQ ID NO: 85], 42-13 [SEQ ID NO:86], 42-3A [SEQ ID NO:87], 42-4 [SEQ ID NO:88], 42-5A [SEQ ID NO:89], 42-1B [SEQ ID NO:90], 42-5B [SEQ ID NO:91], 43-1 [SEQ ID NO: 92], 43-12 [SEQ ID NO: 93], 43-5 [SEQ ID NO:94], 43-21 [SEQ ID NO:96], 43-25 [SEQ ID NO: 97], 43-20 [SEQ ID NO:99], 24.1 [SEQ ID NO: 101], 42.2 [SEQ ID NO: 102], 7.2 [SEQ ID NO: 103], 27.3 [SEQ ID NO: 104], 16.3 [SEQ ID NO: 105], 42.10 [SEQ ID NO: 106], 42-3B [SEQ ID NO: 107], 42-11 [SEQ ID NO: 108], F1 [SEQ ID NO: 109], F5 [SEQ ID NO: 110], F3 [SEQ ID NO: 111], 42-6B [SEQ ID NO: 112], 42-12 [SEQ ID NO: 113]. Novel serotypes AAV8 [SEQ ID NO:95] and AAV9 [SEQ ID NO: 100] are the subject of co-filed patent applications. FIGS. 3A through 3C provide the amino acid sequences of the AAV7 rep proteins [SEQ ID NO:3]. DETAILED DESCRIPTION OF THE INVENTION In the present invention, the inventors have found a method which takes advantage of the ability of adeno-associated virus (AAV) to penetrate the nucleus, and, in the absence of a helper virus co-infection, to integrate into cellular DNA and establish a latent infection. This method utilizes a polymerase chain reaction (PCR)-based strategy for detection, identification and/or isolation of sequences of AAVs from DNAs from tissues of human and non-human primate origin as well as from other sources. Advantageously, this method is also suitable for detection, identification and/or isolation of other integrated viral and non-viral sequences, as described below. The invention further provides nucleic acid sequences identified according to the methods of the invention. One such adeno-associated virus is of a novel serotype, termed herein serotype 7 (AAV7). Other novel adeno-associated virus serotypes provided herein include AAV10, AAV11, and AAV12. Still other novel AAV serotypes identified according to the methods of the invention are provided in the present specification. See, Figures and Sequence Listing, which is incorporated by reference. Also provided are fragments of these AAV sequences. Among particularly desirable AAV fragments are the cap proteins, including the vp1, vp2, vp3, the hypervariable regions, the rep proteins, including rep 78, rep 68, rep 52, and rep 40, and the sequences encoding these proteins. Each of these fragments may be readily utilized in a variety of vector systems and host cells. Such fragments may be used alone, in combination with other AAV sequences or fragments, or in combination with elements from other AAV or non-AAV viral sequences. In one particularly desirable embodiment, a vector contains the AAV cap and/or rep sequences of the invention. As described herein, alignments are performed using any of a variety of publicly or commercially available Multiple Sequence Alignment Programs, such as AClustal W≅, accessible through Web Servers on the internet. Alternatively, Vector NTI utilities are also used. There are also a number of algorithms known in the art which can be used to measure nucleotide sequence identity, including those contained in the programs described above. As another example, polynucleotide sequences can be compared using Fasta, a program in GCG Version 6.1. Fasta provides alignments and percent sequence identity of the regions of the best overlap between the query and search sequences. For instance, percent sequence identity between nucleic acid sequences can be determined using Fasta with its default parameters (a word size of 6 and the NOPAM factor for the scoring matrix) as provided in GCG Version 6.1, herein incorporated by reference. Similar programs are available for amino acid sequences, e.g., the “Clustal X” program. Generally, any of these programs are used at default settings, although one of skill in the art can alter these settings as needed. Alternatively, one of skill in the art can utilize another algorithm or computer program which provides at least the level of identity or alignment as that provided by the referenced algorithms and programs. The term “substantial homology” or “substantial similarity,” when referring to a nucleic acid, or fragment thereof, indicates that, when optimally aligned with appropriate nucleotide insertions or deletions with another nucleic acid (or its complementary strand), there is nucleotide sequence identity in at least about 95 to 99% of the aligned sequences. Preferably, the homology is over full-length sequence, or an open reading frame thereof, or another suitable fragment which is at least 15 nucleotides in length. Examples of suitable fragments are described herein. The term “substantial homology” or “substantial similarity,” when referring to amino acids or fragments thereof, indicates that, when optimally aligned with appropriate amino acid insertions or deletions with another amino acid, there is amino acid sequence identity in at least about 95 to 99% of the aligned sequences. Preferably, the homology is over full-length sequence, or a protein thereof, e.g., a cap protein, a rep protein, or a fragment thereof which is at least 8 amino acids, or more desirably, at least 15 amino acids in length. Examples of suitable fragments are described herein. By the term “highly conserved” is meant at least 80% identity, preferably at least 90% identity, and more preferably, over 97% identity. Identity is readily determined by one of skill in the art by resort to algorithms and computer programs known by those of skill in the art. The term “percent sequence identity” or “identical” in the context of nucleic acid sequences refers to the residues in the two sequences which are the same when aligned for maximum correspondence. The length of sequence identity comparison may be over the full-length of the genome, the full-length of a gene coding sequence, or a fragment of at least about 500 to 5000 nucleotides, is desired. However, identity among smaller fragments, e.g. of at least about nine nucleotides, usually at least about 20 to 24 nucleotides, at least about 28 to 32 nucleotides, at least about 36 or more nucleotides, may also be desired. Similarly, “percent sequence identity” may be readily determined for amino acid sequences, over the full-length of a protein, or a fragment thereof. Suitably, a fragment is at least about 8 amino acids in length, and may be up to about 700 amino acids. Examples of suitable fragments are described herein. The AAV sequences and fragments thereof are useful in production of rAAV, and are also useful as antisense delivery vectors, gene therapy vectors, or vaccine vectors. The invention further provides nucleic acid molecules, gene delivery vectors, and host cells which contain the AAV sequences of the invention. As described herein, the vectors of the invention containing the AAV capsid proteins of the invention are particularly well suited for use in applications in which the neutralizing antibodies diminish the effectiveness of other AAV serotype based vectors, as well as other viral vectors. The rAAV vectors of the invention are particularly advantageous in rAAV readministration and repeat gene therapy. These and other embodiments and advantages of the invention are described in more detail below. As used throughout this specification and the claims, the terms Acomprising≅ and “including” and their variants are inclusive of other components, elements, integers, steps and the like. Conversely, the term “consisting” and its variants is exclusive of other components, elements, integers, steps and the like. I. Methods of the Invention A. Detection of Sequences Via Molecular Cloning In one aspect, the invention provides a method of detecting and/or identifying target nucleic acid sequences in a sample. This method is particularly well suited for detection of viral sequences which are integrated into the chromosome of a cell, e.g., adeno-associated viruses (AAV) and retroviruses, among others. The specification makes reference to AAV, which is exemplified herein. However, based on this information, one of skill in the art may readily perform the methods of the invention on retroviruses [e.g., feline leukemia virus (FeLV), HTLVI and HTLVII], and lentivirinae [e.g., human immunodeficiency virus (HIV), simian immunodeficiency virus (SIV), feline immunodeficiency virus (FIV), equine infectious anemia virus, and spumavirinal)], among others. Further, the method of the invention may also be used for detection of other viral and non-viral sequences, whether integrated or non-integrated into the genome of the host cell. As used herein, a sample is any source containing nucleic acids, e.g., tissue, tissue culture, cells, cell culture, and biological fluids including, without limitation, urine and blood. These nucleic acid sequences may be DNA or RNA from plasmids, natural DNA or RNA from any source, including bacteria, yeast, viruses, and higher organisms such as plants or animals. DNA or RNA is extracted from the sample by a variety of techniques known to those of skill in the art, such as those described by Sambrook, Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory). The origin of the sample and the method by which the nucleic acids are obtained for application of the method of the invention is not a limitation of the present invention. Optionally, the method of the invention can be performed directly on the source of DNA, or on nucleic acids obtained (e.g., extracted) from a source. The method of the invention involves subjecting a sample containing DNA to amplification via polymerase chain reaction (PCR) using a first set of primers specific for a first region of double-stranded nucleic acid sequences, thereby obtaining amplified sequences. As used herein, each of the Aregions≅ is predetermined based upon the alignment of the nucleic acid sequences of at least two serotypes (e.g., AAV) or strains (e.g., lentiviruses), and wherein each of said regions is composed of sequences having a 5′ end which is highly conserved, a middle which is preferably, but necessarily, variable, and a 3′ end which is highly conserved, each of these being conserved or variable relative to the sequences of the at least two aligned AAV serotypes. Preferably, the 5′ and/or 3′ end is highly conserved over at least about 9, and more preferably, at least 18 base pairs (bp). However, one or both of the sequences at the 5= or 3=end may be conserved over more than 18 bp, more than 25 bp, more than 30 bp, or more than 50 bp at the 5′ end. With respect to the variable region, there is no requirement for conserved sequences, these sequences may be relatively conserved, or may have less than 90, 80, or 70% identity among the aligned serotypes or strains. Each of the regions may span about 100 bp to about 10 kilobase pairs in length. However, it is particularly desirable that one of the regions is a Asignature region≅, i.e., a region which is sufficiently unique to positively identify the amplified sequence as being from the target source. For example, in one embodiment, the first region is about 250 bp in length, and is sufficiently unique among known AAV sequences, that it positively identifies the amplified region as being of AAV origin. Further, the variable sequences within this region are sufficiently unique that can be used to identify the serotype from which the amplified sequences originate. Once amplified (and thereby detected), the sequences can be identified by performing conventional restriction digestion and comparison to restriction digestion patterns for this region in any of AAV1, AAV2, AAV3, AAV4, AAV5, or AAV6, or that of AAV7, AAV10, AAV11, AAV12, or any of the other novel serotypes identified by the invention, which is predetermined and provided by the present invention. Given the guidance provided herein, one of skill in the art can readily identify such regions among other integrated viruses to permit ready detection and identification of these sequences. Thereafter, an optimal set of generic primers located within the highly conserved ends can be designed and tested for efficient amplification of the selected region from samples. This aspect of the invention is readily adapted to a diagnostic kit for detecting the presence of the target sequence (e.g., AAV) and for identifying the AAV serotype, using standards which include the restriction patterns for the AAV serotypes described herein or isolated using the techniques described herein. For example, quick identification or molecular serotyping of PCR products can be accomplished by digesting the PCR products and comparing restriction patterns. Thus, in one embodiment, the “signature region” for AAV spans about bp 2800 to about 3200 of AAV 1 [SEQ ID NO:6], and corresponding base pairs in AAV 2, AAV3, AAV4, AAV5, and AAV6. More desirably, the region is about 250 bp, located within bp 2886 to about 3143 bp of AAV 1 [SEQ ID NO:6], and corresponding base pairs in AAV 2 [SEQ ID NO:7], AAV3 [SEQ ID NO8], and other AAV serotypes. See, FIG. 1. To permit rapid detection of AAV in the sample, primers which specifically amplify this signature region are utilized. However, the present invention is not limited to the exact sequences identified herein for the AAV signature region, as one of skill in the art may readily alter this region to encompass a shorter fragment, or a larger fragment of this signature region. The PCR primers are generated using techniques known to those of skill in the art. Each of the PCR primer sets is composed of a 5′ primer and a 3′ primer. See, e.g., Sambrook et al, cited herein. The term “primer” refers to an oligonucleotide which acts as a point of initiation of synthesis when placed under conditions in which synthesis of a primer extension product which is complementary to a nucleic acid strand is induced. The primer is preferably single stranded. However, if a double stranded primer is utilized, it is treated to separate its strands before being used to prepare extension products. The primers may be about 15 to 25 or more nucleotides, and preferably at least 18 nucleotides. However, for certain applications shorter nucleotides, e.g., 7 to 15 nucleotides are utilized. The primers are selected to be sufficiently complementary to the different strands of each specific sequence to be amplified to hybridize with their respective strands. Therefore, the primer sequence need not reflect the exact sequence of the region being amplified. For example, a non-complementary nucleotide fragment may be attached to the 5′ end of the primer, with the remainder of the primer sequence being completely complementary to the strand. Alternatively, non-complementary bases or longer sequences can be interspersed into the primer, provided that the primer sequence has sufficient complementarity with the sequence of the strand to be amplified to hybridize therewith and form a template for synthesis of the extension product of the other primer. The PCR primers for the signature region according to the invention are based upon the highly conserved sequences of two or more aligned sequences (e.g., two or more AAV serotypes). The primers can accommodate less than exact identity among the two or more aligned AAV serotypes at the 5′ end or in the middle. However, the sequences at the 3′ end of the primers correspond to a region of two or more aligned AAV serotypes in which there is exact identity over at least five, preferably, over at least nine base pairs, and more preferably, over at least 18 base pairs at the 3′ end of the primers. Thus, the 3′ end of the primers is composed of sequences with 100% identity to the aligned sequences over at least five nucleotides. However, one can optionally utilize one, two, or more degenerate nucleotides at the 3′ end of the primer. For example, the primer set for the signature region of AAV was designed based upon a unique region within the AAV capsid, as follows. The 5′ primer was based upon nt 2867-2891 of AAV2 [SEQ ID NO:7], 5′-GGTAATTCCTCCGGAAATTGGCATT3′. See, FIG. 1. The 3′ primer was designed based upon nt 3096-3122 of AAV2 [SEQ ID NO:7], 5′-GACTCATCAACAACAACTGGGGATTC-3′. However, one of skill in the art may have readily designed the primer set based upon the corresponding regions of AAV 1, AAV3, AAV4, AAV5, AAV6, or based upon the information provided herein, AAV7, AAV10, AAV11, AAV12, or another novel AAV of the invention. In addition, still other primer sets can be readily designed to amplify this signature region, using techniques known to those of skill in the art. B. Isolation of Target Sequences As described herein, the present invention provides a first primer set which specifically amplifies the signature region of the target sequence, e.g., an AAV serotype, in order to permit detection of the target. In a situation in which further sequences are desired, e.g., if a novel AAV serotype is identified, the signature region may be extended. Thus, the invention may further utilize one or more additional primer sets. Suitably, these primer sets are designed to include either the 5′ or 3′ primer of the first primer set and a second primer unique to the primer set, such that the primer set amplifies a region 5′ or 3′ to the signature region which anneals to either the 5′ end or the 3′ end of the signature region. For example, a first primer set is composed of a 5′ primer, P1 and a 3′ primer P2 to amplify the signature region. In order to extend the signature region on its 3′ end, a second primer set is composed of primer P1 and a 3′ primer P4, which amplifies the signature region and contiguous sequences downstream of the signature region. In order to extend the signature region on its 5′ end, a third primer set is composed of a 5′ primer, P5, and primer P2, such that the signature region and contiguous sequences upstream of the signature region are amplified. These extension steps are repeated (or performed at the same time), as needed or desired. Thereafter, the products results from these amplification steps are fused using conventional steps to produce an isolated sequence of the desired length. The second and third primer sets are designed, as with the primer set for the signature region, to amplify a region having highly conserved sequences among the aligned sequences. Reference herein to the term “second” or “third” primer set is for each of discussion only, and without regard to the order in which these primers are added to the reaction mixture, or used for amplification. The region amplified by the second primer set is selected so that upon amplification it anneals at its 5′ end to the 3′ end of the signature region. Similarly, the region amplified by the third primer set is selected so that upon amplification it anneals at its 3′ end anneals to the 5′ end of the signature region. Additional primer sets can be designed such that the regions which they amplify anneal to the either the 5′ end or the 3′ end of the extension products formed by the second or third primer sets, or by subsequent primer sets. For example, where AAV is the target sequence, a first set of primers (P 1 and P2) are used to amplify the signature region from the sample. In one desirable embodiment, this signature region is located within the AAV capsid. A second set of primers (P1 and P4) is used to extend the 3′ end of the signature region to a location in the AAV sequence which is just before the AAV 3′ ITR, i.e., providing an extension product containing the entire 3′ end of the AAV capsid when using the signature region as an anchor. In one embodiment, the P4 primer corresponds to nt 4435 to 4462 of AAV2 [SEQ ID NO:7], and corresponding sequences in the other AAV serotypes. This results in amplification of a region of about 1.6 kb, which contains the 0.25 kb signature region. A third set of primers (P3 and P2) is used to extend the 5′ end of signature region to a location in the AAV sequences which is in the 3′ end of the rep genes, i.e., providing an extension product containing the entire 5′ end of the AAV capsid when using the signature region as an anchor. In one embodiment, the P3 primer corresponds to nt 1384 to 1409 of AAV2 [SEQ ID NO:7], and corresponding sequences in the other AAV serotypes. This results in amplification of a region of about 1.7 kb, which contains the 0.25 kb signature region. Optionally, a fourth set of primers are used to further extend the extension product containing the entire 5′ end of the AAV capsid to also include the rep sequences. In one embodiment, the primer designated P5 corresponds to nt 108 to 133 of AAV2 [SEQ ID NO:7], and corresponding sequences in the other AAV serotypes and is used in conjunction with the P2 primer. Following completion of the desired number of extension steps, the various extension products are fused, making use of the signature region as an anchor or marker, to construct an intact sequence. In the example provided herein, AAV sequences containing, at a minimum, an intact AAV cap gene are obtained. Larger sequences may be obtained, depending upon the number of extension steps performed. Suitably, the extension products are assembled into an intact AAV sequence using methods known to those of skill in the art. For example, the extension products may be digested with DraIII, which cleaves at the DraIII site located within the signature region, to provide restriction fragments which are re-ligated to provide products containing (at a minimum) an intact AAV cap gene. However, other suitable techniques for assembling the extension products into an intact sequence may be utilized. See, generally, Sambrook et al, cited herein. As an alternative to the multiple extension steps described above, another embodiment of the invention provides for direct amplification of a 3.1 kb fragment which allows isolation of full-length cap sequences. To directly amplify a 3.1 kb full-length cap fragment from NHP tissue and blood DNAs, two other highly conserved regions were identified in AAV genomes for use in PCR amplification of large fragments. A primer within a conserved region located in the middle of the rep gene is utilized (AV Ins: 5′ GCTGCGTCAACTGGACCAATGAGAAC 3′, nt of SEQ ID NO:6) in combination with the 3′ primer located in another conserved region downstream of the Cap gene (AV2cas: 5′ CGCAGAGACCAAAGTTCAACTGAAACGA 3′, SEQ ID NO: 7) for amplification of AAV sequences including the full-length AAV cap. Typically, following amplification, the products are cloned and sequence analysis is performed with an accuracy of ≧99.9%. Using this method, the inventors have isolated at least 50 capsid clones which have subsequently been characterized. Among them, 37 clones were derived from Rhesus macaque tissues (rh.1-rh.37), 6 clones from cynomologous macaques (cy.1-cy.6), 2 clones from Baboons (bb.1 and bb.2) and 5 clones from Chimps (ch.1-ch.5). These clones are identified elsewhere in the specification, together with the species of animal from which they were identified and the tissues in that animal these novel sequences have been located. C. Alternative Method for Isolating Novel AAV In another aspect, the invention provides an alternative method for isolating novel AAV from a cell. This method involves infecting the cell with a vector which provides helper functions to the AAV; isolating infectious clones containing AAV; sequencing the isolated AAV; and comparing the sequences of the isolated AAV to known AAV serotypes, whereby differences in the sequences of the isolated AAV and known AAV serotypes indicates the presence of a novel AAV. In one embodiment, the vector providing helper functions provides essential adenovirus functions, including, e.g., E1a, E1b, E2a, E4ORF6. In one embodiment, the helper functions are provided by an adenovirus. The adenovirus may be a wild-type adenovirus, and may be of human or non-human origin, preferably non-human primate (NHP) origin. The DNA sequences of a number of adenovirus types are available from Genbank, including type Ad5 [Genbank Accession No. M73260]. The adenovirus sequences may be obtained from any known adenovirus serotype, such as serotypes 2, 3, 4, 7, 12 and 40, and further including any of the presently identified human types [see, e.g., Horwitz, cited above]. Similarly adenoviruses known to infect non-human animals (e.g., chimpanzees) may also be employed in the vector constructs of this invention. See, e.g., U.S. Pat. No. 6,083,716. In addition to wild-type adenoviruses, recombinant viruses or non-viral vectors (e.g., plasmids, episomes, etc.) carrying the necessary helper functions may be utilized. Such recombinant viruses are known in the art and may be prepared according to published techniques. See, e.g., U.S. Pat. No. 5,871,982 and U.S. Pat. No. 6,251,677, which describe a hybrid Ad/AAV virus. The selection of the adenovirus type is not anticipated to limit the following invention. A variety of adenovirus strains are available from the American Type Culture Collection, Manassas, Va., or available by request from a variety of commercial and institutional sources. Further, the sequences of many such strains are available from a variety of databases including, e.g., PubMed and GenBank. In another alternative, infectious AAV may be isolated using genome walking technology (Siebert et al., 1995, Nucleic Acid Research, 23:1087-1088, Friezner-Degen et al., 1986, J. Biol. Chem. 261:6972-6985, BD Biosciences Clontech, Palo Alto, Calif.). Genome walking is particularly well suited for identifying and isolating the sequences adjacent to the novel sequences identified according to the method of the invention. For example, this technique may be useful for isolating inverted terminal repeat (ITRs) of the novel AAV serotype, based upon the novel AAV capsid and/or rep sequences identified using the methods of the invention. This technique is also useful for isolating sequences adjacent to other AAV and non-AAV sequences identified and isolated according to the present invention. See, Examples 3 and 4. The methods of the invention may be readily used for a variety of epidemiology studies, studies of biodistribution, monitoring of gene therapy via AAV vectors and vector derived from other integrated viruses. Thus, the methods are well suited for use in pre-packaged kits for use by clinicians, researchers, and epidemiologists. II. Diagnostic Kit In another aspect, the invention provides a diagnostic kit for detecting the presence of a known or unknown adeno-associated virus (AAV) in a sample. Such a kit may contain a first set of 5′ and 3′ PCR primers specific for a signature region of the AAV nucleic acid sequence. Alternatively, or additionally, such a kit can contain a first set of 5′ and 3′ PCR primers specific for the 3.1 kb fragment which includes the full-length AAV capsid nucleic acid sequence identified herein (e.g., the AV1ns and AV2cas primers.) Optionally, a kit of the invention may further contain two or more additional sets of 5′ and 3′ primers, as described herein, and/or PCR probes. These primers and probes are used according to the present invention amplify signature regions of each AAV serotype, e.g., using quantitative PCR. The invention further provides a kit useful for identifying an AAV serotype detected according to the method of the invention and/or for distinguishing novel AAV from known AAV. Such a kit may further include one or more restriction enzymes, standards for AAV serotypes providing their “signature restriction enzyme digestions analyses”, and/or other means for determining the serotype of the AAV detected. In addition, kits of the invention may include, instructions, a negative and/or positive control, containers, diluents and buffers for the sample, indicator charts for signature comparisons, disposable gloves, decontamination instructions, applicator sticks or containers, and sample preparator cups, as well as any desired reagents, including media, wash reagents and concentration reagents. Such reagents may be readily selected from among the reagents described herein, and from among conventional concentration reagents. In one desirable embodiment, the wash reagent is an isotonic saline solution which has been buffered to physiologic pH, such as phosphate buffered saline (PBS); the elution reagent is PBS containing 0.4 M NaCl, and the concentration reagents and devices. For example, one of skill in the art will recognize that reagents such as polyethylene glycol (PEG), or NH4SO4 may be useful, or that devices such as filter devices. For example, a filter device with a 100 K membrane would concentrate rAAV. The kits provided by the present invention are useful for performing the methods described herein, and for study of biodistribution, epidemiology, mode of transmission of novel AAV serotypes in human and NHPs. Thus, the methods and kits of the invention permit detection, identification, and isolation of target viral sequences, particularly integrated viral sequences. The methods and kits are particularly well suited for use in detection, identification and isolation of AAV sequences, which may include novel AAV serotypes. In one notable example, the method of the invention facilitated analysis of cloned AAV sequences by the inventors, which revealed heterogeneity of proviral sequences between cloned fragments from different animals, all of which were distinct from the known six AAV serotypes, with the majority of the variation localized to hypervariable regions of the capsid protein. Surprising divergence of AAV sequences was noted in clones isolated from single tissue sources, such as lymph node, from an individual rhesus monkey. This heterogeneity is best explained by apparent evolution of AAV sequence within individual animals due, in part, to extensive homologous recombination between a limited number of co-infecting parenteral viruses. These studies suggest sequence evolution of widely disseminated virus during the course of a natural AAV infection that presumably leads to the formation of swarms of quasispecies which differ from one another in the array of capsid hypervariable regions. This is the first example of rapid molecular evolution of a DNA virus in a way that formerly was thought to be restricted to RNA viruses. Sequences of several novel AAV serotypes identified by the method of the invention and characterization of these serotypes is provided. III. Novel AAV Serotypes A. Nucleic Acid Sequences Nucleic acid sequences of novel AAV serotypes identified by the methods of the invention are provided. See, SEQ ID NO: 1, 9-59, and 117-120, which are incorporated by reference herein. See also, FIG. 1 and the sequence listing. For novel serotype AAV7, the full-length sequences, including the AAV 5′ ITRs, capsid, rep, and AAV 3′ ITRs are provided in SEQ ID NO: 1. For other novel AAV serotypes of the invention, the approximately 3.1 kb fragment isolated according to the method of the invention is provided. This fragment contains sequences encoding full-length capsid protein and all or part of the sequences encoding the rep protein. These sequences include the clones identified below. For still other novel AAV serotypes, the signature region encoding the capsid protein is provided. For example, the AAV10 nucleic acid sequences of the invention include those illustrated in FIG. 1 [See, SEQ ID NO: 117, which spans 255 bases]. The AAV11 nucleic acid sequences of the invention include the DNA sequences illustrated in FIG. 1 [See, SEQ ID NO: 118 which spans 258 bases]. The AAV12 nucleic acid sequences of the invention include the DNA sequences illustrated in FIG. 1 [See, SEQ ID NO: 119, which consists of 255 bases]. Using the methodology described above, further AAV10, AAV11 and AAV12 sequences can be readily identified and used for a variety of purposes, including those described for AAV7 and the other novel serotypes herein. FIG. 1 provides the non-human primate (NHP) AAV nucleic acid sequences of the invention in an alignment with the previously published AAV serotypes, AAV 1 [SEQ ID NO:6], AAV2 [SEQ ID NO:7], and AAV3 [SEQ ID NO:8]. These novel NHP sequences include those provided in the following Table I, which are identified by clone number: TABLE 1 AAV Cap Clone Source SEQ ID NO Sequence Number Species Tissue (DNA) Rh.1 Clone 9 Rhesus Heart 5 (AAV9) Rh.2 Clone 43.1 Rhesus MLN 39 Rh.3 Clone 43.5 Rhesus MLN 40 Rh.4 Clone 43.12 Rhesus MLN 41 Rh.5 Clone 43.20 Rhesus MLN 42 Rh.6 Clone 43.21 Rhesus MLN 43 Rh.7 Clone 43.23 Rhesus MLN 44 Rh.8 Clone 43.25 Rhesus MLN 45 Rh.9 Clone 44.1 Rhesus Liver 46 Rh.10 Clone 44.2 Rhesus Liver 59 Rh.11 Clone 44.5 Rhesus Liver 47 Rh.12 Clone Rhesus MLN 30 42.1B Rh.13 42.2 Rhesus MLN 9 Rh.14 Clone Rhesus MLN 32 42.3A Rh.15 Clone Rhesus MLN 36 42.3B Rh.16 Clone 42.4 Rhesus MLN 33 Rh.17 Clone Rhesus MLN 34 42.5A Rh.18 Clone Rhesus MLN 29 42.5B Rh.19 Clone Rhesus MLN 38 42.6B Rh.20 Clone 42.8 Rhesus MLN 27 Rh.21 Clone 42.10 Rhesus MLN 35 Rh.22 Clone 42.11 Rhesus MLN 37 Rh.23 Clone 42.12 Rhesus MLN 58 Rh.24 Clone 42.13 Rhesus MLN 31 Rh.25 Clone 42.15 Rhesus MLN 28 Rh.26 Clone 223.2 Rhesus Liver 49 Rh.27 Clone 223.4 Rhesus Liver 50 Rh.28 Clone 223.5 Rhesus Liver 51 Rh.29 Clone 223.6 Rhesus Liver 52 Rh.30 Clone 223.7 Rhesus Liver 53 Rh.31 Clone Rhesus Liver 48 223.10 Rh.32 Clone C1 Rhesus Spleen, Duo, 19 Kid & Liver Rh.33 Clone C3 Rhesus 20 Rh.34 Clone C5 Rhesus 21 Rh.35 Clone F1 Rhesus Liver 22 Rh.36 Clone F3 Rhesus 23 Rh.37 Clone F5 Rhesus 24 Cy.1 Clone 1.3 Cyno Blood 14 Cy.2 Clone Cyno Blood 15 13.3B Cy.3 Clone 24.1 Cyno Blood 16 Cy.4 Clone 27.3 Cyno Blood 17 Cy.5 Clone 7.2 Cyno Blood 18 Cy.6 Clone 16.3 Cyno Blood 10 bb.1 Clone 29.3 Baboon Blood 11 bb.2 Clone 29.5 Baboon Blood 13 Ch.1 Clone A3.3 Chimp Blood 57 Ch.2 Clone A3.4 Chimp Blood 54 Ch.3 Clone A3.5 Chimp Blood 55 Ch.4 Clone A3.7 Chimp Blood 56 A novel NHP clone was made by splicing capsids fragments of two chimp adenoviruses into an AAV2 rep construct. This new clone, A3. 1, is also termed Ch.5 [SEQ ID NO:20]. Additionally, the present invention includes two human AAV sequences, termed H6 [SEQ ID NO:25] and H2 [SEQ ID NO:26]. The AAV nucleic acid sequences of the invention further encompass the strand which is complementary to the strands provided in the sequences provided in FIG. 1 and the Sequence Listing [SEQ ID NO: 1, 9-59, 117-120], nucleic acid sequences, as well as the RNA and cDNA sequences corresponding to the sequences provided in FIG. 1 and the Sequence Listing [SEQ ID NO: 1, 9-59, 117-120], and their complementary strands. Also included in the nucleic acid sequences of the invention are natural variants and engineered modifications of the sequences of FIG. 1 and the Sequence Listing [SEQ ID NO:1, 9-59, 117-120], and their complementary strands. Such modifications include, for example, labels which are known in the art, methylation, and substitution of one or more of the naturally occurring nucleotides with a degenerate nucleotide. Further included in this invention are nucleic acid sequences which are greater than 85%, preferably at least about 90%, more preferably at least about 95%, and most preferably at least about 98 to 99% identical or homologous to the sequences of the invention, including FIG. 1 and the Sequence Listing [SEQ ID NO: 1, 9-59, 117-120]. These terms are as defined herein. Also included within the invention are fragments of the novel AAV sequences identified by the method described herein. Suitable fragments are at least 15 nucleotides in length, and encompass functional fragments, i.e., fragments which are of biological interest. In one embodiment, these fragments are fragments of the novel sequences of FIG. 1 and the Sequence Listing [SEQ ID NO: 1, 9-59, 117-120], their complementary strands, cDNA and RNA complementary thereto. Examples of suitable fragments are provided with respect to the location of these fragments on AAV1, AAV2, or AAV7. However, using the alignment provided herein (obtained using the Clustal W program at default settings), or similar techniques for generating an alignment with other novel serotypes of the invention, one of skill in the art can readily identify the precise nucleotide start and stop codons for desired fragments. Examples of suitable fragments include the sequences encoding the three variable proteins (vp) of the AAV capsid which are alternative splice variants: vp1 [e.g., nt 825 to 3049 of AAV7, SEQ ID NO: 1]; vp2 [e.g., nt 1234-3049 of AAV7, SEQ ID NO: 1]; and vp3 [e.g., nt 1434-3049 of AAV7, SEQ ID NO: 1]. It is notable that AAV7 has an unusual GTG start codon. With the exception of a few house-keeping genes, such a start codon has not previously been reported in DNA viruses. The start codons for vp1, vp2 and vp3 for other AAV serotypes have been believed to be such that they permit the cellular mechanism of the host cell in which they reside to produce vp1, vp2 and vp3 in a ratio of 10%: 10%:80%, respectively, in order to permit efficient assembly of the virion. However, the AAV7 virion has been found to assemble efficiently even with this rare GTG start codon. Thus, the inventors anticipate this it is desirable to alter the start codon of the vp3 of other AAV serotypes to contain this rare GTG start codon, in order to improve packaging efficiency, to alter the virion structure and/or to alter location of epitopes (e.g., neutralizing antibody epitopes) of other AAV serotypes. The start codons may be altered using conventional techniques including, e.g., site directed mutagenesis. Thus, the present invention encompasses altered AAV virions of any selected serotype, composed of a vp3, and/or optionally, vp1 and/or vp2 having start codons altered to GTG. Other suitable fragments of AAV, include a fragment containing the start codon for the AAV capsid protein [e.g., nt 468 to 3090 of AAV7, SEQ ID NO: 1, nt 725 to 3090 of AAV7, SEQ ID NO: 1, and corresponding regions of the other AAV serotypes]. Still other fragments of AAV7 and the other novel AAV serotypes identified using the methods described herein include those encoding the rep proteins, including rep 78 [e.g., initiation codon 334 of FIG. 1 for AAV7], rep 68 [initiation codon nt 334 of FIG. 1 for AAV7], rep 52 [initiation codon 1006 of FIG. 1 for AAV7], and rep 40 [initiation codon 1006 of FIG. 1 for AAV7] Other fragments of interest may include the AAV 5′ inverted terminal repeats ITRs, [nt 1 to 107 of FIG. 1 for AAV7]; the AAV 3′ ITRs [nt 4704 to 4721 of FIG. 1 for AAV7], P19 sequences, AAV P40 sequences, the rep binding site, and the terminal resolute site (TRS). Still other suitable fragments will be readily apparent to those of skill in the art. The corresponding regions in the other novel serotypes of the invention can be readily determined by reference to FIG. 1, or by utilizing conventional alignment techniques with the sequences provided herein. In addition to including the nucleic acid sequences provided in the figures and Sequence Listing, the present invention includes nucleic acid molecules and sequences which are designed to express the amino acid sequences, proteins and peptides of the AAV serotypes of the invention. Thus, the invention includes nucleic acid sequences which encode the following novel AAV amino acid sequences: C1 [SEQ ID NO:60], C2 [SEQ ID NO:61], C5 [SEQ ID NO:62], A3-3 [SEQ ID NO:66], A3-7 [SEQ ID NO:67], A3-4 [SEQ ID NO:68], A3-5 [SEQ ID NO: 69], 3.3b [SEQ ID NO: 62], 223.4 [SEQ ID NO: 73], 223-5 [SEQ ID NO:74], 223-10 [SEQ ID NO:75], 223-2 [SEQ ID NO:76], 223-7 [SEQ ID NO: 77], 223-6 [SEQ ID NO: 78], 44-1 [SEQ ID NO: 79], 44-5 [SEQ ID NO:80], 44-2 [SEQ ID NO:81], 42-15 [SEQ ID NO: 84], 42-8 [SEQ ID NO: 85], 42-13 [SEQ ID NO:86], 42-3A [SEQ ID NO:87], 42-4 [SEQ ID NO:88], 42-5A [SEQ ID NO:89], 42-1B [SEQ ID NO:90], 42-5B [SEQ ID NO:91], 43-1 [SEQ ID NO: 92], 43-12 [SEQ ID NO: 93], 43-5 [SEQ ID NO:94], 43-21 [SEQ ID NO:96], 43-25 [SEQ ID NO: 97], 43-20 [SEQ ID NO:99], 24.1 [SEQ ID NO: 101], 42.2 [SEQ ID NO: 102], 7.2 [SEQ ID NO: 103], 27.3 [SEQ ID NO: 104], 16.3 [SEQ ID NO: 105], 42.10 [SEQ ID NO: 106], 42-3B [SEQ ID NO: 107], 42-11 [SEQ ID NO: 108], F1 [SEQ ID NO: 109], F5 [SEQ ID NO: 110], F3 [SEQ ID NO:111], 42-6B [SEQ ID NO: 112], and/or 42-12 [SEQ ID NO: 113], and artificial AAV serotypes generated using these sequences and/or unique fragments thereof. As used herein, artificial AAV serotypes include, without limitation, AAV with a non-naturally occurring capsid protein. Such an artificial capsid may be generated by any suitable technique, using a novel AAV sequence of the invention (e.g., a fragment of a vp1 capsid protein) in combination with heterologous sequences which may be obtained from another AAV serotype (known or novel), non-contiguous portions of the same AAV serotype, from a non-AAV viral source, or from a non-viral source. An artificial AAV serotype may be, without limitation, a chimeric AAV capsid, a recombinant AAV capsid, or a “humanized” AAV capsid. B. AAV Amino Acid Sequences, Proteins and Peptides The invention provides proteins and fragments thereof which are encoded by the nucleic acid sequences of the novel AAV serotypes identified herein, including, e.g., AAV7 [nt 825 to 3049 of AAV7, SEQ ID NO: 1] the other novel serotypes provided herein. Thus, the capsid proteins of the novel serotypes of the invention, including: H6 [SEQ ID NO: 25], H2 [SEQ ID NO: 26], 42-2 [SEQ ID NO:9], 42-8 [SEQ ID NO:27], 42-15 [SEQ ID NO:28], 42-5b [SEQ ID NO: 29], 42-1b [SEQ ID NO:30]; 42-13 [SEQ ID NO: 31], 42-3a [SEQ ID NO: 32], 42-4 [SEQ ID NO:33], 42-5a [SEQ ID NO: 34], 42-10 [SEQ ID NO:35], 42-3b [SEQ ID NO: 36], 42-11 [SEQ ID NO: 37], 42-6b [SEQ ID NO:38], 43-1 [SEQ ID NO: 39], 43-5 [SEQ ID NO: 40], 43-12 [SEQ ID NO:41], 43-20 [SEQ ID NO:42], 43-21 [SEQ ID NO: 43], 43-23 [SEQ ID NO:44], 43-25 [SEQ ID NO: 45], 44.1 [SEQ ID NO:47], 44.5 [SEQ ID NO:47], 223.10 [SEQ ID NO:48], 223.2 [SEQ ID NO:49], 223.4 [SEQ ID NO:50], 223.5 [SEQ ID NO: 51], 223.6 [SEQ ID NO: 52], 223.7 [SEQ ID NO: 53], A3.4 [SEQ ID NO: 54], A3.5 [SEQ ID NO:55], A3.7 [SEQ ID NO: 56], A3.3 [SEQ ID NO:57], 42.12 [SEQ ID NO: 58], and 44.2 [SEQ ID NO: 59], can be readily generated using conventional techniques from the open reading frames provided for the above-listed clones. The invention further encompasses AAV serotypes generated using sequences of the novel AAV serotypes of the invention, which are generated using synthetic, recombinant or other techniques known to those of skill in the art. The invention is not limited to novel AAV amino acid sequences, peptides and proteins expressed from the novel AAV nucleic acid sequences of the invention and encompasses amino acid sequences, peptides and proteins generated by other methods known in the art, including, e.g., by chemical synthesis, by other synthetic techniques, or by other methods. For example, the sequences of any of C1 [SEQ ID NO:60], C2 [SEQ ID NO:61], C5 [SEQ ID NO:62], A3-3 [SEQ ID NO:66], A3-7 [SEQ ID NO:67], A3-4 [SEQ ID NO:68], A3-5 [SEQ ID NO: 69], 3.3b [SEQ ID NO: 62], 223.4 [SEQ ID NO: 73], 223-5 [SEQ ID NO:74], 223-10 [SEQ ID NO:75], 223-2 [SEQ ID NO:76], 223-7 [SEQ ID NO: 77], 223-6 [SEQ ID NO: 78], 44-1 [SEQ ID NO: 79], 44-5 [SEQ ID NO:80], 44-2 [SEQ ID NO:81], 42-15 [SEQ ID NO: 84], 42-8 [SEQ ID NO: 85], 42-13 [SEQ ID NO:86], 42-3A [SEQ ID NO:87], 42-4 [SEQ ID NO:88], 42-5A [SEQ ID NO:89], 42-1B [SEQ ID NO:90], 42-5B [SEQ ID NO:91], 43-1 [SEQ ID NO: 92], 43-12 [SEQ ID NO: 93], 43-5 [SEQ ID NO:94], 43-21 [SEQ ID NO:96], 43-25 [SEQ ID NO: 97], 43-20 [SEQ ID NO:99], 24.1 [SEQ ID NO: 101], 42.2 [SEQ ID NO: 102], 7.2 [SEQ ID NO: 103], 27.3 [SEQ ID NO: 104], 16.3 [SEQ ID NO: 105], 42.10 [SEQ ID NO: 106], 42-3B [SEQ ID NO: 107], 42-11 [SEQ ID NO: 108], F1 [SEQ ID NO: 109], F5 [SEQ ID NO: 110], F3 [SEQ ID NO: 111], 42-6B [SEQ ID NO: 112], and/or 42-12 [SEQ ID NO: 113] by be readily generated using a variety of techniques. Suitable production techniques are well known to those of skill in the art. See, e.g., Sambrook et al, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press (Cold Spring Harbor, N.Y.). Alternatively, peptides can also be synthesized by the well known solid phase peptide synthesis methods (Merrifield, J. Am. Chem. Soc., 85:2149 (1962); Stewart and Young, Solid Phase Peptide Synthesis (Freeman, San Francisco, 1969) pp. 27-62). These and other suitable production methods are within the knowledge of those of skill in the art and are not a limitation of the present invention. Particularly desirable proteins include the AAV capsid proteins, which are encoded by the nucleotide sequences identified above. The sequences of many of the capsid proteins of the invention are provided in an alignment in FIG. 2 and/or in the Sequence Listing, SEQ ID NO: 2 and 60 to 115, which is incorporated by reference herein. The AAV capsid is composed of three proteins, vp1, vp2 and vp3, which are alternative splice variants. The full-length sequence provided in these figures is that of vp1. Based on the numbering of the AAV7 capsid [SEQ ID NO:2], the sequences of vp2 span amino acid 138-737 of AAV7 and the sequences of vp3 span amino acids 203-737 of AAV7. With this information, one of skill in the art can readily determine the location of the vp2 and vp3 proteins for the other novel serotypes of the invention. Other desirable proteins and fragments of the capsid protein include the constant and variable regions, located between hypervariable regions (HPV) and the sequences of the HPV regions themselves. An algorithm developed to determine areas of sequence divergence in AAV2 has yielded 12 hypervariable regions (HVR) of which 5 overlap or are part of the four previously described variable regions. [Chiorini et al, J. Virol, 73:1309-19 (1999); Rutledge et al, J. Virol., 72:309-319] Using this algorithm and/or the alignment techniques described herein, the HVR of the novel AAV serotypes are determined. For example, with respect to the number of the AAV2 vp11 [SEQ ID NO:70], the HVR are located as follows: HVR1, aa 146-152; HVR2, aa 182-186; HVR3, aa 262-264; HVR4, aa 381-383; HVR5, aa 450-474; HVR6, aa 490-495; HVR7, aa500-504; HVR8, aa 514-522; HVR9, aa 534-555; HVR10, aa 581-594; HVR11, aa 658-667; and HVR12, aa 705-719. Utilizing an alignment prepared in accordance with conventional methods and the novel sequences provided herein [See, e.g., FIG. 2], one can readily determine the location of the HVR in the novel AAV serotypes of the invention. For example, utilizing FIG. 2, one can readily determine that for AAV7 [SEQ ID NO:2]. HVR1 is located at aa 146-152; HVR2 is located at 182-187; HVR3 is located at aa 263-266, HVR4 is located at aa 383-385, HVR5 is located at aa 451-475; HVR6 is located at aa 491-496 of AAV7; HVR7 is located at aa 501-505; HVR8 is located at aa 513-521; HVR9 is located at 533-554; HVR10 is located at aa 583-596; HVR11 is located at aa 660-669; HVR12 is located at aa 707-721. Using the information provided herein, the HVRs for the other novel serotypes of the invention can be readily determined. In addition, within the capsid, amino acid cassettes of identity have been identified. These cassettes are of particular interest, as they are useful in constructing artificial serotypes, e.g., by replacing a HVR1 cassette of a selected serotype with an HVR1 cassette of another serotype. Certain of these cassettes of identity are noted in FIG. 2. See, FIG. 2, providing the Clustal X alignment, which has a ruler is displayed below the sequences, starting at 1 for the first residue position. The line above the ruler is used to mark strongly conserved positions. Three characters (*, : , .) are used. “*” indicates positions which have a single, fully conserved residue. “:” indicates that a “strong” group is fully conserved “.” Indicates that a “weaker” group is fully conserved. These are all the positively scoring groups that occur in the Gonnet Pam250 matrix. The strong groups are defined as a strong score >0.5 and the weak groups are defined as weak score <0.5. Additionally, examples of other suitable fragments of AAV capsids include, with respect to the numbering of AAV2 [SEQ ID NO:70], aa 24-42, aa 25-28; aa 81-85; aa133-165; aa 134-165; aa 137-143; aa 154-156; aa 194-208; aa 261-274; aa 262-274; aa 171-173; aa 413-417; aa 449-478; aa 494-525; aa 534-571; aa 581-601; aa 660-671; aa 709-723. Still other desirable fragments include, for example, in AAV7, amino acids 1 to 184 of SEQ ID NO:2, amino acids 199 to 259; amino acids 274 to 446; amino acids 603 to 659; amino acids 670 to 706; amino acids 724 to 736; aa 185 to 198; aa 260 to 273; aa447 to 477; aa495 to 602; aa660 to 669; and aa707 to 723. Still other desirable regions, based on the numbering of AAV7 [SEQ ID NO:2], are selected from among the group consisting of aa 185 to 198; aa 260 to 273; aa447 to 477;aa495 to 602; aa660 to 669; and aa707 to 723. Using the alignment provided herein performed using the Clustal X program at default settings, or using other commercially or publicly available alignment programs at default settings, one of skill in the art can readily determine corresponding fragments of the novel AAV capsids of the invention. Other desirable proteins are the AAV rep proteins [aa 1 to 623 of SEQ ID NO:3 for AAV7] and functional fragments thereof, including, e.g., aa 1 to 171, aa 172 to 372, aa 373 to 444, aa 445 to 623 of SEQ ID NO:3, among others. Suitably, such fragments are at least 8 amino acids in length. See, FIG. 3. Comparable regions can be identified in the proteins of the other novel AAV of the invention, using the techniques described herein and those which are known in the art. In addition, fragments of other desired lengths may be readily utilized. Such fragments may be produced recombinantly or by other suitable means, e.g., chemical synthesis. The sequences, proteins, and fragments of the invention may be produced by any suitable means, including recombinant production, chemical synthesis, or other synthetic means. Such production methods are within the knowledge of those of skill in the art and are not a limitation of the present invention. IV. Production of rAAV with Novel AAV Capsids The invention encompasses novel, wild-type AAV serotypes identified by the invention, the sequences of which wild-type AAV serotypes are free of DNA and/or cellular material with these viruses are associated in nature. In another aspect, the present invention provides molecules which utilize the novel AAV sequences of the invention, including fragments thereof, for production of molecules useful in delivery of a heterologous gene or other nucleic acid sequences to a target cell. The molecules of the invention which contain sequences of a novel AAV serotype of the invention include any genetic element (vector) which may be delivered to a host cell, e.g., naked DNA, a plasmid, phage, transposon, cosmid, episome, a protein in a non-viral delivery vehicle (e.g., a lipid-based carrier), virus, etc. which transfer the sequences carried thereon. The selected vector may be delivered by any suitable method, including transfection, electroporation, liposome delivery, membrane fusion techniques, high velocity DNA-coated pellets, viral infection and protoplast fusion. The methods used to construct any embodiment of this invention are known to those with skill in nucleic acid manipulation and include genetic engineering, recombinant engineering, and synthetic techniques. See, e.g., Sambrook et al, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, Cold Spring Harbor, N.Y. In one embodiment, the vectors of the invention contain sequences encoding a novel AAV capsid of the invention (e.g., AAV7 capsid, AAV 44-2 (rh.10), an AAV10 capsid, an AAV11 capsid, an AAV12 capsid), or a fragment of one or more of these AAV capsids. Alternatively, the vectors may contain the capsid protein, or a fragment thereof, itself. Optionally, vectors of the invention may contain sequences encoding AAV rep proteins. Such rep sequences may be from the same AAV serotype which is providing the cap sequences. Alternatively, the present invention provides vectors in which the rep sequences are from an AAV serotype which differs from that which is providing the cap sequences. In one embodiment, the rep and cap sequences are expressed from separate sources (e.g., separate vectors, or a host cell and a vector). In another embodiment, these rep sequences are expressed from the same source as the cap sequences. In this embodiment, the rep sequences may be fused in frame to cap sequences of a different AAV serotype to form a chimeric AAV vector. Optionally, the vectors of the invention further contain a minigene comprising a selected transgene which is flanked by AAV 5′ ITR and AAV 3′ ITR. Thus, in one embodiment, the vectors described herein contain nucleic acid sequences encoding an intact AAV capsid which may be from a single AAV serotype (e.g., AAV7 or another novel AAV). Alternatively, these vectors contain sequences encoding artificial capsids which contain one or more fragments of the AAV7 (or another novel AAV) capsid fused to heterologous AAV or non-AAV capsid proteins (or fragments thereof). These artificial capsid proteins are selected from non-contiguous portions of the AAV7 (or another novel AAV) capsid or from capsids of other AAV serotypes. For example, it may be desirable to modify the coding regions of one or more of the AAV vp1, e.g., in one or more of the hypervariable regions (i.e., HPV1-12), or vp2, and/or vp3. In another example, it may be desirable to alter the start codon of the vp3 protein to GTG. These modifications may be to increase expression, yield, and/or to improve purification in the selected expression systems, or for another desired purpose (e.g., to change tropism or alter neutralizing antibody epitopes). The vectors described herein, e.g., a plasmid, are useful for a variety of purposes, but are particularly well suited for use in production of a rAAV containing a capsid comprising AAV sequences or a fragment thereof. These vectors, including rAAV, their elements, construction, and uses are described in detail herein. In one aspect, the invention provides a method of generating a recombinant adeno-associated virus (AAV) having an AAV serotype 7 (or another novel AAV) capsid, or a portion thereof. Such a method involves culturing a host cell which contains a nucleic acid sequence encoding an adeno-associated virus (AAV) serotype 7 (or another novel AAV) capsid protein, or fragment thereof, as defined herein; a functional rep gene; a minigene composed of, at a minimum, AAV inverted terminal repeats (ITRs) and a transgene; and sufficient helper functions to permit packaging of the minigene into the AAV7 (or another novel AAV) capsid protein. The components required to be cultured in the host cell to package an AAV minigene in an AAV capsid may be provided to the host cell in trans. Alternatively, any one or more of the required components (e.g., minigene, rep sequences, cap sequences, and/or helper functions) may be provided by a stable host cell which has been engineered to contain one or more of the required components using methods known to those of skill in the art. Most suitably, such a stable host cell will contain the required component(s) under the control of an inducible promoter. However, the required component(s) may be under the control of a constitutive promoter. Examples of suitable inducible and constitutive promoters are provided herein, in the discussion of regulatory elements suitable for use with the transgene. In still another alternative, a selected stable host cell may contain selected component(s) under the control of a constitutive promoter and other selected component(s) under the control of one or more inducible promoters. For example, a stable host cell may be generated which is derived from 293 cells (which contain E1 helper functions under the control of a constitutive promoter), but which contains the rep and/or cap proteins under the control of inducible promoters. Still other stable host cells may be generated by one of skill in the art. The minigene, rep sequences, cap sequences, and helper functions required for producing the rAAV of the invention may be delivered to the packaging host cell in the form of any genetic element which transfer the sequences carried thereon. The selected genetic element may be delivered by any suitable method, including those described herein. The methods used to construct any embodiment of this invention are known to those with skill in nucleic acid manipulation and include genetic engineering, recombinant engineering, and synthetic techniques. See, e.g., Sambrook et al, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, Cold Spring Harbor, N.Y. Similarly, methods of generating rAAV virions are well known and the selection of a suitable method is not a limitation on the present invention. See, e.g., K. Fisher et al, J. Virol., 70:520-532 (1993) and U.S. Pat. No. 5,478,745. A. The Minigene The minigene is composed of, at a minimum, a transgene and its regulatory sequences, and 5= and 3=AAV inverted terminal repeats (ITRs). It is this minigene which is packaged into a capsid protein and delivered to a selected host cell. 1. The Transgene The transgene is a nucleic acid sequence, heterologous to the vector sequences flanking the transgene, which encodes a polypeptide, protein, or other product, of interest. The nucleic acid coding sequence is operatively linked to regulatory components in a manner which permits transgene transcription, translation, and/or expression in a host cell. The composition of the transgene sequence will depend upon the use to which the resulting vector will be put. For example, one type of transgene sequence includes a reporter sequence, which upon expression produces a detectable signal. Such reporter sequences include, without limitation, DNA sequences encoding β-lactamase, β-galactosidase (LacZ), alkaline phosphatase, thymidine kinase, green fluorescent protein (GFP), chloramphenicol acetyltransferase (CAT), luciferase, membrane bound proteins including, for example, CD2, CD4, CD8, the influenza hemagglutinin protein, and others well known in the art, to which high affinity antibodies directed thereto exist or can be produced by conventional means, and fusion proteins comprising a membrane bound protein appropriately fused to an antigen tag domain from, among others, hemagglutinin or Myc. These coding sequences, when associated with regulatory elements which drive their expression, provide signals detectable by conventional means, including enzymatic, radiographic, colorimetric, fluorescence or other spectrographic assays, fluorescent activating cell sorting assays and immunological assays, including enzyme linked immunosorbent assay (ELISA), radioimmunoassay (RIA) and immunohistochemistry. For example, where the marker sequence is the LacZ gene, the presence of the vector carrying the signal is detected by assays for beta-galactosidase activity. Where the transgene is green fluorescent protein or luciferase, the vector carrying the signal may be measured visually by color or light production in a luminometer. However, desirably, the transgene is a non-marker sequence encoding a product which is useful in biology and medicine, such as proteins, peptides, RNA, enzymes, or catalytic RNAs. Desirable RNA molecules include tRNA, dsRNA, ribosomal RNA, catalytic RNAs, and antisense RNAs. One example of a useful RNA sequence is a sequence which extinguishes expression of a targeted nucleic acid sequence in the treated animal. The transgene may be used to correct or ameliorate gene deficiencies, which may include deficiencies in which normal genes are expressed at less than normal levels or deficiencies in which the functional gene product is not expressed. A preferred type of transgene sequence encodes a therapeutic protein or polypeptide which is expressed in a host cell. The invention further includes using multiple transgenes, e.g., to correct or ameliorate a gene defect caused by a multi-subunit protein. In certain situations, a different transgene may be used to encode each subunit of a protein, or to encode different peptides or proteins. This is desirable when the size of the DNA encoding the protein subunit is large, e.g., for an immunoglobulin, the platelet-derived growth factor, or a dystrophin protein. In order for the cell to produce the multi-subunit protein, a cell is infected with the recombinant virus containing each of the different subunits. Alternatively, different subunits of a protein may be encoded by the same transgene. In this case, a single transgene includes the DNA encoding each of the subunits, with the DNA for each subunit separated by an internal ribozyme entry site (IRES). This is desirable when the size of the DNA encoding each of the subunits is small, e.g., the total size of the DNA encoding the subunits and the IRES is less than five kilobases. As an alternative to an IRES, the DNA may be separated by sequences encoding a 2A peptide, which self-cleaves in a post-translational event. See, e.g., M. L. Donnelly, et al, J. Gen. Virol., 78(Pt 1):13-21 (January 1997); Furler, S., et al, Gene Ther., 8(11):864-873 (June 2001); Klump H., et al., Gene Ther., 8(10):811-817 (May 2001). This 2A peptide is significantly smaller than an IRES, making it well suited for use when space is a limiting factor. However, the selected transgene may encode any biologically active product or other product, e.g., a product desirable for study. Suitable transgenes may be readily selected by one of skill in the art. The selection of the transgene is not considered to be a limitation of this invention. 2. Regulatory Elements In addition to the major elements identified above for the minigene, the vector also includes conventional control elements necessary which are operably linked to the transgene in a manner which permits its transcription, translation and/or expression in a cell transfected with the plasmid vector or infected with the virus produced by the invention. As used herein, Aoperably linked≅ sequences include both expression control sequences that are contiguous with the gene of interest and expression control sequences that act in trans or at a distance to control the gene of interest. Expression control sequences include appropriate transcription initiation, termination, promoter and enhancer sequences; efficient RNA processing signals such as splicing and polyadenylation (polyA) signals; sequences that stabilize cytoplasmic mRNA; sequences that enhance translation efficiency (i.e., Kozak consensus sequence); sequences that enhance protein stability; and when desired, sequences that enhance secretion of the encoded product. A great number of expression control sequences, including promoters which are native, constitutive, inducible and/or tissue-specific, are known in the art and may be utilized. Examples of constitutive promoters include, without limitation, the retroviral Rous sarcoma virus (RSV) LTR promoter (optionally with the RSV enhancer), the cytomegalovirus (CMV) promoter (optionally with the CMV enhancer) [see, e.g., Boshart et al, Cell, 41:521-530 (1985)], the SV40 promoter, the dihydrofolate reductase promoter, the β-actin promoter, the phosphoglycerol kinase (PGK) promoter, and the EF1α promoter [Invitrogen]. Inducible promoters allow regulation of gene expression and can be regulated by exogenously supplied compounds, environmental factors such as temperature, or the presence of a specific physiological state, e.g., acute phase, a particular differentiation state of the cell, or in replicating cells only. Inducible promoters and inducible systems are available from a variety of commercial sources, including, without limitation, Invitrogen, Clontech and Ariad. Many other systems have been described and can be readily selected by one of skill in the art. Examples of inducible promoters regulated by exogenously supplied promoters include the zinc-inducible sheep metallothionine (MT) promoter, the dexamethasone (Dex)-inducible mouse mammary tumor virus (MMTV) promoter, the T7 polymerase promoter system [WO 98/10088]; the ecdysone insect promoter [No et al, Proc. Natl. Acad. Sci. USA, 93:3346-3351 (1996)], the tetracycline-repressible system [Gossen et al, Proc. Natl. Acad. Sci. USA, 89:5547-5551 (1992)], the tetracycline-inducible system [Gossen et al, Science, 268:1766-1769 (1995), see also Harvey et al, Curr. Opin. Chem. Biol., 2:512-518 (1998)], the RU486-inducible system [Wang et al, Nat. Biotech., 15:239-243 (1997) and Wang et al, Gene Ther., 4:432-441 (1997)] and the rapamycin-inducible system [Magari et al, J. Clin. Invest., 100:2865-2872 (1997)]. Still other types of inducible promoters which may be useful in this context are those which are regulated by a specific physiological state, e.g., temperature, acute phase, a particular differentiation state of the cell, or in replicating cells only. In another embodiment, the native promoter for the transgene will be used. The native promoter may be preferred when it is desired that expression of the transgene should mimic the native expression. The native promoter may be used when expression of the transgene must be regulated temporally or developmentally, or in a tissue-specific manner, or in response to specific transcriptional stimuli. In a further embodiment, other native expression control elements, such as enhancer elements, polyadenylation sites or Kozak consensus sequences may also be used to mimic the native expression. Another embodiment of the transgene includes a transgene operably linked to a tissue-specific promoter. For instance, if expression in skeletal muscle is desired, a promoter active in muscle should be used. These include the promoters from genes encoding skeletal β-actin, myosin light chain 2A, dystrophin, muscle creatine kinase, as well as synthetic muscle promoters with activities higher than naturally-occurring promoters (see Li et al., Nat. Biotech., 17:241-245 (1999)). Examples of promoters that are tissue-specific are known for liver (albumin, Miyatake et al., J. Virol., 71:5124-32 (1997); hepatitis B virus core promoter, Sandig et al., Gene Ther., 3:1002-9 (1996); alpha-fetoprotein (AFP), Arbuthnot et al., Hum. Gene Ther., 7:1503-14 (1996)), bone osteocalcin (Stein et al., Mol. Biol. Rep., 24:185-96 (1997)); bone sialoprotein (Chen et al., J. Bone Miner. Res., 11:654-64 (1996)), lymphocytes (CD2, Hansal et al., J. Immunol., 161:1063-8 (1998); immunoglobulin heavy chain; T cell receptor a chain), neuronal such as neuron-specific enolase (NSE) promoter (Andersen et al., Cell. Mol. Neurobiol., 13:503-15 (1993)), neurofilament light-chain gene (Piccioli et al., Proc. Natl. Acad. Sci. USA, 88:5611-5 (1991)), and the neuron-specific vgf gene (Piccioli et al., Neuron, 15:373-84 (1995)), among others. Optionally, plasmids carrying therapeutically useful transgenes may also include selectable markers or reporter genes may include sequences encoding geneticin, hygromicin or purimycin resistance, among others. Such selectable reporters or marker genes (preferably located outside the viral genome to be rescued by the method of the invention) can be used to signal the presence of the plasmids in bacterial cells, such as ampicillin resistance. Other components of the plasmid may include an origin of replication. Selection of these and other promoters and vector elements are conventional and many such sequences are available [see, e.g., Sambrook et al, and references cited therein]. The combination of the transgene, promoter/enhancer, and 5= and 3=ITRs is referred to as a “minigene” for ease of reference herein. Provided with the teachings of this invention, the design of such a minigene can be made by resort to conventional techniques. 3. Delivery of the Minigene to a Packaging Host Cell The minigene can be carried on any suitable vector, e.g., a plasmid, which is delivered to a host cell. The plasmids useful in this invention may be engineered such that they are suitable for replication and, optionally, integration in prokaryotic cells, mammalian cells, or both. These plasmids (or other vectors carrying the 5′ AAV ITR-heterologous molecule-3′ITR) contain sequences permitting replication of the minigene in eukaryotes and/or prokaryotes and selection markers for these systems. Selectable markers or reporter genes may include sequences encoding geneticin, hygromicin or purimycin resistance, among others. The plasmids may also contain certain selectable reporters or marker genes that can be used to signal the presence of the vector in bacterial cells, such as ampicillin resistance. Other components of the plasmid may include an origin of replication and an amplicon, such as the amplicon system employing the Epstein Barr virus nuclear antigen. This amplicon system, or other similar amplicon components permit high copy episomal replication in the cells. Preferably, the molecule carrying the minigene is transfected into the cell, where it may exist transiently. Alternatively, the minigene (carrying the 5′ AAV ITR-heterologous molecule-3′ ITR) may be stably integrated into the genome of the host cell, either chromosomally or as an episome. In certain embodiments, the minigene may be present in multiple copies, optionally in head-to-head, head-to-tail, or tail-to-tail concatamers. Suitable transfection techniques are known and may readily be utilized to deliver the minigene to the host cell. Generally, when delivering the vector comprising the minigene by transfection, the vector is delivered in an amount from about 5 μg to about 100 μg DNA, and preferably about 10 to about 50 μg DNA to about 1×104 cells to about 1×1013 cells, and preferably about 105 cells. However, the relative amounts of vector DNA to host cells may be adjusted, taking into consideration such factors as the selected vector, the delivery method and the host cells selected. B. Rep and Cap Sequences In addition to the minigene, the host cell contains the sequences which drive expression of the novel AAV capsid protein (e.g., AAV7 or other novel AAV capsid or an artificial capsid protein comprising a fragment of one or more of these capsids) in the host cell and rep sequences of the same serotype as the serotype of the AAV ITRs found in the minigene. The AAV cap and rep sequences may be independently obtained from an AAV source as described above and may be introduced into the host cell in any manner known to one in the art as described above. Additionally, when pseudotyping a novel AAV capsid of the invention, the sequences encoding each of the essential rep proteins may be supplied by the same AAV serotype, or the sequences encoding the rep proteins may be supplied by different AAV serotypes (e.g., AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, or one of the novel serotypes identified herein). For example, the rep78/68 sequences may be from AAV2, whereas the rep52/40 sequences may from AAV1. In one embodiment, the host cell stably contains the capsid protein under the control of a suitable promoter, such as those described above. Most desirably, in this embodiment, the capsid protein is expressed under the control of an inducible promoter. In another embodiment, the capsid protein is supplied to the host cell in trans. When delivered to the host cell in trans, the capsid protein may be delivered via a plasmid which contains the sequences necessary to direct expression of the selected capsid protein in the host cell. Most desirably, when delivered to the host cell in trans, the plasmid carrying the capsid protein also carries other sequences required for packaging the rAAV, e.g., the rep sequences. In another embodiment, the host cell stably contains the rep sequences under the control of a suitable promoter, such as those described above. Most desirably, in this embodiment, the essential rep proteins are expressed under the control of an inducible promoter. In another embodiment, the rep proteins are supplied to the host cell in trans. When delivered to the host cell in trans, the rep proteins may be delivered via a plasmid which contains the sequences necessary to direct expression of the selected rep proteins in the host cell. Most desirably, when delivered to the host cell in trans, the plasmid carrying the capsid protein also carries other sequences required for packaging the rAAV, e.g., the rep and cap sequences. Thus, in one embodiment, the rep and cap sequences may be transfected into the host cell on a single nucleic acid molecule and exist stably in the cell as an episome. In another embodiment, the rep and cap sequences are stably integrated into the genome of the cell. Another embodiment has the rep and cap sequences transiently expressed in the host cell. For example, a useful nucleic acid molecule for such transfection comprises, from 5′ to 3′, a promoter, an optional spacer interposed between the promoter and the start site of the rep gene sequence, an AAV rep gene sequence, and an AAV cap gene sequence. Optionally, the rep and/or cap sequences may be supplied on a vector that contains other DNA sequences that are to be introduced into the host cells. For instance, the vector may contain the rAAV construct comprising the minigene. The vector may comprise one or more of the genes encoding the helper functions, e.g., the adenoviral proteins E1, E2a, and E4ORF6, and the gene for VAI RNA. Preferably, the promoter used in this construct may be any of the constitutive, inducible or native promoters known to one of skill in the art or as discussed above. In one embodiment, an AAV P5 promoter sequence is employed. The selection of the AAV to provide any of these sequences does not limit the invention. In another preferred embodiment, the promoter for rep is an inducible promoter, as are discussed above in connection with the transgene regulatory elements. One preferred promoter for rep expression is the T7 promoter. The vector comprising the rep gene regulated by the T7 promoter and the cap gene, is transfected or transformed into a cell which either constitutively or inducibly expresses the T7 polymerase. See WO 98/10088, published Mar. 12, 1998. The spacer is an optional element in the design of the vector. The spacer is a DNA sequence interposed between the promoter and the rep gene ATG start site. The spacer may have any desired design; that is, it may be a random sequence of nucleotides, or alternatively, it may encode a gene product, such as a marker gene. The spacer may contain genes which typically incorporate start/stop and polyA sites. The spacer may be a non-coding DNA sequence from a prokaryote or eukaryote, a repetitive non-coding sequence, a coding sequence without transcriptional controls or a coding sequence with transcriptional controls. Two exemplary sources of spacer sequences are the λ phage ladder sequences or yeast ladder sequences, which are available commercially, e.g., from Gibco or Invitrogen, among others. The spacer may be of any size sufficient to reduce expression of the rep78 and rep68 gene products, leaving the rep52, rep40 and cap gene products expressed at normal levels. The length of the spacer may therefore range from about 10 bp to about 10.0 kbp, preferably in the range of about 100 bp to about 8.0 kbp. To reduce the possibility of recombination, the spacer is preferably less than 2 kbp in length; however, the invention is not so limited. Although the molecule(s) providing rep and cap may exist in the host cell transiently (i.e., through transfection), it is preferred that one or both of the rep and cap proteins and the promoter(s) controlling their expression be stably expressed in the host cell, e.g., as an episome or by integration into the chromosome of the host cell. The methods employed for constructing embodiments of this invention are conventional genetic engineering or recombinant engineering techniques such as those described in the references above. While this specification provides illustrative examples of specific constructs, using the information provided herein, one of skill in the art may select and design other suitable constructs, using a choice of spacers, P5 promoters, and other elements, including at least one translational start and stop signal, and the optional addition of polyadenylation sites. In another embodiment of this invention, the rep or cap protein may be provided stably by a host cell. C. The Helper Functions The packaging host cell also requires helper functions in order to package the rAAV of the invention. Optionally, these functions may be supplied by a herpesvirus. Most desirably, the necessary helper functions are each provided from a human or non-human primate adenovirus source, such as those described above and/or are available from a variety of sources, including the American Type Culture Collection (ATCC), Manassas, Va. (US). In one currently preferred embodiment, the host cell is provided with and/or contains an E1a gene product, an E1b gene product, an E2a gene product, and/or an E4 ORF6 gene product. The host cell may contain other adenoviral genes such as VAI RNA, but these genes are not required. In a preferred embodiment, no other adenovirus genes or gene functions are present in the host cell. By Aadenoviral DNA which expresses the E1a gene product≅, it is meant any adenovirus sequence encoding E1a or any functional E1a portion. Adenoviral DNA which expresses the E2a gene product and adenoviral DNA which expresses the E4 ORF6 gene products are defined similarly. Also included are any alleles or other modifications of the adenoviral gene or functional portion thereof. Such modifications may be deliberately introduced by resort to conventional genetic engineering or mutagenic techniques to enhance the adenoviral function in some manner, as well as naturally occurring allelic variants thereof. Such modifications and methods for manipulating DNA to achieve these adenovirus gene functions are known to those of skill in the art. The adenovirus E1a, E1b, E2a, and/or E4ORF6 gene products, as well as any other desired helper functions, can be provided using any means that allows their expression in a cell. Each of the sequences encoding these products may be on a separate vector, or one or more genes may be on the same vector. The vector may be any vector known in the art or disclosed above, including plasmids, cosmids and viruses. Introduction into the host cell of the vector may be achieved by any means known in the art or as disclosed above, including transfection, infection, electroporation, liposome delivery, membrane fusion techniques, high velocity DNA-coated pellets, viral infection and protoplast fusion, among others. One or more of the adenoviral genes may be stably integrated into the genome of the host cell, stably expressed as episomes, or expressed transiently. The gene products may all be expressed transiently, on an episome or stably integrated, or some of the gene products may be expressed stably while others are expressed transiently. Furthermore, the promoters for each of the adenoviral genes may be selected independently from a constitutive promoter, an inducible promoter or a native adenoviral promoter. The promoters may be regulated by a specific physiological state of the organism or cell (i.e., by the differentiation state or in replicating or quiescent cells) or by exogenously-added factors, for example. D. Host Cells and Packaging Cell Lines The host cell itself may be selected from any biological organism, including prokaryotic (e.g., bacterial) cells, and eukaryotic cells, including, insect cells, yeast cells and mammalian cells. Particularly desirable host cells are selected from among any mammalian species, including, without limitation, cells such as A549, WEHI, 3T3, 10T 1/2, BHK, MDCK, COS 1, COS 7, BSC 1, BSC 40, BMT 10, VERO, WI38, HeLa, 293 cells (which express functional adenoviral E1), Saos, C2C12, L cells, HT1080, HepG2 and primary fibroblast, hepatocyte and myoblast cells derived from mammals including human, monkey, mouse, rat, rabbit, and hamster. The selection of the mammalian species providing the cells is not a limitation of this invention; nor is the type of mammalian cell, i.e., fibroblast, hepatocyte, tumor cell, etc. The most desirable cells do not carry any adenovirus gene other than E1, E2a and/or E4 ORF6; nor do they contain any other virus gene which could result in homologous recombination of a contaminating virus during the production of rAAV; and it is capable of infection or transfection of DNA and expression of the transfected DNA. In a preferred embodiment, the host cell is one that has rep and cap stably transfected in the cell. One host cell useful in the present invention is a host cell stably transformed with the sequences encoding rep and cap, and which is transfected with the adenovirus E1, E2a, and E4ORF6 DNA and a construct carrying the minigene as described above. Stable rep and/or cap expressing cell lines, such as B-50 (PCT/US98/19463), or those described in U.S. Pat. No. 5,658,785, may also be similarly employed. Another desirable host cell contains the minimum adenoviral DNA which is sufficient to express E4 ORF6. Yet other cell lines can be constructed using the novel AAV rep and/or novel AAV cap sequences of the invention. The preparation of a host cell according to this invention involves techniques such as assembly of selected DNA sequences. This assembly may be accomplished utilizing conventional techniques. Such techniques include cDNA and genomic cloning, which are well known and are described in Sambrook et al., cited above, use of overlapping oligonucleotide sequences of the adenovirus and AAV genomes, combined with polymerase chain reaction, synthetic methods, and any other suitable methods which provide the desired nucleotide sequence. Introduction of the molecules (as plasmids or viruses) into the host cell may also be accomplished using techniques known to the skilled artisan and as discussed throughout the specification. In preferred embodiment, standard transfection techniques are used, e.g., CaPO4 transfection or electroporation, and/or infection by hybrid adenovirus/AAV vectors into cell lines such as the human embryonic kidney cell line HEK 293 (a human kidney cell line containing functional adenovirus E1 genes which provides trans-acting E1 proteins). These novel AAV-based vectors which are generated by one of skill in the art are beneficial for gene delivery to selected host cells and gene therapy patients since no neutralization antibodies to AAV7 have been found in the human population. Further, early studies show no neutralizing antibodies in cyno monkey and chimpanzee populations, and less than 15% cross-reactivity of AAV7 in rhesus monkeys, the species from which the serotype was isolated. One of skill in the art may readily prepare other rAAV viral vectors containing the AAV7 capsid proteins provided herein using a variety of techniques known to those of skill in the art. One may similarly prepare still other rAAV viral vectors containing AAV7 sequence and AAV capsids of another serotype. Similar advantages are conferred by the vectors based on the other novel AAV of the invention. Thus, one of skill in the art will readily understand that the AAV7 sequences of the invention can be readily adapted for use in these and other viral vector systems for in vitro, ex vivo or in vivo gene delivery. Similarly, one of skill in the art can readily select other fragments of the novel AAV genome of the invention for use in a variety of rAAV and non-rAAV vector systems. Such vectors systems may include, e.g., lentiviruses, retroviruses, poxviruses, vaccinia viruses, and adenoviral systems, among others. Selection of these vector systems is not a limitation of the present invention. Thus, the invention further provides vectors generated using the nucleic acid and amino acid sequences of the novel AAV of the invention. Such vectors are useful for a variety of purposes, including for delivery of therapeutic molecules and for use in vaccine regimens. Particularly desirable for delivery of therapeutic molecules are recombinant AAV containing capsids of the novel AAV of the invention. These, or other vector constructs containing novel AAV sequences of the invention may be used in vaccine regimens, e.g., for co-delivery of a cytokine, or for delivery of the immunogen itself. V. Recombinant Viruses and Uses Thereof Using the techniques described herein, one of skill in the art may generate a rAAV having a capsid of a novel serotype of the invention, or a novel capsid containing one or more novel fragments of an AAV serotype identified by the method of the invention. In one embodiment, a full-length capsid from a single serotype, e.g., AAV7 [SEQ ID NO: 2] can be utilized. In another embodiment, a full-length capsid may be generated which contains one or more fragments of a novel serotype of the invention fused in frame with sequences from another selected AAV serotype. For example, a rAAV may contain one or more of the novel hypervariable region sequences of an AAV serotype of the invention. Alternatively, the unique AAV serotypes of the invention may be used in constructs containing other viral or non-viral sequences. It will be readily apparent to one of skill in the art one embodiment, that certain serotypes of the invention will be particularly well suited for certain uses. For example, vectors based on AAV7 capsids of the invention are particularly well suited for use in muscle; whereas vectors based on rh.10 (44-2) capsids of the invention are particularly well suited for use in lung. Uses of such vectors are not so limited and one of skill in the art may utilize these vectors for delivery to other cell types, tissues or organs. Further, vectors based upon other capsids of the invention may be used for delivery to these or other cells, tissues or organs. A. Delivery of Transgene In another aspect, the present invention provides a method for delivery of a transgene to a host which involves transfecting or infecting a selected host cell with a vector generated with the sequences of the AAV of the invention. Methods for delivery are well known to those of skill in the art and are not a limitation of the present invention. In one desirable embodiment, the invention provides a method for AAV-mediated delivery of a transgene to a host. This method involves transfecting or infecting a selected host cell with a recombinant viral vector containing a selected transgene under the control of sequences which direct expression thereof and AAV capsid proteins. Optionally, a sample from the host may be first assayed for the presence of antibodies to a selected AAV serotype. A variety of assay formats for detecting neutralizing antibodies are well known to those of skill in the art. The selection of such an assay is not a limitation of the present invention. See, e.g., Fisher et al, Nature Med., 3(3):306-312 (March 1997) and W. C. Manning et al, Human Gene Therapy, 9:477-485 (Mar. 1, 1998). The results of this assay may be used to determine which AAV vector containing capsid proteins of a particular serotype are preferred for delivery, e.g., by the absence of neutralizing antibodies specific for that capsid serotype. In one aspect of this method, the delivery of vector with a selected AAV capsid proteins may precede or follow delivery of a gene via a vector with a different serotype AAV capsid protein. Similarly, the delivery of vector with other novel AAV capsid proteins of the invention may precede or follow delivery of a gene via a vector with a different serotype AAV capsid protein. Thus, gene delivery via rAAV vectors may be used for repeat gene delivery to a selected host cell. Desirably, subsequently administered rAAV vectors carry the same transgene as the first rAAV vector, but the subsequently administered vectors contain capsid proteins of serotypes which differ from the first vector. For example, if a first vector has AAV7 capsid proteins [SEQ ID NO:2], subsequently administered vectors may have capsid proteins selected from among the other serotypes, including AAV1, AAV2, AAV3A, AAV3B, AAV4, AAV6, AAV10, AAV11, and AAV12, or any of the other novel AAV capsids identified herein including, without limitation: A3.1, H2, H6, C1, C2, C5, A3-3, A3-7, A3-4, A3-5, 3.3b, 223.4, 223-5, 223-10, 223-2, 223-7, 223-6, 44-1, 44-5, 44-2, 42-15, 42-8, 42-13, 42-3A, 42-4, 42-5A, 42-1B, 42-5B, 43-1, 43-12, 43-5, 43-21, 43-25, 43-20, 24.1, 42.2, 7.2, 27.3, 16.3, 42.10, 42-3B, 42-11, F1, F5, F3, 42-6B, and/or 42-12. The above-described recombinant vectors may be delivered to host cells according to published methods. The rAAV, preferably suspended in a physiologically compatible carrier, may be administered to a human or non-human mammalian patient. Suitable carriers may be readily selected by one of skill in the art in view of the indication for which the transfer virus is directed. For example, one suitable carrier includes saline, which may be formulated with a variety of buffering solutions (e.g., phosphate buffered saline). Other exemplary carriers include sterile saline, lactose, sucrose, calcium phosphate, gelatin, dextran, agar, pectin, peanut oil, sesame oil, and water. The selection of the carrier is not a limitation of the present invention. Optionally, the compositions of the invention may contain, in addition to the rAAV and carrier(s), other conventional pharmaceutical ingredients, such as preservatives, or chemical stabilizers. Suitable exemplary preservatives include chlorobutanol, potassium sorbate, sorbic acid, sulfur dioxide, propyl gallate, the parabens, ethyl vanillin, glycerin, phenol, and parachlorophenol. Suitable chemical stabilizers include gelatin and albumin. The viral vectors are administered in sufficient amounts to transfect the cells and to provide sufficient levels of gene transfer and expression to provide a therapeutic benefit without undue adverse effects, or with medically acceptable physiological effects, which can be determined by those skilled in the medical arts. Conventional and pharmaceutically acceptable routes of administration include, but are not limited to, direct delivery to the selected organ (e.g., intraportal delivery to the liver), oral, inhalation (including intranasal and intratracheal delivery), intraocular, intravenous, intramuscular, subcutaneous, intradermal, and other parental routes of administration. Routes of administration may be combined, if desired. Dosages of the viral vector will depend primarily on factors such as the condition being treated, the age, weight and health of the patient, and may thus vary among patients. For example, a therapeutically effective human dosage of the viral vector is generally in the range of from about 1 ml to about 100 ml of solution containing concentrations of from about 1×1013 to 1×1016 genomes virus vector. A preferred human dosage may be about 1×1013 to 1×1016 AAV genomes. The dosage will be adjusted to balance the therapeutic benefit against any side effects and such dosages may vary depending upon the therapeutic application for which the recombinant vector is employed. The levels of expression of the transgene can be monitored to determine the frequency of dosage resulting in viral vectors, preferably AAV vectors containing the minigene. Optionally, dosage regimens similar to those described for therapeutic purposes may be utilized for immunization using the compositions of the invention. Examples of therapeutic products and immunogenic products for delivery by the AAV-containing vectors of the invention are provided below. These vectors may be used for a variety of therapeutic or vaccinal regimens, as described herein. Additionally, these vectors may be delivered in combination with one or more other vectors or active ingredients in a desired therapeutic and/or vaccinal regimen. B. Therapeutic Transgenes Useful therapeutic products encoded by the transgene include hormones and growth and differentiation factors including, without limitation, insulin, glucagon, growth hormone (GH), parathyroid hormone (PTH), growth hormone releasing factor (GRF), follicle stimulating hormone (FSH), luteinizing hormone (LH), human chorionic gonadotropin (hCG), vascular endothelial growth factor (VEGF), angiopoietins, angiostatin, granulocyte colony stimulating factor (GCSF), erythropoietin (EPO), connective tissue growth factor (CTGF), basic fibroblast growth factor (bFGF), acidic fibroblast growth factor (aFGF), epidermal growth factor (EGF), transforming growth factor α (TGFα), platelet-derived growth factor (PDGF), insulin growth factors I and II (IGF-I and IGF-II), any one of the transforming growth factor β superfamily, including TGF β, activins, inhibins, or any of the bone morphogenic proteins (BMP) BMPs 1-15, any one of the heregluin/neuregulin/ARIA/neu differentiation factor (NDF) family of growth factors, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophins NT-3 and NT-4/5, ciliary neurotrophic factor (CNTF), glial cell line derived neurotrophic factor (GDNF), neurturin, agrin, any one of the family of semaphorins/collapsins, netrin-1 and netrin-2, hepatocyte growth factor (HGF), ephrins, noggin, sonic hedgehog and tyrosine hydroxylase. Other useful transgene products include proteins that regulate the immune system including, without limitation, cytokines and lymphokines such as thrombopoietin (TPO), interleukins (IL) IL-1 through IL-25 (including, IL-2, IL-4, IL-12, and IL-18), monocyte chemoattractant protein, leukemia inhibitory factor, granulocyte-macrophage colony stimulating factor, Fas ligand, tumor necrosis factors α and β, interferons α, β, and γ, stem cell factor, flk-2/flt3 ligand. Gene products produced by the immune system are also useful in the invention. These include, without limitations, immunoglobulins IgG, IgM, IgA, IgD and IgE, chimeric immunoglobulins, humanized antibodies, single chain antibodies, T cell receptors, chimeric T cell receptors, single chain T cell receptors, class I and class II MHC molecules, as well as engineered immunoglobulins and MHC molecules. Useful gene products also include complement regulatory proteins such as complement regulatory proteins, membrane cofactor protein (MCP), decay accelerating factor (DAF), CR1, CF2 and CD59. Still other useful gene products include any one of the receptors for the hormones, growth factors, cytokines, lymphokines, regulatory proteins and immune system proteins. The invention encompasses receptors for cholesterol regulation, including the low density lipoprotein (LDL) receptor, high density lipoprotein (HDL) receptor, the very low density lipoprotein (VLDL) receptor, and the scavenger receptor. The invention also encompasses gene products such as members of the steroid hormone receptor superfamily including glucocorticoid receptors and estrogen receptors, Vitamin D receptors and other nuclear receptors. In addition, useful gene products include transcription factors such asjun, fos, max, mad, serum response factor (SRF), AP-1, AP2, myb, MyoD and myogenin, ETS-box containing proteins, TFE3, E2F, ATF1, ATF2, ATF3, ATF4, ZF5, NFAT, CREB, HNF-4, C/EBP, SP1, CCAAT-box binding proteins, interferon regulation factor (IRF-1), Wilms tumor protein, ETS-binding protein, STAT, GATA-box binding proteins, e.g., GATA-3, and the forkhead family of winged helix proteins. Other useful gene products include, carbamoyl synthetase I, ornithine transcarbamylase, arginosuccinate synthetase, arginosuccinate lyase, arginase, fumarylacetacetate hydrolase, phenylalanine hydroxylase, alpha-1 antitrypsin, glucose-6-phosphatase, porphobilinogen deaminase, factor VIII, factor IX, cystathione beta-synthase, branched chain ketoacid decarboxylase, albumin, isovaleryl-coA dehydrogenase, propionyl CoA carboxylase, methyl malonyl CoA mutase, glutaryl CoA dehydrogenase, insulin, beta-glucosidase, pyruvate carboxylate, hepatic phosphorylase, phosphorylase kinase, glycine decarboxylase, H-protein, T-protein, a cystic fibrosis transmembrane regulator (CFTR) sequence, and a dystrophin cDNA sequence. Still other useful gene products include enzymes such as may be useful in enzyme replacement therapy, which is useful in a variety of conditions resulting from deficient activity of enzyme. For example, enzymes that contain mannose-6-phosphate may be utilized in therapies for lysosomal storage diseases (e.g., a suitable gene includes that encoding β-glucuronidase (GUSB)). Other useful gene products include non-naturally occurring polypeptides, such as chimeric or hybrid polypeptides having a non-naturally occurring amino acid sequence containing insertions, deletions or amino acid substitutions. For example, single-chain engineered immunoglobulins could be useful in certain immunocompromised patients. Other types of non-naturally occurring gene sequences include antisense molecules and catalytic nucleic acids, such as ribozymes, which could be used to reduce overexpression of a target. Reduction and/or modulation of expression of a gene is particularly desirable for treatment of hyperproliferative conditions characterized by hyperproliferating cells, as are cancers and psoriasis. Target polypeptides include those polypeptides which are produced exclusively or at higher levels in hyperproliferative cells as compared to normal cells. Target antigens include polypeptides encoded by oncogenes such as myb, myc, fyn, and the translocation gene bcr/abl, ras, src, P53, neu, trk and EGRF. In addition to oncogene products as target antigens, target polypeptides for anti-cancer treatments and protective regimens include variable regions of antibodies made by B cell lymphomas and variable regions of T cell receptors of T cell lymphomas which, in some embodiments, are also used as target antigens for autoimmune disease. Other tumor-associated polypeptides can be used as target polypeptides such as polypeptides which are found at higher levels in tumor cells including the polypeptide recognized by monoclonal antibody 17-1A and folate binding polypeptides. Other suitable therapeutic polypeptides and proteins include those which may be useful for treating individuals suffering from autoimmune diseases and disorders by conferring a broad based protective immune response against targets that are associated with autoimmunity including cell receptors and cells which produce Aself≅-directed antibodies. T cell mediated autoimmune diseases include Rheumatoid arthritis (RA), multiple sclerosis (MS), Sjõgren's syndrome, sarcoidosis, insulin dependent diabetes mellitus (IDDM), autoimmune thyroiditis, reactive arthritis, ankylosing spondylitis, scleroderma, polymyositis, dermatomyositis, psoriasis, vasculitis, Wegener's granulomatosis, Crohn's disease and ulcerative colitis. Each of these diseases is characterized by T cell receptors (TCRs) that bind to endogenous antigens and initiate the inflammatory cascade associated with autoimmune diseases. C. Immunogenic Transgenes Alternatively, or in addition, the vectors of the invention may contain AAV sequences of the invention and a transgene encoding a peptide, polypeptide or protein which induces an immune response to a selected immunogen. For example, immunogens may be selected from a variety of viral families. Example of desirable viral families against which an immune response would be desirable include, the picornavirus family, which includes the genera rhinoviruses, which are responsible for about 50% of cases of the common cold; the genera enteroviruses, which include polioviruses, coxsackieviruses, echoviruses, and human enteroviruses such as hepatitis A virus; and the genera apthoviruses, which are responsible for foot and mouth diseases, primarily in non-human animals. Within the picornavirus family of viruses, target antigens include the VP1, VP2, VP3, VP4, and VPG. Another viral family includes the calcivirus family, which encompasses the Norwalk group of viruses, which are an important causative agent of epidemic gastroenteritis. Still another viral family desirable for use in targeting antigens for inducing immune responses in humans and non-human animals is the togavirus family, which includes the genera alphavirus, which include Sindbis viruses, RossRiver virus, and Venezuelan, Eastern & Western Equine encephalitis, and rubivirus, including Rubella virus. The flaviviridae family includes dengue, yellow fever, Japanese encephalitis, St. Louis encephalitis and tick borne encephalitis viruses. Other target antigens may be generated from the Hepatitis C or the coronavirus family, which includes a number of non-human viruses such as infectious bronchitis virus (poultry), porcine transmissible gastroenteric virus (pig), porcine hemagglutinating encephalomyelitis virus (pig), feline infectious peritonitis virus (cats), feline enteric coronavirus (cat), canine coronavirus (dog), and human respiratory coronaviruses, which may cause the common cold and/or non-A, B or C hepatitis. Within the coronavirus family, target antigens include the E1 (also called M or matrix protein), E2 (also called S or Spike protein), E3 (also called HE or hemagglutin-elterose) glycoprotein (not present in all coronaviruses), or N (nucleocapsid). Still other antigens may be targeted against the rhabdovirus family, which includes the genera vesiculovirus (e.g., Vesicular Stomatitis Virus), and the general lyssavirus (e.g., rabies). Within the rhabdovirus family, suitable antigens may be derived from the G protein or the N protein. The family filoviridae, which includes hemorrhagic fever viruses such as Marburg and Ebola virus may be a suitable source of antigens. The paramyxovirus family includes parainfluenza Virus Type 1, parainfluenza Virus Type 3, bovine parainfluenza Virus Type 3, rubulavirus (mumps virus, parainfluenza Virus Type 2, parainfluenza virus Type 4, Newcastle disease virus (chickens), rinderpest, morbillivirus, which includes measles and canine distemper, and pneumovirus, which includes respiratory syncytial virus. The influenza virus is classified within the family orthomyxovirus and is a suitable source of antigen (e.g., the HA protein, the N1 protein). The bunyavirus family includes the genera bunyavirus (California encephalitis, La Crosse), phlebovirus (Rift Valley Fever), hantavirus (puremala is a hemahagin fever virus), nairovirus (Nairobi sheep disease) and various unassigned bungaviruses. The arenavirus family provides a source of antigens against LCM and Lassa fever virus. The reovirus family includes the genera reovirus, rotavirus (which causes acute gastroenteritis in children), orbiviruses, and cultivirus (Colorado Tick fever, Lebombo (humans), equine encephalosis, blue tongue). The retrovirus family includes the sub-family oncorivirinal which encompasses such human and veterinary diseases as feline leukemia virus, HTLVI and HTLVII, lentivirinal (which includes human immunodeficiency virus (HIV), simian immunodeficiency virus (SIV), feline immunodeficiency virus (FIV), equine infectious anemia virus, and spumavirinal). Between the HIV and SIV, many suitable antigens have been described and can readily be selected. Examples of suitable HIV and SIV antigens include, without limitation the gag, pol, Vif, Vpx, VPR, Env, Tat and Rev proteins, as well as various fragments thereof. In addition, a variety of modifications to these antigens have been described. Suitable antigens for this purpose are known to those of skill in the art. For example, one may select a sequence encoding the gag, pol, Vif, and Vpr, Env, Tat and Rev, amongst other proteins. See, e.g., the modified gag protein which is described in U.S. Pat. No. 5,972,596. See, also, the HIV and SIV proteins described in D. H. Barouch et al, J. Virol., 75(5):2462-2467 (March 2001), and R. R. Amara, et al, Science, 292:69-74 (6 Apr. 2001). These proteins or subunits thereof may be delivered alone, or in combination via separate vectors or from a single vector. The papovavirus family includes the sub-family polyomaviruses (BKU and JCU viruses) and the sub-family papillomavirus (associated with cancers or malignant progression of papilloma). The adenovirus family includes viruses (EX, AD7, ARD, O.B.) which cause respiratory disease and/or enteritis. The parvovirus family feline parvovirus (feline enteritis), feline panleucopeniavirus, canine parvovirus, and porcine parvovirus. The herpesvirus family includes the sub-family alphaherpesvirinae, which encompasses the genera simplexvirus (HSVI, HSVII), varicellovirus (pseudorabies, varicella zoster) and the sub-family betaherpesvirinae, which includes the genera cytomegalovirus (HCMV, muromegalovirus) and the sub-family gammaherpesvirinae, which includes the genera lymphocryptovirus, EBV (Burkitts lymphoma), infectious rhinotracheitis, Marek=s disease virus, and rhadinovirus. The poxvirus family includes the sub-family chordopoxvirinae, which encompasses the genera orthopoxvirus (Variola (Smallpox) and Vaccinia (Cowpox)), parapoxvirus, avipoxvirus, capripoxvirus, leporipoxvirus, suipoxvirus, and the sub-family entomopoxvirinae. The hepadnavirus family includes the Hepatitis B virus. One unclassified virus which may be suitable source of antigens is the Hepatitis delta virus. Still other viral sources may include avian infectious bursal disease virus and porcine respiratory and reproductive syndrome virus. The alphavirus family includes equine arteritis virus and various Encephalitis viruses. The present invention may also encompass immunogens which are useful to immunize a human or non-human animal against other pathogens including bacteria, fungi, parasitic microorganisms or multicellular parasites which infect human and non-human vertebrates, or from a cancer cell or tumor cell. Examples of bacterial pathogens include pathogenic gram-positive cocci include pneumococci; staphylococci; and streptococci. Pathogenic gram-negative cocci include meningococcus; gonococcus. Pathogenic enteric gram-negative bacilli include enterobacteriaceae; pseudomonas, acinetobacteria and eikenella; melioidosis; salmonella; shigella; haemophilus; moraxella; H. ducreyi (which causes chancroid); brucella; Franisella tularensis (which causes tularemia); yersinia (pasteurella); streptobacillus moniliformis and spirillum; Gram-positive bacilli include listeria monocytogenes; erysipelothrix rhusiopathiae; Corynebacterium diphtheria (diphtheria); cholera; B. anthracis (anthrax); donovanosis (granuloma inguinale); and bartonellosis. Diseases caused by pathogenic anaerobic bacteria include tetanus; botulism; other clostridia; tuberculosis; leprosy; and other mycobacteria. Pathogenic spirochetal diseases include syphilis; treponematoses: yaws, pinta and endemic syphilis; and leptospirosis. Other infections caused by higher pathogen bacteria and pathogenic fungi include actinomycosis; nocardiosis; cryptococcosis, blastomycosis, histoplasmosis and coccidioidomycosis; candidiasis, aspergillosis, and mucormycosis; sporotrichosis; paracoccidiodomycosis, petriellidiosis, torulopsosis, mycetoma and chromomycosis; and dermatophytosis. Rickettsial infections include Typhus fever, Rocky Mountain spotted fever, Q fever, and Rickettsialpox. Examples of mycoplasma and chlamydial infections include: mycoplasma pneumoniae; lymphogranuloma venereum; psittacosis; and perinatal chlamydial infections. Pathogenic eukaryotes encompass pathogenic protozoans and helminths and infections produced thereby include: amebiasis; malaria; leishmaniasis; trypanosomiasis; toxoplasmosis; Pneumocystis carinii; Trichans; Toxoplasma gondii; babesiosis; giardiasis; trichinosis; filariasis; schistosomiasis; nematodes; trematodes or flukes; and cestode (tapeworm) infections. Many of these organisms and/or toxins produced thereby have been identified by the Centers for Disease Control [(CDC), Department of Heath and Human Services, USA], as agents which have potential for use in biological attacks. For example, some of these biological agents, include, Bacillus anthracis (anthrax), Clostridium botulinum and its toxin (botulism), Yersinia pestis (plague), variola major (smallpox), Francisella tularensis (tularemia), and viral hemorrhagic fever, all of which are currently classified as Category A agents; Coxiella burnetti (Q fever); Brucella species (brucellosis), Burkholderia mallei (glanders), Ricinus communis and its toxin (ricin toxin), Clostridium perfringens and its toxin (epsilon toxin), Staphylococcus species and their toxins (enterotoxin B), all of which are currently classified as Category B agents; and Nipan virus and hantaviruses, which are currently classified as Category C agents. In addition, other organisms, which are so classified or differently classified, may be identified and/or used for such a purpose in the future. It will be readily understood that the viral vectors and other constructs described herein are useful to deliver antigens from these organisms, viruses, their toxins or other by-products, which will prevent and/or treat infection or other adverse reactions with these biological agents. Administration of the vectors of the invention to deliver immunogens against the variable region of the T cells elicit an immune response including CTLs to eliminate those T cells. In rheumatoid arthritis (RA), several specific variable regions of T cell receptors (TCRs) which are involved in the disease have been characterized. These TCRs include V-3, V-14, V-17 and Vα-17. Thus, delivery of a nucleic acid sequence that encodes at least one of these polypeptides will elicit an immune response that will target T cells involved in RA. In multiple sclerosis (MS), several specific variable regions of TCRs which are involved in the disease have been characterized. These TCRs include V-7 and Vα-10. Thus, delivery of a nucleic acid sequence that encodes at least one of these polypeptides will elicit an immune response that will target T cells involved in MS. In scleroderma, several specific variable regions of TCRs which are involved in the disease have been characterized. These TCRs include V-6, V-8, V-14 and Vα-16, Vα-3C, Vα-7, Vα-14, Vα-15, Vα-16, Vα-28 and Vα-12. Thus, delivery of a nucleic acid molecule that encodes at least one of these polypeptides will elicit an immune response that will target T cells involved in scleroderma. Optionally, vectors containing AAV sequences of the invention may be delivered using a prime-boost regimen. A variety of such regimens have been described in the art and may be readily selected. See, e.g., WO 00/11140, published Mar. 2, 2000, incorporated by reference. Such prime-boost regimens typically involve the administration of a DNA (e.g., plasmid) based vector to prime the immune system to second, booster, administration with a traditional antigen, such as a protein or a recombinant virus carrying the sequences encoding such an antigen. In one embodiment, the invention provides a method of priming and boosting an immune response to a selected antigen by delivering a plasmid DNA vector carrying said antigen, followed by boosting, e.g., with a vector containing AAV sequences of the invention. In one embodiment, the prime-boost regimen involves the expression of multiproteins from the prime and/or the boost vehicle. See, e.g., R. R. Amara, Science, 292:69-74 (6 Apr. 2001) which describes a multiprotein regimen for expression of protein subunits useful for generating an immune response against HIV and SIV. For example, a DNA prime may deliver the Gag, Pol, Vif, VPX and Vpr and Env, Tat, and Rev from a single transcript. Alternatively, the SIV Gag, Pol and HIV-1 Env is delivered. However, the prime-boost regimens are not limited to immunization for HIV or to delivery of these antigens. For example, priming may involve delivering with a first chimp vector of the invention followed by boosting with a second chimp vector, or with a composition containing the antigen itself in protein form. In one or example, the prime-boost regimen can provide a protective immune response to the virus, bacteria or other organism from which the antigen is derived. In another desired embodiment, the prime-boost regimen provides a therapeutic effect that can be measured using convention assays for detection of the presence of the condition for which therapy is being administered. The priming vaccine may be administered at various sites in the body in a dose dependent manner, which depends on the antigen to which the desired immune response is being targeted. The invention is not limited to the amount or situs of injection(s) or to the pharmaceutical carrier. Rather, the priming step encompasses treatment regimens which include a single dose or dosage which is administered hourly, daily, weekly or monthly, or yearly. As an example, the mammals may receive one or two priming injection containing between about 10 μg to about 50 μg of plasmid in carrier. A desirable priming amount or dosage of the priming DNA vaccine composition ranges between about 1 μg to about 10,000 μg of the DNA vaccine. Dosages may vary from about 1 μg to 1000 μg DNA per kg of subject body weight. The amount or site of injection is desirably selected based upon the identity and condition of the mammal being vaccinated. The dosage unit of the DNA vaccine suitable for delivery of the antigen to the mammal is described herein. The DNA vaccine is prepared for administration by being suspended or dissolved in a pharmaceutically or physiologically acceptable carrier such as isotonic saline, isotonic salts solution or other formulations which will be apparent to those skilled in such administration. The appropriate carrier will be evident to those skilled in the art and will depend in large part upon the route of administration. The compositions of the invention may be administered to a mammal according to the routes described above, in a sustained release formulation using a biodegradable biocompatible polymer, or by on-site delivery using micelles, gels and liposomes. Optionally, the priming step of this invention also includes administering with the priming DNA vaccine composition, a suitable amount of an adjuvant, such as are defined herein. Preferably, a boosting composition is administered about 2 to about 27 weeks after administering the priming DNA vaccine to the mammalian subject. The administration of the boosting composition is accomplished using an effective amount of a boosting vaccine composition containing or capable of delivering the same antigen as administered by the priming DNA vaccine. The boosting composition may be composed of a recombinant viral vector derived from the same viral source or from another source. Alternatively, the “boosting composition” can be a composition containing the same antigen as encoded in the priming DNA vaccine, but in the form of a protein or peptide, which composition induces an immune response in the host. In another embodiment, the boosting vaccine composition includes a composition containing a DNA sequence encoding the antigen under the control of a regulatory sequence directing its expression in a mammalian cell, e.g., vectors such as well-known bacterial or viral vectors. The primary requirements of the boosting vaccine composition are that the antigen of the vaccine composition is the same antigen, or a cross-reactive antigen, as that encoded by the DNA vaccine. Suitably, the vectors of the invention are also well suited for use in regimens which use non-AAV vectors as well as proteins, peptides, and/or other biologically useful therapeutic or immunogenic compounds. These regimens are particularly well suited to gene delivery for therapeutic poses and for immunization, including inducing protective immunity. Such uses will be readily apparent to one of skill in the art. Further, a vector of the invention provides an efficient gene transfer vehicle which can deliver a selected transgene to a selected host cell in vivo or ex vivo even where the organism has neutralizing antibodies to one or more AAV serotypes. In one embodiment, the vector (e.g., an rAAV) and the cells are mixed ex vivo; the infected cells are cultured using conventional methodologies; and the transduced cells are re-infused into the patient. Further, the vectors of the invention may also be used for production of a desired gene product in vitro. For in vitro production, a desired product (e.g., a protein) may be obtained from a desired culture following transfection of host cells with a rAAV containing the molecule encoding the desired product and culturing the cell culture under conditions which permit expression. The expressed product may then be purified and isolated, as desired. Suitable techniques for transfection, cell culturing, purification, and isolation are known to those of skill in the art. The following examples illustrate several aspects and embodiments of the invention. EXAMPLES Example 1: PCR Amplification, Cloning and Characterization of Novel AAV Sequences Tissues from nonhuman primates were screened for AAV sequences using a PCR method based on oligonucleotides to highly conserved regions of known AAVs. A stretch of AAV sequence spanning 2886 to 3143 bp of AAV1 [SEQ ID NO:6] was selected as a PCR amplicon in which a hypervariable region of the capsid protein (Cap) that is unique to each known AAV serotype, which is termed herein a “signature region,” is flanked by conserved sequences. In later analysis, this signature region was shown to be located between conserved residues spanning hypervariable region 3. An initial survey of peripheral blood of a number of nonhuman primate species revealed detectable AAV in a subset of animals from species such as rhesus macaques, cynomologous macaques, chimpanzees and baboons. However, there were no AAV sequences detected in some other species tested, including Japanese macaques, pig-tailed macaques and squirrel monkeys. A more extensive analysis of vector distribution was conducted in tissues of rhesus monkeys of the University of Pennsylvania and Tulane colonies recovered at necropsy. This revealed AAV sequence throughout a wide array of tissues. A. Amplification of an AAV Signature Region DNA sequences of AAV1-6 and AAVs isolated from Goose and Duck were aligned to each other using “Clustal W” at default settings. The alignment for AAV1-6, and including the information for the novel AAV7, is provided in FIG. 1. Sequence similarities among AAVs were compared. In the line of study, a 257 bp region spanning 2886 bp to 3143 bp of AAV 1 [SEQ ID NO: 6], and the corresponding region in the genomes of AAV 2-6 genomes [See, FIG. 1], was identified by the inventors. This region is located with the AAV capsid gene and has highly conserved sequences among at both 5′ and 3′ ends and is relatively variable sequence in the middle. In addition, this region contains a DraIII restriction enzyme site (CACCACGTC, SEQ ID NO: 15). The inventors have found that this region serves as specific signature for each known type of AAV DNA. In other words, following PCR reactions, digestion with endonucleases that are specific to each known serotypes and gel electrophoresis analysis, this regions can be used to definitively identify amplified DNA as being from serotype 1, 2, 3, 4, 5, 6, or another serotype. The primers were designed, validated and PCR conditions optimized with AAV1, 2 and 5 DNA controls. The primers were based upon the sequences of AAV2: 5′ primer, 1S: bp 2867-2891 of AAV2 (SEQ ID NO:7) and 3′ primer, 18as, bp 3095-3121 of AAV2 (SEQ ID NO:7). Cellular DNAs from different tissues including blood, brain, liver, lung, testis, etc. of different rhesus monkeys were studied utilizing the strategy described above. The results revealed that DNAs from different tissues of these monkeys gave rise to strong PCR amplifications. Further restriction analyses of PCR products indicated that they were amplified from AAV sequences different from any published AAV sequences. PCR products (about 255 bp in size) from DNAs of a variety of monkey tissues have been cloned and sequenced. Bioinformatics study of these novel AAV sequences indicated that they are novel AAV sequences of capsid gene and distinct from each other. FIG. 1 includes in the alignment the novel AAV signature regions for AAV10-12 [SEQ ID NO: 117, 118 and 119, respectively]. Multiple sequence alignment analysis was performed using the Clustal W (1.81) program. The percentage of sequence identity between the signature regions of AAV 1-7 and AAV 10-12 genomes is provided below. TABLE 2 Sequences for Analysis Sequence # AAV Serotype Size (bp) 1 AAV1 258 2 AAV2 255 3 AAV3 255 4 AAV4 246 5 AAV5 258 6 AAV6 258 7 AAV7 258 10 AAV10 255 11 AAV11 258 12 AAV12 255 TABLE 3 Pairwise Alignment (Percentage of Identity) AAV2 AAV3 AAV4 AAV5 AAV6 AAV7 AAV10 AAV11 AAV12 AAV1 90 90 81 76 97 91 93 94 93 AAV2 93 79 78 90 90 93 93 92 AAV3 80 76 90 92 92 92 92 AAV4 76 81 84 82 81 79 AAV5 75 78 79 79 76 AAV6 91 92 94 94 AAV7 94 92 92 AAV10 95 93 AAV11 94 Over 300 clones containing novel AAV serotype sequences that span the selected 257 bp region were isolated and sequenced. Bioinformatics analysis of these 300+ clones suggests that this 257 bp region is critical in serving as a good land marker or signature sequence for quick isolation and identification of novel AAV serotype. B. Use of the Signature Region for PCR Amplification. The 257 bp signature region was used as a PCR anchor to extend PCR amplifications to 5′ of the genome to cover the junction region of rep and cap genes (1398 bp-3143 bp, SEQ ID NO:6) and 3′ of the genome to obtain the entire cap gene sequence (2866 bp-4600 bp, SEQ ID NO:6). PCR amplifications were carried out using the standard conditions, including denaturing at 95° C. for 0.5-1 min, annealing at 60-65° C. for 0.5-1 min and extension at 72° C. for 1 min per kb with a total number of amplification cycles ranging from 28 to 42. Using the aligned sequences as described in “A”, two other relative conserved regions were identified in the sequence located in 3′ end of rep genes and 5′ to the 257 bp region and in the sequence down stream of the 257 bp fragment but before the AAV′ 3 ITR. Two sets of new primers were designed and PCR conditions optimized for recovery of entire capsid and a part of rep sequences of novel AAV serotypes. More specifically, for the 5′ amplification, the 5′ primer, AV1Ns, was GCTGCGTCAACTGGACCAATGAGAAC [nt 1398-1423 of AAV1, SEQ ID NO:6] and the 3′ primer was 18as, identified above. For the 3′ amplification, the 5′ primer was is, identified above, and the 3′ primer was AV2Las, TCGTTTCAGTTGAACTTTGGTCTCTGCG [nt 4435-4462 of AAV2, SEQ ID NO:7]. In these PCR amplifications, the 257 bp region was used as a PCR anchor and land marker to generate overlapping fragments to construct a complete capsid gene by fusion at the DraIII site in the signature region following amplification of the 5′ and 3′ extension fragments obtained as described herein. More particularly, to generate the intact AAV7 cap gene, the three amplification products (a) the sequences of the signature region; (b) the sequences of the 5′ extension; and (c) the sequences of the 3′ extension were cloned into a pCR4-Topo [Invitrogen] plasmid backbone according to manufacturer's instructions. Thereafter, the plasmids were digested with DraIII and recombined to form an intact cap gene. In this line of work, about 80% of capsid sequences of AAV7 and AAV 8 were isolated and analyzed. Another novel serotype, AAV9, was also discovered from Monkey #2. Using the PCR conditions described above, the remaining portion of the rep gene sequence for AAV7 is isolated and cloned using the primers that amplify 108 bp to 1461 bp of AAV genome (calculated based on the numbering of AAV2, SEQ ID NO:7). This clone is sequenced for construction of a complete AAV7 genome without ITRs. C. Direct Amplification of 3.1 kb Cap Fragment To directly amplify a 3.1 kb full-length Cap fragment from NHP tissue and blood DNAs, two other highly conserved regions were identified in AAV genomes for use in PCR amplification of large fragments. A primer within a conserved region located in the middle of the rep gene was selected (AV Ins: 5′ GCTGCGTCAACTGGACCAATGAGAAC 3′, nt 1398-1423 of SEQ ID NO:6) in combination with the 3′ primer located in another conserved region downstream of the Cap gene (AV2cas: 5′ CGCAGAGACCAAAGTTCAACTGAAACGA 3′, SEQ ID NO:7) for amplification of full-length cap fragments. The PCR products were Topo-cloned according to manufacturer's directions (Invitrogen) and sequence analysis was performed by Qiagengenomics (Qiagengenomics, Seattle, Wash.) with an accuracy of ≧99.9%. A total of 50 capsid clones were isolated and characterized. Among them, 37 clones were derived from Rhesus macaque tissues (rh.1-rh.37), 6 clones from cynomologous macaques (cy.1-cy.6), 2 clones from Baboons (bb.1 and bb.2) and 5 clones from Chimps (ch.1-ch.5). To rule out the possibility that sequence diversity within the novel AAV family was not an artifact of the PCR, such as PCR-mediated gene splicing by overlap extension between different partial DNA templates with homologous sequences, or the result of recombination process in bacteria, a series of experiments were performed under identical conditions for VP1 amplification using total cellular DNAs. First, intact AAV7 and AAV8 plasmids were mixed at an equal molar ratio followed by serial dilutions. The serially diluted mixtures were used as templates for PCR amplification of 3.1 kb VP1 fragments using universal primers and identical PCR conditions to that were used for DNA amplifications to see whether any hybrid PCR products were generated. The mixture was transformed into bacteria and isolated transformants to look for hybrid clones possibly derived from recombination process in bacterial cells. In a different experiment, we restricted AAV7 and AAV8 plasmids with Msp I, Ava I and HaeI, all of which cut both genomes multiple times at different positions, mixed the digestions in different combinations and used them for PCR amplification of VP1 fragments under the same conditions to test whether any PCR products could be generated through overlap sequence extension of partial AAV sequences. In another experiment, a mixture of gel purified 5′ 1.5 kb AAV7 VP1 fragment and 3′ 1.7 kb AAV8 VP1 fragment with overlap in the signature region was serially diluted and used for PCR amplification in the presence and absence of 200 ng cellular DNA extracted from a monkey cell line that was free of AAV sequences by TaqMan analysis. None of these experiments demonstrated efficient PCR-mediated overlap sequence production under the conditions of the genomic DNA Cap amplification (data not shown). As a further confirmation, 3 pairs of primers were designed, which were located at different HVRs, and were sequence specific to the variants of clone 42s from Rhesus macaque F953, in different combinations to amplify shorter fragments from mesenteric lymph node (MLN) DNA from F953 from which clone 42s were isolated. All sequence variations identified in full-length Cap clones were found in these short fragments (data not shown). Example 2: Adeno-Associated Viruses Undergo Substantial Evolution in Primates During Natural Infections Sequence analysis of selected AAV isolates revealed divergence throughout the genome that is most concentrated in hypervariable regions of the capsid proteins. Epidemiologic data indicate that all known serotypes are endemic to primates, although isolation of clinical isolates has been restricted to AAV2 and AAV3 from anal and throat swabs of human infants and AAV5 from a human condylomatous wart. No known clinical sequalae have been associated with AAV infection. In an attempt to better understand the biology of AAV, nonhuman primates were used as models to characterize the sequlae of natural infections. Tissues from nonhuman primates were screened for AAV sequences using the PCR method of the invention based on oligonucleotides to highly conserved regions of known AAVs (see Example 1). A stretch of AAV sequence spanning 2886 to 3143 bp of AAV1 [SEQ ID NO:6] was selected as a PCR amplicon in which conserved sequences are flanked by a hypervariable region that is unique to each known AAV serotype, termed herein a “signature region.” An initial survey of peripheral blood of a number of nonhuman primate species including rhesus monkeys, cynomologous monkeys, chimpanzees, and baboons revealed detectable AAV in a subset of animals from all species. A more extensive analysis of vector distribution was conducted in tissues of rhesus monkeys of the University of Pennsylvania and Tulane colonies recovered at necropsy. This revealed AAV sequence throughout a wide array of tissues. The amplified signature sequences were subcloned into plasmids and individual transformants were subjected to sequence analysis. This revealed substantial variation in nucleotide sequence of clones derived from different animals. Variation in the signature sequence was also noted in clones obtained within individual animals. Tissues harvested from two animals in which unique signature sequences were identified (i.e., colon from 98E044 and heart from 98E056) were further characterized by expanding the sequence amplified by PCR using oligonucleotides to highly conserved sequences. In this way, complete proviral structures were reconstructed for viral genomes from both tissues as described herein. These proviruses differ from the other known AAVs with the greatest sequence divergence noted in regions of the Cap gene. Additional experiments were performed to confirm that AAV sequences resident to the nonhuman primate tissue represented proviral genomes of infectious virus that is capable of being rescued and form virions. Genomic DNA from liver tissue of animal 98E056, from which AAV8 signature sequence was detected, was digested with an endonuclease that does not have a site within the AAV sequence and transfected into 293 cells with a plasmid containing an E1 deleted genome of human adenovirus serotype 5 as a source of helper functions. The resulting lysate was passaged on 293 cells once and the lysate was recovered and analyzed for the presence of AAV Cap proteins using a broadly reacting polyclonal antibody to Cap proteins and for the presence and abundance of DNA sequences from the PCR amplified AAV provirus from which AAV8 was derived. Transfection of endonuclease restricted heart DNA and the adenovirus helper plasmid yielded high quantities of AAV8 virus as demonstrated by the detection of Cap proteins by Western blot analysis and the presence of 104 AAV8 vector genomes per 293 cell. Lysates were generated from a large-scale preparation and the AAV was purified by cesium sedimentation. The purified preparation demonstrated 26 nm icosohedral structures that look identical to those of AAV serotype 2. Transfection with the adenovirus helper alone did not yield AAV proteins or genomes, ruling out contamination as a source of the rescued AAV. To further characterize the inter and intra animal variation of AAV signature sequence, selected tissues were subjected to extended PCR to amplify entire Cap open reading frames. The resulting fragments were cloned into bacterial plasmids and individual transformants were isolated and fully sequenced. This analysis involved mesenteric lymph nodes from three rhesus monkeys (Tulane/V223—6 clones; Tulane/T612—7 clones; Tulane/F953—14 clones), liver from two rhesus monkeys (Tulane/V251—3 clones; Penn/00E033—3 clones), spleen from one rhesus monkey (Penn/97E043—3 clones), heart from one rhesus monkey (IHGT/98E046—1 clone) and peripheral blood from one chimpanzee (New Iberia/X133—5 clones), six cynomologous macaques (Charles River/A 1378, A3099, A3388, A3442, A2821, A3242—6 clones total) and one Baboon (SFRB/8644—2 clones). Of the 50 clones that were sequenced from 15 different animals, 30 were considered non-redundant based on the finding of at least 7 amino acid differences from one another. The non-redundant VP1 clones are numbered sequentially as they were isolated, with a prefix indicating the species of non-human primate from which they were derived. The structural relationships between these 30 non-redundant clones and the previously described 8 AAV serotypes were determined using the SplitsTree program [Huson, D. H. SplitsTree: analyzing and visualizing evolutionary data. Bioinformatics 14, 68-73 (1998)] with implementation of the method of split decomposition. The analysis depicts homoplasy between a set of sequences in a tree-like network rather than a bifurcating tree. The advantage is to enable detection of groupings that are the result of convergence and to exhibit phylogenetic relationships even when they are distorted by parallel events. Extensive phylogenetic research will be required in order to elucidate the AAV evolution, whereas the intention here only is to group the different clones as to their sequence similarity. To confirm that the novel VP1 sequences were derived from infectious viral genomes, cellular DNA from tissues with high abundance of viral DNA was restricted with an endonuclease that should not cleave within AAV and transfected into 293 cells, followed by infection with adenovirus. This resulted in rescue and amplification of AAV genomes from DNA of tissues from two different animals (data not shown). VP1 sequences of the novel AAVs were further characterized with respect to the nature and location of amino acid sequence variation. All 30 VP1 clones that were shown to differ from one another by greater than 1% amino acid sequence were aligned and scored for variation at each residue. An algorithm developed to determine areas of sequence divergence yielded 12 hypervariable regions (HVR) of which 5 overlap or are part of the 4 previously described variable regions [Kotin, cited above; Rutledge, cited above]. The three-fold-proximal peaks contain most of the variability (HVR5-10). Interestingly the loops located at the 2 and 5 fold axis show intense variation as well. The HVRs 1 and 2 occur in the N-terminal portion of the capsid protein that is not resolved in the X-ray structure suggesting that the N-terminus of the VP1 protein is exposed on the surface of the virion. Real-time PCR was used to quantify AAV sequences from tissues of 21 rhesus monkeys using primers and probes to highly conserved regions of Rep (one set) and Cap (two sets) of known AAVs. Each data point represents analysis from tissue DNA from an individual animal. This confirmed the wide distribution of AAV sequences, although the quantitative distribution differed between individual animals. The source of animals and previous history or treatments did not appear to influence distribution of AAV sequences in rhesus macaques. The three different sets of primers and probes used to quantify AAV yielded consistent results. The highest levels of AAV were found consistently in mesenteric lymph nodes at an average of 0.01 copies per diploid genome for 13 animals that were positive. Liver and spleen also contained high abundance of virus DNA. There were examples of very high AAV, such as in heart of rhesus macaque 98E056, spleen of rhesus macaque 97E043 and liver of rhesus macaque RQ4407, which demonstrated 1.5, 3 and 20 copies of AAV sequence per diploid genome respectively. Relatively low levels of virus DNA were noted in peripheral blood mononuclear cells, suggesting the data in tissue are not due to resident blood components (data not shown). It should be noted that this method would not necessarily capture all AAVs resident to the nonhuman primates since detection requires high homology to both the oligonucleotides and the real time PCR probe. Tissues from animals with high abundance AAV DNA was further analyzed for the molecular state of the DNA, by DNA hybridization techniques, and its cellular distribution, by in situ hybridization. The kind of sequence variation revealed in AAV proviral fragments isolated from different animals and within tissues of the same animals is reminiscent of the evolution that occurs for many RNA viruses during pandemics or even within the infection of an individual. In some situations the notion of a wild-type virus has been replaced by the existence of swarms of quasispecies that evolve as a result of rapid replication and mutations in the presence of selective pressure. One example is infection by HIV, which evolves in response to immunologic and pharmacologic pressure. Several mechanisms contribute to the high rate of mutations in RNA viruses, including low fidelity and lack of proof reading capacity of reverse transcriptase and non-homologous and homologous recombination. Evidence for the formation of quasispecies of AAV was illustrated in this study by the systematic sequencing of multiple cloned proviral fragments. In fact, identical sequences could not be found within any extended clones isolated between or within animals. An important mechanism for this evolution of sequence appears to be a high rate of homologous recombination between a more limited number of parenteral viruses. The net result is extensive swapping of hypervariable regions of the Cap protein leading to an array of chimeras that could have different tropisms and serologic specificities (i.e., the ability to escape immunologic responses especially as it relates to neutralizing antibodies). Mechanisms by which homologous recombination could occur are unclear. One possibility is that + and − strands of different single stranded AAV genomes anneal during replication as has been described during high multiplicity of infections with AAV recombinants. It is unclear if other mechanisms contribute to sequence evolution in AAV infections. The overall rate of mutation that occurs during AAV replication appears to be relatively low and the data do not suggest high frequencies of replication errors. However, substantial rearrangements of the AAV genome have been described during lytic infection leading to the formation of defective interfering particles. Irrespective of the mechanisms that lead to sequence divergence, with few exceptions, vp1 structures of the quasispecies remained intact without frameshifts or nonsense mutations suggesting that competitive selection of viruses with the most favorable profile of fitness contribute to the population dynamics. These studies have implications in several areas of biology and medicine. The concept of rapid virus evolution, formerly thought to be a property restricted to RNA viruses, should be considered in DNA viruses, which classically have been characterized by serologic assays. It will be important in terms of parvoviruses to develop a new method for describing virus isolates that captures the complexity of its structure and biology, such as with HIV, which are categorized as general families of similar structure and function called Clades. An alternative strategy is to continue to categorize isolates with respect to serologic specificity and develop criteria for describing variants within serologic groups. Example 3: Vectorology of Recombinant AAV Genomes Equipped with AAV2 ITRs Using Chimeric Plasmids Containing AAV2 Rep and Novel AAV Cap Genes for Serological and Gene Transfer Studies in Different Animal Models Chimeric packaging constructs are generated by fusing AAV2 rep with cap sequences of novel AAV serotypes. These chimeric packaging constructs are used, initially, for pseudotyping recombinant AAV genomes carrying AAV2 ITRs by triple transfection in 293 cell using Ad5 helper plasmid. These pseudotyped vectors are used to evaluate performance in transduction-based serological studies and evaluate gene transfer efficiency of novel AAV serotypes in different animal models including NHP and rodents, before intact and infectious viruses of these novel serotypes are isolated. A. pAAV2GFP The AAV2 plasmid which contains the AAV2 ITRs and green fluorescent protein expressed under the control of a constitutitive promoter. This plasmid contains the following elements: the AAV2 ITRs, a CMV promoter, and the GFP coding sequences. B. Cloning of Trans Plasmid To construct the chimeric trans-plasmid for production of recombinant pseudotyped AAV7 vectors, p5E18 plasmid (Xiao et al., 1999, J. Virol 73:3994-4003) was partially digested with Xho I to linearize the plasmid at the Xho I site at the position of 3169 bp only. The Xho I cut ends were then filled in and ligated back. This modified p5E18 plasmid was restricted with Xba I and Xho I in a complete digestion to remove the AAV2 cap gene sequence and replaced with a 2267 bp Spe I/Xho I fragment containing the AAV7 cap gene which was isolated from pCRAAV7 6-5+15-4 plasmid. The resulting plasmid contains the AAV2 rep sequences for Rep78/68 under the control of the AAV2 P5 promoter, and the AAV2 rep sequences for Rep52/40 under the control of the AAV2 P19 promoter. The AAV7 capsid sequences are under the control of the AAV2 P40 promoter, which is located within the Rep sequences. This plasmid further contains a spacer 5′ of the rep ORF. C. Production of Pseudotyped rAAV The rAAV particles (AAV2 vector in AAV7 capsid) are generated using an adenovirus-free method. Briefly, the cis plasmid (pAAV2.1 lacZ plasmid containing AAV2 ITRs), and the trans plasmid pCRAAV7 6-5+15-4 (containing the AAV2 rep and AAV7 cap) and a helper plasmid, respectively, were simultaneously co-transfected into 293 cells in a ratio of 1:1:2 by calcium phosphate precipitation. For the construction of the pAd helper plasmids, pBG10 plasmid was purchased from Microbix (Canada). A RsrII fragment containing L2 and L3 was deleted from pBHG10, resulting in the first helper plasmid, pAdΔF13. Plasmid AdΔ F1 was constructed by cloning Asp700/SalI fragment with a PmeI/SgfI deletion, isolating from pBHG10, into Bluescript. MLP, L2, L2 and L3 were deleted in the pAdΔF1. Further deletions of a 2.3 kb NruI fragment and, subsequently, a 0.5 kb RsrII/NruI fragment generated helper plasmids pAdΔF5 and pAdΔF6, respectively. The helper plasmid, termed pΔF6, provides the essential helper functions of E2a and E4 ORF6 not provided by the E1-expressing helper cell, but is deleted of adenoviral capsid proteins and functional E1 regions). Typically, 50 μg of DNA (cis:trans:helper) was transfected onto a 150 mm tissue culture dish. The 293 cells were harvested 72 hours post-transfection, sonicated and treated with 0.5% sodium deoxycholate (37EC for 10 min.) Cell lysates were then subjected to two rounds of a CsCl gradient. Peak fractions containing rAAV vector are collected, pooled and dialyzed against PBS. Example 4: Creation of Infectious Clones Carrying Intact Novel AAV Serotypes for Study of Basic Virology in Human and NHP Derived Cell Lines and Evaluation of Pathogenesis of Novel AAV Serotypes in NHP and Other Animal Models To achieve this goal, the genome walker system is employed to obtain 5′ and 3′ terminal sequences (ITRs) and complete construction of clones containing intact novel AAV serotype genomes. Briefly, utilizing a commercially available Universal Genome Walker Kit [Clontech], genomic DNAs from monkey tissues or cell lines that are identified as positive for the presence of AAV7 sequence are digested with Dra I, EcoR V, Pvu II and Stu I endonucleases and ligated to Genome Walker Adaptor to generate 4 individual Genome Walker Libraries (GWLs). Using DNAs from GWLs as templates, AAV7 and adjacent genomic sequences will be PCR-amplified by the adaptor primer 1 (AP 1, provided in the kit) and an AAV7 specific primer 1, followed by a nested PCR using the adaptor primer 2 (AP2) and another AAV7 specific primer 2, both of which are internal to the first set of primers. The major PCR products from the nested PCR are cloned and characterized by sequencing analysis. In this experiment, the primers covering the 257 bp or other signature fragment of a generic AAV genome are used for PCR amplification of cellular DNAs extracted from Human and NHP derived cell lines to identify and characterize latent AAV sequences. The identified latent AAV genomes are rescued from the positive cell lines using adenovirus helpers of different species and strains. To isolate infectious AAV clones from NHP derived cell lines, a desired cell line is obtained from ATCC and screened by PCR to identify the 257 bp amplicon, i.e., signature region of the invention. The 257 bp PCR product is cloned and serotyped by sequencing analysis. For these cell lines containing the AAV7 sequence, the cells are infected with SV-15, a simian adenovirus purchased from ATCC, human Ad5 or transfected with plasmid construct housing the human Ad genes that are responsible for AAV helper functions. At 48 hour post infection or transfection, the cells are harvested and Hirt DNA is prepared for cloning of AAV7 genome following Xiao et al., 1999, J. Virol, 73:3994-4003. Example 5—Production of AAV Vectors A pseudotyping strategy similar to that of Example 3 for AAV1/7 was employed to produce AAV2 vectors packaged with AAV1, AAV5 and AAV8 capsid proteins. Briefly, recombinant AAV genomes equipped with AAV2 ITRs were packaged by triple transfection of 293 cells with cis-plasmid, adenovirus helper plasmid and a chimeric packaging construct where the AAV2 rep gene is fused with cap genes of novel AAV serotypes. To create the chimeric packaging constructs, the Xho I site of p5E18 plasmid at 3169 bp was ablated and the modified plasmid was restricted with Xba I and Xho I in a complete digestion to remove the AAV2 cap gene and replace it with a 2267 bp Spe I/Xho I fragment containing the AAV8 cap gene [Xiao, W., et al., (1999) J Virol 73, 3994-4003]. A similar cloning strategy was used for creation of chimeric packaging plasmids of AAV2/1 and AAV2/5. All recombinant vectors were purified by the standard CsCl2 sedimentation method except for AAV2/2, which was purified by single step heparin chromatography. Genome copy (GC) titers of AAV vectors were determined by TaqMan analysis using probes and primers targeting SV40 poly A region as described previously [Gao, G., et al., (2000) Hum Gene Ther 11, 2079-91]. Vectors were constructed for each serotype for a number of in vitro and in vivo studies. Eight different transgene cassettes were incorporated into the vectors and recombinant virions were produced for each serotype. The recovery of virus, based on genome copies, is summarized in Table 4 below. The yields of vector were high for each serotype with no consistent differences between serotypes. Data presented in the table are average genome copy yields with standard deviation ×1013 of multiple production lots of 50 plate (150 mm) transfections. TABLE 4 Production of Recombinant Vectors AAV2/1 AAV2/2 AAV2/5 AAV2/7 AAV2/8 CMV 7.30 ± 4.33 4.49 ± 2.89 5.19 ± 5.19 3.42 0.87 LacZ (n = 9) (n = 6) (n = 8) (n = 1) (n = 1) CMV 6.43 ± 2.42 3.39 ± 2.42 5.55 ± 6.49 2.98 ± 2.66 3.74 ± 3.88 EGFP (n = 2) (n = 2) (n = 4) (n = 2) (n = 2) TBG LacZ 4.18 0.23 0.704 ± 0.43 2.16 0.532 (n = 1) (n = 1) (n = 2) (n = 1) (n = 1) Alb A1AT 4.67 ± 0.75 4.77 4.09 5.04 2.02 (n = 2) (n = 1) (n = 1) (n = 1) (n = 1) CB A1AT 0.567 0.438 2.82 2.78 0.816 ± 0.679 (n = 1) (n = 1) (n = 1) (n = 1) (n = 2) TBG 8.51 ± 6.65 3.47 ± 2.09 5.26 ± 3.85 6.52 ± 3.08 1.83 ± 0.98 rhCG (n = 6) (n = 5) (n = 4) (n = 4) (n = 5) TBG cFIX 1.24 ± 1.29 0.63 ± 0.394 3.74 ± 2.48 4.05 15.8 ± 15.0 (n = 3) (n = 6) (n = 7) (n = 1) (n = 5) Example 6—Serologic Analysis of Pseudotyped Vectors C57BL/6 mice were injected with vectors of different serotypes of AAVCBA1AT vectors intramuscularly (5×1011 GC) and serum samples were collected 34 days later. To test neutralizing and cross-neutralizing activity of sera to each serotype of AAV, sera was analyzed in a transduction based neutralizing antibody assay [Gao, G. P., et al., (1996) J Virol 70, 8934-43]. More specifically, the presence of neutralizing antibodies was determined by assessing the ability of serum to inhibit transduction of 84-31 cells by reporter viruses (AAVCMVEGFP) of different serotypes. Specifically, the reporter virus AAVCMVEGFP of each serotype [at multiplicity of infection (MOI) that led to a transduction of 90% of indicator cells] was pre-incubated with heat-inactivated serum from animals that received different serotypes of AAV or from naïve mice. After 1-hour incubation at 37° C., viruses were added to 84-31 cells in 96 well plates for 48 or 72-hour, depending on the virus serotype. Expression of GFP was measured by Fluorolmagin (Molecular Dynamics) and quantified by Image Quant Software. Neutralizing antibody titers were reported as the highest serum dilution that inhibited transduction to less than 50%. The availability of GFP expressing vectors simplified the development of an assay for neutralizing antibodies that was based on inhibition of transduction in a permissive cell line (i.e., 293 cells stably expressing E4 from Ad5). Sera to selected AAV serotypes were generated by intramuscular injection of the recombinant viruses. Neutralization of AAV transduction by 1:20 and 1:80 dilutions of the antisera was evaluated (See Table 5 below). Antisera to AAV1, AAV2, AAV5 and AAV8 neutralized transduction of the serotype to which the antiserum was generated (AAV5 and AAV8 to a lesser extent than AAV1 and AAV2) but not to the other serotype (i.e., there was no evidence of cross neutralization suggesting that AAV 8 is a truly unique serotype). TABLE 5 Serological Analysis of New AAV Serotypes. % Infection on 84-31 cells with AAVCMVEGFP virus: AAV2/1 AAV2/2 AAV2/5 AAV2/7 AAV2/8 Immunization Serum dilution: Serum dilution: Serum dilution: Serum dilution: Serum dilution: Sera: Vector 1/20 1/80 1/20 1/80 1/20 1/80 1/20 1/80 1/20 1/80 Group 1 AAV2/1 0 0 100 100 100 100 100 100 100 100 Group 2 AAV2/2 100 100 0 0 100 100 100 100 100 100 Group 3 AAV2/5 100 100 100 100 16.5 16.5 100 100 100 100 Group 4 AAV2/7 100 100 100 100 100 100 61.5 100 100 100 Group 5 AAV2/8 100 100 100 100 100 100 100 100 26.3 60 Human sera from 52 normal subjects were screened for neutralization against selected serotypes. No serum sample was found to neutralize AAV2/7 and AAV2/8 while AAV2/2 and AAV2/1 vectors were neutralized in 20% and 10% of sera, respectively. A fraction of human pooled IgG representing a collection of 60,000 individual samples did not neutralize AAV2/7 and AAV2/8, whereas AAV2/2 and AAV2/1 vectors were neutralized at titers of serum equal to 1/1280 and 1/640, respectively. Example 7—In Vivo Evaluation of Different Serotypes of AAV Vectors In this study, 7 recombinant AAV genomes, AAV2CBhA1AT, AAV2AlbhA1AT, AAV2CMVrhCG, AAV2TBGrhCG, AAV2TBGcFIX, AAV2CMVLacZ and AAV2TBGLacZ were packaged with capsid proteins of different serotypes. In all 7 constructs, minigene cassettes were flanked with AAV2 ITRs. cDNAs of human α-antitrypsin (A1AT) [Xiao, W., et al., (1999) J Virol 73, 3994-4003] β-subunit of rhesus monkey choriogonadotropic hormone (CG) [Zoltick, P. W. & Wilson, J. M. (2000) Mol Ther 2, 657-9] canine factor IX [Wang, L., et al., (1997) Proc Natl Acad Sci USA 94, 11563-6] and bacterial β-glactosidase (i.e., Lac Z) genes were used as reporter genes. For liver-directed gene transfer, either mouse albumin gene promoter (Alb) [Xiao, W. (1999), cited above] or human thyroid hormone binding globulin gene promoter (TBG) [Wang (1997), cited above] was used to drive liver specific expression of reporter genes. In muscle-directed gene transfer experiments, either cytomegalovirus early promoter (CMV) or chicken β-actin promoter with CMV enhancer (CB) was employed to direct expression of reporters. For muscle-directed gene transfer, vectors were injected into the right tibialis anterior of 4-6 week old NCR nude or C57BL/6 mice (Taconic, Germantown, N.Y.). In liver-directed gene transfer studies, vectors were infused intraportally into 7-9 week old NCR nude or C57BL/6 mice (Taconic, Germantown, N.Y.). Serum samples were collected intraorbitally at different time points after vector administration. Muscle and liver tissues were harvested at different time points for cryosectioning and Xgal histochemical staining from animals that received the lacZ vectors. For the re-administration experiment, C56BL/6 mice initially received AAV2/1, 2/2, 2/5, 2/7 and 2/8CBA1AT vectors intramuscularly and followed for A1AT gene expression for 7 weeks. Animals were then treated with AAV2/8TBGcFIX intraportally and studied for cFIX gene expression. ELISA based assays were performed to quantify serum levels of hA1AT, rhCG and cFIX proteins as described previously [Gao, G. P., et al., (1996) J Virol 70, 8934-43; Zoltick, P. W. & Wilson, J. M. (2000) Mol Ther 2, 657-9; Wang, L., et al., Proc Natl Acad Sci USA 94, 11563-6]. The experiments were completed when animals were sacrificed for harvest of muscle and liver tissues for DNA extraction and quantitative analysis of genome copies of vectors present in target tissues by TaqMan using the same set of primers and probe as in titration of vector preparations [Zhang, Y., et al., (2001) Mol Ther 3, 697-707]. The performance of vectors base on the new serotypes were evaluated in murine models of muscle and liver-directed gene transfer and compared to vectors based on the known serotypes AAV1, AAV2 and AAV5. Vectors expressing secreted proteins (alpha-antitrypsin (A1AT) and chorionic gonadotropin (CG)) were used to quantitate relative transduction efficiencies between different serotypes through ELISA analysis of sera. The cellular distribution of transduction within the target organ was evaluated using lacZ expressing vectors and X-gal histochemistry. The performance of AAV vectors in skeletal muscle was analyzed following direct injection into the tibialis anterior muscles. Vectors contained the same AAV2 based genome with the immediate early gene of CMV or a CMV enhanced β-actin promoter driving expression of the transgene. Previous studies indicated that immune competent C57BL/6 mice elicit limited humoral responses to the human A1AT protein when expressed from AAV vectors [Xiao, W., et al., (1999) J Virol 73, 3994-4003]. In each strain, AAV2/1 vector produced the highest levels of A1AT and AAV2/2 vector the lowest, with AAV2/7 and AAV2/8 vectors showing intermediate levels of expression. Peak levels of CG at 28 days following injection of nu/nu NCR mice showed the highest levels from AAV2/7 and the lowest from AAV2/2 with AAV2/8 and AAV2/1 in between. Injection of AAV2/1 and AAV2/7 lacZ vectors yielded gene expression at the injection sites in all muscle fibers with substantially fewer lacZ positive fibers observed with AAV2/2 and AAV 2/8 vectors. These data indicate that the efficiency of transduction with AAV2/7 vectors in skeletal muscle is similar to that obtained with AAV2/1, which is the most efficient in skeletal muscle of the previously described serotypes [Xiao, W. (1999), cited above; Chao, H., et al., (2001) Mol Ther 4, 217-22; Chao, H., et al., (2000) Mol Ther 2, 619-23]. Similar murine models were used to evaluate liver-directed gene transfer. Identical doses of vector based on genome copies were infused into the portal veins of mice that were analyzed subsequently for expression of the transgene. Each vector contained an AAV2 based genome using previously described liver-specific promoters (i.e., albumin or thyroid hormone binding globulin) to drive expression of the transgene. More particularly, CMVCG and TBGCG minigene cassettes were used for muscle and liver-directed gene transfer, respectively. Levels of rhCG were defined as relative units (RUs×103). The data were from assaying serum samples collected at day 28, post vector administration (4 animals per group). As shown in Table 3, the impact of capsid proteins on the efficiency of transduction of A1AT vectors in nu/nu and C57BL/6 mice and CG vectors in C57BL/6 mice was consistent (See Table 6). TABLE 6 Expression of β-unit of Rhesus Monkey Chorionic Gonadotropin (rhCG) Vector Muscle Liver AAV2/1 4.5 ± 2.1 1.6 ± 1.0 AAV2 0.5 ± 0.1 0.7 ± 0.3 AAV2/5 ND* 4.8 ± 0.8 AAV2/7 14.2 ± 2.4 8.2 ± 4.3 AAV2/8 4.0 ± 0.7 76.0 ± 22.8 *Not determined in this experiment. In all cases, AAV2/8 vectors yielded the highest levels of transgene expression that ranged from 16 to 110 greater than what was obtained with AAV2/2 vectors; expression from AAV2/5 and AAV2/7 vectors was intermediate with AAV2/7 higher than AAV2/5. Analysis of X-Gal stained liver sections of animals that received the corresponding lacZ vectors showed a correlation between the number of transduced cells and overall levels of transgene expression. DNAs extracted from livers of C57BL/6 mice who received the A1AT vectors were analyzed for abundance of vector DNA using real time PCR technology. The amount of vector DNA found in liver 56 days after injection correlated with the levels of transgene expression (See Table 7). For this experiment, a set of probe and primers targeting the SV40 polyA region of the vector genome was used for TaqMan PCR. Values shown are means of three individual animals with standard deviations. The animals were sacrificed at day 56 to harvest liver tissues for DNA extraction. These studies indicate that AAV8 is the most efficient vector for liver-directed gene transfer due to increased numbers of transduced hepatocytes. TABLE 7 Real Time PCR Analysis for Abundance of AAV Vectors in nu/nu Mouse Liver Following Injection of 1 × 1011 Genome Copies of Vector. AAV vectors/Dose Genome Copies per Cell AAV2/1AlbA1AT 0.6 ± 0.36 AAV2AlbA1AT 0.003 ± 0.001 AAV2/5AlbA1AT 0.83 ± 0.64 AAV2/7AlbA1AT 2.2 ± 1.7 AAV2/8AlbA1AT 18 ± 11 The serologic data described above suggest that AAV2/8 vector should not be neutralized in vivo following immunization with the other serotypes. C57BL/6 mice received intraportal injections of AAV2/8 vector expressing canine factor IX (1011 genome copies) 56 days after they received intramuscular injections of A1AT vectors of different serotypes. High levels of factor IX expression were obtained 14 days following infusion of AAV2/8 into naïve animals (17±2 μg/ml, n=4) which were not significantly different that what was observed in animals immunized with AAV2/1 (31±23 μg/ml, n=4), AAV2/2 (16 μg/ml, n=2), and AAV2/7 (12 μg/ml, n=2). This contrasts to what was observed in AAV2/8 immunized animals that were infused with the AAV2/8 factor IX vector in which no detectable factor IX was observed (<0.1 μg/ml, n=4). Oligonucleotides to conserved regions of the cap gene did amplify sequences from rhesus monkeys that represented unique AAVs. Identical cap signature sequences were found in multiple tissues from rhesus monkeys derived from at least two different colonies. Full-length rep and cap open reading frames were isolated and sequenced from single sources. Only the cap open reading frames of the novel AAVs were necessary to evaluate their potential as vectors because vectors with the AAV7 or AAV8 capsids were generated using the ITRs and rep from AAV2. This also simplified the comparison of different vectors since the actual vector genome is identical between different vector serotypes. In fact, the yields of recombinant vectors generated using this approach did not differ between serotypes. Vectors based on AAV7 and AAV8 appear to be immunologically distinct (i.e., they are not neutralized by antibodies generated against other serotypes). Furthermore, sera from humans do not neutralize transduction by AAV7 and AAV8 vectors, which is a substantial advantage over the human derived AAVs currently under development for which a significant proportion of the human population has pre-existing immunity that is neutralizing [Chirmule, N., et al., (1999) Gene Ther 6, 1574-83]. The tropism of each new vector is favorable for in vivo applications. AAV2/7 vectors appear to transduce skeletal muscle as efficiently as AAV2/1, which is the serotype that confers the highest level of transduction in skeletal muscle of the primate AAVs tested to date [Xiao, W., cited above; Chou (2001), cited above, and Chou (2000), cited above]. Importantly, AAV2/8 provides a substantial advantage over the other serotypes in terms of efficiency of gene transfer to liver that until now has been relatively disappointing in terms of the numbers of hepatocytes stably transduced. AAV2/8 consistently achieved a 10 to 100-fold improvement in gene transfer efficiency as compared to the other vectors. The basis for the improved efficiency of AAV2/8 is unclear, although it presumably is due to uptake via a different receptor that is more active on the basolateral surface of hepatocytes. This improved efficiency will be quite useful in the development of liver-directed gene transfer where the number of transduced cells is critical, such as in urea cycle disorders and familial hypercholesterolemia. Thus, the present invention provides a novel approach for isolating new AAVs based on PCR retrieval of genomic sequences. The amplified sequences were easily incorporated into vectors and tested in animals. The lack of pre-existing immunity to AAV7 and the favorable tropism of the vectors for muscle indicates that AAV7 is suitable for use as a vector in human gene therapy and other in vivo applications. Similarly, the lack of pre-existing immunity to the AAV serotypes of the invention, and their tropisms, renders them useful in delivery of therapeutic molecules and other useful molecules. Example 9—Tissue Tropism Studies In the design of a high throughput functional screening scheme for novel AAV constructs, a non-tissue specific and highly active promoter, CB promoter (CMV enhanced chicken β actin promoter) was selected to drive an easily detectable and quantifiable reporter gene, human α anti-trypsin gene. Thus only one vector for each new AAV clone needs to be made for gene transfer studies targeting 3 different tissues, liver, lung and muscle to screen for tissue tropism of a particular AAV construct. The following table summarizes data generated from 4 novel AAV vectors in the tissue tropism studies (AAVCBA1AT), from which a novel AAV capsid clone, 44.2, was found to be a very potent gene transfer vehicle in all 3 tissues with a big lead in the lung tissue particularly. Table 8 reports data obtained (in μg A1AT/mL serum) at day 14 of the study. TABLE 8 Target Tissue Vector Lung Liver Muscle AAV2/1 ND ND 45 ± 11 AAV2/5 0.6 ± 0.2 ND ND AAV2/8 ND 84 ± 30 ND AAV2/rh.2 (43.1) 14 ± 7 25 ± 7.4 35 ± 14 AAV2/rh.10 (44.2) 23 ± 6 53 ± 19 46 ± 11 AAV2/rh.13 (42.2) 3.5 ± 2 2 ± 0.8 3.5 ± 1.7 AAV2/rh.21 (42.10) 3.1 ± 2 2 ± 1.4 4.3 ± 2 A couple of other experiments were then performed to confirm the superior tropism of AAV 44.2 in lung tissue. First, AAV vector carried CC10hA1AT minigene for lung specific expression were pseudotyped with capsids of novel AAVs were given to Immune deficient animals (NCR nude) in equal volume (50 μl each of the original preps without dilution) via intratracheal injections as provided in the following table. In Table 9, 50 μl of each original prep per mouse, NCR Nude, detection limit ≧0.033 μg/ml, Day 28 TABLE 9 Relative μg of Gene Total GC μg of A1AT/ml transfer as in A1AT/ml with compared to 50 μl with 1 × 1011 rh.10 (clone Vector vector 50 μl vector vector 44.2) 2/1 3 × 1012 2.6 ± 0.5 0.09 ± 0.02 2.2 2/2 5.5 × 1011 <0.03 <0.005 <0.1 2/5 3.6 × 1012 0.65 ± 0.16 0.02 ± 0.004 0.5 2/7 4.2 × 1012 1 ± 0.53 0.02 ± 0.01 0.5 2/8 7.5 × 1011 0.9 ± 0.7 0.12 ± 0.09 2.9 2/ch.5 (A.3.1) 9 × 1012 1 ± 0.7 0.01 ± 0.008 0.24 2/rh.8 (43.25) 4.6 × 1012 26 ± 21 0.56 ± 0.46 13.7 2/rh.10 (44.2) 2.8 × 1012 115 ± 38 4.1 ± 1.4 100 2/rh.13 (42.2) 6 × 1012 7.3 ± 0.8 0.12 ± 0.01 2.9 2/rh.21 (42.10) 2.4 × 1012 9 ± 0.9 0.38 ± 0.04 9.3 2/rh.22 (42.11) 2.6 × 1012 6 ± 0.4 0.23 ± 0.02 5.6 2/rh.24 (42.13) 1.1 × 1011 0.4 ± 0.3 0.4 ± 0.3 1 The vectors were also administered to immune competent animals (C57BL/6) in equal 5 genome copies (1×1011 GC) as shown in the Table 10. (1×1011 GC per animal, C57BL/6, day 14, detection limit ≧0.033 g/ml) TABLE 10 Relative Gene transfer as μg of A1AT/ml compared to rh.10 (clone AAV Vector with 1 × 1011 vector 44.2) 2/1 0.076 ± 0.031 2.6 2/2 0.1 ± 0.09 3.4 2/5 0.0840.033 2.9 2/7 0.33 ± 0.01 11 2/8 1.92 ± 1.3 2.9 2/ch.5 (A.3.1) 0.048 ± 0.004 1.6 2/rh.8 (43.25) 1.7 ± 0.7 58 2/rh.10 (44.2) 2.93 ± 1.7 100 2/rh.13 (42.2) 0.45 ± 0.15 15 2/rh.21 (42.10) 0.86 ± 0.32 29 2/rh.22 (42.11) 0.38 ± 0.18 13 2/rh.24 (42.13) 0.3 ± 0.19 10 The data from both experiments confirmed the superb tropism of clone 44.2 in lung-directed gene transfer. Interestingly, performance of clone 44.2 in liver and muscle directed gene transfer was also outstanding, close to that of the best liver transducer, AAV8 and the best muscle transducer AAV1, suggesting that this novel AAV has some intriguing biological significance. To study serological properties of those novel AAVs, pseudotyped AAVGFP vectors were created for immunization of rabbits and in vitro transduction of 84-31 cells in the presence and absence of antisera against different capsids. The data are summarized below: TABLE 11a Cross-NAB assay in 8431 cells and adenovirus (Adv) coinfection Infection in 8431 cells (coinfected with Adv) with: Serum from rabbit immunized with: 109 GC 109 GC 109 GC 1010 GC rh.13 rh.21 rh.22 rh.24 AAV2/42.2 AAV2/42.10 AAV2/42.11 AAV2/42.13 AAV2/1 1/20 1/20 1/20 No NAB AAV2/2 1/640 1/1280 1/5120 No NAB AAV2/5 No NAB 1/40 1/160 No NAB AAV2/7 1/81920 1/81920 1/40960 1/640 AAV2/8 1/640 1/640 1/320 1/5120 Ch.5 AAV2/A3 1/20 1/160 1/640 1/640 rh.8 1/20 1/20 1/20 1/320 AAV2/43.25 rh.10 No NAB No NAB No NAB 1/5120 AAV2/44.2 rh.13 1/5120 1/5120 1/5120 No NAB AAV2/42.2 rh.21 1/5120 1/10240 1/5120 1/20 AAV2/42.10 rh.22 1/20480 1/20480 1/40960 No NAB AAV2/42.11 rh.24 No NAB 1/20 1/20 1/5120 AAV2/42.13 TABLE 11b Cross-NAB assay in 8431 cells and Adv coinfection Infection in 8431 cells (coinfected with Adv) with: Serum from rabbit immunized with: 109 GC 1010 GC 1010GC 109 GC 109 GC rh.12 ch.5 rh.8 rh.10 rh.20 AAV2/42.1B AAV2/A3 AAV2/43.25 AAV2/44.2 AAV2/42.8.2 AAV2/1 No NAB 1/20480 No NAB 1/80 ND AAV2/2 1/20 No NAB No NAB No NAB ND AAV2/5 No NAB 1/320 No NAB No NAB ND AAV2/7 1/2560 1/640 1/160 1/81920 ND AAV2/8 1/10240 1/2560 1/2560 1/81920 ND ch.5 AAV2/A3 1/1280 1/10240 ND 1/5120 1/320 rh.8 AAV2/43.25 1/1280 ND 1/20400 1/5120 1/2560 rh.10 AAV2/44.2 1/5120 ND ND 1/5120 1/5120 rh.13 AAV2/42.2 1/20 ND ND No NAB 1/320 rh.21 AAV2/42.10 1/20 ND ND 1/40 1/80 rh.22 AAV2/42.11 No NAB ND ND ND No NAB rh.24 AAV2/42.13 1/5120 ND ND ND 1/2560 TABLE 12 Titer of rabbit sera Titer after Vector Titer d21 Boosting ch.5 AAV2/A3 1/10,240 1/40,960 rh.8 AAV2/43.25 1/20,400 1/163,840 rh.10 AAV2/44.2 1/10,240 1/527,680 rh.13 AAV2/42.2 1/5,120 1/20,960 rh.21 AAV2/42.10 1/20,400 1/81,920 rh.22 AAV2/42.11 1/40,960 ND rh.24 AAV2/42.13 1/5,120 ND TABLE 13 a Infection in 8431 cells (coinfected with Adv) with GFP 109 GC/well 109 GC/well 109 GC/well 109 GC/well 109 GC/well 109 GC/well ch.5 AAV2/1 AAV2/2 AAV2/5 AAV2/7 AAV2/8 AAV2/A3 # GFU/field 128 >200 95 56 13 1 83 >200 65 54 11 1 TABLE 13b Infection in 8431 cells (coinfected with Adv) with GFP 109 GC/well 109 GC/well 109 GC/well 109 GC/well 109 GC/well 109 GC/well 109 GC/well rh.8 rh.10 rh.13 rh.21 rh.22 rh.24 rh.12 AAV2/43.25 AAV2/44.2 AAV2/42.2 AAV2/42.10 AAV2/42.11 AAV2/42.13 AAV2/42.1B # GFU/field 3 13 54 62 10 3 18 2 12 71 60 14 2 20 48 47 16 3 12 Example 10—Mouse Model of Familial Hypercholesterolemia The following experiment demonstrates that the AAV2/7 construct of the invention delivers the LDL receptor and express LDL receptor in an amount sufficient to reduce the levels of plasma cholesterol and triglycerides in animal models of familial hypercholesterolemia. A. Vector Construction AAV vectors packaged with AAV7 or AAV8 capsid proteins were constructed using a pseudotyping strategy [Hildinger M, et al., J. Virol 2001; 75:6199-6203]. Recombinant AAV genomes with AAV2 inverted terminal repeats (ITR) were packaged by triple transfection of 293 cells with the cis-plasmid, the adenovirus helper plasmid and a chimeric packaging construct, a fusion of the capsids of the novel AAV serotypes with the rep gene of AAV2. The chimeric packaging plasmid was constructed as previously described [Hildinger et al, cited above]. The recombinant vectors were purified by the standard CsCl2 sedimentation method. To determine the yield TaqMan (Applied Biosystems) analysis was performed using probes and primers targeting the SV40 poly(A) region of the vectors [Gao G P, et al., Hum Gene Ther. 2000 Oct. 10; 11(15):2079-91]. The resulting vectors express the transgene under the control of the human thyroid hormone binding globulin gene promoter (TBG). B. Animals LDL receptor deficient mice on the C57Bl/6 background were purchased from the Jackson Laboratory (Bar Harbor, Me., USA) and maintained as a breeding colony. Mice were given unrestricted access to water and obtained a high fat Western Diet (high % cholesterol) starting three weeks prior vector injection. At day −7 as well at day 0, blood was obtained via retroorbital bleeds and the lipid profile evaluated. The mice were randomly divided into seven groups. The vector was injected via an intraportal injection as previously described ([Chen S J et al., Mol Therapy 2000; 2(3), 256-261]. Briefly, the mice were anaesthetized with ketamine and xylazine. A laparotomy was performed and the portal vein exposed. Using a 30 g needle the appropriate dose of vector diluted in 100 ul PBS was directly injected into the portal vein. Pressure was applied to the injection site to ensure a stop of the bleeding. The skin wound was closed and draped and the mice carefully monitored for the following day. Weekly bleeds were performed starting at day 14 after liver directed gene transfer to measure blood lipids. Two animals of each group were sacrificed at the time points week 6 and week 12 after vector injection to examine atherosclerotic plaque size as well as receptor expression. The remaining mice were sacrificed at week 20 for plaque measurement and determination of transgene expression. TABLE 14 Vector dose n Group 1 AAV2/7-TBG-hLDLr 1 × 1012 gc 12 Group 2 AAV2/7-TBG-hLDLr 3 × 1011 gc 12 Group 3 AAV2/7-TBG-hLDLr 1 × 1011 gc 12 Group 4 AAV2/8-TBG-hLDLr 1 × 1012 gc 12 Group 5 AAV2/8-TBG-hLDLr 3 × 1011 gc 12 Group 6 AAV2/8-TBG-hLDLr 1 × 1011 gc 12 Group 7 AAV2/7-TBG-LacZ 1 × 1011 gc 16 C. Serum Lipoprotein and Liver Function Analysis Blood samples were obtained from the retroorbital plexus after a 6 hour fasting period. The serum was separated from the plasma by centrifugation. The amount of plasma lipoproteins and liver transaminases in the serum were detected using an automatized clinical chemistry analyzer (ACE, Schiapparelli Biosystems, Alpha Wassermann) D. Detection of Transgene Expression LDL receptor expression was evaluated by immuno-fluorescence staining and Western blotting. For Western Blot frozen liver tissue was homogenized with lysis buffer (20 mM Tris, pH7.4, 130 mM NaCl, 1% Triton X 100, proteinase inhibitor (complete, EDTA-free, Roche, Mannheim, Germany). Protein concentration was determined using the Micro BCA Protein Assay Reagent Kit (Pierce, Rockford, Ill.). 40 μg of protein was resolved on 4-15% Tris-HCl Ready Gels (Biorad, Hercules, Calif.) and transferred to a nitrocellulose membrane (Invitrogen,). To generate Anti-hLDL receptor antibodies a rabbit was injected intravenously with an AdhLDLr prep (1×1013 GC). Four weeks later the rabbit serum was obtained and used for Western Blot. A 1:100 dilution of the serum was used as a primary antibody followed by a HRP-conjugated anti-rabbit IgG and ECL chemiluminescent detection (ECL Western Blot Detection Kit, Amersham, Arlington Heights, Ill.). E. Immunocytochemistry For determination of LDL receptor expression in frozen liver sections immunohistochemistry analyses were performed. 10 um cryostat sections were either fixed in acetone for 5 minutes, or unfixed. Blocking was obtained via a 1 hour incubation period with 10% of goat serum. Sections were then incubated for one hour with the primary antibody at room temperature. A rabbit polyclonal antibody anti-human LDL (Biomedical Technologies Inc., Stoughton, Mass.) was used diluted accordingly to the instructions of the manufacturer. The sections were washed with PBS, and incubated with 1:100 diluted fluorescein goat anti-rabbit IgG (Sigma, St Louis, Mo.). Specimens were finally examined under fluorescence microscope Nikon Microphot-FXA. In all cases, each incubation was followed by extensive washing with PBS. Negative controls consisted of preincubation with PBS, omission of the primary antibody, and substitution of the primary antibody by an isotype-matched non-immune control antibody. The three types of controls mentioned above were performed for each experiment on the same day. F. Gene Transfer Efficiency Liver tissue was obtained after sacrificing the mice at the designated time points. The tissue was shock frozen in liquid nitrogen and stored at −80° C. until further processing. DNA was extracted from the liver tissue using a QIAamp DNA Mini Kit (QIAGEN GmbH, Germany) according to the manufacturers protocol. Genome copies of AAV vectors in the liver tissue were evaluated using Taqman analysis using probes and primers against the SV40 poly(A) tail as described above. G. Atherosclerotic Plaque Measurement For the quantification of the atherosclerotic plaques in the mouse aorta the mice were anaesthetized (10% ketamine and xylazine, ip), the chest opened and the arterial system perfused with ice-cold phosphate buffered saline through the left ventricle. The aorta was then carefully harvested, slit down along the ventral midline from the aortic arch down to the femoral arteries and fixed in formalin. The lipid-rich atherosclerotic plaques were stained with Sudan IV (Sigma, Germany) and the aorta pinned out flat on a black wax surface. The image was captured with a Sony DXC-960 MD color video camera. The area of the plaque as well as of the complete aortic surface was determined using Phase 3 Imaging Systems (Media Cybernetics). H. Clearance of I125 LDL Two animals per experimental group were tested. A bolus of I125-labeled LDL (generously provided by Dan Rader, U Penn) was infused slowly through the tail vein over a period of 30 sec (1,000,000 counts of [I125]-LDL diluted in 100 μl sterile PBS/animal). At time points 3 min, 30 min, 1.5 hr, 3 hr, 6 hr after injection a blood sample was obtained via the retro-orbital plexus. The plasma was separated off from the whole blood and 10 μl plasma counted in the gamma counter. Finally the fractional catabolic rate was calculated from the lipoprotein clearance data. I. Evaluation of Liver Lipid Accumulation Oil Red Staining of frozen liver sections was performed to determine lipid accumulation. The frozen liver sections were briefly rinsed in distilled water followed by a 2 minute incubation in absolute propylene glycol. The sections were then stained in oil red solution (0.5% in propylene glycol) for 16 hours followed by counterstaining with Mayer's hematoxylin solution for 30 seconds and mounting in warmed glycerin jelly solution. For quantification of the liver cholesterol and triglyceride content liver sections were homogenized and incubated in chloroform/methanol (2:1) overnight. After adding of 0.05% H2SO4 and centrifugation for 10 minutes, the lower layer of each sample was collected, divided in two aliquots and dried under nitrogen. For the cholesterol measurement the dried lipids of the first aliquot were dissolved in 1% Triton X-100 in chloroform. Once dissolved, the solution was dried under nitrogen. After dissolving the lipids in ddH20 and incubation for 30 minutes at 37° C. the total cholesterol concentration was measured using a Total Cholesterol Kit (Wako Diagnostics). For the second aliquot the dried lipids were dissolved in alcoholic KOH and incubated at 60° C. for 30 minutes. Then 1M MgCl2 was added, followed by incubation on ice for 10 minutes and centrifugation at 14,000 rpm for 30 minutes. The supernatant was finally evaluated for triglycerides (Wako Diagnostics). All of the vectors pseudotyped in an AAV2/8 or AAV2/7 capsid lowered total cholesterol, LDL and triglycerides as compared to the control. These test vectors also corrected phenotype of hypercholesterolemia in a dose-dependent manner. A reduction in plaque area for the AAV2/8 and AAV2/7 mice was observed in treated mice at the first test (2 months), and the effect was observed to persist over the length of the experiment (6 months). Example 10—Functional Factor IX Expression and Correction of Hemophilia A. Knock-Out Mice Functional canine factor IX (FIX) expression was assessed in hemophilia B mice. Vectors with capsids of AAV1, AAV2, AAV5, AAV7 or AAV8 were constructed to deliver AAV2 5′ ITR—liver-specific promoter [LSP]—canine FIX—woodchuck hepatitis post-regulatory element (WPRE)—AAV2 3′ ITR. The vectors were constructed as described in Wang et al, 2000, Molecular Therapy 2: 154-158), using the appropriate capsids. Knock-out mice were generated as described in Wang et al, 1997. Proc. Natl. Acad. Sci. USA 94: 11563-11566. This model closely mimic the phenotypes of hemophilia B in human. Vectors of different serotypes (AAV1, AAV2, AAV5, AAV7 and AAV8) were delivered as a single intraportal injection into the liver of adult hemophiliac C57Bl/6 mice in a dose of 1×1011 GC/mouse for the five different serotypes and one group received an AAV8 vector at a lower dose, 1×1010 GC/mouse. Control group was injected with 1×1011 GC of AAV2/8 TBG LacZ3. Each group contains 5-10 male and female mice. Mice were bled bi-weekly after vector administration. 1. ELISA The canine FIX concentration in the mouse plasma was determined by an ELISA assay specific for canine factor IX, performed essentially as described by Axelrod et al, 1990, Proc. Natl. Acad. Sci. USA, 87:5173-5177 with modifications. Sheep anti-canine factor IX (Enzyme Research Laboratories) was used as primary antibody and rabbit anti-canine factor IX ((Enzyme Research Laboratories) was used as secondary antibody. Beginning at two weeks following injection, increased plasma levels of cFIX were detected for all test vectors. The increased levels were sustained at therapeutic levels throughout the length of the experiment, i.e., to 12 weeks. Therapeutic levels are considered to be 5% of normal levels, i.e., at about 250 ng/mL. The highest levels of expression were observed for the AAV2/8 (at 101) and AAV2/7 constructs, with sustained superphysiology levels cFIX levels (ten-fold higher than the normal level). Expression levels for AAV2/8 (1011) were approximately 10 fold higher than those observed for AAV2/2 and AAV2/8 (1010). The lowest expression levels, although still above the therapeutic range, were observed for AAV2/5. 2. In Vitro Activated Partial Thromboplastin Time (aPTT) Assay Functional factor IX activity in plasma of the FIX knock-out mice was determined by an in vitro activated partial thromboplastin time (aPTT) assay-Mouse blood samples were collected from the retro-orbital plexus into 1/10 volume of citrate buffer. The aPTT assay was performed as described by Wang et al, 1997, Proc. Natl. Acad. Sci. USA 94: 11563-11566. Clotting times by aPTT on plasma samples of all vector injected mice were within the normal range (approximately 60 sec) when measured at two weeks post-injection, and sustained clotting times in the normal or shorter than normal range throughout the study period (12 weeks). Lowest sustained clotting times were observed in the animals receiving AAV2/8 (1011) and AAV2/7. By week 12, AAV2/2 also induced clotting times similar to those for AAV2/8 and AAV2/7. However, this lowered clotting time was not observed for AAV2/2 until week 12, whereas lowered clotting times (in the 25-40 sec range) were observed for AAV2/8 and AAV2/7 beginning at week two. Immuno-histochemistry staining on the liver tissues harvested from some of the treated mice is currently being performed. About 70-80% of hepatocytes are stained positive for canine FIX in the mouse injected with AAV2/8.cFIX vector. B. Hemophilia B Dogs Dogs that have a point mutation in the catalytic domain of the F.IX gene, which, based on modeling studies, appears to render the protein unstable, suffer from hemophilia B [Evans et al, 1989, Proc. Natl. Acad. Sci. USA, 86:10095-10099). A colony of such dogs has been maintained for more than two decades at the University of North Carolina, Chapel Hill. The homeostatic parameters of these dogs are well described and include the absence of plasma F.IX antigen, whole blood clotting times in excess of 60 minutes, whereas normal dogs are 6-8 minutes, and prolonged activated partial thromboplastin time of 50-80 seconds, whereas normal dogs are 13-28 seconds. These dogs experience recurrent spontaneous hemorrhages. Typically, significant bleeding episodes are successfully managed by the single intravenous infusion of 10 ml/kg of normal canine plasma; occasionally, repeat infusions are required to control bleeding. Four dogs are injected intraportally with AAV.cFIX according to the schedule below. A first dog receives a single injection with AAV2/2.cFIX at a dose of 3.7×1011 genome copies (GC)/kg. A second dog receives a first injection of AAV2/2.cFIX (2.8×1011 GC/kg), followed by a second injection with AAV2/7.cFIX (2.3×1013 GC/kg) at day 1180. A third dog receives a single injection with AAV2/2.cFIX at a dose of 4.6×1012 GC/kg. The fourth dog receives an injection with AAV2/2.cFIX (2.8×1012 GC/kg) and an injection at day 995 with AAV2/7.cFIX (5×1012 GC/kg). The abdomen of hemophilia dogs are aseptically and surgically opened under general anesthesia and a single infusion of vector is administered into the portal vein. The animals are protected from hemorrhage in the peri-operative period by intravenous administration of normal canine plasma. The dog is sedated, intubated to induce general anesthesia, and the abdomen shaved and prepped. After the abdomen is opened, the spleen is moved into the operative field. The splenic vein is located and a suture is loosely placed proximal to a small distal incision in the vein. A needle is rapidly inserted into the vein, then the suture loosened and a 5 F cannula is threaded to an intravenous location near the portal vein threaded to an intravenous location near the portal vein bifurcation. After hemostasis is secured and the catheter balloon inflated, approximately 5.0 ml of vector diluted in PBS is infused into the portal vein over a 5 minute interval. The vector infusion is followed by a 5.0 ml infusion of saline. The balloon is then deflated, the callula removed and venous hemostasis is secured. The spleen is then replaced, bleeding vessels are cauterized and the operative wound is closed. The animal is extubated having tolerated the surgical procedure well. Blood samples are analyzed as described. [Wang et al, 2000, Molecular Therapy 2: 154-158] Results showing correction or partial correction are anticipated for AAV2/7. All publications cited in this specification including priority applications, U.S. patent application Ser. No. 13/633,971, U.S. patent application Ser. No. 12/962,793, U.S. patent application Ser. No. 10/291,583, and U.S. provisional patent application Nos. 60/386,675, 60/377,066, 60/341,117, and 60/350,607, are incorporated herein by reference. While the invention has been described with reference to particularly preferred embodiments, it will be appreciated that modifications can be made without departing from the spirit of the invention. Such modifications are intended to fall within the scope of the claims. | <SOH> BACKGROUND OF THE INVENTION <EOH>Adeno-associated virus (AAV), a member of the Parvovirus family, is a small nonenveloped, icosahedral virus with single-stranded linear DNA genomes of 4.7 kilobases (kb) to 6 kb. AAV is assigned to the genus, Dependovirus, because the virus was discovered as a contaminant in purified adenovirus stocks. AAV's life cycle includes a latent phase at which AAV genomes, after infection, are site specifically integrated into host chromosomes and an infectious phase in which, following either adenovirus or herpes simplex virus infection, the integrated genomes are subsequently rescued, replicated, and packaged into infectious viruses. The properties of non-pathogenicity, broad host range of infectivity, including non-dividing cells, and potential site-specific chromosomal integration make AAV an attractive tool for gene transfer. Recent studies suggest that AAV vectors may be the preferred vehicle for gene therapy. To date, there have been 6 different serotypes of AAVs isolated from human or non-human primates (NHP) and well characterized. Among them, human serotype 2 is the first AAV that was developed as a gene transfer vector; it has been widely used for efficient gene transfer experiments in different target tissues and animal models. Clinical trials of the experimental application of AAV2 based vectors to some human disease models are in progress, and include such diseases as cystic fibrosis and hemophilia B. What are desirable are AAV-based constructs for gene delivery. | <SOH> SUMMARY OF THE INVENTION <EOH>In one aspect, the invention provides a novel method of detecting and identifying AAV sequences from cellular DNAs of various human and non-human primate (NHP) tissues using bioinformatics analysis, PCR based gene amplification and cloning technology, based on the nature of latency and integration of AAVs in the absence of helper virus co-infection. In another aspect, the invention provides method of isolating novel AAV sequences detected using the above described method of the invention. The invention further comprises methods of generating vectors based upon these novel AAV serotypes, for serology and gene transfer studies solely based on availability of capsid gene sequences and structure of rep/cap gene junctions. In still another aspect, the invention provides a novel method for performing studies of serology, epidemiology, biodistribution and mode of transmission, using reagents according to the invention, which include generic sets of primers/probes and quantitative real time PCR. In yet another aspect, the invention provides a method of isolating complete and infectious genomes of novel AAV serotypes from cellular DNA of different origins using RACE and other molecular techniques. In a further aspect, the invention provides a method of rescuing novel serotypes of AAV genomes from human and NHP cell lines using adenovirus helpers of different origins. In still a further aspect, the invention provides novel AAV serotypes, vectors containing same, and methods of using same. These and other aspects of the invention will be readily apparent from the following detailed description of the invention. | C12N1586 | 20171013 | 20180201 | 70891.0 | C12N1586 | 1 | SALVOZA, M FRANCO G | METHOD OF DETECTING AND/OR IDENTIFYING ADENO-ASSOCIATED VIRUS (AAV) SEQUENCES AND ISOLATING NOVEL SEQUENCES IDENTIFIED THEREBY | UNDISCOUNTED | 1 | CONT-ACCEPTED | C12N | 2,017 |
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15,784,631 | PENDING | ATTACHMENT DEVICE | The invention relates to an attachment device for two elements of a watch band to allow said two elements to be hooked into place or unhooked, wherein the first element comprises at least one bar on one of its ends. According to the invention the second element comprises two grooves, each comprising a longitudinal opening respectively opposite one another, and one of the two elements can move from an unhooked position, wherein one of the elements is oriented in a predetermined angular position in relation to the other element, to a hooked position, in which the two elements are coplanar after a rotation of a predetermined angle of one of the two elements in relation to the other so that each groove is articulated on the bar to hold the two elements hooked to one another. | 1. An attachment device for two elements of a watch band to allow said two elements to be hooked into place or unhooked, wherein the first element comprises at least one bar on one of its ends, wherein the second element comprises two fixed grooves, each comprising a longitudinal opening respectively opposite one another, and one of the two elements can move from an unhooked position, wherein one of the elements is oriented in a predetermined angular position in relation to the other element, to a hooked position, wherein the two elements are coplanar after a rotation of a predetermined angle of one of the two elements in relation to the other so that each groove is articulated on the bar to hold the two elements hooked to one another. 2. The attachment device according to claim 1, wherein the dimension of the longitudinal opening of the grooves is slightly smaller than the bar. 3. The attachment device according to claim 1, wherein the grooves comprise a straight cylindrical slot, the diameter of which is slightly larger than the diameter of the bar. 4. The attachment device according to claim 1, wherein the first element comprises a central element surrounding the bar. 5. The attachment device according to claim 4, wherein the second element comprises a free space arranged between the two grooves and arranged to receive said central element of the first element. 6. The attachment device according to claim 1, wherein the predetermined angular position is in the range of between 45° and 90°. 7. The attachment device according to claim 1, wherein the second element is made in a single block. | This application claims priority from European Patent Application No. 16197192.4 filed on Nov. 4, 2016; the entire disclosure of which is incorporated herein by reference FIELD OF THE INVENTION The invention relates to the field of attachment devices, and more specifically to attachment devices for timepieces to attach a strand to a case or a clasp to a strand. The invention also relates to an attachment device for a leather wristband or jewellery bracelet. BACKGROUND OF THE INVENTION Classically, the device for attaching a wristband to a case or a clasp is configured in the form of a bar or a pin. The pin must be attached or detached by means of a tool to be able to remove the wristband from the watch, for example, or to be able to change the clasp. It is desirable to be able to separate the wristband into two parts to make the attachment/detachment of the wristband on the case and/or the clasp on the wristband easier. In the prior art wristbands or clasps require the use of tools to be able to attach and/or detach the wristband and clasp, which is not practical for the user when he/she wishes to change the wristband or clasp. SUMMARY OF THE INVENTION An object of the present invention is to remedy all or some of the disadvantages mentioned above by providing an attachment device that allows a quick attachment/detachment, in particular without requiring use of a tool. Another object of the invention, at least in a particular embodiment, is to provide an attachment device that is easy to use and inexpensive. For this purpose, the invention relates to an attachment device for two elements of a watch band to allow said two elements to be hooked into place or unhooked, wherein the first element comprises at least one bar on one of its ends. According to the invention the second element comprises two fixed grooves, each comprising a longitudinal opening respectively opposite one another, and one of the two elements can move from an unhooked position, in which one of the elements is oriented in a predetermined angular position in relation to the other element, to a hooked position, in which the two elements are coplanar after a rotation of a predetermined angle of one of the two elements in relation to the other so that each groove is articulated on the bar to hold the two elements hooked to one another. Because of these characteristics, such an attachment device enables a clasp to be attached and detached easily and quickly to/from a wristband strand, for example. In accordance with other advantageous variants of the invention: the dimension of the longitudinal opening of the grooves is slightly smaller than the bar; the grooves comprise a straight cylindrical slot, the diameter of which is slightly larger than the diameter of the bar; the first element comprises a central element surrounding the bar; the second element comprises a free space arranged between the two grooves and arranged to receive said central element of the first element; the predetermined angular position is in the range of between 45° and 90°; the second element is made in a single block. BRIEF DESCRIPTION OF THE DRAWINGS Other characteristics and advantages of the invention will become clearer on reading the following description of a particular embodiment of the invention given as non-restrictive illustrative example and of the attached drawings, wherein: FIG. 1 is a perspective view of a device of the invention according to a first embodiment; FIGS. 2a to 2d illustrate the different stages for using a device according to the invention. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS An attachment device according to the invention will now be described in the following with reference to FIGS. 1 and 2a to 2d in combination. As illustrated in FIG. 1, the attachment device comprises two elements 1 and 2 of a watch band to enable the two elements 1,2 to be hooked in place or unhooked. As can be seen, the first element 1 comprises at least one bar 10 at one of its ends. The two elements 1, 2 can consist of a wristband strand for the first element and a clasp for the second element, for example. The second element 2 comprises two fixed grooves 20, 21, each comprising a longitudinal opening 210, 220 respectively opposite one another. Advantageously, the second element 2 is formed from a single block. According to the invention one of the two elements can move from an unhooked position, in which one of the two elements is oriented in a predetermined angular position in relation to the other element, to a hooked position, in which the two elements 1, 2 are coplanar after a rotation of a predetermined angle of one of the two elements in relation to the other so that each groove is articulated on the bar 10 to hold the two elements 1, 2 hooked to one another. Preferably, one of the two elements is positioned perpendicularly in relation to the other, wherein one of the elements is in the transverse plane and the other in the sagittal plane. Thus, the rotation of one of the two elements is in the range of between 0° and 90°, and more preferred between 45° and 90°. The rotation can be conducted in clockwise or anticlockwise direction, depending on the orientation of the grooves 20, 21. Advantageously, the dimensions of the respective longitudinal openings 210, 220 of the grooves 20, 21 are slightly smaller than the bar 10 in order to prevent any untimely detachment, and the opening has a width slightly smaller than the diameter of the bar 10. Thus, during placement of the grooves 20, 21 on the bar 10, the user must use a light force to insert the bar 10 and hear a “click” signifying that the grooves 20, 21 have been properly positioned on the bar 10. As can be seen in FIG. 1, the grooves 20 and 21 each comprise a straight cylindrical slot, into which the longitudinal openings 210, 220 open, wherein the diameter of the slot is provided to be slightly larger than the diameter of the bar 10 to limit friction and facilitate the rotation during the pivoting of one element in relation to the other. However, the diameter of the slot should not be too much larger to prevent too great a play that would be uncomfortable for the wearer. As can be seen in FIG. 1, the first element comprises a central element 11 surrounding the bar 10, and the second element 2 comprises a free space 22 arranged between the two grooves 20, 21 and arranged to receive the central element 11 of the first element 1. The two grooves 20, 21 are distant from one another and define a space 22 between them that is arranged to receive the central element 11 during positioning of the first element with the second element. According to the invention such an attachment device can be used equally well for a flexible wristband made from leather, textile or a plastic material to attach the wristband to a case or to a clasp as for attaching a linked wristband to a clasp. FIGS. 2a to 2d illustrate the different stages for assembly of the two elements 1 and 2. Initially, the first element 1 and the second element 2 are arranged perpendicularly to one another, as illustrated in FIG. 2a. The two elements 1 and 2 are then disposed perpendicularly one against the other so that the central element 10 rests in the space 22, as illustrated in FIG. 2b. The user then causes one of the two elements to pivot in relation to the other around the central element 11, as visible in FIG. 2, until the bar 10 comes to sit in each of the grooves 20, 21. A first element without a central element 11 surrounding the bar 10 is clearly also conceivable, wherein the central element 11 facilitates the positioning of the second element 2 and serving as reference for the rotation. Because of these different aspects of the invention an attachment device is provided that enables two elements of a wristband to be attached and/or detached or a wristband to be attached/detached to a watch case quickly and easily without any special tools. The present invention is, of course, not limited to the illustrated example and is open to different variants and modifications that would be evident to a person skilled in the art. | <SOH> BACKGROUND OF THE INVENTION <EOH>Classically, the device for attaching a wristband to a case or a clasp is configured in the form of a bar or a pin. The pin must be attached or detached by means of a tool to be able to remove the wristband from the watch, for example, or to be able to change the clasp. It is desirable to be able to separate the wristband into two parts to make the attachment/detachment of the wristband on the case and/or the clasp on the wristband easier. In the prior art wristbands or clasps require the use of tools to be able to attach and/or detach the wristband and clasp, which is not practical for the user when he/she wishes to change the wristband or clasp. | <SOH> SUMMARY OF THE INVENTION <EOH>An object of the present invention is to remedy all or some of the disadvantages mentioned above by providing an attachment device that allows a quick attachment/detachment, in particular without requiring use of a tool. Another object of the invention, at least in a particular embodiment, is to provide an attachment device that is easy to use and inexpensive. For this purpose, the invention relates to an attachment device for two elements of a watch band to allow said two elements to be hooked into place or unhooked, wherein the first element comprises at least one bar on one of its ends. According to the invention the second element comprises two fixed grooves, each comprising a longitudinal opening respectively opposite one another, and one of the two elements can move from an unhooked position, in which one of the elements is oriented in a predetermined angular position in relation to the other element, to a hooked position, in which the two elements are coplanar after a rotation of a predetermined angle of one of the two elements in relation to the other so that each groove is articulated on the bar to hold the two elements hooked to one another. Because of these characteristics, such an attachment device enables a clasp to be attached and detached easily and quickly to/from a wristband strand, for example. In accordance with other advantageous variants of the invention: the dimension of the longitudinal opening of the grooves is slightly smaller than the bar; the grooves comprise a straight cylindrical slot, the diameter of which is slightly larger than the diameter of the bar; the first element comprises a central element surrounding the bar; the second element comprises a free space arranged between the two grooves and arranged to receive said central element of the first element; the predetermined angular position is in the range of between 45° and 90°; the second element is made in a single block. | A44C5185 | 20171016 | 20180510 | 96248.0 | A44C518 | 0 | LEE, MICHAEL S | ATTACHMENT DEVICE | UNDISCOUNTED | 0 | ACCEPTED | A44C | 2,017 |
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15,784,655 | PENDING | Portable Lubrication Unit For A Hydraulic Fracturing Valve Assembly, and Method For Pre-Pressurizing Valves | A method for pre-pressurizing fluid control valves is provided. The fluid control valves may be part of a hydraulic fracturing tree, or may be part of a so-called zipper frac manifold. In either instance, the method uses a lubrication unit for pre-pressurizing the cavity of a valve by injecting lubricant under high pressure. The fracturing tree or zipper frac manifold is useful for conducting hydraulic fracturing operations as part of the completion of a well. Each control valve has an upper lube fitting extending to an upper lube channel which communicates with an upper pocket. Similarly, each control valve includes a lower lube fitting extending to a lower lube channel which communicates with a lower pocket. A pressurized lubricating fluid is forced into the lube fittings to pre-pressurize the control valves prior to the fracturing fluid passing through the control valves. The method of pre-pressurizing the control valve restricts scarring by the fracturing fluid of the internal components of the control valve by equalizing pressure. | 1. A method of pre-pressurizing a valve, comprising: placing a lubricant pressurization system onto a portable platform, the lubricant pressurization system comprising: an air compressor; a lubricant reservoir and associated fluid pump; a high pressure air hose for delivering compressed air from the air compressor to the lubricant reservoir; and a high pressure lubricant line; moving the portable platform with the lubricant pressurization system to a well site; placing the high pressure lubricant line in fluid communication with one or more fluid control valves associated with a fracturing valve assembly; actuating the air compressor to power the fluid pump and to pressurize the lubricant within the high pressure lubricant lines; moving gates associated with the one or more fluid control valves into their open positions; and injecting lubricating fluid from the high pressure lubricant lines into a cavity of each of the fluid control valves in order to pre-pressurize the respective cavities to a pressure of at least a determined formation fracturing pressure for a wellbore at the wellsite. 2. The method of pre-pressurizing a valve of claim 1, wherein: the portable platform is a trailer, a skid, or the bed of a truck; and the fracturing valve assembly is a high pressure fracturing tree comprising a series of fluid control valves placed vertically over the wellbore, or a frac zipper manifold comprising a series of fluid control valves residing remote from the wellbore. 3. The method of pre-pressurizing a valve of claim 2, wherein the lubricant pressurization system further comprises: a pressure regulator placed in line along the high pressure air hose; a check valve placed in line along the high pressure lubricant line; and a pressure switch also placed in line along the high pressure lubricant line. 4. The method of pre-pressurizing a valve of claim 3, wherein: the fracturing valve assembly is a fracturing tree; the fluid control valves are in selective fluid communication with the wellbore; and the method further comprises: shutting off power to the air compressor when pressure in the high pressure lubricant line reaches a designated level; injecting a hydraulic fracturing fluid down a central bore of the fracturing tree and down flow channels of the one or more fluid control valves while the respective cavities are packed with the lubricating fluid; and further injecting the hydraulic fracturing fluid in order to fracture a subsurface formation. 5. The method of pre-pressurizing a valve of claim 3, wherein: the fracturing valve assembly is a fracturing tree; and each of the one or more fluid control valves comprises: an upper flange and a lower flange, with each of the upper and lower flanges configured to be mechanically and sealingly connected in line with a body of the fracturing tree; an internal gate cavity in fluid communication with a flow passage of the body, the internal gate cavity residing between the upper flange and the lower flange; a gate movably mounted within the internal gate cavity for movement between a gate open position and a gate closed position, the gate in combination with the body defining an upper pocket and a lower pocket; an upper seat placed above the upper pocket, and a lower seat placed below the lower pocket; a stem mechanically coupled to the gate; an actuator coupled to the stem configured to translate the stem and coupled gate linearly within the internal gate cavity; an upper lube channel extending through the body and in fluid communication with the upper pocket, and a lower lube channel extending through the body and in fluid communication with the lower pocket; and an upper lube fitting coupled to the upper lube channel, and a lower lube fitting coupled to the lower lube channel. 6. The method of pre-pressurizing a valve of claim 5, wherein: the at least one fluid control valve comprises at least three fluid control valves; and the gate of each fluid control valve comprises a channel such that when the gate is seated in its valve open position, the channel is aligned with the flow passage of the body, but when the gate is translated to its valve closed position, the channel is out-of-alignment with the flow channel and floatingly prevents the flow of injection fluids through the gate cavity. 7. A portable lubrication unit, comprising: a portable platform; an air compressor; a lubricant reservoir and associated fluid pump powered by the air compressor; a high pressure air hose for delivering compressed air from the air compressor to the fluid pump when the air compressor is actuated; and a high pressure lubricant line fluidically connected at one end to the lubricant reservoir, and at a second opposite end to a plurality of lube channels associated with fluid control valves along a fracturing valve assembly; wherein the air compressor, the lubricant reservoir and the high pressure air hose reside on the portable platform. 8. The portable lubrication unit of claim 7, wherein: the portable platform is a trailer, a skid, or the bed of a truck; and the fracturing valve assembly is a high pressure fracturing tree comprising a series of fluid control valves placed vertically in series, or a frac zipper manifold comprising a series of fluid control valves. 9. The portable lubrication unit of claim 8, wherein the lubricant pressurization system further comprises: a pressure regulator placed in line along the high pressure air hose, with the pressure regulator also residing on the portable platform; a check valve placed in line along the high pressure lubricant line; and a pressure switch also placed in line along the high pressure lubricant line. 10. The portable lubrication unit of claim 8, wherein: the fracturing valve assembly is a frac tree disposed vertically over a wellbore, the frac tree defining a body forming a vertical bore; and at least one fluid control valve sealingly placed along the body, the at least one fluid control valve comprising: a housing forming an internal gate cavity in fluid communication with the flow passage of the body; a gate movably mounted within the internal gate cavity for movement between a valve open position and a valve closed position, the gate in combination with the internal gate cavity defining an upper pocket and a lower pocket; a seat placed along each side of the gate; a stem coupled to the gate; an actuator coupled to the stem; an upper lube channel extending through the body and in fluid communication with the upper pocket; a lower lube channel extending through the body and in fluid communication with the lower pocket; an upper lube fitting coupled to the upper lube channel; a lower lube fitting coupled to the lower lube channel; and wherein the gate cavity is configured to be pressurized to a pressure of at least a determined downhole formation parting pressure by passing the lubricating fluid through the upper lube fitting, through the lower lube fitting, or both, while the gate is in its valve open position but before hydraulic fracturing fluid is injected through the fluid control valve. 11. The portable lubrication unit of claim 10, wherein: the gate cavity is further configured to be pressurized to a pressure in excess of a determined hydraulic fracturing pressure; and the gate of each control valve comprises a channel such that when the gate is seated in its valve open position, the channel is aligned with the flow passage of the body, but when the gate is translated to its valve closed position, the channel is out-of-alignment with the flow channel and floatingly prevents the flow of injection fluids through the gate cavity. 12. A hydraulic fracturing tree, comprising: a body have a flow passage in fluid communication with a subsurface wellbore; and at least one fluid control valve sealingly placed along the body, the at least one fluid control valve comprising: a housing forming an internal gate cavity in fluid communication with the flow passage of the body; a gate movably mounted within the internal gate cavity for movement between a valve open position and a valve closed position, the gate in combination with the housing defining an upper pocket and a lower pocket; a seat placed along each side of the gate; a stem coupled to the gate; an actuator coupled to the stem; an upper lube channel extending through the body and in fluid communication with the upper pocket; a lower lube channel extending through the body and in fluid communication with the lower pocket; an upper lube fitting coupled to the upper lube channel; a lower lube fitting coupled to the lower lube channel; a lubricant reservoir; and a high pressure pump configured to pump lubricating fluid from the reservoir into the gate cavity, wherein the gate cavity is configured to be pressurized to a pressure in excess of a determined downhole formation parting pressure by passing the lubricating fluid through the upper lube fitting, through the lower lube fitting, or both, while the gate is in its valve open position but before hydraulic fracturing fluid is injected through the fluid control valve. 13. The hydraulic fracturing tree of claim 12, wherein: the at least one control valve comprises at least two control valves spaced vertically along the body; at least one spacer spool is placed between the at least two control valves; and the gate of each control valve comprises a channel such that when the gate is seated in its valve open position, the channel is aligned with the flow passage of the body, but when the gate is seated in its valve closed position, the channel is out-of-alignment with the flow channel and floatingly prevents the flow of injection fluids through the gate cavity. 14. The hydraulic fracturing tree of claim 13, wherein: the stem of each control valve comprises a proximal end that is operatively connected to the actuator, and a distal end mechanically connected to the gate; and the actuator comprises a hand lever configured such that manual rotation of the lever selectively translates the gate between its valve open position and its valve closed position. 15. The hydraulic fracturing tree of claim 12, wherein: each of the at least one fluid control valves further comprises a bonnet configured to receive the stem; and an upper flange residing above the upper gate cavity and a lower flange residing below the lower gate cavity and securing the fluid control valve to the body of the tree. 16. The hydraulic fracturing tree of claim 12, wherein the gate cavity is configured to be pre-pressurized to a pressure of at least a determined pressure for the injection of hydraulic fracturing fluid. 17. A fluid control valve, comprising: an upper flange and a lower flange, with each of the upper and lower flanges configured to be mechanically and sealingly connected in line with a body of a wellhead tree; an internal gate cavity in fluid communication with a flow passage of the body, the internal gate cavity residing between the upper flange and the lower flange; a gate movably mounted within the internal gate cavity for movement between a gate open position and a gate closed position, the gate in combination with the body defining an upper pocket and a lower pocket; an upper seat placed above the upper pocket, and a lower seat placed below the lower pocket; a stem mechanically coupled to the gate; an actuator coupled to the stem configured to translate the stem and coupled gate linearly within the internal gate cavity; an upper lube channel extending through the body and in fluid communication with the upper pocket, and a lower lube channel extending through the body and in fluid communication with the lower pocket; an upper lube fitting coupled to the upper lube channel, and a lower lube fitting coupled to the lower lube channel, a lubricant reservoir; and a high pressure pump configured to pump lubricating fluid from the lubricant reservoir and into the gate cavity, wherein the gate cavity is configured to be pressurized to a pressure in excess of a determined subsurface formation parting pressure by passing the lubricating fluid through the upper lube fitting and the upper lube channel, through the lower lube fitting and the lower lube channel, or both, while the gate is in its gate open position but before hydraulic fracturing fluid is injected into the control valve. 18. The fluid control valve of claim 16, wherein the gate comprises a channel such that when the gate is seated in its gate open position, the channel is aligned with the flow passage of the body, but when the gate is translated to its gate closed position, the channel is out-of-alignment with the flow channel and floatingly prevents the flow of injection fluids through the gate cavity. 19. The fluid control valve of claim 18, further comprising: a bonnet configured to receive the stem; and wherein the stem comprises a proximal end that is operatively connected to the actuator, and a distal end mechanically connected to the gate. 20. A control valve system, comprising: a body have a flow passage in fluid communication with a subsurface wellbore; at least two control valves sealingly placed along the body, the at least two control valves each comprising: an internal gate cavity in fluid communication with the flow passage of the body; a gate movably mounted within the internal gate cavity for movement between a valve open position and a valve closed position, the gate in combination with the body defining an upper pocket and a lower pocket; a seat placed along each side of the gate; a stem mechanically coupled to the gate; an actuator coupled to the stem configured to translate the stem and coupled gate linearly within the internal gate cavity; an upper lube channel extending through the body and in fluid communication with the upper pocket, and a lower lube channel extending through the body and in fluid communication with the lower pocket; an upper lube fitting coupled to the upper lube channel, and a lower lube fitting coupled to the lower lube channel; a lubricant reservoir; and a high pressure pump configured to pump lubricating fluid from the lubricant reservoir into the gate cavity, at least one high pressure line extending from the high pressure pump and fluidically coupled to the upper lube fitting, the lower lube fitting, or both, wherein the high pressure pump and the at least one high pressure line are configured to selectively deliver the lubricating fluid into the upper pocket and the lower pocket so as to pre-pressurize the gate cavity to a pressure in excess of a determined formation parting pressure while the gate is in its valve open position but before hydraulic fracturing fluid is injected into the two or more control valves. 21. The control valve system of claim 20, wherein: the gate cavity is further configured to be pressurized to a pressure in excess of a determined hydraulic fracturing pressure; and the gate of each control valve comprises a channel such that when the gate is seated in its valve open position, the channel is aligned with the flow passage of the body, but when the gate is translated to its valve closed position, the channel is out-of-alignment with the flow channel and floatingly prevents the flow of injection fluids through the gate cavity. 22. The control valve system of claim 21, wherein: the stem comprises a proximal end that is threadedly connected to the actuator, and a distal end mechanically connected to the gate; and the actuator comprises a hand lever configured such that manual rotation of the lever selectively moves the gate between its valve open position and its valve closed position. 23. The control valve system of claim 21, further comprising a manifold coupled to the at least one high pressure line, and wherein the at least one pressure line includes an upper high pressure line extending from the manifold to the upper lube fitting and a lower high pressure line extending from the manifold to the lower lube fitting. 24. The control valve system of claim 23, wherein: the body comprises a fracturing tree; each of the control valves further comprises an upper flange and a lower flange, with each of the upper and lower flanges configured to be mechanically and sealingly connected in line with the body of the fracturing tree; and the internal gate cavity resides between the upper flange and the lower flange. 25. A method of pressurizing at least one fluid control valve, comprising the steps of: providing at least one fluid control valve along either a hydraulic fracturing tree or a zipper frac manifold, with the at least one fluid control valve having a body with an internal gate cavity, a gate movably mounted within the gate cavity for movement between a gate open position and a gate closed position, the gate in combination with the body defining an upper pocket and a lower pocket, a stem coupled to the gate, an actuator operatively coupled to the stem, an upper lube channel extending through the body and in fluid communication with the upper pocket, a lower lube channel extending through the body and in fluid communication with the lower pocket, an upper lube fitting coupled to the upper lube channel, a lower lube fitting coupled to the lower lube channel, a high pressure pump, and at least one high pressure line extending from the high pressure pump and fluidically coupled to both the upper lube fitting and the lower lube fitting; determining a downhole formation parting pressure for a subsurface formation; actuating the actuator to move the stem to place the at least one fluid control valve in its gate open position; actuating the high pressure pump to pressurize a lubricating fluid to a pressure above the surface pressure required to achieve the downhole formation parting pressure; and passing the pressurized lubricating fluid from the high pressure pump, through the at least one high pressure line, into both the upper lube fitting and the lower lube fitting, and through the upper lube channel and the lower lube channel to pressurize the gate cavity with the lubricating fluid prior to passing a fracturing fluid through a flow passage within each of the at least one control valve and down into a subsurface wellbore. 26. The method of pressurizing at least one fluid control valve of claim 25, wherein: the at least one control valve comprises a plurality of fluid control valves placed in series vertically along a hydraulic fracturing tree; the hydraulic fracturing tree comprises a central bore in selective fluid communication with the subsurface wellbore; the subsurface wellbore extends down to the subsurface formation; and the method further comprises pre-pressuring each of the plurality of fluid control valves while each of the fluid control valves is in its gate open position before pumping hydraulic fracturing fluid into the central bore and down into the wellbore. 27. The method of pressurizing at least one fluid control valve of claim 26, wherein: the plurality of control valves comprises at least three fluid control valves; the stem of each control valve comprises a proximal end that is operatively connected to the actuator, and a distal end mechanically connected to the gate; the actuator comprises a hand lever configured such that manual rotation of the lever selectively translates the gate between its gate open position and its gate closed position; and each gate is configured to float within its respective gate cavity in response to fluid pressure within the central bore. 28. The method of pressurizing at least one fluid control valve of claim 27, wherein each of the at least one control valves further comprises: a bonnet configured to receive the stem; and an upper flange residing above the upper gate cavity and a lower flange residing below the lower gate cavity and securing the control valve to the body of the fracturing tree. 29. The method of pressurizing at least one fluid control valve of claim 27, wherein passing the pressurized lubricating fluid from the high pressure pump comprises pre-pressuring the gate cavity to a pressure of at least a fracturing fluid injection pressure. 30. The method of pressurizing at least one fluid control valve of claim 27, wherein the gate cavity of each of the fluid control valves is pre-pressurized to a pressure that is at least 2% greater than the determined fracturing fluid injection pressure. | STATEMENT OF RELATED APPLICATIONS This application claims the benefit of U.S. Ser. No. 62/411,984 entitled “Hydraulic Fracturing Tree Having Lubrication Unit, and Method.” That application was filed on Oct. 24, 2016, and is incorporated herein in its entirety by reference. This application also claims the benefit of U.S. Ser. No. 62/415,001 entitled “Portable Lubrication Unit For a Hydraulic Fracturing Valve Assembly, and Method for Pre-Pressurizing Valves.” That application was filed on Oct. 31, 2016, and is incorporated herein in its entirety by reference. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT Not applicable. THE NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT Not applicable. BACKGROUND OF THE INVENTION This section is intended to introduce selected aspects of the art, which may be associated with various embodiments of the present disclosure. This discussion is believed to assist in providing a framework to facilitate a better understanding of particular aspects of the present disclosure. Accordingly, it should be understood that this section should be read in this light, and not necessarily as admissions of prior art. FIELD OF THE INVENTION The present disclosure relates to the field of well completion. More specifically, the present disclosure relates to fluid control valves for a completion tree used for hydraulic fracturing. The present disclosure further relates to an automatic lubrication unit configured for use with a hydraulic fracturing tree. DISCUSSION OF TECHNOLOGY In the drilling of an oil and gas well, a near-vertical wellbore is formed through the earth using a drill bit urged downwardly at a lower end of a drill string. The drill bit is rotated in order to form the wellbore, while drilling fluid is pumped through the drill string and back up to the surface on the back side of the pipe. The drilling fluid serves to cool the bit and flush drill cuttings during rotation. After drilling to a predetermined vertical depth, the wellbore may be deviated. The deviation may be at a “kick-off” angle of, for example, 45 degrees or 60 degrees. Alternatively, the deviation may be about 90 degrees. In this instance, a wellbore having a substantially horizontal leg is formed. Within the last two decades, advances in drilling technology have enabled oil and gas operators to economically “kick-off” and steer wellbore trajectories from a generally vertical orientation to a generally horizontal orientation. The horizontal “leg” of each of these wellbores now often exceeds a length of one mile. This significantly multiplies the wellbore exposure to a target hydrocarbon-bearing formation (or “pay zone”). For example, for a given target pay zone having a (vertical) thickness of 100 feet, a one-mile horizontal leg exposes 52.8 times as much pay zone to a horizontal wellbore as compared to the 100-foot exposure of a conventional vertical wellbore. During the drilling process, the drill string and bit are periodically removed and the wellbore is lined with a string of casing. An annular area is formed between the string of casing and the formation penetrated by the wellbore. A cementing operation is then conducted in order to fill or “squeeze” the annular volume with cement along the length of the wellbore casing. The combination of cement and casing strengthens the wellbore and facilitates the zonal isolation, and subsequent completion, of certain sections of potentially hydrocarbon-producing pay zones behind the casing. During wellbore formation, it is common to place several strings of casing having progressively smaller outer diameters into the wellbore. A first string may be referred to as surface casing. The surface casing serves to isolate and protect the shallower, fresh water-bearing aquifers from contamination by any other wellbore fluids. Accordingly, this casing string is almost always cemented entirely back to the surface. The process of drilling and then cementing progressively smaller strings of casing is repeated several times below the surface casing until the well has reached total depth. In some instances, the final string of casing is a liner, that is, a string of casing that is not tied back to the surface but is hung from the lowest intermediate string of casing. FIG. 1 provides a cross-sectional view of a wellbore 100 having been completed in a horizontal orientation. It can be seen that a wellbore 100 has been formed from the earth surface 101, through numerous earth strata 20a, 20b, . . . 20h and down to a hydrocarbon-producing formation 150. The subsurface formation 150 represents a “pay zone” for the oil and gas operator. The wellbore 100 includes a vertical section 105 above the pay zone 150, and a horizontal section 107. The horizontal section 107 defines a heel 115 and a toe 117, along with an elongated leg there between that extends along the pay zone 150. In connection with the completion of the wellbore 100, several strings of casing having progressively smaller outer diameters have been cemented into the wellbore 100. These include a string of surface casing 120, and may include one or more strings of intermediate casing 130, and finally, a production casing 140. The final string of casing 140, referred to as a production casing, is typically cemented 143 into place. In some completions, the production casing 140 has external casing packers (“ECP's), swell packers, or some combination thereof spaced across the productive interval. This creates compartments between the swell packers for isolation of zones and specific stimulation treatments. In FIG. 1, a column of cement 127 is placed into an annular space residing between the surface casing 120 and the surrounding formation 20a, 20b. A so-called cement shoe 128 is provided at the lower end of the surface casing 120. Similarly, a column of cement 137 is optionally placed in an annular space residing between the intermediate casing string 130 and the surrounding formation 20d, 20e. A cement shoe 138 is again provided at the lower end of the casing string 130. As part of the completion process and before the production tubing string is installed, the production casing 140 is perforated at a desired level 107. This means that lateral holes (or “perforations” 145) are shot through the casing 140 and the cement column 143 surrounding the casing 140. The perforations 145 allow reservoir fluids to flow into the wellbore 100. Where swell (or other) packers are provided, the perforating gun penetrates the casing 140, allowing reservoir fluids to flow from the rock formation 20h into the horizontal leg 107 of the wellbore 100 and into selected zones. After perforating, the formation 20h is typically fractured at the corresponding zone. Hydraulic fracturing consists of injecting water with friction reducers or viscous fluids (usually shear thinning, non-Newtonian gels or emulsions) into a formation at such high pressures and rates that the reservoir rock parts and forms a network of fractures 146. The fracturing fluid is typically mixed with a proppant material such as sand, ceramic beads or other granular materials. The proppant serves to hold the fractures 146 open after the hydraulic pressures are released. In the case of so-called “tight” or unconventional formations, the combination of fractures and injected proppant substantially increases the flow capacity, or permeability, of the treated reservoir. FIG. 1 demonstrates a series of fracture half-planes 146 along the horizontal section 107 of the wellbore 100. The fracture half-planes 146 represent the orientation of fractures that will form in connection with a perforating/fracturing operation. According to principles of geo-mechanics, fracture planes will generally form in a direction that is perpendicular to the plane of least principal stress in a rock matrix. Stated more simply, in most wellbores, the rock matrix will part along vertical lines when the horizontal section of a wellbore resides below 3,000 feet, and sometimes as shallow as 1,500 feet, below the surface. In this instance, hydraulic fractures will tend to propagate from the wellbore's perforations 145 in a vertical, elliptical plane perpendicular to the plane of least principal stress. If the orientation of the least principal stress plane is known, the longitudinal axis of the leg 107 of a horizontal wellbore 100 is ideally oriented parallel to it such that the multiple fracture planes 146 will intersect the wellbore at-or-near orthogonal to the horizontal leg 107 of the wellbore, as depicted in FIG. 1. In support of the formation fracturing process, a so-called hydraulic “frac” tree 50 is installed at the surface 101. An illustrative tree is seen at 200 in FIG. 2. The tree 5 serves to connect fluid hoses and pumps, and to direct hydraulic fracturing fluid into the wellbore. Those of ordinary skill in the art understand that formation fracturing fluid is pump through the hoses, through control valves associated with the fracturing tree, and down the wellbore 4 until it exits exposed perforations. This pumping process is frequently done in horizontal stages, enabling specific zones to be sequentially isolated along the horizontal section 4c. The ability to replicate multiple vertical completions along a single horizontal wellbore is what has made the pursuit of hydrocarbon reserves from unconventional reservoirs, and particularly shales, economically viable within relatively recent times. This revolutionary technology has had such a profound impact that Baker Hughes Rig Count information for the United States indicates only about one-fourth (26%) of wells being drilled in the U.S. are classified as “Vertical”, whereas the other three-fourths are classified as either “Horizontal” or “Directional” (62% and 12%, respectively). That is, horizontal wells currently comprise approximately two out of every three wells being drilled in the United States. A complication associated with the formation fracturing process is the wear upon the surface equipment used during the fracturing process. In this respect, the proppant placed within the fracturing fluid is highly abrasive, particularly when pumped through control valves at high flow rates. The control valves include a body in which is placed a movable gate which functions to controllably allow or prevent the flow of fluids through the control valve. The internal gate loosely abuts a pair of seats positioned on either side of the gate. Oftentimes, the control valves are arranged in series, forming a so-called hydraulic fracturing tree or “valve tree.” During the fracturing process, the fracturing fluid passes through internal components of the valves along the valve tree. The passage of the fracturing fluid, and especially the abrasive proppant which constitutes a part of the fracturing fluid, causes scarring, pitting or other damage to the internal components of the valves, such as the gates, seats, stem and body. Once the valve becomes scarred or damaged, the valves and, possibly, the entire tree, must be repaired or replaced to ensure the safe operation of the well. Such repairs are both costly and time consuming to the operator of the completion equipment. Some operators have attempted to cure this problem by lubricating the gate of the valves. This is currently done by applying a viscous lubrication fluid to the valves, cycling the gate of each of the valves, lubricating the valves again, and then moving the gate again. However, when moving the gate from a closed position to an open position, pressure in the body of the tree is released. This, in turn, creates a pressure differential from the bore of the fracturing tree to the body of the valves when the fracturing operation begins. Upon pressurization, the pressure in the bore is typically 6,500 to 8,500 psi but only 0 psi in the gate cavity and seats. Thus, there is a 6,500 to 8,500 psi differential. When the gate is moved to its open position, the pressure differential allows the abrasive fracturing fluid and proppant to be forced between the gate and seat in the opened valve until the body cavity equalizes with the pumping pressure applied to the valve bore and well. Thus, once again the fracturing fluid and proppant is potentially damaging the internal valve components, creating scarring and pits therein. The build-up of such damage may result in gates no longer being capable of moving between open and closed positions. In a worst-case scenario, well control may be compromise since the tree cannot be fully shut in. Accordingly, it is desirable provide a portable lubrication unit that may be carried to a well site, and then fluidically connected to the control valves of a fracturing tree. In this way, the gate cavity may be pre-pressurized in such a manner as to restrict the abrasive fluids associated with the perforating process from entering the cavity and damaging the internal components of the valves. Further, a need exists for a frac tree fitted with a lubricant pump that enables lubricating fluid to be pumped into the gate cavity at very high pressure before fracturing fluid is pumped downhole. Still further, a need exists for a process of pre-pressurizing control valves along an injection tree or injection manifold before a hydraulic fracturing fluid is injected into a wellbore for formation fracturing. SUMMARY OF THE INVENTION A portable lubrication unit for a hydraulic fracturing tree is provided herein. The hydraulic fracturing tree is configured to reside over a wellbore, and to enable the control of injection fluids into the wellbore and to contain wellbore pressure. Thus, the fracturing tree is essentially a high pressure wellhead. The lubrication unit first comprises a portable platform. The platform may be a trailer, a skid or the bed of a truck. The portable platform carries the equipment necessary for pressurization of fluid control valves associated with the fracturing tree. The platform is taken to well sites, which frequently are in remote locations. The lubrication unit also includes an air compressor and a pressure regulator. Because of the extremely high pressures involved, the pressure regulator will likely be separate from the vessel that makes up the air compressor. Thus, an air line will carry pressurized air from the air compressor to the pressure regulator. The lubrication unit will further include a lubricating fluid reservoir. The lubricating fluid reservoir defines a vessel holding a lubricating fluid. Suitable pipes, gauges and valves are provided for receiving pressurized air from the pressure regulator, monitoring pressure of the reservoir, and releasing the pressurized lubricating fluid from the reservoir. A high pressure lubrication line then extends from the lubricating fluid reservoir to the fracturing tree. It is preferred that the portable lubrication unit also include an in-line check valve along the high pressure lubrication line. The check valve prevents lubricating fluid from backing back into the lubricating fluid reservoir from the wellhead. In addition, a pressure switch is preferably provided. In one aspect, the pressure switch generates an electrical signal when a certain pressure level is reached. The signal may initiate a shut-off of the air compressor or send a separate signal to an operator. The high pressure lubrication line may feed into a manifold, that then distributes lubrication fluid directly to individual fluid control valves along the fracturing tree. Alternatively, the lubrication line may travel along the fracturing tree, and tee off to individual lube fittings adjacent the control valves. A hydraulic fracturing tree having a novel lubrication unit is also provided herein. The hydraulic fracturing tree first comprises a body. The body has a cylindrical flow passage that is in fluid communication with the subsurface wellbore. The body is generally made up of a series of spacers having cylindrical bores therein. The hydraulic fracturing tree also has at least one fluid control valve along the body. Preferably, the at least one control valve is at least three control valves spaced vertically along the body. Closing the valves limits fluid communication between the cylindrical body of the tree and the wellbore, and vice versa. The spaces reside between the respective control valves. Each of the at least one fluid control valves includes an internal gate cavity. The gate cavity is in fluid communication with the flow passage of the body. Each of the at least one fluid control valves also has a gate. The gate is movably mounted within the internal gate cavity. Preferably, this is done through rotation of an actuator arm that produces linear movement of the gate within the internal gate cavity. Movement of the gate is between a valve open position and a valve closed position. In combination with the body, the gate defines an upper pocket and a lower pocket. Each of the at least one fluid control valves also includes a pair of seats. The seats are placed at opposing sides of the gate. In operation, if a frac valve is in the run of the frac tree, there will be one seat on top of the gate and one seat on the bottom of the gate. The gate is movable, or “floating.” This means if the gate is in its gate-closed position and the well has more pressure coming from the formation than what is on top of the frac tree, the gate will push against the top seat and form a seal. This would be an example of the frac valve containing wellbore pressure. If the well is undergoing hydraulic fracturing and the gate is in its gate-closed position, the greatest pressure is on top of the gate. In this instance, the gate seals against the bottom seat, preventing the frac fluid from going downhole. Each of the at least one fluid control valves further comprises a stem. The stem is mechanically coupled to the gate. Preferably, the stem sealingly extends through a bonnet. An actuator is coupled to the stem to translate the gate linearly between valve open and valve closed positions. In one aspect, the stem comprises a proximal end that is threadedly connected to the actuator, and a distal end mechanically connected to the gate. Preferably, the actuator comprises a hand lever and associated threaded cylinder configured such that manual rotation of the lever and cylinder selectively translates the gate between its valve open and its valve closed positions. Each of the at least one fluid control valves also has an upper lube channel extending through the body and in fluid communication with the upper pocket, and a lower lube channel extending through the body and in fluid communication with the lower pocket. The control valve further has an upper lube fitting coupled to the upper lube channel, and a lower lube fitting coupled to the lower lube channel. The upper pocket and/or the lower pocket are configured to be pressurized by a lubricating fluid that is placed under pressure. The pre-pressurization is at least as great as a determined formation parting pressure, and preferably at least as great as a hydraulic fracturing pressure. Pre-pressurization occurs by passing the lubricating fluid through the upper lube fitting, through the lower lube fitting, or both, and into the gate cavity. Pre-pressurization is done before hydraulic fluid is passed through the fracturing tree. Preferably, each of the at least one control valves further comprises an upper flange and a lower flange, with each of the upper and lower flanges configured to be mechanically and sealingly connected in line with the body by means of a plurality of bolts. Preferably, the fracturing tree comprises several control valves in series, each of which has an upper flange and a lower flange, and each of which is pre-pressurized. The tree further comprises a reservoir of lubricant, and a high pressure pump. The pump is configured to pump the lubricating fluid from the reservoir, through the lube fittings and into the cavity pockets of the gates. Appropriate pressure sensors, pressure gauges, lines and fittings are provided for pumping as described above. A method of pressurizing at least one fluid control valve is also provided herein. Pressurization is provided to each of the control valves along a fracturing tree, with the valves being in their valve open positions during pressurization. Thereafter, hydraulic fracturing fluid is injected through the valves and down into the wellbore. In this way, fracturing fluid is directed through the flow channel while high pressure provided by the lubricating fluid within the upper pocket and/or lower pocket of the gate cavity substantially prevents the hydraulic fracturing fluid from traveling around the gate and scarring the seats and related hardware. BRIEF DESCRIPTION OF THE DRAWINGS So that the manner in which the present inventions can be better understood, certain illustrations, charts and/or flow charts are appended hereto. It is to be noted, however, that the drawings illustrate only selected embodiments of the inventions and are therefore not to be considered limiting of scope, for the inventions may admit to other equally effective embodiments and applications. FIG. 1 is a cross-sectional view of an illustrative wellbore. The wellbore has been horizontally completed, with half-fracture planes shown in 3-D along a horizontal leg of the wellbore to illustrate fracture stages and fracture orientation relative to a subsurface formation. FIG. 2 is a perspective view of a vertical series of control valves of the present invention arranged as a fracturing tree, in one embodiment. Spacer bodies (or “spools”) are provided between the fluid control valves. FIG. 3 is a perspective view, shown in partial cross-section, of a single control valve of FIG. 2. The valve has been rotated 90 degrees for better illustration. FIG. 4A is a perspective view of a portion of an illustrative control valve of the fracturing tree of FIG. 2. The valve is shown in cross-section. FIG. 4B is an enlarged view of a portion of the control valve of FIG. 4A. FIG. 5A is a perspective view of the illustrative control valve of FIG. 4A. Here, pressure is being pre-applied to the cavity of the control valve. FIG. 5B is an enlarged view of a portion of the control valve of FIG. 5A. FIG. 6A is a flow chart showing a progression of components used for a portable lubrication unit of the present invention, in one embodiment. FIG. 6B is an enlarged view of a portion of the hydraulic fracturing tree of FIG. 6A. Darkened lines indicate areas of high pressure experienced within the frac tree during a formation fracturing operation. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS Definitions As used herein, the term “hydrocarbon” refers to an organic compound that includes primarily, if not exclusively, the elements hydrogen and carbon. Hydrocarbons generally fall into two classes: aliphatic, or straight chain hydrocarbons, and cyclic, or closed ring hydrocarbons, including cyclic terpenes. Examples of hydrocarbon-containing materials include any form of natural gas, oil, coal, and bitumen that can be used as a fuel or upgraded into a fuel. As used herein, the term “hydrocarbon fluids” refers to a hydrocarbon or mixtures of hydrocarbons that are gases or liquids. For example, hydrocarbon fluids may include a hydrocarbon or mixtures of hydrocarbons that are gases or liquids at formation conditions, at processing conditions, or at ambient conditions. Hydrocarbon fluids may include, for example, oil, natural gas, condensate, coal bed methane, shale oil, shale gas, and other hydrocarbons that are in a gaseous or liquid state. As used herein, the term “fluid” refers to gases, liquids, and combinations of gases and liquids, as well as to combinations of gases and fine solids, and combinations of liquids and fine solids. As used herein, the term “subsurface” refers to geologic strata occurring below the earth's surface. The term “subsurface interval” refers to a formation or a portion of a formation wherein formation fluids may reside. The fluids may be, for example, hydrocarbon liquids, hydrocarbon gases, aqueous fluids, or combinations thereof. The terms “zone” or “zone of interest” refer to a portion of a formation containing hydrocarbons. Sometimes, the terms “target zone,” “pay zone,” or “interval” may be used. As used herein, the term “wellbore” refers to a hole in the subsurface made by drilling or insertion of a conduit into the subsurface. A wellbore may have a substantially circular cross section, or other cross-sectional shape. As used herein, the term “well,” when referring to an opening in the formation, may be used interchangeably with the term “wellbore.” The term “abrasive material” or “abrasives” refers to small, solid particles mixed with or suspended in the jetting fluid to enhance erosional penetration of: (1) the pay zone; and/or (2) the cement sheath between the production casing and pay zone; and/or (3) the wall of the production casing at the point of desired casing exit. The terms “tubular” or “tubular member” refer to any pipe, such as a joint of casing, a portion of a liner, a joint of tubing, a pup joint, or coiled tubing. DESCRIPTION OF SPECIFIC EMBODIMENTS FIG. 2 is a perspective view of a hydraulic fracturing tree 200. The fracturing tree 200 comprises a series of control valves 210. The control valves 210 are arranged vertically along a metal body to form the fracturing tree 200. The control valves 210 provide selective fluid communication between fluid lines (not shown in FIG. 2) such as hydraulic fracturing fluid lines, and a wellbore. In the illustrative view of FIG. 2, Arrows 201 are shown. The Arrows 201 indicate a direction of travel of a hydraulic fracturing fluid. The fracturing fluid is injected through an uppermost flow control valve 210U, down the tree 200, and into a wellbore (such as wellbore 100) at a pressure that is in excess of a determined formation parting pressure. In this way, the subsurface formation 20h may be fractured under hydraulic pressure. For example, a subsurface formation parting pressure may be 6,500 psi, while a hydraulic pumping pressure for the fracturing fluid may be at 8,000 psi. Each control valve 210 comprises a gate (shown at 260 in FIG. 3) fabricated from a metal material. The gate 260 is translated linearly within a gate cavity (shown at 250 in FIG. 3) in response to movement of an actuator. In the arrangement of FIG. 2, the actuators are valve handles 215. Each handle 215 is manually rotated to open and close a respective valve 210. Of course, it is understood that the gates 260 may alternatively be translated remotely using a motor (not shown) controlled through a wireless receiver and/or hydraulic pistons controlled by an HPU or accumulator unit. The control valves 210 are stacked along a central body 205. In one aspect, the control valves 210 form the central body 205. In another aspect, the central body 205 is made up of a series of so-called spacer spools. The spacer spools are essentially tubular subs that are added between adjacent fluid control valves (or “frac valves”) 210. The spacer spools 205 have studs coming out of the bodies instead of bodies that have API flanges on them. If the frac valves 210 have API flanges, those flanges are bolted to the flanges of the spacer spools 205. In any instance, the flow channels of the spacer spools 205 and the in-line control valves 210 form a continuous vertical bore, or flow channel (seen at 208 in FIG. 3 and in FIG. 4A). The bore 208 receives injection fluids through the respective control valves 210 as each gate 260 is translated to its open position. FIG. 3 is an enlarged perspective view of a control valve 210 from FIG. 2, in one embodiment. The control valve 210 is shown in partial cross-section. In addition, the control valve 210 is rotated 90 degrees for illustrative purposes. Visible in FIG. 3 is a handle 215, or “hand wheel.” The handle 215 resides at a proximal end of an elongated stem 220, and serves as a manual actuator. The handle 215 is shown oriented above the valve 210, though it is understood that the handle 215 actually extends laterally from the valve 210 in a horizontal manner as illustrated in FIG. 2. The stem 220 extends into and resides rotationally within a barrel 225. The barrel 225, in turn, is “tee'd” to a flange 230. The flange 230 secures the barrel 225 to the central body 205. In the parlance of the industry, the flange 230 is referred to as a “bonnet.” The bonnet 230 is secured to the body 205 through a plurality of bolts 231. It is observed that opposing ends of the vertical bore 208 for the central body 205 itself also comprises a pair of opposing flanges 232, 234. A first port 242 is formed on one end of the body 205 associated with an upper flange 232, while a second port 244 is formed on another end of the body 205 and is associated with a lower flange 234. Generally, the ports 242 and 244 are aligned and form part of the vertical flow passage that defines the bore 208. Each of the flanges 232, 234 includes a seal surface 246 for placement of a flange seal (not shown). The flange seal may be a gasket or an o-ring. The seal surface 246 enables sealing between an adjacent flange and connecting equipment. Other types of connections can be formed, although flanges are common for the pressure ratings of the control valves 210. As noted, the valve barrel 225 includes a gate cavity 250 disposed between the first port 242 and the second port 244. The gate cavity 250 is configured to intersect the flow passage 208. Generally, the gate cavity 250 is disposed perpendicular to the flow passage 208, although other angles can be used. The gate 260 resides within the gate cavity 250 and may be selectively positioned to block the flow passage 208 and control fluid flow there through. The gate 260 defines an elongated body 262. In the illustrative arrangement of FIG. 3, the body 262 has a rectangular profile. When the gate 260 is in its closed position, the body 262 blocks the flow of fluids through the flow passage 208. However, the body 262 includes a through opening, or channel 265. The body 262 may be translated to align the channel 265 with the flow passage 208 in order to provide an open position that allows the flow of fluids down the vertical flow passage 208 en route to the wellbore 100. The combination of the gate 260 and the gate cavity 250 forms an upper gate pocket (seen at 252 in FIGS. 4A and 5A) above the gate 260, and a lower gate pocket (seen at 254 in FIGS. 4A and 5A) below the gate 260. The pockets 252, 254 provide clearance that allows the gate 260 to flex up and down within the gate cavity 250 in response to fluid pressure. The size and volume of the gate pockets 252 and 254 are dependent upon the location of the gate 260 within the gate cavity 250, for as the gate 260 flexes downwardly, the volume of the upper gate pocket 252 increases, while the volume of the lower gate pocket 254 decreases, and visa-versa as the gate 260 flexes upwardly. To effectively control the flow of fluids through the flow passage 208, a seat 267 is generally disposed on each side of the gate cavity 250 and the gate 260. In the closed position, the seat 267 generally abuts the gate 260 to limit the flow of fluids there through. When the valve 210 is closed, meaning that the flow channel 265 is out of alignment with the flow passage 208, it can be said that the gate 260 is seated in a closed position, and when the valve 210 is open, meaning that the flow channel 265 is aligned with the flow passage 208, it can be said that the gate 260 is seated in an open position. It can be appreciated that when a gate 260 is moved to its valve open position, hydraulic fracturing fluids under extremely high pressure, e.g., greater than 7,000 psi, will surge through the gate cavity 250. This has the potential to create significant damage to the seats 267, the gate body 262 and all hardware associated with the valve 210. Therefore, it is desirable herein to provide a valve system and associated completion process wherein each of the valves 210 is pre-pressurized as described further below. Referring again to the upper flange 232, the upper flange 232 resides above the upper gate pocket 252. The stem 220 extends through the upper flange 232 and into the upper gate pocket 252. The stem 220 can be rotated within the bonnet 230 in response to rotation of the handle 215. Rotation of the stem 220 linearly translates the gate 260 within the gate cavity 250. This linear movement is caused by rotation of a threaded surface 226 formed along the stem 220 such that rotation of the cylinder 218 effectively moves the stem 220 and the gate 260 in a translating motion. In the embodiment shown, the movement of the gate 260 is at a perpendicular angle to the flow passage 208, although the angle can vary if so designed. As noted, the stem 220 can be translated by a manual or motorized mechanical actuator. Generally, an actuator 215 can be a hand wheel, motor-driven gear, or other movable element. One or more seals 228 is disposed between the stem 220 and the barrel 225 to generally eliminate leakage to the outside of the valve 210. A cylinder 218 is mounted to the top end of the bonnet barrel 225 and about the stem 220. Rotation of the actuator 215 turns the cylinder 218, which threadedly engages the stem 220 to translate the gate 260. The valve 210 also includes grease (or lube) fittings 270. An upper fitting 270U resides along a first end of the body 205, while a lower fitting 270L resides along a second end of the body 205. The upper lube fitting 270U is coupled to and in fluid communication with an upper lube channel 27U, while the lower lube fitting 270L is coupled to and in fluid communication with a lower lube channel 27L. Each of the upper 27U and lower 27L lube channels extends through the body 205. Each of the upper 270U and lower 270L lube fittings is configured to receive a high pressure line 300. High pressure lines 300 are shown in FIG. 3 extending away from the lube fittings 270U, 270L. The lines 300 define a pair of novel high pressure lubricating lines 300. The lubricating lines 300 receive lubricating (or viscous) fluid and direct the fluid into the cavity 250. Each of the high pressure lubricating (or “lube”) lines 300 is coupled to a high pressure pump 320. A viscous high pressure cleaning or lubricating fluid is pressurized by the high pressure pump 320. The lubricating fluid is then pumped through the high pressure lines 300 into the upper 270U and lower 270L lube fittings where it is conveyed through the lube channels and into the upper 252 and/or lower 254 gate pockets, respectively. The high pressure pump 285 and the high pressure lines 200 may be part of a high pressure pumping system which will operate off of an electrical or pneumatic power source. The high pressure system will include a high flow air compressor having a pressure regulator with a pressure gauge. The high pressure pumping system will also include an air lubricator, a lubrication fluid, an in-line check valve and pressure switch. Optionally, the high pressure pumping system will include an air dryer. In one aspect, the high pressure pump 320 pumps lubricating fluid through a single lubrication line 325 and into a manifold 310. From the manifold 310, lubricating fluid is distributed to appropriate high pressure lines 310 and then delivered to the upper 270U and lower 270L lube fittings. Where three or four flow control valves 210 are placed in a frac tree 200 in series, the manifold 310 may distribute lubricating fluid to corresponding sets of upper 270U and lower 270L lube fittings for each valve 210. FIG. 4A is a perspective view of a portion of an illustrative control valve 210 of the fracturing tree 200 of FIG. 2. The valve 210 is shown in cross-section. FIG. 4B is an enlarged view of a portion of the control valve 210 of FIG. 4A. In FIG. 4B, the valve has been rotated 90 degrees for illustrative purposes, allowing a view into the flow passage, or central bore 208 of a fracturing tree. In each of FIGS. 4A and 4B, fracturing fluids are being pumped down the bore 208. The upper 232 and lower 234 flanges of the valve 210 of the tree 200 are visible, along with the bonnet 230 of the valve 210. The flow path for the fracturing fluids is indicated by Arrow 400. The fracturing fluids are being pumped by a high pressure pumping system, typically built into the bed of an over-the-road trailer (not shown) or onto a skid. It can be seen from FIGS. 4A and 4B that fluids are flowing down the bore 208 and through the cavity 250. As discussed above, the cavity 250 comprises an upper gate pocket 252 and a lower gate pocket 254. As noted, the injection of the fracturing fluids (Arrow 400) with its abrasive proppant is extremely hard on the seat 267 of the valve 210. This is particularly true during start-up when fluids are first thrust across the valve 210, causing pitting and scarring. Accordingly, an improved high pressure pumping system is provided along with a method of injecting a fracturing fluid into a wellbore. In use, a fracturing tree having one more control valves 210 is provided. The tree may be in accordance with FIG. 2. Before the pumping operation begins, the high pressure lubrication lines 300 are coupled to the upper 270U and lower 270L lube fittings. The high pressure lines 300 are also coupled to a conventional manifold 310 or, alternatively directly to a high pressure pump 320 and tested to ensure proper well control. Once the high pressure lines 300 are properly connected to the lube fittings 270U, 270L, a pressure regulator 330 is set to an air pressure above a formation parting pressure. Moreover, the pressure regulator 330 is set to an air pressure that is above a desired fracturing pumping pressure. The high pressure pump 320 is then activated to pressurize the high pressure lines 300, wherein the pressure regulator 330 turns off the pump 320 when the set pressure is achieved through the sensing of pressure switches. Hence, lubricating or cleaning fluid passes through the high pressure lines 300 to the upper 270U and lower 270L lube fittings. The lubrication fluid flowing through the lube fittings 270U, 270L passes into the upper and lower lube channels and into the upper gate pocket 252 and/or the lower gate pocket 254, depending on the position of the gate 260. The lubrication fluid thus fills and pressurizes the space between the gate 260 and the gate cavity 250. In this way, the valve 210 is pre-pressurized to a high pressure so that the incoming fracturing fluid and its proppant material does not flow about the gate 260, causing scarring or other damage to the gate 260 and its seat 267 or other internal components along the bore 208. Preferably, pre-pressurization is to a pressure that is 2%, or optionally 3 to 5%, greater than the determined hydraulic fracturing pressure. This minimizes the flow of the abrasive fracturing fluid into the cavity 250, and keeps hydraulic fracturing fluid moving through the flow channels 208, 244. FIG. 5A is a perspective view of the illustrative control valve 210 of FIG. 4A. Here, pressure is pre-applied to the seat 267 of the control valve 210. FIG. 5B is an enlarged view of a portion of the control valve 210 of FIG. 5A. Here, the valve 210 has been rotated 90-degrees for illustrative purposes, allowing a view into the flow passage, or central bore 208 of a fracturing tree. In the views of FIGS. 5A and 5B, it can be seen that a hydraulic fracturing fluid (Arrows 500) is being injected into the bore 208 of the frac tree 200. In addition, a lubricating fluid (Arrows 510) has been injected into the upper gate cavity 252 and the lower gate cavity 254. The valve 210 is in its gate-open position. FIGS. 5A and 5B also provide beneficial views of the seats 267. As noted, the seats 267 reside at opposing ends of the gate cavity 250. Once the valve 210, or a set of valves 210 in a frac tree 200, is pressurized, the high pressure fracturing pumping operations may begin. At this point, each of the valves 210 has been moved to its open position and has been pre-pressurized with lubricating fluid so that fracturing fluid may pass through the control valve 210 without scarring the gate 260 or seats 267. During this time, a lower most valve 210L on the frac tree 200 may be closed in order to seal the frac tree 200 during pre-pressurization. The valve 210, the high pumping system and the methods herein permit the operator to pre-pressurize an individual valve 210 or a plurality of valves 210 along a valve tree 200 prior to the operation of the fracturing equipment. The pre-pressurization prevents or restricts the flow of abrasive fluids through the cavity of the valve and the resulting damage done to the internal components of the valve to eliminate the pressure differential between the cavity of the control valve and the well. Preferably, the operator will also pre-pressurize the wing valves on the fracturing tree 200. This pre-pressurization takes place while the wing valves are in their closed position. As part of the present disclosure, a portable lubrication unit is also offered herein. The lubrication unit is intended to be used with a hydraulic fracturing tree (including a zippered frac manifold) 200. The hydraulic fracturing tree offers one or more fluid control valves that control the injection of fluids into a wellbore 100. FIG. 6A is a flow chart showing a progression of components used for a portable lubrication unit 600 of the present invention, in one embodiment. The illustrative lubrication unit 600 is configured to be used in pre-pressurizing fluid control valves 210 along a hydraulic frac tree 200. In FIG. 6A, a fracturing tree 200 is presented, comprising a stack of fluid control valves 210. The lubrication unit 600 first comprises a portable platform 605. The platform 605 may be a trailer, a skid or the bed of a truck. In the view of FIG. 6A, a flatbed trailer is shown. The illustrative trailer 605 includes a bed 602, options side walls or rails 604, and wheels 606. The portable platform 605 carries the equipment necessary for pressurization of fluid control valves 210 associated with the fracturing tree 200. In this instance, the platform 605 will support at least an air compressor 610, a pressure regulator 620, a lubricating fluid reservoir 630, and associated high pressure hoses. In operation, the platform 605 and supported lubrication unit 600 are taken to different well sites for hydraulic fracturing operations. Those of ordinary skill in the art will understand that such well sites are frequently in remote locations such as wells located in the Permian Basin, the Fayetteville Shale, the Eagle Ford Shale, the Marcellus Shale, the Bakken Shale, or other regions. The lubrication unit 600 also includes an air compressor 610. The air compressor 610 is a device that converts power (using an electric motor, or a diesel or gasoline engine) into potential energy stored in pressurized air. The air compressor 610 will include a vessel that receives air in response to mechanical action of pistons, rotary screws or vanes, depending on the arrangement. When activated, air is directed into the vessel where it is held under pressure. The pressure is then released through an outlet that is fluidically connected to a high pressure air hose 615. The lubrication unit 600 will also include a pressure regulator 620. Because of the uniquely high pressures involved, the pressure regulator 620 will likely be separate from the vessel that makes up the air compressor 610. Thus, the air hose 615 will carry pressurized air from the air compressor 610 to the pressure regulator 620. A pressure regulator hose 625, in turn, will direct the pressurized air on to a lubricating fluid reservoir 630. The lubrication unit 600 will further include the lubricating fluid reservoir 630. The lubricating fluid reservoir 630 defines a vessel holding a lubricating fluid. Suitable pipes, gauges and valves are provided for receiving pressurized air from the pressure regulator, monitoring pressure of the lubricating fluid reservoir 630, and releasing the pressurized lubricating fluid from the reservoir 630. A high pressure lubrication line 635 then extends from the lubricating fluid reservoir 630 to the fracturing tree 200. It is preferred that the portable lubrication unit 600 also include an in-line check valve 640. The in-line check valve 640 is placed along the high pressure lubrication line 635. The check valve 640 prevents lubricating fluid from backing back into the lubricating fluid reservoir 630 from the fracturing tree 200. In addition, a pressure switch 650 is preferably provided. In one aspect, the pressure switch 650 generates an electrical signal when a certain pressure level in the lubrication line 635 is reached. The signal may initiate a shut-off of the air compressor 630 or, alternatively, send a separate warning signal to an operator. The high pressure lubrication line 635 may feed into a manifold (such as manifold 310 of FIG. 3, that then distributes lubrication fluid to individual fluid control valves 210 along the fracturing tree 200. Specifically, lubricating fluid will be delivered to respective flow control valves 210 through upper 270U and lower 270L lube fittings associated with each valve 210. Alternatively, the lubrication line 635 may travel to the fracturing tree 200, and then tee off to individual lube fittings 270U, 270L adjacent the control valves 210. In FIG. 6A, a lubricating fluid line 655 having multiple tee's is shown running along the frac tree 200. FIG. 6B is an enlarged view of a portion of the hydraulic fracturing tree 200 of FIG. 6A. The high pressure lubricating fluid line 655 is more clearly seen. The line 655 is shown directing lubricating fluid (darkened lines) into the valves 210. Before pumping operations begin, the lubrication line 635 is fixed to the frac tree 200 and the high pressure lubrication lines 655 will be connected to each valve (one line at the front and one line at the back of each valve 210). Once connected, the equipment and all connections will be pressure tested to ensure 100% well control. The pressure regulator 620 will be set to the necessary pressure required to operate the air compressor 610 and associated lubricant reservoir 630 to frac pumping pressure. Ideally, the fluid pressure regulator 620 will be set above pumping pressures. The pressure regulator switch 650 is set to shut off power source if a pre-set pressure is reached. Before the pressure pumping begins, the power source will supply the air compressor 610, any condensed fluid should be removed from the compressed air. Compressed air will drive a fluid pump associated with the lubricant reservoir. The fluid pump will supply lubricant to the single line 635 to the frac tree 200/frac manifold 310. The individual valve bodies will be supplied with lubrication fluid in front of the gate 260 and behind the gate 260 (such as through lube lines 270U and 270L). Once supplied, the valve bodies will build pressure which will in turn build pressure to the supply line 655 and back to the fluid pump associated with the lubricant reservoir 630 where the pressure switch 650 will shut off the power to the air compressor 610. Frac pumping operations can begin. The portable high pressure lubrication unit and the pre-pressurization methods described herein have various benefits in the conducting of oil and gas completions, and especially the formation fracturing process. For example, it is observed that pre-pressurizing the valves with lubricant not only prevents abrasive hydraulic fracturing fluid from invading the gate cavity and scarring the seats, but also prevents the valves from becoming packed with proppant, e.g., sand. Variations of the lubrication unit 600, the control valve 210 and the method of pre-pressurizing a control valve 210 are within the spirit of the claims, below. For example, an operator may pre-pressurize flow control valves associated with a so-called zipper frac manifold. A zipper frac manifold is used for fracturing multiple wells from a single valve system. It will be appreciated that the inventions are susceptible to modification, variation and change without departing from the spirit thereof. | <SOH> BACKGROUND OF THE INVENTION <EOH>This section is intended to introduce selected aspects of the art, which may be associated with various embodiments of the present disclosure. This discussion is believed to assist in providing a framework to facilitate a better understanding of particular aspects of the present disclosure. Accordingly, it should be understood that this section should be read in this light, and not necessarily as admissions of prior art. | <SOH> SUMMARY OF THE INVENTION <EOH>A portable lubrication unit for a hydraulic fracturing tree is provided herein. The hydraulic fracturing tree is configured to reside over a wellbore, and to enable the control of injection fluids into the wellbore and to contain wellbore pressure. Thus, the fracturing tree is essentially a high pressure wellhead. The lubrication unit first comprises a portable platform. The platform may be a trailer, a skid or the bed of a truck. The portable platform carries the equipment necessary for pressurization of fluid control valves associated with the fracturing tree. The platform is taken to well sites, which frequently are in remote locations. The lubrication unit also includes an air compressor and a pressure regulator. Because of the extremely high pressures involved, the pressure regulator will likely be separate from the vessel that makes up the air compressor. Thus, an air line will carry pressurized air from the air compressor to the pressure regulator. The lubrication unit will further include a lubricating fluid reservoir. The lubricating fluid reservoir defines a vessel holding a lubricating fluid. Suitable pipes, gauges and valves are provided for receiving pressurized air from the pressure regulator, monitoring pressure of the reservoir, and releasing the pressurized lubricating fluid from the reservoir. A high pressure lubrication line then extends from the lubricating fluid reservoir to the fracturing tree. It is preferred that the portable lubrication unit also include an in-line check valve along the high pressure lubrication line. The check valve prevents lubricating fluid from backing back into the lubricating fluid reservoir from the wellhead. In addition, a pressure switch is preferably provided. In one aspect, the pressure switch generates an electrical signal when a certain pressure level is reached. The signal may initiate a shut-off of the air compressor or send a separate signal to an operator. The high pressure lubrication line may feed into a manifold, that then distributes lubrication fluid directly to individual fluid control valves along the fracturing tree. Alternatively, the lubrication line may travel along the fracturing tree, and tee off to individual lube fittings adjacent the control valves. A hydraulic fracturing tree having a novel lubrication unit is also provided herein. The hydraulic fracturing tree first comprises a body. The body has a cylindrical flow passage that is in fluid communication with the subsurface wellbore. The body is generally made up of a series of spacers having cylindrical bores therein. The hydraulic fracturing tree also has at least one fluid control valve along the body. Preferably, the at least one control valve is at least three control valves spaced vertically along the body. Closing the valves limits fluid communication between the cylindrical body of the tree and the wellbore, and vice versa. The spaces reside between the respective control valves. Each of the at least one fluid control valves includes an internal gate cavity. The gate cavity is in fluid communication with the flow passage of the body. Each of the at least one fluid control valves also has a gate. The gate is movably mounted within the internal gate cavity. Preferably, this is done through rotation of an actuator arm that produces linear movement of the gate within the internal gate cavity. Movement of the gate is between a valve open position and a valve closed position. In combination with the body, the gate defines an upper pocket and a lower pocket. Each of the at least one fluid control valves also includes a pair of seats. The seats are placed at opposing sides of the gate. In operation, if a frac valve is in the run of the frac tree, there will be one seat on top of the gate and one seat on the bottom of the gate. The gate is movable, or “floating.” This means if the gate is in its gate-closed position and the well has more pressure coming from the formation than what is on top of the frac tree, the gate will push against the top seat and form a seal. This would be an example of the frac valve containing wellbore pressure. If the well is undergoing hydraulic fracturing and the gate is in its gate-closed position, the greatest pressure is on top of the gate. In this instance, the gate seals against the bottom seat, preventing the frac fluid from going downhole. Each of the at least one fluid control valves further comprises a stem. The stem is mechanically coupled to the gate. Preferably, the stem sealingly extends through a bonnet. An actuator is coupled to the stem to translate the gate linearly between valve open and valve closed positions. In one aspect, the stem comprises a proximal end that is threadedly connected to the actuator, and a distal end mechanically connected to the gate. Preferably, the actuator comprises a hand lever and associated threaded cylinder configured such that manual rotation of the lever and cylinder selectively translates the gate between its valve open and its valve closed positions. Each of the at least one fluid control valves also has an upper lube channel extending through the body and in fluid communication with the upper pocket, and a lower lube channel extending through the body and in fluid communication with the lower pocket. The control valve further has an upper lube fitting coupled to the upper lube channel, and a lower lube fitting coupled to the lower lube channel. The upper pocket and/or the lower pocket are configured to be pressurized by a lubricating fluid that is placed under pressure. The pre-pressurization is at least as great as a determined formation parting pressure, and preferably at least as great as a hydraulic fracturing pressure. Pre-pressurization occurs by passing the lubricating fluid through the upper lube fitting, through the lower lube fitting, or both, and into the gate cavity. Pre-pressurization is done before hydraulic fluid is passed through the fracturing tree. Preferably, each of the at least one control valves further comprises an upper flange and a lower flange, with each of the upper and lower flanges configured to be mechanically and sealingly connected in line with the body by means of a plurality of bolts. Preferably, the fracturing tree comprises several control valves in series, each of which has an upper flange and a lower flange, and each of which is pre-pressurized. The tree further comprises a reservoir of lubricant, and a high pressure pump. The pump is configured to pump the lubricating fluid from the reservoir, through the lube fittings and into the cavity pockets of the gates. Appropriate pressure sensors, pressure gauges, lines and fittings are provided for pumping as described above. A method of pressurizing at least one fluid control valve is also provided herein. Pressurization is provided to each of the control valves along a fracturing tree, with the valves being in their valve open positions during pressurization. Thereafter, hydraulic fracturing fluid is injected through the valves and down into the wellbore. In this way, fracturing fluid is directed through the flow channel while high pressure provided by the lubricating fluid within the upper pocket and/or lower pocket of the gate cavity substantially prevents the hydraulic fracturing fluid from traveling around the gate and scarring the seats and related hardware. | E21B3402 | 20171016 | 20180426 | 62570.0 | E21B3402 | 1 | LEMBO, AARON LLOYD | Portable Lubrication Unit For A Hydraulic Fracturing Valve Assembly, and Method For Pre-Pressurizing Valves | SMALL | 0 | ACCEPTED | E21B | 2,017 |
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15,785,658 | PENDING | TWO-LEVEL LED SECURITY LIGHT WITH MOTION SENSOR | A two-level LED security light with a motion sensor. At night, the LED security light is turned on for a low level illumination. When the motion sensor detects any intrusion, the LED security light is switched from the low level illumination to a high level illumination for a short duration time and then returns to the low level illumination for saving energy. The LED security light includes a power supply unit, a light sensing control unit, a motion sensing unit, a loading and power control unit, and a lighting-emitting unit. The lighting-emitting unit includes one or a plurality of LEDs which may be turned on or turned off according to the sensing results from the light sensing control unit. When the motion sensing unit detects an intrusion, the LED security light can be immediately turned on to the high level illumination to scare away intruder. | 1. A two-level LED security light comprising: a light-emitting unit; a loading and power control unit; a light sensing control unit; a motion sensing unit; and a power supply unit; wherein the light-emitting unit comprises a plurality of LEDs divided into two sets with the first set having N number of LEDs and the second set having M number of LEDs; wherein the loading and power control unit comprises a controller and at least two switching devices including at least a first switching device and at least a second switching device, wherein the controller is electrically coupled to the light sensing control unit, the motion sensing unit and the at least two switching devices; wherein the first switching device(s) and the second switching device(s) are respectively coupled with the first set of the light-emitting unit having N number LEDs and the second set of the light-emitting unit having M number LEDs, wherein the first switching device(s) and the second switching device(s) are controlled by the controller to be conducting or cut-off to perform at least a first switching mode and a second switching mode respectively; wherein in the first switching mode the controller outputs at least a first control signal to turn on the first set of the light-emitting unit having N number LEDs to perform a low level illumination mode and in the second switching mode the controller outputs at least a second control signal to turn on the second set of the light-emitting unit having M number LEDs to perform a high level illumination mode; wherein when an ambient light detected by the light sensing control unit is lower than a first predetermined value, the loading and power control unit manages to operate the first switching mode to turn on the first set of the light-emitting unit having N number LEDs to generate a low level illumination; wherein when the ambient light detected by the light sensing control unit is higher than a second predetermined value, the loading and power control unit manages to turn off all the LEDs in the light-emitting unit; and wherein when a motion intrusion is detected by the motion sensing unit, the loading and power control unit manages to operate the second switching mode to turn on the second set of the light-emitting unit having M number LEDs to generate a high level illumination for a predetermined duration before resuming to the low level illumination. 2. The two-level LED security light according to claim 1, wherein when the second set of the light-emitting unit having M number LEDs is turned on upon detecting the motion intrusion, the loading and power control unit continues to turn on the first set of the light-emitting unit having N number LEDs. 3. The two-level LED security light according to claim 1, wherein when the second set of the light-emitting unit having M number LEDs is turned on upon detecting the motion intrusion the loading and power control unit manages to turn off the first set of the light-emitting unit having N number LEDs, wherein the total wattage of the M number LEDs is higher than the total wattage of the N number LEDs. 4. The two-level LED security light according to claim 1, wherein the N number LEDs and the M number LEDs are non-detachably coupled to the switching devices. 5. The two-level LED security light according to claim 1, wherein the power supply unit outputs DC powers for operating the two-level LED security light, wherein the first set of the light-emitting unit having N number LEDs and the second set of the light-emitting unit having M number LEDs are connected in series, wherein the first switching device is electrically connected in parallel with the second set of the light-emitting unit having M number LEDs , wherein the second switching device is electrically connected in parallel with the first set of the light-emitting unit having N number LEDs; wherein a control circuit is configured in the power supply unit to control a constant electric current passing through LEDs such that an electric current level for driving the LEDs remains stable in light of a drastic change of lighting load between driving the N number LEDs for generating the low level illumination and driving at least the M number LEDs for generating the high level illumination. 6. The two-level LED security light according to claim 5, wherein when the light-emitting unit is in the low level illumination mode with the first set of N number LEDs in a conduction state, the light intensity is further adjustable by the controller; wherein the first set of the light-emitting unit having N number LEDs is configured to include a plurality of switching devices coupled to the two ends associated with each LED and to the controller, wherein the controller is configured to control the number of LEDs to be turned on in the N number LEDs through bypassing unwanted LEDs in the N number LEDs with the associated switching device(s) according to an external control signal played by an user or according to a value of a voltage divider set by the user. 7. The two-level LED security light according to claim 5, wherein the loading and power control unit further comprises a third switching device controlled by the controller and electrically coupled in series with the light-emitting unit and the power supply unit for controlling a conduction or a cutoff of the light-emitting unit, wherein when the light-emitting unit is in the low level illumination mode with the first set of N number LEDs in a conduction state, the light intensity is further adjustable by the controller; wherein the controller in response to an external control signal played by an user outputs a PWM signal to control a time length of conduction period of the third switching device in each duty cycle of the PWM signal such that an average electric current proportional to the time length of conduction period is delivered to the light-emitting unit for performing a dimming work of the low level illumination. 8. The two-level LED security light according to claim 5, wherein when the light-emitting unit is in the high level illumination mode, the light intensity is further adjustable by the controller, wherein the second set of the light-emitting unit having M number LEDs is configured to include a plurality of switching devices coupled to the two ends associated with each LED and to the controller, wherein the controller is configured to control the number of LEDs to be turned on in the M number LEDs through bypassing unwanted LEDs in the M number LEDs with the associated switching device(s) according to an external control signal played by an user or according to a value of a voltage divider set by the user. 9. The two-level LED security light according to claim 5, wherein the loading and power control unit further comprises a third switching device controlled by the controller and electrically coupled in series with the light-emitting unit and the power supply unit for controlling a conduction or a cutoff of the light-emitting unit, wherein when the light-emitting unit is in the high level illumination mode, the light intensity is further adjustable by the controller; wherein the controller in response to an external control signal played by an user outputs a PWM signal to control a time length of conduction period of the third switching device in each duty cycle of the PWM signal such that an average electric current proportional to the time length of conduction period is delivered to the light-emitting unit for performing a dimming work of the high level illumination. 10. The two-level LED security light according to claim 1, wherein the power supply unit outputs DC powers for operating the two-level LED security light, wherein the first set of the light-emitting unit having N number LEDs and the second set of the light-emitting unit having M number LEDs are electrically connected in series; wherein the first switching device is electrically connected in parallel with the second set of the light-emitting unit having M number LEDs and the second switching device is electrically connected between the power supply unit and the light-emitting unit; wherein when the first switching mode is performed, the first switching device is conducted for bypassing the second set of the light-emitting unit having M number LEDs and the second switching device is conducted for turning on the light-emitting unit for generating the low level illumination; wherein when the second switching mode is performed, the first switching device is cutoff and the second switching device is conducted for turning on the light-emitting unit for generating the high level illumination; wherein a control circuit is configured in the power supply unit to control a constant electric current passing through LEDs such that an electric current level for driving the LEDs remains stable in light of a drastic change of lighting load between driving the N number LEDs for generating the low level illumination and driving at least the M number LEDs for generating the high level illumination. 11. The two-level LED security light according to claim 1, wherein the power supply unit outputs DC voltages for operating the two-level LED security light; wherein the first set of the N number LEDs and the second set of M number LEDs are connected in parallel, wherein the first switching device is electrically connected in series between the first set of the N number LEDs and the power supply unit, wherein the second switching device is electrically connected in series between the second set of the M number LEDs and the power supply unit; wherein the first set of the light-emitting unit having N number LEDs and the second set of the light-emitting unit having M number LEDs are respectively designed with a configuration of in series and or in parallel connections such that when incorporated with an adequate level setting of constant voltage(s) an electric current passing through each LED of the M number LEDs and each LED of the N number LEDs remains at an adequate level such that a voltage V across each LED complies with an operating constraint of Vth<V<Vmax featuring electrical characteristics of a LED, where Vth is a minimum threshold voltage required to trigger the LED to start emitting light and Vmax is a cap of maximum voltage across each LED to avoid an effect of a thermal runaway which may burn out the LED or damage LED construction resulting in shortened LED lifetime. 12. The two-level LED security light according to claim 11, wherein when the first set of N number LEDs is in a conduction state, the light intensity is further adjustable by the controller; wherein the first set of the light-emitting unit having N number LEDs is configured to include a plurality of switching devices coupled to the two ends associated with each LED and to the controller, wherein the controller is configured to control the number of LEDs to be turned on in the N number LEDs through bypassing unwanted LEDs in the N number LEDs with the associated switching device(s) according to an external control signal played by an user or according to a value of a voltage divider set by the user. 13. The two-level LED security light according to claim 11, wherein when the first set of N number LEDs is in a conduction state, the light intensity of the light emitting unit is further adjustable by the controller; wherein the controller in response to an external control signal played by an user outputs a PWM signal to control a time length of conduction period of the first switching device in each duty cycle of the PWM signal such that an average electric current proportional to the time length of conduction period is delivered to the first set of N number LEDs for performing a dimming work of the low level illumination mode. 14. The two-level LED security light according to claim 11, wherein when the second set of M number LEDs is in a conduction state, the light intensity is further adjustable by the controller, wherein the second set of the light-emitting unit having M number LEDs is configured to include a plurality of switching devices coupled to the two ends associated with each LED and to the controller, wherein the controller is configured to control the number of LEDs to be turned on in the M number LEDs through bypassing unwanted LEDs in the M number LEDs with the associated switching device(s) according to an external control signal played by an user or according to a value of a voltage divider set by the user. 15. The two-level LED security light according to claim 11, wherein when the second set of M number LED is in a conduction state, the light intensity of the light-emitting unit is further adjustable by the controller; wherein the controller in response to an external control signal played by an user outputs a PWM signal to control a time length of conduction period of the second switching device in each duty cycle of the PWM signal such that an average electric current proportional to the time length of conduction period is delivered to the second set of M number LEDs for performing a dimming work of the high level illumination mode. 16. The two-level LED security light according to claim 11, wherein the value of Vmax ranges between 3 volts and 20 volts depending on packaging specification of the LED, wherein the value Vth ranges between 1.5 volts and 2.5 volts depending on color temperature of the LED and the packaging specification of the LED. 17. The two-level LED security light according to claim 16, wherein the value of the voltage V across the LED is confined to be in an operating range from 2.5 volts to 20 volts. 18. A two-level LED security light comprising: a light-emitting unit; a loading and power control unit; a light sensing control unit; a motion sensing unit; and a power supply unit; wherein the light-emitting unit comprises a plurality of LEDs divided into two sets with the first set having N number of LEDs and the second set having M number of LEDs; wherein the loading and power control unit comprises a controller electrically coupled to the light sensing control unit, the motion sensing unit and at least two switching devices including at least a first switching device and at least a second switching device; wherein the first switching device and the second switching device are respectively coupled with the first set of the light-emitting unit having N number LED loads and the second set of the light-emitting unit having M number LED load; wherein the two switching devices are controlled by the controller to be respectively conducting or cut-off to perform at least respectively a first switching mode and a second switching mode; wherein in the first switching mode the first set of the light-emitting unit having N number LEDs is turned on to perform a low level illumination mode and in the second switching mode the second set of the light-emitting unit having M number LEDs is turned on to perform a high level illumination mode; wherein when an ambient light detected by the light sensing control unit is lower than a first predetermined value, the loading and power control unit manages to turn on the first set of the light-emitting unit having N number LEDs to generate a low level illumination; wherein when the ambient light detected by the light sensing control unit is higher than a second predetermined value, the loading and power control unit manages to turn off all the LEDs in the light-emitting unit; wherein when a motion intrusion is detected by the motion sensing unit, the loading and power control unit manages to turn on the second set of the light-emitting unit with M number of LEDs to generate a high level illumination for a predetermined duration; and wherein the N number LEDs are of low color temperature to produce soft evening light while the M number LEDs are of high color temperature to produce a much brighter day light with a dual effect of security alert by means of creating drastic changes in both light intensity from low to high and light color temperature from warm to cool upon detecting the motion intrusion. 19. The two-level LED security light according to claim 18, wherein when the second set of the light-emitting unit having M number LEDs is turned on upon detecting the motion intrusion, the loading and power control unit continues to turn on the first set of the light-emitting unit having N number LEDs. 20. The two-level LED security light according to claim 18, wherein when the second set of the light-emitting unit having M number LEDs is turned on upon detecting the motion intrusion, the loading and power control unit manages to turn off the first set of the light-emitting unit having N number LEDs. 21. The two-level LED security light according to claim 18, wherein the power supply unit outputs DC powers for operating the two-level LED security light, wherein the first set of the light-emitting unit having N number LEDs and the second set of the light-emitting unit having M number LEDs are connected in series, wherein the first switching device is electrically connected in parallel with the second set of the light-emitting unit having M number LEDs, wherein the second switching device is electrically connected in parallel with the first set of the light-emitting unit having N number LEDs, wherein a control circuit is configured in the power supply unit to control a constant electric current passing through LEDs such that an electric current level for driving the LEDs remains stable in light of a drastic change of lighting load between driving the N number LEDs for generating the low level illumination and driving at least the M number LEDs for generating the high level illumination. 22. The two-level LED security light according to claim 21, wherein when the light-emitting unit is in the low level illumination mode, the light intensity is further adjustable by the controller; wherein the first set of the light-emitting unit having N number LEDs is configured to include a plurality of switching devices coupled to the two ends associated with each LED and to the controller, wherein the controller is configured to control the number of LEDs to be turned on in the N number LEDs through bypassing unwanted LEDs in the N number LEDs with the associated switching device(s) according to an external control signal played by an user or according to a value of a voltage divider set by the user. 23. The two-level LED security light according to claim 21, wherein the loading and power control unit further comprises a third switching device controlled by the controller and electrically coupled in series with the light-emitting unit and the power supply unit for controlling a conduction or a cutoff of the light-emitting unit, wherein when the light-emitting unit is in the low level illumination mode, the light intensity is further adjustable by the controller; wherein the controller in response to an external control signal played by an user outputs a PWM signal to control a time length of conduction period of the third switching device in each duty cycle of the PWM signal such that an average electric current proportional to the time length of conduction period is delivered to the first set of N number LEDs for performing a dimming work of the low level illumination mode. 24. The two-level LED security light according to claim 21, wherein when the light-emitting unit is in the high level illumination mode, the light intensity is further adjustable by the controller, wherein the second set of the light-emitting unit having M number LEDs is configured to include a plurality of switching devices coupled to the two ends associated with each LED and to the controller, wherein the controller is configured to control the number of LEDs to be turned on in the M number LEDs through bypassing unwanted LEDs in the M number LEDs with the associated switching device(s) according to an external control signal played by an user or according to a value of a voltage divider set by the user. 25. The two-level LED security light according to claim 21, wherein the loading and power control unit further comprises a third switching device controlled by the controller and electrically coupled in series with the light-emitting unit and the power supply unit for controlling a conduction or a cutoff of the light-emitting unit, wherein when the-light-emitting unit is in the high level illumination mode, the light intensity is further adjustable by the controller; wherein the controller in response to an external control signal played by an user outputs a PWM signal to control a time length of conduction period of the third switching device in each duty cycle of the PWM signal such that an average electric current proportional to the time length of conduction period is delivered to the light emitting unit for performing a dimming work of the high level illumination mode; 26. The two-level LED security light according to claim 18, wherein the power supply unit outputs DC powers for operating the two-level LED security light, wherein the first set of the light-emitting unit having N number LEDs and the second set of the light-emitting unit having M number LEDs are electrically connected in series; wherein the first switching device is electrically connected in parallel with the second set of the light-emitting unit having M number LEDs and the second switching device is electrically connected between the power supply unit and the light-emitting unit; wherein when the first switching mode is performed, the first switching device is conducted for bypassing the second set of the light-emitting unit having M number LEDs and the second switching device is conducted for turning on the light-emitting unit for generating the low level illumination; wherein when the second switching mode is performed, the first switching device is cutoff and the second switching device is conducted for turning on the light-emitting unit for generating the high level illumination; wherein a control circuit is configured in the power supply unit to control a constant electric current passing through LEDs such that an electric current level for driving the LEDs remains stable in light of a drastic change of lighting load between driving the N number LEDs for generating the low level illumination and driving at least the M number LEDs for generating the high level illumination. 27. The two-level LED security light according to claim 18, wherein the power supply unit outputs DC voltages for operating the two-level security light; wherein the first set of the light-emitting unit having N number LEDs and the second set of the light-emitting unit having M number LEDs are connected in parallel, wherein the first switching device is electrically connected in series between the first set of the light-emitting unit having N number LEDs and the power supply unit, wherein the second switching device is electrically connected in series between the second set of the light-emitting unit having M number LEDs and the power supply unit; wherein the first set of the light-emitting unit having N number LEDs and the second set of the light-emitting unit having M number LEDs are respectively designed with an adequate configuration of in series and or in parallel connections such that when incorporated with an adequate level of the constant voltage(s), an electric current passing through each LED of the M number LEDs and each LED of the N number LEDs remains at an adequate level such that a voltage V across each LED complies with an operating constraint of Vth<V<Vmax featuring electrical characteristics of a LED, wherein Vth is a minimum threshold voltage required to trigger the LED to start emitting light and Vmax is a cap of maximum voltage across each LED to avoid an effect of a thermal runaway which may burn out the LED or damage LED construction resulting in shortened LED lifetime. 28. The two-level LED security light according to claim 27, wherein when the first set of N number LEDs is in a conduction state, the light intensity of the low level illumination mode is further adjustable by the controller; wherein the controller in response to an external control signal played by an user outputs a PWM signal to control a time length of conduction period of the first switching device in each duty cycle of the PWM signal such that an average electric current proportional to the time length of conduction period is delivered to the first set of N number LEDs for performing a dimming work of the low level illumination mode. 29. The two-level LED security light according to claim 27.wherein when the light emitting unit is in the high level illumination mode, the light intensity of the is further adjustable by the controller; wherein the controller in response to an external control signal played by an user outputs a PWM signal to control a time length of conduction period of the second switching device in each duty cycle of the PWM signal such that an average electric current proportional to the time length of conduction period is delivered to the second set of M number LEDs for performing a dimming work of the high level illumination mode. 30. The two-LED security light according to claim 27, wherein the value of Vmax ranges between 3 volts and 20 volts depending on packaging specification of the LED , wherein the value of Vth is ranges between 1.5 volts and 2.5 volts depending on color temperature and packaging specification of the LED. 31. The two-level LED security light according to claim 30, wherein the value of the voltage V across the LED is confined to be in an operating range from 2.5 volts to 20 volts. 32. A multi-level LED security light comprising: a light-emitting unit; a loading and power control unit; a light sensing control unit; a motion sensing unit; a power supply unit; and a time setting unit; wherein the light-emitting unit comprises a plurality of LEDs divided into two sets with the first set having N number LEDs and the second set having M number LEDs; wherein the N number LEDs are of low color temperature and the M number LEDs are of high color temperature; wherein the loading and power control unit comprises a controller electrically coupled to the light sensing control unit, the motion sensing unit and at least three switching devices including at least a first switching device, at least a second switching device and at least a third switching device; wherein the first switching device, the second switching device and the third switching device are respectively controlled by the controller to perform a first illumination mode, a second illumination mode and a third illumination mode; wherein when the first illumination mode is performed, the controller outputs a first control signal to control the first switching device to turn on the first set of the light-emitting unit having N number LEDs to generate a first level illumination with a low color temperature for a first preset time duration set by the time setting unit, wherein when the second illumination mode is performed upon maturity of the first preset time duration the controller outputs a second control signal to control the second switching device to reduce the illumination level of the first set of the light-emitting unit with N number LEDs for generating a low level illumination with the low color temperature; wherein when the third illumination mode is performed, the controller outputs a third control signal to control the third switching device to turn on the second set of the light-emitting unit having M number LEDs for generating a high level illumination with a high color temperature; wherein the first switching device and the third switching device are controlled by the controller to be respectively conducting or cut-off to perform respectively a low color temperature illumination and a high color temperature illumination; wherein the second switching device is controlled by the controller to perform a dimming work for generating a low level illumination with the low color temperature; wherein when an ambient light detected by the light sensing control unit is lower than a first predetermined value, the loading and power control unit operates the first switching mode to turn on the first set of the light-emitting unit having N number LEDs to perform the first illumination mode with the low color temperature for the first preset time duration set by the time setting unit while the motion sensing unit being deactivated; wherein upon a maturity of the first preset time duration set by the time setting unit, the loading and power control unit operates the second switching mode to perform the second illumination mode for generating the low level illumination with the low color temperature and meantime activates the motion sensing unit; wherein when the ambient light detected by the light sensing control unit is higher than a second predetermined value, the loading and power control unit manages to turn off all the LEDs in the light-emitting unit; wherein when a motion intrusion is detected by the motion sensing unit, the loading and power control unit operates the third switching mode to turn on the second set of the light-emitting unit with M number of LEDs to generate the high level illumination for a second predetermined duration set by the time setting unit; and wherein the N number LEDs are of low color temperature to produce soft evening light while the M number LEDs are of high color temperature to produce a much brighter day light with a dual effect of security alert by means of creating drastic changes in both light intensity from low to high and light color temperature from warm to cool upon detecting the motion intrusion. 33. The multi-level LED security light according to claim 32, wherein the illumination level of the first illumination mode is further adjustable by the controller thru operating a dimming circuit. 34. The multi-level LED security light according to claim 32, wherein the low level illumination of the second illumination mode is further adjustable by the controller thru operating a dimming circuit. 35. The multi-level LED security light according to claim 32, wherein when the second set of the light-emitting unit having M number LEDs is turned on upon detecting the motion intrusion, the loading and power control unit continues to turn on the first set of the light-emitting unit having N number LEDs. 36. The multi-level LED security light according to claim 32, wherein when the second set of the light-emitting unit having M number LEDs is turned on upon detecting the motion intrusion, the loading and power control unit manages to turn off the first set of the light-emitting unit having N number LEDs. | CROSS-REFERENCE TO RELATED APPLICATION This is a continuation application of prior application Ser. No. 15/375,777, filed on 12 Dec. 2016, currently pending. Ser. No. 15/375,777 is a continuation application of prior application Ser. No. 14/836,000 filed on 26 Aug. 2015, which issued as U.S. Pat. No. 9,622,325, and which is a divisional application of Ser. No. 14/478,150, filed on 5 Sep. 2014, and entitled A TWO-LEVEL LED SECURITY LIGHT WITH MOTION SENSOR, issued as U.S. Pat. No. 9,445,474, which is a continuation application of Ser. No. 13/222,090, filed 31 Aug. 2011, which issued as U.S. Pat. No. 8,866,392 on 21 Oct. 2014. BACKGROUND OF THE INVENTION 1. Technical Field The present disclosure relates to a lighting apparatus, in particular, to a two-level security LED light with motion sensor 2. Description of Related Art Lighting sources such as the fluorescent lamps, the incandescent lamps, the halogen lamps, and the light-emitting diodes (LED) are commonly found in lighting apparatuses for illumination purpose. Photoresistors are often utilized in outdoor lighting applications for automatic illuminations, known as the Photo-Control (PC) mode. Timers may be used in the PC mode for turning off the illumination or for switching to a lower level illumination of a lighting source after the lighting source having delivered a high level illumination for a predetermined duration, referred as the Power-Saving (PS) mode. Motion sensors are often used in the lighting apparatus for delivering full-power illumination thereof for a short duration when a human motion is detected, then switching back to the PS mode. Illumination operation controls such as auto-illumination in accordance to the background brightness detection, illumination using timer, illumination operation control using motion sensing results (e.g., dark or low luminous power to fully illuminated), and brightness control are often implemented by complex circuitries. In particular, the design and construction of LED drivers are still of a complex technology with high fabrication cost. Therefore, how to develop a simple and effective design method on illumination controls such as enhancing contrast in illumination and color temperature for various types lighting sources, especially the controls for LEDs are the topics of the present disclosure. SUMMARY OF THE INVENTION An exemplary embodiment of the present disclosure provides a two-level LED security light with motion sensor which may switch to high level illumination in the Power-Saving (PS) mode for a predetermined duration time when a human motion is detected thereby achieve warning purpose using method of electric current or lighting load adjustment. Furthermore, prior to the detection of an intrusion, the LED security light may be constantly in the low level illumination to save energy. An exemplary embodiment of the present disclosure provides a two-level LED security light including a power supply unit, a light sensing control unit, a motion sensing unit, a loading and power control unit, and a light-emitting unit. The light-emitting unit further includes one or a plurality of series-connected LEDs; when the light sensing control unit detects that the ambient light is lower than a predetermined value, the loading and power control unit turns on the light-emitting unit to generate a high level or a low level illumination; when the light sensing control unit detects that the ambient light is higher than the predetermined value, the loading and power control unit turns off the light-emitting unit; when the motion sensing unit detects a human motion in the PS mode, the loading and power control unit increases the electric current that flows through the light-emitting unit so as to generate the high level illumination for a predetermined duration. Another exemplary embodiment of the present disclosure provides a two-level LED security light including a power supply unit, a light sensing control unit, a motion sensing unit, a loading and power control unit, a light-emitting unit. The light-emitting unit includes a plurality of series-connected LEDs. When the light sensing control unit detects that the ambient light is lower than a predetermined value, the loading and power control unit turns on a portion or all the LEDs of the light-emitting unit to generate a low level or a high level illumination; when the light sensing control unit detects that the ambient light is higher than the predetermined value, the loading and power control unit turns off all the LEDs in the light-emitting unit; when the motion sensing unit detects a human motion in the PS mode, the loading and power control unit turns on a plurality of LEDs in the light-emitting unit and generates the high level illumination for a predetermine duration. An electric current control circuit is integrated in the exemplary embodiment for providing constant electric current to drive the LEDS in the light-emitting unit. One exemplary embodiment of the present disclosure provides a two-level LED security light including a power supply unit, a light sensing control unit, a motion sensing unit, a loading and power control unit, and a light-emitting unit. The light-emitting unit includes a phase controller and one or a plurality of parallel-connected alternating current (AC)LEDs. The phase controller is coupled between the described one or a plurality parallel-connected ACLEDs and AC power source. The loading and power control unit may through the phase controller control the average power of the light-emitting unit; when the light sensing control unit detects that the ambient light is lower than a predetermined value, the loading and power control unit turns on the light-emitting unit to generate a high level or a lower level illumination; when the light sensing control unit detects that the ambient light is higher than the predetermined value, the loading and power control unit turns off the light-emitting unit; when the motion sensing unit detects a human motion in the PS mode, the loading and power control unit increases the average power of the light-emitting unit thereby generates the high level illumination for a predetermine duration. According to an exemplary embodiment of the present disclosure, a two-level LED security light includes a power supply unit, a light sensing control unit, a motion sensing unit, a loading and power control unit, and a light-emitting unit. The light-emitting unit includes X high wattage ACLEDs and Y low wattage ACLEDs connected in parallel. When the light sensing control unit detects that the ambient light is lower than a predetermined value, the loading and power control unit turns on the plurality of low wattage ACLEDs to generate a low level illumination; when the light sensing control unit detects that the ambient light is higher than a predetermined value, the loading and power control unit turns off the light-emitting unit; when the motion sensor detects an intrusion, the loading and power control unit turns on both the high wattage ACLEDs and the low wattage ACLEDs at same time thereby generates a high level illumination for a predetermine duration, wherein X and Y are of positive integers. According to an exemplary embodiment of the present disclosure, a two-level LED security light with motion sensor includes a power supply unit, a light sensing control unit, a motion sensing unit, a loading and power control unit, and a light-emitting unit. The light-emitting unit includes a rectifier circuit connected between one or a plurality of parallel-connected AC lighting sources and AC power source. The loading and power control unit may through the rectifier circuit adjust the average power of the light-emitting unit. When the light sensing control unit detects that the ambient light is lower than a predetermined value, the loading and power control unit turns on the light-emitting unit to generate a low level illumination; when the light sensing control unit detects that the ambient light is higher than the predetermined value, the loading and power control unit turns off the light-emitting unit; when the motion sensing unit detects an intrusion, the loading and power control unit increases the average power of the light-emitting unit thereby generates a high level illumination for a predetermine duration. The rectifier circuit includes a switch parallel-connected with a diode, wherein the switch is controlled by the loading and power control unit. To sum up, a two-level LED security light with motion sensor provided by an exemplary embodiment in the preset disclosure, may execute Photo-Control (PC) and Power-Saving (PS) modes. When operates in the PC mode, the lighting apparatus may auto-illuminate at night and auto-turnoff at dawn. The PC mode may generate a high level illumination for a predetermined duration then automatically switch to the PS mode by a control unit to generate a low level illumination. When the motion sensor detects a human motion, the disclosed LED security light may immediate switch to the high level illumination for a short predetermined duration thereby achieve illumination or warning effect. After the short predetermined duration, the LED security light may automatically return to the low level illumination for saving energy. In order to further understand the techniques, means and effects of the present disclosure, the following detailed descriptions and appended drawings are hereby referred, such that, through which, the purposes, features and aspects of the present disclosure can be thoroughly and concretely appreciated; however, the appended drawings are merely provided for reference and illustration, without any intention to be used for limiting the present disclosure. BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings are included to provide a further understanding of the present disclosure, and are incorporated in and constitute a part of this specification. The drawings illustrate exemplary embodiments of the present disclosure and, together with the description, serve to explain the principles of the present disclosure. FIG. 1 schematically illustrates a block diagram of a two-level LED security light in accordance with an exemplary embodiment of the present disclosure. FIG. 2A illustrates a schematic diagram of a two-level LED security light in accordance to the first exemplary embodiment of the present disclosure. FIG. 2B graphically illustrates a timing waveform of a pulse width modulation (PWM) signal in accordance to the first exemplary embodiment of the present disclosure. FIG. 3A illustrates a schematic diagram of a two-level LED security light in accordance to the second exemplary embodiment of the present disclosure. FIG. 3B illustrates a schematic diagram of a two-level LED security light in accordance to the second exemplary embodiment of the present disclosure. FIG. 4A illustrates a schematic diagram of a two-level LED security light in accordance to the third exemplary embodiment of the present disclosure. FIG. 4B illustrates a timing waveform of two-level LED security light in accordance to the third exemplary embodiment of the present disclosure. FIG. 5 illustrates a schematic diagram of a two-level LED security light in accordance to the third exemplary embodiment of the present disclosure. FIG. 6 illustrates a schematic diagram of a two-level LED security light in accordance to the fourth exemplary embodiment of the present disclosure. FIG. 7 illustrates a schematic diagram of a two-level LED security light in accordance to the fifth exemplary embodiment of the present disclosure. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS Reference is made in detail to the exemplary embodiments of the present disclosure, examples of which are illustrated in the accompanying drawings. Wherever possible, the same reference numbers are used in the drawings and the description to refer to the same or alike parts. First Exemplary Embodiment Refer to FIG. 1, which schematically illustrates a block diagram of a two-level LED security light in accordance to the first exemplary embodiment of the present disclosure. A two-level LED security light (herein as the lighting apparatus)100 includes a power supply unit 110, a light sensing control unit 120, a motion sensing unit 130, a loading and power control unit 140, and a light-emitting unit 150. The power supply unit 110 is used for supplying power required to operate the system, wherein the associated structure includes the known AC/DC voltage converter. The light sensing control unit 120 may be a photoresistor, which may be coupled to the loading and power control unit 140 for determining daytime or nighttime in accordance to the ambient light. The motion sensing unit 130 may be a passive infrared sensor (PIR), which is coupled to the loading and power control unit 140 and is used to detect intrusions. When a person is entering a predetermined detection zone of the motion sensing unit 130, a sensing signal thereof may be transmitted to the loading and power control unit 140. The loading and power control unit 140 which is coupled to the light-emitting unit 150 may be implemented by a microcontroller. The loading and power control unit 140 may control the illumination levels of the light-emitting unit 150 in accordance to the sensing signal outputted by the light sensing control unit 120 and the motion sensing unit 130. The light-emitting unit 150 may include a plurality of LEDs and switching components. The loading and power control unit 140 may control the light-emitting unit 150 to generate at least two levels of illumination variations. When the light sensing control unit 120 detects that the ambient light is lower than a predetermined value (i.e., nighttime), the loading and power control unit 140 executes the Photo-Control (PC) mode by turning on the light-emitting unit 150 to generate a high level illumination for a predetermined duration then return to a low level illumination for Power-Saving (PS) mode. When the light sensing control unit 120 detects that the ambient light is higher than a predetermined value (i.e., dawn), the loading and power control unit 140 turns off the light-emitting unit 150. In the PS mode, when the motion sensing unit 130 detects a human motion, the loading and power control unit 140 may increase the electric current which flow through the light-emitting unit 150, to generate the high level illumination for a short predetermined duration. After the short predetermined duration, the loading and power control unit 140 may automatically lower the electric current that flow through the light-emitting unit 150 thus have the light-emitting unit 150 return to low level illumination for saving energy. Refer to 2A, which illustrates a schematic diagram of a two-level LED security light in accordance to the first exemplary embodiment of the present disclosure. The light sensing control unit 120 may be implemented by a light sensor 220; the motion sensing unit 130 may be implemented by a motion sensor 230; the loading and power control unit 140 may be implemented by a microcontro11er 240. The light-emitting unit 250 includes three series-connected LEDs L1˜L3. The LEDs L1˜L3 is connected between a DC source and a transistor Q1, wherein the DC source may be provided by the power supply unit 110. The transistor Q1 may be an N-channel metal-oxide-semiconductor field-effect-transistor (NMOS). The transistor Q1 is connected between the three series-connected LEDs L1˜L3 and a ground GND. The loading and power control unit 140 implemented by the microcontroller 240 may output a pulse width modulation (PWM) signal to the gate of transistor Q1 to control the average electric current. It is worth to note that the electric components depicted in FIG. 2A only serves as an illustration for the exemplary embodiment of the present disclose and hence the present disclosure is not limited thereto. Refer to FIG. 2B concurrently, which graphically illustrates a timing waveform of a pulse width modulation (PWM) signal in accordance to the first exemplary embodiment of the present disclosure. In the PC mode, the PWM signal may be used to configure the transistor Q1 to have the conduction period Toff being longer than the cut-off period Toff. On the other hand in the PS mode, the PWM signal may configure the transistor Q1 to have the conduction period Ton being shorter than the cut-off period Toff. In comparison of the illumination levels between the PC and PS modes, as the conduction period Ton of transistor Q1 being longer under the PC mode, therefore have higher average electric current driving the light-emitting unit 250 thereby generate high illumination, which may be classified as the high level illumination; whereas as the conduction period Ton of transistor Q1 is shorter in the PS mode, therefore have lower average electric current driving the light-emitting unit 250 thereby generate low illumination, which may be classified as the low level illumination. The microcontro11er 240 turns off the light-emitting unit 250 during the day and activates the PC mode at night by turning on the light-emitting unit 250 to generate the high level illumination for a short predetermined duration then return to the low level illumination thereby entering the PS mode. When the motion sensor 230 detects a human motion in the PS mode, the light-emitting unit 250 may switch to the high level illumination for illumination or warning application. The light-emitting unit 250 may return to the low level illumination after maintaining at the high level illumination for a short predetermined duration to save energy. In addition, the microcontroller 240 is coupled to a time setting unit 260, wherein the time setting unit 260 may allow the user to configure the predetermined duration associated with the high level illumination in the PC mode, however the present disclosure is not limited thereto. Second Exemplary Embodiment Refer again to FIG. 1, wherein the illumination variations of the light-emitting unit 150 may be implemented through the number of light-source loads being turned on to generate more than two levels of illumination. The lighting apparatus 100 in the instant exemplary embodiment may be through turning on a portion of LEDs or all the LEDs to generate a low and a high level of illuminations. Refer to FIG. 3A concurrently, which illustrates a schematic diagram of a two-level LED security light 100 in accordance to the second exemplary embodiment of the present disclosure. The main difference between FIG. 3A and FIG. 2A is in the light-emitting unit 350, having three series-connected LEDs L1˜L3 and NMOS transistors Q1 and Q2. The LEDs L1˜L3 are series connected to the transistor Q1 at same time connected between the DC source and a constant electric current control circuit 310. Moreover, transistor Q2 is parallel connected to the two ends associated with LEDs L2 and L3. The gates of the transistors Q1 and Q2 are connected respectively to a pin PC and a pin PS of the microcontroller 240. The constant electric current control circuit 310 in the instant exemplary embodiment maintains the electric current in the activated LED at a constant value, namely, the LEDs L1˜L3 are operated in constant-current mode. Refer to FIG. 3A, the pin PC of the microcontroller 240 controls the switching operations of the transistor Q1; when the voltage level of pin PC being either a high voltage or a low voltage, the transistor Q1 may conduct or cut-off, respectively, to turn the LEDs L1˜L3 on or off. The pin PS of the microcontroller 240 controls the switch operations of the transistor Q2, to form two current paths 351 and 352 on the light-emitting unit 350. When the voltage at the pin PS of the microcontroller 240 is high, the transistor Q2 conducts, thereby forming the current path 351 passing through the LED L1 and the transistor Q2; when the voltage at the pin PS being low, the transistor Q2 cuts-off, thereby forming the current path 352 passing through all the LEDs L1˜L3. The microcontroller 240 may then control the switching operation of the transistor Q2 to turn on the desired number of LEDs so as to generate a high or a low level illumination. When light sensor 220 detects that the ambient light is higher than a predetermined value, the microcontroller 240 through the pin PC outputs a low voltage, which causes the transistor Q1 to cut-off and turns off all the LEDs L1˜L3 in the light-emitting unit 350. Conversely, when the light sensor 220 detects that the ambient light is lower than the predetermined value, the microcontroller 240 activates the PC mode, i.e., outputting a high voltage from pin PC and a low voltage from pin PS, to activate the transistor Q1 while cut-off the transistor Q2, thereby forming the current path 352, to turn on the three LEDs L1˜L3 in the light-emitting unit 350 so as to generate the high level illumination for a predetermined duration. After the predetermined duration, the microcontroller 240 may switch to the PS mode by having the pin PC continue outputting a high voltage and the pin PS outputting a high voltage, to have the transistor Q2 conducts, thereby forming the current path 351. Consequently, only the LED L1 is turned on and the low level illumination is generated. When the motion sensor detects a human motion in the PS mode, the pin PS of the microcontroller 240 temporarily switches from the high voltage to a low voltage, to have the transistor Q2 temporarily cuts-off thus forming the current path 352 to activate all the LEDs in the light-emitting unit 350, thereby temporarily generates the high level illumination. The light-emitting unit 350 is driven by a constant electric current, therefore the illumination level generated thereof is directly proportional to the number of LEDs activated. FIG. 3B illustrates another implementation for FIG. 3A, wherein the relays J1 and J2 are used in place of NMOS transistors to serve as switches. The microcontroller 240 may control the relays J2 and J1 through regulating the switching operations of the NPN bipolar junction transistors Q4 and Q5. Moreover, resistors R16 and R17 are current-limiting resistors. In the PC mode, the relay J1 being pull-in while the relay J2 bounce off to have constant electric current driving all the LEDs L1˜L3 to generate the high level illumination; in PS mode, the relays J1 and J2 both pull-in to have constant electric current only driving the LED L1 thus the low level illumination may be thereby generated. Furthermore, when the motion sensor 230 detects a human motion, the pin PS of the microcontroller 240 may temporarily switch from high voltage to low voltage, forcing the relay J2 to temporarily bounce off and the relay J1 pull-in so as to temporarily generate the high level illumination. The LED L1 may adopt a LED having color temperature of 2700K while the LEDs L2 and L3 may adopt LEDs having color temperature of 5000K in order to increase the contrast between the high level and the low level illuminations. The number of LEDs included in the light-emitting unit 350 may be more than three, for example five or six LEDs. The transistor Q2 may be relatively parallel to the two ends associated with a plurality of LEDs to adjust the illumination difference between the high and the low illumination levels. Additionally, the light-emitting unit 350 may include a plurality of transistors Q2, which are respectively coupled to the two ends associated with each LED to provide more lighting variation selections. The microcontroller 240 may decide the number of LEDs to turn on in accordance to design needs at different conditions. Based on the explanation of the aforementioned exemplary embodiment, those skills in the art should be able to deduce other implementation and further descriptions are therefore omitted. Third Exemplary Embodiment Refer back to FIG. 1, wherein the light-emitting unit 150 may include a phase controller and one or more parallel-connected alternating current (AC) LEDs. The phase controller is coupled between the described one or more parallel-connected ACLEDs and AC power source. The loading and power controller 140 in the instant exemplary embodiment may through the phase controller adjust the average power of the light-emitting unit 150 so as to generate variations in the low level and the high level illuminations. Refer to FIG. 4A, which illustrates a schematic diagram of a two-level LED security light 100 in accordance to the third exemplary embodiment of the present disclosure. The main difference between FIG. 4A and FIG. 3 is in that the light-source load is an ACLED, which is coupled to the AC power source, and further the light-emitting unit 450 includes a phase controller 451. The phase controller 451 includes a bi-directional switching device 452, here, a triac, a zero-crossing detection circuit 453, and a resistor R. The microcontroller 240 turns off the light-emitting unit 450 when the light sensor 220 detects that the ambient light is higher than a predetermined value. Conversely, when the light sensor 220 detects that the ambient light is lower than the predetermined value, the microcontroller 240 activates the PC mode by turning on the light-emitting unit 450. In the PC mode, the microcontroller 240 may select a control pin for outputting a pulse signal which through a resistor R triggers the triac 452 to have a large conduction angle. The large conduction angle configures the light-emitting unit 450 to generate a high level illumination for a predetermined duration. Then the microcontroller 240 outputs the pulse signal for PS mode through the same control pin to trigger the triac 452 to have a small conduction angle for switching the light-emitting unit 450 from the high level illumination to the low level illumination of the PS mode. Moreover, when the motion sensor 230 (also called motion sensing unit) detects a human motion in the PS mode, the microcontroller 240 temporarily outputs the PC-mode pulse signal through the same control pin to have the light-emitting unit 450 generated the high level illumination for a short predetermined duration. After the short predetermined duration, the light-emitting unit 450 returns to the low level illumination. In the illumination control of the ACLED, the microcontroller 240 may utilize the detected zero-crossing time (e.g., the zero-crossing time of an AC voltage waveform) outputted from the zero-crossing detection circuit 453 to send an AC synchronized pulse signal thereof which may trigger the triac 452 of the phase controller 451 thereby to change the average power input to the light-emitting unit 450. As the ACLED has a cut-in voltage Vt for start conducting, thus if the pulse signal inaccurately in time triggers the conduction of the triac 452, then the instantaneous value of AC voltage may be lower than the cut-in voltage Vt of ACLED at the trigger pulse. Consequently, the ACLED may result in the phenomenon of either flashing or not turning on. Therefore, the pulse signal generated by the microcontroller 240 must fall in a proper time gap behind the zero-crossing point associated with the AC sinusoidal voltage waveform. Supposing an AC power source having a voltage amplitude Vm and frequency f, then the zero-crossing time gap tD of the trigger pulse outputted by the microcontroller 240 should be limited according to to<tD<1/2f−to for a light-source load with a cut-in voltage Vt, wherein to=(1/2πf)sin−1(Vt/Vm). The described criterion is applicable to all types of ACLEDs to assure that the triac 452 can be stably triggered in both positive and negative half cycle of the AC power source. Take ACLED with Vt(rms)=80V as an example, and supposing the Vm(rms)=110V and f=60 Hz , then to=2.2 ms and (1/2f)=8.3 ms may be obtained. Consequently, the proper zero-crossing time gap tD associated with the phase modulation pulse outputted by the microcontroller 240 which lagged the AC sinusoidal voltage waveform should be designed in the range of 2.2 ms<tD<6.1 ms. Refer to FIG. 4B, which illustrates a timing waveform of the two-level LED security light in accordance to the third exemplary embodiment of the present disclosure. Waveforms (a)˜(d) of FIG. 4B respectively represent the AC power source, the output of the zero-crossing detection circuit 453, the zero-crossing delay pulse at the control pin of the microcontroller 240, and the voltage waveform across the two ends of the ACLED in the light-emitting unit 450. The zero-crossing detection circuit 453 converts the AC voltage sinusoidal waveform associated with the AC power source to a symmetric square waveform having a low and a high voltage levels as shown in FIG. 4B(b). At the zero-crossing point of the AC voltage sinusoidal wave, the symmetric square waveform may transit either from the low voltage level to the high voltage level or from the high voltage level to the low voltage level. Or equivalently, the edge of the symmetric square waveform in the time domain corresponds to the zero-crossing point of the AC voltage sinusoidal waveform. As shown in FIG. 4B(c), the microcontroller 240 outputs a zero-crossing delay pulse in correspondence to the zero-crossing point of the AC sinusoidal waveform in accordance to the output waveform of the zero-crossing detection circuit 453. The zero-crossing delay pulse is relative to an edge of symmetric square waveform behind a time gap tD in the time domain. The tD should fall in a valid range, as described previously, to assure that the triac 452 can be stably triggered thereby to turn on the ACLED. FIG. 4B(d) illustrates a voltage waveform applied across the two ends associated with the ACLED. The illumination level of the light-emitting unit 450 is related to the conduction period ton of the ACLED, or equivalently, the length ton is directly proportional to the average power inputted to the ACLED. The difference between the PC mode and the PS mode being that in the PC mode, the ACLED has longer conduction period, thereby generates the high level illumination; whereas in the PS mode, the ACLED conduction period is shorter, hence generates the low level illumination. Refer to FIG. 5, which illustrates a schematic diagram of a two-level LED security light 100 in accordance to the third exemplary embodiment of the present disclosure. The light-emitting unit 550 of the lighting apparatus 100 includes an ACLED1, an ACLED2, and a phase controller 551. The phase controller 551 includes triacs 552 and 553, the zero-crossing detection circuit 554 as well as resistorsRl and R2. The light-emitting unit 550 of FIG. 5 is different from the light-emitting unit 450 of FIG. 4 in that the light-emitting unit 550 has more than one ACLEDs and more than one bi-directional switching devices. Furthermore, the color temperatures of the ACLED1 and the ACLED2 may be selected to be different. In the exemplary embodiment of FIG.5, the ACLED1 has a high color temperature, and the ACLED2 has a low color temperature. In the PC mode, the microcontroller 240 uses the phase controller 551 to trigger both ACLED1 and ACLED2 to conduct for a long period, thereby to generate the high level illumination as well as illumination of mix color temperature. In the PS mode, the microcontroller 240 uses the phase controller 551 to trigger only the ACLED2 to conduct for a short period, thereby generates the low level illumination as well as illumination of low color temperature. Moreover, in the PS mode, when the motion sensor 230 detects a human motion, the microcontroller 240 may through the phase controller 551 trigger the ACLED1 and ACLED2 to conduct for a long period. Thereby, it may render the light-emitting unit 450 to generate the high level illumination of high color temperature and to produce high contrast in illumination and hue, for a short predetermined duration to warn the intruder. Consequently, the lighting apparatus may generate the high level or the low level illumination of different hue. The rest of operation theories associated with the light-emitting unit 550 are essentially the same as the light-emitting unit 450 and further descriptions are therefore omitted. Fourth Exemplary Embodiment Refer to FIG. 6, which illustrates a schematic diagram of a two-level LED security light 100 in accordance to the fourth exemplary embodiment of the present disclosure. The light-emitting unit 150 of FIG.1 may be implemented by the light-emitting unit 650, wherein the light-emitting unit 650 includes three ACLED1˜3 having identical luminous power as well as switches 651 and 652. In which, switches 651 and 652 may be relays. The parallel-connected ACLED1 and ACLED2 are series-connected to the switch 652 to produce double luminous power, and of which the ACLED3 is parallel connected to, to generate triple luminous power, and of which an AC power source is further coupled to through the switch 651. Moreover, the microcontroller 240 implements the loading and power control unit 140 of FIG. 1. The pin PC and pin PS are respectively connected to switches 651 and 652 for outputting voltage signals to control the operations of switches 651 and 652 (i.e., open or close). In the PC mode, the pin PC and pin PS of the microcontroller 240 control the switches 651 and 652 to be closed at same time. Consequently, the ACLED1˜3 are coupled to the AC power source and the light-emitting unit 650 may generate a high level illumination of triple luminous power. After a short predetermined duration, the microcontroller 240 returns to PS mode. In which the switch 651 is closed while the pin PS controls the switch 652 to be opened, consequently, only the ACLED3 is connected to AC power source, and the light-emitting unit 650 may thus generate the low level illumination of one luminous power. In the PS mode, when the motion sensor 230 detects a human motion, the microcontroller 240 temporarily closes the switch 652 to generate high level illumination with triple luminous power for a predetermined duration. After the predetermined duration, the switch 652 returns to open status thereby to generate the low level illumination of one luminous power. The lighting apparatus of FIG. 6 may therefore through controlling switches 651 and 652 generate two level illuminations with illumination contrast of at least 3 to 1. The ACLED1 and ACLED2 of FIG. 6 may be high power lighting sources having color temperature of 5000K. The ACLED3 may be a low power lighting source having color temperature of 2700K. Consequently, the ACLED may generate two levels of illuminations with high illumination and hue contrast without using a zero-crossing detection circuit. Fifth Exemplary Embodiment Refer to FIG. 7, which illustrates a schematic diagram of a two-level LED security light in accordance to the fifth exemplary embodiment of the present disclosure. The light-emitting unit 750 of FIG. 7 is different from the light-emitting unit 640 of FIG. 6 in that the ACLED3 is series-connected to a circuit with a rectified diode D and a switch 753 parallel-connected together, and of which is further coupled through a switch 751 to AC power source. When the switch 753 closes, the AC electric current that passes through the ACLED3 may be a full sinusoidal waveform. When the switch 753 opens, the rectified diode rectifies the AC power, thus only one half cycle of the AC electric current may pass through the ACLED, consequently the luminous power of ALCED3 is cut to be half. The pin PS of the microcontroller 240 synchronously controls the operations of switches 752 and 753.If the three ACLED1˜3 have identical luminous power, then in the PC mode, the pin PC and pin PS of the microcontroller 240 synchronously close the switches 751˜753 to render ACLED1˜3 illuminating, thus the light-emitting unit 750 generates a high level illumination which is three-times higher than the luminous power of a single ACLED. When in the PS mode, the microcontroller 240 closes the switch 751 while opens switches 752 and 753. At this moment, only the ACLED3 illuminates and as the AC power source is rectified by the rectified diode D, thus the luminous power of ACLED3 is half of the AC power source prior to the rectification. The luminous power ratio between the high level and the low level illuminations is therefore 6 to 1. Consequently, strong illumination contrast may be generated to effectively warn the intruder. It should be noted that the light-emitting unit in the fifth exemplary embodiment is not limited to utilizing ACLEDs. In other words, the light-emitting unit may include any AC lighting sources such as ACLEDs, incandescent lamps, or fluorescent lamps. A lighting apparatus may be implemented by integrating a plurality of LEDs with a microcontroller and various types of sensor components in the controlling circuit in accordance to the above described five exemplary embodiments. This lighting apparatus may automatically generate high level illumination when the ambient light detected is insufficient and time-switch to the low level illumination. In addition, when a person is entering the predetermined detection zone, the lighting apparatus may switch from the low level illumination to the high level illumination, to provide the person with sufficient illumination or to generate strong illumination and hue contrast for monitoring the intruder. The above-mentioned descriptions represent merely the exemplary embodiment of the present disclosure, without any intention to limit the scope of the present disclosure thereto. Various equivalent changes, alternations or modifications based on the claims of present disclosure are all consequently viewed as being embraced by the scope of the present disclosure. | <SOH> BACKGROUND OF THE INVENTION <EOH> | <SOH> SUMMARY OF THE INVENTION <EOH>An exemplary embodiment of the present disclosure provides a two-level LED security light with motion sensor which may switch to high level illumination in the Power-Saving (PS) mode for a predetermined duration time when a human motion is detected thereby achieve warning purpose using method of electric current or lighting load adjustment. Furthermore, prior to the detection of an intrusion, the LED security light may be constantly in the low level illumination to save energy. An exemplary embodiment of the present disclosure provides a two-level LED security light including a power supply unit, a light sensing control unit, a motion sensing unit, a loading and power control unit, and a light-emitting unit. The light-emitting unit further includes one or a plurality of series-connected LEDs; when the light sensing control unit detects that the ambient light is lower than a predetermined value, the loading and power control unit turns on the light-emitting unit to generate a high level or a low level illumination; when the light sensing control unit detects that the ambient light is higher than the predetermined value, the loading and power control unit turns off the light-emitting unit; when the motion sensing unit detects a human motion in the PS mode, the loading and power control unit increases the electric current that flows through the light-emitting unit so as to generate the high level illumination for a predetermined duration. Another exemplary embodiment of the present disclosure provides a two-level LED security light including a power supply unit, a light sensing control unit, a motion sensing unit, a loading and power control unit, a light-emitting unit. The light-emitting unit includes a plurality of series-connected LEDs. When the light sensing control unit detects that the ambient light is lower than a predetermined value, the loading and power control unit turns on a portion or all the LEDs of the light-emitting unit to generate a low level or a high level illumination; when the light sensing control unit detects that the ambient light is higher than the predetermined value, the loading and power control unit turns off all the LEDs in the light-emitting unit; when the motion sensing unit detects a human motion in the PS mode, the loading and power control unit turns on a plurality of LEDs in the light-emitting unit and generates the high level illumination for a predetermine duration. An electric current control circuit is integrated in the exemplary embodiment for providing constant electric current to drive the LEDS in the light-emitting unit. One exemplary embodiment of the present disclosure provides a two-level LED security light including a power supply unit, a light sensing control unit, a motion sensing unit, a loading and power control unit, and a light-emitting unit. The light-emitting unit includes a phase controller and one or a plurality of parallel-connected alternating current (AC)LEDs. The phase controller is coupled between the described one or a plurality parallel-connected ACLEDs and AC power source. The loading and power control unit may through the phase controller control the average power of the light-emitting unit; when the light sensing control unit detects that the ambient light is lower than a predetermined value, the loading and power control unit turns on the light-emitting unit to generate a high level or a lower level illumination; when the light sensing control unit detects that the ambient light is higher than the predetermined value, the loading and power control unit turns off the light-emitting unit; when the motion sensing unit detects a human motion in the PS mode, the loading and power control unit increases the average power of the light-emitting unit thereby generates the high level illumination for a predetermine duration. According to an exemplary embodiment of the present disclosure, a two-level LED security light includes a power supply unit, a light sensing control unit, a motion sensing unit, a loading and power control unit, and a light-emitting unit. The light-emitting unit includes X high wattage ACLEDs and Y low wattage ACLEDs connected in parallel. When the light sensing control unit detects that the ambient light is lower than a predetermined value, the loading and power control unit turns on the plurality of low wattage ACLEDs to generate a low level illumination; when the light sensing control unit detects that the ambient light is higher than a predetermined value, the loading and power control unit turns off the light-emitting unit; when the motion sensor detects an intrusion, the loading and power control unit turns on both the high wattage ACLEDs and the low wattage ACLEDs at same time thereby generates a high level illumination for a predetermine duration, wherein X and Y are of positive integers. According to an exemplary embodiment of the present disclosure, a two-level LED security light with motion sensor includes a power supply unit, a light sensing control unit, a motion sensing unit, a loading and power control unit, and a light-emitting unit. The light-emitting unit includes a rectifier circuit connected between one or a plurality of parallel-connected AC lighting sources and AC power source. The loading and power control unit may through the rectifier circuit adjust the average power of the light-emitting unit. When the light sensing control unit detects that the ambient light is lower than a predetermined value, the loading and power control unit turns on the light-emitting unit to generate a low level illumination; when the light sensing control unit detects that the ambient light is higher than the predetermined value, the loading and power control unit turns off the light-emitting unit; when the motion sensing unit detects an intrusion, the loading and power control unit increases the average power of the light-emitting unit thereby generates a high level illumination for a predetermine duration. The rectifier circuit includes a switch parallel-connected with a diode, wherein the switch is controlled by the loading and power control unit. To sum up, a two-level LED security light with motion sensor provided by an exemplary embodiment in the preset disclosure, may execute Photo-Control (PC) and Power-Saving (PS) modes. When operates in the PC mode, the lighting apparatus may auto-illuminate at night and auto-turnoff at dawn. The PC mode may generate a high level illumination for a predetermined duration then automatically switch to the PS mode by a control unit to generate a low level illumination. When the motion sensor detects a human motion, the disclosed LED security light may immediate switch to the high level illumination for a short predetermined duration thereby achieve illumination or warning effect. After the short predetermined duration, the LED security light may automatically return to the low level illumination for saving energy. In order to further understand the techniques, means and effects of the present disclosure, the following detailed descriptions and appended drawings are hereby referred, such that, through which, the purposes, features and aspects of the present disclosure can be thoroughly and concretely appreciated; however, the appended drawings are merely provided for reference and illustration, without any intention to be used for limiting the present disclosure. | H05B330854 | 20171017 | 20180208 | 57220.0 | H05B3308 | 1 | LE, TUNG X | TWO-LEVEL LED SECURITY LIGHT WITH MOTION SENSOR | SMALL | 1 | CONT-ACCEPTED | H05B | 2,017 |
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15,786,499 | PENDING | END TREATMENTS AND TRANSITIONS FOR WATER-BALLASTED PROTECTION BARRIER ARRAYS | An end treatment array for crash attenuation includes a transition barrier module formed of side walls, end walls, a top wall, and a bottom wall, wherein the module walls together define an enclosed interior space. The end treatment array further includes a containment impact sled having an axially extending frame. The frame has a width sufficient to contain the transition barrier module within the frame when in an assembled configuration, and has an axial length which is at least one-half the length of the transition barrier module. The frame defines an interior volume, the purpose of which is to contain a substantial portion of the transition barrier module in the assembled configuration, and to contain debris caused by destruction of the plastic barrier modules in a vehicular impact. The containment impact sled is attached to the transition barrier module. | 1. An end treatment array for attenuating the forces generated by a vehicular impact, comprising: a transition barrier module comprising first and second side walls, first and second end walls, a top wall, and a bottom wall, the module walls together defining a substantially enclosed interior space, the transition barrier module having a predetermined width and length; and a containment impact sled comprising an axially extending frame, said frame having a width sufficient to contain the transition barrier module within said frame when in an assembled configuration, and having an axial length which is at least one-half the length of said transition barrier module, the frame defining an interior volume; wherein the containment impact sled is attached to the transition barrier module in said assembled configuration. 2. The end treatment array as recited in claim 1, wherein the transition barrier module is fabricated of plastic and the interior space is hollow and unfilled with any ballasting material. 3. The end treatment array as recited in claim 1, wherein said containment impact sled further comprises an upright wall connected to said frame which substantially covers the first front-facing end wall of the transition barrier module when the sled is in said assembled configuration, with the transition barrier module at least partially contained within the frame of the sled. 4. The end treatment array as recited in claim 3, wherein the containment impact sled further comprises a floor. 5. The end treatment array as recited in claim 4, wherein the containment impact sled frame comprises a first side frame member attached to one side of said floor and upright wall and a second side frame member attached to an opposing side of said floor and said upright wall. 6. The end treatment array as recited in claim 5, wherein each of said side frame members comprise a bottom frame member and a top frame member, wherein the bottom frame member is disposed substantially horizontally, and the top frame member extends downwardly at an angle from its frontmost end to its rearmost end, with the frontmost end of the top frame member being connected to said upright wall near a top of said upright wall and the rearmost end of the top frame member being connected to a rearmost end of the bottom frame member near ground level, such that each side frame member is triangular in shape. 7. The end treatment array as recited in claim 1, and further comprising: apertures in each of said transition barrier module and said sled which are aligned when the transition barrier module and the sled are in said assembled configuration; and a pin extending through said aligned apertures in said assembled configuration to attach the transition barrier module to the sled. 8-12. (canceled) 13. The end treatment array as recited in claim 1, and further comprising a barrier module connected at a first end to the transition barrier module which is filled with a ballasting material. 14. (canceled) 15. The end treatment array as recited in claim 13, and further comprising a second transition barrier module connected at a first end thereof to a second end of the barrier module, the second transition barrier module being constructed substantially similarly to the first transition barrier module and being unfilled with ballasting material. 16. The end treatment array as recited in claim 15, and further comprising end treatment hardware for attaching a second end of the second transition barrier module to a fixed structure. 17. The end treatment array as recited in claim 16, wherein said end treatment hardware comprises a frame which is securable to the second end of the second transition barrier module. 18-23. (canceled) 24. A containment impact sled for use in an end treatment array for attenuating the forces generated by a vehicular impact, the containment impact sled comprising: a frame extending in an axial direction and comprising: a first side frame member; a second side frame member spaced from the first side frame member; and an end frame member extending across a width of the frame and securing the first side frame member to the second side frame member, said frame members together defining an interior space; wherein the containment impact sled is adapted for attachment to an adjacent barrier module in an assembled end treatment array in such a manner as to contain a substantial portion of said adjacent barrier module within said interior space when the end treatment array is assembled. 25-30. (canceled) 31. A method of assembling an end treatment array for protecting a fixed structure from an impact by a passing vehicle, the method comprising: securing a plurality of ballast-filled hollow plastic barrier modules together in an axial array; securing one end of a transition barrier module to one end of the array of ballast-filled hollow plastic barrier modules, the transition barrier module being unfilled with ballasting material; and securing a containment impact sled to the other end of the transition barrier module, wherein the containment impact sled comprises a frame defining an interior space, the securing step including disposing the frame about the transition barrier module so that a substantial portion of the transition barrier module is contained within the interior space. 32-34. (canceled) | This application is a continuation application under 35 U.S.C. 120 of U.S. application Ser. No. 14/831,600, entitled End Treatments and Transitions for Water-Ballasted Protection Barrier Arrays and filed on Aug. 20, 2015, which in turn is a continuation application of both U.S. application Ser. No. 14/257,389, entitled End Treatments and Transitions for Water-Ballasted Protection Barrier Arrays and filed on Apr. 21, 2014, now issued as U.S. Pat. No. 9,145,652 on Sep. 29, 2015, and U.S. application Ser. No. 14/270,348, entitled End Treatments and Transitions for Water-Ballasted Protection Barrier Arrays and filed on May 5, 2014, now issued as U.S. Pat. No. 9,133,591 on Sep. 15, 2015, each of which is in turn a divisional application under 35 U.S.C. 120 of U.S. application Ser. No. 13/371,269, entitled End Treatments and Transitions for Water-Ballasted Protection Barrier Arrays and filed on Feb. 10, 2012, now issued as U.S. Pat. No. 8,777,510 on Jul. 15, 2014, which in turn claims the benefit under 35 U.S.C. 119(e) of the filing date of Provisional U.S. Application Ser. No. 61/442,091, entitled End Treatments and Transitions for Water-Ballasted Protection Barrier Arrays, filed on Feb. 11, 2011. This application is also related to U.S. application Ser. No. 12/699,770, entitled Water-Ballasted Protection Barriers and Methods, filed on Feb. 3, 2010. All of the foregoing prior applications are commonly assigned with this one, and herein expressly incorporated by reference, in their entirety. BACKGROUND OF THE INVENTION The present invention relates generally to vehicle protection barriers, and more particularly to movable water ballasted vehicle traffic protection barriers for applications such as pedestrian protection, traffic work zone separation, airport runway divisions, and industrial commercial uses. SUMMARY OF THE INVENTION The present invention comprises an end treatment array for attenuating the forces generated by a vehicular impact. The inventive end treatment array include a transition barrier module comprising first and second side walls, first and second end walls, a top wall, and a bottom wall, wherein the module walls together define a substantially enclosed interior space. The transition barrier module has a predetermined width and length. The end treatment array advantageously further includes an innovative containment impact sled which comprises an axially extending frame. The frame has a width sufficient to contain the transition barrier module within the frame when in an assembled configuration, and has an axial length which is at least one-half the length of the transition barrier module. The frame defines an interior volume, the purpose of which is to contain a substantial portion of the transition barrier module in the assembled configuration, and to contain debris caused by destruction of the plastic barrier modules in a vehicular impact. The containment impact sled is attached to the transition barrier module in the aforementioned assembled configuration. As noted above, the transition barrier module is fabricated of plastic. Importantly, the interior space is hollow and, unlike the regular barrier modules, is unfilled with any ballasting material for maximum initial energy absorption. The containment impact sled further comprises an upright wall connected to the frame which substantially covers the first front-facing end wall of the transition barrier module when the sled is in its assembled configuration, with the transition barrier module at least partially contained within the frame of the sled. The containment impact sled further comprises a floor. The containment impact sled frame comprises a first side frame member attached to one side of the floor and upright wall and a second side frame member attached to an opposing side of the floor and the upright wall. Each of the side frame members comprise a bottom frame member and a top frame member, wherein the bottom frame member is disposed substantially horizontally, and the top frame member extends downwardly at an angle from its frontmost end to its rearmost end, with the frontmost end of the top frame member being connected to the upright wall near a top of the upright wall and the rearmost end of the top frame member being connected to a rearmost end of the bottom frame member near ground level, such that each side frame member is triangular in shape. Apertures are provided in each of the transition barrier module and the sled, which are aligned when the transition barrier module and the sled are in the assembled configuration. A pin extends through the aligned apertures in the assembled configuration to attach the transition barrier module to the sled. The transition barrier module comprises a plurality of vertically spaced lugs on the first end wall, wherein each of the lugs have one of the apertures therein for receiving the pin. Additionally, one of the apertures is disposed in the upright wall of the sled. Preferably, the transition barrier module comprises holes in a lower end thereof to prevent the containment of ballasting material in the interior space. The end treatment array further comprises a plurality of vertically spaced lugs on the second transition barrier module end wall, for attaching the transition barrier module to a first end of an adjacent barrier module. In certain arrays, the adjacent barrier module is also a transition barrier module, constructed similarly to the first transition barrier module, and is also unfilled with ballasting material. The array further comprises a barrier module connected at a first end to the transition barrier module which is filled with a ballasting material, which is preferably water. It should be noted that it is within the scope of the present invention to employ any number of transition barrier modules and any number of ballasted barrier modules in the array, depending upon desired crash attenuation characteristics and particular roadway conditions. So, the use of the term “connected” or “attached” herein does not necessarily mean a direct connection or attachment, but could mean an indirect connection through intermediate modules, unless specific language used requires otherwise. Importantly, for ease of assembly by on-site personnel, the transition barrier modules and the ballast-filled barrier modules are differently colored. Another important aspect of the present invention is that the end treatment array comprises a second transition barrier module connected at a first end thereof to a second end of the barrier module, wherein the second transition barrier module is constructed substantially similarly to the first transition barrier module and is unfilled with ballasting material. This second end of the end treatment array is adapted for attachment to the fixed structure, such as a concrete abutment, which is being protected. Thus, end treatment hardware is provided for attaching a second end of the second transition barrier module to the fixed structure. The end treatment hardware, in disclosed embodiments, comprises a metal frame which is securable to the second end of the second transition barrier module. The frame comprises a plurality of vertically spaced horizontal cross members, each of which has an aperture in a middle portion thereof for receiving a pin, wherein in an assembled state the apertures are aligned. Additional components of the end treatment hardware are first and second hinge posts disposed at opposing ends of each of the assembled vertically spaced horizontal cross members, a first hinge pin, a second hinge pin, a left panel, and a right panel. The left panel is pivotally securable to aligned first hinge posts using the first hinge pin and the right panel is pivotally securable to aligned second hinge posts using the second hinge pin, so that the left and right panels can be rotated to extend along a length of the fixed structure. Each of the left and right panels have apertures therein for receiving hardware to secure each panel to the fixed structure. A pin is provided for insertion into the aligned apertures on each of the plurality of vertically spaced horizontal cross members. In another aspect of the invention, there is provided a containment impact sled for use in an end treatment array for attenuating the forces generated by a vehicular impact, which comprises a frame extending in an axial direction and comprising a first side frame member, a second side frame member spaced from the first side frame member, and an end frame member extending across a width of the frame and securing the first side frame member to the second side frame member. The frame members together define an interior space. The containment impact sled is adapted for attachment to an adjacent barrier module in an assembled end treatment array, in such a manner as to contain a substantial portion of the adjacent barrier module within the interior space when the end treatment array is assembled. The frame further comprises a floor attached to and extending between each of the side frame members and the end frame member, and further comprises an upright wall attached to a front end of the end frame member. The upright wall comprises an end cap. Each of the side frame members comprise a bottom frame member and a top frame member, wherein the bottom frame member is disposed substantially horizontally, and the top frame member extends downwardly at an angle from its frontmost end to its rearmost end, with the frontmost end of the top frame member being connected to the end frame member near a top of the end frame member and the rearmost end of the top frame member being connected to a rearmost end of the bottom frame member near ground level, such that each side frame member is triangular in shape. An aperture is provided in the upright wall for attaching the containment impact sled to an adjacent barrier module. The frame is preferably comprised of metal, though it would not necessarily have to be, if another suitably durable material were available. In yet another aspect of the invention, there is disclosed a method of assembling an end treatment array for protecting a fixed structure from an impact by a passing vehicle. The method comprises steps of securing a plurality of ballast-filled hollow plastic barrier modules together in an axial array and securing one end of a transition barrier module to one end of the array of ballast-filled hollow plastic barrier modules. The transition barrier module is unfilled with ballasting material. A further method step is to secure a containment impact sled to the other end of the transition barrier module, wherein the containment impact sled comprises a frame defining an interior space, and wherein the securing step includes disposing the frame about the transition barrier module so that a substantial portion of the transition barrier module is contained within the interior space. The securing step further comprises inserting a pin through aligned holes in both the containment impact sled and the transition barrier module and a step of securing a second transition barrier module to a second end of the axial array of ballast-filled barrier modules, wherein the second transition barrier module is unfilled with ballasting material. Additionally, the method comprises a step of securing the second transition barrier module to the fixed structure, using end treatment hardware comprising metal cross-members attached to the second transition barrier module and metal plates pivotally mounted to the metal cross-members. The invention, together with additional features and advantages thereof, may best be understood by reference to the following description taken in conjunction with the accompanying illustrative drawings. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is an end elevation view showing a configuration of a water barrier segment or module constructed in accordance with one embodiment of the present invention; FIG. 2 is a perspective view of a portion of the barrier module of FIG. 1; FIG. 3 is a perspective view of the barrier module of FIGS. 1 and 2; FIG. 4 is a front elevation view of the barrier module of FIG. 3; FIG. 5 is a left end elevation view of the barrier module of FIGS. 1-4; FIG. 6 is a right end elevation view of the barrier module of FIGS. 1-4 FIG. 7 is a front elevation view showing two barrier module such as that shown in FIG. 4, wherein the modules are detached; FIG. 8 is a front elevation view similar to FIG. 7, showing the barrier modules after they have been attached to one another; FIG. 9 is a perspective view, in isolation, of an interlocking knuckle for use in attaching two barrier modules together; FIG. 10 is a cross-sectional view showing a double wall reinforcement area for a pin lug on the barrier module; FIG. 11 is a front elevation view similar to FIG. 7 showing a barrier module; FIG. 12 is a plan view from the top showing two connected barrier modules rotating with respect to one another upon vehicular impact; FIG. 13 is a cross-sectional plan view taken along lines A-A of FIG. 8, after vehicular impact and relative rotation of the two barrier modules; FIG. 14 is a cross-sectional plan view of the detail section C of FIG. 13; FIG. 15 is an elevation view of a barrier module of the type shown in FIG. 7, showing some of the constructional details of the module; FIG. 16 is a top plan view of the barrier module of FIG. 15; FIG. 17 is an end elevation view of the barrier module of FIG. 15; FIG. 18 is a perspective view showing three barrier modules secured together; FIG. 19 is a perspective view of a second, presently preferred embodiment of a barrier module constructed in accordance with the principles of the present invention; FIG. 20 is a front elevation view of the barrier module shown in FIG. 19; FIG. 21 is an end elevation view of the barrier module shown in FIGS. 19-20; FIG. 22 is a top plan view of the barrier module shown in FIGS. 19-21; FIG. 23 is a perspective view of the barrier module shown in FIGS. 19-22, taken from an opposing orientation; FIG. 24 is an end elevation view of the barrier module of FIG. 23; FIG. 25 is a sectioned perspective view of the barrier module of FIG. 23, showing internal constructional features of the barrier module, and in particular a unique cable reinforcement system; FIG. 26 is a front sectioned view of the barrier module of FIG. 25; FIG. 27 is a sectioned detail view of the portion of FIG. 26 identified as detail A; FIG. 28 is a perspective view of the barrier module of FIGS. 19-27; FIG. 29 is a top plan view of the barrier module of FIG. 28; FIG. 30 is a sectioned detail view of the portion of FIG. 29 identified as detail A; FIG. 31 is a perspective view showing three barrier modules secured together; FIG. 32 is a front elevation view of a barrier module constructed in accordance with the principles of the invention, in which is disposed a drain aperture having an inventive buttress thread configuration; FIG. 33 is an enlarged view of the drain aperture of FIG. 32; and FIG. 34 is an enlarged perspective view of the drain aperture of FIG. 32; FIG. 35 is an isometric view of another modified embodiment of a fluid-ballasted barrier module constructed in accordance with the present invention; FIG. 36 is a cross-sectional isometric view taken along lines A-A of FIG. 35, illustrating certain interior features of the barrier module of FIG. 35; FIG. 37 is a plan view illustrating the construction of a presently preferred configuration for the wire rope assembly of the present invention, in isolation; FIG. 38 is a top view of the assembly illustrated in FIG. 37; FIG. 39 is an enlarged view of the portion of FIG. 37 denoted by the circle A; FIG. 40 is an isometric view of the assembly illustrated in FIGS. 37 and 38; FIG. 41 is an enlarged isometric view of the portion of FIG. 40 denoted by the circle B; FIG. 42 is a plan view illustrating two of the barrier modules of the present invention in a vertically stacked configuration; FIG. 43 is an end view of the stacked array of FIG. 42; FIG. 44 is a top view of an end treatment array in accordance with the present invention; FIG. 45 is a plan view of the array of FIG. 44; FIG. 46 is an isometric view of the array of FIGS. 44 and 45; FIG. 47 is a plan view showing the left side of a transition barrier module and containment impact sled assembly in accordance with the present invention; FIG. 48 is an isometric view of the structures shown in FIG. 47; FIG. 49 is a plan view similar to FIG. 47 of the right side of a transition barrier module and containment impact sled assembly; FIG. 50 is an isometric view of the structures shown in FIG. 49; FIG. 51 is an isometric view of a containment impact sled in accordance with the present invention; FIG. 52 is a top view of the sled of FIG. 51; FIG. 53 is an elevational view of the sled of FIG. 51; FIG. 54 is an end view of the sled of FIG. 51; FIG. 55 is a plan view of a pin for use in securing the sled to the barrier transition module; FIG. 56 is an isometric view of the pin of FIG. 55; FIG. 57 is a right-side plan view of a sled and barrier transition module assembly in accordance with the present invention; FIG. 58 is a left-side plan view of the assembly shown in FIG. 57; FIG. 59 is a plan view of a barrier transition module, showing end treatment hardware for attachment to an end thereof; FIG. 60 is an isometric view of the assembly shown in FIG. 59; FIG. 61 is a plan view similar to FIG. 59, showing the end treatment hardware for attachment to an opposing end of the barrier transition module; FIG. 62 is an isometric view of the assembly shown in FIG. 61; FIG. 63 is an exploded isometric view of the end treatment hardware for use in the present invention; and FIG. 64 is a plan view of the assorted hardware forming the set of end treatment hardware for securing the end treatment array to a fixed structure. DESCRIPTION OF THE PREFERRED EMBODIMENT Referring now more particularly to the drawings, there is shown in FIGS. 1-3 and 15-17 a water-ballasted barrier segment or module 10 constructed in accordance with one embodiment of the present invention. The illustrated barrier module preferably has dimensions of approximately 18 in. W×32 in. H×78 in. L, with a material thickness of about ¼ in. The material used to fabricate the module 10 may be a linear medium density polyethylene, and is preferably rotationally molded, although it may also be molded using other methods, such as blow molding. The module 10 preferably has an empty weight of approximately 75-80 lb., and a filled weight (when filled with water ballast) of approximately 1100 lb. Particularly with respect to FIGS. 1-2, the barrier module 10 has been constructed using a unique concave redirective design, wherein outer walls 12 of the barrier module 10 are configured in a concave manner, as shown. In a preferred configuration, the concave section is approximately 71 inches long, and runs the entire length of the barrier module. The concave section is designed to minimize the tire of a vehicle, impacting the barrier along the direction of arrow 14, from climbing up the side of the barrier module, by pocketing the tire in the curved center portion of the barrier wall 12. When the vehicle tire is captured and pocketed inside the curved portion, the reaction force of the impact then diverges the vehicle in a downward direction, as shown by arrow 16 in FIG. 1. The concave diverging design will thus assist in forcing the vehicle back toward the ground rather than up the side of the water barrier module 10. In a preferred configuration, as shown in FIG. 1, the concave center portion of the outer wall 12 has a curve radius of approximately 24¾ in., and is about 23 inches in height. FIGS. 3-11 illustrate an interlocking knuckle design for securing adjacent barrier modules 10 together. The interlocking knuckle design is a lug pin connection system, comprising four lugs 18 disposed in interweaved fashion on each end of the barrier module 10. Each lug 18 is preferably about 8 inches in diameter, and approximately 2 inches thick, although various dimensions would be suitable for the inventive purpose. To achieve the interweaved effect, on a first end 20 of the barrier module 10, the first lug 18 is disposed 4 inches from the top of the module 10. The remaining three lugs 18 are equally spaced vertically approximately 3½ inches apart. On a second end 22 of the barrier module 10, the first lug 18 is disposed about 7 inches from the top of the barrier module 10, with the remaining three lugs 18 being again equally spaced vertically approximately 3½ inches apart. These dimensions are preferred, but again, may be varied within the scope of the present invention. When the ends of two adjacent barrier modules 10 are placed together, as shown sequentially in FIGS. 7 and 8, the complementary lugs 18 on the mating ends of the adjoined modules 10 slide between one another in interweaved fashion, due to the offset distance of each lug location, as described above, and shown in FIGS. 4 and 7. The lugs' dimensional offset permit each module 10 to be linked together with one lug atop an adjacent lug. This results in a total of eight lugs on each end of the water barrier module 10 that lock together, as seen in FIG. 8. Each lug 18 has a pin receiving hole 24 disposed therein, as best shown in FIGS. 9 and 10. When the eight lugs 18 are engaged, as discussed above, upon the adjoining of two adjacent barrier modules 10, these pin receiving holes 24, which are preferably approximately 1½ inches in diameter, and are disposed through the two inch thick portion of the lug 18, correspond to one another. Thus, a T-pin 26 is slid vertically downwardly through the corresponding pin receiving holes 24 of all eight lugs or knuckles 18, as shown in FIG. 8, in order to lock the two adjoined barrier modules 10 together. To reduce the bearing load on the pin lug connection, a double wall reinforcement 28 may be included on the backside of the hole 24 on the lug 18, as shown in FIG. 10. The double reinforced wall is created by molding an indentation 30 on an outer curved section 32 of the lug 18, as shown in FIG. 9. The removal of material on the outside curved section 32 of the lug 18 creates a double reinforced wall on the inside section of the lug. The wall created by the recessed section 30 on the outside of the lug creates a reinforcement section 28 against the vertical hole 24 in the lug 18, as shown in sectioned FIG. 10. By creating this double wall reinforcement section 28, the T-pin 26 has two approximately ¼ inch thick surfaces to transfer the load to the T-pin 26 during vehicular impact. This arrangement will distribute the bearing load over a larger area, with thicker material and more strength. During impact, the water barrier can rotate at the pin lug connection, resulting in large stresses at the pin lug connection during maximum rotation of the water wall upon impact. To reduce the stresses at the pin lug connection, a concave inward stress transfer zone is formed between the male protruding lugs 18, as shown in FIGS. 12-14. The concave inward section creates a concave female portion 34 at the ends of each water wall module where the male end of each lug 18 will slide inside when aligned, as illustrated. Before vehicular impact, the male lugs 18 are not in contact with any surface inside the concave female portion 34 of the barrier module 10. However, when the module 10 is impacted, and is displaced through its full range of rotation (approximately 30 degrees), as shown in the figures, the external curved surface of the male lugs will come into contact with the external surface of the inside wall of the concave female portion, as shown in FIG. 14. This transfers the load from the pin lug connection to the lug contact point of the male/female portion. By transferring the load of the vehicular impact from the pin lug connection to the female/male contact point, the load is distributed into the male/female surface contact point before the pin connection begins to absorb the load. This significantly reduces the load on the T-pin 26, minimizing the pin's tendency to bend and deform during the impact. To accommodate the ability to dispose a fence 36 or any other type of device to block the view or prevent access to the other side of the barrier 10, the t-pins 26 are designed to support a square or round tubular fence post 38, as shown in FIG. 18. The tubular post 38 is adapted to slip over the t-pin, with suitable retaining structure disposed to ensure that the post 38 is firmly retained thereon. In a preferred method, each barrier module 10 is placed at a desired location while empty, and relatively light. This placement may be accomplished using a forklift, for example, utilizing forklift apertures 39. Once the modules are in place, and connected as described above, they can then be filled with water, using fill apertures 39a as shown in FIG. 3. When it is desired to drain a barrier module, drain apertures, such as aperture 39b in FIG. 15, may be utilized. Now referring in particular to FIGS. 19-21, a second embodiment of a water-ballasted barrier module 110 is illustrated, wherein like elements are designated by like reference numerals, preceded by the numeral 1. This barrier module 110 is preferably constructed to have overall dimensions of approximately 22 in. W×42 in. H×78 in. L, with a material thickness of about ¼ inches. As in the prior embodiment, these dimensions are presently preferred, but not required, and may be varied in accordance with ordinary design considerations. The material of which the barrier module 110 is fabricated is preferably a high density polyethylene, and the preferred manufacturing process is rotational molding, although other known processes, such as blow molding, may be used. The illustrated embodiment utilizes a unique configuration to minimize that chances that an impacting vehicle will drive up and over the module 110 upon impact. This configuration comprises a saw tooth profile, as illustrated, which is designed into the top portion of the barrier module 110, as shown in FIGS. 19-24. The design intent of the saw tooth profile is to snag the bumper, wheel, or any portion of a vehicle impacting the barrier 110 from a direction indicated by arrow 114 (FIG. 23) and to deflect the vehicle in a downward direction as indicated by arrow 116 (FIG. 23). The saw tooth profile shape runs the entire length of each section of the barrier module 110, as shown. A first protruding module or sawtooth 40, forming the sawtooth profile, begins to protrude approximately 20 inches above the ground, and second and third protruding modules 42, 44, respectively are disposed above the module 40, as shown. Of course, more or fewer sawtooth modules, or anti-climbing ribs, may be utilized, depending upon particular design considerations. The design intent of using a plurality of sawtooth modules is that, if the first anti-climbing rib 40 does not succeed in containing the vehicle and re-directing it downwardly to the ground, the second or third climbing ribs 42, 44, respectively, should contain the vehicle before it can successfully climb over the barrier 110. The first embodiment of the invention, illustrated in FIGS. 1-18, is capable of meeting the earlier described TL-1 crash test, but plastic construction alone has been found to be insufficient for withstanding the impact of a vehicle traveling 70 kph or 100 kph, respectively, as required under TL-2 and TL-3 testing regimes. The plastic does not have sufficient physical properties alone to stay together, pocket, or re-direct an impacting vehicle at this velocity. In order to absorb the energy of a vehicle traveling at 70 to 100 kph, the inventors have found that steel components need to be incorporated into the water barrier system design. Using steel combined with a large volume of water for ballast and energy absorption enables the properly designed plastic wall to absorb the necessary energy to meet the federal TL-2 and TL-3 test requirements at such an impact. To contain the 70 to 100 kph impacting vehicle, the inventors have used the interlocking plastic knuckle design described earlier in connection with the TL-1 water barrier system described and shown in FIGS. 1-18 of this application. The same type of design principles are used in connection with this larger and heavier TL-2 and TL-3 water barrier system, which includes the same interlocking knuckle attachment system disclosed in connection with the first embodiment. The TL-2 and TL-3 barrier system described herein in connection with FIGS. 19-31 absorbs energy by plastic deformation, water displacement, wire rope cable fencing tensioning, water dissipation, and overall displacement of the water barrier itself. Since it is known that plastic alone cannot withstand the stringent test requirements of the 70-100 kph TL-2 and TL-3 vehicular impact protocols, internally molded into the barrier module 110 is a wire rope cable 46, which is used to create a submerged fence inside the water barrier module 110 as shown in FIGS. 25 and 26. Before the barrier module 110 is molded, the wire rope cables 46 are placed inside the mold tool. The cables are made with an eyelet or loop 48 (FIG. 30) at each end, and are placed in the mold so that the cable loops 48 wrap around the t-pin hole 124 outside diameter as shown in FIG. 27. Preferably, the wire rope cables 46 are each comprised of stainless steel, or galvanized and stranded steel wire cable to resist corrosion due to their contact with the water ballast, and are preferably formed of ⅜ inch 7×19 strands, though alternative suitable cable strands may be used as well. By placing the cables 46 around the t-pin holes 124, dual fence posts are created on each side of the barrier module 110, with four cable lines 46 disposed in between, thereby forming an impenetrable cable fence in addition to the water ballast. It is noted that the wire cable loop ends are completely covered in plastic during the rotational molding process, to prevent water leakage. By placing the wire rope cable 46 and wrapping it around the t-pin hole 124, a high strength area in the interlocking knuckles is created. When the t-pin 126 is dropped into the hole 124, to connect a series of barrier fence modules 110, it automatically becomes a steel post by default, since the wire rope cable modules 46 are already molded into the barrier modules. Since the loop of each cable end wraps around the t-pin in each knuckle, the impacting vehicle will have to break the wire rope cable 46, t-pin 126, and knuckle in order to break the barrier. FIGS. 28-30 illustrate how the wire rope cables 46 wrap the T-pin holes 124. The wire rope cables 46 are an integral part of each barrier module 110, and cannot be inadvertently omitted or removed once the part has been manufactured. The current design uses up to four wire rope cables 46 per barrier module 110, as illustrated. This creates an eleven piece interlocking knuckle section. More or fewer knuckles and wire rope cables may be utilized, depending upon whether a lower or taller barrier is desired. The wire rope fence construction disclosed in connection with this second TL-2 or TL-3 embodiment can also be incorporated into the lower height barrier illustrated and described in FIGS. 1-18. When large numbers of barrier modules are used to create a longitudinal barrier, a wire rope cable fence is formed, with a t-pin post, with the whole assembly being ballasted by water without seeing the cable fencing. FIG. 31 illustrates such a plurality of modules 110, interlocked together to form a barrier as just described. As illustrated, each barrier module is approximately 2100 lb when filled with water. As the barrier illustrated in FIG. 31 is impacted by a vehicle, the plastic begins to deform and break, the barrier wall in the impact zone begins to slide, further absorbing energy, water ballast is displaced, and water is dispersed while the wire rope cables 46 continue the work of absorbing the impact energy by pulling along the knuckles and placing the series of wire rope cables in tension within the impact zone. The entire area of impact immediately becomes a wire rope cable fence in tension, holding the impacting vehicle on one side of the water ballasted barrier. Otherwise, the normal status of the barrier is for the wire rope cables 46 to be in a slack state. The excellent energy absorption of this system is enhanced by the progressive nature of the events that occur, in sequence, as described above, resulting in a progressive deceleration of the vehicle and full absorption of the impact energy with minimum harm to vehicle occupants and nearby vehicles, pedestrians, and structures. With reference particularly to FIGS. 32-34, an inventive embodiment of the drain aperture 39b will be more particularly described. This particular feature is applicable to any of the above described embodiments of the invention. The aperture 39b is disposed within a recess 50 in a bottom portion of the barrier module 10. A closure or cap 52 is provided for closing and sealing the aperture 39b to prevent leakage of ballast from the barrier module 10. The closure 52 is secured in place by means of a series of buttress threads 54 (FIGS. 33, 34). The buttress threads 54 are coarse and square cut, with flat edges 55, and advantageously function to create a hydraulic seal through the interference fit between the threads 54 on the aperture 39b and mating threads 56 on the closure 52. The closure 52 comprises, in the preferred embodiment, a plastic plug which is threaded into the barrier module outer wall 12 by means of the interengaging buttress threads 54, 56, as described above. A sealing washer on the plug 52 seats, in a flat profile, on the sealing surface on the barrier wall 12 once the threads are engaged and tightened. This flat profile results in a lower chance of leakage, with no need to over-tighten the plug 52. Advantageously, the unique design results in a much reduced chance of cross-threading the plug when threading it into the wall, compared with prior art approaches, and it is much easier to start the thread of the plug into the barrier wall. Because of the recess 50, the plug 52 is flush or even recessed relative to the wall, which reduces the chances of damage to the plug during use. The thread 54 is uniquely cast-molded into the wall, which is typically roto-molded. Avoidance of spin-welding, which is a typical prior art technique for fabricating threads of this type in a roto-molded device, surprisingly greatly reduces the chance of damage to the barrier and closure due to cracking and stripping. Referring now to FIGS. 35-41, yet another modified embodiment of the present invention is illustrated, wherein like elements to those in the previous embodiments are designated by like reference numerals, preceded by the numeral 2. Thus, in FIGS. 35 and 36 a barrier module 210 is shown, which is similar in many respects to barrier module 110, but differs in ways that will be described herein. The barrier module 210 comprises forklift and pallet jack lift points 239 disposed on a bottom edge of the module, as well as a second set of forklift lift points 239 disposed above the first set. A drain aperture 239b is disposed between the two lower lift points 239. The drain aperture preferably employs the cap and buttress thread features illustrated and described in connection with FIGS. 32-34. A fill aperture 239a is disposed on a top surface of the module, having a diameter, in one preferred embodiment, of approximately 8 inches. Advantageously, the fill aperture also comprises a lid 58, which is molded with fittings designed to ensure water-tight securement with an easy ¼ turn of the lid. As illustrated, each barrier module weighs approximately 160 lb when empty, and approximately 2000 lb when filled with approximately 220 gallons of water. The module 210 is approximately 72 inches in length (excluding the lugs), 46 inches in height, and 22 inches wide. In the illustrated embodiment, the right side of each barrier module 210 preferably includes five lugs 218, while the left side comprises six lugs 218. These lugs are configured to be interleaved when two adjacent barrier modules 210 are joined, as in the prior embodiments, so that the pin receiving holes 224 are aligned for receiving a T-pin 226. The T-pin 226 comprises a T-pin handle 60 at its upper end, and a keeper pin 62 insertable through a hole in its lower end, as illustrated in FIG. 36. To join the barrier modules 210 together, the T-pin 226 is inserted downwardly through all of the aligned holes 224. Then, the keeper pin 62 is inserted through the hole in the lower end of the pin 226, to ensure that the T-pin cannot be inadvertently removed. In a preferred embodiment, the diameter of the T-pin is approximately 1¼″. Stacking lugs 64 are disposed on the top surface of each barrier module, and corresponding molded recesses 65 are disposed in the lower surface of the barrier module 210. Thus, as shown in FIGS. 42 and 43, the barrier modules 210 may be stacked vertically, with the stacking lugs 64 on the lower barrier module 210 engaging with their counterpart stacking recesses 65 on the upper barrier module 210. Two barrier modules, stacked vertically, have a total height of approximately 87 inches, in one preferred embodiment. One significant difference between the embodiment of FIGS. 19-31 and the embodiment of FIGS. 35-41 is the particular design of the sawtooth modules 240, 242, and 244. As is evident from inspection of the various figures, the latter embodiment retains substantially flat barrier side walls, with recesses into which the sawtooth modules extend, in an upward slanting direction, as shown. The resulting anti-climb function is similar to that of the FIGS. 19-31 embodiment, but the manufacturing process is greatly simplified. In one preferred embodiment, the angle of slant of each sawtooth module is approximate 43 degrees. Now, with reference particularly to FIGS. 37-41, details of the innovative wire rope cable system are illustrated. In this embodiment, an insertion sleeve or bushing 66 is molded into each lug or knuckle 218, where a wire rope cable 246 is placed. The bushing 66 is preferably cylindrical, and its interior diameter comprises the pin receiving hole 224 of the corresponding knuckle 218 in which the bushing is molded. The bushing 66 is preferably comprised of steel, though other suitable materials may be employed. As in prior embodiments, the wire rope cables preferably comprise ⅜ inch 7×19 galvanized steel cable, though other suitable materials may also be utilized. Because of the advantageous molding techniques of the present invention, which causes the cable loops 248 to be completely encapsulated in molded plastic, stainless steel cables need not be used. The inventors have found that galvanized braided carbon steel cable is stronger. Both the bushing 66 and the cable 246 is preferably hot-dipped galvanized. Each end of the steel cable 246 is extended around the bushing 66 to form eyelet or loop 248, and secured to the remaining cable 246 by a swage or clamp 68. The bushing 66 is sized to allow it to be inserted into the mold prior to molding. The assembly illustrated in FIG. 38 is then placed in the barrier module mold (not shown), together with the other similar assemblies, preferably four in total, as shown in FIG. 36, so that corresponding knuckles 218 on each side of the barrier are tied together by a wire rope cable assembly 246. The cables are relatively taut when placed into the mold. When the rotational molding process is completed, including the cooling of the barrier module, the cables become slack. The amount of slack contributes to the effectiveness of the bushing-cable assembly during an impact by allowing the plastic and the water to absorb some of the impact energy before the cables are engaged. The bushing and a portion of the cable loop become encapsulated in plastic as a result of the molding process, forming an integrally molded-in, leak-proof connection. In a preferred configuration, the bushing 66 comprises steps 70 at the top and bottom ends thereof. The bushing 66 is approximately 3⅛″ in length, with a 1½″ ID and a 1¾″ OD. The steps 70 are preferably approximately 0.095 inches, and serve to create an edge for plastic to form an extra thick layer around the top and bottom sections of the bushing during the molding process. By creating the thicker plastic layer in these portions, the sleeve edge design inherently prevents water from leaking at these top and bottom edges. This thicker plastic layer prevents water seepage from occurring between the steel and plastic mating surfaces. The entire assembly of a wire rope cable 246 and, on each end, a clamped loop 248 and bushing 66 is approximately 77½″ in length when taut, from the center of one bushing to the center of the other. An actual vehicular impact produces the following energy absorbing actions: 1. One or more of the high density polyethylene (HDPE) barrier modules which are impacted, slide, deform from the impact, and finally burst; 2. The water in each burst section is released and dispersed over a wide area; 3. The cables 246 are engaged and prevent breaching or climbing by the impacting vehicle of the barrier; 4. Many modules 210 of the barrier remain assembled together, but are moved during the impact. They are either dragged closer to the point of impact if they are in tension, or pushed away if they are in compression. It should be noted that relatively few barrier modules 210 will burst, depending upon the severity of the impact. Many modules will move and will remain undamaged, with a few having minor leaks which are readily repaired. The bushing 66 serves several advantageous purposes. First, it is a significant contributor to the molding process, making it easier to manufacture and minimizes leaks when the barrier module 210 is completed during the molding process. Also, during impact, the bushing spreads the impact load that is transmitted from the steel cables 246 to the knuckles 218, and the load is further transferred to the connecting pin 226. This ensures that the assembled barrier, comprised of a plurality of modules which are joined together, as shown in FIGS. 7, 8, 12, 13, 18, and 31, for example, will not be breached during an impact. Moreover, the location of the cables 246 prevents a vehicle from climbing over the wall during an impact. Crash tests conducted on the inventive barrier system demonstrate that the displacement of barrier walls formed of assembled barrier modules 210, upon vehicular impact, are displaced significantly less than is the case with competing prior art products. This is a considerable advantage, in that clear space required behind the barrier can be substantially less, meaning that less roadway area requires closure. It will also be noted, from review of the figures, that the knuckles 218 of this modified embodiment are differently constructed than those illustrated in the prior embodiments. In particular, in the prior embodiments, the knuckles do not extend substantially the full width of the barrier module. Rather, the outside radius of each knuckle meets a flat surface at the end of the barrier module, and the knuckle only extends about ¾ of the full width of the end wall. The flat surface then extends out to the outer profile of the module, creating the shape of the wall. Under certain conditions, this construction can cause tearing of the knuckles away from the end wall of the barrier module. Accordingly, the knuckles 218 in the embodiment of FIGS. 35-41 are designed to extend substantially the entire width of the barrier module, as shown, so that the knuckle radius meets the outer, lengthwise walls of the barrier module. This change surprisingly serves to significantly increase the strength of the walls of the barrier module. Another modified embodiment of the inventive concept may comprise barrier modules 210, molded in 3 foot lengths, with lug connections and cables, as shown and discussed above, for the purpose of functioning as a barricade end treatment. In this embodiment, the T-pins 226 extend downwardly through the connection lugs 218 and bushings 66, to ground. Such a device comprises a non-gating device, because, with the cable connections, a vehicle cannot get through it. This embodiment may comprise a cast “New Jersey” barrier wall, wherein one end is squared off. In this embodiment, female sockets are molded internally on the squared-off end, and sized the same as the male lugs on the other end, so that they fit together for reception of a drop or T-pin. This embodiment results in a flush connection between two adjoining barricade modules 210, which means there is no surface interruption and no relative rotation between those barrier modules. As noted above, the T-pin extends to ground, and into a hole drilled into the ground, so that there is no wall translation, thus creating the non-gating barrier. It is noted that there is no requirement that the barrier module 210 be ballasted with water. Alternative ballasts, particularly if dispersible, may be utilized. It is also within the scope of the invention, particularly if a particular module 210 is to be used as an end treatment, to fill the module with foam. The foam would be installed during the manufacturing process, and the fill and drain apertures could be eliminated. The cables 246 would still be used. Now, with reference to FIGS. 44-46, there is illustrated an array 72 of barrier modules, such as barrier modules 210 shown in FIGS. 35-41, connected end-to-end, using pin and lug connections as has been described previously in connection with prior embodiments. However, this array 72 is an end treatment array. End treatment arrays are known in the prior art, and have been briefly discussed above, in conjunction with prior disclosed embodiments. The concept of an end treatment or end treatment array is to secure a crash attenuating device to the front end of a substantially immovable structure, such as a bridge abutment, pillar, or the like, so that an impacting vehicle, rather than crashing directly into the substantially immovable structure, will impact the end treatment array and “ride down” before reaching the immovable structure, thereby protecting the vehicle occupants from serious injury or death. In the present invention, the end treatment array 72 comprises a plurality of barrier modules 210, secured to one another as shown, and as described above. However, on each end of the array 72 is positioned a transition barrier module 74. The transition barrier module 74 is illustrated more particularly in FIGS. 47-50 and 59-62, for example. In many respects, the transition barrier module 74 is constructed similarly to regular barrier modules 210, except that it is preferably differently colored, for ready identification. For example, in certain preferred embodiments, the transition barrier module 74 is yellow, while regular barrier modules 210 are orange and white. Additionally, because it is desired that the transition barrier module 74 always be empty, rather than filled with ballast, it may be constructed without a ballast fill hole, and may alternatively or additionally be constructed to have substantial (perhaps approximately 1½ inch diameter) holes near its base to ensure that the hollow barrier module 74 is never filled. A very significant improvement in the inventive end treatment array 72 is the employment of a containment impact sled 76, shown, for example, in FIGS. 45-54. The containment impact sled 76 comprises a frame having side frame members 78, 80, each joined to opposing edges of a front cap 82 and a floor portion 84 (FIG. 52). The frame is preferably made of galvanized steel, having a steel tube frame and sheet metal construction, though other suitable structural materials may also be used. The side frame members 78, 80 are each generally triangular in shape, each comprising, respectively, a bottom frame member 86, 88, extending lengthwise along the floor portion 84 from the front cap 82 to the opposing end of the floor portion 84, a cap end frame member 90, 92, and a top frame member 94, 96. The top frame member 94, 96 extends from an upper end of its respective cap end frame member 90, 92, and the front cap 82, downwardly toward the opposing end of each respective bottom frame member 86, 88, as shown in the drawings. Additional right frame brace members 98, 100 and left frame brace members 102, 104 are preferably employed to reinforce the strengthen the structural integrity of the containment impact sled 76. Thus, the containment impact sled 76 is a longitudinal energy disperser which comprises a structure having a defined volume, supported by the floor portion 84 and contained by the side frames 78, 80 and front cap 82. The function of this volume, as will be described below, is to collect and contain debris resultant from the impact of a vehicle with the barrier array 72, thus preventing that debris from flying about, striking adjacent people, vehicles, and/or structures, or collecting underneath the impacting vehicle and causing that vehicle to ride up over that debris and flip over, or “vault”. As illustrated in FIGS. 45-50, for example, the containment impact sled 76 is configured to be attached to one end of a transition barrier module 74. Attachment is accomplished by sliding the transition barrier module 74 into the sled 76, so that the barrier module 74 rests on the floor 84 of the sled 76. The barrier module 74 may be oriented in either direction, so that either end, i.e. the end having five lugs 218 or the end having six lugs 218, faces the inside surface of the front cap 82. This capability for dual orientation is shown, for example, in FIGS. 47-48 and 58, where the six lug end is secured to the front cap, and in FIGS. 49-50 and 57, where the five lug end is secured to the front cap. Once in place, the barrier module 74 is oriented so that a pin hole 106 in the front cap 82 is aligned with the pin holes 224 in each respective lug 218, as shown. A t-pin 108, as shown in FIGS. 55 and 56, is then disposed through the hole 106 and each lug hole 224 to secure the sled 76 to the barrier module 74. As noted above in connection with FIGS. 44-46, depicting the end treatment array 72, in addition to the end of the array 72 which includes the sled 76, there is a second transition barrier module 74 at the opposing end of the array, for the purpose of securing the array 72 to a fixed structural member which the array is positioned to shield from an impacting vehicle, such as a bridge abutment or the like. As is the case with the first transition barrier module 74, one end of this second transition barrier module is secured to an opposing end of a regular barrier module 210, as shown. However, the opposing end of this second transition barrier module 74 is fitted with end treatment hardware 410, which is shown as a set in FIGS. 63 and 64. This hardware 410 comprises a left panel 412, a right panel 414, a frame 416, a long pin 418, two short pins 420, and a cap panel 422 (FIG. 60). As shown in FIGS. 59-63, the end treatment hardware 410 is assembled to the end of the second barrier module 74. Specifically, the frame 416 comprises horizontal cross-members 424 secured at either end to short vertical hollow hinge posts 426. The horizontal cross-members 424 each include a pin hole 428. The frame 416 is assembled to the left and right panels 412, 414, respectively, by assembling the short vertical hollow hinge posts 426 to interleave with respect vertical hollow hinge posts 430 disposed on each of the left and right panels 412, 414, respectively, so that they are aligned. The short pins 420 are then inserted through each of the short vertical hollow hinge posts 426 and 430, as shown in FIG. 63, to thereby secure the frame 416 to each of the left and right panels 412 and 414. The securement method is such that the panels 412, 414 are pivotable relative to the frame 416, about the axis of each short pin 420. As shown in the Figures, at the same time the frame 416 is situated so that the pin holes 428 in each horizontal cross-member 424 of the frame 416 are interleaved with, and aligned with the pin holes in the lugs 218 of the barrier module 74. As shown, the end treatment hardware 410 can be adapted to fit to either the six-lug or five-lug end of the barrier module 74 by appropriately positioning the frame relative to the lugs. Once the holes in the lugs and in the frame cross-members 424 are aligned, the long pin 418 may be inserted through those aligned holes to join the hardware 410 to the barrier module 74. As shown in FIGS. 59-62, the cap panel 422 may be secured with the frame 416 to the barrier module. A significant advantage of the hardware system 410 is that, because of the hinged left and right panels 412, 414, the barrier module 74 may be secured to structures of differing sizes. To complete this attachment, the panels 412, 414 are pivoted until the extend rearwardly along the opposed sides of the abutment or other structure, at which time suitable fastening hardware 432 is inserted through the respective holes 434 in each panel to secure the panels respectively to each side of the abutment. In operation, when the end treatment array 72 is impacted by a vehicle, the empty forward barrier module 74 quickly crumples from the impact. The sled, joined to this module as described above, moves rearwardly as the module 74 crumples, scooping up and containing the debris within its volume onto its deck, thus preventing that debris from getting loose and potentially vaulting the vehicle. As the ensuing ballasted modules 210 deform, rupture, and release their ballast, the sled moves rearwardly into the array, scooping up additional deformed and ruptured modules and continuing to contain debris until the vehicle is safely stopped. The inventive system functions as a non-redirective, gating, crash cushion. Accordingly, although an exemplary embodiment of the invention has been shown and described, it is to be understood that all the terms used herein are descriptive rather than limiting, and that many changes, modifications, and substitutions may be made by one having ordinary skill in the art without departing from the spirit and scope of the invention. | <SOH> BACKGROUND OF THE INVENTION <EOH>The present invention relates generally to vehicle protection barriers, and more particularly to movable water ballasted vehicle traffic protection barriers for applications such as pedestrian protection, traffic work zone separation, airport runway divisions, and industrial commercial uses. | <SOH> SUMMARY OF THE INVENTION <EOH>The present invention comprises an end treatment array for attenuating the forces generated by a vehicular impact. The inventive end treatment array include a transition barrier module comprising first and second side walls, first and second end walls, a top wall, and a bottom wall, wherein the module walls together define a substantially enclosed interior space. The transition barrier module has a predetermined width and length. The end treatment array advantageously further includes an innovative containment impact sled which comprises an axially extending frame. The frame has a width sufficient to contain the transition barrier module within the frame when in an assembled configuration, and has an axial length which is at least one-half the length of the transition barrier module. The frame defines an interior volume, the purpose of which is to contain a substantial portion of the transition barrier module in the assembled configuration, and to contain debris caused by destruction of the plastic barrier modules in a vehicular impact. The containment impact sled is attached to the transition barrier module in the aforementioned assembled configuration. As noted above, the transition barrier module is fabricated of plastic. Importantly, the interior space is hollow and, unlike the regular barrier modules, is unfilled with any ballasting material for maximum initial energy absorption. The containment impact sled further comprises an upright wall connected to the frame which substantially covers the first front-facing end wall of the transition barrier module when the sled is in its assembled configuration, with the transition barrier module at least partially contained within the frame of the sled. The containment impact sled further comprises a floor. The containment impact sled frame comprises a first side frame member attached to one side of the floor and upright wall and a second side frame member attached to an opposing side of the floor and the upright wall. Each of the side frame members comprise a bottom frame member and a top frame member, wherein the bottom frame member is disposed substantially horizontally, and the top frame member extends downwardly at an angle from its frontmost end to its rearmost end, with the frontmost end of the top frame member being connected to the upright wall near a top of the upright wall and the rearmost end of the top frame member being connected to a rearmost end of the bottom frame member near ground level, such that each side frame member is triangular in shape. Apertures are provided in each of the transition barrier module and the sled, which are aligned when the transition barrier module and the sled are in the assembled configuration. A pin extends through the aligned apertures in the assembled configuration to attach the transition barrier module to the sled. The transition barrier module comprises a plurality of vertically spaced lugs on the first end wall, wherein each of the lugs have one of the apertures therein for receiving the pin. Additionally, one of the apertures is disposed in the upright wall of the sled. Preferably, the transition barrier module comprises holes in a lower end thereof to prevent the containment of ballasting material in the interior space. The end treatment array further comprises a plurality of vertically spaced lugs on the second transition barrier module end wall, for attaching the transition barrier module to a first end of an adjacent barrier module. In certain arrays, the adjacent barrier module is also a transition barrier module, constructed similarly to the first transition barrier module, and is also unfilled with ballasting material. The array further comprises a barrier module connected at a first end to the transition barrier module which is filled with a ballasting material, which is preferably water. It should be noted that it is within the scope of the present invention to employ any number of transition barrier modules and any number of ballasted barrier modules in the array, depending upon desired crash attenuation characteristics and particular roadway conditions. So, the use of the term “connected” or “attached” herein does not necessarily mean a direct connection or attachment, but could mean an indirect connection through intermediate modules, unless specific language used requires otherwise. Importantly, for ease of assembly by on-site personnel, the transition barrier modules and the ballast-filled barrier modules are differently colored. Another important aspect of the present invention is that the end treatment array comprises a second transition barrier module connected at a first end thereof to a second end of the barrier module, wherein the second transition barrier module is constructed substantially similarly to the first transition barrier module and is unfilled with ballasting material. This second end of the end treatment array is adapted for attachment to the fixed structure, such as a concrete abutment, which is being protected. Thus, end treatment hardware is provided for attaching a second end of the second transition barrier module to the fixed structure. The end treatment hardware, in disclosed embodiments, comprises a metal frame which is securable to the second end of the second transition barrier module. The frame comprises a plurality of vertically spaced horizontal cross members, each of which has an aperture in a middle portion thereof for receiving a pin, wherein in an assembled state the apertures are aligned. Additional components of the end treatment hardware are first and second hinge posts disposed at opposing ends of each of the assembled vertically spaced horizontal cross members, a first hinge pin, a second hinge pin, a left panel, and a right panel. The left panel is pivotally securable to aligned first hinge posts using the first hinge pin and the right panel is pivotally securable to aligned second hinge posts using the second hinge pin, so that the left and right panels can be rotated to extend along a length of the fixed structure. Each of the left and right panels have apertures therein for receiving hardware to secure each panel to the fixed structure. A pin is provided for insertion into the aligned apertures on each of the plurality of vertically spaced horizontal cross members. In another aspect of the invention, there is provided a containment impact sled for use in an end treatment array for attenuating the forces generated by a vehicular impact, which comprises a frame extending in an axial direction and comprising a first side frame member, a second side frame member spaced from the first side frame member, and an end frame member extending across a width of the frame and securing the first side frame member to the second side frame member. The frame members together define an interior space. The containment impact sled is adapted for attachment to an adjacent barrier module in an assembled end treatment array, in such a manner as to contain a substantial portion of the adjacent barrier module within the interior space when the end treatment array is assembled. The frame further comprises a floor attached to and extending between each of the side frame members and the end frame member, and further comprises an upright wall attached to a front end of the end frame member. The upright wall comprises an end cap. Each of the side frame members comprise a bottom frame member and a top frame member, wherein the bottom frame member is disposed substantially horizontally, and the top frame member extends downwardly at an angle from its frontmost end to its rearmost end, with the frontmost end of the top frame member being connected to the end frame member near a top of the end frame member and the rearmost end of the top frame member being connected to a rearmost end of the bottom frame member near ground level, such that each side frame member is triangular in shape. An aperture is provided in the upright wall for attaching the containment impact sled to an adjacent barrier module. The frame is preferably comprised of metal, though it would not necessarily have to be, if another suitably durable material were available. In yet another aspect of the invention, there is disclosed a method of assembling an end treatment array for protecting a fixed structure from an impact by a passing vehicle. The method comprises steps of securing a plurality of ballast-filled hollow plastic barrier modules together in an axial array and securing one end of a transition barrier module to one end of the array of ballast-filled hollow plastic barrier modules. The transition barrier module is unfilled with ballasting material. A further method step is to secure a containment impact sled to the other end of the transition barrier module, wherein the containment impact sled comprises a frame defining an interior space, and wherein the securing step includes disposing the frame about the transition barrier module so that a substantial portion of the transition barrier module is contained within the interior space. The securing step further comprises inserting a pin through aligned holes in both the containment impact sled and the transition barrier module and a step of securing a second transition barrier module to a second end of the axial array of ballast-filled barrier modules, wherein the second transition barrier module is unfilled with ballasting material. Additionally, the method comprises a step of securing the second transition barrier module to the fixed structure, using end treatment hardware comprising metal cross-members attached to the second transition barrier module and metal plates pivotally mounted to the metal cross-members. The invention, together with additional features and advantages thereof, may best be understood by reference to the following description taken in conjunction with the accompanying illustrative drawings. | E01F15145 | 20171017 | 20180510 | 63417.0 | E01F1514 | 1 | RISIC, ABIGAIL ANNE | END TREATMENTS AND TRANSITIONS FOR WATER-BALLASTED PROTECTION BARRIER ARRAYS | SMALL | 1 | CONT-ACCEPTED | E01F | 2,017 |
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15,786,958 | PENDING | PROCESS CARTRIDGE AND IMAGE FORMING APPARATUS | A process cartridge is detachably mountable to a main assembly of an electrophotographic image forming apparatus. The cartridge includes an electrophotographic photosensitive drum, a developing roller, a drum unit containing the drum, a developing unit containing the roller and being movable so the roller contacts and is spaced from the drum, and a first force receiver receiving a force from a main-assembly first force applier by movement of a door from open to closed positions when mounting the cartridge and a second force receiver movable from a stand-by position by movement of the first force receiver by a force received from the first force applier. The second force receiver takes a projected position receiving a force from the second force applier to move the developing unit so the roller moves out of contact with the drum, the projected position being higher than the stand-by position. | 1. A process cartridge detachably mountable to a main assembly of an electrophotographic image forming apparatus, the main assembly including an opening, a door movable between a close position for closing the opening and an open position for opening the opening, a first force application member movable with movement of the door from the open position to the closing position and a second force application member movable by a driving force from a driving source, said process cartridge comprising: an electrophotographic photosensitive drum; a developing roller for developing an electrostatic latent image formed on said electrophotographic photosensitive drum; a drum unit containing said electrophotographic photosensitive drum; a developing unit which contains said developing roller and which is movable relative to said drum unit such that developing roller is movable between a contact position in which said developing roller is contacted to said electrophotographic photosensitive drum and a spaced position in which said developing roller is spaced from said electrophotographic photosensitive drum; and a force receiving device including a first force receiving portion for receiving a force from the first force application member by movement of said door from the open position to the close position in the state that process cartridge is mounted to the main assembly of the apparatus through the opening, and a second force receiving portion movable from a stand-by position by movement of said first force receiving portion by a force received from the first force application member, wherein said second force receiving portion takes a projected position for receiving a force from the second force application member to move said developing unit from the contact position to the spaced position, the projected position being higher than the stand-by position. 2-24. (canceled) | FIELD OF THE INVENTION The present invention relates to a process cartridge in which an electrophotographic photosensitive drum and a developing roller actable on the electrophotographic photosensitive drum are contactable to each other and spaceable from each other, and an electrophotographic image forming apparatus to which the process cartridge is detachably mountable. RELATED ART In an image forming apparatus using an electrophotographic image forming process, a process cartridge type is conventional wherein an electrophotographic photosensitive drum and a developing roller actable on the electrophotographic photosensitive drum are unified into a process cartridge detachably mountable to a main assembly of the image forming apparatus. With the process cartridge type, the maintenance operation of the apparatus can be carried out in effect without a service person. Therefore, the process cartridge type is widely used in the field of electrophotographic image forming apparatus. When the image forming operation is carried out, the developing roller is kept urged to the electrophotographic photosensitive drum at a predetermined pressure. In a contact developing system in which a developing roller is contacted to the photosensitive drum during the developing operation, an elastic layer of the developing roller is in contact with the surface of the photosensitive drum at a predetermined pressure. Therefore, when the process cartridge is not used for a long time with the process cartridge kept mounted to the main assembly of the image forming apparatus, the elastic layer of the developing roller may be deformed. If this occurs, non-uniformity may result in the formed image. Since the developing roller is contacted to the photosensitive drum, a developer may be deposited from the developing roller to the photosensitive drum since the photosensitive drum and the developing roller are rotated in contact with each other even when the developing operation is not carried out. As a structure for solving this problem, there is provided an image forming apparatus in which when the image forming operation is not carried out, a mechanism acts on the process cartridge to space the developing roller from the electrophotographic photosensitive drum (Japanese Laid-open Patent Application 2003-167499). In the apparatus disclosed in this publication, four process cartridges are demountably mounted to the main assembly of the image forming apparatus. The process cartridge comprises a photosensitive member unit having a photosensitive drum, and a developing unit for supporting the developing roller swingably provided in the photosensitive member unit. By moving a spacing plate provided in the main assembly of the image forming apparatus, a force receiving portion provided in the developing unit receives a force from the spacing plate. By moving the developing unit relative to the photosensitive member unit, the developing roller moves away from the photosensitive drum. In the conventional example, the force receiving portion for spacing the developing roller from the photosensitive drum is projected from the outer configuration of the developing unit. Therefore, when the user handles the process cartridge, and/or when the process cartridge is transported, the force receiving portion tends to be damaged. The existence of the force receiving portion may hinder the downsizing of the process cartridge in which the electrophotographic photosensitive drum and the developing roller are contactable to each other and spaceable from each other and the main assembly of the image forming apparatus to which the process cartridge is detachably mountable. SUMMARY OF THE INVENTION Accordingly, it is a principal object of the present invention to provide a downsized process cartridge in which the electrophotographic photosensitive drum and the developing roller are contactable to each other and spaceable from each other and a downsized electrophotographic image forming apparatus to which the process cartridge is detachably mountable. It is another object of the present invention to provide a process cartridge in which the electrophotographic photosensitive drum and the developing roller are contactable to each other and spaceable from each other with which when the process cartridge is handled, or when the process cartridge is transported, the force receiving portion is not damaged. According to an aspect of the present invention, there is provided a process cartridge detachably mountable to a main assembly of an electrophotographic image forming apparatus. The main assembly includes an opening, a door movable between a closed position for closing the opening and an open position for opening the opening, a first force application member movable with movement of the door from the open position to the closing position and a second force application member movable by a driving force from a driving source. The process cartridge comprises: an electrophotographic photosensitive drum; a developing roller for developing an electrostatic latent image formed on the electrophotographic photosensitive drum; a drum unit containing the electrophotographic photosensitive drum; a developing unit which contains the developing roller and which is movable relative to the drum unit such that developing roller is movable between a contact position in which the developing roller is contacted to the electrophotographic photosensitive drum and a spaced position in which said developing roller is spaced from the electrophotographic photosensitive drum; and a force receiving device including a first force receiving portion for receiving a force from the first force application member by movement of the door from the open position to the closed position in the state that process cartridge is mounted to the main assembly of the apparatus through the opening, and a second force receiving portion movable from a stand-by position by movement of the first force receiving portion by a force received from the first force application member. The second force receiving portion takes a projected position for receiving a force from the second force application member to move the developing unit from the contact position to the spaced position, the projected position being higher than the stand-by position. According to another aspect of the present invention, there is provided an electrophotographic image forming apparatus for forming an image on a recording material, to which a process cartridge is detachably mountable. The apparatus comprises (i) an opening; (ii) a door movable between a closed position for closing said opening and an open position for opening the opening; (iii) a first force application member movable with movement of the door from the open position to the closed position; (iv) a second force application member movable by a driving force from a driving source; and (v) mounting means for detachably mounting a process cartridge. The process cartridge includes an electrophotographic photosensitive drum, a developing roller for developing an electrostatic latent image formed on the electrophotographic photosensitive drum, a drum unit containing the electrophotographic photosensitive drum, a developing unit which contains the developing roller and which is movable relative to the drum unit such that developing roller is movable between a contact position in which the developing roller is contacted to the electrophotographic photosensitive drum and a spaced position in which the developing roller is spaced from the electrophotographic photosensitive drum, and a force receiving device including a first force receiving portion for receiving a force from the first force application member by movement of the door from the open position to the closed position in the state that the process cartridge is mounted to a main assembly of the apparatus through the opening, and a second force receiving portion movable from a stand-by position by movement of the first force receiving portion by a force received from the first force application member. The second force receiving portion takes a projected position for receiving a force from the second force application member to move the developing unit from the contact position to the spaced position, the projected position being higher than the stand-by position. The apparatus also includes feeding means for feeding the recording material. These and other objects, features and advantages of the present invention will become more apparent upon a consideration of the following description of the preferred embodiments of the present invention taken in conjunction with the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 illustrates a general arrangement of an electrophotographic image forming apparatus according to a first embodiment of the present invention. FIG. 2 is a sectional view of a process cartridge according to the first embodiment of the present invention. FIG. 3 illustrates a general arrangement of an electrophotographic image forming apparatus according to a first embodiment of the present invention. FIG. 4 illustrates exchange of a process cartridge according to the first embodiment of the present invention. FIG. 5 is a sectional view of the process cartridge as seen in the direction of an axial direction of the photosensitive drum according to the first embodiment of the present invention. FIG. 6 is a sectional view of the process cartridge as seen in the direction of an axial direction of the photosensitive drum according to the first embodiment of the present invention. FIG. 7 is a sectional view of the process cartridge as seen in the direction of an axial direction of the photosensitive drum according to the first embodiment of the present invention. FIG. 8 is a sectional view of the process cartridge as seen in the direction of an axial direction of the photosensitive drum according to the first embodiment of the present invention. FIG. 9 is a perspective view of the process cartridge as seen from drives side according to the first embodiment of the present invention. FIG. 10 is a perspective view of the process cartridge as seen from the drive side according to the first embodiment the present invention. FIG. 11 is a perspective view of the process cartridge as seen from a non-driving side according to the first embodiment the present invention. FIG. 12 is a perspective view of the process cartridge as seen from a non-driving side according to the first embodiment the present invention. FIG. 13 is a perspective view of the process cartridge as seen from a non-driving side according to the first embodiment the present invention. FIG. 14 is a perspective view of the process cartridge as seen from a non-driving side according to the first embodiment the present invention. FIG. 15 is a perspective view showing a force receiving device of the process cartridge according to the first embodiment of the present invention. FIG. 16 is a perspective view showing a force receiving device of the process cartridge according to the first embodiment of the present invention. FIG. 17 is a perspective view showing a force receiving device of the process cartridge according to the first embodiment of the present invention. FIG. 18 is a perspective view showing a force receiving device of the process cartridge according to the first embodiment of the present invention. FIG. 19 is a perspective view showing a force receiving device of the process cartridge according to the first embodiment of the present invention. FIG. 20 is a perspective view showing a force receiving device of the process cartridge according to the first embodiment of the present invention. FIG. 21 is a perspective view showing a force receiving device of the process cartridge according to the first embodiment of the present invention. FIG. 22, parts (a) and (b), illustrates a process cartridge according to the first embodiment of the present invention wherein a first force receiving member and a second force receiving member are worked on by a first force receiving member and a second force receiving member of the electrophotographic image forming apparatus. FIG. 23 shows the general arrangement of the electrophotographic image forming apparatus according to the first embodiment of the present invention. FIG. 24 shows a general arrangement of the electrophotographic image forming apparatus according to the first embodiment of the present invention. FIG. 25 shows a general arrangement of the electrophotographic image forming apparatus according to the first embodiment of the present invention. FIG. 26 shows a general arrangement of the electrophotographic image forming apparatus according to the first embodiment of the present invention. FIG. 27, parts (a) and (b) illustrates an operation of a first force application member according to the first embodiment of the present invention. FIG. 28, parts (a) and (b), illustrates a second force application member operation according to the first embodiment of the present invention. FIG. 29 is a perspective view of the electrophotographic image forming apparatus according to the first embodiment of the present invention. FIG. 30 is a perspective view of the electrophotographic image forming apparatus according to the first embodiment of the present invention. FIG. 31 illustrates exchange of the process cartridge according to the first embodiment of the present invention. FIG. 32 illustrates exchange of the process cartridge according to the first embodiment of the present invention. FIG. 33 is a sectional view of the process cartridge as seen in the axial direction of the photosensitive drum according to the first embodiment of the present invention, illustrating an operation of the force receiving member of the process cartridge. FIG. 34 is a sectional view of the process cartridge as seen in the axial direction of the photosensitive drum according to the first embodiment of the present invention, illustrating an operation of the force receiving member of the process cartridge. FIG. 35 is a sectional view of the process cartridge as seen in the axial direction of the photosensitive drum according to the first embodiment of the present invention, illustrating an operation of the force receiving member of the process cartridge. FIG. 36 illustrates a spacing operation in the process cartridge according to the first embodiment of the present invention. FIG. 37 illustrates a spacing operation in the process cartridge according to the first embodiment of the present invention. FIG. 38 illustrates a spacing operation in the process cartridge according to the first embodiment of the present invention. FIG. 39 shows a general arrangement of an electrophotographic image forming apparatus according to a second embodiment of the present invention. FIG. 40 shows a general arrangement of the electrophotographic image forming apparatus according to the second embodiment of the present invention. FIG. 41 shows a general arrangement of the electrophotographic image forming apparatus according to the second embodiment of the present invention. FIG. 42, parts (a) and (b), illustrates an operation of a first force applying operation member of the electrophotographic image forming apparatus according to the second embodiment of the present invention. FIG. 43 is an illustration of an operation of the first force application member according to the second embodiment of the present invention. FIG. 44 is an illustration of an operation of the first force application member according to the second embodiment of the present invention. FIG. 45 is an illustration of an operation of the first force application member according to the second embodiment of the present invention. FIG. 46 is a sectional view of the process cartridge as seen in the axial direction of the photosensitive drum according to the second embodiment of the present invention. FIG. 47 illustrates a sectional view of the process cartridge as seen in the axial direction of the photosensitive drum according to the second embodiment of the present invention, illustrating a force receiving device of the process cartridge. FIG. 48 illustrates a sectional view of the process cartridge as seen in the axial direction of the photosensitive drum according to the second embodiment of the present invention, illustrating a force receiving device of the process cartridge. FIG. 49 illustrates a sectional view of the process cartridge as seen in the axial direction of the photosensitive drum according to the second embodiment of the present invention, illustrating a force receiving device of the process cartridge. FIG. 50 illustrates a sectional view of the process cartridge as seen in the axial direction of the photosensitive drum according to the second embodiment of the present invention, illustrating a force receiving device of the process cartridge. FIG. 51 is a sectional view of a process cartridge according to a third embodiment of the present invention, illustrating an operation of a force receiving member of the process cartridge. FIG. 52 is a sectional view of the process cartridge according to the third embodiment of the present invention, illustrating the operation of the force receiving member of the process cartridge. FIG. 53 is a sectional view of the process cartridge according to the third embodiment of the present invention, illustrating the operation of a force receiving member of the process cartridge. FIG. 54 is a sectional view of the process cartridge according to the third embodiment of the present invention, illustrating the operation of a force receiving member of the process cartridge. FIG. 55 is a sectional view of a process cartridge as seen in the axial direction of the photosensitive drum according to a fourth embodiment of the present invention, illustrating a force receiving device of the process cartridge. FIG. 56 is a sectional view of the process cartridge as seen in the axial direction of the photosensitive drum according to the fourth embodiment of the present invention, illustrating a force receiving device of the process cartridge. FIG. 57 is a sectional view of the process cartridge as seen in the axial direction of the photosensitive drum according to the fourth embodiment of the present invention, illustrating the force receiving device of the process cartridge. FIG. 58 is a sectional view of the process cartridge as seen in the axial direction of the photosensitive drum according to the fourth embodiment of the present invention, illustrating a force receiving device of the process cartridge. FIG. 59 is a perspective view of a process cartridge according to a fifth embodiment of the present invention, as seen from a drive side. FIG. 60 is a perspective view of the process cartridge according to a fifth embodiment of the present invention, as seen from a drive side. FIG. 61 is a sectional view of a process cartridge according to a sixth embodiment of the present invention. FIG. 62 is a sectional view of the process cartridge according to the sixth embodiment of the present invention. FIG. 63 is a sectional view of the process cartridge according to the sixth embodiment of the present invention. FIG. 64 is a sectional view of the process cartridge according to the sixth embodiment of the present invention. FIG. 65 is a perspective view of a process cartridge according to a seventh embodiment, illustrating a force receiving device of a process cartridge. FIG. 66 is a perspective view of the process cartridge according to the seventh embodiment, illustrating the force receiving device of a process cartridge. FIG. 67 is a perspective view of the process cartridge according to the seventh embodiment, illustrating the force receiving device of a process cartridge. FIG. 68 is a perspective view of the process cartridge according to the seventh embodiment, illustrating the force receiving device of a process cartridge. DESCRIPTION OF THE PREFERRED EMBODIMENTS First Embodiment FIGS. 1-4 show the process cartridge and the electrophotographic image forming apparatus according to the first embodiment of the present invention. FIG. 1 shows an electrophotographic image forming apparatus (main assembly of the apparatus) 100 including process cartridges (cartridges) 50y, 50m, 50c, 50k detachably mounted thereto. The cartridges 50y, 50m, 50c, 50k contain or accommodate yellow color toner (developer), magenta color toner (developer), cyan color toner (developer) and black color toner (developer), respectively. FIG. 2 is a sectional side elevation of the cartridge alone; FIGS. 3 and 4 are illustrations of removing the cartridges 50y, 50m, 50c, 50k from the main assembly 100 of the apparatus. General Arrangement of Electrophotographic Image Forming Apparatus As shown in FIG. 1, in the main assembly 100 of the apparatus, the electrophotographic photosensitive drums (photosensitive drums) 30y, 30m, 30c, 30k are exposed to the laser beams 11 modulated in accordance with the image signal by the laser scanner 10, so that electrostatic latent images are formed on the surfaces thereof. The electrostatic latent images are developed by developing rollers 42 into toner images (developed images) on the respective surfaces of the photosensitive drums 30. By applying voltages to the transfer rollers 18y, 18m, 18c, 18k, the toner images of respective colors formed on the photosensitive drums 30y, 30m, 30c, 30k are sequentially transferred onto the transfer belt 19. Thereafter, the toner image formed on the transfer belt 19 is transferred by the transfer roller 3 onto the recording material P fed by the feeding roller 1 (feeding means). Thereafter, the recording material P is fed to the fixing unit 6 including a driving roller and a fixing roller containing a heater. Here, by applying heat and pressure on the recording material P, the toner image transferred onto the recording material P is fixed. Thereafter, the recording material having the toner image fixed thereon is discharged to a discharging portion 9 by a pair 7 of discharging rollers. General Arrangement of Process Cartridge Referring to FIGS. 1, 2, 5 and 22, 29, 30, the cartridges 50y, 50m, 50c and 50k of this embodiment will be described. Since the cartridges 50y, 50m, 50c, 50k are all the same except that the colors contained therein are different from each other, the following description will be made only as to the cartridge 50y. The cartridge 50yincludes a photosensitive drum 30, and process means actable on the photosensitive drum 30. The process means includes a charging roller 32 functioning as charging means for charging electrically the photosensitive drum 30, a developing roller 42 functioning as developing means for developing a latent image formed on the photosensitive drum 30, and/or a blade 33 functioning as cleaning means for removing residual toner remaining on the surface of the photosensitive drum 30. The cartridge 50y comprises a drum unit 31 and a developing unit 41. Structure of Drum Unit As shown in FIGS. 2, 10, the drum unit 31 contains the photosensitive drum 30, the charging means 32, the cleaning means 33, the residual toner accommodating portion 35, the drum frame 34, and the covering members 36, 37. One longitudinal end of the photosensitive drum 30, as shown in FIG. 9, is supported rotatably by a supporting portion 36b of the covering member 36. The other longitudinal end of the photosensitive drum 30, as shown in FIG. 11-FIG. 14, is rotatably supported by a supporting portion 37b of a covering member 37. The covering members 36, 37 are fixed to the drum frame 34 at the opposite longitudinal ends of the drum frame 34. As shown in FIGS. 9, 10, one longitudinal end of the photosensitive drum 30 is provided with a coupling member 30a for receiving a driving force for rotating the photosensitive drum 30. The coupling member 30a is engaged with first main assembly coupling member 105 shown in FIGS. 4, 30 when the cartridge 50y is mounted to the main assembly 100 of the apparatus. The photosensitive drum 30 is rotated in the direction of an arrow u as shown in FIG. 2 by a driving force transmitted from a driving motor (unshown) provided in the main assembly 100 of the apparatus to the coupling member 30a. The charging means 32 is supported on the drum frame 34 and is rotated by the photosensitive drum 30 to which the charging means 32 is contacted. The cleaning means 33 is supported by the drum frame 34 and is contacted to the peripheral surface of the photosensitive drum 30. The covering members 36, 37 are provided with supporting hole portions 36a, 37a for rotatably (movably) supporting the developing unit 41. Structure of Developing Unit As shown in FIG. 2, the developing unit 41 contains the developing roller 42, the developing blade 43, the developing device frame 48, the bearing unit 45 and the covering member 46. The developing device frame 48 comprises a toner accommodating portion 49 for accommodating the toner to be supplied to the developing roller 42, and a developing blade 43 for regulating a layer thickness of the toner of the peripheral surface of the developing roller 42. As shown in FIG. 9, the bearing unit 45 is fixed to the one longitudinal end side of the developing device frame 48, and supports rotatably the developing roller 42 having a developing roller gear 69 at the end thereof. The bearing unit 45 is provided with a coupling member 67, and an idler gear 68 for transmitting a driving force to the developing roller gear 69 from the coupling member 67. The covering member 46 is fixed to the longitudinally outside of the bearing unit 45 so as to cover the coupling member 67 and the idler gear 68. The covering member 46 is provided with a cylindrical portion 46b which is projected beyond the surface of the covering member 46. The coupling member 67 is exposed through an inside opening of the cylindrical portion 46b. Here, the coupling member 67 is engaged with the second main assembly coupling member 106 shown in FIG. 30 to transmit the driving force from the driving motor (unshown) provided in the main assembly 100 of the apparatus when the cartridge 50y is mounted to the main assembly 100 of the apparatus. Assembling of Drum Unit and Developing Unit As shown in FIGS. 9 and 11 to FIG. 14, when the developing unit 41 and the drum unit 31 are assembled with each other, an outside circumference of the cylindrical portion 46b is engaged with the supporting hole portion 36a at one end side, and the projected portion 48b projected from the developing device frame 48 is engaged with the supporting hole portion 37a at the other end side. By doing so, the developing unit 41 is rotatably supported relative to the drum unit 31. As shown in FIG. 2, the developing unit 41 is urged by the urging spring 95 (elastic member) so that developing roller 42 rotates about the cylindrical portion 46b and the projected portion 48b to contact to the photosensitive drum 30. More specifically, the developing unit 41 is urged in the direction of an arrow G by the urging force of the urging spring 95 so that the developing unit 41 receives a moment H about the cylindrical portion 46b and the projected portion 48b. By this, the developing roller 42 can be contacted to the photosensitive drum 30 with a predetermined pressure. The position of the developing unit 41 at this time is “contact position”. As shown in FIG. 10, the urging spring 95 of this embodiment is provided on the end which is opposite the one longitudinal end provided with the coupling member 30a for the photosensitive drum 30 and with the coupling member 67 for the developing roller gear 69. Because of such a structure, the force g (FIG. 6) received by the first force receiving member 75 of a force receiving device 90 (which will be described hereinafter) which is provided on the one longitudinal end, from the first force application member 61, produces a moment about the cylindrical portion 46b in the developing unit 41. In other words, at the one longitudinal end, the moment h thus produced is effective to urge the developing roller 42 to the photosensitive drum 30 with a predetermined pressure. At the other end, the urging spring 95 functions to urge the developing roller 42 to the photosensitive drum 30 with a predetermined pressure. Force Receiving Device As shown in FIG. 2, the cartridge 50y is provided with a force receiving device 90 for effecting contact and spacing between the developing roller 42 and the photosensitive drum 30 in the main assembly 100 of the apparatus. As shown in FIGS. 9, 15 and FIG. 19, the force receiving device 90 includes a first force receiving member 75, a second force receiving member 70 and a spring 73 (urging means). As shown in FIG. 9, the first force receiving portion 75 is mounted to the bearing unit 45 by engaging an engaging portion 75d of the first force receiving member with a guide portion 45b of the bearing unit 45. On the other hand, the second force receiving member 70 is mounted to the bearing unit 45 by engaging a shaft 70a of the second force receiving member 70 with the guide portion 45a of the bearing unit 45. The bearing unit 45 thus having the first force receiving member 75 and the second force receiving member 70 is fixed to the development accommodating portion 48, and then as shown in FIG. 10, the covering member 46 is fixed so as to cover the bearing unit 45 from an outside in the axial direction of the developing roller 42 of the bearing unit 45. The first force receiving member 75 and the second force receiving member 70 are disposed above the cartridge 50y in the state that cartridge 50y is mounted to the main assembly 100 of the apparatus. The operations of the force receiving device 90 will be described in detail hereinafter. Drawer Member of Main Assembly of Electrophotographic Image Forming Apparatus A description will be provided as to a cartridge tray 13, which is a drawer member. As shown in FIG. 4, the cartridge tray 13 is movable (inserting and drawing) along a rectilinear line which is substantially horizontal (D1, D2 directions) relative to the main assembly 100 of the apparatus. More particularly, the cartridge tray 13 is movable between a mounted position in the main assembly 100 of the apparatus shown in FIG. 1 and a drawn-out position outside the main assembly 100 of the apparatus shown in FIG. 4. In the state that cartridge tray 13 is at the drawn-out position, the cartridges 50y, 50m, 50c, 50k are mounted on the cartridge tray 13 by the operator substantially vertically (arrow C) as shown in FIG. 4. The cartridges 50y, 50m, 50c, 50k are arranged in parallel with each other such that longitudinal directions (axial directions of the photosensitive drum 30 and the developing roller 42) thereof are substantially perpendicular to the moving direction of the cartridge tray 13. The cartridges 50y, 50m, 50c, 50k enter into the main assembly 100 of the apparatus while being carried on the cartridge tray 13. At this time, the cartridges 50y, 50m, 50c, 50k are moved keeping a distance (gap f2) (FIG. 5) between the intermediary transfer belt 19 provided below them and the photosensitive drum 30. When the cartridge tray 13 is positioned at the mounted position, the cartridges 50y, 50m, 50c, 50k are positioned in place by the positioning portion 101a provided in the main assembly of the image forming apparatus 100. The positioning operation will be described in detail hereinafter. Therefore, the user can mount with certainty the cartridges 50y, 50m, 50c, 50k into the main assembly 100 of the apparatus by entering the cartridge tray 13 and closing the door 12. Therefore, the operationality is improved over the structure with which the cartridges 50y, 50m, 50c, 50k are mounted individually into the main assembly 100 of the apparatus by the user. Referring to FIGS. 23 to 25 and 36 to 38, the operation of the cartridge tray 13 will be described. Here, the cartridges are omitted for simplicity of explanation of the operation of the cartridge tray 13. The cartridge tray 13 is supported drawably relative to a tray holding member 14. The tray holding member 14 is movable in interrelation with movement of the door 12 (opening and closing member). The door 12 is provided on the main assembly 100 of the apparatus and is rotatable about a rotational center 12a. When the cartridge is taken out of the main assembly 100 of the apparatus, the door 12 is moved from the closed position to the open position. With the movement of the door 12, an engaging portion 15 provided on the door 12 moves clockwise about the rotational center 12a. Then, as shown in FIG. 24, the engaging portion 15 moves from the lower end 14c2 toward the upper end 14c1 in the elongated hole 14c provided in the tray holding member 14. Together with this operation, the engaging portion 15 moves the holding member 14 in the direction z1. At this time, as shown in FIG. 25, the projections 14d1, 14d2 projected from the tray holding member 14 are guided by a guide slot or groove 107 provided in the main assembly 100 of the apparatus. As shown in FIG. 26, the guide groove includes a horizontal portion 107a1, an inclined portion 107a2 extending from the horizontal portion 107a1 and inclining upwardly and a horizontal portion 107a3 extending from the inclined portion 107a2. Therefore, as shown in FIG. 24, when the door 12 is moved to the open position, the projections 14d1, 14d2 are guided along horizontal portion 107a1, the inclined portion 107a2 and the horizontal portion 107a3 in this order. Thus, the tray holding member 14 moves in the direction of arrow z1 and in the direction of an arrow y1 away from the transfer belt 19. In this state, as shown in FIG. 25, the cartridge tray 13 can be drawn toward outside of the main assembly 100 of the apparatus in the direction of an arrow D2 through the opening 80. FIG. 30 is a partly broken perspective view of this state. A description will be provided as to the case of mounting the cartridge into the main assembly 100 of the apparatus. In the state that door 12 is at the open position as shown in FIG. 25 , the cartridge tray 13 enters the main assembly 100 of the apparatus in the direction of the arrow D1 through the opening 80. Thereafter, as shown in FIG. 23, the door 12 is moved to the closing position. With the movement of the door 12, the engaging portion 15 provided on the door 12 moves counterclockwise about the rotational center 12a. Then, as shown in FIG. 23, the engaging portion 15 moves along the elongated hole 14c provided in the tray holding member 14 toward the lower end 14c2 of the elongated hole 14c. Together with this operation, the engaging portion 15 moves the holding member 14 in the direction z2. Therefore, as shown in FIG. 23, when the door 12 is moved to the closing position, the projections 14d1, 14d2 are guided by the horizontal portion 107a3, the inclined portion 107a2 and the horizontal portion 107a1 in this order. Thus, the tray holding member 14 moves in the direction z2, and moves in the direction of an arrow y2 toward the transfer belt 19. Positioning of Process Cartridge Relative to Main Assembly of Electrophotographic Image Forming Apparatus Referring to FIGS. 5, 15 and FIGS. 19, 27, 29, 30, a description will be provided as to the positioning of the cartridges 50y, 50m, 50c, 50k relative to the main assembly 100 of the apparatus. As shown in FIG. 30, there are provided positioning portions 101a for positioning the cartridges 50y, 50m, 50c, 50k in the main assembly 100 of the apparatus. The positioning portions 101a are provided for the respective cartridges 50y, 50m, 50c, 50k interposing the transfer belt 19 with respect to the longitudinal direction. As shown in FIG. 27, parts(a) and (b), a first force application member 61 is rotatably supported by the supporting shaft 55 of the main assembly 100 of the apparatus engaged with the supporting hole 61d at a position above the tray holding member 14. As shown in FIG. 27, parts (a) and (b), the first force application member 61 moves with the movement of the door 12 from the open position to the closing position. As shown in FIG. 20, the projected portion 61f provided on the first force application member 61 urges the projection 31a provided on the upper surface portion of the drum frame 34. By this, the cartridge 50y is urged in the direction of an arrow P (FIG. 19), so that the portion to be positioned 31b (FIG. 7) provided on the drum unit 31y is abutted to the positioning portion 101a provided in the main assembly 100 of the apparatus by which the cartridge 50y is positioned in place (FIG. 6). The same operation is carried out adjacent the opposite longitudinal ends. Also, the same operation is carried out for the other cartridges 50m, 50c, 50k. The mechanism for movement of the first force application member 61 in interrelation with the movement of the door 12 will be described. The first force application member 61 is engaged with a connecting member 62 for interrelation with the movement of the door 12. As shown in FIG. 15 to FIG. 19, the connecting member 62 includes a supporting hole 62c engaged with the supporting shaft 55, a hole 62a engaged with the projected portion 61f, and a supporting pin 62b engaged with the elongated hole 14b (FIG. 27, part (b)) provided in the tray holding member 14. As shown in FIG. 27, parts (a) and (b), by the movement of the door 12 from the open position to the closed position, the tray holding member 14 moves in the direction of the arrow y2 (FIG. 27, parts (a) and (b)). By this, the supporting pin 62b engaged with the elongated hole 14b also receives the force in the direction of the arrow y2. Therefore, the connecting member 62 rotates in the direction of an arrow Z (Figure, parts 27(a) and (b)) about the supporting hole 62c. As shown in FIG. 19, between the first force application member 61 and the connecting member 62, there is provided a spring 66. The spring 66 is supported by the supporting shaft 55, and is contacted to the projection 62e provided on the connecting member 62 and to the projected portion 61f provided on the first force application member 61. By the urging force of the spring 66, the projected portion 61f urges the projection 31a provided on the drum frame 34 in the direction of an arrow P so as to position the cartridges 50y, 50m, 50c, 50k to the positioning portions 101a of the main assembly 100 of the apparatus. As shown in FIG. 21, the projection 31a may be urged directly by the spring 66. Thus, the structure for the connecting member 62 to interrelate with the movement of the door 12 is same as with FIG. 15 to FIG. 20. When the door 12 is at the open position, one end 66b of the spring 66 is engaged with the hook 62e provided on the connecting member 62, and the other end 66b of the spring 66 is engaged with the projection 62f provided on the connecting member 62. By the door 12 moving from the open position to the closed position, the other end 66b moves away from the projection 62f and directly urges the projection 31a to position the cartridges 50y, 50m, 50c, 50k to the positioning portion 101a of the main assembly 100 of the apparatus. Spacing Mechanism of Main Assembly of Electrophotographic Image Forming Apparatus Referring to FIG. 5 to FIG. 8 and FIG. 11 to FIG. 19, a description will be provided as to the mechanism for operating the force receiving device 90 provided on the cartridge 50y. FIG. 5-FIG. 8 are sectional views of the cartridge as seen in the axial direction of the photosensitive drum 30, and FIG. 11-FIG. 14 are perspective views as seen from the non-driving side of the cartridge 50y. The state shown in FIG. 5 corresponds to the state shown in FIG. 11 and to the state shown in FIG. 15. The state shown in FIG. 6 corresponds to the state shown in FIG. 12 and to the state shown in FIG. 16. The state shown in FIG. 7 corresponds to the state shown in FIG. 13, and the state of FIG. 8 corresponds to the state of FIG. 14. As described hereinbefore, with the closing operation of the door 12 from the open position, the first force application member 61 moves about the supporting shaft 55 from the state of FIGS. 5, 11 and 15 to the state of FIGS. 6, 12, 16. At this time, the first force application member 61 not only positions the cartridge 50y relative to the main assembly 100 of the apparatus but also acts on the first force receiving member 75 of the cartridge 50y. More particularly, an urging portion 61e of the first force application member 61 abuts the first urged portion of the first force receiving member 75. Thereafter, the first force receiving member 75 biases the cam surface 70c (third urged portion) provided in the second force receiving member 70 by which the second force receiving member 70 is rotated about the shaft 70a. Then, the second force receiving member 70 is moved from the stand-by position as shown in FIGS. 5, 11, 15 to an outside of the developing unit 41 of the cartridge 50y, that is, away from the rotation axis 46b of the developing unit 41. With the structure shown in FIG. 21, the projected portion 62g projected from the connecting member 62 functions as the first force application member 61. Referring to FIG. 28, parts (a) and (b), a description will be provided as to the operation of the second force applying portion 60. A driving force from a motor 110 (driving source) provided in the main assembly 100 of the apparatus is transmitted to the gear 112 by way of the gear 111. The gear 112 receiving the driving force rotates in the direction of an arrow L to rotate a cam portion 112a provided integrally with the gear 112 in the direction of the arrow L. The cam portion 112a is engaged with a shifting force receiving portion 60b provided on the second force application member 60. Therefore, with rotation of the cam portion 112a, the second force application member 60 moves in the direction of an arrow E or B. FIG. 28, part (a), illustrates the case in which the second force application member 60 moves in the direction of the arrow E and in which the developing roller 42 and the photosensitive drum 30 are still in contact with each other (FIG. 7). FIG. 28, part (b), illustrates the case in which the second force application member 60 moves in the direction of the arrow B and in which the second force receiving member 70 receives a force from the engaging rib 60y. By doing so, the developing unit 41 is rotated (moved) about the rotation axis 46b, so that developing roller 42 and the photosensitive drum 30 become spaced from each other. The position of the developing unit 41 at this time is a spaced position. As shown in FIG. 15, the second force application member 60 is provided with an elongated hole portion 60c for permitting movement of a supporting shaft 55 on which the first force application member 61 is provided rotatably. Therefore, even when the second force application member 60 moves in the direction of the arrow B (FIG. 8) or in the direction of the arrow E (FIG. 7), the second force application member 60 can move without being disturbed by the first force application member 61. Similarly to the first force application member 61, the second force application member 60 is provided facing the movement path of the cartridges so as to be above the cartridges 50y, 50m, 50c, 50k entering the main assembly 100 of the apparatus on the cartridge tray 13. In the step of advancement of the cartridges 50y, 50m, 50c, 50k into the main assembly 100 of the apparatus, the second force receiving member 70 is kept at the stand-by position (FIG. 15). Therefore, the first force application member 61 and the second force application member 60 can be very close to the cartridges 50y, 50m, 50c, 50k as long as they do not interfere therewith, so that wasteful space can be removed. Therefore, the main assembly 100 of the apparatus can be downsized with respect to the vertical direction and the longitudinal direction of the cartridge 50y (axial direction of the photosensitive drum 30). The operation will be described hereinafter in detail. Mounting of Process Cartridge to Main Assembly of Electrophotographic Image Forming Apparatus and Operation of Force Receiving Device A description will be provided as to the series of operations from the mounting of the cartridges 50y, 50m, 50c, 50k to the main assembly 100 of the apparatus to the spacing of the developing roller 42 from the photosensitive drum 30. As shown in FIG. 4, the cartridges 50y, 50m, 50c, 50k are mounted from the top to the cartridge tray 13 drawn out to the drawn-out position in the direction of an arrow C. By moving the cartridge tray 13 in the direction of the arrow D1, the cartridges 50y, 50m, 50c, 50k are passed through the opening 80 into the main assembly 100 of the apparatus. Thus, in this embodiment, the cartridges 50y, 50m, 50c, 50k are inserted into the main assembly 100 of the apparatus in the direction substantially perpendicular to the axial direction of the photosensitive drum 30. As shown in FIGS. 31, 32, the cartridge 50y is mounted at the most downstream position in the cartridge tray 13 with respect to the inserting or entering direction. The cartridge 50y advances from the upstream side toward the downstream side below the first force application members 61k, 61c, 61m and the engaging ribs 60k, 60c, 60m of the second force application member 60, which are actable on the cartridges 50m, 50c, 50k. The cartridge 50m is mounted at the second position from the downstream side on the cartridge tray 13 with respect to the entering direction. The cartridge 50m advances from the upstream side toward the downstream side below the first force application members 61k, 61c and the engaging ribs 60k, 60c of the second force application member 60, which are actable on the cartridges 50c, 50k. The cartridge 50c is mounted at the third position from the downstream side on the cartridge tray 13 with respect to the entering direction. The cartridge 50c passes from the upstream side toward the downstream side below the engaging ribs 60k of the first force application member 61k and the second force application member 60, which are actable on the cartridge 50k. The most upstream cartridge 50k on the cartridge tray 13 with respect to the entering direction enters from the upstream side toward the downstream side such that second force receiving member 70 thereof passes below the first force application member 61 actable on the cartridge 50k. The passing of the second force receiving member 70 below the first force application member 61k from the upstream side toward the downstream side is the same with respect to the cartridges 50y, 50m, 50c. That is, when the process cartridge is inserted with the second force receiving member 70 projected, the first force application member 61 and the second force application member 60 have to be at an upper part so as to avoid interference of the second force receiving member 70 with the first force application member 61 and second force application member 60. However, if the second force receiving member 70 is at the stand-by position, the first force application member 61 and the second force application member 60 can be disposed close to the cartridges 50y, 50m, 50c, 50k without the necessity of taking into account the degree of projection of the second force receiving member 70. Therefore, the main assembly 100 of the apparatus can be downsized with respect to the vertical direction. In addition, as shown in FIGS. 31, 32, the positions of the force receiving device 90, the first force application member 61 and the second force application member 60 are such that the force receiving device 90 overlaps with the first force application member 61 and the second force application member 60 in the drum axial direction, and therefore, the cartridge can be downsized with respect to the longitudinal direction thereof. When the cartridge tray 13 is inserted into the main assembly 100 of the apparatus, a gap f1 is maintained between the second force application member 60 and the force receiving device 90 as shown in FIG. 5. Also, a gap f2 is maintained between the photosensitive drum 30 and the transfer belt 19. Therefore, the cartridges 50y, 50m, 50c, 50k can enter without interference with the main assembly 100 of the apparatus. Thereafter, as shown in FIG. 23, by moving the door 12 to the closed position, the tray holding member 14 moves in the direction of approaching the transfer belt 19 (arrow y2). A vertical component of the movement distance in the direction of an arrow y2 is f2. By doing so, as shown in FIG. 6, the cartridges 50y, 50m, 50c, 50k also move so that surface of the photosensitive drum 30 is brought into contact with the surface of the transfer belt 19. In this state, the gap f1 between the force receiving device 90 and the second force application member engaging portion 60 expands to f1+f2. In addition, by moving the door 12 to the closed position, the first force application member 61 is moved so that the projection 31a provided on the upper surface portion of the drum frame 34 is urged by the projected portion 61f. By this, as shown in FIG. 6, the positioning portions 31b of the cartridges 50y, 50m, 50c, 50k are abutted to the respective positioning portions 101a provided in the main assembly 100 of the apparatus, so that the cartridges 50y, 50m, 50c, 50k are positioned to the main assembly 100 of the apparatus. The cartridges 50y, 50m, 50c, 50k are prevented from moving in the direction of the arrow a (FIG. 1) in the main assembly 100 of the apparatus by engaging the shaft 36d provided on the covering member 36 shown in FIG. 10 with a rotation preventing portion 13a provided on the cartridge tray 13. The urging portion 61e of the first force application member 61 contacts and urges the urged portion 75a (FIG. 15) of the first force receiving member 75 positioned at the first position (FIG. 15). Thereafter, the first force receiving member 75 is moved in the direction of an arrow r to be positioned at the second position (FIG. 16). At the second position, the urging portion 75b urges the cam surface 70c of the second force receiving member 70 shown in FIG. 15. By doing so, the second force receiving member 70 rotates about the axis of the shaft 70a from the stand-by position to a position outside the developing unit 41 of the cartridges 50y, 50m, 50c, 50k, that is, in the direction away from the rotation axis 46b of the developing unit 41. However, at this time, the upper surface 70 of the second force receiving member 70 interferes with the lower surface of the engaging rib 60y of the second force application member 60 which is placed at the home position, by which the movement of the second force receiving member 70 is regulated by the engaging rib 60y (FIGS. 6, 12). The position of the second force receiving member 70 at this time is called regulating position. Here, this position is made the home position for the following reason: After the cartridges 50y, 50m, 50c, 50k are mounted to the main assembly 100 of the apparatus, the state is as shown in FIG. 8 until the image forming operation is carried out. More particularly, the second force application member 60 has been moved in the direction of the arrow B, so that engaging rib 60y urges the second force receiving member 70. In this state, the photosensitive drum 30 and the developing roller 42 are spaced from each other. In the state of FIG. 8, cartridges 50y, 50m, 50c, 50k are dismounted from the main assembly 100 of the apparatus. Thereafter, when cartridges 50y, 50m, 50c, 50k are mounted to the main assembly 100 of the apparatus again, the second force application member 60 is at the position shown in FIG. 8, and therefore, when the second force receiving member 70 moves from the stand-by position, it is contacted to the rib 60y. As shown in FIG. 8, the direction (arrow J) of the force received by the first force receiving member 75 from the first force application member 61 is substantially opposite the direction of the force received by the second force receiving member 70 from the second force application member 60. The surface of the second force receiving member 70 which receives the force from the second force application member 60 direction faces the direction of entrance of the cartridges 50y, 50m, 50c, 50k into the main assembly 100 of the apparatus. By selecting the direction of the receiving force, when the second force receiving member 70 receives the force from the second force application member 60, the developing unit 41 can be efficiently moved relative to the drum unit 31 with certainty. Furthermore, the state that photosensitive drum 30 and the developing roller 42 are spaced can be maintained stably. However, even when the movement of the second force receiving member 70 is limited by the engaging rib 60y, the force receiving device 90 including the second force application member 60 and the second force receiving member 70 is not damaged. As shown in FIG. 22, part (a), since the movement of the second force receiving member 70 is regulated, the movement of the urging portion 75b for urging the cam surface 70c is also regulated. Even if the urging portion 61e of the first force application member 61 further urges the urged portion 75a, an elastic portion 75c in the form of arch provided on the first force receiving member 75 flexes (elastic deformation). Therefore, even if the movement of the second force receiving member 70 is regulated, the force receiving device 90 is not damaged. And, when the second force application member 60 is moved from the position of FIGS. 6, 12 in the direction of the arrow E as shown in FIGS. 7, 13, the second force receiving member 70 moves outwardly of the cartridge 50y to enter the movement path of the engaging rib 60y. The position of the second force application member 60 at this time is called the projected position. Thus, the second force application member 60 is projected beyond the above-described stand-by position when it is at the projected position. The degree of projection of the second force receiving member 70 at the projected position is larger than the gap f1+f2 in order to engage with the second force application member 60. The operation of the second force application member 60 is carried out prior to the image formation after cartridges 50y, 50m, 50c, 50k are mounted to the main assembly 100 of the apparatus. Then, as shown in FIGS. 8, 14, the second force application member 60 moves in the direction of the arrow B, so that the side surface 70b which is the second urged portion of the second force receiving member 70 entering the movement path, receives the force from the engaging rib 60y. By doing so, the developing unit 41 rotates (moves) about the rotation axis 46b, so that developing roller 42 is spaced from the photosensitive drum 30 by a gap α. The second force receiving member 70 receives the force from the second force receiving member 70 in the projected position. Thus, as compared to a structure in which the second force receiving member moves toward the process cartridge and engages with the developing unit to effect the developing device spacing, the distance from the rotation axis 46b of the developing unit 41 can be made large. Therefore, the driving torque required for spacing the developing roller 42 from the photosensitive drum 30 can be made small. In addition, by the movement of the second force application member 60 in the direction of the arrow B, the position where the first force receiving member 75 is pushed by the first force application member 61 and the position where the second force receiving member 70 receives the force from the engaging rib 60y change with respect to the horizontal direction. In other words, the relation between a distance I shown in FIG. 7 and a distance II shown in FIG. 8 is distance I>distance II. The change of the distance is accommodated by the elastic portion 75c provided on the second force receiving member 70. As shown in FIG. 22, part (a), the elastic portion 75c is in the form of a flexible arch configuration. Inside the elastic portion 75c, there is provided a spring 76 which is an elastic member. The spring 76 prevents the elastic portion 75c from flexing beyond necessity and functions to restore the flexed elastic portion 75c. The arch configuration of the elastic portion 75c is not inevitable, and the elastic member may be a simple elastic member. In order to effect the image forming operation, the developing roller 42 is contacted to the photosensitive drum 30 by moving the second force application member 60 in the direction of the arrow E. By this, as shown in FIGS. 7, 13, the second force receiving member 70 is brought into a state of not receiving the force from the engaging rib 60y. Therefore, by the urging force of the spring 95 provided between the developing unit 41 and the drum unit 31, the developing roller 42 and the photosensitive drum 30 are contacted to each other so that cartridges 50y, 50m, 50c, 50k become capable of forming the image. On this occasion, prior to the contact of the developing roller 42 to the photosensitive drum 30, the photosensitive drum 30 rotates, and the developing roller 42 also receives the driving force from the main assembly 100 of the apparatus and rotates. This is accomplished by providing the coupling portion 67a co-axially with the cylindrical portion 46b so that even if the developing unit 41 moves about the cylindrical portion 46b, the position of the coupling portion 67a does not change. Thus, the photosensitive drum 30 and the developing roller 42 are rotated before the developing roller 42 and the photosensitive drum 30 are contacted to each other. Therefore, when the developing roller 42 is brought into contact to the photosensitive drum 30, the speed difference between the peripheral surfaces of the photosensitive drum 30 and the developing roller 42 can be made small, and therefore, wearing of the photosensitive drum 30 and the developing roller 42 can be reduced. When image formation is completed, the developing roller 42 and the photosensitive drum 30 are spaced from each other by moving the second force application member 60 in the direction of the arrow B, as described hereinbefore. After the spacing, the rotations of the developing roller 42 and the photosensitive drum 30 are stopped. Thus, the speed difference between the peripheral surfaces of the photosensitive drum 30 and the developing roller 42 is reduced, and therefore, the wearing of the photosensitive drum 30 and the developing roller 42 can be reduced. Therefore, the image quality can be improved. The elastic portion can be replaced with the structure shown in FIGS. 33, 34, 35. Here, a force receiving device 190 comprises a first force receiving member 179 and a second force receiving member 178. As shown in FIGS. 34, 35, the first force application member 165 is provided with a sliding portion 165a (inclined surface), and the first force receiving member 179 is provided with a sliding portion 179a (inclined surface). FIG. 33 shows the state before the first force application member 165 moves. FIG. 34 shows the state in which the second force receiving member 178 is projected from the cartridge 150y by the first force application member 165 moving to abut the first force receiving member 179. FIG. 35 shows the state after the second force application member 164 moves in the direction of the arrow E. The change from I to II of the distance between the first force receiving member 179 and the second force receiving member 178 shown in FIGS. 34, 35 is permitted by the slidability between the sliding portion 179a and the sliding portion 165a and by the movability of the first force receiving member 179 in the direction of an arrow F shown in FIG. 35. In the cartridge 50y used for the description of this embodiment, the developing unit 41 is rotatable relative to the drum unit 31 in order to contact and space the developing roller 42 and the photosensitive drum 30 relative to each other. However, FIG. 36 shows an alternative structure wherein the portion to be guided 544 is in the form of a square pole configuration, and the drum unit 531 is provided with an elongated hole 536a engageable with the portion to be guided 544, wherein the developing unit 541 is slidable relative to the drum unit 531. More particularly, as shown in FIG. 37, when the second force application member 560 does not act on the second force receiving member 570, the developing roller 542 is urged by an urging spring (unshown) (elastic member) so as to contact the developing roller 542 to the photosensitive drum. Then, as shown in FIG. 38, the second force application member 560 moves in the direction of the arrow B to act on the second force receiving member 570. By this, the developing unit 541 slides in the direction the relative to the drum unit 531 so that the developing roller 542 and the photosensitive drum 530 are spaced by the gap g. Similarly to the first embodiment, the force receiving device 590 includes the first force receiving member 575 and the second force receiving member 570. A description will be provided as to the operation of taking the cartridges 50y, 50m, 50c, 50k out of the main assembly 100 of the apparatus. With the movement of the door 12 from the closed position to the open position, the first force application member 61 rotates from the position shown in FIGS. 6, 12 to the position shown in FIGS. 5, 11. By this, the first force receiving member 75 is released from the urging force of the first force application member 61, so that first force receiving member 75 moves from the state shown in FIGS. 6, 12 to the state shown in FIGS. 5, 11. More particularly, the second force receiving member 70 becomes free from the urging portion 75b of the first force receiving member 75. As shown in FIG. 5, the second force receiving member 70 also returns to the stand-by position (non-operating position) about the shaft 70a by the force of the spring 73 shown in FIG. 19 in the direction of an the arrow A. With the movement of the door 12 from the closed position to the open position, the tray holding member 14 is raised away from the transfer belt 19 as shown in FIGS. 3, 4. By this, the cartridges 50y, 50m, 50c, 50k are raised, and therefore, the photosensitive drum 30 is separated from the transfer belt 19. As described in the foregoing, the second force receiving member 70 for moving the developing unit 41 is constituted such that it projects outwardly from the developing unit 41 when the cartridges 50y, 50m, 50c, 50k are mounted to the main assembly 100 of the apparatus and the door 12 moves to the closed position. Therefore, the cartridges 50y, 50m, 50c, 50k can be downsized. In addition, since the mounting is effected when the second force receiving member 70 is at the stand-by position, the space in the main assembly 100 of the apparatus required for the movement of the cartridges 50y, 50m, 50c, 50k may be small. In other words, the size of the opening 80 may be small, and the first force application member 61 and the second force application member 60 can be close to the cartridges 50y, 50m, 50c, 50k. Therefore, the size of the main assembly 100 of the apparatus can be reduced with respect to the vertical direction. In addition, as seen in the vertical direction of the main assembly 100 of the apparatus, as shown in FIGS. 31, 32, the force receiving device 90 is overlapped with the first force application member 61 and the second force application member 60 with respect to the drum axial direction, and therefore, the cartridge can be downsized with respect to the longitudinal direction. When the cartridges 50y, 50m, 50c, 50k are handled by the user or when they are transported, the second force receiving member 70 can be placed at the stand-by position, and therefore, the second force receiving member 70 is not easily damaged. Second Embodiment In the first embodiment, the cartridges 50y, 50m, 50c, 50k are mounted to the main assembly 100 of the apparatus in the direction substantially perpendicular to the axis of the photosensitive drum 30. In Embodiment 2, the cartridges 450y, 450m, 450c, 450k are mounted to the main assembly 401 of the electrophotographic image apparatus (main assembly of the apparatus) in the direction substantially parallel with the axial direction of the electrophotographic photosensitive drum the photosensitive drum) 430. In the following description, the points different from the first embodiment will be described mainly. General Arrangement of Electrophotographic Image Forming Apparatus As shown in FIG. 39 FIGS. 41, the main assembly 401 of the apparatus is loaded with the cartridges 450y, 450m, 450c, 450k in the direction (arrow K) substantially parallel with the axial direction (longitudinal direction) of the photosensitive drum 430. In this embodiment, the cartridges 450y, 450m, 450c, 450k are mounted to the mounting member 480c provided in the main assembly 401 of the apparatus, in the direction of the arrow K. The cartridges 450y, 450m, 450c, 450k accommodate yellow color, magenta color, cyan color and black color toner particles (developers), respectively. The cartridges 450y, 450m, 450c, 450k are each provided with a force receiving device 490 having a first force receiving member 475 and a second force receiving member 470. At the rear side of the main assembly 401 of the apparatus with respect to the cartridge entering direction, there are provided a first force application member 461 and a second force application member 460 actable on the first force receiving member 475 and the second force receiving member 470, respectively. As shown in FIG. 42, parts (a) and (b), the main assembly 401 of the apparatus is provided with an opening 408 for permitting the cartridges 450y, 450m, 450c, 450k to enter the main assembly 401 of the apparatus and a door 412 movable between a closed position closing the opening 408 and an open position opening the opening 408. The door 412 is rotatable about the rotation axis 412a. As shown in FIG. 45, the mounting member 480 integrally includes holding portions 480c for holding the cartridges 450y, 450m, 450c, 450k, respectively, an operation member 480b for moving the first force application member 461, and a connecting portion 480a for connecting the operation member 480b and the door 412 with each other. As shown in FIG. 42, the connecting portion 480a and the door 412 are connected with each other by engagement between an elongated hole 480g provided in the connecting portion 480a and a projection 412b provided on the door 412. Therefore, with movement of the door 412 from the open position to the closed position in the direction of an arrow m, projections 480d, 480e provided on the connecting portion 480a move along guide grooves 401a, 401b provided in the main assembly 401 of the apparatus as shown in FIG. 42, parts (a) and (b). Thus, a holding portion 480c integral with the operation member 480b moves in the direction of an arrow n. Thus, the photosensitive drums 430 of the cartridges 450y, 450m, 450c, 450k supported on the holding portion 480c are moved from the positions spaced from the transfer belt 419 shown in FIG. 47 to the position contacting the transfer belt 419 shown in FIG. 48. Simultaneously, the portion to be positioned 431b provided on the drum unit 431 is abutted to the positioning portion 401a provided in the main assembly 401 of the apparatus by which the cartridges 450y, 450m, 450c, 450k are positioned correctly. Each of the cartridges 450y, 450m, 450c, 450k is prevented from movement in the direction of the arrow a in FIG. 39 in the main assembly 401 of the apparatus by engaging the shaft 436d provided on the covering member 436 with a rotation preventing portion 485a provided in the main assembly 401 of the apparatus. When the cartridges 450y, 450m, 450c, 450k are dismounted from the main assembly 401 of the apparatus, the operations are reverse to the mounting operations. Operations First Force Application Member and Second Force Applying Portion Referring to FIG. 40-FIG. 45, the operations of the first force application member 461 will be described. Similarly to the first embodiment, the first force application member 461 is engaged with a connecting member 462 to interrelate with the operation of the operation member 480b. The structure of the connecting member 462 is the same as in the first embodiment. FIGS. 40 and 42, (a) and FIG. 43 show the state in which the door 412 is at the open position and in which the operation member 480b takes an upper position. FIGS. 41 and 42, (b) and FIG. 44 show the state in which the door 412 is at the closed position. When the door 412 is closed, the operation member 480b moves down (in the direction of an arrow n). As shown in FIGS. 43, 44, a projection 462b provided on the connecting member 462 is in engagement with an elongated hole 480h provided in the mounting member 480. Therefore, with movement of the operation member 480b, the connecting member 462 rotates in the direction of an arrow Q about the rotational center 461d. Similarly to the first embodiment, the first force application member 461 rotates with the rotation of the connecting member 462. When the door 412 is moved from the closed position to the open position, the operations are reverse to the above-described operations. The other operations are the same as with the first embodiment. The operations of the second force applying portion 460 are the same as with the first embodiment. General Arrangement of Process Cartridge A description will be provided as to the structure of the process cartridge of this embodiment. The structures of the cartridges 450y, 450m, 450c, 450k are the same, and therefore, the description will be provided as to the cartridge 450y referring to FIG. 46. The cartridge 450y includes a photosensitive drum 430, and process means actable on the photosensitive drum 430. The process means includes a charging roller 432 functioning as charging means for charging electrically the photosensitive drum 430, a developing roller 442 functioning as developing means for developing a latent image formed on the photosensitive drum 430, and/or blade 433 functioning as cleaning means for removing residual toner remaining on the surface of the photosensitive drum 430. The cartridge 450y comprises a drum unit 431 and a developing unit 441. The structures of the drum unit 431 and the developing unit 441 and the connecting structure between the drum unit 431 and the developing unit 441 are the same as with the first embodiment. Force Receiving Device Similarly to the first embodiment, as shown in FIG. 47, the cartridge 450y includes a force receiving device 490 for contacting the developing roller 442 and the photosensitive drum 430 to each other and for spacing them from each other. The detailed structures thereof are the same as with FIGS. 9 and 15-19. As shown in FIG. 47, the force receiving device 490 of this embodiment comprises a first force receiving member 475, a second force receiving member 470 and a spring which is urging means (unshown). Spacing Mechanism of Main Assembly of Electrophotographic Image Forming Apparatus and Urging Mechanism for Process Cartridge FIG. 49 shows the state after the second force application member 460 moves in the direction of an arrow E from the home position (FIG. 48) in which the developing roller 442 and the photosensitive drum 430 are still in contact with each other. FIG. 50 shows the state after the second force application member 460 moves in the direction of an arrow B in which the developing roller 442 and the photosensitive drum 430 are spaced from each other. Similarly to the first embodiment, the second force applying portion 460 is provided with an elongated hole portion 460c for avoiding the rotation axis 461d of the first force application member 461. Even when the second force applying portion 460 moves in the direction of an arrow E or arrow B, the second force applying portion 460 can move without interference with the first force application member 461. The first force application member 461 and the second force application member 460, as shown in FIGS. 39, 40, are provided above the cartridges 450y, 450m, 450c, 450k entering the main assembly 401 of the apparatus. When the cartridges 450y, 450m, 450c, 450k are in the process of entering the main assembly 401 of the apparatus, the second force receiving member 470 is kept in the stand-by position. Also in this embodiment, the second force receiving member 470 is projected outwardly of the developing unit 441 when the cartridges 450y, 450m, 450c, 450k are mounted to the main assembly 401 of the apparatus and the door 412 is moved to the closed position. Therefore, the cartridges 50y, 50m, 50c, 50k can be downsized. Since the cartridges 450y, 450m, 450c, 450k are inserted with the second force receiving members 470 at the stand-by positions, the space required for entering the cartridges 450y, 450m, 450c, 450k may be small. In other words, the size of the opening 480 may be small, and the first force application member 461 and the second force application member 460 can be close to the cartridges 450y, 450m, 450c, 450k. Therefore, the main assembly 401 of the apparatus can be downsized with respect to the vertical direction. Since the arrangement is such that force receiving device 90 is overlapped with the first force application member 61 and the second force application member 60 in the drum axial direction as seen in the vertical direction, the cartridge can be downsized in the longitudinal direction. When the cartridges 450y, 450m, 450c, 450k are handled by the user or when they are transported, the second force receiving member 470 can be placed at the stand-by position, and therefore, the second force receiving member 470 is not easily damaged. Third Embodiment This embodiment relates to a modification of the force receiving device. This embodiment will be described also with a yellow cartridge 250y accommodating a yellow color developer as an exemplary cartridge. As shown in FIG. 51-FIG. 54, the developing unit 241 is provided with a force receiving member 277 (force receiving device). The force receiving member 277 includes a shaft portion 277c supported rotatably on the developing device frame 248, a first force receiving portion 277a on which the first force application member 261 is actable, and a second force receiving portion 277b on which the second force application member 263 is actable. The force receiving member 277 is integrally constituted by the first force receiving portion and the second force receiving portion. The spring 298 has one end fixed to the force receiving member 277 and another end fixed to the developing device frame 248. The force receiving member 277 is kept in the state shown in FIG. 51 by the spring 298. As shown in FIG. 52, similarly to the first embodiment, by movement of the door (unshown) from the open position to the closed position, the first force application member 262 is contacted to the first force receiving portion 277a of the force receiving member 277. By doing so, the force receiving member 277 rotates in the direction of an arrow S shown in FIG. 52 about the shaft 277c. The second force receiving portion 277b of the force receiving member 277 moves outwardly of the developing unit 241. Thereafter, as shown in FIG. 53, the second force application member 263 moves in the direction of an arrow B by the driving force from the main assembly of the apparatus to contact to the second force receiving portion 277b of the force receiving member 277. Further, when the second force application member 263 moves in the direction of an arrow B, the developing unit 241 rotates about the connecting portion 246b with the drum unit 231, by which the developing roller 242 is spaced from the electrophotographic photosensitive drum 230 by a gap γ. At this time, as shown in FIG. 53, the portion to be locked 277d of the force receiving member 277 is contacted to the locking portion 248a of the developing device frame 248 to regulate the movement of the force receiving member 277 shown in FIG. 52 in the direction of the arrow S. Therefore, by movement of the second force application member 263 in the direction of the arrow E, the developing unit 241 is rotated relative to the drum unit 31. By the movement of the second force application member 263 in the direction of the arrow B, the first force receiving portion 277a of the force receiving member 277 slides on and deforms the free end portion 262a of the first force application member 262 from the shape indicated by a solid lines to the shape indicated by broken lines in FIG. 54. To accomplish this, the free end portion 262a of the first force application member 262 is elastically deformable. In addition, the first force receiving portion 277a constitutes a sliding surface slidable relative to the first force application member 262. The elastic deformability of the free end portion 262a of the first force application member 262 assures the urging of the force receiving member 277 to the locking portion 248a even when the second force application member 263 moves in the direction of the arrow B in the state of FIG. 53. As regards the contact between the developing roller 242 and the photosensitive drum 230, by the movement of the second force application member 263 in the direction of the arrow E in FIG. 53 from the state shown in FIG. 53, the movement to the second force receiving member 277 by the second force application member 263 is permitted. By the urging force of the spring 295, the developing unit 241 is rotated to contact the developing roller 242 to the photosensitive drum 230. In this embodiment, the structures other than the force receiving member 277 are the same as those of the cartridge 50y described in the first embodiment. The operations of the first force application member 261 in this embodiment are the same as those of the first force application member 61 in the first embodiment or the first force application member 461 in the second embodiment. As described in the foregoing, in the force receiving device of this embodiment, the number of parts is smaller than the number of parts of the force receiving device 90 of the first embodiment. Fourth Embodiment This embodiment relates to a modification of the force receiving device. This embodiment will be described also with a yellow cartridge 250y accommodating a yellow color developer as an exemplary cartridge. As shown in FIG. 55-FIG. 58, the developing unit 341 is provided with a force receiving device 370. The force receiving device 370 includes a first force receiving member 370a, a second force receiving member 370b, a first spring 370c, and a second spring 370d. The force receiving device 370 is movably supported in a guide 341a provided in the developing device frame 348. The second spring 370d is provided between a locking portion 341c provided at one end of the guide 341a and a locking portion 370e provided on the second force receiving member 370b. The first spring 370c is provided between the first force receiving member 370a and the second force receiving member 370b. When the door (unshown) is at the open position, the second force receiving member 370b is retracted to the position (stand-by position) where the locking portion 370e is contacted to the second locking portion 341b provided in the guide 341a as shown in FIG. 55 by the urging force of the second spring 370d. At this time, a gap f1 is provided between the second force receiving member 370b and the second force application member 360 provided in the main assembly side of the apparatus. In other words, since the second force receiving member 370b does not receive a force from the second force application member 360, the photosensitive drum 330 and the developing roller 342 are contacted to each other. Similarly to the first embodiment, by movement of the door (unshown) from the open position to the closed position, as shown in FIG. 56, the first force application member 361 is brought into contact to the first urged portion 370a1 of the first force receiving member 370a. By doing so, the second force receiving member 370b is urged through the spring 370c to move the second force receiving member 370b to an outer part of the developing unit 241 (arrow P). At this time, the second force application member 360 is contacted by the upper surface 370b1 of the second force receiving member 370b to regulate a further movement. However, since the spring 370c elastically deforms, the force receiving device 370 is not damaged even if the first force application member 361 continues pressing against the first force receiving member 370a with the movement of the second force receiving member 370b regulated. As shown in FIG. 57, when the second force application member 360 moves in the direction of an arrow E, the second force receiving member 370b is further moved by the urging force of the spring 370c into the movement path of the second force application member 360. Then, as shown in FIG. 58, by the movement of the second force application member 360 in the direction of the arrow B, the side surface 370b2 (second urged portion) provided on the second force receiving member 370b receives a force from the second force application member 360. Further, where the second force application member 360 moves in the direction of an arrow E, the developing unit 341 rotates about the connecting portion 346b with the drum unit 331, by which the developing roller 342 is spaced from the electrophotographic photosensitive drum 330 by a gap 5. Here, the position where the first force receiving member 370a is urged by the first force application member 361 is fixed, and the second force receiving member 370b is moved by the movement on the second force application member 360 in the direction of the arrow B shown in FIG. 58. Therefore, the distance I between the first force receiving member 370a and the second force receiving member 370b and the distance II between the first force receiving member 370a and the second force receiving member 370b, satisfy distance I>distance II. In the force receiving device 370 of this embodiment, the change of the distance can be accommodated by the sliding of the spring 370c and the first force application member 361 relative to the first force receiving member 370a. By the movement of the second force application member 360 from the position shown in FIG. 58 in the direction indicated by the arrow E in FIG. 57, the movement of the second force receiving member 370b by the second force application member 360 is permitted. Similarly to the first embodiment, by the urging spring 395 provided on the cartridge 350y, the developing roller 342 and the photosensitive drum 330 are brought into contact to each other. Also in this embodiment, the structures other than the force receiving device 370 are the same as those of the cartridge 50y of the first embodiment. The operations of the first force application member 361 in this embodiment are the same as those of the first force application member 61 in the first embodiment or the first force application member 461 in the second embodiment. Fifth Embodiment This embodiment relates to a modified example of a supporting structure for the force receiving device (FIGS. 59, 60). This embodiment will be described also with a yellow cartridge 650y accommodating a yellow color developer as an exemplary cartridge. The cartridge 650y is provided with a force receiving device 690 for providing contact between and spacing of the developing roller 642 and the photosensitive drum 630. The force receiving device 690 comprises a first force receiving member 675 and a second force receiving member 670 shown in FIGS. 59, 60, similarly to the first embodiment. The first force receiving member 675 is mounted to the drum frame 634 by engagement between the engaging portion 675d provided on the first force receiving member 675 with the guide portion 638 of the drum frame 634. The first force receiving member 675 mounted to the drum frame 634 is prevented from disengagement from the drum frame 634 by a regulating portion 639 provided on the drum frame 634. A shaft 670a of the second force receiving member 670 is engaged with a guide portion 645a provided on the bearing unit 645. The bearing unit 645 including a second force receiving member 670 is fixed to one longitudinal end of the developing device frame 648 and rotatably supports the developing roller 642 having a developing roller gear 669 at the end. Similarly to the first embodiment, the bearing unit 645 is provided with a coupling member 667 for receiving the driving force from the driving motor (unshown), and an idler gear 668 for transmitting the driving force from the coupling member 667 to the developing roller gear 669. The covering member 646 is fixed to the longitudinally outside of the bearing unit 645 so as to cover the coupling member 667 and the idler gear 668. The covering member 646 is provided with a cylindrical portion 646b which is projected beyond the surface of the covering member 646. The coupling member 667 is exposed through an inside opening of the cylindrical portion 646b. Assembling of Drum Unit and Developing Unit As shown in FIGS. 59, 60, when the developing unit 641 and the drum unit 631 are assembled, an outside circumference of the cylindrical portion 646b are engaged with the supporting hole portion 636a at one end. On the other hand, at the other end, the supporting hole portion 637a is engaged by the projected portion 648b provided projected from the developing device frame 648. The covering member 37 in the first embodiment shown in FIG. 11-FIG. 14 corresponds to the covering member 637 of this embodiment, and the supporting hole portion 37a shown in FIG. 11-FIG. 14 corresponds to the supporting hole portion 637a of this embodiment. The projected portion 48b provided projected from the developing device frame 48 in the first embodiment correspond to the projected portion 648b provided projected from the developing device frame 648 of this embodiment. By doing so, the developing unit 641 is rotatably supported on the drum unit 631. FIG. 60 shows the cartridge 650y in which the developing unit 641 and the drum unit 631 have been combined with each other. Similarly to the first embodiment, the assembling is such that the urging portion 675b of the first force receiving member 675 is capable of acting on a cam surface 671 (third urged portion) provided on the second force receiving member 670, and similarly to the first embodiment, the contacting and spacing can be accomplished between the electrophotographic photosensitive drum 630 and the developing roller 642. Thus, the similar advantageous effects as with the first embodiment can be provided. Sixth Embodiment This embodiment relates to a modification of the force receiving device. This embodiment will be described also with a yellow cartridge 750y accommodating a yellow color developer as an exemplary cartridge. As shown in FIG. 61-FIG. 63, the developing unit 741 is provided with a force receiving device 790. The force receiving device 790 comprises a first force receiving member 775 and a second force receiving member 770. The first force receiving member 775 comprises a supporting portion 775c supported rotatably on the developing device frame 748. Similarly to the first embodiment shown in FIG. 15-FIG. 19, the second force receiving member 770 is urged normally to provide the state shown in FIG. 61 by urging means (unshown). In other words, since the second force receiving member 770 does not receive a force from the second force application member 760, the photosensitive drum 730 and the developing roller 742 are contacted to each other. Similarly to the first embodiment, by movement of the door (unshown) from the open position to the closed position, the first force application member 761 is brought into contact to the first urged portion 775a of the first force receiving member 775 from the top side, as shown in FIG. 62. By this, the first force receiving member 775 is rotated about the supporting portion 775c, and the urging portion 775b of the first force receiving member 775 acts on the third urged portion 770b of the second force receiving member 770. Then, the second force receiving member 770 moves to an outside (arrow P) of the developing unit 741. At this time, the upper surface portion 770c of the second force receiving member 770b abuts the second force application member 760 to prevent further movement. The position of the second force receiving member 770 at this time is called regulating position. However, even when the second force receiving member 770 is prevented from moving by the engaging rib 760, the force receiving device 790 including the second force application member 760 and the second force receiving member 770 is not damaged. This is because the elastic portion 775d formed by a thin portion provided in the first force receiving member 775 flexes (elastic deformation) as shown in FIG. 62. Therefore, even if the movement of the second force receiving member 770 is regulated, the force receiving device 790 is not damaged. As shown in FIG. 63, when the second force application member 760 moves in the direction of an arrow E, the regulation by the second force application member 760 is released. Then, the elastic portion 775d of the first force receiving member 775 restores to the original position from the elastically deformed position to permit the urging portion 775b to move the second force receiving member 770b outwardly. Then, the second force receiving member 770b moves into the movement path of the second force application member 760. As shown in FIG. 64, by movement of the second force application member 760 in the direction of the arrow B, the side surface 770d (second urged portion) receives a force from the second force application member 760. Further, when the second force application member 760 moves in the direction of an arrow B, the developing unit 741 rotates about the connecting portion 746b with the drum unit 731, by which the developing roller 742 is spaced from the electrophotographic photosensitive drum 730 by a gap A. Here, the position where the first force receiving member 775 is urged by the first force application member 761 is fixed, and the second force receiving member 760b is moved by the movement on the second force application member 770 in the direction of the arrow B shown in FIG. 64. Therefore, the distance I between the first force receiving member 775 and the second force receiving member 770b and the distance II between the first force receiving member 775 and the second force receiving member 770b, satisfy distance I>distance II. In the force receiving device 790 of this embodiment, the distance change can be accommodated by the sliding of the first force application member 761 relative to the first force receiving member 775a and the deformation of the elastic portion 775d formed by a thin portion provided on the first force receiving member 775. By the movement of the second force application member 760 from the position shown in FIG. 64 in the direction indicated by the arrow E in FIG. 63, the movement of the second force receiving member 770b by the second force application member 760 is permitted. Similarly to the first embodiment, the developing roller 742 and the photosensitive drum 730 are contacted to each other by the urging spring 795 provided on the cartridge 750y. Also in this embodiment, the structures other than the force receiving device 790 are the same as those of the cartridge 50y of the first embodiment. The operations of the first force application member 761 in this embodiment are the same as those of the first force application member 61 in the first embodiment or the first force application member 461 in the second embodiment. The force receiving device 790 of this embodiment provides the similar advantageous effects as with the first embodiment. Seventh Embodiment FIG. 65 to FIG. 68 show a modified example of the modified example. This embodiment will be described also with a yellow cartridge 850y accommodating a yellow color developer as an exemplary cartridge. FIG. 65 is a perspective view of a process cartridge 850y as seen from a coupling member 830a side of the photosensitive drum 830 wherein an urging member 820 of the main assembly of the apparatus has moved in the direction of an arrow V (upward) in FIG. 67. FIG. 66 is a perspective view of the process cartridge 850y as seen from the side opposite from the coupling member 830a of the photosensitive drum 830 in the same state as of FIG. 65. FIG. 67 is a perspective view of the process cartridge 850y as seen from the coupling member 830a side of the photosensitive drum 830 wherein the urging member 820 of the main assembly of the apparatus has moved in the direction of an arrow U in FIG. 67. FIG. 68 is a perspective view of the process cartridge 850y as seen from the side opposite from the coupling member 830a of the photosensitive drum 830 in the same state as of FIG. 67. In this embodiment, as shown in FIGS. 65, 66, the main assembly of the apparatus comprises an urging member 820 for urging the cartridge 850y to a positioning portion 801a provided in the main assembly of the apparatus. The photosensitive drum 830 is provided with a coupling member 830a for receiving the driving force, and a developing roller is provided with a developing roller gear 869 provided in turn with a coupling member 867 for receiving the driving force, and the urging member 820 urges the cartridge 850y at the longitudinal end opposite from the other longitudinal end where the coupling member 830a and the coupling member 867 are provided. The urging member 820 has a guide portion 820a, an urging portion 822 and an urging spring 821. The urging portion 822 is supported by the guide portion 820a for movement toward the cartridge 850y. The urging portion 822 is urged by an urging spring 821 in the direction of an arrow U in FIG. 67. The operations of the urging member 820 are similar to the operations of the first force application member 61 of the first embodiment, and with the opening operation of the door of the main assembly of the apparatus, the urging member 820 moves in the direction of an arrow V in FIG. 67, and with the closing operation of the door of the main assembly of the apparatus, it moves in the direction of an arrow U in FIG. 67. Thus, when the urging member 820 moves in the direction of the arrow U, the urging portion 822 is contacted to the cartridge 850y to urge the cartridge 850y by a force of the urging spring 821. By the urging force, the cartridge 850y is positioned relative to the main assembly of the image forming apparatus 100 by positioning the projection 831a provided on the drum frame 834 to the positioning portion 801a of the main assembly of the apparatus, similarly to the positioning operation of the cartridge 50y to the main assembly 100 of the apparatus of the first embodiment. Also in this embodiment, as shown in FIGS. 65, 66, the developing unit 841 is provided with a force receiving device 890. The force receiving device 890 comprises a first force receiving member 875, a second force receiving member 870 and a rod 872. In this embodiment, the drum frame 834 is provided with a rod 872, and the hole 872a provided in the rod 872 is engaged by the shaft 834a provided on the drum frame 834, and the rod 872 is supported on the drum frame 834 rotatably about the hole 872a. The rod 872 is urging in the direction of an arrow S in FIG. 65 by a pressure of the spring 840. In other words, since the second force receiving member 870b does not receive a force from the second force application member 860, the photosensitive drum 830 and the developing roller 842 are contacted to each other. Similarly to the first embodiment, by movement of the door (unshown) from the open position to the closed position, the urging portion 822 contacts the cartridge 850y and urges the cartridge 850y by the force of the urging spring 821, as shown in FIG. 67. At this time, the contact portion 822a of the urging portion 822 relative to the contact portion 822a moves the contact portion 872a of the rod 872 to rotate the rod 872 about the hole 872a. As shown in FIGS. 67, 68, an operating portion 872b of the rod 872 moves the first force receiving member 875 in the direction of an arrow W. When the first force receiving member 875 moves in the direction of the arrow W, the second force receiving member 870 moves (projects) outwardly of the developing unit 841 of the cartridge 850y from the stand-by position, similarly to the first embodiment. The operations are the same as with the first embodiment. The process cartridge of this embodiment has the same structure as the cartridge 50y of the first embodiment. The operations of the second force application member 860 of this embodiment are the same as the second force application member 60 of the first embodiment. The force receiving device 790 of this embodiment provides the similar advantageous effects as with the first embodiment. According to the present invention, the process cartridge in which the electrophotographic photosensitive drum and the developing roller are contactable to and spaceable from each other, and the electrophotographic image forming apparatus to which such a process cartridge is detachably mountable can be downsized. In addition, a force receiving portion for spacing the developing roller and the electrophotographic photosensitive drum from each other is not easily damaged, when the process cartridge is handled and/or when the process cartridge is transported. While the invention has been described with reference to the structures disclosed herein, it is not confined to the details set forth and this application is intended to cover such modifications or changes as may come within the purpose of the improvements or the scope of the following claims. This application claims priority from Japanese Patent Applications No. 004106/2006 filed Jan. 11, 2006 and No. 346270/2006 filed Dec. 22, 2006 which are hereby incorporated by reference. | <SOH> FIELD OF THE INVENTION <EOH>The present invention relates to a process cartridge in which an electrophotographic photosensitive drum and a developing roller actable on the electrophotographic photosensitive drum are contactable to each other and spaceable from each other, and an electrophotographic image forming apparatus to which the process cartridge is detachably mountable. | <SOH> SUMMARY OF THE INVENTION <EOH>Accordingly, it is a principal object of the present invention to provide a downsized process cartridge in which the electrophotographic photosensitive drum and the developing roller are contactable to each other and spaceable from each other and a downsized electrophotographic image forming apparatus to which the process cartridge is detachably mountable. It is another object of the present invention to provide a process cartridge in which the electrophotographic photosensitive drum and the developing roller are contactable to each other and spaceable from each other with which when the process cartridge is handled, or when the process cartridge is transported, the force receiving portion is not damaged. According to an aspect of the present invention, there is provided a process cartridge detachably mountable to a main assembly of an electrophotographic image forming apparatus. The main assembly includes an opening, a door movable between a closed position for closing the opening and an open position for opening the opening, a first force application member movable with movement of the door from the open position to the closing position and a second force application member movable by a driving force from a driving source. The process cartridge comprises: an electrophotographic photosensitive drum; a developing roller for developing an electrostatic latent image formed on the electrophotographic photosensitive drum; a drum unit containing the electrophotographic photosensitive drum; a developing unit which contains the developing roller and which is movable relative to the drum unit such that developing roller is movable between a contact position in which the developing roller is contacted to the electrophotographic photosensitive drum and a spaced position in which said developing roller is spaced from the electrophotographic photosensitive drum; and a force receiving device including a first force receiving portion for receiving a force from the first force application member by movement of the door from the open position to the closed position in the state that process cartridge is mounted to the main assembly of the apparatus through the opening, and a second force receiving portion movable from a stand-by position by movement of the first force receiving portion by a force received from the first force application member. The second force receiving portion takes a projected position for receiving a force from the second force application member to move the developing unit from the contact position to the spaced position, the projected position being higher than the stand-by position. According to another aspect of the present invention, there is provided an electrophotographic image forming apparatus for forming an image on a recording material, to which a process cartridge is detachably mountable. The apparatus comprises (i) an opening; (ii) a door movable between a closed position for closing said opening and an open position for opening the opening; (iii) a first force application member movable with movement of the door from the open position to the closed position; (iv) a second force application member movable by a driving force from a driving source; and (v) mounting means for detachably mounting a process cartridge. The process cartridge includes an electrophotographic photosensitive drum, a developing roller for developing an electrostatic latent image formed on the electrophotographic photosensitive drum, a drum unit containing the electrophotographic photosensitive drum, a developing unit which contains the developing roller and which is movable relative to the drum unit such that developing roller is movable between a contact position in which the developing roller is contacted to the electrophotographic photosensitive drum and a spaced position in which the developing roller is spaced from the electrophotographic photosensitive drum, and a force receiving device including a first force receiving portion for receiving a force from the first force application member by movement of the door from the open position to the closed position in the state that the process cartridge is mounted to a main assembly of the apparatus through the opening, and a second force receiving portion movable from a stand-by position by movement of the first force receiving portion by a force received from the first force application member. The second force receiving portion takes a projected position for receiving a force from the second force application member to move the developing unit from the contact position to the spaced position, the projected position being higher than the stand-by position. The apparatus also includes feeding means for feeding the recording material. These and other objects, features and advantages of the present invention will become more apparent upon a consideration of the following description of the preferred embodiments of the present invention taken in conjunction with the accompanying drawings. | G03G211814 | 20171018 | 20180208 | 63812.0 | G03G2118 | 3 | HYDER, G.M. ALI | PROCESS CARTRIDGE AND IMAGE FORMING APPARATUS | UNDISCOUNTED | 1 | CONT-ACCEPTED | G03G | 2,017 |
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15,787,389 | PENDING | FOLDING KNIFE WITH REPLACEABLE BLADE | A knife is provided that includes a replaceable blade element. The knife employs a blade carrier that is fixedly interconnected to or foldable with respect to a handle. The blade carrier selectively receives the replaceable blade element that is locked into the blade carrier by way of a hook and movable pin combination. The replaceable blade element is designed to be inserted within the blade carrier quickly, easily, and safely. | 1. A knife, comprising: a handle with an outer surface; a first blade carrier having a proximal end positioned within the handle and a first distal end, the first blade carrier having a having a first outer surface, which generally corresponds with the outer surface of the handle, and a first inner surface positioned opposite from the first outer surface, wherein the first distal end interconnects the first outer surface and the first inner surface; a second blade carrier spaced from the first blade carrier, the second blade carrier having a proximal end positioned within the handle and a second distal end, the second blade carrier having a having a second outer surface, which generally corresponds with the outer surface of the handle, and a second inner surface positioned opposite from the second outer surface, wherein the second distal end interconnects the second outer surface and the second inner surface; an outer wall interconnecting the first outer surface and the second outer surface; wherein a majority of the first inner surface and the second inner surface are generally of the same profile shape, and wherein the distance between the first outer surface and the first inner surface is less than the distance between the second outer surface and the second inner surface; a replaceable blade positioned between the first blade carrier and the second blade carrier, the replaceable blade having a cutting edge, the majority of which is exposed when the replaceable blade is positioned between the first blade carrier and the second blade carrier, and an outer surface positioned opposite the cutting edge, the replaceable blade also having a hooked portion extending from the outer surface of the replaceable blade; a replaceable blade release mechanism associated with at least one of the first and the second blade carrier; and a seat member configured to selectively receive a portion of the replaceable blade, the seat member positioned between the first blade carrier and the second blade carrier, and wherein a portion of the seat member spaced from the outer wall. 2. The knife of claim 1, wherein the portion of the replaceable blade that is selectively received by the seat member includes a hook. 3. The knife of claim 1, wherein the first blade carrier and the second blade carrier are selectively rotatable relative to the handle and selectively lockable thereto. 4. The knife of claim 1, wherein the replaceable blade includes a blade end with and an inner surface spaced from the cutting edge. 5. The knife of claim 1, wherein the blade release button is moved relative to the handle to release the replaceable blade from the first blade carrier and the second blade carrier. 6. A knife adapted to receive a replaceable blade, comprising: a handle with an outer surface; a first blade carrier having a proximal end positioned within the handle and a first distal end, the first blade carrier having a having a first outer surface, which generally corresponds with the outer surface of the handle, and a first inner surface positioned opposite from the first outer surface, wherein the first distal end interconnects the first outer surface and the first inner surface; a second blade carrier spaced from the first blade carrier, the second blade carrier having a proximal end positioned within the handle and a second distal end, the second blade carrier having a having a second outer surface, which generally corresponds with the outer surface of the handle, and a second inner surface positioned opposite from the second outer surface, wherein the second distal end interconnects the second outer surface and the second inner surface; an outer wall interconnecting the first outer surface and the second outer surface; wherein a majority of the first inner surface and the second inner surface are generally of the same profile shape, and wherein the distance between the first outer surface and the first inner surface is less than the distance between the second outer surface and the second inner surface; the replaceable blade adapted to be positioned between the first blade carrier and the second blade carrier, the replaceable blade having a cutting edge, the majority of which is exposed when the replaceable blade is positioned between the first blade carrier and the second blade carrier, and an outer surface positioned opposite the cutting edge, the replaceable blade also having a hooked portion extending from the outer surface of the replaceable blade, and wherein the replaceable blade includes a blade end with an inner surface spaced from the cutting edge; a replaceable blade release mechanism associated with at least one of the first blade carrier and the second blade carrier; a seat member configured to selectively receive the hooked portion, the seat member positioned between the first blade carrier and the second blade carrier, and wherein a portion of the seat member spaced from the outer wall; and wherein the blade release button is moved relative to the handle to release the replaceable blade from the first blade carrier and the second blade carrier. 7. The knife of claim 6, wherein the first blade carrier and the second blade carrier are selectively rotatable relative to the handle and selectively lockable thereto. 8. A knife with a handle, a first blade carrier, a second blade carrier spaced from the first blade carrier, a replaceable blade adapted to be positioned between the first blade carrier and the second blade carrier, the replaceable blade comprising: a cutting edge originating at a point, and further comprised of an arcuate portion interconnected to a longitudinal portion; a first portion extending from the point to about the center of the replaceable blade, the first portion further comprising a hooked portion; and a second portion extending from the first portion to an end positioned adjacent to the handle when the replaceable blade is positioned within the first blade carrier and the second blade carrier, the end having an inner surface spaced from the cutting edge. 9. The knife of claim 8, further comprising a replaceable blade release mechanism associated with the at least one of the first blade carrier and the second blade carrier. 10. The knife of claim 8, further comprising a seat member configured to selectively receive the hooked portion, the seat member positioned between the first blade carrier and the second blade carrier. 11. The knife of claim 8, wherein the first blade carrier has a proximal end positioned within the handle and a first distal end, the first blade carrier having a first outer surface and a first inner surface positioned opposite from the first outer surface, wherein the first distal end interconnects the first outer surface and the first inner surface; wherein the second blade has a proximal end positioned within the handle and a second distal end, the second blade carrier having a having a second outer surface and a second inner surface positioned opposite from the second outer surface, wherein the second distal end interconnects the second outer surface and the second inner surface; and wherein a majority of the first inner surface and the second inner surface are generally of the same profile shape, and wherein the distance between the first outer surface and the first inner surface is less than the distance between the second outer surface and the second inner surface. | This application is a continuation of U.S. patent application Ser. No. 15/165,830, filed May 26, 2016, which is a continuation-in-part of U.S. patent application Ser. No. 14/063,333, filed Oct. 25, 2013, now U.S. Pat. No. 9,687,987, issued June 27, 2017, which claims the benefit of U.S. Provisional Patent Application Ser. No. 61/721,000, filed Oct. 31, 2012, and Chinese Patent Application No. CN201210418907.0, filed Oct. 26, 2012, now Chinese Patent No. CN103786170, the entire disclosures of which are incorporated by reference herein. This application is also related to U.S. Patent No. D592,033, which discloses a locking version of the knife described in U.S. Patent Application Publication No. 2005/0229404 and European Patent No. EP1570959, the entirety of each of these references being incorporated by reference herein. FIELD OF THE INVENTION Embodiments of the present invention generally relate to knives. More specifically, one embodiment of the present invention is a folding knife that has a replaceable blade element. Another embodiment is a non-folding knife with a replaceable blade element. BACKGROUND OF THE INVENTION Knives are usually comprised of a handle with a blade that is interconnected thereto. Some knives employ blades that are rotatably interconnected, and selectively lockable, to the handle. When the knife is not in use, it is sheathed or, in the case of folding knives, the blade is folded into the handle. When in use, the rotatable blade is extended from the handle and locked in place. Such locking mechanisms are known and engage a portion of the blade to hold it in place until the user disengages the lock mechanism, which allows the blade to be folded into an opening in the handle to conceal all or a portion of the blade. Regardless of knife type, it is desirable to provide a cutting edge that is very sharp, similar to the sharpness provided by a razor blade. However, razor blade sharpness comes at a price. More specifically, razor blades often possess very thin edges that are brittle and wear, i.e., lose their edge, relatively quickly. Blade performance can be repaired by sharpening, but doing so will reduce blade size and durability. In addition, thin razor blades lack lateral strength and are thus flimsy and can fracture easily when put to hard use to cut forcibly or when cutting at an angle that applies lateral side-force to the blade. Thus, some knives employ a razor-sharp replaceable blade element that fits within a blade carrier, which may be foldable within a handle. Once the replaceable blade element becomes dull, or after repeated sharpening, it is removed from the blade carrier and discarded. Another razor blade is then inserted into the carrier. Some knives of this type employ a complicated blade interconnection mechanism. For example, U.S. Pat. Nos. 5,689,889 and 6,574,868 to Overholt disclose razor blades for interconnecting to a blade carrier of folding knife. These knives receive the replacement blade member in a complicated fashion wherein the replaceable blade element must be first introduced into the blade carrier at and angle and then rotated into place. Finally, the replaceable blade element is locked within the blade carrier. As one of skill in the art will appreciate, replacing a blade in this fashion is difficult and, because the replaceable blade members are extremely sharp, manipulating the blade into place can cause injury. To lock and secure the blade, Overholt discloses the use of a separate threaded fastener that attaches to the blade carrier. To replace the blade, the fastener must first be loosened and completely detached from the blade carrier before the sharpened razor blade portion can be removed. This is time consuming and dangerous because the user must remove the fastener by hand from the blade carrier, which is located in close proximity to the sharp cutting edge of the razor blade. Further, loosening or removing the fastener requires the use of both hands, which makes it not possible to safely hold the knife or secure the knife by the handle while removing the fastener. Further, the fastener is commonly made up of two or more small parts that must be detached from the blade carrier to replace the blade. The fastener parts can easily be dropped and lost, especially when used in the outdoors. If one or more small parts of the fastener are lost when changing the blade, the new blade cannot be attached to the blade carrier and the knife is no longer functional. The following disclosure describes a knife with the replaceable blade that is selectively inserted into blade carrier in a way that facilitates easy interconnection, reduces the chance of injury, and eliminates the need for separate parts that must be detached from the knife to remove and insert a new blade. SUMMARY OF THE INVENTION It is one aspect of embodiments of the present invention to provide a folding knife with a replaceable blade. More specifically, one embodiment of the present invention includes a handle having a first portion and a second portion spaced from the first portion. The space between the first handle portion and the second handle portion receives the replaceable blade when the knife is not in use. A blade carrier is rotatably interconnected to the handle and operates as in a traditional folding knife: 1) in a first position of use wherein at least a portion of the blade carrier is positioned within the housing; and 2) in a second position of use wherein the blade carrier is locked in an open position and extended from the housing. The blade carrier selectively receives a replaceable blade element. It is another aspect of embodiments of the present invention to provide a non-folding knife with the replaceable blade portion. More specifically, one embodiment of the present invention includes a handle with a fixed blade carrier. The blade carrier of embodiments of the present invention have a first carrier portion and a second carrier portion, which is spaced from the first carrier portion, which receives the replaceable blade. The first carrier also includes a channel that selectively receives a pin. The second blade carrier includes a flexible member with a pin that selectively engages an aperture in the replaceable blade member to secure it to the blade carrier. To replace the blade, a release button, which is spring-biased relative to the handle, is depressed which deflects portion of the second blade carrier. Deflection of the blade carrier removes the pin from the aperture, which allows the blade to be removed. The blade is inserted in a direction generally parallel to the longitudinal axis of the handle, i.e., in a direction parallel to the length of the handle. Thus complicated blade rotation is not necessary to secure the blade to the blade carrier. It is another aspect of embodiments of the present invention to provide a knife that includes a replaceable blade that is safe and easy to remove. More specifically, as mentioned above, replaceable blades of the prior art are in many respects difficult to engage into the blade carrier and require a complicated interconnection sequence requiring the use of both hands to remove the locking/retaining portion of the blade from the blade carrier. The contemplated replaceable blade portion is inserted longitudinally relative to the handle. Also, the blade is designed to extend from the carrier so that is easy to grasp with the thumb and forefinger of one hand while the other hand securely grasps the handle portion and depresses the lock release button with one finger. This makes it much easier, faster, and safer to attach and remove the replaceable blade. It is another aspect of embodiments of the present invention to provide a knife that eliminates the need for small separate parts (other than the replacement blades) that must be detached from the knife to change the blade. The prior art teaches a blade fastener that requires small parts that must be detached and can easily be lost when replacing the blade. With embodiments of the present invention, there are no separate parts required to fasten and detach the replaceable blade from the knife. It is another aspect of embodiments of the invention to provide a knife, comprising: a blade carrier having a first portion that is spaced from a second portion, the blade carrier being connected to a handle; a first blade liner portion associated with the first blade carrier; a second blade liner portion associated with the second portion of the blade carrier; a replaceable blade positioned between the first blade carrier and the second portion of the blade carrier; a replaceable blade release button associated with a deflectable portion of the first blade liner portion; a guard surrounding at least a portion of the replaceable blade release button; and a pin interconnected to the second portion of the blade carrier that is deflected to release the replaceable blade when the release button is depressed. It is yet another aspect of embodiments of the present invention to provide a cutting tool having a blade carrier that is connected to a handle and selectively lockable relative thereto, a blade liner associated with the carrier, and a replaceable blade selectively interconnected to the blade carrier, the improvement comprising: a release button associated with a deflectable portion of the blade liner portion; a guard surrounding at least a portion of the release button; a pin interconnected to the blade carrier and adapted to be received within an aperture of the replaceable blade that is deflected by the release button to release the replaceable blade; and wherein the replaceable blade includes a hook on an upper edge thereof that selectively engages a member integrated within the blade carrier, and wherein the replaceable blade is positioned within the blade carrier along a longitudinal axis of the blade carrier. It is still yet another aspect of embodiments of the present invention to provide a method of replacing a replaceable blade into a knife comprising a blade carrier having a first portion that is spaced from a second portion, the blade carrier being connected to a handle; a first blade liner portion associated with the first blade carrier; a second blade liner portion associated with the second portion of the blade carrier; a replaceable blade positioned between the first blade carrier and the second portion of the blade carrier; a replaceable blade release button associated with a biasing member of the first blade liner portion; a guard surrounding at least a portion of the replaceable blade release button; and a pin interconnected to the second portion of the blade carrier, comprising: depressing the release button; engaging an end of the release button onto the second portion of the blade carrier; deflecting a portion of the second portion of the blade carrier; removing the pin away from an aperture of the replaceable blade; and moving the replaceable blade from the blade carrier. It is still yet another aspect of embodiments of the present invention to provide a guard having a surface texture that is different than a surface texture of a portion of the handle surrounding the guard. It is still yet another aspect of embodiments of the present invention to provide a guard having a surface texture that is different than a surface texture of the replaceable blade release button. It is still yet another aspect of embodiments of the present invention to provide a guard that comprises a raised ridge, at least a portion of which extends from the handle by approximately the same distance as the replaceable blade release button. It is still yet another aspect of embodiments of the present invention to provide a guard that is attached to the handle by an adhesive or a fastener. It is still yet another aspect of embodiments of the present invention to provide a guard that is formed of the same material as the handle. It is still yet another aspect of embodiments of the present invention to provide a guard that comprises portions extending from the handle by a greater distance than other portions. The Summary of the Invention is neither intended nor should it be construed as being representative of the full extent and scope of the present invention. Moreover, references made herein to “the present invention” or aspects thereof should be understood to mean certain embodiments of the present invention and should not necessarily be construed as limiting all embodiments to a particular description. The present invention is set forth in various levels of detail in the Summary of the Invention as well as in the attached drawings and the Detailed Description of the Invention and no limitation as to the scope of the present invention is intended by either the inclusion or non-inclusion of elements, components, etc. in this Summary of the Invention. Additional aspects of the present invention will become more readily apparent from the Detail Description, particularly when taken together with the drawings. BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings, which are incorporated in and constitute a part of the specification, illustrate embodiments of the invention and together with the general description of the invention given above and the detailed description of the drawings given below, serve to explain the principles of these inventions. FIG. 1 is a front elevation view of a folding knife with a replaceable blade of one embodiment of the present invention; FIG. 2 is a front elevation view of FIG. 1; FIG. 3 is a front elevation view of FIG. 1 wherein the replaceable blade has been removed; FIG. 4 is a perspective view of FIG. 1; FIG. 5 is a perspective view of FIG. 1, wherein the blade is partially inserted in the carrier portion of the knife but not locked in a position of use; FIG. 6 is a partial cross-section of FIG. 1; FIG. 7 is a detailed front perspective view wherein a first handle portion has been removed for clarity; FIG. 8 is another detailed front perspective view wherein a first handle portion has been removed for clarity; FIG. 9 is yet another detailed from perspective view wherein a first handle portion has been removed for clarity; and FIG. 10 is a perspective view of another embodiment of the present invention wherein the removable blade element is used in conjunction with a fixed blade; FIG. 11 is a front elevation view of FIG. 10; FIG. 12 is a top plan view of FIG. 10; FIG. 13 is a front elevation view of FIG. 10 showing the removable blade element partially inserted in the carrier portion of the knife but not locked in a position of use; FIG. 14 is a cross-sectional view of FIG. 11; FIG. 15 is a detailed view of FIG. 14; FIG. 16 is a detailed view of FIG. 14, showing an alternate embodiment; FIG. 17 is a perspective view showing a fixed blade version of the knife without the handle; FIG. 18 is a detailed view of FIG. 17; FIG. 19 is a perspective view is a rear perspective view of a fixed blade version if the knife wherein half the handle is omitted for clarity; FIG. 20 is a perspective view of the fixed blade version of the knife; FIG. 21 is a perspective view of a folding knife with a replaceable blade of another embodiment of the present invention; FIG. 22 is a front elevation view of FIG. 21; and FIG. 23 is a top plan view of FIG. 21. To assist in the understanding of one embodiment of the present invention the following list of components and associated numbering found in the drawings is provided herein: # Component 2 Knife 6 Handle 10 Blade 11 Longitudinal axis 12 Transverse asis 14 Blade carrier 15 Member 16 Blade carrier lock release 17 Guide surface 18 Replaceable blade 22 Blade carrier lock 24 Cutting edge 26 Upper portion 30 Replaceable blade lock release button 34 Front blade portion 38 Front edge 46 Replaceable blade lock protrusion 50 Hook 54 Blade carrier liner 58 Lock release button pin end 62 Channel 64 Pin 66 Biasing member 68 Recess 70 Tab 72 Recess 74 Aperture 78 Sloped surface 82 Blade end 84 Blade carrier proximal portion 86 Blade carrier distal portion 90 Carrier point 92 Carrier edge 102 Knife 106 Handle 110 Blade 114 Blade carrier 115 Member 118 Replaceable blade 130 Replaceable blade lock release button 134 Front blade portion 138 Front edge 146 Replaceable blade lock protrusion 150 Hook 154 Blade carrier support 158 Lock release button pin end 162 Opening 166 Biasing member 168 Recess 169 Spring plate 170 Tab 172 Recess 174 Aperture 178 Sloped surface 182 Blade end 184 Sloped surface 202 Knife 206 Handle 210 Blade 214 Blade carrier 216 Blade carrier lock release 218 Replaceable blade 230 Replaceable blade lock release button 324 Guard It should be understood that the drawings are not necessarily to scale. In certain instances, details that are not necessary for an understanding of the invention or that render other details difficult to perceive may have been omitted. It should be understood, of course, that the invention is not necessarily limited to the particular embodiments illustrated herein. DETAILED DESCRIPTION FIGS. 1-9 show a knife 2 of one embodiment of the present invention that includes a handle 6 that is operably interconnected to a blade 10. The handle defines a longitudinal axis 11 and a transverse axis 12. The blade 10 is comprised of a blade carrier 14 that selectively receives a replaceable blade 18. The blade carrier 14 is locked in place by a common locking mechanism 22 (see, FIGS. 8 and 9). In one embodiment of the present invention a lock 22 selectively engages an upper portion 26 of the blade carrier 14 wherein a release button 16 is used to move the lock 22 in a lateral direction which unseats the lock 22 from the blade carrier 14. The replaceable blade 18 has a cutting edge 24, the majority of which is exposed when the replaceable blade is positioned between a first blade carrier portion 14′ and a second blade carrier portion 14″. FIGS. 2 and 3 show the replaceable blade 18 captured by the blade carrier 14 and removed therefrom, respectively. A front blade portion 34 of the replaceable blade 18 extends from a front edge 38 of the blade carrier 14, which facilitates grasping of the replaceable blade 18. That is, the replaceable blade 18 also extends from the front edge 38 of the blade carrier 14, which provides ample room for the user to grasp the replaceable blade 18 with their thumb and forefinger. In addition, the majority of the length of the replaceable blade 18 is supported by the carrier 14, which provides enhanced stiffness and support. More specifically, the blade carrier in some instances will support the replaceable blade 18 such that it can be sharpened. To release the replaceable blade 18, which will be discussed in further detail below, the user engages a replaceable blade lock release button 30. The replaceable blade 18 is secured to the carrier 14 on one end by a lock pin 46 and on the other end by a member 15 positioned between the first blade carrier 14′ and the second blade carrier 14″ that receives a hook 50 on the replaceable blade 18. The member 15 also includes a guide surface 17 that facilitates interconnection of the replaceable blade 18 and the carrier 14. FIG. 3 shows that in one embodiment of the present invention the first blade carrier portion 14′ and the second blade carrier portion 14″ have different widths and/or lengths. More specifically, the first blade carrier portion 14′ may have a width/length that is less than the width/length of the second blade carrier portion 14″. In operation, the replaceable blade 18 is abutted against a portion of the second blade carrier portion 14″ that extends beyond the width or length of the first blade carrier portion 14′. The offset surface between the blade carrier portion forms a ledge that acts as a guide that facilitates interconnection of the replaceable blade 18 into the carrier 14. Without this offset surface, the replaceable blade 18 must be aligned and inserted directly into the small gap between the first blade carrier 14′ and the second blade carrier 14″, thus requiring greater skill and dexterity to facilitate the interconnection of the replaceable blade 18 into the carrier 14. In addition, to facilitate interconnection, an end of the replaceable blade 82 is abutted against the guide surface 17 and slid rewardly until the hook 50 is engaged onto a corresponding portion of the member 15. In this fashion, a user must only grasp the front blade portion 34 of the replaceable blade 18 and safety is enhanced. FIG. 6 is a cross-sectional view of one embodiment of the present invention. The handle is composed of a first handle portion 6′ and a second handle portion 6″ that are spaced to provide a gap for receipt of a proximal portion 84′ of the first blade carrier portion 14′ and a proximal portion 84″ of the second blade carrier portion 14″, wherein a distal portion 86′ of the first blade carrier portion 14′ and a distal portion 84″ of the second blade carrier portion 14″ is located away from the handle as shown in FIG. 4. The first blade carrier 14′ and the second blade carrier 14″ may be of different lengths, wherein a first point 90′ of the first blade carrier 14′ is spaced from a second point 90″ of the second blade carrier relative to the longitudinal axis 11. The first blade carrier 14′ and the second blade carrier 14″ may be of different widths, wherein a first edge 92′ of the first blade carrier 14′ is spaced from a second edge 92″ of the second blade carrier relative to the transverse axis 12. A first blade carrier liner 54′ is associated with the first handle portion 6′ and a second blade carrier liner 54″ is associated with the second handle portion 6″. The first blade carrier liner 54′ and the second blade carrier liner 54″ are associated with corresponding blade carrier portions and provide support thereto. The blade lock release button 30 is associated with the first blade carrier liner 54′ and has an end 58 that selectively engages a flexible portion of the second blade carrier 14″. The first blade carrier 14′ also has an arcuate channel 62 (FIG. 8) that receives a portion of the blade lock release button 30. FIG. 8 shows an arcuate channel 62 in the first blade carrier 14′. The arcuate channel 62 is positioned at least partially around a pin 64 that allows the first blade carrier portion 14′ and the second blade carrier portion 14″ to rotate relative to the handle. The arcuate channel receives a portion of the blade lock release button 30. The pin 64 is interconnected to the first blade liner 54′ or the second blade liner 54″ as shown in FIGS. 7 and 8. FIG. 7 shows the first blade carrier liner 54′ in greater detail. The first blade carrier liner 54′ has a biasing member 66, i.e., an outwardly extending portion thereof that biases the blade release button 30 in a locked position. Depression of the blade release button 30 flexes the biasing member 66 inwardly which forces a portion of the second carrier 14″ into a recess 68 (FIG. 6) of the second blade carrier liner 54″ which removes the lock pin 46 from the replaceable blade 18. One of skill in the art will appreciate that the biasing member may be a deflectable portion of the carrier liner 54′, a leaf spring, a coil spring associated with the blade lock release button 30, or any other spring device known in the art. More specifically, the blade lock release button 30, when depressed, selectively engages a flexible tab 70 of the second blade carrier. The tab also includes the lock pin 46. Depression of the release button 30 deflects the tab 70 and moves the lock pin 46 in a lateral direction which moves the lock pin 46 out of an aperture 74 of the blade 18. The flexible tab 70 may further include a recess 72, indent, or scalloped portion that facilitates deflection. When the obstruction created by the lock pin 46 is removed, the blade 18 can be removed from the blade carriers 14. The lock pin 46 may have a sloped surface 78 that when contacted by an inserting blade deflects the tab 70 so that the blade can be fully inserted. More specifically, sliding the blade 18 in a direction parallel to the longitudinal axis of the knife 2 will engage the rear surface 82 of the blade 18 against the sloped surface 78 of the pin, which will deflect the tab 70. The blade end 82 may employ a corresponding sloped surface (see, FIG. 15, reference no. 184) that interacts with the sloped surface 78 of the pin, which facilitates insertion of the replaceable blade. Once the end portion 82 of the blade 18 is positioned past the lock pin 46, the aperture 74 will eventually be positioned over the lock pin 46 and the pin will recoil to secure the blade. FIGS. 10-20 show a knife 102 of one embodiment of the present invention that includes a handle 106 that is fixedly interconnected to a blade 110. The blade 110 is comprised of a blade carrier 114 that selectively receives a replaceable blade 118. FIGS. 11-13 show the replaceable blade 118 captured by the blade carrier 114 and removed therefrom, respectively. A front blade portion 134 of the replaceable blade 118 extends from a front edge 138 of the blade carrier 14, which facilitates grasping of the replaceable blade 118. That is, the replaceable blade 118 also extends from the front edge 138 of the blade carrier 114, which provides ample room for the user to grasp the replaceable blade 118 with their thumb and forefinger. In addition, the majority of the length of the replaceable blade 118 is supported by the blade carrier 114, which provides enhanced support. To release the replaceable blade 118, which will be discussed in further detail below, the user engages a replaceable blade lock release button 130. As described above with respect to FIGS. 2 and 3, the replaceable blade 118 is secured to the carrier 114 on one end by a lock pin 146 (FIG. 15) and on the other end by a member 115 positioned between the first blade carrier 114′ and the second blade carrier 114″ that receives a hook 150 on the replaceable blade 118. The member 115 also includes a guide surface similar to that described above that facilitates interconnection of the replaceable blade 118 and the carrier 114. Similar to the embodiment shown in FIG. 3, this embodiment of the present invention may also have a first blade carrier portion 114′ and the second blade carrier portion 114″ have different widths and/or lengths. More specifically, the first blade carrier portion 114′ may have a width/length that is less than the width/length of the second blade carrier portion 114″. In operation, the replaceable blade 118 is abutted against a portion of the second blade carrier portion 114″ that extends beyond the width and/or length of the first blade carrier portion 114′. The offset surface between the blade carrier portion forms a ledge that acts as a guide that facilitates interconnection of the replaceable blade 118 into the carrier 114. Without this offset surface, the replaceable blade 118 must be aligned and inserted directly into the small gap between the first blade carrier 114′ and the second blade carrier 114″, thus requiring greater skill and dexterity to facilitate the interconnection of the replaceable blade 118 into the carrier 114. In addition, to facilitate interconnection, an end of the replaceable blade 182 (FIG. 15) is abutted against the guide surface (not show, but similar to the guide surface 17 described above) and slid rewardly until the hook 150 is engaged onto a corresponding portion of the member 115 (FIG. 12). In this fashion, a user must only grasp the front blade portion 134 of the replaceable blade 18 and safety is enhanced. FIGS. 14 and 15 are cross-sectional views of a fixed blade embodiment of the present invention. The handle 106 is composed of a first handle portion 106′ and a second handle portion 106″. A first blade carrier support 154′ is associated with the first handle portion 106′ and a second blade carrier support 154″ is associated with the second handle portion 106″. The blade lock release button 130 is associated with the first blade carrier support 154′ and has an end 158 that selectively engages a flexible portion of the second blade carrier 114″. FIG. 15 shows the first blade carrier support 154′ in greater detail. The first blade carrier support 154′ has a biasing member 166, i.e., an outwardly extending portion thereof that biases the blade release button 130, which is secured thereto. Depression of the blade release button 130 flexes the biasing member 166 inwardly which forces a portion of the second carrier 114″ into a recess 168 which removes the lock pin 146 from the blade 118. One of skill in the art will appreciate that the biasing member may be a deflectable portion of the carrier support 54′, a leaf spring, a coil spring associated with the blade lock release button 30, or any other spring device known in the art. FIG. 16 shows the first blade carrier 114′ in greater detail. In this embodiment the first blade carrier 114′ and the second blade carrier 114″ extend towards the midpoint of the handle 106. Further, the biasing member 166 is integral with the first blade carrier 114′. In addition, liners described above are not needed. Depression of the blade release button 130 flexes the biasing member 166 inwardly which forces a portion of the second carrier 114″ into a recess 168 which removes the lock pin 146 from the blade 118. One of skill in the art will appreciate that the biasing member may be a leaf spring, a coil spring associated with the blade lock release button 30, or any other spring device known in the art. More specifically, the blade lock release button 130, when depressed, selectively engages a flexible tab 170 of the second blade carrier 114″. The tab 170 also includes the lock pin 146. The flexible tab 170 may further include a recess 172, indent, or scalloped portion that facilitates deflection. Depression of the release button 130 deflects the tab 170and moves the lock pin 146 in a lateral direction which moves the lock pin 146 out of an aperture 174 of the blade 118. When the obstruction created by the lock pin 146 is removed, the blade 118 can be removed from the blade carriers 114. The lock pin 146 may have a sloped surface 178 that when contacted by an inserting blade deflects the tab 170 so that the blade can be fully inserted. The blade end 182 may employ a corresponding sloped surface 184 that interacts with the sloped surface 178 of the pin, which facilitates insertion of the replaceable blade. More specifically, sliding the blade 118 in a direction parallel to the longitudinal axis of the knife 102 will engage the rear surface of the blade 118 against the sloped surface 78 of the pin, which will deflect the tab 170. Once the end portion 182 of the blade 118 is positioned past the lock pin 146, the aperture 174 will eventually be positioned over the lock pin 146 and the pin will recoil to secure the blade. FIGS. 21-23 show a knife 202 of one embodiment of the present invention that includes a handle 206 that is operatively interconnected to a blade 210. The blade 210 is comprised of a blade carrier 214 that selectively receives a replaceable blade 218. Replaceable blade lock release button 230 is surrounded in this embodiment by a guard 234, which forms a raised ridge around replaceable blade lock release button 230. During use of the knife 202, the guard 234 protects replaceable blade lock release button 230 from accidental operation. More specifically, the raised ridge of guard 234 provides a surface can be easily felt by the user, such that the user can detect when his or her fingers or hands are in close proximity to replaceable blade lock release button 230 and exercise a heightened degree of caution. The surface texture of the guard 234 may also be different than the surface texture of the handle 206 and/or the replaceable blade lock release button 230. This allows a user to distinguish the guard 234 from the handle 206 and/or the replaceable blade lock release button 230, thus further enhancing the user's ability to determine, by touch, when a finger, hand, or other member is close to the replaceable blade lock release button 230, and thus to avoid accidental operation thereof. Additionally, portions of the guard 234 extend from the handle 206 by approximately the same distance that the replaceable blade lock release button 230 extends from the handle 206. As a result, a depressing force must be applied directly to the replaceable blade lock release button 230 to operate the button 230. If a finger, hand, or other member applies a depressing force not just to the replaceable blade lock release button 230 but also to the guard 234, then the guard 234, which is fixed and will not yield to the depressing force, will prevent the finger, hand, or other member from completely depressing the replaceable blade lock release button 230. As persons of ordinary skill in the art will recognize based on the foregoing disclosure, a guard 234 be utilized in any knife of an embodiment according to the present disclosure to guard against accidental or inadvertent depression of the replaceable blade lock release button 230. Persons skilled in the art will also recognize, based on the present disclosure, that a guard 234 may take many shapes, in addition to the shape depicted in FIGS. 21-23. In particular, the guard 234 may be, without limitation, circular, elliptical, triangular, square, or rectangular. The guard 234 may have straight edges, curved edges, or both. The guard 234 may form a raised ridge around the entirety of the replaceable blade lock release button 230, or around just a portion of lock release button 230. A ridge formed by the guard 234 may extend from the handle 206 of the knife 202 by the same distance as replaceable blade lock release button 230, or by a greater distance, or by a lesser distance. The ridge formed by the guard 234 may extend from the handle 206 a greater distance in some portions than in other portions. In some embodiments, the guard may be centered around the replaceable blade lock release button 230, while in other embodiments, the guard may not be centered around the replaceable blade lock release button 230. The guard 234 may be initially formed as part of the handle 206, or it may be formed separately and attached to the handle 206 via an adhesive (e.g. glue) or a fastener (e.g. a clip or screw). The guard 234 may be formed of the same material as the handle 206, or of a different material. The blade of embodiments of the present invention is made out of high carbon or high carbon stainless steel and is approximately 2.5-4.0 inches (about 63.5-102 mm) long. The blade carriers are made of stainless steel and are spaced about 0.02-0.15 inches (about 0.55-3.8 mm) from each other. The blade carrier supports are made out of stainless steel or plastic however, one of skill in the art will appreciate that the replaceable blade, blade carriers, and blade supports may be made of any suitable material. While various embodiments of the present invention have been described in detail, it is apparent that modifications and alterations of those embodiments will occur to those skilled in the art. However, it is to be expressly understood that such modifications and alterations are within the scope and spirit of the present invention, as set forth in the following claims. Further, the invention(s) described herein is capable of other embodiments and of being practiced or of being carried out in various ways. In addition, it is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of “including,” “comprising,” or “having” and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items. | <SOH> BACKGROUND OF THE INVENTION <EOH>Knives are usually comprised of a handle with a blade that is interconnected thereto. Some knives employ blades that are rotatably interconnected, and selectively lockable, to the handle. When the knife is not in use, it is sheathed or, in the case of folding knives, the blade is folded into the handle. When in use, the rotatable blade is extended from the handle and locked in place. Such locking mechanisms are known and engage a portion of the blade to hold it in place until the user disengages the lock mechanism, which allows the blade to be folded into an opening in the handle to conceal all or a portion of the blade. Regardless of knife type, it is desirable to provide a cutting edge that is very sharp, similar to the sharpness provided by a razor blade. However, razor blade sharpness comes at a price. More specifically, razor blades often possess very thin edges that are brittle and wear, i.e., lose their edge, relatively quickly. Blade performance can be repaired by sharpening, but doing so will reduce blade size and durability. In addition, thin razor blades lack lateral strength and are thus flimsy and can fracture easily when put to hard use to cut forcibly or when cutting at an angle that applies lateral side-force to the blade. Thus, some knives employ a razor-sharp replaceable blade element that fits within a blade carrier, which may be foldable within a handle. Once the replaceable blade element becomes dull, or after repeated sharpening, it is removed from the blade carrier and discarded. Another razor blade is then inserted into the carrier. Some knives of this type employ a complicated blade interconnection mechanism. For example, U.S. Pat. Nos. 5,689,889 and 6,574,868 to Overholt disclose razor blades for interconnecting to a blade carrier of folding knife. These knives receive the replacement blade member in a complicated fashion wherein the replaceable blade element must be first introduced into the blade carrier at and angle and then rotated into place. Finally, the replaceable blade element is locked within the blade carrier. As one of skill in the art will appreciate, replacing a blade in this fashion is difficult and, because the replaceable blade members are extremely sharp, manipulating the blade into place can cause injury. To lock and secure the blade, Overholt discloses the use of a separate threaded fastener that attaches to the blade carrier. To replace the blade, the fastener must first be loosened and completely detached from the blade carrier before the sharpened razor blade portion can be removed. This is time consuming and dangerous because the user must remove the fastener by hand from the blade carrier, which is located in close proximity to the sharp cutting edge of the razor blade. Further, loosening or removing the fastener requires the use of both hands, which makes it not possible to safely hold the knife or secure the knife by the handle while removing the fastener. Further, the fastener is commonly made up of two or more small parts that must be detached from the blade carrier to replace the blade. The fastener parts can easily be dropped and lost, especially when used in the outdoors. If one or more small parts of the fastener are lost when changing the blade, the new blade cannot be attached to the blade carrier and the knife is no longer functional. The following disclosure describes a knife with the replaceable blade that is selectively inserted into blade carrier in a way that facilitates easy interconnection, reduces the chance of injury, and eliminates the need for separate parts that must be detached from the knife to remove and insert a new blade. | <SOH> SUMMARY OF THE INVENTION <EOH>It is one aspect of embodiments of the present invention to provide a folding knife with a replaceable blade. More specifically, one embodiment of the present invention includes a handle having a first portion and a second portion spaced from the first portion. The space between the first handle portion and the second handle portion receives the replaceable blade when the knife is not in use. A blade carrier is rotatably interconnected to the handle and operates as in a traditional folding knife: 1) in a first position of use wherein at least a portion of the blade carrier is positioned within the housing; and 2) in a second position of use wherein the blade carrier is locked in an open position and extended from the housing. The blade carrier selectively receives a replaceable blade element. It is another aspect of embodiments of the present invention to provide a non-folding knife with the replaceable blade portion. More specifically, one embodiment of the present invention includes a handle with a fixed blade carrier. The blade carrier of embodiments of the present invention have a first carrier portion and a second carrier portion, which is spaced from the first carrier portion, which receives the replaceable blade. The first carrier also includes a channel that selectively receives a pin. The second blade carrier includes a flexible member with a pin that selectively engages an aperture in the replaceable blade member to secure it to the blade carrier. To replace the blade, a release button, which is spring-biased relative to the handle, is depressed which deflects portion of the second blade carrier. Deflection of the blade carrier removes the pin from the aperture, which allows the blade to be removed. The blade is inserted in a direction generally parallel to the longitudinal axis of the handle, i.e., in a direction parallel to the length of the handle. Thus complicated blade rotation is not necessary to secure the blade to the blade carrier. It is another aspect of embodiments of the present invention to provide a knife that includes a replaceable blade that is safe and easy to remove. More specifically, as mentioned above, replaceable blades of the prior art are in many respects difficult to engage into the blade carrier and require a complicated interconnection sequence requiring the use of both hands to remove the locking/retaining portion of the blade from the blade carrier. The contemplated replaceable blade portion is inserted longitudinally relative to the handle. Also, the blade is designed to extend from the carrier so that is easy to grasp with the thumb and forefinger of one hand while the other hand securely grasps the handle portion and depresses the lock release button with one finger. This makes it much easier, faster, and safer to attach and remove the replaceable blade. It is another aspect of embodiments of the present invention to provide a knife that eliminates the need for small separate parts (other than the replacement blades) that must be detached from the knife to change the blade. The prior art teaches a blade fastener that requires small parts that must be detached and can easily be lost when replacing the blade. With embodiments of the present invention, there are no separate parts required to fasten and detach the replaceable blade from the knife. It is another aspect of embodiments of the invention to provide a knife, comprising: a blade carrier having a first portion that is spaced from a second portion, the blade carrier being connected to a handle; a first blade liner portion associated with the first blade carrier; a second blade liner portion associated with the second portion of the blade carrier; a replaceable blade positioned between the first blade carrier and the second portion of the blade carrier; a replaceable blade release button associated with a deflectable portion of the first blade liner portion; a guard surrounding at least a portion of the replaceable blade release button; and a pin interconnected to the second portion of the blade carrier that is deflected to release the replaceable blade when the release button is depressed. It is yet another aspect of embodiments of the present invention to provide a cutting tool having a blade carrier that is connected to a handle and selectively lockable relative thereto, a blade liner associated with the carrier, and a replaceable blade selectively interconnected to the blade carrier, the improvement comprising: a release button associated with a deflectable portion of the blade liner portion; a guard surrounding at least a portion of the release button; a pin interconnected to the blade carrier and adapted to be received within an aperture of the replaceable blade that is deflected by the release button to release the replaceable blade; and wherein the replaceable blade includes a hook on an upper edge thereof that selectively engages a member integrated within the blade carrier, and wherein the replaceable blade is positioned within the blade carrier along a longitudinal axis of the blade carrier. It is still yet another aspect of embodiments of the present invention to provide a method of replacing a replaceable blade into a knife comprising a blade carrier having a first portion that is spaced from a second portion, the blade carrier being connected to a handle; a first blade liner portion associated with the first blade carrier; a second blade liner portion associated with the second portion of the blade carrier; a replaceable blade positioned between the first blade carrier and the second portion of the blade carrier; a replaceable blade release button associated with a biasing member of the first blade liner portion; a guard surrounding at least a portion of the replaceable blade release button; and a pin interconnected to the second portion of the blade carrier, comprising: depressing the release button; engaging an end of the release button onto the second portion of the blade carrier; deflecting a portion of the second portion of the blade carrier; removing the pin away from an aperture of the replaceable blade; and moving the replaceable blade from the blade carrier. It is still yet another aspect of embodiments of the present invention to provide a guard having a surface texture that is different than a surface texture of a portion of the handle surrounding the guard. It is still yet another aspect of embodiments of the present invention to provide a guard having a surface texture that is different than a surface texture of the replaceable blade release button. It is still yet another aspect of embodiments of the present invention to provide a guard that comprises a raised ridge, at least a portion of which extends from the handle by approximately the same distance as the replaceable blade release button. It is still yet another aspect of embodiments of the present invention to provide a guard that is attached to the handle by an adhesive or a fastener. It is still yet another aspect of embodiments of the present invention to provide a guard that is formed of the same material as the handle. It is still yet another aspect of embodiments of the present invention to provide a guard that comprises portions extending from the handle by a greater distance than other portions. The Summary of the Invention is neither intended nor should it be construed as being representative of the full extent and scope of the present invention. Moreover, references made herein to “the present invention” or aspects thereof should be understood to mean certain embodiments of the present invention and should not necessarily be construed as limiting all embodiments to a particular description. The present invention is set forth in various levels of detail in the Summary of the Invention as well as in the attached drawings and the Detailed Description of the Invention and no limitation as to the scope of the present invention is intended by either the inclusion or non-inclusion of elements, components, etc. in this Summary of the Invention. Additional aspects of the present invention will become more readily apparent from the Detail Description, particularly when taken together with the drawings. | B26B500 | 20171018 | 20180208 | 71389.0 | B26B500 | 1 | RILEY, JONATHAN G | FOLDING KNIFE WITH REPLACEABLE BLADE | SMALL | 1 | CONT-ACCEPTED | B26B | 2,017 |
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15,787,498 | PENDING | CHEWING GUM COMPOSITION COMPRISING CANNABINOIDS AND OPIOID AGONISTS AND/OR ANTAGONISTS | A chewing gum composition comprising cannabinoids or derivatives thereof and at least one opioid and optionally an opioid antagonist is provided. The chewing gum composition is formulated to provide controlled release of cannabinoids and opioid agonists and/or opioid antagonist during mastication. Methods to provide opioid addiction or dependence treatment, opioid addiction or dependence with concurrent cannabis addiction or dependence treatment, or pain treatment using the chewing gum composition according to this invention are also provided. | 1. A chewing gum composition comprising, based on total weight of the composition: 0.1 to 5% by weight of at least one cannabinoid; 0.01 to 1% by weight of at least one opioid; 20 to 95% by weight of a gum base; 5 to 35% by weight of at least one buffering agent selected from the group consisting of acetates, glycinates, phosphates, carbonates, glycerophosphates, citrates, and borates; 1 to 10% by weight of at least one flavoring agent selected from the group consisting of peppermint, spearmint, licorice, cinnamon, watermelon, vanilla, pineapple, apple, and cranberry; 1 to 65% by weight of at least one sweetening agent selected from the group consisting of isomalt, sorbitol, stevia, maltitol, and xylitol; at least one anti-oxidant selected from the group consisting of ascorbyl palminate and sodium ascorbate; and at least one preservative. 2. The chewing gum composition of claim 1, wherein the at least one cannabinoid is cannabidiol, Δ9-tetrahydrocannabinol, cannabichromene, cannabigerol, cannabidivarin, derivatives thereof, or their acid metabolites. 3. The chewing gum composition of claim 1, wherein the at least one cannabinoid is provided in combination with at least one suitable carrier selected from the group consisting of sugar alcohol, microcrystalline cellulose derivatives, dextran, agarose, agar, pectin, alginate, xanthan, chitosan, and starch. 4. The chewing gum composition of claim 1, wherein the at least one cannabinoid is provided in microencapsulated form, nanoencapsulated form, or in freeze dried form. 5. The chewing gum composition of claim 1, wherein the at least one cannabinoid is provided in internal voids within a suitable solid carrier. 6. The chewing gum composition of claim 1, wherein the at least one cannabinoid is provided in a granule within the gum matrix. 7. The chewing gum composition of claim 1, wherein the at least one cannabinoid is procured from natural sources or synthetic. 8. The chewing gum composition of claim 1, wherein the at least one opioid is an opioid agonist selected from the group consisting of morphine, codeine, thebaine, hydrocodone, hydromorphone, oxycodone, oxymorphone, buprenorphine, fentanyl, methadone, pethidine, levorphanol, tramadol, and dextropropoxyphene. 9. The chewing gum composition of claim 1, wherein the at least one opioid is an opioid prodrug selected from the group consisting of 6-monoacetyl morphine, nicomorphine, dipropanoylmorphine, desomorphine, methyldesorphine, acetylpropionyl morphine, dibenzoyl morphine, and diacetyl dihydromorphine. 10. The chewing gum composition of claim 1, wherein the at least one opioid is an opioid antagonist selected from the group consisting of Naloxone hydrochloride dehydrate and natrexone hydrochloride. 11. The chewing gum composition of claim 1, wherein the at least one opioid comprises both opioid agonist and opioid antagonist. 12. The chewing gum composition of claim 1, wherein the at least one opioid is provided in nanoencapsulated or microencapsulated form. 13. The chewing gum composition of claim 1, wherein the preservative is citric acid. 14. The chewing gum composition of claim 1, further comprising at least one pharmaceutically acceptable excipient selected from the group consisting of fillers, disintegrants, binders, and lubricants. 15. The chewing gum composition of claim 14, further comprising silicon dioxide or magnesium stearate. 16. A method to treat opioid addiction or dependence in a mammal in need thereof, comprising administering to the mammal the chewing gum composition of claim 1. 17. The method of claim 16, wherein the mammal receives the chewing gum administration 1 to 6 times a day. 18. A method to treat opioid addiction or dependence concurrent with cannabis addiction or dependence in a mammal in need thereof, comprising administering to the mammal the chewing gum composition of claim 1. 19. The method of claim 18, wherein the mammal receives the chewing gum administration 1 to 6 times a day. 20. A method to treat pain in a mammal in need thereof, comprising administering to the mammal the chewing gum composition of claim 1. | CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62/410,469, filed Oct. 20, 2016, the content of which is hereby incorporated by reference in its entirety. BACKGROUND OF THE INVENTION Field of the Invention Opioid addiction treatment and cannabis dependence treatment are developing areas with many proposed techniques and remedies. This invention involves a chewing gum composition with controlled release of cannabinoids and opioid agonists and/or antagonists for opioid and cannabis addiction and/or dependence treatment. This chewing gum may also be used for treatment of chronic pain. Description of the Related Technology Opioids are a group of analgesic agents commonly used in clinical practice but are also commonly seen as addictive agents. Opioids bind to opioid receptors, which are found in the central and peripheral nervous system and the gastrointestinal tract. These receptors mediate both psychoactive and the somatic effects of opioids. Opioids agonists include morphine, codeine, thebaine, hydrocodone, hydromorphone, oxycodone, oxymorphone, buprenorphine, fentanyl, methadone, pethidine, levorphanol, tramadol, and dextropropoxyphene. Opioids cause euphoria and thus are used illicitly. In 2011, an estimated of 4 million people in the United States used opioids recreationally and were dependent on them. Opioid dependency may start with prescription use of opioid which turns into illicit drug use. Physical dependence is the physiological adaptation of the body to the presence of a substance, in this case an opioid. It is the development of withdrawal symptoms when the substance is discontinued. Withdrawal symptoms of opiates may include severe dysphoria, craving, irritability, sweating, nausea, tremor, vomiting, and myalgia. The speed and severity of withdrawal symptoms occurrence depend on half-life of the opioid. Heroin and morphine withdrawal occur more quickly and are more severe than methadone withdrawal. The acute withdrawal phase is often followed by a protracted phase of depression and insomnia that can last for months. Addiction is marked by a change in behavior caused by the biochemical changes in the brain after continued substance abuse. Substance use becomes the main priority of the addict, regardless of the harm they may cause to themselves or others. An addiction causes people to act irrationally when they don't have the substance they are addicted to in their system. Addiction encompasses both mental and physical reliance on the substance. Opioid addiction therapy depends on a variety of techniques. Among them is replacement therapy, wherein an opioid is replaced with another less addictive opioid, which curbs the craving feeling and reduces withdrawal symptoms, while maintains the subject's mental state such that the subject is still able to function normally. Opioid replacement therapy is not without adverse effect. Methadone used long term may lead to potentially deadly slowed breathing. The analgesic effect in methadone ends long before the methadone half life, thus more methadone is needed, causing a built up of methadone. The cannabis plant has many naturally occurring substances that are of great interest in the fields of science and medicine. Isolated compounds from the cannabis plant include Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabichromene (CBC), cannabigerol (CBG), cannabidivarin (CBDV), among other compounds. While THC has psychoactive effects, CBD, CBC, CBG, and CBDV do not. Isolated compounds from the cannabis plant are called cannabinoids. There are a total of one hundred and forty one (141) cannabinoids that have been isolated from the cannabis plant. Many researchers have confirmed the medicinal value of cannabinoids. Cannabinoids have been investigated for possible treatment of seizures, nausea, vomiting, lack of appetite, pain, arthritis, inflammation, and other conditions. The IUPAC nomenclature of THC is (-)-(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a, 7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol. CBD's IUPAC nomenclature is 2-((1S, 65)-3-methyl-6-(prop-1-en-2-yl)cyclo-hex-2-enyl)-5-pentylbenzene-1,3 -diol). CBC has the IUPAC nomenclature of 2-methyl-2-(4-methylpent-3-enyl)-7pentyl-5-chromenol. These are among the most prominent compounds in the family of compounds extracted from the cannabis plant referred to as cannabinoids. Cannabinoids may be isolated by extraction or cold pressing of cannabis plants. Plants in the cannabis genus include Cannabis sativa, Cannabis ruderalis, and Cannabis indica. These plants are the natural sources of cannabinoids. Cannabinoids are also available in synthetic forms. Methods to synthesize cannabinoids in lab settings were discovered and are still currently practiced. Synthetic cannabinoids are more targeted, in that the synthetic compound usually comes isolated without other cannabinoids mixed in. Cannabinoids from industrial hemp are marketed in the United States, such as cannabidiol. Various products containing cannabinoids have been marketed in recent years. Cannabinoids may be consumed by ingestion, by inhalation, via transmucosal, or by transdermal delivery. Cannabis dependence is mainly due to Δ9-THC presence in cannabis. When a mammal consumes cannabis, Δ9-THC gives the “high” feeling. Cannabis addiction in the form of smoking cannabis also gives rise to lung cancer risk similar to tobacco smoking. Opioid addiction treatment remains a challenge. This invention proposes a product to treat opioid addiction standing alone or concurrent opioid and Δ9-THC addiction/dependence. ABBREVIATIONS CBC: cannabichromene CBD: cannabidiol CBDV: cannabidivarin CBG: cannabigerol Δ9-THC: delta-9-tetrahydrocannabinol SUMMARY The present invention relates to a chewing gum composition comprising cannabinoids or derivatives thereof and at least one opioid agonist and/or antagonist. Cannabinoids or derivatives thereof and opioid agonists and/or antagonists are under controlled release during mastication and consumption. This invention further relates to the use of this chewing gum composition in treating opioid addiction or dependence, concurrent cannabis and opioid addiction and/or dependence, or pain. This invention provides a chewing composition comprising, based on total weight of the composition: 0.1 to 5% by weight of at least one cannabinoid; 0.01 to 1% by weight of at least one opioid; 20 to 95% by weight of a gum base; 5 to 35% by weight of at least one buffering agent selected from the group consisting of acetates, glycinates, phosphates, carbonates, glycerophosphates, citrates, and borates; 1 to 10% by weight of at least one flavoring agent selected from the group consisting of peppermint, spearmint, licorice, cinnamon, watermelon, vanilla, pineapple, apple, and cranberry; 1 to 65% by weight of at least one sweetening agent selected from the group consisting of isomalt, sorbitol, stevia, maltitol, and xylitol; at least one anti-oxidant selected from the group consisting of ascorbyl palminate and sodium ascorbate; and at least one preservative. This invention provides a chewing gum composition according to embodiments wherein the at least one cannabinoid is cannabidiol, A9-tetrahydrocannabinol, cannabichromene, cannabigerol, cannabidivarin, derivatives thereof, or their acid metabolites. This invention provides a chewing gum composition according to embodiments wherein the at least one cannabinoid is provided in combination with at least one suitable carrier selected from the group consisting of sugar alcohol, microcrystalline cellulose derivatives, dextran, agarose, agar, pectin, alginate, xanthan, chitosan, and starch. This invention provides a chewing gum composition according to embodiments wherein the at least one cannabinoid is provided in microencapsulated form, nanoencapsulated form, or in freeze dried form. This invention provides a chewing gum composition according to embodiments wherein the at least one cannabinoid is provided in internal voids within a suitable solid carrier. This invention provides a chewing gum composition according to embodiments wherein the at least one cannabinoid is provided in a granule within the gum matrix. This invention provides a chewing gum composition according to embodiments wherein the at least one cannabinoid is procured from natural sources, such as deriving or extracting from cannabis plants, or synthetic. This invention provides a chewing gum composition according to embodiments wherein the at least one opioid is an opioid agonist selected from the group consisting of morphine, codeine, thebaine, hydrocodone, hydromorphone, oxycodone, oxymorphone, buprenorphine, fentanyl, methadone, pethidine, levorphanol, tramadol, and dextropropoxyphene. This invention provides a chewing gum composition according to embodiments wherein the at least one opioid is an opioid prodrug selected from the group consisting of 6-monoacetyl morphine, nicomorphine, dipropanoylmorphine, desomorphine, methyldesorphine, acetylpropionyl morphine, dibenzoyl morphine, and diacetyl dihydromorphine. This invention provides a chewing gum composition according to embodiments wherein the at least one opioid is an opioid antagonist selected from the group consisting of Naloxone hydrochloride dehydrate and natrexone hydrochloride. This invention provides a chewing gum composition according to embodiments wherein the at least one opioid comprises both opioid agonist and opioid antagonist. This invention provides a chewing gum composition according to embodiments wherein the at least one opioid is provided in nanoencapsulated or microencapsulated form. This invention provides a chewing gum composition according to embodiments wherein the preservative is citric acid. The invention provides a chewing gum composition according to embodiments which may further comprise at least one pharmaceutically acceptable excipient selected from the group consisting of fillers, disintegrants, binders, and lubricants. This invention provides a chewing gum composition according to embodiments which may further comprise silicon dioxide or magnesium stearate. This invention provides a method to treat opioid addiction in a mammal in need thereof, comprising administering to the mammal a chewing gum composition according to this invention. This invention provides a method to treat opioid addiction or dependence in a mammal in need thereof, comprising administering to the mammal a chewing gum composition according to this invention, wherein the mammal receives the chewing gum administration 1 to 6 times a day. This invention provides a method to treat opioid addiction or dependence concurrent with cannabis addiction or dependence in a mammal in need thereof, comprising administering to the mammal a chewing gum composition according to this invention. This invention provides a method to treat opioid addiction concurrent with cannabis dependence in a mammal in need thereof, comprising administering to the mammal a chewing gum composition according to this invention, wherein the mammal receives the chewing gum administration 1 to 6 times a day. This invention provides a method to treat pain in a mammal in need thereof, comprising administering to the mammal a chewing gum composition according to this invention. DETAILED DESCRIPTION OF CERTAIN INVENTIVE EMBODIMENTS Embodiments of this application relate to a chewing gum composition comprising cannabinoids and opioid agonists and/or antagonists, wherein cannabinoids and opioid agonists and/or antagonists are incorporated into the chewing gum for controlled release. The chewing gum composition may be consumed by a human for cessation of opioid and/or cannabis dependence and/or addiction. In embodiments, the chewing composition may comprise 0.1-5% by weight of at least one cannabinoid or derivatives thereof based on total weight of the composition. In a 2 g chewing gum piece, cannabinoids or derivatives thereof may comprise 2-100 mg. Cannabinoids in the chewing gum composition according to embodiments may be synthetic or procured from natural source. Cannabinoids may also be in oily form, as cannabis oil, hemp oil, or hashish oil. In these embodiments, cannabinoids may be provided in a carrier to prevent absorption into the gum matrix. It is contemplated that cannabinoids provided in oily form may be used in the embodiments described herein. Cannabinoids may be provided in a solid material carrier composed of an edible solid, such as a sugar alcohol, and cannabinoids, to prevent binding with the gum base. Cannabinoids may be embedded into the sugar alcohol. Other solids suitable for embedding cannabinoids are contemplated, such that cannabinoids are provided within internal voids of solid materials. Alternatively, cannabinoids or derivatives thereof may be provided in a granule embedded into the gum matrix. Cannabinoids provided in these manners may improve cannabinoid release during mastication of the chewing gum according to embodiments. Cannabinoids may also be provided in microencapsulated or nanoencapsulated form or in freeze dried form. Microencapsulated or nanoencapsulated and freeze dried cannabinoids may improve the chewing gum's taste, improve stability, prevent binding with the gum matrix, control cannabinoid release during mastication, and further improve bioavailability of the cannabinoids once entering the gastrointestinal tract. In embodiments, cannabinoids provided in encapsulated form may be particles of size 20-40 nm, which may improve bioavailability profiles of cannabinoids and prevent degradation in gastric fluid. Encapsulation may result in liposomal particles containing cannabinoids and derivatives thereof. In these embodiments, cannabinoids may be Δ9-tetrahydrocannabinol (THC), cannabichromene (CBC), cannabigerol (CBG), cannabidivarin (CBDV), cannabidiol (CBD), other cannabinoids, derivatives thereof, their acid metabolites, or a combination of cannabinoids and/or their acid metabolites and/or derivatives thereof. Cannabinoids described herein may be natural or synthetic cannabinoids. Other suitable carriers which may be combined with cannabinoids before inclusion into the gum matrix may include certain celluloses, such as microcrystalline cellulose derivatives, dextran, agarose, agar, pectin, alginate, xanthan, chitosan, or starch. The combination of cannabinoids and suitable carriers may result in cannabinoid being present within internal voids of these carriers. Providing cannabinoids by combining with a suitable carrier or by providing cannabinoids in a capsule within the gum matrix may enable controlled release of cannabinoids during chewing of the chewing gum composition. Providing cannabinoids in microencapsulated, nanoencapsulated, or freeze dried form may also enable controlled release of cannabinoids during chewing of the chewing gum composition. In embodiments, the chewing gum composition may further comprise at least one opioid to act as opioid agonist and/or antagonist. Opioids may be present in the chewing gum composition at 0.01-1% by weight based on the total weight composition. In a 2 g chewing gum piece, opioid may comprise 0.2-20 mg. Opioids in the chewing gum composition according to embodiments may be opioid agonists. Opioid agonists may be derived from plant, such as morphine, codeine, or thebaine. Semi-synthetic opioids may be used, such as hydrocodone, hydromorphone, oxycodone, oxymorphone, or buprenorphine. Buprenorphine, in particular, is both an opioid agonist and antagonist, and thus its effect in opioid addiction in treatment is both as a replacement opioid and an antagonist of opioids. Synthetic opioids may also be used, such as fentanyl, methadone, pethidine, levorphanol, tramadol, or dextropropoxyphene. Prodrugs of the above opioids may also be used, such as 6-monoacetyl morphine, nicomorphine (morphine dinicotinate), dipropanoylmorphine (morphine dipropionate), desomorphine (di-hydro-desoxy morphine), methyldesorphine, acetylpropionyl morphine, dibenzoyl morphine, or diacetyl dihydromorphine. Opioid antagonists such as Naloxone hydrochloride dehydrate (C19H21NO4) and naltrexone hydrochloride (C20H23NO4) may also be included in the chewing gum composition according to embodiments in addition to opioid agonists. Where opioid antagonists are included, opioid antagonists may be at 3:1 to 5:1, more specifically 4:1 ratio by weight for opioid agonist:opioid antagonist. Certain opioids may reduce craving sensation while minimizing adverse effects on users. In opioid addiction treatments, withdrawal symptoms may be the main obstacle to recovery. When opioid agonists are provided, they may bind to opioid receptors, reducing the adverse effect of opioid withdrawal. Moreover, opioids consumed by injection, such as heroin injection, may pose additional risks to users. By providing replacement opioids in a controlled release chewing gum, replacement opioids may curb craving sensation while reducing adverse withdrawal symptoms and preventing adverse effects caused by injection. On the other hand, adding an opioid antagonist may counteract the effects of the agonists, for example the addictive opioid such as heroin, and thus eventually reduce opioid addiction. Cannabinoids, on the other hand, may also curb craving sensation. Finally, by providing replacement opioids such as opioid agonists and/or antagonists and cannabinoids in a chewing gum form, users may avoid adverse effects caused by injection and/or smoking. In embodiments, opioids provided may be microencapsulated or nanoencapsulated. Encapsulation may improve the chewing gum's taste as a whole. Encapsulation may aid with dissolution in the subject's oral cavity and transmucosal delivery mechanism. Encapsulation may also enable controlled release of opioids during chewing of the chewing gum composition. Encapsulation may improve opioids' bioavailability profile upon mastication of the chewing gum composition. Methods to encapsulate opioids may be methods commonly used in the art, such as precision particle encapsulation. A method to encapsulate active ingredients in described in Berkland, C., M. King, et al. (2002). “Precise control of PLG microsphere size provides enhanced control of drug release rate.” J Control Release 82(1): 137-147. This reference is hereby included in its entirety. Gum base provided for the chewing gun composition according to these embodiments may be non-disintegrating. Gum base such as Gum powder PG 11 TA, Gum powder PG 11 TA New, Gum powder PG 5 TA, Gum powder PG 5 TA New, and Gum powder PG N12 TA may be used. Gum base may comprise 20-95% by weight of the composition. In embodiments, at least one buffering agent may be included in this chewing gum composition. Suitable buffering agents may include acetates, glycinates, phosphates, carbonates, glycerophosphates, citrates, borates, and/or mixtures thereof. Buffering agents may be present at 5-35% by weight. In embodiments, the chewing gum composition may have other ingredients to improve organoleptic properties. The chewing gum composition according to embodiments may include at least one flavoring agent and at least one sweetening agent. Ingredients such as certain flavoring agents may be included. Flavoring agents may include peppermint, spearmint, licorice, cinnamon, watermelon, vanilla, pineapple, apple, cranberry, and/or other suitable flavoring agents. Certain food colorants may be included to improve the aesthetic appearance of the chewing gum composition. Flavoring agents may be present in this chewing composition at 1-10% by weight. Sweetening agents may be present at 1-65% of by weight of the composition according to embodiments. Sweetening agents used in chewing gums according to embodiments may be isomalt, sorbitol, stevia, maltitol, xylitol, or other suitable sweetening agents, and/or combinations thereof. In embodiments, the chewing gum composition may comprise ingredients for preservation such as citric acid. Additional ingredient to assist with powder flow and prevent the gum base from sticking to manufacturing surfaces may be included. Such ingredient may be silicon dioxide or magnesium stearate. Other ingredients for preservation and manufacturing management may also be used. Additional pharmaceutically acceptable excipients used in the chewing gum composition according to embodiments may be fillers, disintegrants, binders, or lubricants. Anti-oxidants such as ascorbyl palminate and sodium ascorbate may also be included. The chewing gum composition according to embodiments may comprise at least one pharmaceutically acceptable excipient and/or at least one anti-oxidant. The chewing gum composition according to embodiments may be made by a compressing process or by a hot process. In the compressing process, ingredients are mixed and compressed into the gum base using a compress machine. In the hot process, ingredients are mixed and heated before the gum base is poured in. The gum mixture is then molded and left to cure. The gum mixture may then be cut into appropriate size for consumption, such as 2 grams for each piece. The gum pieces may be coated with a polyol coating such as sorbitol, maltitol, isomalt, or starch. The coating layer may prevent moisture from penetrating into the gum matrix. The gum pieces may be wrapped in separate pieces of wrapping materials and packaged into a pack or box, or packaged into a blister package. The chewing gum composition according to embodiments may be used for opioid dependence and/or addiction treatment. Opioid dependence and/or addiction may be treated or alleviated by consumption of chewing gums according to embodiments. Cannabinoids and opioid agonists and/antagonists in these chewing gums may be released in a controlled manner and absorbed by a subject via transmucosal delivery mechanism. A mammal, such as a human being, may chew the chewing gum composition according to embodiments 1-6 times a day to aid with opioid craving sensation whiling curbing this craving. The chewing gum composition according to embodiments may be used in treatment of cannabis dependence, in particular Δ9-tetrahydrocannabinol dependence, concurrent with opioid addiction. Cannabis dependence, in particular Δ9-THC dependence, concurrent with opioid addiction may be treated or alleviated by consumption of chewing gums according to embodiments. A mammal, such as a human being, may chew the chewing gum composition according to embodiments 1-6 times a day to aid opioid and/or Δ9-THC craving sensation while curbing this craving. The chewing gum composition according to embodiments may be used in treatment of pain and/or chronic pain. A mammal, such as a human being, may chew the chewing gum composition according to embodiments as need for treatment of pain. A mammal, such as a human being, may chew the chewing gum composition according to embodiments 1-6 times a day to treat and/or alleviate pain. EXAMPLES Example 1 Chewing Gum Composition Preparation Chewing gum compositions having 10 mg of CBD and 1 mg of buprenorphine are prepared by cold pressing. Percentages are given in weight percentage. TABLE 1 Phase Raw material Percentage (%) A1 Isomalt 28.89 A2 CBD (microencapsulated) 0.50 A3 Cellulose 0.50 A4 Buprenorphine (microencapsulated) 0.04 A5 Naltrexone hydrochloride (microencapsulated) 0.01 B1 Gum base 24.50 B2 Sorbitol 10.00 B3 Maltitol 10.00 B4 Citric acid 0.50 B5 Magnesium stearate 2.00 B6 Silicon dioxide 0.40 B7 Xylitol 13.60 B8 Stevia 1.05 B9 Vanilla 4.00 B10 Spearmint/peppermint 4.00 B11 Colorants FD&C blue 0.01 Total 100.00 Step 1: Make a blend of A2, A3, A4, and A5 into A1 to form Phase 1. Step 2: Mix B1-B11 in a separate vessel to form Phase 2. Step 3: Use a double layer chewing gum machine to compress Phase 1 and Phase 2 together. Chewing gum composition may be cut into 2 gram pieces as appropriate. Chewing gum compositions with a mass at about 2 grams and containing 10 mg of CBD and 1 mg of buprenorphine were prepared. Example 2 Chewing Gum Composition Preparation Chewing gum compositions having 10 mg of Δ9-THC and 1 mg of buprenorphine are prepared. Percentages are given in weight percentage. TABLE 2 Phase Raw material Percentage (%) A1 Gum base 75.00 A2 Xylitol 14.00 A3 Glycerine 4.50 B1 Sacharrine 0.40 B2 Water 1.50 B3 Buprenorphine (microencapsulated) 0.05 B4 Citric acid 0.50 C1 Peppermint aroma oil 1.50 A4 Vanilla/cranberry flavor 1.50 C2 Δ9-THC (microencapsulated) 0.50 A5 Cellulose 0.50 Total 100.00 Step 1: Heat the gum base (A1) to 90° C., then add A2-A5 to form Phase 1. Step 2: Dissolve B1 and B4 in B2 to form Phase 2. Step 3: Heat the peppermint oil (C1) to 60-70° C., then add C2 and B3 to form Phase 3. Step 4: Add Phase 2 to Phase 1, stir vigorously and add Phase 3, stir for 7 minutes. Step 5: Pour the gum mixture out and prepare chewing gum tablets by molding as need. Chewing gum composition may be cut into 2 gram pieces as appropriate. Chewing gums with a mass at about 2 grams and containing 10 mg of Δ9-THC and 1 mg of buprenorphine were prepared. Example 3 Chewing Gum Composition Preparation Chewing gums having 10 mg of CBD, 0.8 mg of thebaine, and 0.2 mg of Naloxone hydrochloride are prepared. Percentages are given in weight percentage. TABLE 3 Phase Raw material Percentage (%) A1 Isomalt 28.89 A2 CBD (microencapsulated) 0.50 A3 Cellulose 0.50 A4 Thebaine (microencapsulated) 0.04 A5 Naloxone hydrochloride (microencapsulated) 0.01 B1 Gum base 24.50 B2 Sorbitol 10.00 B3 Maltitol 10.00 B4 Citric acid 0.50 B5 Magnesium stearate 2.00 B6 Silicon dioxide 0.40 B7 Xylitol 13.60 B8 Stevia 1.05 B9 Licorice 4.00 B10 Spearmint 4.00 B11 Colorants FD&C blue 0.01 Total 100.00 Step 1: Make a blend of A2, A3, A4, and A5 into A1 to form Phase 1. Step 2: Mix B1-B11 in a separate vessel to form Phase 2. Step 3: Use a double layer chewing gum machine to compress Phase 1 and Phase 2 together. Chewing gum composition may be cut into 2 gram pieces as appropriate. Chewing gums with a mass at about 2 grams and containing 10 mg of CBD, 0.8 mg of thebaine (semi-synthetic), and 0.2 mg of Naloxone hydrochloride were prepared. Variations and modifications will occur to those of skill in the art after reviewing this disclosure. The disclosed features may be implemented, in any combination and sub-combination (including multiple dependent combinations and sub-combinations), with one or more other features described herein. The various features described or illustrated above, including any components thereof, may be combined or integrated in other systems. Moreover, certain features may be omitted or not implements. Examples of changes, substitutions, and alterations are ascertainable by one skilled in the art and could be made without departing from the scope of the information disclosed herein. All references cited are hereby incorporated by reference herein in their entireties and made part of this application. | <SOH> BACKGROUND OF THE INVENTION <EOH> | <SOH> SUMMARY <EOH>The present invention relates to a chewing gum composition comprising cannabinoids or derivatives thereof and at least one opioid agonist and/or antagonist. Cannabinoids or derivatives thereof and opioid agonists and/or antagonists are under controlled release during mastication and consumption. This invention further relates to the use of this chewing gum composition in treating opioid addiction or dependence, concurrent cannabis and opioid addiction and/or dependence, or pain. This invention provides a chewing composition comprising, based on total weight of the composition: 0.1 to 5% by weight of at least one cannabinoid; 0.01 to 1% by weight of at least one opioid; 20 to 95% by weight of a gum base; 5 to 35% by weight of at least one buffering agent selected from the group consisting of acetates, glycinates, phosphates, carbonates, glycerophosphates, citrates, and borates; 1 to 10% by weight of at least one flavoring agent selected from the group consisting of peppermint, spearmint, licorice, cinnamon, watermelon, vanilla, pineapple, apple, and cranberry; 1 to 65% by weight of at least one sweetening agent selected from the group consisting of isomalt, sorbitol, stevia, maltitol, and xylitol; at least one anti-oxidant selected from the group consisting of ascorbyl palminate and sodium ascorbate; and at least one preservative. This invention provides a chewing gum composition according to embodiments wherein the at least one cannabinoid is cannabidiol, A 9 -tetrahydrocannabinol, cannabichromene, cannabigerol, cannabidivarin, derivatives thereof, or their acid metabolites. This invention provides a chewing gum composition according to embodiments wherein the at least one cannabinoid is provided in combination with at least one suitable carrier selected from the group consisting of sugar alcohol, microcrystalline cellulose derivatives, dextran, agarose, agar, pectin, alginate, xanthan, chitosan, and starch. This invention provides a chewing gum composition according to embodiments wherein the at least one cannabinoid is provided in microencapsulated form, nanoencapsulated form, or in freeze dried form. This invention provides a chewing gum composition according to embodiments wherein the at least one cannabinoid is provided in internal voids within a suitable solid carrier. This invention provides a chewing gum composition according to embodiments wherein the at least one cannabinoid is provided in a granule within the gum matrix. This invention provides a chewing gum composition according to embodiments wherein the at least one cannabinoid is procured from natural sources, such as deriving or extracting from cannabis plants, or synthetic. This invention provides a chewing gum composition according to embodiments wherein the at least one opioid is an opioid agonist selected from the group consisting of morphine, codeine, thebaine, hydrocodone, hydromorphone, oxycodone, oxymorphone, buprenorphine, fentanyl, methadone, pethidine, levorphanol, tramadol, and dextropropoxyphene. This invention provides a chewing gum composition according to embodiments wherein the at least one opioid is an opioid prodrug selected from the group consisting of 6-monoacetyl morphine, nicomorphine, dipropanoylmorphine, desomorphine, methyldesorphine, acetylpropionyl morphine, dibenzoyl morphine, and diacetyl dihydromorphine. This invention provides a chewing gum composition according to embodiments wherein the at least one opioid is an opioid antagonist selected from the group consisting of Naloxone hydrochloride dehydrate and natrexone hydrochloride. This invention provides a chewing gum composition according to embodiments wherein the at least one opioid comprises both opioid agonist and opioid antagonist. This invention provides a chewing gum composition according to embodiments wherein the at least one opioid is provided in nanoencapsulated or microencapsulated form. This invention provides a chewing gum composition according to embodiments wherein the preservative is citric acid. The invention provides a chewing gum composition according to embodiments which may further comprise at least one pharmaceutically acceptable excipient selected from the group consisting of fillers, disintegrants, binders, and lubricants. This invention provides a chewing gum composition according to embodiments which may further comprise silicon dioxide or magnesium stearate. This invention provides a method to treat opioid addiction in a mammal in need thereof, comprising administering to the mammal a chewing gum composition according to this invention. This invention provides a method to treat opioid addiction or dependence in a mammal in need thereof, comprising administering to the mammal a chewing gum composition according to this invention, wherein the mammal receives the chewing gum administration 1 to 6 times a day. This invention provides a method to treat opioid addiction or dependence concurrent with cannabis addiction or dependence in a mammal in need thereof, comprising administering to the mammal a chewing gum composition according to this invention. This invention provides a method to treat opioid addiction concurrent with cannabis dependence in a mammal in need thereof, comprising administering to the mammal a chewing gum composition according to this invention, wherein the mammal receives the chewing gum administration 1 to 6 times a day. This invention provides a method to treat pain in a mammal in need thereof, comprising administering to the mammal a chewing gum composition according to this invention. detailed-description description="Detailed Description" end="lead"? | A61K90058 | 20171018 | 20180426 | 85442.0 | A61K968 | 0 | COHEN, MICHAEL P | CHEWING GUM COMPOSITION COMPRISING CANNABINOIDS AND OPIOID AGONISTS AND/OR ANTAGONISTS | SMALL | 0 | PENDING | A61K | 2,017 |
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15,787,969 | PENDING | Casement Window Hinge with Enhanced Pullout Resistance | A casement window hinge provides a shoe sliding on a track to support a sash arm. The shoe is held captive within the track against outward movement by a T-bar extending rearwardly from the shoe and retained by upwardly and downwardly extending flanges from the track. | 1. A casement window hinge comprising: a longitudinally extending track attachable to a window opening, the track providing a horizontal track surface and a first capture flange being proximate to the horizontal track surface and extending vertically away from the track surface and a second capture flange removed from the track surface and extending vertically toward the track surface; a shoe having a first slide surface abutting the horizontal track surface to slide longitudinally therealong, the shoe further providing first and second opposed, vertically extending projections engaging respective of the first and second capture flanges in sliding contact to allow the shoe to move longitudinally therealong while being constrained against outward motion perpendicular to the longitudinal extent of the track; a sash arm pivotally attached to the shoe at one end and extending therefrom for attachment to a window sash; and a guide arm pivotally attached at one end of the longitudinally extending track and pivotally attached at another end to the sash arm. 2. The casement window hinge of claim 1 wherein the longitudinally extending track is an L-shaped metal channel having a first and second perpendicularly extending wall, wherein the first wall provides the horizontal track surface and the second wall is positioned rearwardly to extend vertically away from the horizontal track surface from a rear edge of the horizontal track surface and wherein the second capture flange is an upper edge of the second wall rolled to extend toward the horizontal track surface to be constrained against. 3. The casement window hinge of claim 1 further including a fence strip attached to the horizontal track surface and wherein the first capture flange is a vertically extending lip formed at an inner edge of the fence strip. 4. The casement window hinge of claim 3 wherein the shoe provides a longitudinal channel proximate to the horizontal track surface separating the first slide surface from a second slide surface, both in sliding contact with the horizontal track surface, and wherein the second slide surface fits between the first capture flange and the second perpendicularly extending rear wall to be constrained against inward and outward motion perpendicular to the longitudinal extent of the track. 5. The casement window hinge of claim 4 wherein the first projection provides the second slide surface. 6. The casement window hinge of claim 4 wherein the fence strip fits within the longitudinal channel. 7. The casement window hinge of claim 3 wherein the fence strip and horizontal track surface have holes therethrough for attachment of the track to a window. 8. The casement window hinge of claim 7 wherein the fence strip and horizontal track surface are individual stainless-steel strips formed and attached together. 9. The casement window hinge of claim 4 wherein the shoe is fabricated at least in part from a polymer material exposed at the first and second slide surfaces to provide contact between the first and second slide surfaces and the horizontal track surface and exposed at the first and second projections to provide contact between the first and second projections and the first and second capture flanges. 10. The casement window hinge of claim 9 further including a metal framework within the polymer material providing a T-frame having a horizontally extending stem positioned over the first slide surface and the longitudinal channel and perpendicular T-arms extending vertically into the first and second projections to reinforce the same. 11. The casement window hinge of claim 10 further including a bore exposing an undersurface of the stem to abut a rivet head of a rivet extending upwardly through a hole in the stem portion to pivotally attach to the sash arm. 12. The casement window hinge of claim 11 wherein the polymer material provides an overlying polymer layer positioned above an upper surface of the stem portion positioned between the stem portion and the sash arm around the rivet. 13. The casement window hinge of claim 10 wherein a polymer material is injection molded around the metal framework. 14. The casement window hinge of claim 10 wherein the metal framework is folded from a single strip of metal. 15. A casement window hinge of claim 1 wherein the shoe provides a main body pivotally attached to the sash arm and having a rearwardly extending T-bar with a span of the T-bar attached to the main body and extending horizontally therefrom and arms of the T-bar providing the first and second opposed vertically extending projections. | CROSS REFERENCE TO RELATED APPLICATION This application claims the benefit of U.S. Provisional application 62/410,594 filed Oct. 20, 2016, and hereby incorporated in its entirety. BACKGROUND OF THE INVENTION The present invention relates to casement window hinges and in particular to a casement window hinge better resisting pullout, for example, caused by increased window weight. Casement window hinges allow a window to open by pivoting about a vertical axis that moves inward as the window opens. This combination motion is provided by special casement window hinges that slide along a track supporting the window sash. A separate operator moves the window as mounted on the hinges, typically using a crank mechanism. Casement window hinges typically employ a two-bar linkage of a sash arm and guide arm. The sash arm is attached along the window sash, for example, by countersunk wood screws directed up through the sash arm into the wood or other material of the sash. An inward end of the sash arm is pivotally attached to a slide or “shoe” that may move along the track attached to the window opening and that defines the movable pivot point or hinge point of the window. A center of the sash arm is pivotally attached to one end of a guide arm. The remaining end of the guide arm is pivotally attached to the track displaced from the slide. Normally each window is supported by two casement window hinges on corresponding shoes, one positioned at a lower edge of the window and the other positioned at the upper edge of the window, the hinges being generally mirror images of each other. Increased interest in energy conservation has led to the introduction of triple glazed windows providing three layers of glass separated by air gaps. Triple glazed windows have substantially higher weight than so-called double pane windows and can exert substantial outward lateral threes on the casement window shoe leading to premature failure and pullout of the shoe from the track. This can also be true for large windows or windows that have greater weight. BRIEF SUMMARY OF THE INVENTION The present invention provides a T-bar engagement between the track and the shoe providing an increased sliding contact area against lateral forces reducing both wear and the possibility of pullout of the shoe in a lateral direction. A channel surface for a lower arm of the T-bar is provided through the use of a fence strip attached to the bottom of the track fitting within an undercut bridge portion of the shoe, the latter placed to provide clearance with respect to the screws holding the track to the windowsill. More specifically, the invention provides a casement window hinge having a longitudinally extending track attachable to a window opening, the track providing a horizontal track surface and a first capture flange being proximate to the horizontal track surface and extending vertically away from the track surface and a second capture flange removed from the track surface and extending vertically toward the track surface. A shoe having a first slide surface abuts the horizontal track surface to slide longitudinally therealong, the shoe further providing first and second opposed, vertically extending projections engaging respective of the first and second capture flanges in sliding contact to allow the shoe to move longitudinally therealong while being constrained against outward motion perpendicular to the longitudinal extent of the track. A sash arm pivotally attaches to the shoe at one end and extends therefrom for attachment to a window sash, and a guide arm pivotally attaches at one end of the longitudinally extending track and pivotally attaches at another end to the sash arm. It is thus a feature of at least one embodiment of the invention to provide a casement window hinge that can better handle improved energy saving windows or other windows of greater weight. The longitudinally extending track may be an L-shaped metal channel having first and second perpendicularly extending walls where the first wall provides the horizontal track surface and the second wall is positioned rearwardly to extend vertically away from the horizontal track surface at a rear edge of the horizontal track surface, and wherein the second capture flange is an upper edge of the second wall rolled to extend toward the horizontal track surface. It is thus a feature of at least one embodiment of the invention to provide an improved hinge that may make use of existing technology for track fabrication using a rolled lip. The casement window hinge may further include a fence strip attached to the horizontal track surface, and wherein the first capture flange may be a vertically extending lip formed at an inner edge of the fence strip. It is thus a feature of at least one embodiment of the invention to provide two surfaces of opposed shoe engagement from simple formed shapes of robust strips. The shoe may provide a longitudinal channel proximate to the horizontal track surface separating the first slide surface from a second slide surface, both in sliding contact with the horizontal track surface, and wherein the second slide surface fits between the first capture flange and the second perpendicularly extending rear wall to be constrained against inward and outward motion perpendicular to the longitudinal extent of the track. The first projection may provide the second slide surface. It is thus a feature of at least one embodiment of the invention to provide improved pullout resistance without significant reduction in the separation width of the sliding contact areas such as provides improved stability against rocking of the shoe. The fence strip may fit within the longitudinal channel. It is thus a feature of at least one embodiment of the invention to provide improved pullout resistance without increasing the height of the shoe. The fence strip and horizontal track surface may have holes therethrough for attachment of the track to a window. It is thus a feature of at least one embodiment of the invention to displace screw heads and holes from contact with the shoe such as might otherwise provide points of resistance or wear. The fence strip and horizontal track surface may be individual stainless-steel strips formed and attached together. It is thus a feature of at least one embodiment of the invention to provide a casement window hinge with improved pull-out resistance that can be effectively fabricated from stainless steel elements resistant to corrosion. The shoe may be fabricated at least in part from a polymer material exposed at the first and second slide surfaces to provide contact between the first and second slide surfaces and the horizontal track surface and exposed at the first and second projections to provide contact between the first and second projections and the first and second capture flanges. It is thus a feature of at least one embodiment of the invention to provide low friction between the shoe in sliding contact with the track against both vertical and outward loading of the shoe. The shoe may include a metal framework within the polymer material providing a T-frame having a horizontally extending stem positioned over the first slide surface and longitudinal channel perpendicular and having T-arms extending vertically into the first and second projections to reinforce the same. It is thus a feature of at least one embodiment of the invention to increase the ability of thin cross-sections of polymer material to handle substantial bending loads thereby providing a compact but robust shoe. The shoe may include a bore exposing an undersurface of the stem portion to abut a rivet head of a rivet extending upwardly through a hole in the stem portion to pivotally attach to the sash arm. It is thus a feature of at least one embodiment of the invention to employ the stem to spread the point contact forces of the rivet over the polymer body of the shoe. The polymer material may provide an overlying polymer layer positioned above the upper surface of the stem portion positioned between the stem portion and the sash arm around the rivet. It is thus a feature of at least one embodiment of the invention to provide a low friction material at the point of pivoting of the sash arm against the shoe. The polymer material may be injection molded around the metal framework. It is thus a feature of at least one embodiment of the invention to provide a design that can be readily fabricated in injection molding. The metal framework maybe folded from a single strip of metal. It is thus a feature of at least one embodiment of the invention to permit the use of lightweight and strong strip forms of metal in the fabrication of the hinge track. These particular features and advantages may apply to only some embodiments falling within the claims and thus do not define the scope of the invention. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a top plan view of the casement window hinge showing the sash arm, guide arm, shoe, fence strip and track of the present invention; FIG. 2 is a fragmentary cross-sectional view taken along line 2-2 of FIG. 1 showing the T-bar engagement between the shoe and the track and the fence strip providing retention of the T-bar; FIG. 3 is a front elevational view in fragment of the shoe of the casement window hinge when the window is in the closed position showing support of the sash on an elevated portion of the shoe during shipping; FIGS. 4a and 4b are perspective front and rear views of a metallic spine molded into the shoe to provide greater strength; and FIGS. 5a and 5b are front fragmentary elevational and top plan views of a portion of the track showing a flaring of the track at an entrance point for receiving the shoe and a resilient stop to prevent accidental disengagement of the shoe from the track. DETAILED DESCRIPTION OF THE INVENTION Referring now to FIG. 1, a casement window hinge 10 may include a sash arm 12 that may be attached to a window sash 15 by means of mounting holes 14 receiving countersunk head wood screws (not shown in FIG. 1) upward through the sash arm 12. A proximal end of the sash arm 12 is pivotally attached to a shoe 16 that may move along a length of a metal track 18. The shoe 16 is retained by a rolled edge 20 in the metal track 18 and a fence strip 26 as will be discussed in more detail below. A proximal end of a guide arm 22 is pivotally attached to the track 18 at a pivot 23 on the track 18 removed from the travel range of the shoe 16, and a distal end of the guide arm 22 is pivotally attached to a midpoint of the sash arm 12 at a second pivot 24. The sash arm 12 and guide arm 22 form a two-bar linkage providing a simultaneous pivoting and translation of an attached window sash. The general structure of hinges of this type is described in U.S. Pat. No. 6,088,880 and U.S. Pat. No. 8,495,797 to LaSee, assigned to the assignee of the present invention and hereby incorporated by reference. As noted, a fence strip 26 is placed on top of the horizontal upper surface of the track 18 to complement the rolled edge 20 for retaining the shoe 16 as will be described. The fence strip 26 may be tack welded, for example, by spot welding to the track 18 and/or attached by screws 27 passing through the horizontal extent of the fence strip 26 and track 18 into the sill 19. The track 18 and fence strip 26 may be constructed of strips of stainless steel folded by roller forming or other folding techniques for simple manufacture. Referring now also to FIG. 2, the shoe 16 may provide a main body 28 having a downwardly extending front ridge 30 terminating at a horizontal sliding surface 32 contacting an upper surface of the track 18 at its outer edge and extending generally along the axis of the track 18. The main body 28 is connected at its rear edge to a T-bar 34, the latter oriented horizontally and spaced inwardly away from the main body 28 as joined by a horizontal narrow bar 36. Opposed vertically extending arms of the T-bar 34 are positioned beneath the downwardly concave surface of the rolled edge 20. Specifically, an upwardly extending upper arm 44 of the T-bar 34 is retained against lateral force indicated by arrow 40 by a downward lip of the rolled edge 20. Conversely, downwardly extending lower arm 46 of the T-bar 34 is retained by an upwardly extending flange 42 formed in a rear edge of the fence strip 26 extending along the axis of the track 18. Desirably, the upwardly extending flange 42 presents a surface generally parallel to and abutting an opposed surface of the lower arm 46 of the T-bar 34 to provide a broad area of contact therebetween. The downwardly extending lower arm 46 of the T-bar 34 terminates at a downwardly extending rear rim 47 abutting the upper horizontal rim of the track 18 inwardly from the surface 32 at a sliding surface 49, supporting the shoe 16 to slide along the upper surface of the track 18. The shoe 16 provides a bridge region 48 over the upper surface of the track 18 between the sliding surfaces 49 and 32 removed from the surface of the track 18 preventing contact or interference between the shoe 16 and the screws 27 and/or the fence strip 26. Referring also to FIG. 4, the shoe 16 may be an injection molded thermoplastic material over a metallic spine 50, the latter having a horizontal portion embedded within the shoe 16 below an upper surface 52 of the shoe 16, spanning the bridge region 48 and extending through the narrow bar 36 into the T-bar 34. The metallic spine 50 may, for example, be formed from a strip of steel and may include holes 53 for passage of a rivet to be described. The exposed thermoplastic material may provide natural lubricity or be lubricated at places where it contacts the track 18. A rearward edge of the strip of metallic spine 50 is folded vertically upward providing an upper rim 56 extending into the upper arm 44 of the T-bar 34. A cutout 54 is provided in the horizontal portion of the metallic spine 50 near the upper rim 56 releasing a tab 58 that may swing downwardly when the rearward edge of the strip of the metallic spine 50 is folded vertically. This tab 58 projects downwardly toward the lower arm 46 of the T-bar 34. Referring again to FIG. 2, the metallic spine 50 will generally have a portion parallel to but positioned below the horizontal upper surface 52 of the track 18 and above the sliding surfaces 32 and 49 so that contact with the track 18 and the sash arm 12 is through the thermoplastic material providing improved lubricity and reduced wear. A lower surface of the shoe 16 in the bridge region 48 may have a counterbore 60 receiving the head 62 of a rivet 63 so that the head 62 may fit against a lower surface of the metallic spine 50. The rivet body may then pass upwardly through the shoe 16 out of the upper surface 52 and through a corresponding bore in the proximal end of the sash arm 12 so that the sash arm is pivotally retained against the shoe by a second rivet head 65. The sash arm 12 proceeding horizontally away from the pivot point of the rivet 63 is offset upward through a dog-leg bend to so that an area of contact 66 between the upper surface of the sash area 12 and the lower surface of the sash 15 is above the rivet head 65 and the rolled edge 20 preventing interference therebetween. Referring now to FIG. 3, a portion of the shoe 16 removed from the rivet head 65 may provide an elevated support surface 70 abutting and supporting the under surface of the sash arm 12 in the area of contact 66 when the sash arm 12 is in a closed position to reduce damage to the casement window hinge 10 during shipping, for example. Referring now to FIGS. 1, 2, 5a and 5b, a portion of the rolled edge 20 toward the pivot 23 may be expanded in a flare 72 to assist in engagement between the T-bar 34 of the shoe 16 and the roiled edge 20 during assembly of the casement window hinge 10. The flange 42 of the fence strip 26 may be offset from this flare 72 by a further distance away from pivot 23 to also assist in engagement of the T-bar 34 of the shoe 16. Removal of the shoe 16 from engagement with the rolled edge 20 and the fence strip 26 as it moves toward the pivot 23 is resisted by a cantilevered spring tab 74, for example, being a partially cut-out portion of a vertical rear wall 78 of the track 18 flexing inwardly to provide a stop end 76 that resists removal of this shoe 16 unless the stop end 76 is first pressed inward to be aligned with a vertical rear wall 78 of the track 18. Certain terminology is used herein for purposes of reference only, and thus is not intended to be limiting. For example, terms such as “upper”, “lower”, “above”, and “below” typically refer to directions in the drawings to which reference is made. Terms such as “left”, “right”, “front”, “back”, “rear”, “bottom” and “side”, describe the orientation of portions of the component within a consistent but arbitrary frame of reference which is made clear by reference to the text and the associated drawings describing the component under discussion. Such terminology may include the words specifically mentioned above, derivatives thereof, and words of similar import. Similarly, the terms “first”, “second” and other such numerical terms referring to structures do not imply a sequence, or order unless clearly indicated by the context. When introducing elements or features of the present disclosure and the exemplary embodiments, the articles “a”, “an”, “the” and “said” are intended to mean that there are one or more of such elements or features. The terms “comprising”, “including” and “having” are intended to be inclusive and mean that there may be additional elements or features other than those specifically noted. It is further to be understood that the method steps, processes, and operations described herein are not to be construed as necessarily requiring their performance in the particular order discussed or illustrated, unless specifically identified as an order of performance. It is also to be understood that additional or alternative steps may be employed. Various features of the invention are set forth in the following claims. It should be understood that the invention is not limited in its application to the details of construction and arrangements of the components set forth herein. The invention is capable of other embodiments and of being practiced or carried out in various ways. Variations and modifications of the foregoing are within the scope of the present invention. It also being understood that the invention disclosed and defined herein extends to all alternative combinations of two or more of the individual features mentioned or evident from the text and/or drawings. All of these different combinations constitute various alternative aspects of the present invention. The embodiments described herein explain the best modes known for practicing the invention and will enable others skilled in the art to utilize the invention. | <SOH> BACKGROUND OF THE INVENTION <EOH>The present invention relates to casement window hinges and in particular to a casement window hinge better resisting pullout, for example, caused by increased window weight. Casement window hinges allow a window to open by pivoting about a vertical axis that moves inward as the window opens. This combination motion is provided by special casement window hinges that slide along a track supporting the window sash. A separate operator moves the window as mounted on the hinges, typically using a crank mechanism. Casement window hinges typically employ a two-bar linkage of a sash arm and guide arm. The sash arm is attached along the window sash, for example, by countersunk wood screws directed up through the sash arm into the wood or other material of the sash. An inward end of the sash arm is pivotally attached to a slide or “shoe” that may move along the track attached to the window opening and that defines the movable pivot point or hinge point of the window. A center of the sash arm is pivotally attached to one end of a guide arm. The remaining end of the guide arm is pivotally attached to the track displaced from the slide. Normally each window is supported by two casement window hinges on corresponding shoes, one positioned at a lower edge of the window and the other positioned at the upper edge of the window, the hinges being generally mirror images of each other. Increased interest in energy conservation has led to the introduction of triple glazed windows providing three layers of glass separated by air gaps. Triple glazed windows have substantially higher weight than so-called double pane windows and can exert substantial outward lateral threes on the casement window shoe leading to premature failure and pullout of the shoe from the track. This can also be true for large windows or windows that have greater weight. | <SOH> BRIEF SUMMARY OF THE INVENTION <EOH>The present invention provides a T-bar engagement between the track and the shoe providing an increased sliding contact area against lateral forces reducing both wear and the possibility of pullout of the shoe in a lateral direction. A channel surface for a lower arm of the T-bar is provided through the use of a fence strip attached to the bottom of the track fitting within an undercut bridge portion of the shoe, the latter placed to provide clearance with respect to the screws holding the track to the windowsill. More specifically, the invention provides a casement window hinge having a longitudinally extending track attachable to a window opening, the track providing a horizontal track surface and a first capture flange being proximate to the horizontal track surface and extending vertically away from the track surface and a second capture flange removed from the track surface and extending vertically toward the track surface. A shoe having a first slide surface abuts the horizontal track surface to slide longitudinally therealong, the shoe further providing first and second opposed, vertically extending projections engaging respective of the first and second capture flanges in sliding contact to allow the shoe to move longitudinally therealong while being constrained against outward motion perpendicular to the longitudinal extent of the track. A sash arm pivotally attaches to the shoe at one end and extends therefrom for attachment to a window sash, and a guide arm pivotally attaches at one end of the longitudinally extending track and pivotally attaches at another end to the sash arm. It is thus a feature of at least one embodiment of the invention to provide a casement window hinge that can better handle improved energy saving windows or other windows of greater weight. The longitudinally extending track may be an L-shaped metal channel having first and second perpendicularly extending walls where the first wall provides the horizontal track surface and the second wall is positioned rearwardly to extend vertically away from the horizontal track surface at a rear edge of the horizontal track surface, and wherein the second capture flange is an upper edge of the second wall rolled to extend toward the horizontal track surface. It is thus a feature of at least one embodiment of the invention to provide an improved hinge that may make use of existing technology for track fabrication using a rolled lip. The casement window hinge may further include a fence strip attached to the horizontal track surface, and wherein the first capture flange may be a vertically extending lip formed at an inner edge of the fence strip. It is thus a feature of at least one embodiment of the invention to provide two surfaces of opposed shoe engagement from simple formed shapes of robust strips. The shoe may provide a longitudinal channel proximate to the horizontal track surface separating the first slide surface from a second slide surface, both in sliding contact with the horizontal track surface, and wherein the second slide surface fits between the first capture flange and the second perpendicularly extending rear wall to be constrained against inward and outward motion perpendicular to the longitudinal extent of the track. The first projection may provide the second slide surface. It is thus a feature of at least one embodiment of the invention to provide improved pullout resistance without significant reduction in the separation width of the sliding contact areas such as provides improved stability against rocking of the shoe. The fence strip may fit within the longitudinal channel. It is thus a feature of at least one embodiment of the invention to provide improved pullout resistance without increasing the height of the shoe. The fence strip and horizontal track surface may have holes therethrough for attachment of the track to a window. It is thus a feature of at least one embodiment of the invention to displace screw heads and holes from contact with the shoe such as might otherwise provide points of resistance or wear. The fence strip and horizontal track surface may be individual stainless-steel strips formed and attached together. It is thus a feature of at least one embodiment of the invention to provide a casement window hinge with improved pull-out resistance that can be effectively fabricated from stainless steel elements resistant to corrosion. The shoe may be fabricated at least in part from a polymer material exposed at the first and second slide surfaces to provide contact between the first and second slide surfaces and the horizontal track surface and exposed at the first and second projections to provide contact between the first and second projections and the first and second capture flanges. It is thus a feature of at least one embodiment of the invention to provide low friction between the shoe in sliding contact with the track against both vertical and outward loading of the shoe. The shoe may include a metal framework within the polymer material providing a T-frame having a horizontally extending stem positioned over the first slide surface and longitudinal channel perpendicular and having T-arms extending vertically into the first and second projections to reinforce the same. It is thus a feature of at least one embodiment of the invention to increase the ability of thin cross-sections of polymer material to handle substantial bending loads thereby providing a compact but robust shoe. The shoe may include a bore exposing an undersurface of the stem portion to abut a rivet head of a rivet extending upwardly through a hole in the stem portion to pivotally attach to the sash arm. It is thus a feature of at least one embodiment of the invention to employ the stem to spread the point contact forces of the rivet over the polymer body of the shoe. The polymer material may provide an overlying polymer layer positioned above the upper surface of the stem portion positioned between the stem portion and the sash arm around the rivet. It is thus a feature of at least one embodiment of the invention to provide a low friction material at the point of pivoting of the sash arm against the shoe. The polymer material may be injection molded around the metal framework. It is thus a feature of at least one embodiment of the invention to provide a design that can be readily fabricated in injection molding. The metal framework maybe folded from a single strip of metal. It is thus a feature of at least one embodiment of the invention to permit the use of lightweight and strong strip forms of metal in the fabrication of the hinge track. These particular features and advantages may apply to only some embodiments falling within the claims and thus do not define the scope of the invention. | E05D1530 | 20171019 | 20180426 | 94928.0 | E05D1530 | 0 | MAH, CHUCK Y | Casement Window Hinge with Enhanced Pullout Resistance | SMALL | 0 | ACCEPTED | E05D | 2,017 |
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15,788,059 | PENDING | METHODS AND COMPOSITIONS FOR THE TREATMENT OF FABRY DISEASE | Nucleases and methods of using these nucleases for inserting a sequence encoding a therapeutic α-Gal A protein such as an enzyme into a cell, thereby providing proteins or cell therapeutics for treatment and/or prevention of Fabry disease. | 1. A method of expressing at least one α galactosidase A (α-Gal A) protein in a cell, the method comprising administering a GLA transgene encoding the at least one α-Gal A protein to the cell such that the α-Gal A protein is expressed in the cell. 2. The method of claim 1, wherein the cell is in a subject with Fabry's disease. 3. The method of claim 1, wherein the transgene comprises a cDNA. 4. The method of claim 2, wherein the transgene is administered to the liver of the subject. 5. The method of claim 4, further comprising administering one or more nucleases that cleave an endogenous albumin gene in a liver cell in a subject such that the transgene is integrated into and expressed from the albumin gene. 6. The method of claim 2, wherein the α-Gal A protein expressed from the transgene decreases the amount of glycospingolipids in the subject by at least 2 fold. 7. The method of claim 1, wherein the transgene comprises a wild-type GLA-sequence or a codon optimized GLA sequence. 8. The method of claim 1, wherein the transgene further encodes a signal peptide. 9. A genetically modified cell comprising an exogenous GLA transgene, made by the method of claim 1. 10. The genetically modified cell of claim 9, wherein the cell is a stem cell or a precursor cell. 11. The genetically modified cell of claim 9, wherein the cell is a liver or muscle cell. 12. The genetically modified cell of claim 9, wherein the GLA transgene is integrated into the genome of the cell. 13. The genetically modified cell of claim 9, wherein the GLA transgene is not integrated into the genome of the cell. 14. Use of a GLA transgene encoding at least one α-Gal A protein for the treatment of Fabry's disease. 15. A pharmaceutically acceptable composition comprising a GLA transgene encoding at least one α-Gal A protein for the treatment of Fabry's disease. 16. A method of producing an α-Gal A protein for the treatment of Fabry's disease, the method comprising expressing the α-Gal A protein in an isolated cell according to the method of claim 1, and isolating the α-Gal A protein produced by the cell. 17. A vector comprising a GLA transgene for use in the method of claim 1. 18. The vector of claim 17, wherein the vector is a viral vector or a lipid nanoparticle (LNP). | CROSS-REFERENCE TO RELATED APPLICATIONS The present application claims the benefit of U.S. Provisional Application No. 62/410,543, filed Oct. 20, 2016; U.S. Provisional Application No. 62/444,093, filed Jan. 9, 2017; U.S. Provisional Application No. 62/458,324, filed Feb. 13, 2017; U.S. Provisional Application No. 62/502,058, filed May 5, 2017; U.S. Provisional No. 62/516,373, filed Jun. 7, 2017; and U.S. Provisional Application No. 62/552,792, filed Aug. 31, 2017, the disclosures of which are hereby incorporated by reference in their entireties. TECHNICAL FIELD The present disclosure is in the field of the prevention and/or treatment of Fabry Disease and gene therapy. BACKGROUND Gene therapy holds enormous potential for a new era of human therapeutics. These methodologies will allow treatment for conditions that heretofore have not been addressable by standard medical practice. One area that is especially promising is the ability to add a transgene to a cell to cause that cell to express a product that previously was not being produced in that cell or was being produced suboptimally. Examples of uses of this technology include the insertion of a gene encoding a therapeutic protein, insertion of a coding sequence encoding a protein that is somehow lacking in the cell or in the individual and insertion of a sequence that encodes a structural nucleic acid such as a microRNA. Transgenes can be delivered to a cell by a variety of ways, such that the transgene becomes integrated into the cell's own genome and is maintained there. In recent years, a strategy for transgene integration has been developed that uses cleavage with site-specific nucleases for targeted insertion into a chosen genomic locus (see, e.g., co-owned U.S. Pat. No. 7,888,121). Nucleases, such as zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), or nuclease systems such as the RNA guided CRISPR/Cas system (utilizing an engineered guide RNA), are specific for targeted genes and can be utilized such that the transgene construct is inserted by either homology directed repair (HDR) or by end capture during non-homologous end joining (NHEJ) driven processes. See, e.g., U.S. Pat. Nos. 9,394,545; 9,255,250; 9,200,266; 9,045,763; 9,005,973; 9,150,847; 8,956,828; 8,945,868; 8,703,489; 8,586,526; 6,534,261; 6,599,692; 6,503,717; 6,689,558; 7,067,317; 7,262,054; 7,888,121; 7,972,854; 7,914,796; 7,951,925; 8,110,379; 8,409,861; U.S. Patent Publications 20030232410; 20050208489; 20050026157; 20050064474; 20060063231; 20080159996; 201000218264; 20120017290; 20110265198; 20130137104; 20130122591; 20130177983; 20130196373; 20140120622; 20150056705; 20150335708; 20160030477 and 20160024474, the disclosures of which are incorporated by reference in their entireties. Transgenes may be introduced and maintained in cells in a variety of ways. Following a “cDNA” approach, a transgene is introduced into a cell such that the transgene is maintained extra-chromosomally rather than via integration into the chromatin of the cell. The transgene may be maintained on a circular vector (e.g. a plasmid, or a non-integrating viral vector such as AAV or Lentivirus), where the vector can include transcriptional regulatory sequences such as promoters, enhancers, polyA signal sequences, introns, and splicing signals (U.S. Publication No. 20170119906). An alternate approach involves the insertion of the transgene in a highly expressed safe harbor location such as the albumin gene (see U.S. Pat. No. 9,394,545). This approach has been termed the In Vivo Protein Replacement Platform® or IVPRP. Following this approach, the transgene is inserted into the safe harbor (e.g., Albumin) gene via nuclease-mediated targeted insertion where expression of the transgene is driven by the Albumin promoter. The transgene is engineered to comprise a signal sequence to aid in secretion/excretion of the protein encoded by the transgene. “Safe harbor” loci include loci such as the AAVS1, HPRT, Albumin and CCR5 genes in human cells, and Rosa26 in murine cells. See, e.g., U.S. Pat. Nos. 7,888,121; 7,972,854; 7,914,796; 7,951,925; 8,110,379; 8,409,861; 8,586,526; U.S. Patent Publications 20030232410; 20050208489; 20050026157; 20060063231; 20080159996; 201000218264; 20120017290; 20110265198; 20130137104; 20130122591; 20130177983; 20130177960 and 20140017212. Nuclease-mediated integration offers the prospect of improved transgene expression, increased safety and expressional durability, as compared to classic integration approaches that rely on random integration of the transgene, since it allows exact transgene positioning for a minimal risk of gene silencing or activation of nearby oncogenes. While delivery of the transgene to the target cell is one hurdle that must be overcome to fully enact this technology, another issue that must be conquered is insuring that after the transgene is inserted into the cell and is expressed, the gene product so encoded must reach the necessary location with the organism, and be made in sufficient local concentrations to be efficacious. For diseases characterized by the lack of a protein or by the presence of an aberrant non-functional one, delivery of a transgene encoded wild type protein can be extremely helpful. Lysosomal storage diseases (LSDs) are a group of rare metabolic monogenic diseases characterized by the lack of functional individual lysosomal proteins normally involved in the breakdown of waste lipids, glycoproteins and mucopolysaccharides. These diseases are characterized by a buildup of these compounds in the cell since it is unable to process them for recycling due to the mis-functioning of a specific enzyme. The most common examples are Gaucher's (glucocerebrosidase deficiency—gene name: GBA), Fabry's (α galactosidase A deficiency—GLA), Hunter's (iduronate-2-sulfatase deficiency—IDS), Hurler's (alpha-L iduronidase deficiency—IDUA), Pompe's (alpha-glucosidase (GAA)) and Niemann-Pick's (sphingomyelin phosphodiesterase 1 deficiency—SMPD1) diseases. When grouped all together, LSDs have an incidence in the population of about 1 in 7000 births. See, also, U.S. Patent Publication Nos. 20140017212; 2014-0112896; and 20160060656. For instance, Fabry disease is an X-linked disorder of glycosphingolipid metabolism caused by a deficiency of the α-galactosidase A enzyme (α-GalA). It is associated with the progressive deposition of glycospingolipids including globotriaosylceramide (also known as GL-3 and Gb3) and globotriaosylsphingosine (lyso-Gb3), galabioasylceramide, and group B substance. Symptoms of the disease are varied and can include burning, tingling pain (acroparesthesia) or episodes of intense pain which are called ‘Fabry crises’ which can last from minutes to days. Other symptoms include impaired sweating, low tolerance for exercise, reddish-purplish rash called angiokeratoma, eye abnormalities, gastrointestinal problems, heart problems such as enlarged heart and heart attack, kidney problems that can lead to renal failure and CNS problems and in general, life expectancy for Fabry patients is shortened substantially. Current treatment for Fabry disease can involve enzyme replacement therapy (ERT) with two different preparations of human α-GalA, agalsidase beta or agalsidase alfa, which requires costly and time consuming infusions (typically between about 0.2-1 mg/kg) for the patient every two weeks. Such treatment is only to treat the symptoms and is not curative, thus the patient must be given repeated dosing of these proteins for the rest of their lives, and potentially may develop neutralizing antibodies to the injected protein. Furthermore, adverse reactions are associated with ERT, including immune reactions such as the development of anti-α-GalA antibodies in subjects treated with the α-GalA preparations. In fact, 50% of males treated with agalsidase alfa and 88% of males treated with agalsidase beta developed α-GalA antibodies. Importantly, a significant proportion of those antibodies are neutralizing antibodies and, accordingly, reduce the therapeutic impact of the therapy (Meghdari et al (2015) PLoS One 10(2):e0118341. Doi:10.1371/journal.pone.0118341). In addition, ERT does not halt disease progression in all patients. Thus, there remains a need for non-ERT methods and compositions that can be used to treat Fabry disease, including treatment through genome editing, for instance, to deliver an expressed transgene encoded gene product at a therapeutically relevant level. SUMMARY Disclosed herein are methods and compositions for treating and/or preventing Fabry disease. The invention describes methods for insertion of a transgene sequence into a suitable target cell (e.g., a subject with Fabry disease) wherein the transgene encodes at least one protein (e.g., at least one α-GalA protein) that treats the disease. The methods may be in vivo (delivery of the transgene sequence to a cell in a living subject) or ex vivo (delivery of modified cells to a living subject). The invention also describes methods for the transfection and/or transduction of a suitable target cell with an expression system such that an α-GalA encoding transgene expresses a protein that treats (e.g., alleviates one or more of the symptoms associated with) the disease. The α-GalA protein may be excreted (secreted) from the target cell such that it is able to affect or be taken up by other cells that do not harbor the transgene (cross correction). The invention also provides for methods for the production of a cell (e.g., a mature or undifferentiated cell) that produces high levels of α-GalA where the introduction of a population of these altered cells into a patient will supply that needed protein to treat a disease or condition. In addition, the invention provides methods for the production of a cell (e.g. a mature or undifferentiated cell) that produces a highly active form (therapeutic) of α-GalA where the introduction of, or creation of, a population of these altered cells in a patient will supply that needed protein activity to treat (e.g., reduce or eliminate one or more symptoms) Fabry's disease. The highly active form of α-GalA produced as described herein can also be isolated from cells as described herein and administered to a patient in need thereof using standard enzyme replacement procedures known to the skilled artisan. Described herein are methods and compositions for expressing at least one α galactosidase A (α-Gal A) protein. The compositions and methods can be for use in vitro, in vivo or ex vivo, and comprise administering a GLA transgene (e.g., cDNA with wild-type or codon optimized GLA sequences) encoding the at least one α-Gal A protein to the cell such that the α-Gal A protein is expressed in the cell. In certain embodiments, the cell is in a subject with Fabry's disease. In any of the methods described herein, the transgene can be administered to the liver of the subject. Optionally, the methods further comprise administering one or more nucleases that cleave an endogenous albumin gene in a liver cell in a subject such that the transgene is integrated into and expressed from the albumin gene. In any of the methods described herein, the α-Gal A protein expressed from the transgene can decrease the amount of glycospingolipids in the subject by at least 2-fold. The GLA transgene may further comprise additional elements, including, for example, a signal peptide and/or one or more control elements. Genetically modified cells (e.g., stem cells, precursor cells, liver cells, muscle cells, etc.) comprising an exogenous GLA transgene (integrated or extrachromosomal) are also provided, including cells made by the methods described herein. These cells can be used to provide an α-Gal A protein to a subject with Fabry's disease, for example by administering the cell(s) to a subject in need thereof or, alternatively, by isolating the α-Gal A protein produced by the cell and administering the protein to the subject in need thereof (enzyme replacement therapies). Also provided are vectors (e.g., viral vectors such as AAV or Ad or lipid nanoparticles) comprising a GLA transgene for use in any of the methods described herein, including for use in treatment of Fabry's. In one aspect, the invention describes a method of expressing a transgene encoding one or more corrective GLA transgenes in a cell of the subject. The transgene may be inserted into the genome of a suitable target cell (e.g., blood cell, liver cell, brain cell, stem cell, precursor cell, etc.) such that the α-GalA product encoded by that corrective transgene is stably integrated into the genome of the cell (also referred to as a IVPRP® approach) or, alternatively, the transgene may be maintained in the cell extra-chromosomally (also referred to as a “cDNA” approach). In one embodiment, the corrective GLA transgene is introduced (stably or extra-chromosomally) into cells of a cell line for the in vitro production of the replacement protein, which (optionally purified and/or isolated) protein can then be administered to a subject for treating a subject with Fabry disease (e.g., by reducing and/or eliminating one or more symptoms associates with Fabry disease). In certain embodiments, the α-GalA product encoded by that corrective transgene increases α-GalA activity in a tissue a subject by any amount as compared to untreated subjects, for example, 2 to 1000 more (or any value therebetween) fold, including but not limited to 2 to 100 fold (or any value therebetween including 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 fold), 100 to 500 fold (or any value therebetween), or 500 to 1000 fold or more. In another aspect, described herein are ex vivo or in vivo methods of treating a subject with Fabry disease (e.g., by reducing and/or eliminating one or more symptoms associates with Fabry disease), the methods comprising inserting an GLA transgene into a cell as described herein (cDNA and/or IVPRP approaches) such that the protein is produced in a subject with Fabry disease. In certain embodiments, isolated cells comprising the GLA transgene can be used to treat a patient in need thereof, for example, by administering the cells to a subject with Fabry disease. In other embodiments, the corrective GLA transgene is inserted into a target tissue in the body such that the replacement protein is produced in vivo. In some preferred embodiments, the corrective transgene is inserted into the genome of cells in the target tissue, while in other preferred embodiments, the corrective transgene is inserted into the cells of the target tissue and is maintained in the cells extra-chromosomally. In any of the methods described herein, the expressed α-GalA protein may be excreted from the cell to act on or be taken up by secondary targets, including by other cells in other tissues (e.g. via exportation into the blood) that lack the GLA transgene (cross correction). In some instances, the primary and/or secondary target tissue is the liver. In other instances, the primary and/or secondary target tissue is the brain. In other instances, the primary and/or secondary target is blood (e.g., vasculature). In other instances, the primary and/or secondary target is skeletal muscle. In certain embodiments, the methods and compositions described herein are used to decrease the amount of glycospingolipids including globotriaosylceramide (also known as GL-3 and Gb3) and globotriaosylsphingosine (lyso-Gb3), galabioasylceramide deposited in tissues of a subject suffering Fabry disease. In certain embodiments, the α-GalA product encoded by that corrective transgene decreases glycospingolipids in a tissue of a subject by any amount as compared to untreated subjects, for example, 2 to 100 more (or any value therebetween) fold, including but not limited to 2 to 100 fold (or any value therebetween including 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 fold). In any of the methods described herein, the corrective GLA transgene comprises the wild type sequence of the functioning GLA gene, while in other embodiments, the sequence of the corrective GLA transgene is altered in some manner to give enhanced biological activity (e.g., optimized codons to increase biological activity and/or alteration of transcriptional and translational regulatory sequences to improve gene expression). In some embodiments, the GLA gene is modified to improve expression characteristics. Such modifications can include, but are not limited to, insertion of a translation start site (e.g. methionine), addition of an optimized Kozak sequence, insertion of a signal peptide, and/or codon optimization. In some embodiments, the signal peptide can be chosen from an albumin signal peptide, a F.IX signal peptide, a IDS signal peptide and/or an α-GalA signal peptide. In any embodiments described herein, the GLA donor may comprise a donor as shown in any of FIGS. 1B, 1C, 10 and/or 13. In any of the methods described herein, the GLA transgene may be inserted into the genome of a target cell using a nuclease. Non-limiting examples of suitable nucleases include zinc-finger nucleases (ZFNs), TALENs (Transcription activator like protein nucleases) and/or CRISPR/Cas nuclease systems, which include a DNA-binding molecule that binds to a target site in a region of interest (e.g., a disease associated gene, a highly-expressed gene, an albumin gene or other or safe harbor gene) in the genome of the cell and one or more nuclease domains (e.g., cleavage domain and/or cleavage half-domain). Cleavage domains and cleavage half domains can be obtained, for example, from various restriction endonucleases, Cas proteins and/or homing endonucleases. In certain embodiments, the zinc finger domain recognizes a target site in an albumin gene or a globin gene in red blood precursor cells (RBCs). See, e.g., U.S. Publication No. 2014001721, incorporated by reference in its entirety herein. In other embodiments, the nuclease (e.g., ZFN, TALEN, and/or CRISPR/Cas system) binds to and/or cleaves a safe-harbor gene, for example a CCR5 gene, a PPP1R12C (also known as AAVS1) gene, albumin, HPRT or a Rosa gene. See, e.g., U.S. Pat. Nos. 7,888,121; 7,972,854; 7,914,796; 7,951,925; 8,110,379; 8,409,861; 8,586,526; U.S. Patent Publications 20030232410; 20050208489; 20050026157; 20060063231; 20080159996; 201000218264; 20120017290; 20110265198; 20130137104; 20130122591; 20130177983; 20130177960 and 20140017212. The nucleases (or components thereof) may be provided as a polynucleotide encoding one or more nucleases (e.g., ZFN, TALEN, and/or CRISPR/Cas system) described herein. The polynucleotide may be, for example, mRNA. In some aspects, the mRNA may be chemically modified (See e.g. Kormann et al, (2011) Nature Biotechnology 29(2):154-157). In other aspects, the mRNA may comprise an ARCA cap (see U.S. Pat. Nos. 7,074,596 and 8,153,773). In further embodiments, the mRNA may comprise a mixture of unmodified and modified nucleotides (see U.S. Patent Publication 20120195936). In still further embodiments, the mRNA may comprise a WPRE element (see U.S. Patent Publication No. 20160326548). In another aspect, the invention includes genetically modified cells (e.g., stem cells, precursor cells, liver cells, muscle cells, etc.) with the desired GLA transgene (optionally integrated using a nuclease). In some aspects, the edited stem or precursor cells are then expanded and may be induced to differentiate into a mature edited cells ex vivo, and then the cells are given to the patient. Thus, cells descended from the genetically edited (modified) GLA-producing stem or precursor cells as described herein may be selected for use in this invention. In other aspects, the edited precursors (e.g., CD34+ stem cells) are given in a bone marrow transplant which, following successful implantation, proliferate producing edited cells that then differentiate and mature in vivo and contain the biologic expressed from the GLA transgene. In some embodiments, the edited CD34+ stem cells are given to a patient intravenously such that the edited cells migrate to the bone marrow, differentiate and mature, producing the α-Gal A protein. In other aspects, the edited stem cells are muscle stem cells which are then introduced into muscle tissue. In some aspects, the engineered nuclease is a Zinc Finger Nuclease (ZFN) (the term “ZFN” includes a pair of ZFNs) and in others, the nuclease is a TALE nuclease (TALEN) (the term “TALENs” include a pair of TALENs), and in other aspects, a CRISPR/Cas system is used. The nucleases may be engineered to have specificity for a safe harbor locus, a gene associated with a disease, or for a gene that is highly expressed in cells. By way of non-limiting example only, the safe harbor locus may be the AAVS1 site, the CCR5 gene, albumin or the HPRT gene while the disease associated gene may be the GLA gene encoding α-galactosidase A. In another aspect, described herein is a nuclease (e.g., ZFN, ZFN pair, TALEN, TALEN pair and/or CRISPR/Cas system) expression vector comprising a polynucleotide, encoding one or more nucleases as described herein, operably linked to a promoter. In one embodiment, the expression vector is a viral vector. In a further aspect, described herein is a GLA expression vector comprising a polynucleotide encoding α-GalA as described herein, operably linked to a promoter. In one embodiment, the expression is a viral vector. In another aspect, described herein is a host cell comprising one or more nucleases (e.g., ZFN, ZFN pair, TALEN, TALEN pair and/or CRISPR/Cas system) expression vectors and/or an α-GalA expression vector as described herein. The host cell may be stably transformed or transiently transfected or a combination thereof with one or more nuclease expression vectors. In some embodiments, the host cell is a liver cell. In other embodiments, methods are provided for replacing a genomic sequence in any target gene with a therapeutic GLA transgene as described herein, for example using a nuclease (e.g., ZFN, ZFN pair, TALEN, TALEN pair and/or CRISPR/Cas system) (or one or more vectors encoding said nuclease) as described herein and a “donor” sequence or GLA transgene that is inserted into the gene following targeted cleavage with the nuclease. The donor GLA sequence may be present in the vector carrying the nuclease (or component thereof), present in a separate vector (e.g., Ad, AAV or LV vector or mRNA) or, alternatively, may be introduced into the cell using a different nucleic acid delivery mechanism. Such insertion of a donor nucleotide sequence into the target locus (e.g., highly expressed gene, disease associated gene, other safe-harbor gene, etc.) results in the expression of the GLA transgene under control of the target locus's (e.g., albumin, globin, etc.) endogenous genetic control elements. In some aspects, insertion of the GLA transgene, for example into a target gene (e.g., albumin), results in expression of an intact α-GalA protein sequence and lacks any amino acids encoded by the target (e.g., albumin). In other aspects, the expressed exogenous α-GalA protein is a fusion protein and comprises amino acids encoded by the GLA transgene and by the endogenous locus into which the GLA transgene is inserted (e.g., from the endogenous target locus or, alternatively from sequences on the transgene that encode sequences of the target locus). The target may be any gene, for example, a safe harbor gene such as an albumin gene, an AAVS1 gene, an HPRT gene; a CCR5 gene; or a highly-expressed gene such as a globin gene in an RBC precursor cell (e.g., beta globin or gamma globin). In some instances, the endogenous sequences will be present on the amino (N)-terminal portion of the exogenous α-GalA protein, while in others, the endogenous sequences will be present on the carboxy (C)-terminal portion of the exogenous α-GalA protein. In other instances, endogenous sequences will be present on both the N- and C-terminal portions of the α-GalA exogenous protein. In some embodiments, the endogenous sequences encode a secretion signal peptide that is removed during the process of secretion of the α-GalA protein from the cell. The endogenous sequences may include full-length wild-type or mutant endogenous sequences or, alternatively, may include partial endogenous amino acid sequences. In some embodiments, the endogenous gene-transgene fusion is located at the endogenous locus within the cell while in other embodiments, the endogenous sequence-transgene coding sequence is inserted into another locus within a genome (e.g., a GLA-transgene sequence inserted into an albumin, HPRT or CCR5 locus). In some embodiments, the GLA transgene is expressed such that a therapeutic α-GalA protein product is retained within the cell (e.g., precursor or mature cell). In other embodiments, the GLA transgene is fused to the extracellular domain of a membrane protein such that upon expression, a transgene α-GalA fusion will result in the surface localization of the therapeutic protein. In some aspects, the extracellular domain is chosen from those proteins listed in Table 1. In some aspects, the edited cells further comprise a trans-membrane protein to traffic the cells to a particular tissue type. In one aspect, the trans-membrane protein comprises an antibody, while in others, the trans-membrane protein comprises a receptor. In certain embodiments, the cell is a precursor (e.g., CD34+ or hematopoietic stem cell) or mature RBC (descended from a genetically modified GAL-producing cell as described herein). In some aspects, the therapeutic α-GalA protein product encoded on the transgene is exported out of the cell to affect or be taken up by cells lacking the transgene. In certain embodiments, the cell is a liver cell which releases the therapeutic α-GalA protein into the blood stream to act on distal tissues (e.g., kidney, spleen, heart, brain, etc.). The invention also supplies methods and compositions for the production of a cell (e.g., RBC) carrying an α-GalA therapeutic protein for treatment of Fabry disease that can be used universally for all patients as an allogenic product. This allows for the development of a single product for the treatment of patients with Fabry disease, for example. These carriers may comprise trans-membrane proteins to assist in the trafficking of the cell. In one aspect, the trans-membrane protein comprises an antibody, while in others, the trans-membrane protein comprises a receptor. In one embodiment, the GLA transgene is expressed from the albumin promoter following insertion into the albumin locus. The biologic encoded by the GLA transgene then may be released into the blood stream if the transgene is inserted into a hepatocyte in vivo. In some aspects, the GLA transgene is delivered to the liver in vivo in a viral vector through intravenous administration. In some embodiments, the donor GLA transgene comprises a Kozak consensus sequence prior to the α-GalA coding sequence (Kozak (1987) Nucl Acid Res 15(20):8125-48), such that the expressed product lacks the albumin signal peptide. In some embodiments, the donor α-GalA transgene contains an alternate signal peptide, such as that from the Albumin, IDS or F9 genes, in place of the native GLA signal sequence. Thus, the donor may include a signal peptide as shown in any of SEQ ID NO:1 to 5 or a sequence exhibiting homology to these sequences that acts as a signal peptide (see e.g. FIGS. 1B, 10, 13 and 25). In some embodiments, the GLA transgene donor is transfected or transduced into a cell for episomal or extra-chromosomal maintenance of the transgene. In some aspects, the GLA transgene donor is maintained on a vector comprising regulatory domains to regulate expression of the transgene donor. In some instances, the regulatory domains to regulate transgene expression are the domains endogenous to the transgene being expressed while in other instances, the regulatory domains are heterologous to the transgene. In some embodiments, the GLA transgene is maintained on a viral vector, while in others, it is maintained on a plasmid or mini circle. In some embodiments, the viral vector is an AAV, Ad or LV. In further aspects, the vector comprising the transgene donor is delivered to a suitable target cell in vivo, such that the α-GalA therapeutic protein encoded by the transgene donor is released into the blood stream when the transgene donor vector is delivered to a hepatocyte. In another embodiment, the invention describes precursor cells (muscle stem cells, progenitor cells or CD34+ hematopoietic stem cell (HSPC) cells) into which the GLA transgene has been inserted such that mature cells derived from these precursors contain high levels of the α-GalA product encoded by the transgene. In some embodiments, these precursors are induced pluripotent stem cells (iPSC). In some embodiments, the methods of the invention may be used in vivo in transgenic animal systems. In some aspects, the transgenic animal may be used in model development where the transgene encodes a human α-GalA protein. In some instances, the transgenic animal may be knocked out at the corresponding endogenous locus, allowing the development of an in vivo system where the human protein may be studied in isolation. Such transgenic models may be used for screening purposes to identify small molecules, or large biomolecules or other entities which may interact with or modify the human protein of interest. In some aspects, the GLA transgene is integrated into the selected locus (e.g., highly expressed or safe-harbor) into a stem cell (e.g., an embryonic stem cell, an induced pluripotent stem cell, a hepatic stem cell, a neural stem cell etc.) or non-human animal embryo obtained by any of the methods described herein and those standard in the art, and then the embryo is implanted such that a live animal is born. The animal is then raised to sexual maturity and allowed to produce offspring wherein at least some of the offspring comprise the integrated GLA transgene. In a still further aspect, provided herein is a method for site specific integration of a nucleic acid sequence into an endogenous locus (e.g., disease-associated, highly expressed such as an albumin locus in a liver cell or globin locus in RBC precursor cells of a chromosome, for example into the chromosome of a non-human embryo. In certain embodiments, the method comprises: (a) injecting a non-human embryo with (i) at least one DNA vector, wherein the DNA vector comprises an upstream sequence and a downstream sequence flanking the α-GalA encoding nucleic acid sequence to be integrated, and (ii) at least one polynucleotide molecule encoding at least one nuclease (zinc finger, ZFN pair, TALE nuclease, TALEN pair or CRISPR/Cas system) that recognizes the site of integration in the target locus, and (b) culturing the embryo to allow expression of the nuclease (ZFN, TALEN, and/or CRISPR/Cas system, wherein a double stranded break introduced into the site of integration by the nuclease is repaired, via homologous recombination with the DNA vector, so as to integrate the nucleic acid sequence into the chromosome. In some embodiments, the polynucleotide encoding the nuclease is an RNA. In any of the previous embodiments, the methods and compounds of the invention may be combined with other therapeutic agents for the treatment of subjects with Fabry disease. In some embodiments, the methods and compositions include the use of a molecular chaperone (Hartl et al (2011) Nature 465: 324-332) to insure the correct folding of the Fabry protein. In some aspects, the chaperone can be chosen from well-known chaperone proteins such as AT1001 (Benjamin et al (2012) Mol Ther 20(4):717-726), AT2220 (Khanna et al (2014) PLoS ONE 9(7): e102092, doi:10.1371), and Migalastat (Benjamin et al (2016) Genet Med doi: 10.1038/gim.2016.122). In some aspects, the methods and compositions are used in combination with methods and compositions to allow passage across the blood brain barrier. In other aspects, the methods and compositions are used in combination with compounds known to suppress the immune response of the subject. A kit, comprising a nuclease system and/or a GLA donor as described herein is also provided. The kit may comprise nucleic acids encoding the one or more nucleases (ZFNs, ZFN pairs, TALENs, TALEN pairs and/or CRISPR/Cas system), (e.g. RNA molecules or the ZFN, TALEN, and/or CRISPR/Cas system encoding genes contained in a suitable expression vector), donor molecules, expression vectors encoding the single-guide RNA suitable host cell lines, instructions for performing the methods of the invention, and the like. These and other aspects will be readily apparent to the skilled artisan in light of disclosure as a whole. BRIEF DESCRIPTION OF THE DRAWINGS FIGS. 1A through 1C show the enzyme reaction performed by the wild type α-GalA enzyme and the initial donor and transgene expression cassettes. FIG. 1A shows the reaction performed by α-GalA where in wild type mammals, the Gb3 substrate is broken down. In Fabry organisms, the Gb3 substrate builds up to toxic levels. FIG. 1B shows the initial viral vector used for expressing α-GalA from a cDNA, while FIG. 1C shows the initial viral vector used for expressing the α-GalA following nuclease-mediated insertion into the albumin gene. FIG. 2 is a graph showing the α-GalA activity detected in HepG2/C3A cell media over a period of seven days of cells transduced with albumin-specific nucleases (ZFNs) and the donor depicted in FIG. 1C (shown in the right panel labeled “IVPRP” an acronym of “In Vivo Protein Replacement Platform®”). The levels of activity in media from cells that have undergone a mock transduction procedure are shown in the left panel. The bars from left to right show activity at day 3, day 5, day 7 and cells only. FIGS. 3A and 3B are graphs showing the levels of α-GalA activity detected using the cDNA approach. FIG. 3A shows the activity in the HepG2/C3A cell media detected over a period of 6 days at varying doses of AAV virus comprising the cDNA expression cassette shown in FIG. 1B (bars from left to right show mock transfections, 10K, 30K, 100K, 300K, 1000K, 3000K and 9000K). FIG. 3B is a graph showing the activity detected in the cell pellets of the cells from FIG. 3A at the last time point of the experiment. FIGS. 4A and 4B are graphs depicting the in vivo activity in GLAKO mice treated with the cDNA containing AAV. FIG. 4A shows the results for each individual mouse treated with 2.0e12 vector genomes per kilogram body weight (VG/kg) AAV2/6 comprising the cDNA construct while FIG. 4B shows the results for each mouse treated with 2.0e13 VG/kg AAV2/6-cDNA. In FIG. 4A, one mouse was additionally treated with the molecular chaperone DGJ on the day indicated. Also shown by a dotted line in both figures, is the levels of α-GalA activity found in wild type mice. As shown, the treated mice show levels above wild-type indicative of therapeutically beneficial levels. FIGS. 5A through 5F are graphs depicting the levels of the Gb3 lipid substrate in GLAKO mice and in mice treated with the AAV2/6 comprising the cDNA construct. FIG. 5A shows substrate levels detected in plasma and FIG. 5B shows substrate in heart tissue. FIG. 5C shows substrate detected in the liver and FIG. 5D depicts the substrate detected in the kidney tissues. In all tissues shown, the levels of Gb3 are lower than in the untreated GLAKO mice. Also indicated in FIG. 5D is the lowest level of quantitation (LLOQ) for this assay. The levels of Gb3 and lyso-Gb3 in the treated mice were also expressed in terms of the amount of substrate found relative to the untreated mice. FIG. 5E shows the percent of Gb3 remaining in specific tissues relative to untreated GLAKO mice and FIG. 5F shows the percent of lyso-Gb3 remaining in specific tissues relative to the untreated GLAKO mice. The tissue data sets in 5E and 5F are shown in each treatment group (untreated GLAKO), low and high dose treated GLAKO and wild type mice) where the bars represent the data from (left to right) plasma, liver, heart and kidney. FIGS. 6A though 6E depict the results for the IVPRP approach as tested in vivo. FIG. 6A depicts the α-Gal A activity detected in the plasma of GLAKO mice treated with the AAV2/8 virus comprising the transgene donor shown in FIG. 1C over time, where some mice received immunosuppression (see Example 4). Also shown is the level found in wild type mice. FIG. 6B is a graph showing the level of indels detected in the liver of the treated animals at day 90. Indels (insertions and/or deletions) are an indication of nuclease activity. FIGS. 6C, 6D and 6E are time courses of activity detected in the plasma of the treated mice over a period of nearly 30 days. FIG. 6C shows the activity in animals that were additionally treated with low amounts of immunosuppression while FIG. 6D shows the activity in animals treated with moderate immunosuppression and FIG. 6E shows the animals treated with high levels of immunosuppression. Also shown in FIGS. 6C, 6D and 6E and the levels found in wild type mice for comparison (dotted line). FIGS. 7A through 7C are graphs depicting the α-Gal A activity detected over time in animals treated with both immunosuppression (“IS”) and the DGJ chaperone. FIG. 7A shows the results for the animals treated with low levels of immunosuppression, where the arrows depict the timing of the chaperone dose and the mice treated. In FIG. 7A, all mice were treated with the chaperone and the results demonstrate that the activity increased. FIG. 7B shows the results for animals under moderate immunosuppression where two mice were treated with the DGJ. Those two mice saw an increase in the α-Gal A activity in their plasma. FIG. 7C depicts the results for the mice under the high dose of immunosuppression, and again indicates when the three mice were treated with the DGJ. These results demonstrate that the chaperone increased the amount of activity detected. The dotted line indicates activity levels found in wild type mice for comparison. FIG. 8 is a graph showing the comparison of α-Gal A activity in the tissues of the mice treated either via the cDNA or IVPRP approach. Also shown for comparison are levels in wild type mice and in the untreated GLAKO mice. Tissues shown are liver, plasma, spleen, heart and kidney. Note that the Y axis is split, indicating that the cDNA approach at the 2.0e13 VG/kg dose produces α-GalA activity at nearly 100 times the wild-type level and that activity is detectable in all of the tested tissues. FIGS. 9A through 9C depict the levels of α-GalA activity and Gb3 lipid substrate detected as a result of both the cDNA and In Vivo Protein Replacement Platform® (IVPRP) approaches. FIG. 9A shows the average activity numbers detected from the different treatment groups. FIG. 9B shows the amount of the Gb3 detected in plasma, liver and heart tissues for the various groups, and demonstrates that the cDNA approach results in a decrease of Gb3 approaching the wild type mice, indicating the protein expressed from the transgene is effective in acting on its target substrate. FIG. 9C is a graph showing the amount of α-GalA activity in individual mice from the table in 9A (ZFN+Donor+DGJ group not shown). The cDNA high dose mice (2.0e13 vg/kg cDNA donor vector) are shown with black circles on a black line. The cDNA low dose mice (2e12 vg/kg cDNA donor vector) are shown with shaded triangles on a dashed line. The wild type mice are shown as black open circles on a grey line and the GLAKO mice are shown with the black squares on the black line. Three of the four high dose cDNA mice had levels over 100 times that of the wild type mice. FIG. 10 is a schematic showing various exemplary donor constructs (Variants #A through #L, also referred to as Variants A through L) used for the IVPRP® approach. Abbreviations in the schematics are as follows: “ITR” is the AAV inverted terminal repeat region. “HA-R” and “HA-L” are the right (R) and left (L) homology arms that have homology to the albumin sequence flanking the ZFN cleavage site. “SA” is the splice acceptor site from the F9 gene while “HBB-IGG” is an intron sequence, “GLAco” is the codon optimized α-GalA coding sequence while “GLAco v.2” is an alternate codon optimization of the α-GalA coding sequence “bGHpA” is the poly A sequence from bovine growth hormone, “GLA Signal pept” is the signal peptide from the GLA gene, “fusion” refers to a construct with 2-5 additional amino acids inserted between the splice acceptor site and the GLA transgene, “T2A” and “F2A” are self-cleaving sequences from T. assigna and Foot and Mouth Disease virus, respectively. “IDS Signal pept” is the signal peptide for the IDS gene while “FIX Signal pept” is the signal peptide from the FIX gene. “TI” is a 5′ NGS primer binding sequence added at 3′ end of transgene followed by a targeted integration (TI)-specific sequence with the same base composition as the wild type locus, allowing next generation sequencing to measure indels and HDR-mediated transgene integration simultaneously. See Examples for more details. FIGS. 11A and 11B are graphs depicting α-GalA activity in vitro in HepG2/C3A cells. Shown in FIG. 11A are the activity detected in the cells and in the cell supernatant using the initial donor and the donor variants #A, #B, and #E as shown in FIG. 10. “Z+D” refers to ZFN and donor administration. The data indicate that Variants #A and #B had greater activity than the initial donor. FIG. 11B is a graph showing α-GalA activity comparing Variants #A, #K, #J, #H and #I (Variants A, K, J, H and I) at either a low (300,000/600,000 VG/cell ZFN/donor) or high (600,000/1,200,000 VG/cell ZFN/donor) dose of the ZFNs and GLA donors. ‘Donor only’ data set represents cells treated with only the donor construct without any ZFNs. Bars represent group averages with the standard deviations indicated with the error bars. The data indicated that Variant #K lead to the highest activity in this set. FIG. 12 is a graph showing the activity of the variants #A, #B and #E in vivo. GLAKO mice were used and plasma samples were taken once per week. FIG. 12 shows the data for each group to day 56 post injection, and also shows the data for the cDNA approach for comparison. At day 28, the mice treated with the “new” variant donors had a great deal more α-GalA activity than the initial donor. “Initial” donor refers to the donor used prior to optimization, see FIG. 10 and is shown in FIG. 12 as the black bar at the left of each grouping. cDNA results are presented only for day 56 at far right of the graph. Dotted line indicates 50-fold the activity level in wild type mice, indicating that all samples displayed at least 40-fold more activity than wild type at day 28. FIGS. 13A and 13B are schematics of exemplary cDNA expression cassettes. FIG. 13A shows the layout of a cDNA expression system described previously (see U.S. Publication No. 20170119906) where a GLA coding sequence has been inserted using a different codon optimization protocol (DNA 2.0 v1 versus GeneArt v2, “GLAco v.2”). FIG. 13B shows the cDNA expression cassette used in this work with the alternate codon optimization protocol, and shows Variants #1 to #6 (also referred to as Variants 1 to 6) using signal peptides from the IDS, FIX or ALB genes in combination with GLA coding sequences optimized using the two different protocols. FIGS. 14A and 14B are graphs showing the expression of α-GalA activity using the cDNA approach. In the figure, HepG2/C3A cells were transduced with AAV comprising the indicated cDNA construct, where the effects of varying the signal peptides as shown in FIG. 13B were tested. α-Gal A activity was measured in the cell supernatant at day 3 and day 5, and the results indicated that the IDS and FIX (F9) leader sequence lead to higher levels of activity than either the GLA or albumin (ALB) leader sequences. FIG. 14B shows α-Gal A activity at day 5 for Variants #1, #2, #4, #5 and #6. For these studies, cells received 3.0 e5 VG/cell of the AAV2/6 GLA cDNA vectors. The bars represent group averages and error bars show the standard deviations. FIGS. 15A through 15C are graphs depicting α-Gal A activity in either plasma (FIG. 15A) or in select tissues (FIG. 15B). GLAKO mice were injected with 3e11 VG of ZFNs designed to create a double strand break in Albumin intron 1 and 1.2e12 VG of the initial GLA donor construct or variants A, B, E or J (total AAV dose/mouse=6e13 VG/kg). FIG. 15A depicts plasmid α-Gal A activity in mice that were followed for 2 months with weekly or bi-weekly assessment. The left panel shows results of animals receiving the initial donor, variant A, variant E or variant B. The right panel shows results of wild-type animals or animals receiving variant E or J. FIG. 15B shows α-Gal A activity as measured in liver, heart, kidney and spleen assayed after the animals shown in FIG. 15A were sacrificed. The graph on the left of FIG. 15B shows data 2 months after treatment with the initial GLA donor construct (“Initial” shown in left-most bars of each group), after treatment with variant A (bars second from the left in each group), Variant B (middle bars for each group), Variant E (bars second from the right in each group) and in wild-type animals (“Wild type” shown in right-most bars in each group). The graph on the right of FIG. 15B depicts the activity for Variants E and J, where in each data set, activity in the untreated GLAKO mice are shown in the left most bar; in the wild type mice, bars second from the left in each group; activity in GLAKO mice treated with Variant #E are shown in bars third from left while activity for Variant J is shown in the right most bar. α-Gal A was many-fold above wild type in plasma and all measured tissues for GLA donor variants A, B, E and J. FIG. 15C depicts the level of plasma α-Gal A activity where the data for each mouse treated with the ZFN pair and the Variant A donor is shown. Note that this is the same experiment as shown in FIG. 15A, labeled Variant A, except that in FIG. 15A, the data for the mice as a group is shown, while in FIG. 15C, the data for each treated mouse is shown. FIGS. 16A and 16B are graphs depicting the amount of α-Gal A glycolipid substrate (Gb3 and lyso-Gb3) remaining following treatment with the ZFN+ different donor variants. Gb3 (FIG. 16A) and lyso-Gb3 (FIG. 16B) content was measured in plasma, heart, liver, kidney and spleen (spleen data not shown) via mass spectrophotometry. Each dataset is shown in groups of 4, depicting the levels (from left to right in each group) in plasma, liver, heart and kidney. The amount of substrate is expressed as the fraction remaining, compared to untreated GLAKO mice. The amount of both Gb3 and lyso-Gb3 was greatly reduced in the tissues of mice treated with GLA donor variants A, B or E. FIGS. 17A through 17C show the effect of treating the α-Gal A protein with the deglycosylation enzyme PNGaseF or Endo H. FIG. 17A shows Western blots made from homogenate derived from the mouse livers of the animals treated by the IVPRP approach. Three mice samples are shown in the top panel (labeled ‘GLA donor Variant A’) as well as a sample from a wild type mouse (‘WT’), an untreated GLAKO mouse (‘GLAKO’) and a sample of recombinant human Gal A (‘rec. hGal A’). In the lower panel, labeled ‘GLA donor Variant J’, two mice samples are shown along with a wild type mouse sample and an untreated GLAKO mouse sample, as well as a sample of recombinant human Gal A. (+) and (−) on both blots indicate treatment with PNGase F or Endo H. FIG. 17B shows a Western blot made as described in FIG. 17A except that the mice were treated using the cDNA approach (“initial” construct). FIG. 17C is a schematic depicting PNGaseF cleavage of complex glycosylation structures. The data demonstrates that the Gal A enzyme expressed in the treated GLAKO animals following either the IVPRP® or cDNA approaches shows similar deglycosylation as the deglycosylated human recombinant protein after PNGaseF treatment. FIGS. 18A through 18C are graphs depicting activities measured using the initial cDNA construct as compared to Variant #4 (shown in 13B above). FIG. 18A depicts the plasma α-GalA activity in GLAKO mice treated with 2e12 VG/kg GLA cDNA comprising AAV2/6 as indicated. Activity was measured for up to 60 days post injection. FIG. 18B indicates the α-GalA activity in tissues as indicated in the mice from FIG. 18A. The data sets, from left to right, show the α-GalA activity in GLAKO untreated mice (left most bar); wild type mice (second to left most bar); GLAKO mice treated with the initial cDNA variant (third to left bar); and the GLAKO mice treated with cDNA variant D. Horizontal dotted lines indicate the activity corresponding to 10× the wild type level for reference. FIG. 18C depicts a Western blot detecting human α-GalA in the liver of 3 GLAKO mice treated with cDNA Variant #4. For comparison are shown activity a wild type mouse (“WT”) and an untreated GLAKO mouse. For comparison purposes, also shown is the recombinant hGalA. The samples were treated with PNGasdF or EndoH as described in FIG. 17. FIG. 19 is a graph depicting the level of α-Gal A activity in the plasma of mice treated with the initial cDNA construct (shown in FIG. 13). Each group was treated with AAV comprising the construct at the doses indicated, from 1.25e11 to 5.0e12 vg/kg (solid lines, group averages indicated by the error bars.) Wild type and untreated GLAKO mice were included as well and are indicated on the figure. FIGS. 20A and 20B are graphs depicting the α-Gal A activity detected following in vivo expression of Variants E and J. FIG. 20A shows the α-Gal A activity detected in the plasma following treatment of GLAKO mice with ZFNs specific for albumin and either the Variant E or Variant J donors (see FIG. 10). FIG. 20B shows the α-Gal A activity detected in various tissues of interest (liver, heart, kidney and spleen). In each dataset of FIG. 20B, from left to right, the bars show the results for GLAKO mice, wildtype (WT) mice, Variant E donor or Variant J donor. FIGS. 21A and 21B are graphs depicting the amount of α-Gal A substrate detected in various tissues of interest (plasma, liver, heart and kidney). FIG. 21A depicts the amount of GB3 detected as a percent of that detected in GLAKO mice (set at 100%). FIG. 21B depicts the amount of lyso-Gb3 detected as a percent of that detected in GLAKO mice (set at 100%). In both FIGS. 21A and 21B, each dataset, from left to right, shows the results detected in the plasma, liver, heart and kidney. FIG. 22 is a graph depicting permanent modification of hepatocytes in a GLAKO mouse model of Fabry disease following nuclease-mediated targeted integration of a GLA transgene and shows the percentage of indels in liver cells treated under the indicated conditions. FIGS. 23A and 23B are graphs depicting α-Gal A expressed from the integrated transgene, secreted into the bloodstream and taken up by secondary tissues. GLAKO mice were treated with ZFNs and one of two hGLA donor constructs. FIG. 23A depicts GalA activity in plasma from animals treated with the indicated constructs or untreated animals. FIG. 23B shows GalA activity in the indicated tissues (liver, spleen, heart and kidney) under the indicated conditions. The left most bar shows activity in untreated animals; the bar second from the left shows activity in animals treated with Donor Variant E only; the middle bar shows activity in wild-type animals; the bar second from the right shows activity in animals treated with ZFN and Donor Variant A; and the right-most bar shows activity in animals treated with ZFN and Donor Variant E. Untreated GLAKO mice, untreated wild type mice and GLAKO mice treated with donor but no ZFNs were included as controls. Stable plasma activity reached up to 80-fold wild type. Graphs display plasma α-Gal A activity over time and tissue activity at study termination (Day 56). FIGS. 24A and 24B are graphs depicting Fabry substrate content in the indicated tissues. FIG. 24A shows Gb3 content and FIG. 24B shows lyso-Gb3 content as % reduction from untreated GLAKO mice in the indicated conditions. The bars under each condition show levels in plasma, liver, heart and kidney from left to right. Mice treated with ZFNs and either variant of the hGLA donor have greatly reduced substrate content. FIGS. 25A and 25B show schematics of Variant L and Variant M and targeted integration into the wild-type albumin locus. FIG. 25A depicts variants L and M and shows that Variant M differs from Variant L in that it comprises an IDS signal peptide rather than a GLA signal peptide. Abbreviations are as described in FIG. 10. FIG. 25B shows integration of the GLA transgene into the Albumin locus. “TI” is a 5′ Next Generation Sequencing (NGS) primer binding sequence added at 3′ end of transgene followed by a targeted integration (TI)-specific sequence with same base composition as the wild type locus, allowing next generation sequencing to measure indels and HDR-mediated transgene integration simultaneously. FIGS. 26A and 26B are graphs depicting modification (percent indels or percent TI) using the indicated donors into the human hematocarcinoma cell line HepG2 at the indicated dosages. FIG. 26A shows results using the Variant L donor and FIG. 26B shows results using the Variant M donor. FIGS. 27A and 27B are graphs depicting how liver-produced α-Gal A is secreted into the bloodstream and taken up by secondary tissues. A GLA donor construct containing an IDS signal peptide and a 3′ sequence for analysis of targeted integration (TI) was used to treat GLAKO mice. FIG. 27A depicts GalA activity in plasma from animals treated with the indicated constructs or untreated animals. FIG. 27B shows GalA activity in the indicated tissues (liver, spleen, heart and kidney) under the indicated conditions. The left most bar shows activity in untreated animals; the bar second from the left shows activity in animals treated with Donor Variant M only; the middle bar shows activity in wild-type animals; the bar second from the right shows activity in animals treated with ZFN and Donor Variant M at a low dose; and the right-most bar shows activity in animals treated with ZFN and Donor Variant M at a high dose. As shown, stable plasma activity up to 250-fold wild type was observed and α-Gal A activity in heart and kidney was over 20-fold wild type and 4-fold wild type, respectively. FIGS. 28A and 28B are graphs depicting α-GAL A activity in cells treated with liver specific constructs comprising a GLA construct. FIG. 28A shows activity in HepG2 cell supernatant and FIG. 28B shows activity in K562 cell pellets cultured in the presence of supernatant from treated or untreated HepG2 cells as shown in FIG. 28A. FIG. 29 is a graph depicting α-GAL A activity in plasma of GLAXO mice dosed with 1.25e11 to 5.0e12 VG/KG of the initial cDNA construct (solid lines, group averages, n=4 to 7 per group) and followed for 6 months. Wild type (grey dotted line, indicated by an arrow) and untreated GLAKO mice (black dotted line, indicated by an arrow) are also shown. FIG. 30 shows graphs depicting α-Gal A activity in the indicated tissues (liver, spleen, heart and kidney) at 6 months post-treatment with the indicated dosages. Also shown are wild-type and untreated animals. FIG. 31 shows graphs depicting a dose-dependent reduction in Fabry substrate Gb3 content in the indicated tissues (liver, spleen, heart and kidney) in GLAKO mice with 1.25e11 to 5.0e12 VG/KG of the initial cDNA construct as % reduction from untreated GLAKO mice (group averages, n=4 to 7 per group). Mice displayed a dose-dependent reduction in Gb3 content in all tissues measured. FIGS. 32A and 32B graphs depicting the percent of Gb3 substrate remaining in various tissues of interest (plasma, liver, heart and kidney) after the indicated treatment protocol (see also FIG. 18). FIG. 32A depicts the amount of GB3 detected as a percent of that detected in untreated GLAKO mice (set at 100%). FIG. 32B depicts the amount of lyso-Gb3 detected as a percent of that detected in untreated GLAKO mice (set at 100%). In both FIGS. 32A and 32B, each dataset, from left to right, shows the results detected in the plasma, liver, heart and kidney. FIGS. 33A and 33B are graphs depicting the percent of Gb3 substrate remaining in various tissues of interest (plasma, liver, heart and kidney) after the indicated treatment protocol (see also FIG. 27). FIG. 33A depicts the amount of GB3 detected as a percent of that detected in untreated GLAKO mice (set at 100%). FIG. 33B depicts the amount of lyso-Gb3 detected as a percent of that detected in untreated GLAKO mice (set at 100%). In both FIGS. 33A and 33B, each dataset, from left to right, shows the results detected in the plasma, liver, heart and kidney. DETAILED DESCRIPTION Disclosed herein are methods and compositions for treating or preventing Fabry disease. The invention provides methods and compositions for insertion of a GLA transgene encoding a protein that is lacking or insufficiently expressed in the subject with Fabry disease such that the gene is expressed in the liver and the therapeutic (replacement) protein is expressed. The invention also describes the alteration of a cell (e.g., precursor or mature RBC, iPSC or liver cell) such that it produces high levels of the therapeutic and the introduction of a population of these altered cells into a patient will supply that needed protein. The transgene can encode a desired protein or structural RNA that is beneficial therapeutically in a patient in need thereof. Thus, the methods and compositions of the invention can be used to express, from a transgene, one or more therapeutically beneficial α-GalA proteins from any locus (e.g., highly expressed albumin locus) to replace the enzyme that is defective and/or lacking in Fabry disease. Additionally, the invention provides methods and compositions for treatment (including the alleviation of one or more symptoms) of Fabry disease by insertion of the transgene sequences into highly-expressed loci in cells such as liver cells. Included in the invention are methods and compositions for delivery of the α-GalA encoding transgene via a viral vector to the liver of a subject in need thereof where the virus may be introduced via injection into the peripheral venus system or via direct injection into a liver-directed blood vessel (e.g. portal vein). The methods and compositions can be used to induce insertion of the transgene into a safe harbor locus (e.g. albumin) or can be used to cause extrachromosomal maintenance of a viral cDNA construct in a liver cell. In either case, the transgene is highly expressed and provides therapeutic benefit to the Fabry patient in need. In addition, the transgene can be introduced into patient derived cells, e.g. patient derived induced pluripotent stem cells (iPSCs) or other types of stems cells (embryonic or hematopoietic) for use in eventual implantation. Particularly useful is the insertion of the therapeutic transgene into a hematopoietic stem cell for implantation into a patient in need thereof. As the stem cells differentiate into mature cells, they will contain high levels of the therapeutic protein for delivery to the tissues. General Practice of the methods, as well as preparation and use of the compositions disclosed herein employ, unless otherwise indicated, conventional techniques in molecular biology, biochemistry, chromatin structure and analysis, computational chemistry, cell culture, recombinant DNA and related fields as are within the skill of the art. These techniques are fully explained in the literature. See, for example, Sambrook et al. MOLECULAR CLONING: A LABORATORY MANUAL, Second edition, Cold Spring Harbor Laboratory Press, 1989 and Third edition, 2001; Ausubel et al., CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, New York, 1987 and periodic updates; the series METHODS IN ENZYMOLOGY, Academic Press, San Diego; Wolffe, CHROMATIN STRUCTURE AND FUNCTION, Third edition, Academic Press, San Diego, 1998; METHODS IN ENZYMOLOGY, Vol. 304, “Chromatin” (P. M. Wassarman and A. P. Wolffe, eds.), Academic Press, San Diego, 1999; and METHODS IN MOLECULAR BIOLOGY, Vol. 119, “Chromatin Protocols” (P. B. Becker, ed.) Humana Press, Totowa, 1999. Definitions The terms “nucleic acid,” “polynucleotide,” and “oligonucleotide” are used interchangeably and refer to a deoxyribonucleotide or ribonucleotide polymer, in linear or circular conformation, and in either single- or double-stranded form. For the purposes of the present disclosure, these terms are not to be construed as limiting with respect to the length of a polymer. The terms can encompass known analogues of natural nucleotides, as well as nucleotides that are modified in the base, sugar and/or phosphate moieties (e.g., phosphorothioate backbones). In general, an analogue of a particular nucleotide has the same base-pairing specificity; i.e., an analogue of A will base-pair with T. The terms “polypeptide,” “peptide” and “protein” are used interchangeably to refer to a polymer of amino acid residues. The term also applies to amino acid polymers in which one or more amino acids are chemical analogues or modified derivatives of corresponding naturally-occurring amino acids. “Binding” refers to a sequence-specific, non-covalent interaction between macromolecules (e.g., between a protein and a nucleic acid). Not all components of a binding interaction need be sequence-specific (e.g., contacts with phosphate residues in a DNA backbone), as long as the interaction as a whole is sequence-specific. Such interactions are generally characterized by a dissociation constant (Kd) of 10−6 M−1 or lower. “Affinity” refers to the strength of binding: increased binding affinity being correlated with a lower Kd. A “binding domain” is a molecule that is able to bind non-covalently to another molecule. A binding molecule can bind to, for example, a DNA molecule (a DNA-binding protein such as a zinc finger protein or TAL-effector domain protein or a single guide RNA), an RNA molecule (an RNA-binding protein) and/or a protein molecule (a protein-binding protein). In the case of a protein-binding molecule, it can bind to itself (to form homodimers, homotrimers, etc.) and/or it can bind to one or more molecules of a different protein or proteins. A binding molecule can have more than one type of binding activity. For example, zinc finger proteins have DNA-binding, RNA-binding and protein-binding activity. Thus, DNA-binding molecules, including DNA-binding components of artificial nucleases and transcription factors include but are not limited to, ZFPs, TALEs and sgRNAs. A “zinc finger DNA binding protein” (or binding domain) is a protein, or a domain within a larger protein, that binds DNA in a sequence-specific manner through one or more zinc fingers, which are regions of amino acid sequence within the binding domain whose structure is stabilized through coordination of a zinc ion. The term zinc finger DNA binding protein is often abbreviated as zinc finger protein or ZFP. Artificial nucleases and transcription factors can include a ZFP DNA-binding domain and a functional domain (nuclease domain for a ZFN or transcriptional regulatory domain for ZFP-TF). The term “zinc finger nuclease” includes one ZFN as well as a pair of ZFNs that dimerize to cleave the target gene. A “TALE DNA binding domain” or “TALE” is a polypeptide comprising one or more TALE repeat domains/units. The repeat domains are involved in binding of the TALE to its cognate target DNA sequence. A single “repeat unit” (also referred to as a “repeat”) is typically 33-35 amino acids in length and exhibits at least some sequence homology with other TALE repeat sequences within a naturally occurring TALE protein. See, e.g., U.S. Pat. No. 8,586,526. Artificial nucleases and transcription factors can include a TALE DNA-binding domain and a functional domain (nuclease domain for a TALEN or transcriptional regulatory domain for TALEN-TF). The term “TALEN” includes one TALEN as well as a pair of TALENs that dimerize to cleave the target gene. Zinc finger and TALE binding domains can be “engineered” to bind to a predetermined nucleotide sequence, for example via engineering (altering one or more amino acids) of the recognition helix region of a naturally occurring zinc finger or TALE protein. Therefore, engineered DNA binding proteins (zinc fingers or TALEs) are proteins that are non-naturally occurring. Non-limiting examples of methods for engineering DNA-binding proteins are design and selection. A designed DNA binding protein is a protein not occurring in nature whose design/composition results principally from rational criteria. Rational criteria for design include application of substitution rules and computerized algorithms for processing information in a database storing information of existing ZFP and/or TALE designs and binding data. See, for example, U.S. Pat. Nos. 8,568,526; 6,140,081; 6,453,242; and 6,534,261; see also WO 98/53058; WO 98/53059; WO 98/53060; WO 02/016536 and WO 03/016496. A “selected” zinc finger protein or TALE is a protein not found in nature whose production results primarily from an empirical process such as phage display, interaction trap or hybrid selection. See e.g., U.S. Pat. Nos. 8,586,526; 5,789,538; U.S. Pat. No. 5,925,523; U.S. Pat. No. 6,007,988; U.S. Pat. No. 6,013,453; U.S. Pat. No. 6,200,759; WO 95/19431; WO 96/06166; WO 98/53057; WO 98/54311; WO 00/27878; WO 01/60970; WO 01/88197; WO 02/099084. “Recombination” refers to a process of exchange of genetic information between two polynucleotides. For the purposes of this disclosure, “homologous recombination (HR)” refers to the specialized form of such exchange that takes place, for example, during repair of double-strand breaks in cells via homology-directed repair mechanisms. This process requires nucleotide sequence homology, uses a “donor” molecule to template repair of a “target” molecule (i.e., the one that experienced the double-strand break), and is variously known as “non-crossover gene conversion” or “short tract gene conversion,” because it leads to the transfer of genetic information from the donor to the target. Without wishing to be bound by any particular theory, such transfer can involve mismatch correction of heteroduplex DNA that forms between the broken target and the donor, and/or “synthesis-dependent strand annealing,” in which the donor is used to re-synthesize genetic information that will become part of the target, and/or related processes. Such specialized HR often results in an alteration of the sequence of the target molecule such that part or all of the sequence of the donor polynucleotide is incorporated into the target polynucleotide. In the methods of the disclosure, one or more targeted nucleases as described herein create a double-stranded break in the target sequence (e.g., cellular chromatin) at a predetermined site, and a “donor” polynucleotide, having homology to the nucleotide sequence in the region of the break, can be introduced into the cell. The presence of the double-stranded break has been shown to facilitate integration of the donor sequence. The donor sequence may be physically integrated or, alternatively, the donor polynucleotide is used as a template for repair of the break via homologous recombination, resulting in the introduction of all or part of the nucleotide sequence as in the donor into the cellular chromatin. Thus, a first sequence in cellular chromatin can be altered and, in certain embodiments, can be converted into a sequence present in a donor polynucleotide. Thus, the use of the terms “replace” or “replacement” can be understood to represent replacement of one nucleotide sequence by another, (i.e., replacement of a sequence in the informational sense), and does not necessarily require physical or chemical replacement of one polynucleotide by another. In any of the methods described herein, additional pairs of zinc-finger or TALEN proteins can be used for additional double-stranded cleavage of additional target sites within the cell. In certain embodiments of methods for targeted recombination and/or replacement and/or alteration of a sequence in a region of interest in cellular chromatin, a chromosomal sequence is altered by homologous recombination with an exogenous “donor” nucleotide sequence. Such homologous recombination is stimulated by the presence of a double-stranded break in cellular chromatin, if sequences homologous to the region of the break are present. In any of the methods described herein, the first nucleotide sequence (the “donor sequence”) can contain sequences that are homologous, but not identical, to genomic sequences in the region of interest, thereby stimulating homologous recombination to insert a non-identical sequence in the region of interest. Thus, in certain embodiments, portions of the donor sequence that are homologous to sequences in the region of interest exhibit between about 80 to 99% (or any integer there between) sequence identity to the genomic sequence that is replaced. In other embodiments, the homology between the donor and genomic sequence is higher than 99%, for example if only 1 nucleotide differs as between donor and genomic sequences of over 100 contiguous base pairs. In certain cases, a non-homologous portion of the donor sequence can contain sequences not present in the region of interest, such that new sequences are introduced into the region of interest. In these instances, the non-homologous sequence is generally flanked by sequences of 50-1,000 base pairs (or any integral value therebetween) or any number of base pairs greater than 1,000, that are homologous or identical to sequences in the region of interest. In other embodiments, the donor sequence is non-homologous to the first sequence, and is inserted into the genome by non-homologous recombination mechanisms. Any of the methods described herein can be used for partial or complete inactivation of one or more target sequences in a cell by targeted integration of donor sequence that disrupts expression of the gene(s) of interest. Cell lines with partially or completely inactivated genes are also provided. Furthermore, the methods of targeted integration as described herein can also be used to integrate one or more exogenous sequences. The exogenous nucleic acid sequence can comprise, for example, one or more genes or cDNA molecules, or any type of coding or non-coding sequence, as well as one or more control elements (e.g., promoters). In addition, the exogenous nucleic acid sequence may produce one or more RNA molecules (e.g., small hairpin RNAs (shRNAs), inhibitory RNAs (RNAis), microRNAs (miRNAs), etc.). “Cleavage” refers to the breakage of the covalent backbone of a DNA molecule. Cleavage can be initiated by a variety of methods including, but not limited to, enzymatic or chemical hydrolysis of a phosphodiester bond. Both single-stranded cleavage and double-stranded cleavage are possible, and double-stranded cleavage can occur as a result of two distinct single-stranded cleavage events. DNA cleavage can result in the production of either blunt ends or staggered ends. In certain embodiments, fusion polypeptides are used for targeted double-stranded DNA cleavage. A “cleavage half-domain” is a polypeptide sequence which, in conjunction with a second polypeptide (either identical or different) forms a complex having cleavage activity (preferably double-strand cleavage activity). The terms “first and second cleavage half-domains;” “+ and − cleavage half-domains” and “right and left cleavage half-domains” are used interchangeably to refer to pairs of cleavage half-domains that dimerize. An “engineered cleavage half-domain” is a cleavage half-domain that has been modified so as to form obligate heterodimers with another cleavage half-domain (e.g., another engineered cleavage half-domain). See, U.S. Pat. Nos. 7,888,121; 7,914,796; 8,034,598 and 8,823,618, incorporated herein by reference in their entireties. The term “sequence” refers to a nucleotide sequence of any length, which can be DNA or RNA; can be linear, circular or branched and can be either single-stranded or double stranded. The term “donor sequence” refers to a nucleotide sequence that is inserted into a genome. A donor sequence can be of any length, for example between 2 and 10,000 nucleotides in length (or any integer value therebetween or thereabove), preferably between about 100 and 1,000 nucleotides in length (or any integer therebetween), more preferably between about 200 and 500 nucleotides in length. A “disease associated gene” is one that is defective in some manner in a monogenic disease. Non-limiting examples of monogenic diseases include severe combined immunodeficiency, cystic fibrosis, hemophilias, lysosomal storage diseases (e.g. Gaucher's, Hurler's, Hunter's, Fabry's, Neimann-Pick, Tay-Sach's etc.), sickle cell anemia, and thalassemia. “Chromatin” is the nucleoprotein structure comprising the cellular genome. Cellular chromatin comprises nucleic acid, primarily DNA, and protein, including histones and non-histone chromosomal proteins. The majority of eukaryotic cellular chromatin exists in the form of nucleosomes, wherein a nucleosome core comprises approximately 150 base pairs of DNA associated with an octamer comprising two each of histones H2A, H2B, H3 and H4; and linker DNA (of variable length depending on the organism) extends between nucleosome cores. A molecule of histone H1 is generally associated with the linker DNA. For the purposes of the present disclosure, the term “chromatin” is meant to encompass all types of cellular nucleoprotein, both prokaryotic and eukaryotic. Cellular chromatin includes both chromosomal and episomal chromatin. A “chromosome,” is a chromatin complex comprising all or a portion of the genome of a cell. The genome of a cell is often characterized by its karyotype, which is the collection of all the chromosomes that comprise the genome of the cell. The genome of a cell can comprise one or more chromosomes. An “episome” is a replicating nucleic acid, nucleoprotein complex or other structure comprising a nucleic acid that is not part of the chromosomal karyotype of a cell. Examples of episomes include plasmids and certain viral genomes. A “target site” or “target sequence” is a nucleic acid sequence that defines a portion of a nucleic acid to which a binding molecule will bind, provided sufficient conditions for binding exist. An “exogenous” molecule is a molecule that is not normally present in a cell, but can be introduced into a cell by one or more genetic, biochemical or other methods. “Normal presence in the cell” is determined with respect to the particular developmental stage and environmental conditions of the cell. Thus, for example, a molecule that is present only during embryonic development of muscle is an exogenous molecule with respect to an adult muscle cell. Similarly, a molecule induced by heat shock is an exogenous molecule with respect to a non-heat-shocked cell. An exogenous molecule can comprise, for example, a functioning version of a malfunctioning endogenous molecule or a malfunctioning version of a normally-functioning endogenous molecule. An exogenous molecule can be, among other things, a small molecule, such as is generated by a combinatorial chemistry process, or a macromolecule such as a protein, nucleic acid, carbohydrate, lipid, glycoprotein, lipoprotein, polysaccharide, any modified derivative of the above molecules, or any complex comprising one or more of the above molecules. Nucleic acids include DNA and RNA, can be single- or double-stranded; can be linear, branched or circular; and can be of any length. Nucleic acids include those capable of forming duplexes, as well as triplex-forming nucleic acids. See, for example, U.S. Pat. Nos. 5,176,996 and 5,422,251. Proteins include, but are not limited to, DNA-binding proteins, transcription factors, chromatin remodeling factors, methylated DNA binding proteins, polymerases, methylases, demethylases, acetylases, deacetylases, kinases, phosphatases, integrases, recombinases, ligases, topoisomerases, gyrases and helicases. An exogenous molecule can be the same type of molecule as an endogenous molecule, e.g., an exogenous protein or nucleic acid. For example, an exogenous nucleic acid can comprise an infecting viral genome, a plasmid or episome introduced into a cell, or a chromosome that is not normally present in the cell. Methods for the introduction of exogenous molecules into cells are known to those of skill in the art and include, but are not limited to, lipid-mediated transfer (i.e., liposomes, including neutral and cationic lipids), electroporation, direct injection, cell fusion, particle bombardment, calcium phosphate co-precipitation, DEAE-dextran-mediated transfer and viral vector-mediated transfer. An exogenous molecule can also be the same type of molecule as an endogenous molecule but derived from a different species than the cell is derived from. For example, a human nucleic acid sequence may be introduced into a cell line originally derived from a mouse or hamster. By contrast, an “endogenous” molecule is one that is normally present in a particular cell at a particular developmental stage under particular environmental conditions. For example, an endogenous nucleic acid can comprise a chromosome, the genome of a mitochondrion, chloroplast or other organelle, or a naturally-occurring episomal nucleic acid. Additional endogenous molecules can include proteins, for example, transcription factors and enzymes. A “fusion” molecule is a molecule in which two or more subunit molecules are linked, preferably covalently. The subunit molecules can be the same chemical type of molecule, or can be different chemical types of molecules. Examples of the first type of fusion molecule include, but are not limited to, fusion proteins (for example, a fusion between a ZFP or TALE DNA-binding domain and one or more activation domains) and fusion nucleic acids (for example, a nucleic acid encoding the fusion protein described supra). Examples of the second type of fusion molecule include, but are not limited to, a fusion between a triplex-forming nucleic acid and a polypeptide, and a fusion between a minor groove binder and a nucleic acid. Expression of a fusion protein in a cell can result from delivery of the fusion protein to the cell or by delivery of a polynucleotide encoding the fusion protein to a cell, wherein the polynucleotide is transcribed, and the transcript is translated, to generate the fusion protein. Trans-splicing, polypeptide cleavage and polypeptide ligation can also be involved in expression of a protein in a cell. Methods for polynucleotide and polypeptide delivery to cells are presented elsewhere in this disclosure. A “gene,” for the purposes of the present disclosure, includes a DNA region encoding a gene product (see infra), as well as all DNA regions which regulate the production of the gene product, whether or not such regulatory sequences are adjacent to coding and/or transcribed sequences. Accordingly, a gene includes, but is not necessarily limited to, promoter sequences, terminators, translational regulatory sequences such as ribosome binding sites and internal ribosome entry sites, enhancers, silencers, insulators, boundary elements, replication origins, matrix attachment sites and locus control regions. “Gene expression” refers to the conversion of the information, contained in a gene, into a gene product. A gene product can be the direct transcriptional product of a gene (e.g., mRNA, tRNA, rRNA, antisense RNA, ribozyme, structural RNA or any other type of RNA) or a protein produced by translation of an mRNA. Gene products also include RNAs which are modified, by processes such as capping, polyadenylation, methylation, and editing, and proteins modified by, for example, methylation, acetylation, phosphorylation, ubiquitination, ADP-ribosylation, myristilation, and glycosylation. “Modulation” of gene expression refers to a change in the activity of a gene. Modulation of expression can include, but is not limited to, gene activation and gene repression. Genome editing (e.g., cleavage, alteration, inactivation, random mutation) can be used to modulate expression. Gene inactivation refers to any reduction in gene expression as compared to a cell that does not include a ZFP, TALE or CRISPR/Cas system as described herein. Thus, gene inactivation may be partial or complete. A “region of interest” is any region of cellular chromatin, such as, for example, a gene or a non-coding sequence within or adjacent to a gene, in which it is desirable to bind an exogenous molecule. Binding can be for the purposes of targeted DNA cleavage and/or targeted recombination. A region of interest can be present in a chromosome, an episome, an organellar genome (e.g., mitochondrial, chloroplast), or an infecting viral genome, for example. A region of interest can be within the coding region of a gene, within transcribed non-coding regions such as, for example, leader sequences, trailer sequences or introns, or within non-transcribed regions, either upstream or downstream of the coding region. A region of interest can be as small as a single nucleotide pair or up to 2,000 nucleotide pairs in length, or any integral value of nucleotide pairs. “Eukaryotic” cells include, but are not limited to, fungal cells (such as yeast), plant cells, animal cells, mammalian cells and human cells (e.g., liver cells, muscle cells, RBCs, T-cells, etc.), including stem cells (pluripotent and multipotent). “Red Blood Cells” (RBCs) or erythrocytes are terminally differentiated cells derived from hematopoietic stem cells. They lack a nuclease and most cellular organelles. RBCs contain hemoglobin to carry oxygen from the lungs to the peripheral tissues. In fact, 33% of an individual RBC is hemoglobin. They also carry CO2 produced by cells during metabolism out of the tissues and back to the lungs for release during exhale. RBCs are produced in the bone marrow in response to blood hypoxia which is mediated by release of erythropoietin (EPO) by the kidney. EPO causes an increase in the number of proerythroblasts and shortens the time required for full RBC maturation. After approximately 120 days, since the RBC do not contain a nucleus or any other regenerative capabilities, the cells are removed from circulation by either the phagocytic activities of macrophages in the liver, spleen and lymph nodes (˜90%) or by hemolysis in the plasma (˜10%). Following macrophage engulfment, chemical components of the RBC are broken down within vacuoles of the macrophages due to the action of lysosomal enzymes. RBCs, in vitro or in vivo, can be descended from genetically modified stem or RBC precursor cells as described herein. “Secretory tissues” are those tissues in an animal that secrete products out of the individual cell into a lumen of some type which are typically derived from epithelium. Examples of secretory tissues that are localized to the gastrointestinal tract include the cells that line the gut, the pancreas, and the gallbladder. Other secretory tissues include the liver, tissues associated with the eye and mucous membranes such as salivary glands, mammary glands, the prostate gland, the pituitary gland and other members of the endocrine system. Additionally, secretory tissues include individual cells of a tissue type which are capable of secretion. The terms “operative linkage” and “operatively linked” (or “operably linked”) are used interchangeably with reference to a juxtaposition of two or more components (such as sequence elements), in which the components are arranged such that both components function normally and allow the possibility that at least one of the components can mediate a function that is exerted upon at least one of the other components. By way of illustration, a transcriptional regulatory sequence, such as a promoter, is operatively linked to a coding sequence if the transcriptional regulatory sequence controls the level of transcription of the coding sequence in response to the presence or absence of one or more transcriptional regulatory factors. A transcriptional regulatory sequence is generally operatively linked in cis with a coding sequence, but need not be directly adjacent to it. For example, an enhancer is a transcriptional regulatory sequence that is operatively linked to a coding sequence, even though they are not contiguous. With respect to fusion polypeptides, the term “operatively linked” can refer to the fact that each of the components performs the same function in linkage to the other component as it would if it were not so linked. For example, with respect to a fusion polypeptide in which a ZFP, TALE or Cas DNA-binding domain is fused to an activation domain, the ZFP or TALE DNA-binding domain and the activation domain are in operative linkage if, in the fusion polypeptide, the ZFP or TALE DNA-binding domain portion is able to bind its target site and/or its binding site, while the activation domain is able to up-regulate gene expression. When a fusion polypeptide in which a ZFP or TALE DNA-binding domain is fused to a cleavage domain, the ZFP or TALE DNA-binding domain and the cleavage domain are in operative linkage if, in the fusion polypeptide, the ZFP or TALE DNA-binding domain portion is able to bind its target site and/or its binding site, while the cleavage domain is able to cleave DNA in the vicinity of the target site. A “functional fragment” of a protein, polypeptide or nucleic acid is a protein, polypeptide or nucleic acid whose sequence is not identical to the full-length protein, polypeptide or nucleic acid, yet retains the same function as the full-length protein, polypeptide or nucleic acid. A functional fragment can possess more, fewer, or the same number of residues as the corresponding native molecule, and/or can contain one or more amino acid or nucleotide substitutions. Methods for determining the function of a nucleic acid (e.g., coding function, ability to hybridize to another nucleic acid) are well-known in the art. Similarly, methods for determining protein function are well-known. For example, the DNA-binding function of a polypeptide can be determined, for example, by filter-binding, electrophoretic mobility-shift, or immunoprecipitation assays. DNA cleavage can be assayed by gel electrophoresis. See Ausubel et al., supra. The ability of a protein to interact with another protein can be determined, for example, by co-immunoprecipitation, two-hybrid assays or complementation, both genetic and biochemical. See, for example, Fields et al. (1989) Nature 340:245-246; U.S. Pat. No. 5,585,245 and PCT WO 98/44350. A “vector” is capable of transferring gene sequences to target cells. Typically, “vector construct,” “expression vector,” and “gene transfer vector,” mean any nucleic acid construct capable of directing the expression of a gene of interest and which can transfer gene sequences to target cells. Thus, the term includes cloning, and expression vehicles, as well as integrating vectors. A “reporter gene” or “reporter sequence” refers to any sequence that produces a protein product that is easily measured, preferably although not necessarily in a routine assay. Suitable reporter genes include, but are not limited to, sequences encoding proteins that mediate antibiotic resistance (e.g., ampicillin resistance, neomycin resistance, G418 resistance, puromycin resistance), sequences encoding colored or fluorescent or luminescent proteins (e.g., green fluorescent protein, enhanced green fluorescent protein, red fluorescent protein, luciferase), and proteins which mediate enhanced cell growth and/or gene amplification (e.g., dihydrofolate reductase). Epitope tags include, for example, one or more copies of FLAG, His, myc, Tap, HA or any detectable amino acid sequence. “Expression tags” include sequences that encode reporters that may be operably linked to a desired gene sequence in order to monitor expression of the gene of interest. The terms “subject” and “patient” are used interchangeably and refer to mammals such as human patients and non-human primates, as well as experimental animals such as rabbits, dogs, cats, rats, mice, and other animals. Accordingly, the term “subject” or “patient” as used herein means any mammalian patient or subject to which the altered cells of the invention and/or proteins produced by the altered cells of the invention can be administered. Subjects of the present invention include those having an LSD. Nucleases Any nuclease may be used in the practice of the present invention including but not limited to, at least one ZFNs, TALENs, homing endonucleases, and systems comprising CRISPR/Cas and/or Ttago guide RNAs, that are useful for in vivo cleavage of a donor molecule carrying a transgene and nucleases for cleavage of the genome of a cell such that the transgene is integrated into the genome in a targeted manner. Thus, described herein are compositions comprising one or more nucleases that cleave a selected gene, which cleavage results in genomic modification of the gene (e.g., insertions and/or deletions into the cleaved gene). In certain embodiments, one or more of the nucleases are naturally occurring. In other embodiments, one or more of the nucleases are non-naturally occurring, i.e., engineered in the DNA-binding molecule (also referred to as a DNA-binding domain) and/or cleavage domain. For example, the DNA-binding domain of a naturally-occurring nuclease may be altered to bind to a selected target site (e.g., a ZFP, TALE and/or sgRNA of CRISPR/Cas that is engineered to bind to a selected target site). In other embodiments, the nuclease comprises heterologous DNA-binding and cleavage domains (e.g., zinc finger nucleases; TAL-effector domain DNA binding proteins; meganuclease DNA-binding domains with heterologous cleavage domains). In other embodiments, the nuclease comprises a system such as the CRISPR/Cas of Ttago system. A. DNA-Binding Domains In certain embodiments, the composition and methods described herein employ a meganuclease (homing endonuclease) DNA-binding domain for binding to the donor molecule and/or binding to the region of interest in the genome of the cell. Naturally-occurring meganucleases recognize 15-40 base-pair cleavage sites and are commonly grouped into four families: the LAGLIDADG family, the GIY-YIG family, the His-Cyst box family and the HNH family. Exemplary homing endonucleases include I-SceI, I-CeuI, PI-PspI, PI-Sce, I-SceIV, I-CsmI, I-PanI, I-SceII, I-PpoI, I-SceIII, I-CreI, I-TevI, I-TevII and I-TevIII. Their recognition sequences are known. See also U.S. Pat. No. 5,420,032; U.S. Pat. No. 6,833,252; Belfort et al. (1997) Nucleic AcidsRes. 25:3379-3388; Duj on et al. (1989) Gene 82:115-118; Perler et al. (1994) Nucleic Acids Res. 22, 1125-1127; Jasin (1996) Trends Genet. 12:224-228; Gimble et al. (1996) J. Mol. Biol. 263:163-180; Argast et al. (1998) J Mol. Biol. 280:345-353 and the New England Biolabs catalogue. In addition, the DNA-binding specificity of homing endonucleases and meganucleases can be engineered to bind non-natural target sites. See, for example, Chevalier et al. (2002) Molec. Cell 10:895-905; Epinat et al. (2003) Nucleic Acids Res. 31:2952-2962; Ashworth et al. (2006) Nature 441:656-659; Paques et al. (2007) Current Gene Therapy 7:49-66; U.S. Patent Publication No. 20070117128. The DNA-binding domains of the homing endonucleases and meganucleases may be altered in the context of the nuclease as a whole (i.e., such that the nuclease includes the cognate cleavage domain) or may be fused to a heterologous cleavage domain. In other embodiments, the DNA-binding domain of one or more of the nucleases used in the methods and compositions described herein comprises a naturally occurring or engineered (non-naturally occurring) TAL effector DNA binding domain. See, e.g., U.S. Pat. No. 8,586,526, incorporated by reference in its entirety herein. The plant pathogenic bacteria of the genus Xanthomonas are known to cause many diseases in important crop plants. Pathogenicity of Xanthomonas depends on a conserved type III secretion (T3 S) system which injects more than 25 different effector proteins into the plant cell. Among these injected proteins are transcription activator-like (TAL) effectors which mimic plant transcriptional activators and manipulate the plant transcriptome (see Kay et al (2007) Science 318:648-651). These proteins contain a DNA binding domain and a transcriptional activation domain. One of the most well characterized TAL-effectors is AvrBs3 from Xanthomonas campestgris pv. Vesicatoria (see Bonas et al (1989) Mol Gen Genet 218: 127-136 and WO2010079430). TAL-effectors contain a centralized domain of tandem repeats, each repeat containing approximately 34 amino acids, which are key to the DNA binding specificity of these proteins. In addition, they contain a nuclear localization sequence and an acidic transcriptional activation domain (for a review see Schornack S, et al (2006) J Plant Physiol 163(3): 256-272). In addition, in the phytopathogenic bacteria Ralstonia solanacearum two genes, designated brg11 and hpx17 have been found that are homologous to the AvrBs3 family of Xanthomonas in the R. solanacearumbiovar 1 strain GMI1000 and in the biovar 4 strain RS1000 (See Heuer et al (2007) Appl and Envir Micro 73(13): 4379-4384). These genes are 98.9% identical in nucleotide sequence to each other but differ by a deletion of 1,575 bp in the repeat domain of hpx17. However, both gene products have less than 40% sequence identity with AvrBs3 family proteins of Xanthomonas. See, e.g., U.S. Pat. No. 8,586,526, incorporated by reference in its entirety herein. Specificity of these TAL effectors depends on the sequences found in the tandem repeats. The repeated sequence comprises approximately 102 bp and the repeats are typically 91-100% homologous with each other (Bonas et al, ibid). Polymorphism of the repeats is usually located at positions 12 and 13 and there appears to be a one-to-one correspondence between the identity of the hypervariable diresidues (RVDs) at positions 12 and 13 with the identity of the contiguous nucleotides in the TAL-effector's target sequence (see Moscou and Bogdanove, (2009) Science 326:1501 and Boch et al (2009) Science 326:1509-1512). Experimentally, the natural code for DNA recognition of these TAL-effectors has been determined such that an HD sequence at positions 12 and 13 leads to a binding to cytosine (C), NG binds to T, NI to A, C, G or T, NN binds to A or G, and ING binds to T. These DNA binding repeats have been assembled into proteins with new combinations and numbers of repeats, to make artificial transcription factors that are able to interact with new sequences and activate the expression of a non-endogenous reporter gene in plant cells (Boch et al, ibid). Engineered TAL proteins have been linked to a FokI cleavage half domain to yield a TAL effector domain nuclease fusion (TALEN) exhibiting activity in a yeast reporter assay (plasmid based target). See, e.g., U.S. Pat. No. 8,586,526; Christian et al ((2010) Genetics epub 10.1534/genetics.110.120717). In certain embodiments, the DNA binding domain of one or more of the nucleases used for in vivo cleavage and/or targeted cleavage of the genome of a cell comprises a zinc finger protein. Preferably, the zinc finger protein is non-naturally occurring in that it is engineered to bind to a target site of choice. See, for example, See, for example, Beerli et al. (2002) Nature Biotechnol. 20:135-141; Pabo et al. (2001) Ann. Rev. Biochem. 70:313-340; Isalan et al. (2001) Nature Biotechnol. 19:656-660; Segal et al. (2001) Curr. Opin. Biotechnol. 12:632-637; Choo et al. (2000) Curr. Opin. Struct. Biol. 10:411-416; U.S. Pat. Nos. 6,453,242; 6,534,261; 6,599,692; 6,503,717; 6,689,558; 7,030,215; 6,794,136; 7,067,317; 7,262,054; 7,070,934; 7,361,635; 7,253,273; and U.S. Patent Publication Nos. 2005/0064474; 2007/0218528; 2005/0267061, all incorporated herein by reference in their entireties. An engineered zinc finger binding domain can have a novel binding specificity, compared to a naturally-occurring zinc finger protein. Engineering methods include, but are not limited to, rational design and various types of selection. Rational design includes, for example, using databases comprising triplet (or quadruplet) nucleotide sequences and individual zinc finger amino acid sequences, in which each triplet or quadruplet nucleotide sequence is associated with one or more amino acid sequences of zinc fingers which bind the particular triplet or quadruplet sequence. See, for example, co-owned U.S. Pat. Nos. 6,453,242 and 6,534,261, incorporated by reference herein in their entireties. Exemplary selection methods, including phage display and two-hybrid systems, are disclosed in U.S. Pat. Nos. 5,789,538; 5,925,523; 6,007,988; 6,013,453; 6,410,248; 6,140,466; 6,200,759; and 6,242,568; as well as WO 98/37186; WO 98/53057; WO 00/27878; and WO 01/88197. In addition, enhancement of binding specificity for zinc finger binding domains has been described, for example, in co-owned WO 02/077227. In addition, as disclosed in these and other references, zinc finger domains and/or multi-fingered zinc finger proteins may be linked together using any suitable linker sequences, including for example, linkers of 5 or more amino acids in length. See, also, U.S. Pat. Nos. 8,772,453; 6,479,626; 6,903,185; and 7,153,949 for exemplary linker sequences-. The proteins described herein may include any combination of suitable linkers between the individual zinc fingers of the protein. Selection of target sites; ZFPs and methods for design and construction of fusion proteins (and polynucleotides encoding same) are known to those of skill in the art and described in detail in U.S. Pat. Nos. 6,140,081; 5,789,538; 6,453,242; 6,534,261; 5,925,523; 6,007,988; 6,013,453; 6,200,759; WO 95/19431; WO 96/06166; WO 98/53057; WO 98/54311; WO 00/27878; WO 01/60970; WO 01/88197; WO 02/099084; WO 98/53058; WO 98/53059; WO 98/53060; WO 02/016536 and WO 03/016496. In addition, as disclosed in these and other references, zinc finger domains and/or multi-fingered zinc finger proteins may be linked together using any suitable linker sequences, including for example, linkers of 5 or more amino acids in length. See, also, U.S. Pat. Nos. 6,479,626; 6,903,185; and 7,153,949 for exemplary linker sequences 6 or more amino acids in length. The proteins described herein may include any combination of suitable linkers between the individual zinc fingers of the protein. In certain embodiments, the DNA-binding domain is part of a CRISPR/Cas nuclease system, including, for example a single guide RNA (sgRNA). See, e.g., U.S. Pat. No. 8,697,359 and U.S. Patent Publication No. 20150056705. The CRISPR (clustered regularly interspaced short palindromic repeats) locus, which encodes RNA components of the system, and the Cas (CRISPR-associated) locus, which encodes proteins (Jansen et al., 2002. Mol. Microbiol. 43: 1565-1575; Makarova et al., 2002. Nucleic Acids Res. 30: 482-496; Makarova et al., 2006. Biol. Direct 1: 7; Haft et al., 2005. PLoS Comput. Biol. 1: e60) make up the gene sequences of the CRISPR/Cas nuclease system. CRISPR loci in microbial hosts contain a combination of CRISPR-associated (Cas) genes as well as non-coding RNA elements capable of programming the specificity of the CRISPR-mediated nucleic acid cleavage. The Type II CRISPR is one of the most well characterized systems and carries out targeted DNA double-strand break in four sequential steps. First, two non-coding RNA, the pre-crRNA array and tracrRNA, are transcribed from the CRISPR locus. Second, tracrRNA hybridizes to the repeat regions of the pre-crRNA and mediates the processing of pre-crRNA into mature crRNAs containing individual spacer sequences. Third, the mature crRNA:tracrRNA complex directs Cas9 to the target DNA via Watson-Crick base-pairing between the spacer on the crRNA and the protospacer on the target DNA next to the protospacer adjacent motif (PAM), an additional requirement for target recognition. Finally, Cas9 mediates cleavage of target DNA to create a double-stranded break within the protospacer. Activity of the CRISPR/Cas system comprises of three steps: (i) insertion of alien DNA sequences into the CRISPR array to prevent future attacks, in a process called ‘adaptation’, (ii) expression of the relevant proteins, as well as expression and processing of the array, followed by (iii) RNA-mediated interference with the alien nucleic acid. Thus, in the bacterial cell, several of the so-called ‘Cas’ proteins are involved with the natural function of the CRISPR/Cas system and serve roles in functions such as insertion of the alien DNA etc. In certain embodiments, Cas protein may be a “functional derivative” of a naturally occurring Cas protein. A “functional derivative” of a native sequence polypeptide is a compound having a qualitative biological property in common with a native sequence polypeptide. “Functional derivatives” include, but are not limited to, fragments of a native sequence and derivatives of a native sequence polypeptide and its fragments, provided that they have a biological activity in common with a corresponding native sequence polypeptide. A biological activity contemplated herein is the ability of the functional derivative to hydrolyze a DNA substrate into fragments. The term “derivative” encompasses both amino acid sequence variants of polypeptide, covalent modifications, and fusions thereof. Suitable derivatives of a Cas polypeptide or a fragment thereof include but are not limited to mutants, fusions, covalent modifications of Cas protein or a fragment thereof. Cas protein, which includes Cas protein or a fragment thereof, as well as derivatives of Cas protein or a fragment thereof, may be obtainable from a cell or synthesized chemically or by a combination of these two procedures. The cell may be a cell that naturally produces Cas protein, or a cell that naturally produces Cas protein and is genetically engineered to produce the endogenous Cas protein at a higher expression level or to produce a Cas protein from an exogenously introduced nucleic acid, which nucleic acid encodes a Cas that is same or different from the endogenous Cas. In some cases, the cell does not naturally produce Cas protein and is genetically engineered to produce a Cas protein. Additional non-limiting examples of RNA guided nucleases that may be used in addition to and/or instead of Cas proteins include Class 2 CRISPR proteins such as Cpf1. See, e.g., Zetsche et al. (2015) Cell 163:1-13. The CRISPR-Cpf1 system, identified in Francisella spp, is a class 2 CRISPR-Cas system that mediates robust DNA interference in human cells. Although functionally conserved, Cpf1 and Cas9 differ in many aspects including in their guide RNAs and substrate specificity (see Fagerlund et al, (2015) Genom Bio 16:251). A major difference between Cas9 and Cpf1 proteins is that Cpf1 does not utilize tracrRNA, and thus requires only a crRNA. The FnCpf1 crRNAs are 42-44 nucleotides long (19-nucleotide repeat and 23-25-nucleotide spacer) and contain a single stem-loop, which tolerates sequence changes that retain secondary structure. In addition, the Cpf1 crRNAs are significantly shorter than the ˜100-nucleotide engineered sgRNAs required by Cas9, and the PAM requirements for FnCpf1 are 5′-TTN-3′ and 5′-CTA-3′ on the displaced strand. Although both Cas9 and Cpf1 make double strand breaks in the target DNA, Cas9 uses its RuvC- and HNH-like domains to make blunt-ended cuts within the seed sequence of the guide RNA, whereas Cpf1 uses a RuvC-like domain to produce staggered cuts outside of the seed. Because Cpf1 makes staggered cuts away from the critical seed region, NHEJ will not disrupt the target site, therefore ensuring that Cpf1 can continue to cut the same site until the desired HDR recombination event has taken place. Thus, in the methods and compositions described herein, it is understood that the term ‘“Cas” includes both Cas9 and Cfp1 proteins. Thus, as used herein, a “CRISPR/Cas system” refers both CRISPR/Cas and/or CRISPR/Cfp1 systems, including both nuclease and/or transcription factor systems. In some embodiments, the DNA binding domain is part of a TtAgo system (see Swarts et al, ibid; Sheng et al, ibid). In eukaryotes, gene silencing is mediated by the Argonaute (Ago) family of proteins. In this paradigm, Ago is bound to small (19-31 nt) RNAs. This protein-RNA silencing complex recognizes target RNAs via Watson-Crick base pairing between the small RNA and the target and endonucleolytically cleaves the target RNA (Vogel (2014) Science 344:972-973). In contrast, prokaryotic Ago proteins bind to small single-stranded DNA fragments and likely function to detect and remove foreign (often viral) DNA (Yuan et al., (2005) Mol. Cell 19, 405; Olovnikov, et al. (2013) Mol. Cell 51, 594; Swarts et al., ibid). Exemplary prokaryotic Ago proteins include those from Aquifex aeolicus, Rhodobacter sphaeroides, and Thermus thermophilus. One of the most well-characterized prokaryotic Ago protein is the one from T thermophilus (TtAgo; Swarts et al. ibid). TtAgo associates with either 15 nt or 13-25 nt single-stranded DNA fragments with 5′ phosphate groups. This “guide DNA” bound by TtAgo serves to direct the protein-DNA complex to bind a Watson-Crick complementary DNA sequence in a third-party molecule of DNA. Once the sequence information in these guide DNAs has allowed identification of the target DNA, the TtAgo-guide DNA complex cleaves the target DNA. Such a mechanism is also supported by the structure of the TtAgo-guide DNA complex while bound to its target DNA (G. Sheng et al., ibid). Ago from Rhodobacter sphaeroides (RsAgo) has similar properties (Olivnikov et al. ibid). Exogenous guide DNAs of arbitrary DNA sequence can be loaded onto the TtAgo protein (Swarts et al. ibid.). Since the specificity of TtAgo cleavage is directed by the guide DNA, a TtAgo-DNA complex formed with an exogenous, investigator-specified guide DNA will therefore direct TtAgo target DNA cleavage to a complementary investigator-specified target DNA. In this way, one may create a targeted double-strand break in DNA. Use of the TtAgo-guide DNA system (or orthologous Ago-guide DNA systems from other organisms) allows for targeted cleavage of genomic DNA within cells. Such cleavage can be either single- or double-stranded. For cleavage of mammalian genomic DNA, it would be preferable to use of a version of TtAgo codon optimized for expression in mammalian cells. Further, it might be preferable to treat cells with a TtAgo-DNA complex formed in vitro where the TtAgo protein is fused to a cell-penetrating peptide. Further, it might be preferable to use a version of the TtAgo protein that has been altered via mutagenesis to have improved activity at 37 degrees Celsius. TtAgo-RNA-mediated DNA cleavage could be used to affect a panoply of outcomes including gene knock-out, targeted gene addition, gene correction, targeted gene deletion using techniques standard in the art for exploitation of DNA breaks. Thus, the nuclease comprises a DNA-binding domain in that specifically binds to a target site in any gene into which it is desired to insert a donor (transgene). B. Cleavage Domains Any suitable cleavage domain can be operatively linked to a DNA-binding domain to form a nuclease. For example, ZFP DNA-binding domains have been fused to nuclease domains to create ZFNs—a functional entity that is able to recognize its intended nucleic acid target through its engineered (ZFP) DNA binding domain and cause the DNA to be cut near the ZFP binding site via the nuclease activity. See, e.g., Kim et al. (1996) Proc Natl Acad Sci USA 93(3):1156-1160. The term “ZFN” includes a pair of ZFNs that dimerize to cleave the target gene. More recently, ZFNs have been used for genome modification in a variety of organisms. See, for example, United States Patent Publications 20030232410; 20050208489; 20050026157; 20050064474; 20060188987; 20060063231; and International Publication WO 07/014275. Likewise, TALE DNA-binding domains have been fused to nuclease domains to create TALENs. See, e.g., U.S. Pat. No. 8,586,526. CRISPR/Cas nuclease systems comprising single guide RNAs (sgRNAs) that bind to DNA and associate with cleavage domains (e.g., Cas domains) to induce targeted cleavage have also been described. See, e.g., U.S. Pat. Nos. 8,697,359 and 8,932,814 and U.S. Patent Publication No. 20150056705. As noted above, the cleavage domain may be heterologous to the DNA-binding domain, for example a zinc finger DNA-binding domain and a cleavage domain from a nuclease or a TALEN DNA-binding domain and a cleavage domain from a nuclease; a sgRNA DNA-binding domain and a cleavage domain from a nuclease (CRISPR/Cas); and/or meganuclease DNA-binding domain and cleavage domain from a different nuclease. Heterologous cleavage domains can be obtained from any endonuclease or exonuclease. Exemplary endonucleases from which a cleavage domain can be derived include, but are not limited to, restriction endonucleases and homing endonucleases. See, for example, 2002-2003 Catalogue, New England Biolabs, Beverly, Mass.; and Belfort et al. (1997) Nucleic Acids Res. 25:3379-3388. Additional enzymes which cleave DNA are known (e.g., 51 Nuclease; mung bean nuclease; pancreatic DNase I; micrococcal nuclease; yeast HO endonuclease; see also Linn et al. (eds.) Nucleases, Cold Spring Harbor Laboratory Press, 1993). One or more of these enzymes (or functional fragments thereof) can be used as a source of cleavage domains and cleavage half-domains. Similarly, a cleavage half-domain can be derived from any nuclease or portion thereof, as set forth above, that requires dimerization for cleavage activity. In general, two fusion proteins are required for cleavage if the fusion proteins comprise cleavage half-domains. Alternatively, a single protein comprising two cleavage half-domains can be used. The two cleavage half-domains can be derived from the same endonuclease (or functional fragments thereof), or each cleavage half-domain can be derived from a different endonuclease (or functional fragments thereof). In addition, the target sites for the two fusion proteins are preferably disposed, with respect to each other, such that binding of the two fusion proteins to their respective target sites places the cleavage half-domains in a spatial orientation to each other that allows the cleavage half-domains to form a functional cleavage domain, e.g., by dimerizing. Thus, in certain embodiments, the near edges of the target sites are separated by 5-8 nucleotides or by 15-18 nucleotides. However, any integral number of nucleotides or nucleotide pairs can intervene between two target sites (e.g., from 2 to 50 nucleotide pairs or more). In general, the site of cleavage lies between the target sites. Restriction endonucleases (restriction enzymes) are present in many species and are capable of sequence-specific binding to DNA (at a recognition site), and cleaving DNA at or near the site of binding. Certain restriction enzymes (e.g., Type IIS) cleave DNA at sites removed from the recognition site and have separable binding and cleavage domains. For example, the Type IIS enzyme Fok I catalyzes double-stranded cleavage of DNA, at 9 nucleotides from its recognition site on one strand and 13 nucleotides from its recognition site on the other. See, for example, U.S. Pat. Nos. 5,356,802; 5,436,150 and 5,487,994; as well as Li et al. (1992) Proc. Natl. Acad. Sci. USA 89:4275-4279; Li et al. (1993) Proc. Natl. Acad. Sci. USA 90:2764-2768; Kim et al. (1994a) Proc. Natl. Acad. Sci. USA 91:883-887; Kim et al. (1994b) J. Biol. Chem. 269:31,978-31,982. Thus, in one embodiment, fusion proteins comprise the cleavage domain (or cleavage half-domain) from at least one Type IIS restriction enzyme and one or more zinc finger binding domains, which may or may not be engineered. An exemplary Type IIS restriction enzyme, whose cleavage domain is separable from the binding domain, is Fok I. This particular enzyme is active as a dimer. Bitinaite et al. (1998) Proc. Natl. Acad. Sci. USA 95: 10,570-10,575. Accordingly, for the purposes of the present disclosure, the portion of the Fok I enzyme used in the disclosed fusion proteins is considered a cleavage half-domain. Thus, for targeted double-stranded cleavage and/or targeted replacement of cellular sequences using zinc finger-Fok I fusions, two fusion proteins, each comprising a FokI cleavage half-domain, can be used to reconstitute a catalytically active cleavage domain. Alternatively, a single polypeptide molecule containing a zinc finger binding domain and two Fok I cleavage half-domains can also be used. Parameters for targeted cleavage and targeted sequence alteration using zinc finger-Fok I fusions are provided elsewhere in this disclosure. A cleavage domain or cleavage half-domain can be any portion of a protein that retains cleavage activity, or that retains the ability to multimerize (e.g., dimerize) to form a functional cleavage domain. Exemplary Type IIS restriction enzymes are described in U.S. Pat. No. 7,888,121, incorporated herein in its entirety. Additional restriction enzymes also contain separable binding and cleavage domains, and these are contemplated by the present disclosure. See, for example, Roberts et al. (2003) Nucleic Acids Res. 31:418-420. In certain embodiments, the cleavage domain comprises one or more engineered cleavage half-domain (also referred to as dimerization domain mutants) that minimize or prevent homodimerization, as described, for example, in U.S. Pat. Nos. 8,772,453; 8,623,618; 8,409,861; 8,034,598; 7,914,796; and 7,888,121, the disclosures of all of which are incorporated by reference in their entireties herein. Amino acid residues at positions 446, 447, 479, 483, 484, 486, 487, 490, 491, 496, 498, 499, 500, 531, 534, 537, and 538 of FokI are all targets for influencing dimerization of the FokI cleavage half-domains. Exemplary engineered cleavage half-domains of FokI that form obligate heterodimers include a pair in which a first cleavage half-domain includes mutations at amino acid residues at positions 490 and 538 of FokI and a second cleavage half-domain includes mutations at amino acid residues 486 and 499. Thus, in one embodiment, a mutation at 490 replaces Glu (E) with Lys (K); the mutation at 538 replaces Iso (I) with Lys (K); the mutation at 486 replaced Gln (Q) with Glu (E); and the mutation at position 499 replaces Iso (I) with Lys (K). Specifically, the engineered cleavage half-domains described herein were prepared by mutating positions 490 (E→K) and 538 (I→K) in one cleavage half-domain to produce an engineered cleavage half-domain designated “E490K:1538K” (“KK”) and by mutating positions 486 (Q→E) and 499 (I→L) in another cleavage half-domain to produce an engineered cleavage half-domain designated “Q486E:1499L”, (“EL”). The engineered cleavage half-domains described herein are obligate heterodimer mutants in which aberrant cleavage is minimized or abolished. U.S. Pat. Nos. 7,914,796 and 8,034,598, the disclosures of which are incorporated by reference in their entireties. In certain embodiments, the engineered cleavage half-domain comprises mutations at positions 486, 499 and 496 (numbered relative to wild-type FokI), for instance mutations that replace the wild type Gln (Q) residue at position 486 with a Glu(E) residue, the wild type Iso (I) residue at position 499 with a Leu (L) residue and the wild-type Asn (N) residue at position 496 with an Asp (D) or Glu (E) residue (also referred to as a “ELD” and “ELE” domains, respectively). In other embodiments, the engineered cleavage half-domain comprises mutations at positions 490, 538 and 537 (numbered relative to wild-type FokI), for instance mutations that replace the wild type Glu (E) residue at position 490 with a Lys (K) residue, the wild type Iso (I) residue at position 538 with a Lys (K) residue, and the wild-type His (H) residue at position 537 with a Lys (K) residue or a Arg (R) residue (also referred to as “KKK” and “KKR” domains, respectively). In other embodiments, the engineered cleavage half-domain comprises mutations at positions 490 and 537 (numbered relative to wild-type FokI), for instance mutations that replace the wild type Glu (E) residue at position 490 with a Lys (K) residue and the wild-type His (H) residue at position 537 with a Lys (K) residue or a Arg (R) residue (also referred to as “KIK” and “KIR” domains, respectively). See, e.g., U.S. Pat. No. 8,772,453. In other embodiments, the engineered cleavage half domain comprises the “Sharkey” mutations (see Guo et al, (2010) J Mol. Biol. 400(1):96-107). Engineered cleavage half-domains described herein can be prepared using any suitable method, for example, by site-directed mutagenesis of wild-type cleavage half-domains (Fok I) as described in U.S. Pat. Nos. 8,623,618; 8,409,861; 8,034,598; 7,914,796; and 7,888,121. Methods and compositions are also used to increase the specificity of a nuclease pair for its intended target relative to other unintended cleavage sites, known as off-target sites (see U.S. Patent Publication No. US-2017-0218349-A1). Thus, nucleases described herein can comprise mutations in one or more of their DNA binding domain backbone regions and/or one or more mutations in their nuclease cleavage domains. These nucleases can include mutations to amino acid within the ZFP DNA binding domain (‘ZFP backbone’) that can interact non-specifically with phosphates on the DNA backbone, but they do not comprise changes in the DNA recognition helices. Thus, the invention includes mutations of cationic amino acid residues in the ZFP backbone that are not required for nucleotide target specificity. In some embodiments, these mutations in the ZFP backbone comprise mutating a cationic amino acid residue to a neutral or anionic amino acid residue. In some embodiments, these mutations in the ZFP backbone comprise mutating a polar amino acid residue to a neutral or non-polar amino acid residue. In preferred embodiments, mutations at made at position (−5), (−9) and/or position (−14) relative to the DNA binding helix. In some embodiments, a zinc finger may comprise one or more mutations at (−5), (−9) and/or (−14). In further embodiments, one or more zinc finger in a multi-finger zinc finger protein may comprise mutations in (−5), (−9) and/or (−14). In some embodiments, the amino acids at (−5), (−9) and/or (−14) (e.g. an arginine (R) or lysine (K)) are mutated to an alanine (A), leucine (L), Ser (S), Asp (N), Glu (E), Tyr (Y) and/or glutamine (Q). In certain embodiments, the engineered cleavage half domains are derived from the FokI nuclease domain and comprise a mutation in one or more of amino acid residues 416, 422, 447, 448, and/or 525, numbered relative to the wild-type full length FokI. In some embodiments, the mutations in amino acid residues 416, 422, 447, 448, and/or 525 are introduced into the FokI “ELD”, “ELE”, “KKK”, “KKR”, “KK”, “EL”, “KIK”, “KIR” and/or Sharkey as described above. Further, described herein are methods to increase specificity of cleavage activity through independent titration of the engineered cleavage half-domain partners of a nuclease complex. In some embodiments, the ratio of the two partners (half cleavage domains) is given at a 1:2, 1:3, 1:4, 1:5, 1:6, 1:8, 1:9, 1:10 or 1:20 ratio, or any value therebetween. In other embodiments, the ratio of the two partners is greater than 1:30. In other embodiments, the two partners are deployed at a ratio that is chosen to be different from 1:1. When used individually or in combination, the methods and compositions of the invention provide surprising and unexpected increases in targeting specificity via reductions in off-target cleavage activity. The nucleases used in these embodiments may comprise ZFNs, a pair of ZFNs, TALENs, a pair of TALENs, CRISPR/Cas, CRISPR/dCas and TtAgo, or any combination thereof. Alternatively, nucleases may be assembled in vivo at the nucleic acid target site using so-called “split-enzyme” technology (see, e.g. U.S. Patent Publication No. 20090068164). Components of such split enzymes may be expressed either on separate expression constructs, or can be linked in one open reading frame where the individual components are separated, for example, by a self-cleaving 2A peptide or IRES sequence. Components may be individual zinc finger binding domains or domains of a meganuclease nucleic acid binding domain. Nucleases can be screened for activity prior to use, for example in a yeast-based chromosomal system as described in U.S. Pat. No. 8,563,314. Expression of the nuclease may be under the control of a constitutive promoter or an inducible promoter, for example the galactokinase promoter which is activated (de-repressed) in the presence of raffinose and/or galactose and repressed in presence of glucose. The Cas9 related CRISPR/Cas system comprises two RNA non-coding components: tracrRNA and a pre-crRNA array containing nuclease guide sequences (spacers) interspaced by identical direct repeats (DRs). To use a CRISPR/Cas system to accomplish genome engineering, both functions of these RNAs must be present (see Cong et al, (2013) Sciencexpress 1/10.1126/science 1231143). In some embodiments, the tracrRNA and pre-crRNAs are supplied via separate expression constructs or as separate RNAs. In other embodiments, a chimeric RNA is constructed where an engineered mature crRNA (conferring target specificity) is fused to a tracrRNA (supplying interaction with the Cas9) to create a chimeric cr-RNA-tracrRNA hybrid (also termed a single guide RNA). (see Jinek ibid and Cong, ibid). Target Sites As described in detail above, DNA domains can be engineered to bind to any sequence of choice in a locus, for example an albumin or other safe-harbor gene. An engineered DNA-binding domain can have a novel binding specificity, compared to a naturally-occurring DNA-binding domain. Engineering methods include, but are not limited to, rational design and various types of selection. Rational design includes, for example, using databases comprising triplet (or quadruplet) nucleotide sequences and individual (e.g., zinc finger) amino acid sequences, in which each triplet or quadruplet nucleotide sequence is associated with one or more amino acid sequences of DNA binding domain which bind the particular triplet or quadruplet sequence. See, for example, co-owned U.S. Pat. Nos. 6,453,242 and 6,534,261, incorporated by reference herein in their entireties. Rational design of TAL-effector domains can also be performed. See, e.g., U.S. Publication No. 20110301073. Exemplary selection methods applicable to DNA-binding domains, including phage display and two-hybrid systems, are disclosed in U.S. Pat. Nos. 5,789,538; 5,925,523; 6,007,988; 6,013,453; 6,410,248; 6,140,466; 6,200,759; and 6,242,568; as well as WO 98/37186; WO 98/53057; WO 00/27878; WO 01/88197 and GB 2,338,237. Selection of target sites; nucleases and methods for design and construction of fusion proteins (and polynucleotides encoding same) are known to those of skill in the art and described in detail in U.S. Pat. Nos. 7,888,121 and 8,409,891, incorporated by reference in their entireties herein. In addition, as disclosed in these and other references, DNA-binding domains (e.g., multi-fingered zinc finger proteins) may be linked together using any suitable linker sequences, including for example, linkers of 5 or more amino acids. See, e.g., U.S. Pat. Nos. 6,479,626; 6,903,185; and 7,153,949 for exemplary linker sequences 6 or more amino acids in length. The proteins described herein may include any combination of suitable linkers between the individual DNA-binding domains of the protein. See, also, U.S. Publication No. 20110301073. Donors As noted above, insertion of an exogenous sequence (also called a “donor sequence” or “donor”), for example for correction of a mutant gene or for increased expression of a gene encoding a protein lacking or deficient in Fabry disease (e.g., α-GalA) is provided. It will be readily apparent that the donor sequence is typically not identical to the genomic sequence where it is placed. A donor sequence can contain a non-homologous sequence flanked by two regions of homology (“homology arms”) to allow for efficient HDR at the location of interest. Additionally, donor sequences can comprise a vector molecule containing sequences that are not homologous to the region of interest in cellular chromatin. A donor molecule can contain several, discontinuous regions of homology to cellular chromatin. For example, for targeted insertion of sequences not normally present in a region of interest, said sequences can be present in a donor nucleic acid molecule and flanked by regions of homology to sequence in the region of interest. Described herein are methods of targeted insertion of a transgene encoding a α-GalA protein for insertion into a chosen location. The GLA transgene may encode a full-length α-GalA protein or may encode a truncated α-GalA protein. Polynucleotides for insertion can also be referred to as “exogenous” polynucleotides, “donor” polynucleotides or molecules or “transgenes.” Non-limiting exemplary GLA donors are shown in FIGS. 1B, 1C, 10, 13, and 25. The donor polynucleotide can be DNA or RNA, single-stranded and/or double-stranded and can be introduced into a cell in linear or circular form. See, e.g., U.S. Pat. Nos. 8,703,489 and 9,255,259. The donor sequence(s) can also be contained within a DNA MC, which may be introduced into the cell in circular or linear form. See, e.g., U.S. Patent Publication No. 20140335063. If introduced in linear form, the ends of the donor sequence can be protected (e.g., from exonucleolytic degradation) by methods known to those of skill in the art. For example, one or more dideoxynucleotide residues are added to the 3′ terminus of a linear molecule and/or self-complementary oligonucleotides are ligated to one or both ends. See, for example, Chang et al. (1987) Proc. Natl. Acad. Sci. USA 84:4959-4963; Nehls et al. (1996) Science 272:886-889. Additional methods for protecting exogenous polynucleotides from degradation include, but are not limited to, addition of terminal amino group(s) and the use of modified internucleotide linkages such as, for example, phosphorothioates, phosphoramidates, and O-methyl ribose or deoxyribose residues. A polynucleotide can be introduced into a cell as part of a viral or non-viral vector molecule having additional sequences such as, for example, replication origins, promoters and genes encoding antibiotic resistance. Moreover, donor polynucleotides can be introduced as naked nucleic acid, as nucleic acid complexed with an agent such as a liposome or poloxamer, or can be delivered by viruses (e.g., adenovirus, AAV, herpesvirus, retrovirus, lentivirus and integrase defective lentivirus (IDLV)). The donor is generally inserted so that its expression is driven by the endogenous promoter at the integration site, namely the promoter that drives expression of the endogenous gene into which the donor is inserted (e.g., highly expressed, albumin, AAVS1, HPRT, etc.). However, it will be apparent that the donor may comprise a promoter and/or enhancer, for example a constitutive promoter or an inducible or tissue specific promoter. In some embodiments, the donor is maintained in the cell in an expression plasmid such that the gene is expressed extra-chromosomally. The donor molecule may be inserted into an endogenous gene such that all, some or none of the endogenous gene is expressed. For example, a transgene as described herein may be inserted into an albumin or other locus such that some (N-terminal and/or C-terminal to the transgene encoding the lysosomal enzyme) or none of the endogenous albumin sequences are expressed, for example as a fusion with the transgene encoding the α-GalA protein(s). In other embodiments, the transgene (e.g., with or without additional coding sequences such as for albumin) is integrated into any endogenous locus, for example a safe-harbor locus. When endogenous sequences (endogenous or part of the transgene) are expressed with the transgene, the endogenous sequences (e.g., albumin, etc.) may be full-length sequences (wild-type or mutant) or partial sequences. Preferably the endogenous sequences are functional. Non-limiting examples of the function of these full length or partial sequences (e.g., albumin) include increasing the serum half-life of the polypeptide expressed by the transgene (e.g., therapeutic gene) and/or acting as a carrier. Furthermore, although not required for expression, exogenous sequences may also include transcriptional or translational regulatory sequences, for example, promoters, enhancers, insulators, internal ribosome entry sites, sequences encoding 2A peptides and/or polyadenylation signals. Exogenous sequences linked to the transgene can also include signal peptides to assist in processing and/or secretion of the encoded protein. Non-limiting examples of these signal peptides include those from Albumin, IDS and Factor IX (see e.g. FIG. 13). In certain embodiments, the exogenous sequence (donor) comprises a fusion of a protein of interest and, as its fusion partner, an extracellular domain of a membrane protein, causing the fusion protein to be located on the surface of the cell. This allows the protein encoded by the transgene to potentially act in the serum. In the case of Fabry disease, the α-GalA enzyme encoded by the transgene fusion acts on the metabolic products that are accumulating in the serum from its location on the surface of the cell (e.g., RBC). In addition, if the RBC is engulfed by a splenic macrophage as is the normal course of degradation, the lysosome formed when the macrophage engulfs the cell would expose the membrane bound fusion protein to the high concentrations of metabolic products in the lysosome at the pH more naturally favorable to that enzyme. Non-limiting examples of potential fusion partners are shown below in Table 1. TABLE 1 Examples of potential fusion partners Name Activity Band 3 Anion transporter, makes up to 25% of the RBC membrane surface protein Aquaporin 1 water transporter Glut1 glucose and L-dehydroascorbic acid transporter Kidd antigen protein urea transporter RhAG gas transporter ATP1A1, ATP1B1 Na+/K+ - ATPase ATP2B1, ATP2B2, Ca2+ - ATPase ATP2B3, ATP2B4 NKCC1, NKCC2 Na+K+ 2Cl− - cotransporter SLC12A3 Na+-Cl− - cotransporter SLC12A1, SLA12A2 Na—K - cotransporter KCC1 K—Cl cotransporter KCNN4 Gardos Channel In some cases, the donor may be an endogenous gene (GLA) that has been modified. For instance, codon optimization may be performed on the endogenous gene to produce a donor. Furthermore, although antibody response to enzyme replacement therapy varies with respect to the specific therapeutic enzyme in question and with the individual patient, a significant immune response has been seen in many Fabry disease patients being treated with enzyme replacement with wild-type α-GalA. The transgene is considered to provide a therapeutic protein when it increases the amount of the protein (and/or its activity) as compared to subjects without the transgene. In addition, the relevance of these antibodies to the efficacy of treatment is also variable (see Katherine Ponder, (2008) J Clin Invest 118(8):2686). Thus, the methods and compositions of the current invention can comprise the generation of donor with modified sequences as compared to wild-type GLA, including, but not limited to, modifications that produce functionally silent amino acid changes at sites known to be priming epitopes for endogenous immune responses, and/or truncations such that the polypeptide produced by such a donor is less immunogenic. Fabry disease patients often have neurological sequelae due the lack of the missing α-GalA enzyme in the brain. Unfortunately, it is often difficult to deliver therapeutics to the brain via the blood due to the impermeability of the blood brain barrier. Thus, the methods and compositions of the invention may be used in conjunction with methods to increase the delivery of the therapeutic into the brain, including but not limited to methods that cause a transient opening of the tight junctions between cells of the brain capillaries such as transient osmotic disruption through the use of an intracarotid administration of a hypertonic mannitol solution, the use of focused ultrasound and the administration of a bradykinin analogue (Matsukado et al (1996) Neurosurgery 39:125). Alternatively, therapeutics can be designed to utilize receptors or transport mechanisms for specific transport into the brain. Examples of specific receptors that may be used include the transferrin receptor, the insulin receptor or the low-density lipoprotein receptor related proteins 1 and 2 (LRP-1 and LRP-2). LRP is known to interact with a range of secreted proteins such as apoE, tPA, PAI-1 etc., and so fusing a recognition sequence from one of these proteins for LRP may facilitate transport of the enzyme into the brain, following expression in the liver of the therapeutic protein and secretion into the blood stream (see Gabathuler, (2010) ibid). Cells Also provided herein are genetically modified cells, for example, liver cells or stem cells comprising a transgene encoding a α-GalA protein, including cells produced by the methods described herein. The GLA transgene may be full-length or modified and can be expressed extra-chromosomally or can integrated in a targeted manner into the cell's genome using one or more nucleases. Unlike random integration, nuclease-mediated targeted integration ensures that the transgene is integrated into a specified gene. The transgene may be integrated anywhere in the target gene. In certain embodiments, the transgene is integrated at or near the nuclease binding and/or cleavage site, for example, within 1-300 (or any number of base pairs therebetween) base pairs upstream or downstream of the site of cleavage and/or binding site, more preferably within 1-100 base pairs (or any number of base pairs therebetween) of either side of the cleavage and/or binding site, even more preferably within 1 to 50 base pairs (or any number of base pairs therebetween) of either side of the cleavage and/or binding site. In certain embodiments, the integrated sequence does not include any vector sequences (e.g., viral vector sequences). Any cell type can be genetically modified as described herein to comprise a transgene, including but not limited to cells or cell lines. Other non-limiting examples of genetically modified cells as described herein include T-cells (e.g., CD4+, CD3+, CD8+, etc.); dendritic cells; B-cells; autologous (e.g., patient-derived), muscle cells, brain cells and the like. In certain embodiments, the cells are liver cells and are modified in vivo. In certain embodiments, the cells are stem cells, including heterologous pluripotent, totipotent or multipotent stem cells (e.g., CD34+ cells, induced pluripotent stem cells (iPSCs), embryonic stem cells or the like). In certain embodiments, the cells as described herein are stem cells derived from patient. The cells as described herein are useful in treating and/or preventing Fabry disease in a subject with the disorder, for example, by in vivo therapies. Ex vivo therapies are also provided, for example when the nuclease-modified cells can be expanded and then reintroduced into the patient using standard techniques. See, e.g., Tebas et al (2014) New Eng J Med 370(10):901. In the case of stem cells, after infusion into the subject, in vivo differentiation of these precursors into cells expressing the functional protein (from the inserted donor) also occurs. Pharmaceutical compositions comprising the cells as described herein are also provided. In addition, the cells may be cryopreserved prior to administration to a patient. Delivery The nucleases, polynucleotides encoding these nucleases, donor polynucleotides and/or compositions (e.g., cells, proteins, polynucleotides, etc.) described herein may be delivered in vivo or ex vivo by any suitable means. Methods of delivering nucleases as described herein are described, for example, in U.S. Pat. Nos. 6,453,242; 6,503,717; 6,534,261; 6,599,692; 6,607,882; 6,689,558; 6,824,978; 6,933,113; 6,979,539; 7,013,219; and 7,163,824, the disclosures of all of which are incorporated by reference herein in their entireties. Nucleases and/or donor constructs as described herein may also be delivered using vectors containing sequences encoding one or more of the zinc finger, TALEN and/or Cas protein(s). Any vector systems may be used including, but not limited to, plasmid vectors, retroviral vectors, lentiviral vectors, adenovirus vectors, poxvirus vectors; herpesvirus vectors and adeno-associated virus vectors, etc. See, also, U.S. Pat. Nos. 6,534,261; 6,607,882; 6,824,978; 6,933,113; 6,979,539; 7,013,219; and 7,163,824, incorporated by reference herein in their entireties. Furthermore, it will be apparent that any of these vectors may comprise one or more of the sequences needed for treatment. Thus, when one or more nucleases and a donor construct are introduced into the cell, the nucleases and/or donor polynucleotide may be carried on the same vector or on different vectors. When multiple vectors are used, each vector may comprise a sequence encoding one or multiple nucleases and/or donor constructs. Conventional viral and non-viral based gene transfer methods can be used to introduce nucleic acids encoding nucleases and donor constructs in cells (e.g., mammalian cells) and target tissues. Non-viral vector delivery systems include DNA plasmids, naked nucleic acid, and nucleic acid complexed with a delivery vehicle such as a liposome or poloxamer. Viral vector delivery systems include DNA and RNA viruses, which have either episomal or integrated genomes after delivery to the cell. For a review of gene therapy procedures, see Anderson, Science 256:808-813 (1992); Nabel & Felgner, TIBTECH 11:211-217 (1993); Mitani & Caskey, TIBTECH 11:162-166 (1993); Dillon, TIBTECH 11:167-175 (1993); Miller, Nature 357:455-460 (1992); Van Brunt, Biotechnology 6(10):1149-1154 (1988); Vigne, Restorative Neurology and Neuroscience 8:35-36 (1995); Kremer & Perricaudet, British Medical Bulletin 51(1):31-44 (1995); Haddada et al., in Current Topics in Microbiology and Immunology Doerfler and Böhm (eds.) (1995); and Yu et al., Gene Therapy 1:13-26 (1994). Methods of non-viral delivery of nucleic acids include electroporation, lipofection, microinjection, biolistics, virosomes, liposomes, immunoliposomes, polycation or lipid:nucleic acid conjugates, naked DNA, artificial virions, and agent-enhanced uptake of DNA. Sonoporation using, e.g., the Sonitron 2000 system (Rich-Mar) can also be used for delivery of nucleic acids. Additional exemplary nucleic acid delivery systems include those provided by Amaxa Biosystems (Cologne, Germany), Maxcyte, Inc. (Rockville, Md.), BTX Molecular Delivery Systems (Holliston, Mass.) and Copernicus Therapeutics Inc, (see for example U.S. Pat. No. 6,008,336). Lipofection is described in e.g., U.S. Pat. Nos. 5,049,386; 4,946,787; and 4,897,355) and lipofection reagents are sold commercially (e.g., Transfectam™ and Lipofectin™). Cationic and neutral lipids that are suitable for efficient receptor-recognition lipofection of polynucleotides include those of Felgner, WO 91/17424, WO 91/16024. The preparation of lipid:nucleic acid complexes, including targeted liposomes such as immunolipid complexes, is well known to one of skill in the art (see, e.g., Crystal, Science 270:404-410 (1995); Blaese et al., Cancer Gene Ther. 2:291-297 (1995); Behr et al., Bioconjugate Chem. 5:382-389 (1994); Remy et al., Bioconjugate Chem. 5:647-654 (1994); Gao et al., Gene Therapy 2:710-722 (1995); Ahmad et al., Cancer Res. 52:4817-4820 (1992); U.S. Pat. Nos. 4,186,183, 4,217,344, 4,235,871, 4,261,975, 4,485,054, 4,501,728, 4,774,085, 4,837,028, and 4,946,787). The compositions described herein (cDNAs and/or nucleases) can also be delivered using nanoparticles, for example lipid nanoparticles (LNP). See, e.g., Lee et al (2016)Am J Cancer Res 6(5):1118-1134; U.S. Patent Publication No. 20170119904; and U.S. Provisional 62/559,186. Additional methods of delivery include the use of packaging the nucleic acids to be delivered into EnGenelC delivery vehicles (EDVs). These EDVs are specifically delivered to target tissues using bispecific antibodies where one arm of the antibody has specificity for the target tissue and the other has specificity for the EDV. The antibody brings the EDVs to the target cell surface and then the EDV is brought into the cell by endocytosis. Once in the cell, the contents are released (see MacDiarmid et al (2009) Nature Biotechnology 27(7):643). The use of RNA or DNA viral based systems for the delivery of nucleic acids encoding engineered ZFPs take advantage of highly evolved processes for targeting a virus to specific cells in the body and trafficking the viral payload to the nucleus. Viral vectors can be administered directly to subjects (in vivo) or they can be used to treat cells in vitro and the modified cells are administered to subjects (ex vivo). Conventional viral based systems for the delivery of ZFPs include, but are not limited to, retroviral, lentivirus, adenoviral, adeno-associated, vaccinia and herpes simplex virus vectors for gene transfer. Integration in the host genome is possible with the retrovirus, lentivirus, and adeno-associated virus gene transfer methods, often resulting in long term expression of the inserted transgene. Additionally, high transduction efficiencies have been observed in many different cell types and target tissues. The tropism of a retrovirus can be altered by incorporating foreign envelope proteins, expanding the potential target population of target cells. Lentiviral vectors are retroviral vectors that are able to transduce or infect non-dividing cells and typically produce high viral titers. Selection of a retroviral gene transfer system depends on the target tissue. Retroviral vectors are comprised of cis-acting long terminal repeats with packaging capacity for up to 6-10 kb of foreign sequence. The minimum cis-acting LTRs are sufficient for replication and packaging of the vectors, which are then used to integrate the therapeutic gene into the target cell to provide permanent transgene expression. Widely used retroviral vectors include those based upon murine leukemia virus (MuLV), gibbon ape leukemia virus (GaLV), Simian Immunodeficiency virus (SIV), human immunodeficiency virus (HIV), and combinations thereof (see, e.g., Buchscher et al., J. Virol. 66:2731-2739 (1992); Johann et al., J. Virol. 66:1635-1640 (1992); Sommerfelt et al., Virol. 176:58-59 (1990); Wilson et al., J. Virol. 63:2374-2378 (1989); Miller et al., J. Virol. 65:2220-2224 (1991)). In applications in which transient expression is preferred, adenoviral based systems can be used. Adenoviral based vectors are capable of very high transduction efficiency in many cell types and do not require cell division. With such vectors, high titer and high levels of expression have been obtained. This vector can be produced in large quantities in a relatively simple system. Adeno-associated virus (“AAV”) vectors are also used to transduce cells with target nucleic acids, e.g., in the in vitro production of nucleic acids and peptides, and for in vivo and ex vivo gene therapy procedures (see, e.g., West et al., Virology 160:38-47 (1987); U.S. Pat. No. 4,797,368; WO 93/24641; Kotin, Human Gene Therapy 5:793-801 (1994); Muzyczka, J. Clin. Invest. 94:1351 (1994). Construction of recombinant AAV vectors are described in a number of publications, including U.S. Pat. No. 5,173,414; Tratschin et al., Mol. Cell. Biol. 5:3251-3260 (1985); Tratschin, et al., Mol. Cell. Biol. 4:2072-2081 (1984); Hermonat & Muzyczka, PNAS 81:6466-6470 (1984); and Samulski et al., J. Virol. 63:03822-3828 (1989). At least six viral vector approaches are currently available for gene transfer in clinical trials, which utilize approaches that involve complementation of defective vectors by genes inserted into helper cell lines to generate the transducing agent. pLASN and MFG-S are examples of retroviral vectors that have been used in clinical trials (Dunbar et al., Blood 85:3048-305 (1995); Kohn et al., Nat. Med. 1:1017-102 (1995); Malech et al., PNAS 94:22 12133-12138 (1997)). PA317/pLASN was the first therapeutic vector used in a gene therapy trial. (Blaese et al., Science 270:475-480 (1995)). Transduction efficiencies of 50% or greater have been observed for MFG-S packaged vectors. (Ellem et al., Immunol Immunother 44(1):10-20 (1997); Dranoff et al., Hum. Gene Ther. 1:111-2 (1997). Recombinant adeno-associated virus vectors (rAAV) are a promising alternative gene delivery systems based on the defective and nonpathogenic parvovirus adeno-associated type 2 virus. All vectors are derived from a plasmid that retains only the AAV 145 bp inverted terminal repeats flanking the transgene expression cassette. Efficient gene transfer and stable transgene delivery due to integration into the genomes of the transduced cell are key features for this vector system. (Wagner et al., Lancet 351:9117 1702-3 (1998), Kearns et al., Gene Ther. 9:748-55 (1996)). Other AAV serotypes, including by non-limiting example, AAV1, AAV3, AAV4, AAV5, AAV6, AAV8, AAV 8.2, AAV9, and AAV rh10 and pseudotyped AAV such as AAV2/8, AAV2/5 and AAV2/6 can also be used in accordance with the present invention. Replication-deficient recombinant adenoviral vectors (Ad) can be produced at high titer and readily infect a number of different cell types. Most adenovirus vectors are engineered such that a transgene replaces the Ad E1a, E1b, and/or E3 genes; subsequently the replication defective vector is propagated in human 293 cells that supply deleted gene function in trans. Ad vectors can transduce multiple types of tissues in vivo, including non-dividing, differentiated cells such as those found in liver, kidney and muscle. Conventional Ad vectors have a large carrying capacity. An example of the use of an Ad vector in a clinical trial involved polynucleotide therapy for anti-tumor immunization with intramuscular injection (Sterman et al., Hum. Gene Ther. 7:1083-9 (1998)). Additional examples of the use of adenovirus vectors for gene transfer in clinical trials include Rosenecker et al., Infection 24:1 5-10 (1996); Sterman et al., Hum. Gene Ther. 9:7 1083-1089 (1998); Welsh et al., Hum. Gene Ther. 2:205-18 (1995); Alvarez et al., Hum. Gene Ther. 5:597-613 (1997); Topf et al., Gene Ther. 5:507-513 (1998); Sterman et al., Hum. Gene Ther. 7:1083-1089 (1998). Packaging cells are used to form virus particles that are capable of infecting a host cell. Such cells include 293 cells, which package adenovirus, and ψ2 cells or PA317 cells, which package retrovirus. Viral vectors used in gene therapy are usually generated by a producer cell line that packages a nucleic acid vector into a viral particle. The vectors typically contain the minimal viral sequences required for packaging and subsequent integration into a host (if applicable), other viral sequences being replaced by an expression cassette encoding the protein to be expressed. The missing viral functions are supplied in trans by the packaging cell line. For example, AAV vectors used in gene therapy typically only possess inverted terminal repeat (ITR) sequences from the AAV genome which are required for packaging and integration into the host genome. Viral DNA is packaged in a cell line, which contains a helper plasmid encoding the other AAV genes, namely rep and cap, but lacking ITR sequences. The cell line is also infected with adenovirus as a helper. The helper virus promotes replication of the AAV vector and expression of AAV genes from the helper plasmid. The helper plasmid is not packaged in significant amounts due to a lack of ITR sequences. Contamination with adenovirus can be reduced by, e.g., heat treatment to which adenovirus is more sensitive than AAV. In many gene therapy applications, it is desirable that the gene therapy vector be delivered with a high degree of specificity to a particular tissue type. Accordingly, a viral vector can be modified to have specificity for a given cell type by expressing a ligand as a fusion protein with a viral coat protein on the outer surface of the virus. The ligand is chosen to have affinity for a receptor known to be present on the cell type of interest. For example, Han et al., Proc. Natl. Acad. Sci. USA 92:9747-9751 (1995), reported that Moloney murine leukemia virus can be modified to express human heregulin fused to gp70, and the recombinant virus infects certain human breast cancer cells expressing human epidermal growth factor receptor. This principle can be extended to other virus-target cell pairs, in which the target cell expresses a receptor and the virus expresses a fusion protein comprising a ligand for the cell-surface receptor. For example, filamentous phage can be engineered to display antibody fragments (e.g., FAB or Fv) having specific binding affinity for virtually any chosen cellular receptor. Although the above description applies primarily to viral vectors, the same principles can be applied to nonviral vectors. Such vectors can be engineered to contain specific uptake sequences which favor uptake by specific target cells. Gene therapy vectors can be delivered in vivo by administration to an individual patient, typically by systemic administration (e.g., intravenous, intraperitoneal, intramuscular, subdermal, or intracranial infusion) or topical application, as described below. Alternatively, vectors can be delivered to cells ex vivo, such as cells explanted from an individual patient (e.g., lymphocytes, bone marrow aspirates, tissue biopsy) or universal donor hematopoietic stem cells, followed by reimplantation of the cells into a patient, usually after selection for cells which have incorporated the vector. Vectors (e.g., retroviruses, adenoviruses, liposomes, etc.) containing nucleases and/or donor constructs can also be administered directly to an organism for transduction of cells in vivo. Alternatively, naked DNA can be administered. Administration is by any of the routes normally used for introducing a molecule into ultimate contact with blood or tissue cells including, but not limited to, injection, infusion, topical application and electroporation. Suitable methods of administering such nucleic acids are available and well known to those of skill in the art, and, although more than one route can be used to administer a particular composition, a particular route can often provide a more immediate and more effective reaction than another route. Vectors suitable for introduction of polynucleotides described herein include non-integrating lentivirus vectors (IDLV). See, for example, Ory et al. (1996) Proc. Natl. Acad. Sci. USA 93:11382-11388; Dull et al. (1998) J. Virol. 72:8463-8471; Zuffery et al. (1998) J. Virol. 72:9873-9880; Follenzi et al. (2000) Nature Genetics 25:217-222; U.S. Patent Publication No 2009/054985. Pharmaceutically acceptable carriers are determined in part by the particular composition being administered, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of pharmaceutical compositions available, as described below (see, e.g., Remington's Pharmaceutical Sciences, 17th ed., 1989). It will be apparent that the nuclease-encoding sequences and donor constructs can be delivered using the same or different systems. For example, a donor polynucleotide can be carried by a plasmid, while the one or more nucleases can be carried by an AAV vector. Furthermore, the different vectors can be administered by the same or different routes (intramuscular injection, tail vein injection, other intravenous injection, intraperitoneal administration and/or intramuscular injection. The vectors can be delivered simultaneously or in any sequential order. Formulations for both ex vivo and in vivo administrations include suspensions in liquid or emulsified liquids. The active ingredients often are mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredient. Suitable excipients include, for example, water, saline, dextrose, glycerol, ethanol or the like, and combinations thereof. In addition, the composition may contain minor amounts of auxiliary substances, such as, wetting or emulsifying agents, pH buffering agents, stabilizing agents or other reagents that enhance the effectiveness of the pharmaceutical composition. Applications The methods of this invention contemplate the treatment and/or prevention of Fabry disease (e.g. lysosomal storage disease). Treatment can comprise insertion of the corrective disease associated GLA transgene in safe harbor locus (e.g. albumin) in a cell for expression of the needed enzyme and release into the blood stream. The corrective α-GalA encoding transgene may encode a wild type or modified protein; and/or may comprise a codon optimized GLA transgene; and/or a transgene in which epitopes may be removed without functionally altering the protein. In some cases, the methods comprise insertion of an episome expressing the α-GalA encoding transgene into a cell for expression of the needed enzyme and release into the blood stream. Insertion into a secretory cell, such as a liver cell for release of the product into the blood stream, is particularly useful. The methods and compositions of the invention also can be used in any circumstance wherein it is desired to supply a GLA transgene encoding one or more therapeutics in a hematopoietic stem cell such that mature cells (e.g., RBCs) derived from (descended from) these cells contain the therapeutic α-GalA protein. These stem cells can be differentiated in vitro or in vivo and may be derived from a universal donor type of cell which can be used for all patients. Additionally, the cells may contain a transmembrane protein to traffic the cells in the body. Treatment can also comprise use of patient cells containing the therapeutic transgene where the cells are developed ex vivo and then introduced back into the patient. For example, HSC containing a suitable α-GalA encoding transgene may be inserted into a patient via a bone marrow transplant. Alternatively, stem cells such as muscle stem cells or iPSC which have been edited using with the α-GalA encoding transgene maybe also injected into muscle tissue. Thus, this technology may be of use in a condition where a patient is deficient in some protein due to problems (e.g., problems in expression level or problems with the protein expressed as sub- or non-functioning). Particularly useful with this invention is the expression of transgenes to correct or restore functionality in subjects with Fabry disease. By way of non-limiting examples, different methods of production of a functional α-Gal A protein to replace the defective or missing α-Gal A protein is accomplished and used to treat Fabry disease. Nucleic acid donors encoding the proteins may be inserted into a safe harbor locus (e.g. albumin or HPRT) and expressed either using an exogenous promoter or using the promoter present at the safe harbor. Especially useful is the insertion of a GLA transgene in an albumin locus in a liver cell, where the GLA transgene further comprises sequences encoding a signal peptide that mediates the secretion of the expressed α-Gal A protein from the liver cell into the blood stream. Alternatively, donors can be used to correct the defective gene in situ. The desired α-GalA encoding transgene may be inserted into a CD34+ stem cell and returned to a patient during a bone marrow transplant. Finally, the nucleic acid donor maybe be inserted into a CD34+ stem cell at a beta globin locus such that the mature red blood cell derived from this cell has a high concentration of the biologic encoded by the nucleic acid donor. The biologic-containing RBC can then be targeted to the correct tissue via transmembrane proteins (e.g. receptor or antibody). Additionally, the RBCs may be sensitized ex vivo via electrosensitization to make them more susceptible to disruption following exposure to an energy source (see WO2002007752). In some applications, an endogenous gene may be knocked out by use of the methods and compositions of the invention. Examples of this aspect include knocking out an aberrant gene regulator or an aberrant disease associated gene. In some applications, an aberrant endogenous gene may be replaced, either functionally or in situ, with a wild type version of the gene. The inserted gene may also be altered to improve the expression of the therapeutic α-GalA protein or to reduce its immunogenicity. In some applications, the inserted α-GalA encoding transgene is a fusion protein to increase its transport into a selected tissue such as the brain. The following Examples relate to exemplary embodiments of the present disclosure in which the nuclease comprises a zinc finger nuclease (ZFN) (or a pair of ZFNs) or TALEN (or a pair of TALENs). It will be appreciated that this is for purposes of exemplification only and that other nucleases or nuclease systems can be used, for instance homing endonucleases (meganucleases) with engineered DNA-binding domains and/or fusions of naturally occurring of engineered homing endonucleases (meganucleases) DNA-binding domains and heterologous cleavage domains and/or a CRISPR/Cas system comprising an engineered single guide RNA. Similarly, it will be appreciated that suitable GLA donors are not limited to the ones exemplified below but include any GLA transgene. EXAMPLES Example 1: Design and Construction of α-GalA Encoding Transgenes Two approaches were taken for the expression of the GLA transgenes. One approach, called In Vivo Protein Replacement Platform® (“IVPRP”) utilizes engineered nucleases to insert the transgene at the albumin locus such that expression is driven by the albumin promoter (see, U.S. Pat. Nos. 9,394,545 and 9,150,847). The second approach involves transduction of a cell with an AAV comprising a cDNA copy of the transgene wherein the cDNA further comprises a promoter and other regulatory sequences. The GLA transgene expression cassette designs for these two approaches are illustrated in FIG. 1. Example 2: Methods HepG2/C3a and K562 Cell Transduction HepG2 cells were transduced using standard techniques in both the cDNA and IVPRP® systems. A. cDNA The cDNA approach can include the use of an AAV delivered expression construct comprising an APOE enhancer linked to the hAAT promoter (Okuyama et al (1996) Hum Gene Ther 7(5):637-45), HBB-IGG intron (a chimeric intron composed of the 5′-donor site from the first intron of the human beta-globin gene and the branch and 3″-acceptor site from the intron of an immunoglobulin gene heavy chain variable region), a signal peptide, a coding sequence (wherein the coding sequence is optionally codon optimized) and a bovine growth hormone (bGH) poly A signal sequence. For cDNA systems, HepG2 cells were transduced with AAV GLA cDNA vectors as described herein and the supernatant collected and tested for α-Gal A activity. In addition, K562 cells were cultured in the supernatant collected from the transduced HepG2 cells in the absence and presence of an excess of Mannose-6 Phosphate (M6P, 5 mM), which saturates the M6P receptors on the cell surface and blocks uptake of α-Gal A. The cell pellets were collected and tested for α-Gal A activity. B. IVPRP® There are three components to Fabry IVPRP®: two rAAV2/6 vectors that encode ZFNs SBS 47171 and SBS 47898, designed to cleave a specific locus in human Albumin intron 1, and one rAAV2/6 vector that encodes the hGLA donor template. The donor hGLA template is a codon optimized version of the hGLA cDNA flanked by homology arms to facilitate homology-directed repair (HDR) integration of the donor into human albumin. HepG2/C3A cells (also referred to as “HepG2” cells) (ATCC, CRL 10741) were maintained in Minimum Essential Medium (MEM) with Earle's Salts and L glutamine (Corning,) with 10% Fetal Bovine Serum (FBS) (Life Technologies) and 1× Penicillin Streptomycin Glutamine (Life Technologies) and incubated at 37° C. and 5% CO2. Cells were passaged every 3 4 days. For IVPRP® transduction, cells were rinsed and trypsinized with 0.25% Trypsin/2.21 mM EDTA (Corning) and re suspended in growth media. A small aliquot was mixed 1:1 with trypan blue solution 0.4% (w/v) in phosphate buffered saline (PBS; Corning) and counted on the TC20 Automated Cell Counter (Bio Rad). The cells were re suspended at a density of 2e5 per mL in growth media and seeded into a 24 well plate (Corning) at 1e5 in 0.5 mL media per well. Recombinant AAV2/6 particles were mixed at the appropriate multiplicity of infection (MOI) with growth media and added to the cells. HepG2 cells were transduced with either hGLA donor only (in duplicate; control) or with the two hALB ZFNs SB 47171 and SB 47931 plus the SB IDS donor (in triplicate). The MOI for the donor only transduction was 6e5 vector genomes (vg)/cell. The MOI for the ZFN+Donor transduction was 3e5 vg/cell for each ZFN and 6e5 vg/cell for the hGLA Donor. This represents a ZFN1:ZFN2:Donor ratio of 1:1:2, which has been previously determined to be the optimal ratio for in vitro experiments. The hGLA donor was added 24 hours after the ZFN vectors to maximize the transduction efficiency in vitro. Following transduction, cells were left in culture for 6-10 days. Supernatant was collected on Days 3, 5, 7 and 10 (where applicable) and replaced with fresh media. After the final supernatant collection step, cells were trypsinized and resuspended as described above, then centrifuged to create a cell pellet, washed with PBS, and stored at −80 C. A similar method was used to transduce HepG2 cells with GLA cDNA constructs. The MOI for the GLA cDNA constructs was either 3e4, 1e5, 3e5 or 1e6 vg/cell. α-GalA Activity Assay α-GalA activity was assessed in a fluorometric assay using the synthetic substrate 4-methylumbelliferyl-α-D-galactopyranoside (4MU-α-Gal, Sigma). Briefly, 10 microliters of HepG2 cell culture supernatant were mixed with 40 μL of 5 mM 4MU-α-Gal dissolved in phosphate buffer (0.1 M citrate/0.2 M phosphate buffer, pH 4.6, 1% Triton X-100). Reactions were incubated at 37° C. and terminated by addition of 100 μL of 0.5 M glycine buffer, pH 10.3. The release of 4 methylumbelliferone (4 MU) was determined by measurement of fluorescence (Ex365/Em450) using a SpectraMax Gemini XS fluorescent reader (Molecular Devices, Sunnyvale Calif.). A standard curve was generated using serial 2 fold dilutions of 4 MU. The resulting data were fitted with a log log curve; concentration of 4 MU in test samples was calculated using this best fit curve. Enzymatic activity is expressed as nmol 4 MU released per hour of assay incubation time, per mL of cell culture supernatant (nmol/hr/mL). Detection of Gb3 Gb3 and Lyso-Gb3 Substrate Quantitation and Analysis: Fabry substrate globotriaosylceramide (Gb3) was measured in selected murine plasma and tissues via mass spectrometry. Briefly, tissues were weighed and mechanically disrupted in tissue destruction fluid (5% MeOH, 95% water and 0.1% ascetic acid) at a ratio of 5 ml fluid per mg of tissue. 10 μl of plasma or tissue slurry were then added to 90 μl of precipitation solvent (MeOH with internal standard N-Tricosanoyl ceramide trihexoside (C23:0, Matreya) spiked into solution) in a siliconized tube, vortexed and placed on a shaking plate at room temp for 30 minutes. Samples were then centrifuged and 10 μl of sample added to 90 μl of single blank matrix (DMSO/MeOH 1:1+0.1% FA) in glass LC-MS vial. Samples were analyzed for Gb3 chain length 24:0, the predominant Gb3 species present in GLAKO mice and measured against a standard curve composed of ceramide trihexoside (Gb3, Matreya). Globotriaosylsphingosine (lyso-Gb3) was measured in a similar manner using Glucosylsphingosine (Matreya) as the internal standard and lyso-Ceramide trihexoside (lyso-Gb3, Matreya) to create the standard curve. Assessment of Gene Modification (% indels) The ZFN target site was subjected to sequence analysis using the MiSeq system (Illumina, San Diego Calif.). A pair of oligonucleotide primers were designed for amplification of a 194 bp fragment spanning the ZFN target site in the human albumin locus or mouse albumin locus, and to introduce binding sequences for a second round of amplification. The products of this PCR amplification were purified, and subjected to a second round of PCR with oligonucleotides designed to introduce an amplicon specific identifier sequence (“barcode”), as well as terminal regions designed for binding sequencing oligonucleotide primers. The mixed population of bar coded amplicons was then subjected to MiSeq analysis, a solid phase sequencing procedure that allows the parallel analysis of thousands of samples on a single assay chip. In Vivo Testing of Fabry IVPRP® and cDNA Vectors in a GLAKO Mouse Model To demonstrate the efficacy of these therapeutics in an animal model of Fabry disease, GLAKO mice were transduced with the same AAV2/6 GLA cDNA construct used in HepG2 cells. Other GLAKO mice were transduced with the mouse version of Fabry IVPRP, which consists of two rAAV2/8 vectors that encode ZFNs SB-48641 and SB-31523, designed for cleaving mouse Albumin, and one rAAV2/8 vector that encodes the hGLA cDNA donor template with mouse homology arms. As controls, additional GLAKO mice and wild type mice were injected with AAV vector formulation buffer (PBS, 35 nM NaCl, 1% sucrose, 0.05% pluronic) F-68, pH 7.1) containing no vector particles. Animals received 50 mg/kg cyclophosphamide every two weeks, starting on the day prior to AAV injection. All mice were 4-12 weeks old at the time of injection. Mice were monitored for 2-3 months, with plasma drawn weekly or bi-weekly via submandibular puncture to measure plasma α-GalA activity. Mice were euthanized at the end of the experiment and α-GalA activity was measured in plasma, liver, kidney, heart and spleen as described above. Gb3 and lyso-Gb3 substrate levels were measured in plasma, liver, kidney, heart and spleen via mass spectrometry. For mice treated with Fabry IVPRP, indels in liver tissue were measured via MiSeq as described above. Western Blot and Deglycosylation Procedures: Mouse livers were homogenized in 0.1 M citrate/0.2 M phosphate buffer, pH 4.6. Liver homogenates were boiled for 10 minutes, then aliquots of each sample were deglycosylated by treating with PNGase F (New England Biolabs, NEB) for 1 hour according to the NEB protocol. 1 ug total protein was loaded onto a NuPage 4-12% Bis-Tris Midi Gel (Invitrogen). 0.5 ng of recombinant human GLA loaded (R&D Systems) before and after PNGase F treatment was included as a size reference. The antibodies used for the Western blot were: Primary antibody: α-GLA, Sino Biological rabbit monoclonal antibody, 1:1000; Secondary antibody: goat α-rabbit IgG-HRP, Thermo Fisher, 1:10,000. Example 3: Expression of the GLA Transgene In Vitro IVPRP® Approach: Methods are described above in Example 2. In brief, HepG2/C3a cells were transduced with AAV2/6 ZFNs and hGLA donor vectors at a dose of 100 k vg/cell for each ZFN and 200 k vg/cell for the GLA donor or a dose of 300 k/600 k for ZFNs and donor, respectively. As shown in FIG. 2, transduced cells had increased α-GalA activity in supernatant and cell pellets, and activity reached 3× mock-transduced HepG2 levels in ZFN+ donor groups. Indels at the albumin locus, a measure of ZFN activity, were measured at each vector dose for GLA donor constructs A and B. Indels in donors A and B were 43.46% and 39.81% for the 300/600 vector dose and 8.81% and 9.69% for the 100/200 vector dose. cDNA Approach: the cDNA construct shown in FIG. 1B was also tested in HepG2/G3 cells as described above. As shown in FIG. 3, HepG2/C3a cells transduced with AAV2/6 GLA cDNA vectors had dose-dependent increased α-GalA activity in supernatant and cell pellets. Each dose is labeled in FIG. 3 and indicates the thousands (K) of viral vector copies per cell. Supernatant α-GalA activity reached 200× mock levels at high cDNA doses. The proteins can be isolated and administered to subject in enzyme replacement therapies. Example 4: In Vivo Testing of Two Approaches Next the two types of approaches (cDNA and IVPRP®) were tested in vivo. The constructs were packaged into AAV 2/6 or AAV 2/8 and then injected intravenously into GLA knock out (GLAKO) mice. This is a mouse model of Fabry disease (Bangari et al (2015) Am J Pathol. 185(3):651-65). The test articles are shown below (Table 2) along with the dosing regimes (Table 3). TABLE 2 Test articles for IVPRP ® and cDNA approaches Test Article Titer Label Test Article (vg/mL) IVPRP Mouse AAV8-hAAT-pCI-Intron-3FN-48641-DNA2.0-FokELD 3.55E+13 AAV2/8 AAV8-hAAT-pCI-Intron-3FN-31523-DNA2.0-FokKKR 3.33E+13 Surrogate AAV2/8-AAV-Fabry-untagged-DNA2.0-MsAlb LS 2.33E+13 Reagents for SB-GLA cDNA Mouse AAV2/6-AAV-hAAT-pCI-GLA-cDNA2.0 1.94E+13 AAV2/6 cDNA for SB-GLA TABLE 3 Dosing regimes for in vivo testing of IVPRP ® and cDNA approaches hGLA hGLA Total ZFN Each Donor cDNA Total AAV AAV AAV Dose Level Dose Level Dose level Dose Dose* Group Designation Genotype serotype (vg/mouse) (vg/mouse) (vg/mouse) (vg/mouse) (vg/kg) Formulation wild type N/A 1.5 × 1011 1.2 × 1012 0 1.5 × 1012 6.0 × 1013 buffer control WT Formulation GLAKO N/A 1.5 × 1011 1.2 × 1012 0 1.5 × 1012 6.0 × 1013 buffer control KO ZFN + donor GLAKO AAV 2/8 1.5 × 1011 1.2 × 1012 0 1.5 × 1012 6.0 × 1013 cDNA low dose GLAKO AAV 2/6 0 0 5.0 × 1010 5.0 × 1010 2.0 × 1012 cDNA high dose GLAKO AAV 2/6 0 0 5.0 × 1011 5.0 × 1011 2.0 × 1013 *Animals dosed on a vg/mouse basis. Assuming 0.020 kg body weight for all mice, the total AAV dose level is 7.5e13 vg/kg for animals receiving ZFNs + Donor cDNA Approach: As shown in FIG. 4, GLAKO mice from cDNA treated groups displayed supraphysiological α-GalA activity in plasma as early as day 7 post-AAV administration. Shown in the figures are the results from the individual mice. Plasma α-GalA activity was measured weekly and high, dose-dependent levels of activity were sustained throughout the duration of the study. Plasma activity reached up to 6× wild type in the low dose (2.0e12 vg/kg) group and 280× wild type in the high dose (2.0e13 vg/kg) group. Mice were euthanized after two months and analyzed for α-GalA activity and Gb3 accumulation in the liver and secondary, distal tissues. As shown in FIG. 5, dose-dependent increase in α-GalA activity was found in the liver, heart and kidneys along with a corresponding reduction in Gb3 substrate content. Gb3 was undetectable in the tissues of some GLAKO mice administered with the high AAV2/6 cDNA dose. The data was also analyzed in terms of the amount of clearance of the substrates relative to untreated GLAKO mice (FIG. 5E and FIG. 5F) and demonstrated that the mice treated with the high cDNA dose had on average less than 10% of the substrate found in untreated GLAKO mice. IVPRP® Approach: Plasma levels were taken for the IVPRP® approach dosed GALKO mice over a period of 90 days. The data (FIG. 6A) indicate that the α-Gla protein activity was detected in the serum at a level of approximately 25-30% of that seen for wild type mice. In this experiment, one group of cells was given a mild immunosuppression regime (50 mg/kg cyclophosphamide every 2 weeks). Measurement of the ZFN activity in the liver (Indels) found that the animals treated with the mild immunosuppression had a slightly higher level of indels (FIG. 6B), but both groups had the expected range of indels present. A second experiment was performed using increasingly stringent immunosuppression (dosing shown below in Table 4) and the data (FIGS. 6C, 6D, and 6E) demonstrated that immunosuppression did not significantly increase the α-Gal A protein activity. TABLE 4 IVPRP ® In vivo study #2, immune suppression titration hGLA hGLA cDNA Group Donor Dose level Total AAV Dose Group Designation Immunosuppression (vg/mouse) (vg/mouse) (vg/kg) 1 Low IS 50 mg/kg 1.2 × 1012 0 6.0 × 1013 cyclophosphamide every 2 weeks 2 Moderate IS 70 mg/kg 1.2 × 1012 0 6.0 × 1013 cyclophosphamide weekly 3 High IS 120 mg/kg 1.2 × 1012 0 6.0 × 1013 cyclophosphamide weekly 4 cDNA 5e10 50 mg/kg 0 5.0 × 1010 2.0 × 1013 cyclophosphamide every 2 weeks 5 cDNA 5e11 50 mg/kg 0 5.0 × 1011 2.0 × 1013 cyclophosphamide every 2 weeks α-Gal A is thought to be susceptible to inactivation due to mis-folding as some mutations that are distal to the active site of the protein lead to Fabry Disease (Garman and Garboczi (2004) J Mot Biol 337(2):319-35), and that use of molecular chaperones including Deoxygalactonojirimycin (DGJ) have been proposed for use with some GLA mutants (Moise et al (2016) J. Am. Soc. Mass Spectrom 27(6): 1071-8). Thus, in the study described above, DGJ was added at approximately day 30-35. Specifically, 3 mg/kg diluted in 200 ul of water was given via oral gavage daily. A rapid rise in α-Gal A activity was detected in animals treated with DGJ (FIG. 7). Tissues from the animals in this study were also examined for α-GLA activity as described above. The results (FIG. 8) demonstrated that activity could be detected in the tissues, especially in the liver and spleen. In all tissues, the activity detected for the high dose cDNA approach was higher than for wild type mice. The levels of α-Gal A primary substrate were also measured in plasma, liver and heart tissue as described above. The data (FIG. 9) showed a decrease in detectable Gb3 in the plasma for the IVPRP® samples, and no detectable Gb3 for the cDNA samples (equivalent to wild type mice). For liver and heart tissue, the IVPRP® samples also showed a decrease in detectable Gb3, which was also true for the low dose cDNA samples. For the high dose cDNA samples, the levels were nearly the same as the wild type samples. These results show that the provision of a GLA transgene by either cDNA or IVPRP® approaches as described herein provides therapeutic benefits in vivo. Example 5: Optimization of the IVPRP® Donor Design The donor design was also investigated for the IVPRP® approach to optimize the design of the GLA coding region and to optimize the signal peptide. To start, the donor design was varied to introduce an α-Gal A (GLA) signal peptide (sequence: MQLRNPELHLGCALALRFLALVSWDIPGARA, SEQ ID NO:1) prior to the GLA coding sequence, and a Kozak sequence (sequence: GCCACCATG, SEQ ID NO:2) was inserted prior to the α-Gal A signal peptide to instigate a new translational event separate from the albumin signal peptide (see FIG. 10, examples are Variant #A, Variant #B). In addition, the use of alternate IDS signal peptide (sequence: MPPPRTGRGLLWLGLVLSSVCVALG, SEQ ID NO:3) was analyzed (FIG. 10, Variant #H) including and the use of a 2A-like sequence from T. asigna (“T2A”) (Luke et al (2008) J Gen Virol. 89(Pt 4): 1036-1042) to remove sequences 5′ of the signal peptide during translation. The new constructs were tested in HepG2/C3A cells as described previously. The results showed that the Variant #A and Variant #B had much higher levels of α-GalA activity than the initial donor (FIG. 11A) in vitro. In addition, Variant K demonstrated even higher levels of α-GalA activity as compared to Variant A or the initial donor (FIG. 11B). The constructs were then tested in vivo in the GLAKO mice using the dosing protocol listed below in Table 5. TABLE 5 In vivo testing of IVPRP ® donor designs in GLAKO mice hGLA Total No. ZEN Each Donor Total AAV AAV Group of Dose Level Dose Level Dose Dose* Group# Designation Genotype Mice (vg/mouse) (vg/mouse) (vg/mouse) (vg/kg) 1 ZFN + initial GLAKO 5 1.5 × 1011 1.2 × 1012 1.5 × 1012 6.0 × 1013 Donor 2 ZEN + new GLAKO 5 1.5 × 1011 1.2 × 1012 1.5 × 1012 6.0 × 1013 Donor #A + GLAsp 3 ZEN + new GLAKO 5 1.5 × 1011 1.2 × 1012 1.5 × 1012 6.0 × 1013 Donor #B + Kozak, +GLAsp 4 ZEN + new GLAKO 5 1.5 × 1011 1.2 × 1012 1.5 × 1012 6.0 × 1013 Donor #E + T2A, +GLAsp Plasma was taken once per week to measure α-Gal A activity as described above. Activity was found in all samples in each mouse, with the new designs showing improvement over the initial donor (FIG. 12), and levels were at least 40-fold higher than wild type at day 28 (indicated by the dotted line). Samples over time showed an increase, where activity was measure at approximately 80× wild type levels for Group 2 (Donor #A) and 50×WT for Group 4 (Donor #E). Tissue samples are taken from the mice and the levels of Gb3 are measured and are found to be reduced as compared to the untreated GLAKO mice. The experiment described above was carried out for 56 days, at which time the animals were sacrificed and analyzed for α-Gal A activity in the liver, heart, kidney and spleen. The extended data (FIG. 15) demonstrates that this approach resulted in increases in α-Gal A activity in tested tissues, including a 100-fold increase in α-Gal A activity in plasma of treated animals as compared to plasma of wild-type animals, a 9-fold increase in α-Gal A activity in the heart of treated animals as compared to the hearts of wild-type (untreated) animals, and an 80% increase in α-Gal A activity in the kidneys of treated animals as compared to untreated (wild-type) animals. Tissue analysis was then done to determine the levels of α-Gal A glycolipid substrates (Gb3 (FIG. 16A) and lyso-Gb3 (FIG. 16B)) in various tissues (plasma, liver, heart and kidney) following treatment. As shown in FIG. 16, treatment as described herein resulted in decreased levels of both substrates (Gb3 and lyso-Gb3) in all tested tissues (plasma, liver, heart and kidney) for animals treated with A, B or E variants as compared to before treatment (initial) and untreated (wild-type) animals, indicating that the compositions and methods described herein provide therapeutically beneficial levels of protein in vivo. The experiments were repeated as described above to assay α-Gal A activity in plasma and in various tissues (liver, hear, kidney and spleen) following administration of Variant E and Variant J (see FIG. 10) with albumin-targeted ZFNs. As shown in FIGS. 20 and 21, α-Gal A activity in plasma (FIG. 20A) and in liver, heart, kidney and spleen (FIG. 20B) of animals receiving Variant J donor produced plasma α-Gal A activity nearly 300× that of wildtype and tissue α-Gal A activity 10-100× or more than that of wildtype in liver, heart and spleen. The concentrations of α-Gal A glycolipid substrates (Gb3 (FIG. 21A) and lyso-Gb3 (FIG. 21B)) in various tissues (plasma, liver, heart and kidney) following treatment were measured as described herein. As shown in FIG. 21, expression of Variant J greatly reduced the substrate levels. Example 6: Optimization of GLA Transgene Cassette Design for cDNA Approach The GLA transgene cassette for the cDNA approach was also optimized. The transgene was linked to sequences encoding different signal peptides, including the α-Gal A peptide, the signal peptide for the IDS gene (iduronate 2-sulfatase), the FIX gene (Factor IX, (sequence: MQRVNMIMAESPGLITICLLGYLLSAEC, SEQ ID NO:4)) and the albumin (sequence: MKWVTFISLLFLFSSAYS, SEQ ID NO:5) signal peptides (FIG. 13B). In addition, the GLA transgene was inserted into an alternate optimized cDNA expression vector (FIG. 13A, also U.S. Publication No. 20170119906). All constructs were tested as described above in HepG2/C3A cells in vitro at doses ranging from 30 to 600 thousand (K) of viral vector copies per cell, and indicated that the IDS and FIX (F9) leader sequences lead to greater α-GalA activity than use of the GLA or ALB (albumin) leader sequences (FIG. 14A). The data for the cDNA variants #4, #5 and #6 (FIG. 13) is shown in FIG. 14B. The constructs are also tested in GLAKO mice as described above and are active in vivo. Example 7: Analysis of α-Gal a Protein by Western Blot and Deglycosylation Plasma from the mice treated with either the IVPRP® approach or the cDNA approach was analyzed for the presence of the α-GalA protein as described in Example 2. Further, the samples were also treated with PNGaseF to cause deglycosylation. As shown in FIG. 17, the α-GalA protein produced in vivo in the GLAKO mice following either IVPRP® (FIG. 17A depicting the results for Variant A and Variant J) or the initial cDNA construct (construct depicted in FIG. 13B, data shown in FIG. 17B) treatment behaved similarly to the recombinant hGalA protein, indicating the composition and methods described herein provides proteins at clinically relevant levels, namely therapeutic levels similar to those recombinant therapeutic proteins currently in use in enzyme replacement therapies. Example 8: In Vitro Protein Production Following cDNA Administration Hep2G cells were transduced with AAV GLA cDNA Variant #4 and the supernatant was collected after 5 days and tested for α-Gal A activity and the supernatant used in culture of K562 cells as described in Example 2. As shown in FIG. 28A, supernatant collected 5 days after transduction of HepG2 cells with the AAV GLA cDNA Variant #4 showed high amounts of α-Gal A activity. FIG. 28B shows α-Gal A from the HepG2 supernatant was taken up by the K562 within 24 hours and that uptake was blocked by M6P. Therefore, cells as described herein produce and secrete α-Gal A in high amounts, which secreted α-Gal A is then taken up by other cells. Accordingly, the systems described herein can be used for the production of α-Gal A for administration of the subjects in need thereof, for example in enzyme replacement therapies. Example 9: In Vivo Activity of Mice Treated with cDNA Variant #4 GLAKO mice were treated intravenously with 2004, of formulation buffer containing 5.0e10 VG (2.0e12 VG/kg) of AAV comprising the cDNA variant #4 (see, FIG. 13) or the initial cDNA construct (FIG. 13B) and plasma α-GalA activity was analyzed for a period of 2 months. α-GalA activity in the plasma of GLAKO mice treated with Variant #4 was approximately 10× that observed for the initial cDNA construct (FIG. 18A). As described above, activity was also measured in the liver, heart, kidney and spleen for the two treatment groups and is displayed in FIG. 18B. Further, α-GalA protein was analyzed in the livers of the treated mice and changes in molecular weight were observed following treatment with PNGase F or Endo H as discussed above (FIG. 18C). Additionally, as shown in FIG. 32, GLAKO mice treated with both the initial and Variant #4 cDNAs exhibited reduced Fabry substrate concentration in all tissues tested. These data demonstrate that the cDNA approach is also a robust platform for the production of α-GalA protein at therapeutically beneficial levels in vivo. Example 10: In Vivo Dose Titration in Mice Treated with the Initial cDNA Construct GLAKO mice were treated intravenously with a dose of AAV comprising the initial cDNA construct (FIG. 13B) ranging from 1.25e11 VG/kg to 5.0e12 VG/kg and plasma α-GalA activity was analyzed for a period of 6 months as described in Examples 4 and 5. GLAKO mice treated with the initial cDNA had dose-dependent α-GalA activity in the plasma ranging from 1× of wild type up to 40× wild type (FIG. 19). In addition, as shown in FIG. 29, α-Gal A activity remained at therapeutic levels (in a dose-dependent manner) for 6 months post-transduction, indicating long-term therapeutic benefit. FIG. 30 shows α-Gal A activity in liver, spleen, heart and kidney at day 180 (6 months post-treatment) and also shows therapeutic levels in these tissues. The dose-dependent increase in α-Gal A activity also corresponded to a reduction in Gb3 substrate content. See, FIGS. 31 and 32, showing a dose-dependent reduction in Gb3 content in all tissues evaluated. The data demonstrate that therapeutic levels of α-Gal A protein are generated in subjects treated with the cDNA approach described herein. Example 11: Further In Vivo IVPRP® Studies GLAKO mice were treated with ZFNs and various exemplary hGLA donor constructs and evaluated as described above for genomic modification, GLA activity in vivo and reduction of Fabry substrates in vivo. See, Example 5. As shown in FIG. 22, nuclease-mediated integration of GLA donors resulted in permanent modification of hepatocytes in the GLAKO mouse model of Fabry disease. FIG. 23 shows α-Gal A activity in the indicated tissues over time (FIG. 23A) and at two months (FIG. 23B) post-administration of nuclease and GLA donors to the animals. As shown, liver-produced α-Gal A is secreted into the bloodstream and taken up by secondary tissues, including that stable plasma activity reached up to 80-fold wild type. FIG. 24 shows the animals treated with nucleases and donors exhibited greatly reduced substrate concentration in all tissues tested, as compared to untreated animals, wild-type animals and animals treated with the donors only. Experiments in HepG2 and GLAKO mice were conducted using Variant L and a modified donor designated Variant M (FIG. 25) which includes an IDS signal peptide in place of the GLA signal peptide of Variant L. For detection of L and M donor integration, a NGS approach was used, based on an unbiased PCR scheme that generates different products when the donor has integrated versus the product generated for the wild type gene devoid of an integration event. Briefly, a 5-NGS primer sequences (identical to Primer 1 in FIG. 25B) was added at the 3′ end of the transgene (see FIG. 25A). Immediately downstream of the NGS primer sequence, a Targeted Integration (TI) sequence was added. The TI sequence has the same base composition and length as the corresponding sequence in the albumin locus, but the base sequence is scrambled such that no PCR bias is introduced for the amplification of the PCR product associated with the wild type locus without an integration as compared with to the locus comprising the transgene integration. The two PCR products thus utilize identical primers, and produce PCR products of identical size and composition, but have differing sequences, allowing ready identification of TI events by NGS, as well as simultaneous analysis of indels and TI events by NGS. For analysis of integration events in human cells, the primers used are the following: Primer 1: 5′ GCACTAAGGAAAGTGCAAAG (SEQ ID NO: 6) Primer 2: 5′ TAATACTCTTTTAGTGTCTA (SEQ ID NO: 7) The TI sequence used in human cells is shown below where the scrambled sequence is shown in italics, and the location of the Primer 1 binding site is shown in underline: (SEQ ID NO: 8) 5′GCACTAAGGAAAGTGCAAAGTAAGATTGACCAGACCAGATAGAAGAAT GTAACTGTAGTTCTAATAGGACTTATTATCCCAAAGAC. Amplification using the two primers produces a 222 bp amplicon as shown below: Wild type amplicon (no insertion): (SEQ ID NO: 9) 5′GCACTAAGGAAAGTGCAAAGTAACTTAGAGTGACTGAAACTTCACAGA ATAGGGTTGAAGATTGAATTCATAACTATCCCAAAGACCTATCCATTGCA CTATGCTTTATTTAAAAACCACAAAACCTGTGCTGTTGATCTCATAAATA GAACTTGTATTTATATTTATTTTCATTTTAGTCTGTCTTCTTGGTTGCTG TTGATAGACACTAAAAGAGTATTA. TI amplicon (italics indicate the scrambled sequence): (SEQ ID NO: 10) 5′GCACTAAGGAAAGTGCAAAGTAAGATTGACCAGACCAGATAGAAGAAT GTAACTGTAGTTCTAATAGGACTTATTATCCCAAAGACCTATCCATTGCA CTATGCTTTATTTAAAAACCACAAAACCTGTGCTGTTGATCTCATAAATA GAACTTGTATTTATATTTATTTTCATTTTAGTCTGTCTTCTTGGTTGCTG TTGATAGACACTAAAAGAGTATTA. Similarly, the TI sequence and primers used for mouse cells is shown below. For analysis of integration events, the primers used are as follows: (SEQ ID NO: 11) Primer 1: 5′ TTGAGTTTGAATGCACAGAT (SEQ ID NO: 12) Primer 2: 5′ GAAACAGGGAGAGAAAAACC. The TI sequence used in mouse cells is shown below where the scrambled sequence is shown in italics, and the location of the Primer 1 binding site is shown in underline: (SEQ ID NO: 13) 5′AAATCTTGAGTTTGAATGCACAGATCAATTGTAAACTAAAGAAATAGT AATATAGAGTTTAAATATAGATAGCTATGACTGCACTTGATAGAAGGTAA CGGTGCCACCTTCAGATTT Amplification using the two primers produces a 247 bp amplicon as shown below: Wild type amplicon (no insertion): (SEQ ID NO: 14) 5′TTGAGTTTGAATGCACAGATATAAACACTTAACGGGTTTTAAAAATAA TAATGTTGGTGAAAAAATATAACTTTGAGTGTAGCAGAGAGGAACCATTG CCACCTTCAGATTTTCCTGTAACGATCGGGAACTGGCATCTTCAGGGAGT AGCTTAGGTCAGTGAAGAGAAGAACAAAAAGCAGCATATTACAGTTAGTT GTCTTCATCAATCTTTAAATATGTTGTGTGGTTTTTCTCTCCCTGTTTC TI amplicon (italics indicate the scrambled sequence): (SEQ ID NO: 15) 5′TTGAGTTTGAATGCACAGATCAATTGTAAACTAAAGAAATAGTAATAT AGAGTTTAAATATAGATAGCTATGACTGCACTTGATAGAAGGTAACGGTG CCACCTTCAGATTTTCCTGTAACGATCGGGAACTGGCATCTTCAGGGAGT AGCTTAGGTCAGTGAAGAGAAGAACAAAAAGCAGCATATTACAGTTAGTT GTCTTCATCAATCTTTAAATATGTTGTGTGGTTTTTCTCTCCCTGTTTC Further, this technique can be used with non-human primates (rhesus macaque, NHP) utilizing the primers and inserted TI sequence shown below: (SEQ ID NO: 16) Primer 1: 5′ CCACTAAGGAAAGTGCAAAG (SEQ ID NO: 17) Primer 2: 5′ TGAAAGTAAATATAAATACAAGTTC The TI sequence used in NHP cells is shown below where the scrambled sequence is shown in italics, and the location of the Primer 1 binding site is shown in underline: (SEQ ID NO: 18) 5′CCACTAAGGAAAGTGCAAAGGAGCGCTAACTGGAACATACTCGCTATT TAAGAACATTATAAGATACTAATTCAGTATTCGAAGAC. Amplification using the two primers produces a 173 bp amplicon as shown below: Wild type amplicon (no insertion): (SEQ ID NO: 19) 5′CCACTAAGGAAAGTGCAAAG TAACTTAGAGTGACTTAAACTTCACAGAACAGAGTTGAAGATTGAATTCA TAACTGTCCCTAAGACCTATCCATTGCACTATGCTTTATTTAAAAGCCAC AAAACCTGTGCTGTTGATCTCATAAATAGAACTTGTATTTATATTTACTT TCA TI amplicon (italics indicate the scrambled sequence): (SEQ ID NO: 20) 5′CCACTAAGGAAAGTGCAAAGGAGCGCTAACTGGAACATACTCGCTATT TAAGAACATTATAAGATACTAATTCAGTATTCGAAGACCTATCCATTGCA CTATGCTTTATTTAAAAGCCACAAAACCTGTGCTGTTGATCTCATAAATA GAACTTGTATTTATATTTACTTTCA. Thus, human cells from the hepatocarinoma cell line HepG2 were treated with ZFNs and GLA donor variant #L, containing a TI sequence for analysis of HDR. DNA was purified from transduced cells 7 days after transduction and analyzed via NGS. As shown in FIG. 26, in vitro indels and TI (HDR) showed a dose-dependent response to a fixed ratio of ZFNs and TI donor. Furthermore, as shown in GLAKO mice, the nuclease-mediated targeted integration (TI) of Variant M yielded stable plasma activity up to 250-fold wild type and α-Gal A activity in heart and kidney was over 20-fold wild type and 4-fold wild type, respectively. Assays were also conducted to further assess whether α-Gal A is taken up by secondary tissues following nuclease-mediated TI of a GLA donor construct. Briefly, as described above, a GLA donor construct containing an IDS signal peptide and a 3′ sequence for analysis of targeted integration (TI) (Donor Variant M) was used to treat GLAKO mice and plasma and tissue samples (e.g., liver, heart, spleen, kidney, brain, etc.) assayed for both α-Gal A activity and substrate concentration. As shown in FIG. 27, α-Gal A stable plasma activity was up to 250-fold wild type and α-Gal A activity in heart and kidney was over 20-fold wild type and 4-fold wild type, respectively. The data demonstrate that therapeutic levels of α-Gal A protein are generated in subjects (including secondary tissues) treated with the IVPRP approach described herein. All patents, patent applications and publications mentioned herein are hereby incorporated by reference in their entirety. Although disclosure has been provided in some detail by way of illustration and example for the purposes of clarity of understanding, it will be apparent to those skilled in the art that various changes and modifications can be practiced without departing from the spirit or scope of the disclosure. Accordingly, the foregoing descriptions and examples should not be construed as limiting. | <SOH> BACKGROUND <EOH>Gene therapy holds enormous potential for a new era of human therapeutics. These methodologies will allow treatment for conditions that heretofore have not been addressable by standard medical practice. One area that is especially promising is the ability to add a transgene to a cell to cause that cell to express a product that previously was not being produced in that cell or was being produced suboptimally. Examples of uses of this technology include the insertion of a gene encoding a therapeutic protein, insertion of a coding sequence encoding a protein that is somehow lacking in the cell or in the individual and insertion of a sequence that encodes a structural nucleic acid such as a microRNA. Transgenes can be delivered to a cell by a variety of ways, such that the transgene becomes integrated into the cell's own genome and is maintained there. In recent years, a strategy for transgene integration has been developed that uses cleavage with site-specific nucleases for targeted insertion into a chosen genomic locus (see, e.g., co-owned U.S. Pat. No. 7,888,121). Nucleases, such as zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), or nuclease systems such as the RNA guided CRISPR/Cas system (utilizing an engineered guide RNA), are specific for targeted genes and can be utilized such that the transgene construct is inserted by either homology directed repair (HDR) or by end capture during non-homologous end joining (NHEJ) driven processes. See, e.g., U.S. Pat. Nos. 9,394,545; 9,255,250; 9,200,266; 9,045,763; 9,005,973; 9,150,847; 8,956,828; 8,945,868; 8,703,489; 8,586,526; 6,534,261; 6,599,692; 6,503,717; 6,689,558; 7,067,317; 7,262,054; 7,888,121; 7,972,854; 7,914,796; 7,951,925; 8,110,379; 8,409,861; U.S. Patent Publications 20030232410; 20050208489; 20050026157; 20050064474; 20060063231; 20080159996; 201000218264; 20120017290; 20110265198; 20130137104; 20130122591; 20130177983; 20130196373; 20140120622; 20150056705; 20150335708; 20160030477 and 20160024474, the disclosures of which are incorporated by reference in their entireties. Transgenes may be introduced and maintained in cells in a variety of ways. Following a “cDNA” approach, a transgene is introduced into a cell such that the transgene is maintained extra-chromosomally rather than via integration into the chromatin of the cell. The transgene may be maintained on a circular vector (e.g. a plasmid, or a non-integrating viral vector such as AAV or Lentivirus), where the vector can include transcriptional regulatory sequences such as promoters, enhancers, polyA signal sequences, introns, and splicing signals (U.S. Publication No. 20170119906). An alternate approach involves the insertion of the transgene in a highly expressed safe harbor location such as the albumin gene (see U.S. Pat. No. 9,394,545). This approach has been termed the In Vivo Protein Replacement Platform® or IVPRP. Following this approach, the transgene is inserted into the safe harbor (e.g., Albumin) gene via nuclease-mediated targeted insertion where expression of the transgene is driven by the Albumin promoter. The transgene is engineered to comprise a signal sequence to aid in secretion/excretion of the protein encoded by the transgene. “Safe harbor” loci include loci such as the AAVS1, HPRT, Albumin and CCR5 genes in human cells, and Rosa26 in murine cells. See, e.g., U.S. Pat. Nos. 7,888,121; 7,972,854; 7,914,796; 7,951,925; 8,110,379; 8,409,861; 8,586,526; U.S. Patent Publications 20030232410; 20050208489; 20050026157; 20060063231; 20080159996; 201000218264; 20120017290; 20110265198; 20130137104; 20130122591; 20130177983; 20130177960 and 20140017212. Nuclease-mediated integration offers the prospect of improved transgene expression, increased safety and expressional durability, as compared to classic integration approaches that rely on random integration of the transgene, since it allows exact transgene positioning for a minimal risk of gene silencing or activation of nearby oncogenes. While delivery of the transgene to the target cell is one hurdle that must be overcome to fully enact this technology, another issue that must be conquered is insuring that after the transgene is inserted into the cell and is expressed, the gene product so encoded must reach the necessary location with the organism, and be made in sufficient local concentrations to be efficacious. For diseases characterized by the lack of a protein or by the presence of an aberrant non-functional one, delivery of a transgene encoded wild type protein can be extremely helpful. Lysosomal storage diseases (LSDs) are a group of rare metabolic monogenic diseases characterized by the lack of functional individual lysosomal proteins normally involved in the breakdown of waste lipids, glycoproteins and mucopolysaccharides. These diseases are characterized by a buildup of these compounds in the cell since it is unable to process them for recycling due to the mis-functioning of a specific enzyme. The most common examples are Gaucher's (glucocerebrosidase deficiency—gene name: GBA), Fabry's (α galactosidase A deficiency—GLA), Hunter's (iduronate-2-sulfatase deficiency—IDS), Hurler's (alpha-L iduronidase deficiency—IDUA), Pompe's (alpha-glucosidase (GAA)) and Niemann-Pick's (sphingomyelin phosphodiesterase 1 deficiency—SMPD1) diseases. When grouped all together, LSDs have an incidence in the population of about 1 in 7000 births. See, also, U.S. Patent Publication Nos. 20140017212; 2014-0112896; and 20160060656. For instance, Fabry disease is an X-linked disorder of glycosphingolipid metabolism caused by a deficiency of the α-galactosidase A enzyme (α-GalA). It is associated with the progressive deposition of glycospingolipids including globotriaosylceramide (also known as GL-3 and Gb3) and globotriaosylsphingosine (lyso-Gb3), galabioasylceramide, and group B substance. Symptoms of the disease are varied and can include burning, tingling pain (acroparesthesia) or episodes of intense pain which are called ‘Fabry crises’ which can last from minutes to days. Other symptoms include impaired sweating, low tolerance for exercise, reddish-purplish rash called angiokeratoma, eye abnormalities, gastrointestinal problems, heart problems such as enlarged heart and heart attack, kidney problems that can lead to renal failure and CNS problems and in general, life expectancy for Fabry patients is shortened substantially. Current treatment for Fabry disease can involve enzyme replacement therapy (ERT) with two different preparations of human α-GalA, agalsidase beta or agalsidase alfa, which requires costly and time consuming infusions (typically between about 0.2-1 mg/kg) for the patient every two weeks. Such treatment is only to treat the symptoms and is not curative, thus the patient must be given repeated dosing of these proteins for the rest of their lives, and potentially may develop neutralizing antibodies to the injected protein. Furthermore, adverse reactions are associated with ERT, including immune reactions such as the development of anti-α-GalA antibodies in subjects treated with the α-GalA preparations. In fact, 50% of males treated with agalsidase alfa and 88% of males treated with agalsidase beta developed α-GalA antibodies. Importantly, a significant proportion of those antibodies are neutralizing antibodies and, accordingly, reduce the therapeutic impact of the therapy (Meghdari et al (2015) PLoS One 10(2):e0118341. Doi:10.1371/journal.pone.0118341). In addition, ERT does not halt disease progression in all patients. Thus, there remains a need for non-ERT methods and compositions that can be used to treat Fabry disease, including treatment through genome editing, for instance, to deliver an expressed transgene encoded gene product at a therapeutically relevant level. | <SOH> SUMMARY <EOH>Disclosed herein are methods and compositions for treating and/or preventing Fabry disease. The invention describes methods for insertion of a transgene sequence into a suitable target cell (e.g., a subject with Fabry disease) wherein the transgene encodes at least one protein (e.g., at least one α-GalA protein) that treats the disease. The methods may be in vivo (delivery of the transgene sequence to a cell in a living subject) or ex vivo (delivery of modified cells to a living subject). The invention also describes methods for the transfection and/or transduction of a suitable target cell with an expression system such that an α-GalA encoding transgene expresses a protein that treats (e.g., alleviates one or more of the symptoms associated with) the disease. The α-GalA protein may be excreted (secreted) from the target cell such that it is able to affect or be taken up by other cells that do not harbor the transgene (cross correction). The invention also provides for methods for the production of a cell (e.g., a mature or undifferentiated cell) that produces high levels of α-GalA where the introduction of a population of these altered cells into a patient will supply that needed protein to treat a disease or condition. In addition, the invention provides methods for the production of a cell (e.g. a mature or undifferentiated cell) that produces a highly active form (therapeutic) of α-GalA where the introduction of, or creation of, a population of these altered cells in a patient will supply that needed protein activity to treat (e.g., reduce or eliminate one or more symptoms) Fabry's disease. The highly active form of α-GalA produced as described herein can also be isolated from cells as described herein and administered to a patient in need thereof using standard enzyme replacement procedures known to the skilled artisan. Described herein are methods and compositions for expressing at least one α galactosidase A (α-Gal A) protein. The compositions and methods can be for use in vitro, in vivo or ex vivo, and comprise administering a GLA transgene (e.g., cDNA with wild-type or codon optimized GLA sequences) encoding the at least one α-Gal A protein to the cell such that the α-Gal A protein is expressed in the cell. In certain embodiments, the cell is in a subject with Fabry's disease. In any of the methods described herein, the transgene can be administered to the liver of the subject. Optionally, the methods further comprise administering one or more nucleases that cleave an endogenous albumin gene in a liver cell in a subject such that the transgene is integrated into and expressed from the albumin gene. In any of the methods described herein, the α-Gal A protein expressed from the transgene can decrease the amount of glycospingolipids in the subject by at least 2-fold. The GLA transgene may further comprise additional elements, including, for example, a signal peptide and/or one or more control elements. Genetically modified cells (e.g., stem cells, precursor cells, liver cells, muscle cells, etc.) comprising an exogenous GLA transgene (integrated or extrachromosomal) are also provided, including cells made by the methods described herein. These cells can be used to provide an α-Gal A protein to a subject with Fabry's disease, for example by administering the cell(s) to a subject in need thereof or, alternatively, by isolating the α-Gal A protein produced by the cell and administering the protein to the subject in need thereof (enzyme replacement therapies). Also provided are vectors (e.g., viral vectors such as AAV or Ad or lipid nanoparticles) comprising a GLA transgene for use in any of the methods described herein, including for use in treatment of Fabry's. In one aspect, the invention describes a method of expressing a transgene encoding one or more corrective GLA transgenes in a cell of the subject. The transgene may be inserted into the genome of a suitable target cell (e.g., blood cell, liver cell, brain cell, stem cell, precursor cell, etc.) such that the α-GalA product encoded by that corrective transgene is stably integrated into the genome of the cell (also referred to as a IVPRP® approach) or, alternatively, the transgene may be maintained in the cell extra-chromosomally (also referred to as a “cDNA” approach). In one embodiment, the corrective GLA transgene is introduced (stably or extra-chromosomally) into cells of a cell line for the in vitro production of the replacement protein, which (optionally purified and/or isolated) protein can then be administered to a subject for treating a subject with Fabry disease (e.g., by reducing and/or eliminating one or more symptoms associates with Fabry disease). In certain embodiments, the α-GalA product encoded by that corrective transgene increases α-GalA activity in a tissue a subject by any amount as compared to untreated subjects, for example, 2 to 1000 more (or any value therebetween) fold, including but not limited to 2 to 100 fold (or any value therebetween including 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 fold), 100 to 500 fold (or any value therebetween), or 500 to 1000 fold or more. In another aspect, described herein are ex vivo or in vivo methods of treating a subject with Fabry disease (e.g., by reducing and/or eliminating one or more symptoms associates with Fabry disease), the methods comprising inserting an GLA transgene into a cell as described herein (cDNA and/or IVPRP approaches) such that the protein is produced in a subject with Fabry disease. In certain embodiments, isolated cells comprising the GLA transgene can be used to treat a patient in need thereof, for example, by administering the cells to a subject with Fabry disease. In other embodiments, the corrective GLA transgene is inserted into a target tissue in the body such that the replacement protein is produced in vivo. In some preferred embodiments, the corrective transgene is inserted into the genome of cells in the target tissue, while in other preferred embodiments, the corrective transgene is inserted into the cells of the target tissue and is maintained in the cells extra-chromosomally. In any of the methods described herein, the expressed α-GalA protein may be excreted from the cell to act on or be taken up by secondary targets, including by other cells in other tissues (e.g. via exportation into the blood) that lack the GLA transgene (cross correction). In some instances, the primary and/or secondary target tissue is the liver. In other instances, the primary and/or secondary target tissue is the brain. In other instances, the primary and/or secondary target is blood (e.g., vasculature). In other instances, the primary and/or secondary target is skeletal muscle. In certain embodiments, the methods and compositions described herein are used to decrease the amount of glycospingolipids including globotriaosylceramide (also known as GL-3 and Gb3) and globotriaosylsphingosine (lyso-Gb3), galabioasylceramide deposited in tissues of a subject suffering Fabry disease. In certain embodiments, the α-GalA product encoded by that corrective transgene decreases glycospingolipids in a tissue of a subject by any amount as compared to untreated subjects, for example, 2 to 100 more (or any value therebetween) fold, including but not limited to 2 to 100 fold (or any value therebetween including 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 fold). In any of the methods described herein, the corrective GLA transgene comprises the wild type sequence of the functioning GLA gene, while in other embodiments, the sequence of the corrective GLA transgene is altered in some manner to give enhanced biological activity (e.g., optimized codons to increase biological activity and/or alteration of transcriptional and translational regulatory sequences to improve gene expression). In some embodiments, the GLA gene is modified to improve expression characteristics. Such modifications can include, but are not limited to, insertion of a translation start site (e.g. methionine), addition of an optimized Kozak sequence, insertion of a signal peptide, and/or codon optimization. In some embodiments, the signal peptide can be chosen from an albumin signal peptide, a F.IX signal peptide, a IDS signal peptide and/or an α-GalA signal peptide. In any embodiments described herein, the GLA donor may comprise a donor as shown in any of FIGS. 1B, 1C, 10 and/or 13 . In any of the methods described herein, the GLA transgene may be inserted into the genome of a target cell using a nuclease. Non-limiting examples of suitable nucleases include zinc-finger nucleases (ZFNs), TALENs (Transcription activator like protein nucleases) and/or CRISPR/Cas nuclease systems, which include a DNA-binding molecule that binds to a target site in a region of interest (e.g., a disease associated gene, a highly-expressed gene, an albumin gene or other or safe harbor gene) in the genome of the cell and one or more nuclease domains (e.g., cleavage domain and/or cleavage half-domain). Cleavage domains and cleavage half domains can be obtained, for example, from various restriction endonucleases, Cas proteins and/or homing endonucleases. In certain embodiments, the zinc finger domain recognizes a target site in an albumin gene or a globin gene in red blood precursor cells (RBCs). See, e.g., U.S. Publication No. 2014001721, incorporated by reference in its entirety herein. In other embodiments, the nuclease (e.g., ZFN, TALEN, and/or CRISPR/Cas system) binds to and/or cleaves a safe-harbor gene, for example a CCR5 gene, a PPP1R12C (also known as AAVS1) gene, albumin, HPRT or a Rosa gene. See, e.g., U.S. Pat. Nos. 7,888,121; 7,972,854; 7,914,796; 7,951,925; 8,110,379; 8,409,861; 8,586,526; U.S. Patent Publications 20030232410; 20050208489; 20050026157; 20060063231; 20080159996; 201000218264; 20120017290; 20110265198; 20130137104; 20130122591; 20130177983; 20130177960 and 20140017212. The nucleases (or components thereof) may be provided as a polynucleotide encoding one or more nucleases (e.g., ZFN, TALEN, and/or CRISPR/Cas system) described herein. The polynucleotide may be, for example, mRNA. In some aspects, the mRNA may be chemically modified (See e.g. Kormann et al, (2011) Nature Biotechnology 29(2):154-157). In other aspects, the mRNA may comprise an ARCA cap (see U.S. Pat. Nos. 7,074,596 and 8,153,773). In further embodiments, the mRNA may comprise a mixture of unmodified and modified nucleotides (see U.S. Patent Publication 20120195936). In still further embodiments, the mRNA may comprise a WPRE element (see U.S. Patent Publication No. 20160326548). In another aspect, the invention includes genetically modified cells (e.g., stem cells, precursor cells, liver cells, muscle cells, etc.) with the desired GLA transgene (optionally integrated using a nuclease). In some aspects, the edited stem or precursor cells are then expanded and may be induced to differentiate into a mature edited cells ex vivo, and then the cells are given to the patient. Thus, cells descended from the genetically edited (modified) GLA-producing stem or precursor cells as described herein may be selected for use in this invention. In other aspects, the edited precursors (e.g., CD34+ stem cells) are given in a bone marrow transplant which, following successful implantation, proliferate producing edited cells that then differentiate and mature in vivo and contain the biologic expressed from the GLA transgene. In some embodiments, the edited CD34+ stem cells are given to a patient intravenously such that the edited cells migrate to the bone marrow, differentiate and mature, producing the α-Gal A protein. In other aspects, the edited stem cells are muscle stem cells which are then introduced into muscle tissue. In some aspects, the engineered nuclease is a Zinc Finger Nuclease (ZFN) (the term “ZFN” includes a pair of ZFNs) and in others, the nuclease is a TALE nuclease (TALEN) (the term “TALENs” include a pair of TALENs), and in other aspects, a CRISPR/Cas system is used. The nucleases may be engineered to have specificity for a safe harbor locus, a gene associated with a disease, or for a gene that is highly expressed in cells. By way of non-limiting example only, the safe harbor locus may be the AAVS1 site, the CCR5 gene, albumin or the HPRT gene while the disease associated gene may be the GLA gene encoding α-galactosidase A. In another aspect, described herein is a nuclease (e.g., ZFN, ZFN pair, TALEN, TALEN pair and/or CRISPR/Cas system) expression vector comprising a polynucleotide, encoding one or more nucleases as described herein, operably linked to a promoter. In one embodiment, the expression vector is a viral vector. In a further aspect, described herein is a GLA expression vector comprising a polynucleotide encoding α-GalA as described herein, operably linked to a promoter. In one embodiment, the expression is a viral vector. In another aspect, described herein is a host cell comprising one or more nucleases (e.g., ZFN, ZFN pair, TALEN, TALEN pair and/or CRISPR/Cas system) expression vectors and/or an α-GalA expression vector as described herein. The host cell may be stably transformed or transiently transfected or a combination thereof with one or more nuclease expression vectors. In some embodiments, the host cell is a liver cell. In other embodiments, methods are provided for replacing a genomic sequence in any target gene with a therapeutic GLA transgene as described herein, for example using a nuclease (e.g., ZFN, ZFN pair, TALEN, TALEN pair and/or CRISPR/Cas system) (or one or more vectors encoding said nuclease) as described herein and a “donor” sequence or GLA transgene that is inserted into the gene following targeted cleavage with the nuclease. The donor GLA sequence may be present in the vector carrying the nuclease (or component thereof), present in a separate vector (e.g., Ad, AAV or LV vector or mRNA) or, alternatively, may be introduced into the cell using a different nucleic acid delivery mechanism. Such insertion of a donor nucleotide sequence into the target locus (e.g., highly expressed gene, disease associated gene, other safe-harbor gene, etc.) results in the expression of the GLA transgene under control of the target locus's (e.g., albumin, globin, etc.) endogenous genetic control elements. In some aspects, insertion of the GLA transgene, for example into a target gene (e.g., albumin), results in expression of an intact α-GalA protein sequence and lacks any amino acids encoded by the target (e.g., albumin). In other aspects, the expressed exogenous α-GalA protein is a fusion protein and comprises amino acids encoded by the GLA transgene and by the endogenous locus into which the GLA transgene is inserted (e.g., from the endogenous target locus or, alternatively from sequences on the transgene that encode sequences of the target locus). The target may be any gene, for example, a safe harbor gene such as an albumin gene, an AAVS1 gene, an HPRT gene; a CCR5 gene; or a highly-expressed gene such as a globin gene in an RBC precursor cell (e.g., beta globin or gamma globin). In some instances, the endogenous sequences will be present on the amino (N)-terminal portion of the exogenous α-GalA protein, while in others, the endogenous sequences will be present on the carboxy (C)-terminal portion of the exogenous α-GalA protein. In other instances, endogenous sequences will be present on both the N- and C-terminal portions of the α-GalA exogenous protein. In some embodiments, the endogenous sequences encode a secretion signal peptide that is removed during the process of secretion of the α-GalA protein from the cell. The endogenous sequences may include full-length wild-type or mutant endogenous sequences or, alternatively, may include partial endogenous amino acid sequences. In some embodiments, the endogenous gene-transgene fusion is located at the endogenous locus within the cell while in other embodiments, the endogenous sequence-transgene coding sequence is inserted into another locus within a genome (e.g., a GLA-transgene sequence inserted into an albumin, HPRT or CCR5 locus). In some embodiments, the GLA transgene is expressed such that a therapeutic α-GalA protein product is retained within the cell (e.g., precursor or mature cell). In other embodiments, the GLA transgene is fused to the extracellular domain of a membrane protein such that upon expression, a transgene α-GalA fusion will result in the surface localization of the therapeutic protein. In some aspects, the extracellular domain is chosen from those proteins listed in Table 1. In some aspects, the edited cells further comprise a trans-membrane protein to traffic the cells to a particular tissue type. In one aspect, the trans-membrane protein comprises an antibody, while in others, the trans-membrane protein comprises a receptor. In certain embodiments, the cell is a precursor (e.g., CD34+ or hematopoietic stem cell) or mature RBC (descended from a genetically modified GAL-producing cell as described herein). In some aspects, the therapeutic α-GalA protein product encoded on the transgene is exported out of the cell to affect or be taken up by cells lacking the transgene. In certain embodiments, the cell is a liver cell which releases the therapeutic α-GalA protein into the blood stream to act on distal tissues (e.g., kidney, spleen, heart, brain, etc.). The invention also supplies methods and compositions for the production of a cell (e.g., RBC) carrying an α-GalA therapeutic protein for treatment of Fabry disease that can be used universally for all patients as an allogenic product. This allows for the development of a single product for the treatment of patients with Fabry disease, for example. These carriers may comprise trans-membrane proteins to assist in the trafficking of the cell. In one aspect, the trans-membrane protein comprises an antibody, while in others, the trans-membrane protein comprises a receptor. In one embodiment, the GLA transgene is expressed from the albumin promoter following insertion into the albumin locus. The biologic encoded by the GLA transgene then may be released into the blood stream if the transgene is inserted into a hepatocyte in vivo. In some aspects, the GLA transgene is delivered to the liver in vivo in a viral vector through intravenous administration. In some embodiments, the donor GLA transgene comprises a Kozak consensus sequence prior to the α-GalA coding sequence (Kozak (1987) Nucl Acid Res 15(20):8125-48), such that the expressed product lacks the albumin signal peptide. In some embodiments, the donor α-GalA transgene contains an alternate signal peptide, such as that from the Albumin, IDS or F9 genes, in place of the native GLA signal sequence. Thus, the donor may include a signal peptide as shown in any of SEQ ID NO:1 to 5 or a sequence exhibiting homology to these sequences that acts as a signal peptide (see e.g. FIGS. 1B, 10, 13 and 25 ). In some embodiments, the GLA transgene donor is transfected or transduced into a cell for episomal or extra-chromosomal maintenance of the transgene. In some aspects, the GLA transgene donor is maintained on a vector comprising regulatory domains to regulate expression of the transgene donor. In some instances, the regulatory domains to regulate transgene expression are the domains endogenous to the transgene being expressed while in other instances, the regulatory domains are heterologous to the transgene. In some embodiments, the GLA transgene is maintained on a viral vector, while in others, it is maintained on a plasmid or mini circle. In some embodiments, the viral vector is an AAV, Ad or LV. In further aspects, the vector comprising the transgene donor is delivered to a suitable target cell in vivo, such that the α-GalA therapeutic protein encoded by the transgene donor is released into the blood stream when the transgene donor vector is delivered to a hepatocyte. In another embodiment, the invention describes precursor cells (muscle stem cells, progenitor cells or CD34+ hematopoietic stem cell (HSPC) cells) into which the GLA transgene has been inserted such that mature cells derived from these precursors contain high levels of the α-GalA product encoded by the transgene. In some embodiments, these precursors are induced pluripotent stem cells (iPSC). In some embodiments, the methods of the invention may be used in vivo in transgenic animal systems. In some aspects, the transgenic animal may be used in model development where the transgene encodes a human α-GalA protein. In some instances, the transgenic animal may be knocked out at the corresponding endogenous locus, allowing the development of an in vivo system where the human protein may be studied in isolation. Such transgenic models may be used for screening purposes to identify small molecules, or large biomolecules or other entities which may interact with or modify the human protein of interest. In some aspects, the GLA transgene is integrated into the selected locus (e.g., highly expressed or safe-harbor) into a stem cell (e.g., an embryonic stem cell, an induced pluripotent stem cell, a hepatic stem cell, a neural stem cell etc.) or non-human animal embryo obtained by any of the methods described herein and those standard in the art, and then the embryo is implanted such that a live animal is born. The animal is then raised to sexual maturity and allowed to produce offspring wherein at least some of the offspring comprise the integrated GLA transgene. In a still further aspect, provided herein is a method for site specific integration of a nucleic acid sequence into an endogenous locus (e.g., disease-associated, highly expressed such as an albumin locus in a liver cell or globin locus in RBC precursor cells of a chromosome, for example into the chromosome of a non-human embryo. In certain embodiments, the method comprises: (a) injecting a non-human embryo with (i) at least one DNA vector, wherein the DNA vector comprises an upstream sequence and a downstream sequence flanking the α-GalA encoding nucleic acid sequence to be integrated, and (ii) at least one polynucleotide molecule encoding at least one nuclease (zinc finger, ZFN pair, TALE nuclease, TALEN pair or CRISPR/Cas system) that recognizes the site of integration in the target locus, and (b) culturing the embryo to allow expression of the nuclease (ZFN, TALEN, and/or CRISPR/Cas system, wherein a double stranded break introduced into the site of integration by the nuclease is repaired, via homologous recombination with the DNA vector, so as to integrate the nucleic acid sequence into the chromosome. In some embodiments, the polynucleotide encoding the nuclease is an RNA. In any of the previous embodiments, the methods and compounds of the invention may be combined with other therapeutic agents for the treatment of subjects with Fabry disease. In some embodiments, the methods and compositions include the use of a molecular chaperone (Hartl et al (2011) Nature 465: 324-332) to insure the correct folding of the Fabry protein. In some aspects, the chaperone can be chosen from well-known chaperone proteins such as AT1001 (Benjamin et al (2012) Mol Ther 20(4):717-726), AT2220 (Khanna et al (2014) PLoS ONE 9(7): e102092, doi:10.1371), and Migalastat (Benjamin et al (2016) Genet Med doi: 10.1038/gim.2016.122). In some aspects, the methods and compositions are used in combination with methods and compositions to allow passage across the blood brain barrier. In other aspects, the methods and compositions are used in combination with compounds known to suppress the immune response of the subject. A kit, comprising a nuclease system and/or a GLA donor as described herein is also provided. The kit may comprise nucleic acids encoding the one or more nucleases (ZFNs, ZFN pairs, TALENs, TALEN pairs and/or CRISPR/Cas system), (e.g. RNA molecules or the ZFN, TALEN, and/or CRISPR/Cas system encoding genes contained in a suitable expression vector), donor molecules, expression vectors encoding the single-guide RNA suitable host cell lines, instructions for performing the methods of the invention, and the like. These and other aspects will be readily apparent to the skilled artisan in light of disclosure as a whole. | A61K480058 | 20171019 | 20180503 | 60063.0 | A61K4800 | 0 | GALISTEO GONZALE, ANTONIO | METHODS AND COMPOSITIONS FOR THE TREATMENT OF FABRY DISEASE | SMALL | 0 | PENDING | A61K | 2,017 |
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15,788,510 | PENDING | METHOD OF PROVIDING EXTERNAL DEVICE LIST AND IMAGE DISPLAY DEVICE | An image display device including a display; a first external interface configured to receive a first image signal input from a first external device connected to the image display device; a second external interface configured to receive a second image signal input from a second external device connected to the image display device; and a controller coupled with the display, the first external interface and the second external interface, the controller configured to display a plurality of external device icons, on a first area of the display, wherein the plurality of external device icons include a first external device icon corresponding to the first external device and a second external device icon corresponding the second external device, and display, on a second area of the display, a first image based on the first image signal in response to the first external device icon being selected if the first external device is connected to the image display device. The controller is further configured to display a symbol representing that the first external device or the second external device is connected to the display device. | 1. An image display device comprising: a display; a first external interface configured to receive a first image signal input from a first external device connected to the image display device; a second external interface configured to receive a second image signal input from a second external device connected to the image display device; and a controller coupled with the display, the first external interface and the second external interface, the controller configured to: display a plurality of external device icons, on a first area of the display, wherein the plurality of external device icons include a first external device icon corresponding to the first external device and a second external device icon corresponding the second external device, and display, on a second area of the display, a first image based on the first image signal in response to the first external device icon being selected if the first external device is connected to the image display device, wherein the controller is further configured to display a symbol representing that the first external device or the second external device is connected to the display device. 2. The image display device according to claim 1, wherein the controller is further configured to: highlight the first external device icon in response to the first external device icon being selected, and highlight the second external device icon in response to the second external device icon being selected. 3. The image display device according to claim 1, wherein the first image displayed on the display is simultaneously displayed with the plurality of external device icons while the first external device icon is selected. 4. The image display device according to claim 1, wherein the first and second external device icons are selectable via a cursor positioned on the first and second external device icons, respectively. 5. The image display device according to claim 4, wherein the cursor is controlled by a remote controller interfacing with the image display device. 6. The image display device according to claim 1, wherein the first image is an image which is currently displayed on the first external device. 7. The image display device according to claim 1, wherein the controller is further configured to display a default image identifying the first external interface. 8. The image display device according to claim 1, wherein the controller is further configured to display the symbol on the first external device icon or the second external device icon. 9. The image display device according to claim 1, wherein the controller is further configured to: display, on the second area of the display, a second image based on the second image signal in response to the second external device icon being selected if the second external device is connected to the image display device. 10. The image display device according to claim 1, wherein the controller is further configured to: transmit a control command for controlling the first external device to the first external device, and display an execution result of the control command on the display. | CROSS-REFERENCE TO RELATED APPLICATIONS This application is a Continuation of co-pending U.S. application Ser. No. 15/390,198, filed on Dec. 23, 2016, which is a Continuation of U.S. application Ser. No. 13/535,735, filed on Jun. 28, 2012 (now U.S. Pat. No. 9,532,102), which claims priority under 35 U.S.C. §119(a) and 35 U.S.C. §365 to Application No. 10-2011-0088863, filed in Republic of Korea on Sep. 2, 2011, all of which are hereby expressly incorporated by reference into the present application. BACKGROUND The present invention relates to an image display device, and more particularly, to a method for providing a list of external devices thereof. Recently, digital TV services using a wire or wireless communication network are becoming more common. The digital TV services provide various services that typical analog broadcasting services cannot provide. For example, an Internet Protocol Television (IPTV) service (i.e., one type of the digital TV services) provides interaction through which a user may actively select kinds of watching programs and watching time. The IPTV service may provide various additional services such as internet search, home shopping, and online game on the basis of the interaction. SUMMARY Embodiments provide a method of providing an external device list, which allows a user to recognize an input switch in advance before an image signal of an external device, which is applied to an image display device, is switched for input, and an image display device thereof. In one embodiment, a method of providing an external device list to an image display device includes: displaying a plurality of external device icons connectible to the image display device; positioning a pointer on a first external device icon among the plurality of external device icons; and displaying on a screen of the image display device an image signal of an external device corresponding to the first external device icon having the pointer thereon. In another embodiment, an image display device includes: a display unit displaying a plurality of external device icons connectible to the image display device; and a control unit performing a control to display an image signal of an external device corresponding to a first external device icon having a pointer thereon when the pointer is positioned on the first external device icon among the plurality of external device icons. The details of one or more embodiments are set forth in the accompanying drawings and the description below. Other features will be apparent from the description and drawings, and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a view illustrating a configuration of a broadcast system according to an embodiment. FIG. 2 is a view illustrating a configuration of a broadcast system according to another embodiment. FIG. 3 is a view illustrating a method for transmitting/receiving data between an image display device and a service provider according to an embodiment. FIG. 4 is a block diagram illustrating a configuration of an image display device according to an embodiment. FIG. 5 is a block diagram illustrating a configuration of an image display device according to another embodiment. FIG. 6 is a view illustrating a platform structure of an image display device according to embodiments. FIG. 7 is a view illustrating a method of controlling an operation of an image display device by using a remote control device according to an embodiment. FIG. 8 is a block diagram illustrating a configuration of a remote control device according to an embodiment. FIG. 9 is a view illustrating a configuration of a home screen displayed on an image display device according to an embodiment. FIG. 10 is a flowchart illustrating a method of providing an external device list according to a first embodiment. FIGS. 11 to 17 are views illustrating a screen that provides an external device list of an image display device according to the first embodiment. DETAILED DESCRIPTION OF THE EMBODIMENTS Hereinafter, a method for providing an external device list and an image display device thereof will be described in more detail with reference to the accompanying drawings. The image display device as an intelligent image display device having a computer supporting function in addition to a broadcasting receiving function further includes an internet function besides a solid broadcasting receiving function so that it may have an easy to use interface such as a handwriting input device, a touch screen, or a space remote controller. Moreover, after accessing internet and a computer with a wire or wireless internet supporting function, a function for e-mail, web browsing, banking, or game may be available. For such various functions, a standardized general OS may be used. Accordingly, the image display device according to an embodiment may perform user-friendly various functions because a variety of applications may be freely added or deleted on a general OS kernel. The image display device may be a network TV, HBBTV, and a smart TV, for a specific example, and may be applied to a smart phone, if necessary. Furthermore, although embodiments of the present invention will be described with reference to the accompanying drawings and contents therein, the present invention is not limited thereto. The terms used in this specification are selected from currently widely used general terms in consideration of functions of the present invention, but may vary according to the intentions or practices of those skilled in the art or the advent of new technology. Additionally, in certain cases, there may be terms that an applicant may arbitrarily select, and in this case, their meanings are described below. Accordingly, the terms used in this specification should be interpreted on the basis of substantial implications that the terms have and the contents across this specification not the simple names of the terms FIG. 1 is a view illustrating a configuration of a broadcasting system, that is, a schematic view illustrating an entire broadcasting system including an image display device according to an embodiment. Referring to FIG. 1, the broadcasting system includes a Content Provider (CP) 10, a Service Provider (SP) 20, a Network Provider (NP) 30 and a Home Network End User (HNED) 40. The FINED 40 may correspond to a client 100, i.e., the image display device according to an embodiment, and for example, the client 100 may be a network TV, a smart TV, and an IPTV. Moreover, the CP 10 manufactures and provides various contents. As shown in FIG. 1, the CP 10 may be a terrestrial broadcaster, a cable System Operator (SO), a Multiple System Operator (MSO), a satellite broadcaster, or an Internet broadcaster. Additionally, the CP 10 may provide various applications besides the broadcast contents. This will be described in more detail later. The SP 20 may package contents that the CP 10 provides, and provides the packaged contents as services. For example, the SP 20 may package first terrestrial broadcast, second terrestrial broadcast, cable MSO, satellite broadcast, various internet broadcasts, and applications, and then, provide them to a user. Moreover, the SP 20 may provide services to the client 100 through a unicast or multicast method. The unicast method is a 1:1 data transmission method between one transmitter and one receiver. For example, in the case of the unicast method, when a receiver requests data to a server, the server transmits the requested data to the receiver in response to the request. The multicast method is to transmit data to a plurality of receivers in a specific group. For example, a server may transmit data to a plurality of pre-registered receivers simultaneously. In order for such a multicast registration, an Internet Group Management Protocol (IGMP) may be used. The NP 30 may provide a network to provide the service to the client 100, and the client 100 may establish a Home Network End User (HNED) to receive the service. Conditional Access or Content Protection may be used as a means to protect contents transmitted from the system. As examples of the Conditional Access or Content Protection, methods such as CableCARD and Downloadable Conditional Access System (DCAS) may be used. Moreover, it is possible for the client 100 to provide contents via a network. In this case, the client 100 may become a CP, and the CP 10 may receive contents from the client 100. Accordingly, a bidirectional contents service or data service may be available. According to an embodiment, the CP 10 may provide a network service such as a Social Network Site (SNS), a blog, a micro blog, or an instant messenger. For example, the CP 10 providing the SNS service may include a server (not shown) storing various kinds of contents such as texts or uploaded images that a plurality of users create in the SNS. In more detail, a user accesses the server of the CP 10 providing the SNS service by using an image display device, and designates accounts that the user wants, so that the user may confirm messages created by the plurality of the designated accounts. Additionally, if a user requests the SNS service, an image display device, i.e., the client 100, accesses the server of the CP 10 in order to receive the messages of the designated accounts, and then, displays the received messages sequentially in order of a corresponding message created, for example, displays them in a top to bottom direction. Referring to FIG. 2, the image display device 100 corresponding to the client of FIG. 1 may be connected to a broadcasting network and internet network. For example, the image display device 100 may include a broadcast interface 101, a section filter 102, an AIT filter 103, an application data processor 104, a broadcast data processor 105, a media player 106, an internet protocol processor 107, an internet interface 108, and a runtime module 109. Moreover, the broadcast interface 101 of the image display device 100 may receive Application Information Table (AIT) data, real time broadcast content, application data or a stream event. The real time broadcast content may be Linear A/V Content. The section filter 102 performs section filtering on four data received through the broadcast interface 101 in order to transmit AIT data into the AIT filter 102, linear A/V content into the broadcast data processor 105, and stream event and application data into the application data processor 104. The internet interface 108 may receive Non-Linear A/V content and application data. For example, the Non-Linear A/V content may be Content On Demand (COD) application. Furthermore, the Non-Linear A/V content may be transmitted to the media player 106, and the application data may be transmitted to the runtime module 109. Additionally, the runtime module 109 may include an application manager and a browser. The application manager may control a life cycle on interactive application by using AIT data, and the browser may display and process the interactive application FIG. 3 is a view illustrating a method for transmitting/receiving data between an image display device and a SP according to an embodiment. Referring to FIG. 3, the SP performs a service provider discovery operation in operation S301. The image display device transmits a SP Attachment Request signal in operation S302. Once the SP attachment is completed, the image display device receives provisioning information in operation S303. Furthermore, the image display device receives a master SI table from the SP in operation S304, a Virtual Channel Map table in operation S305, a Virtual Channel Description table in operation S306, and a Source table in operation S307. For example, the service provider discovery operation may refer to a process that SPs providing IPTV related services search for a server that provides information on the services that the SPs provide. A method of searching for an address list that helps receiving information on a Service Discovery (SD) server, for example, SP discovery information, may be the following three methods. First, an address preset in an image display device or an address manually set by a user may be used. Second, a DHCP based SP discovery method may be used. Third, a DNS SRV-based SP discovery method may be used. Moreover, the image display device accesses a server having an address obtained by one of the three methods in order to receive a service provider discovery record that contains information necessary for service discovery for each SP, and performs a service search operation by using the received service provider discovery record. Moreover, the above processes may be available in a push mode or a pull mode. Furthermore, the image display device accesses a SP attachment server designated as a SP attachment locator of a SP discovery record, and performs a registration procedure (or a service attachment procedure). Moreover, the image display device accesses an authentication service server of the SP designated as the SP authentication locator to perform an additional authentication procedure, and then, performs a service authentication procedure. After the service attachment procedure is successful, data transmitted from the server to the image display device may have a form of a provisioning information table. During the service attachment operation, the image display device includes its ID and position information in data that are transmitted to the server, and a service attachment server may specify a service that the image display device subscribes on the basis of the data. Address information used for obtaining Service Information that the image display device wants to receive may be provided in a form of the provisioning information table. In addition, the address information may correspond to access information on the master SI table. In this case, providing a customized service for each subscriber may be easy. Moreover, the Service Information may include a master SI table record for managing access information on a virtual channel map and its version, a virtual channel map table for providing a service list in a package form, a virtual channel description table including detailed information of each channel, and a source table including access information for accessing an actual service. FIG. 4 is a block diagram illustrating a configuration of an image display device according to an embodiment. Referring to FIG. 4, the image display device 100 includes an Network Interface 111, a TCP/IP Manager 112, a Service Delivery Manager 113, a Demux 115, a PSI&(PSIP and/or SI) decoder 114, an Audio Decoder 116, a Video Decoder 117, a Display A/V and OSD Module 118, a Service Control Manager 119, a Service Discovery Manager 120, a Metadata Manager 122, an SI&Metadata DB 121, a UI manager 124, and a service manager 123. The network interface 111 receives or transmits packets from or to a network. That is, the network interface unit 111 may receive services and contents from a SP via a network. The TCP/IP manager 112 may be involved in delivering packets from a source to a destination, which are received and transmitted by the image display device 100. Moreover, the TCP/IP manager 112 classifies the received packets in order correspond to a proper protocol, and outputs the classified packets into the service delivery manager 113, the service discovery manager 120, the service control manager 119, and the metadata manager 122. Additionally, the service delivery manager 113 is responsible for controlling the received service data. For example, when the service delivery manager 113 controls real-time streaming data, RTP/RTCP may be used. When the real-time streaming data are transmitted using the RTP, the service delivery manager 113 parses the received data packet according to the RTP and transmits the parsed data to the Demux 115, or stores the received data packet in the SI&Metadata DB 121. Moreover, the service delivery manager 113 may feed back the network reception information to a server that provides services by using the RTCP. The Demux 115 demultiplexes the received packet into audio, video, and Program Specific Information (PSI) data in order to transmit them into the audio/video decoders 116 and 117 and the PSI&(PSIP and/or SI) Decoder 114. The PSI&(PSIP and/or SI) Decoder 114 may decode service information such as PSI, and for example, may receive a PSI section, a Program and Service Information Protocol (PSIP) section, or a Service Information (SI) section demultiplexed in the Demux 115 in order to decode them. Moreover, the PSI&(PSIP and/or SI) Decoder 114 may decode the received sections to create a database for service information, and the service information may be stored in the SI&Metadata DB 121. The audio/video decoders 116 and 117 may decode vide data and audio data received from the Demux 115, and the decoded audio and video data may be provided to a user through the Display A/V and OSD Module 118. Moreover, the UI manager 124 and the service manager 123 may manage an overall status of the image display device 100, provide a user interface, and mange another manager. For example, the UI manager 124 provides a Graphic User Interface (GUI) for a user through an On Screen Display (OSD), and receives a key input from a user in order to perform an operation of a receiver according to the key input. Moreover, when receiving a key input signal for a channel selection from a user, the UI manager 124 may transmit the key input signal to the service manager 123. The service manager 123 may control a service related manager such as the service delivery manager 113, the service discovery manager 120, the service control manager 119, and the metadata manager 122. Additionally, the service manager 123 creates a channel map, and selects a channel by using the channel map according to a key input received from the UI manager 124. And, the service manager 123 receives service information on a channel from the PSI&(PSIP and/or SI) Decoder 114, and sets audio/video Packet Identifier (PID) of the selected channel in the Demux 115. The service discovery manager 120 provides information necessary for selecting s SP that provides service. For example, on receiving a signal on channel selection from the service manager 123, the service discovery manager 120 may find a service by using the received signal. Moreover, the service control manager 119 is responsible for service selection and control. For example, when a user selects a Live Broadcasting service like a typical broadcasting method, IGMP or RTSP is used. When a service such as Video On Demand (VOD) is selected, RTSP is used for service selection and control. The RTSP protocol provides a trick mode with respect to real-time streaming. The service control manager 119 may initialize and manage a section passing through an IMC gateway by using an IP Multimedia Subsystem (IMS) and a Session Initiation Protocol (SIP). The metadata manager 122 manages service related metadata and stores the metadata in the SI&Metadata DB 121. And, the SI&Metadata DB 121 may store the service information decoded by the PSI&(PSIP and/or SI) Decoder 114, the metadata that the metadata manager 122 manages, and the information necessary for selecting a SP that the service discovery manager 120 provides. Furthermore, the SI&Metadata DB 121 may store setup data on a system, and for example, may be implemented using NonVolatile RAM (NVRAM) or flash memory. Additionally, an IG 750 may be a gateway including functions necessary for accessing an IMS based IPTV service. FIG. 5 is a block diagram illustrating a configuration of an image display device according to another embodiment. Referring to FIG. 5, the image display device 100 may include a broadcast receiving unit 130, an external device interface unit 135, a storage unit 140, a user input interface unit 150, a control unit 170, a display unit 180, an audio output unit 185, and a power supply unit 190. Moreover, the broadcast receiving unit 130 may include a tuner 131, a demodulation unit 132, and a network interface unit 133. The tuner 131 may select a channel selected by a user among Radio Frequency (RF) broadcast signals received through an antenna, or an RF broadcast signal corresponding to all pre-stored channels, and may convert the selected RF broadcast signal into an intermediate frequency signal or a baseband image or sound signal. For example, the tuner 131 converts the selected RF broadcast signal into a digital IF signal DIF if it is a digital broadcast signal, or into an analog baseband image or sound signal CVBS/SIF if it is an analog broadcast signal. That is, the tuner 131 may process both a digital broadcast signal and an analog broadcast signal, and the analog baseband image or sound signal CVBS/SIF outputted from the tuner 131 may be directly inputted to the control unit 170. Moreover, the tuner 131 may receive an RF broadcast signal of a single carrier according to the Advanced Television System Committee (ATSC) format or an RF broadcast signal of a plurality of carriers according to the Digital Video Broadcasting (DVB) format. Furthermore, the tuner 131 may sequentially select RF broadcast signals of all broadcast channels stored through a channel memory function from RF broadcast signals received through an antenna, and then, may convert the selected RF broadcast signals into an intermediate frequency signal or a baseband image or sound signal. The demodulation unit 132 may receive the digital IF signal DIF converted by the tuner 131, and then, may perform a demodulation operation thereon. For example, if the digital IF signal outputted from the tuner 131 is the ATSC format, the demodulator 132 may perform an 8-Vestigal Side Band (8-VSB) demodulation. Additionally, the demodulation unit 132 may perform channel decoding, and for this, may include a Trellis Decoder, a De-interleaver, and a Reed Solomon Decoder to perform Trellis decoding, de-interleaving, and Reed Solomon decoding. For example, if the digital IF signal outputted from the tuner 131 is the DVB format, the demodulation unit 132 may perform Coded Orthogonal Frequency Division Modulation (COFDMA) modulation. Additionally, the demodulation unit 132 may perform channel decoding, and for this, may include a convolution decoder, a De-interleaver, and a Reed Solomon Decoder to perform convolutional decoding, de-interleaving, and Reed Solomon decoding. The demodulation unit 132 may output a stream signal TS after performing demodulation and channel decoding, and the stream signal may be a signal into which an image signal, sound signal, or a data signal is multiplexed. For example, the stream signal may be an MPEG-2 Transport Stream (TS) into which an MPEG-2 standard image signal and a Dolby AC-3 standard sound signal are multiplexed. In more detail, the MPEG-2 TS may include a 4 byte header and a 184 byte payload. Furthermore, the demodulation unit 132 may include an ATSC demodulation unit and a DVB demodulation unit separately according to the ATSC format and the DVB format. The stream signal outputted from the demodulation unit 132 may be inputted to the control unit 170. The control unit 180 may output an image to the display unit 180 and a sound to the audio output unit 185 after demultiplexing and processing an image/sound signal. The external device interface unit 135 may connect an external device with the image display device 100, and for this, may include an A/V input/output unit (not shown) or a wireless communication unit (not shown). The external device interface unit 135 may be used for wire/wireless connection of an external device such as a Digital Versatile Disk (DVD) player, a Blueray player, a game console, a camera, a camcorder, and a computer (such as a notebook computer). Moreover, the external device interface unit 135 may deliver an image, sound, or data signal inputted from a connected external into the control unit 170 of the image display device 100, and may output the image, sound, or data signal processed in the control unit 170 into the connected external device. The A/V input/output unit may include a USB terminal, a Composite Video Banking Sync (CVBS) terminal, a component terminal, an S-video terminal (i.e., an analog type), a Digital Visual Interface (DVI) terminal, a High Definition Multimedia Interface (HDMI) terminal, an RGB terminal, and a D-SUB terminal, in order to input an image and sound signal of an external device into the image display device 100. Furthermore, the wireless communication unit may perform a short-range wireless communication with another electronic device. For example, the image display device 100 and another electronic device may be connected to a network through communication standards such as Bluetooth, Radio Frequency Identification (RFID), infrared Data Association (IrDA), Ultra Wideband (UWB), ZigBee, and Digital Living Network Alliance (DLNA). Moreover, the external device interface unit 135 is connected to various set top boxes through at least one of the above various terminals in order to perform an input/output operation of a set top box. In addition, the external device interface unit 135 may receive applications or lists of applications in an adjacent external device, and then may deliver them to the control unit 170 or the storage unit 140. The network interface unit 133 may provide an interface for connecting the image display device 100 to a wire/wireless network including an internet network. For example, the network interface unit 133 may include an Ethernet terminal for accessing a wired network or may be connected to a wireless network through a communication standard such as Wireless LAN (WLAN) such as Wi-Fi, Wireless broadband (Wibro), World Interoperability for Microwave Access (Wimax), and High Speed Downlink Packet Access (HSDPA). Moreover, the network interface unit 133 may transmit/receive data to/from another user or another electronic device via a connected network or another network linked to the connected network. Additionally, the network interface unit 133 may transmit some contents data stored in the image display device 100 to a selected user or electronic device among users or other electronic devices pre-registered in the image display device 100. The network interface unit 133 may access a predetermined web page via a connected network or another network linked to the connected network. That is, the network interface unit 133 may access a predetermined web page via a network to transmit/receive data to/from a corresponding sever. Then, the network interface unit 133 may receive contents or data provided from a CP or a network operator. That is, the network interface unit 133 may receive contents such as movies, advertisings, games, VODs, and broadcast signals and information thereon, which are provided from a CP or an NP via a network. Additionally, the network interface unit 133 may receive update information and update files of a firmware provided from a CP or a network operator, and may transmit data to an internet provider, a CP, or a network operator. The network interface unit 133 may select and receive a wanted application from applications open to air via a network. The storage unit 140 may store a program for processing and controlling each signal in the control unit 170, and may store the processed image, sound or data signals. Moreover, the storage unit 140 may perform a function for temporarily storing image, sound or data signals inputted from the external device interface unit 135 or the network interface unit 133, and may store information on a predetermined broadcast channel through a channel memory function. The storage unit 140 may store applications or lists of applications inputted from the external device interface unit 135 or the network interface unit 133. The storage unit 140 may include a storage medium having at least one type of a flash memory type, a hard disk type, a multimedia card micro type, a card memory type (for example, SD or XD memory), a RAM type, and an EEPROM type. The image display device 100 may play contents files stored in the storage unit 140 such as movie files, still image files, music files, document files, and application files and may provide them to a user. The user input interface unit 150 may deliver a signal that a user inputs to the control unit 170 or may deliver a signal from the control unit 170 to a user. For example, the user input interface unit 150 may receive a control signal such as power on/off, channel selection, and screen setting from a remote control device 200 and may process the received control signal according to various communication methods such as an RF communication method or an IR communication method. Or, the user input interface unit 150 may transmit a control signal from the control unit 170 to the remote control device 200. Additionally, the user input interface unit 150 may deliver to the control unit 170 a control signal inputted from a local key (not shown) such as a power key, a channel key, a volume key, and a setting key. For example, the user input interface unit 150 may deliver to the control unit 170 a control signal inputted from a sensing unit (not shown) that senses a gesture of a user, and may transmit a signal from the control unit 170 to a sensing unit (not shown). Moreover, the sensing unit (not shown) may include a touch sensor, a sound sensor, a position sensor, and a motion sensor. The control unit 170 may demultiplex a stream inputted from the tuner 131, the demodulation unit 132, or the external device interface unit 135, or may process demultiplexed signals in order to generate and output a signal for image or sound output. The image signal processed in the control unit 170 is inputted to the display unit 180, and then, is displayed as an image corresponding to a corresponding image signal. Additionally, the image signal processed in the control unit 170 is inputted to an external output device through the external device interface unit 135f. The sound signal processed in the control unit 170 may be outputted to the audio output unit 185 as audio. Moreover, the sound signal processed in the control unit 170 is inputted to an external output device through the external device interface unit 135. Although not shown in FIG. 6, the control unit 170 may include a demultiplexing unit and an image processing unit. This will be described below with reference to FIG. 10. Besides that, the control unit 170 may control overall operations of the image display device 100. For example, the control unit 170 controls the turner 131 to tune an RF broadcast corresponding to a channel that a user selects or a pre-stored channel. Additionally, the control unit 170 may control the image display device 100 through a user command inputted through the user input interface unit 150 or an internal program, and may access a network to download applications that a user wants or lists of applications into the image display device 100. For example, the control unit 170 controls the tuner 131 to receive a signal of a selected channel according to a predetermined channel selection command received through the user input interface unit 150, and may process an image, sound, or data signal of the selected channel. The control unit 170 may output channel information that a user selects in addition to a processed image or sound signal through the display unit 180 or the audio output unit 185. Moreover, the control unit 170 may output an image or sound signal of an external device such as a camera or a camcorder, which is inputted through the external device interface unit 135, through the display unit 180 or the audio output unit 185 according to an external device image play command received through the user input interface unit 150. Furthermore, the control unit 170 may control the display unit 180 to display an image, and for example, the control unit 170 may control the display unit 180 to display a broadcast image inputted through the tuner 131, an external input image inputted through the external device interface unit 135, an image inputted through a network interface unit, or an image stored in the storage unit 140. In this case, an image displayed on the display unit 180 may be a still or moving image or a 2D or 3D image. Additionally, the control unit 170 may play contents stored in the image display device 100, received broadcast contents, or external input contents inputted from an external. The contents may have various formats such as a broadcast image, an external input image, an audio file, a sill image, an accessed web page, and a document file. Moreover, although not shown in FIG. 5, the image display device 100 may further include a channel browsing processing unit for generating a thumbnail image corresponding to a channel signal or an external input signal. The channel browsing processing unit receives a stream signal TS outputted from the demodulation unit 132, or a stream signal outputted from the external device interface unit 135, and extracts an image from the inputted stream signal to generate a thumbnail image. The generated thumbnail image may be inputted to the control unit 170 as it is or after being encoded, or may be inputted to the control unit 170 after being encoded into a stream format. The control unit 170 may display a thumbnail list including a plurality of thumbnail images on the display unit 180 by using the inputted thumbnail image. The plurality of thumbnail images in the thumbnail list may be sequentially or simultaneously updated. Accordingly, a user may simply recognize contents of a plurality of broadcast channels. The display unit 180 converts an image signal, a data signal, and an OSD signal processed in the control unit 170, or an image signal and a data signal received in the external device interface unit 135 into R, G, and B signals in order to generate a driving signal. For this, the display unit 180 may include a PDP, an LCD, an OLED, a flexible display, and a 3D display, or may include a touch screen used as an input device in addition to an output device. The audio output unit 185 receives a signal sound-processed in the control unit 170, for example, a stereo signal, a 3.1 channel signal, or a 5.1 channel signal, and then, outputs the signal as sound. For this, various types of speakers may be used. Moreover, the image display device 100 may further include a capturing unit (not shown) for capturing an image of a user, and image information obtained by the capturing unit (not shown) may be inputted to the control unit 170. In this case, the control unit 170 may detect a user's gesture by combining an image captured through the capturing unit (not shown) and a signal detected through a sensing unit (not shown) or using it separately. The power supply unit 190 supplies corresponding power to the image display device 100 generally. For example, the power supply unit 190 may supply power to the control unit 170, the display unit 180, and the audio output unit 185, which may be realized in a form of a System On Chip (SOC). For this, the power supply unit 190 may include a converter (not shown) for converting AC power into DC power. If the display unit 180 is implemented using a liquid crystal panel including a plurality of backlight lamps, the power supply unit 190 may further include an inverter (not shown) for PWM operation in order to provide brightness adjustment and dimming driving. The remote control device 200 transmits a user input to the user input interface unit 150. For this, the remote control device 200 may use Bluetooth, Radio Frequency (RF) communication, IR communication, Ultra Wideband (UWB), or ZigBee. Additionally, the remote control device 200 receives an image, sound, or data signal outputted from the user input interface unit 150, and then, displays the received signal or outputs sound or vibration. The image display device 100 may be a fixed digital broadcast receiver that receives at least one of an ATSC type (8-VSB type) digital broadcast, a DVB-T type (COFDM type) digital broadcast, and an ISDB-T type (BST-OFDM type) digital broadcast. Moreover, since the image display device 100 of FIG. 5 is just one embodiment of the present invention, some components shown herein may be integrated, added, or omitted according to the specification of the actually-realized image display device 100. That is, more than two components may be integrated into one component, or one component may be divided into more than two components, if necessary. Furthermore, a function in each block is used for describing an embodiment of the present invention, and its specific operation or device does not limit the scope of the present invention. According to another embodiment of the present invention, unlike FIG. 5, the image display device 100 may receive an image through the network interface unit 133 or the external device interface unit 135 and may play the received image without the tuner 131 and the demodulation unit 132 For example, the image display device 100 may include an image processing device such as a set top box for receiving broadcast signals or contents according to various network services and a contents playing device for playing contents inputted from the image processing device. In this case, a method of providing an external device list according to an embodiment may be performed by the above separated image processing device such as a set top box or the above separate contents playing device including the display unit 180 and the audio output unit 185 in addition to the image display device 100 described with reference to FIG. 5. FIG. 6 is a view illustrating a platform structure of an image display device. The platform of the image display device 100 may include OS-based software for performing the above various operations. Referring to FIG. 6A, the platform of the image display device 100 as a separate platform includes a Legacy System platform 400 and a smart system platform 405, which are separately designed. An OS kernel 410 may be commonly used in the Legacy System platform 400 and the smart system platform 405. The Legacy System platform 400 may include a driver 420, a Middleware 430, and an Application 450 on the OS kernel 410. Moreover, the smart system platform 405 may include a Library 435, a Framework 440, and an application 455 on the OS kernel 410. The OS kernel 410 as a core of an operating system may provide hardware driver driving when the image display device 100 is driven, the security of hardware and a processor in the image display device 100, efficient management of a system resource, memory management, an interface for hardware by hardware abstraction, a multi processor, schedule management according to a multi processor, and power management. For example, a hardware driver in the OS kernel 410 may include at least one of a display driver, a Wi-Fi driver, a Bluetooth driver, a USB driver, an audio driver, a power management driver, a binder driver, and a memory driver. Moreover, the hardware driver in the OS kernel 410 as a driver for a hardware device in the OS kernel 410 may include a character device driver, a block device driver, and a network device driver. Furthermore, the block device driver may include a buffer for storing a unit size as data are transmitted by a specific block unit, and the character device driver may not include the buffer as data are transmitted by a basic data unit, i.e., a character unit. The OS kernel 410 may be implemented with various OS based kernels such as Unix base (Linux) kernel and Window base kernel, and may be available for other electronic devices as an open OS. The driver 420 is disposed between the OS kernel 410 and the middleware 430, and drives a device in order for operations of the middleware 430 and the application 450. For example, the driver 420 may include drivers for a micom, a display module, a Graphic Processing Unit (GPU), a Frame Rate Converter (FRC), a General Purpose Input/Output Pin (GPIO), an HDMI, a System Decoder or demultiplexer (SDEC), a Video Decoder (VDEC), an Audio Decoder (ADEC), a Personal Video Recorder (PVR), an Inter-Integrated Circuit (I2C) in the image display device 100. The above drivers may operate in linkage with a hardware driver in the OS kernel 410. Additionally, the driver 420 may further include a driver for a remote control device 200, for example, a space remote controller. The driver for a space remote controller may be included in the OS kernel 410 or the middleware 430 in addition to the driver 420. The middleware 430 is disposed between the OS kernel 410 and the application 450, and serves as a medium to exchange data between other hardware or software. Accordingly, the standardized interface may be available, and various environmental supports and interworking with other tasks having different systems may also be available. For example, the middleware 430 in the legacy system platform 400 may include a Multimedia and Hypermedia information coding Experts Group (MHEG) middleware and an Advanced Common Application Platform (ACAP) middleware, and may further include a PSIP or SI middleware (i.e., a broadcast information related middleware), and a DLNA middleware (i.e., a peripheral communication related middleware). Additionally, the application 450 on the middleware 430, i.e., the application 450 in the legacy system platform 400, may include a User Interface Application for various menus in the image display device 100. The application 450 on the middleware 430 may be edited by a user's choice and may be updated via a network. Through the application 450, it is possible to enter a wanted menu in various user interfaces according to an input of a remote control device while watching a broadcast image. Moreover, the application 450 in the legacy system platform 400 may further include at least one of a TV guide application, a Bluetooth application, a reservation application, a Digital Video Recorder (DVR) application, and a hotkey application. Moreover, the library 435 in the smart system platform 405 is disposed between the OS kernel 410 and the framework 440, and forms a base of the Framework 440. For example, the library 435 may include a Secure Socket Layer (SSL) (i.e., a security related library), a WebKit (i.e., a web engine related library), a libc (i.e., a c library), and a Media Framework (i.e., a media related library such as video formats and audio formats. The library 435 may be programmed with C or C++, so that it may be exposed to developer through the framework 440. The library 435 may include the runtime 437 having a core java library and a Virtual Machine (VM). The runtime 437 may form a basic of the framework 440 in addition to the library 435. The VM may perform a plurality of instances, i.e., multitasking. Furthermore, according to each application in the application 455, each VM may be allocated and executed. In this case, a Binder driver (not shown) in the OS kernel 410 may operate for schedule adjustment or interconnect between plurality of instances. In addition, the binder driver and the runtime 437 may connect a java-based application with a C-based library. The library 436 and the runtime 437 may correspond to the middleware of the legacy system. Moreover, the framework 440 in the smart system platform 405 includes a program, which is a base of an application in the application 455. The framework 440 is compatible with any application. Its component may be reused, moved, or replaced. The framework 440 may include a support program, i.e., a program for binding components of other software. For example, the framework 440 may include a resource manager, an activity manager related to the activity of application, a notification manager, and a content provider for summarizing sharing information between applications. The application 455 on the framework 440 includes various programs that are driven in the image display device 100 to be displayed. For example, the application 455 may include a Core Application that has at least one of email, short message service (SMS), calendar, map, and browser. Furthermore, the above framework 440 or application 450 may be programmed with JAVA. In addition, the application 455 may be divided into an application 460 stored in the image display device 100 and cannot be deleted by a user and an application 475 downloaded via a network and stored and freely installed or deleted by a user. Through applications in the application 455, internet phone service, Video On Demand (VOD) service, web album service, Social Networking Service (SNS), Location Based Service (LBS), map service, web search service, and application search service may be provided. Additionally, various functions such as games and scheduling may be performed. Moreover, as shown in FIG. 6B, the platform of the image display device 100 as an integrated platform may include an OS kernel 510, a driver 520, a Middleware 530, a Framework 540, and an Application 550. When compared to FIG. 6A, there are differences that the library 435 is omitted and the application 550 is an integrated layer in the platform shown in FIG. 6B. Besides that, the driver 520 and the framework 540 are the same as those in FIG. 6A. The platforms shown in FIGS. 6A and 6B may be generally available for various electronic devices in addition to the image display device 100, and may be stored in or loaded into the storage unit 140 or control unit of FIG. 5, or an additional processor (not shown). Moreover, the platform may be stored in or installed into the SI&metadata DB 711, UI manager 714, and service manager 713 of FIG. 4, and may further include an additional application processor (not shown) to execute the application. Furthermore, a method of providing an external device list according to an embodiment, which will be described in detail below, may be implemented with a computer executable program. FIG. 7 is a view illustrating a method of providing an external device list through a remote control device according to an embodiment. As shown in FIG. 7A, a pointer 205 corresponding to the remote control device 200 is displayed on a display unit 180. A user may move the remote control device 200 up and down and left and right, or may rotate it. The pointer 205 displayed on the display unit 180 of the image display device corresponds to the movement of the remote control device 200. Since the corresponding pointer 205 moves and is displayed corresponding to the movement on 3D space as shown in the drawing, the remote control device 200 may be called a space remote controller. As shown in FIG. 7B, when a user moves the remote control device 200 to the left, the pointer 205 displayed on the display unit 180 of the image display device moves to the left in correspondence to the movement of the remote control device 200. Information on the movement of the remote control device 200, which is sensed by a sensor of the remote control device 200, is transmitted to the image display device. The image display device may calculate the coordinates of the pointer 205 from the information on the movement of the remote control device 200. The image display device may display the pointer 205 in correspondence to the calculated coordinates. FIG. 7C illustrates the case that a user moves the remote control device 200 away from the display unit 180 while a specific button in the remote control device 200 is pressed. By doing so, a selected area in the display unit 180 corresponding to the pointer 205 may be zoomed in and enlarged. On the contrary, when a user moves the remote control device 200 closer to the display unit 180, a selected area on the display unit 180 corresponding to the pointer 205 may be zoomed out and reduced. On the other hand, when the remote control device 200 becomes far from the display unit 180, a selected area may be zoomed out, and when the remote control device 200 becomes closer to the display unit 180, a selected area may be zoomed in. Moreover, while a specific button in the remote control device 200 is pressed, up/down and left/right movements may be disregarded. That is, when the remote control device 200 becomes closer to or away from the display unit 180, up/down and left/right movements may be disregarded but only the back and forth movements may be recognized. While a specific button in the remote control device 200 is not pressed, the pointer 205 moves in correspondence to the up/down and left/right movements of the remote control device 200. Moreover, the moving speed or moving direction of the pointer 205 may correspond to that of the remote control device 200. Furthermore, the pointer of this specification means an object displayed on the display unit 180 in correspondence to an operation of the remote control device 200. Accordingly, besides an arrow shape displayed as the pointer 205 in the drawing, the pointer 205 may have various shapes of objects. For example, the pointer 205 conceptually may include a dot, a cursor, and a thick outline. Moreover, the pointer 205 may be displayed on the display unit 180, corresponding to a point on the x-axis and the y-axis, and also a plurality of points such as a line and a surface. FIG. 8 is a block diagram illustrating a configuration of a remote control device according to an embodiment. The remote control device 200 may include a wireless communication unit 225, a user input unit 235, a sensor unit 240, an output unit 250, a power supply unit 260, a storage unit 270, and a control unit 280. Referring to FIG. 8, the wireless communication unit 225 transmits/receives a signal to/from an arbitrary one of the image display devices according to the above-mentioned embodiments. The remote control device 200 includes an RF module 221 for transmitting/receiving a signal to/from the image display device 100 according to RF communication standards, and an IR module 223 for transmitting/receiving a signal to/from the image display device 100 according to IR communication standards. Moreover, the remote control device 200 transmits a signal containing information on the movement thereof to the image display device 100 through the RF module 221. Moreover, the remote control device 200 may receive a signal that the image display device 100 transmits through the RF module 221, and may transmit commands on power on/off, channel change, and volume change to the image display device 100 through the IR module 223, if necessary. The user input unit 235 may be configured with a keypad, a button, a touch pad, or a touch screen. A user may input commands related to the image display device 100 to the remote control device 200 by manipulating the user input unit 235. If the user input unit 235 has a hard key button, a user may input commands related to the image display device 100 to the remote control device 200 through a push operation of the hard key button. If the user input unit 235 has a touch screen, a user may input commands related to the image display device 100 to the remote control device 200 by touching a soft key of the touch screen. Moreover, the user input unit 235 may include various kinds of input means that a user manipulates such as a scroll key and a jog key, and this embodiment does not limit the scope of the present invention. The sensor unit 240 may include a gyro sensor 241 or an acceleration sensor 243. The gyro sensor 241 may sense information on the movement of the remote control device 200. For example, the gyro sensor 241 may sense information on the operation of the remote control device 200 on the bases of x, y, and z axes and the acceleration sensor 243 may sense information on the moving speed of the remote control device 200. Furthermore, the remote control device 200 may further include a distance measurement sensor that senses the distance between the remote control device 200 and the display unit 180 of the image display device 100. The output unit 250 may output an image or sound signal corresponding to the manipulation of the user input unit 235 or a signal transmitted from the image display device 100. A user may recognize the manipulation of the user input unit 235 or the control of the image display device 100 through the output unit 250. For example, the output unit 250 may include an LED module that is turned on/off, a vibration module 253 that vibrates, a sound outputting module 255 that outputs sound, or a display module 257 that outputs an image, when the user input unit 235 is manipulated or a signal is transmitted to or received from the image display device 100 through the wireless communication unit 225. Moreover, the power supply unit 260 supplies power to the remote control device 200, and stops supplying power to the remote control device 200 when the remote control device 200 does not move for a predetermined time, so that power waste may be reduced. The power supply unit 260 may restart to supply power after a predetermined key in the remote control device 200 is manipulated. The storage unit 270 may store various kinds of programs and application data necessary for controls or operations of the remote control device 200. If the remote control device 200 wirelessly transmits and receives a signal through the image display device 100 and the RF module 221, the remote control device 200 and the image display device 100 may transmit/receive a signal in a predetermined frequency band. The control unit 280 of the remote control device 200 may store in the storage unit 270 information on a frequency band for wirelessly transmitting/receiving a signal to/from the image display device 100 paired with the remote control device 200, and may refer to the stored information. The control unit 280 controls general matters related to a control of the remote control device 200. The control unit 280 may transmit to the image display device 100 a signal corresponding to a predetermined key manipulation of the user input unit 235 or a signal corresponding to the movement of the remote control device 200 sensed by the sensing unit 240 through the wireless communication unit 225. FIG. 9 is a view illustrating a configuration of a home screen displayed on an image display device according to an embodiment. The configuration of the home screen shown in FIG. 9 may be an example of a basic screen of the image display device 100. Such a screen may be set with an initial screen when power is on or starting from a standby mode, or a basic screen by an operation of a home key equipped in the remote control device 200. Referring to FIG. 9, the home screen 600 may include a card object region. The card object region may include a plurality of card objects 610, 620, and 630, which are classified by the sources of contents. A card object BROADCAST 610 for displaying a broadcast image, a card object NETCAST 620 for displaying a CP list, and a card object APP STORE for displaying a list of applications provided are shown in the drawing. Moreover, as a card object that is not displayed on the display unit 180 and is disposed on a hidden area 601 but is replaced and displayed when a card object is moved, a card object CHANNEL BROWSER 640 for displaying a thumbnail list of broadcast channels, a card object TV GUIDE 650 for displaying a broadcast guide list, a card object RESERVATION/REC 660 for displaying a reservation list, a card object MY MEDIA 670 for displaying a media list of a device disposed in or connected to the image display device, and a card object TV GUIDE2 680 for displaying a broadcast guide list may be shown in the drawing. The card object BROADCAST 610 for displaying a broadcast image may include a broadcast image 615 received through the tuner 110 or the network interface unit 130, an object 612 for displaying corresponding broadcast image related information, an object 617 for displaying an external device, and a setup object 618. Since the broadcast image 615 is displayed as a card object and its size is fixed by a locking function, a user may continuously watch a broadcast image. The broadcast image 615 may have a size that is changed by the manipulation of a user. For example, the size of the corresponding broadcast image 615 may be enlarged or reduced by drag using the pointer 205 of the remote control device 200. By such an enlargement or reduction, the number of card objects displayed on the display unit 180 may be two or four instead of three in the drawing. Moreover, when the broadcast image 615 in the card object is selected, it may be displayed on the display unit 180 in a full screen. The object 612 for displaying corresponding broadcast image related information may include a channel number DTV7-1, a channel name YBC HD, a broadcast program title Oh! Lady, and a broadcast time pm 08:0008:50. By doing so, a user may intuitively recognize information on the broadcast image 615. When the object 612 for displaying corresponding broadcast image related information is selected, related EPG information may be displayed on the display unit 180. Moreover, an object 602 for displaying a date 03.24, a day of the week THU, and a current time pm 08:13 may be displayed on the card object 610 for displaying a broadcast image. By doing so, a user may intuitively recognize time information. An object 617 for displaying an external device may display an external device connected to the image display device 100. For example, when the object 617 for displaying an external device is selected, a list of external devices connected to the image display device 100 may be displayed. The setup object 618 may be used for inputting various settings of the image display device 100. For example, various settings such as image setting, audio setting, screen setting, reservation setting, pointing setting of the remote control device 200, and network setting may be made. Moreover, the card object 620 for displaying a CP list may include a card object title NETCAST 622 and a CP list 625. In the drawing, Yakoo, Metflix, weather.com, Picason, and My tube are shown as CPs in the CP list 625, but various settings are possible. When the card object title 622 is selected, the corresponding card object 620 may be displayed on the display unit 180 in a full screen. Moreover, when a predetermined CP in the CP list 625 is selected, a screen including a contents list that a corresponding CP provides may be displayed on the display unit 180. The card object 630 for displaying a list of applications provided may include the card object title APP STORE 632 and the application list 635. The application list 635 may be a list, which is aligned being classified by each item in an application store. In the drawing, the list may be displayed being aligned in a popular order HOT and the latest order NEW, but the present invention is not limited thereto. That is, various examples are available. When the card object title 632 is selected, the corresponding card object 630 may be displayed on the display unit 180 in a full screen. Moreover, when a predetermined application item in the application list 635 is selected, a screen for providing information on a corresponding application may be displayed on the display unit 180. A login item 627, a help item 628, and an exit item 629 may be displayed on the card objects 620 and 630. The login item 627 may be used for accessing an application store or logging in a network connected to an image display device. The help item 628 may be used for the help during an operation of the image display device 100. The exit item 629 may be used for exiting from a corresponding home screen. At this point, a broadcast image being received may be displayed in a full screen. An object for displaying the number of entire card objects may be displayed below the card objects 620 and 630. The object may display the number of entire card objects, of course, the number of card objects among the entire card objects displayed on the display unit 180. Moreover, the card object 640 for displaying a thumbnail list of a broadcast channel may include a card object title CHANNEL BROWSER 642 and a thumbnail list 645 of a broadcast channel. Broadcast channels received sequentially are displayed as thumbnail images in the drawing, but the present invention is not limited thereto. That is, a video is possible. The thumbnail list may include a thumbnail image and channel information on a corresponding channel. By doing so, a user may intuitively recognize content of a corresponding channel. Such a thumbnail image may be a thumbnail image on a preference channel that a user registers in advance or a thumbnail image on a channel after or before the broadcast image 615 in the card object 610. Moreover, eight thumbnail images are shown in the drawing, but various settings are possible. Additionally, a thumbnail image in a thumbnail list may be updated. When the card object title 642 is selected, the corresponding card object 640 may be displayed on the display unit 180 in a full screen. That is, content on a thumbnail list may be displayed on the display unit 180. Moreover, when a predetermined thumbnail image in the thumbnail list 645 of a broadcast channel is selected, a broadcast image corresponding to a corresponding thumbnail image may be displayed on the display unit 180. The card object 650 for displaying a broadcast guide list may include a card object title TV GUIDE 652 and a broadcast guide list 655. The broadcast guide list 655 may be a list for broadcast programs or broadcast images of other channels after the broadcast image 615 in the card object 610, but the present invention is not limited thereto. That is, various examples are available. Additionally, when the card object title 652 is selected, the corresponding card object 650 may be displayed on the display unit 180 in a full screen. Moreover, when a predetermined broadcast item in the broadcast guide list 655 is selected, a broadcast image corresponding to a corresponding broadcast item may be displayed on the display unit 180, or broadcast information corresponding to a corresponding broadcast item may be displayed on the display unit 180. The card object 660 for displaying a broadcast reservation list or a recording list may include a card object title RESERVATION/REC 662 and a broadcast reservation list or recording list 665. The broadcast reservation list or recording list 665 may be a list including broadcast items that a user reserves in advance or broadcast items recorded according thereto. In the drawing, a thumbnail image is displayed by each corresponding item, but various examples are available. Additionally, when the card object title 662 is selected, the corresponding card object 660 may be displayed on the display unit 180 in a full screen. Furthermore, a broadcast item set in advance for reservation or a broadcast item recorded in the broadcast reservation list or recording list 665 is selected, broadcast information on a corresponding broadcast or a recorded broadcast image may be displayed on the display unit 180. The card object 670 for displaying a media list may include a card object title MY MEDIA 672 and a media list 675. The media list 675 may be a list of media stored in the image display device 100 or stored in a device connected to thereto. Video, still images, and audio are shown as an example in the drawing, but besides that, various examples such as text documents and e-book documents are available. Additionally, when the card object title 672 is selected, the corresponding card object 670 may be displayed on the display unit 180 in a full screen. Moreover, when a predetermined media item in the media list 675 is selected, a screen corresponding to a corresponding media may be displayed on the display unit 180. The card object TV GUIDE 680 for displaying a broadcast guide list may include a card object title TV GUIDE 682 and a broadcast guide list 685. The broadcast guide list 685 may be a guide list for each broadcast type. A list for each broadcast type is shown in the drawing by classifying broadcasts into entertainments such as drama, news, or sports, but various settings are available. That is, the broadcast guide list may be a list for each type such as drama, movie, news, sports, and animation. By doing so, a user may confirm a guide list that classifies broadcasts into each genre When the card object title 682 is selected, the corresponding card object 680 may be displayed on the display unit 180 in a full screen. Moreover, when a predetermined broadcast item in the broadcast guide list 685 is selected, a screen corresponding to a corresponding broadcast image may be displayed on the display unit 180. The card objects 620 and 630 displayed on the display unit 180 and the card objects 640, 650, 660, 670, and 680 disposed on the hidden area 601 and not displayed on the display unit 180 may be interchangeable by an input for moving a card object. That is, at least one of the card objects 620 and 630 displayed on the display unit 180 may be moved on the hidden area 601, and at least one of the card objects 640, 650, 660, 670, and 680 disposed on the hidden area 601 may be displayed on the display unit 180. Furthermore, the home screen 600 of the image display device 100 may further include a card object for displaying information on software upgrade. Hereinafter, referring to FIGS. 10 to 16, a method of providing an external device list according to a first embodiment will be described. FIG. 10 is a flowchart illustrating the method of providing an external device list according to the first embodiment. FIGS. 11 to 16 are views illustrating a screen that provides an external device list of an image display device according to the first embodiment. Referring to FIGS. 10 to 16, first, the control unit 170 displays a plurality of external device icons, which allows external devices to be connected to the image display device 100, on the display unit 180 of the image display device 100 in operation S700. Here, a plurality of external devices as external devices connected to the image display device 100 via a wired/wireless network may include a Digital Versatile Disc (DVD) player, a DVD recorder, a Blu-ray Disc (BD) player, a set top box, a digital TV, a personal computer (PC), a camera, a camcorder, an HDD player, and a memory card. However, they are just examples of external devices. Thus, a device having a built-in recording medium for recording a file may serve as an external device. As shown in FIG. 11, a plurality of external device icons 820 representing a plurality of external devices are displayed on the full screen 810 of the display unit 180. Moreover, the control unit 170 determines which external device icons 820 are connected to the image display device 100 in order to display specific symbols 830a, 830b, and 830c on the external device icons that are being connected to the image display device 100. Therefore, external device icons that are not being connected to the image display device 100 are distinguished. Here, displaying a specific symbol on an external device icon is used as one example of a method of distinguishing icons from each other, but the present invention is not limited thereto. That is, any one of letters, symbols, colors, and flashing lights may be used for distinction. The control unit 170 determines which one of the plurality of external device icons displayed on the display unit 180 has a pointer thereon in operation S710. As shown in FIG. 12, when the pointer 850 is positioned on the first external device icon 840 among the plurality of external device icons 820, the control unit 170 may display an image signal 860, which is inputted from an external device related the first external device icon 840 (for example, a BD player), on the full screen 810 of the image display device 100 in operation S720. Through this, a user could confirm an image signal in advance, which is inputted from an external device before switching the input of the external device, so that the user's convenience may be improved. Moreover, when the pointer 850 is positioned on the first external device icon 840 among the plurality of external device icons 820, the first external device icon 840 having the pointer 850 thereon may be highlighted. Moreover, as shown in FIG. 13, an image signal 860 of an external device related to the first external device icon 840 having the pointer 850 thereon may be displayed on the area where the first external device icon 840 is displayed. Moreover, as shown in FIG. 14, when the pointer 850 is positioned on the first external device icon 840, a predetermined popup window 861 is displayed on an area adjacent to the first external device icon 840, and an image signal 860 of an external device related to the first external device icon 840 may be displayed on the popup window 861. As shown in FIG. 15, when the pointer 850 is positioned on one of the plurality of external device icons 820 (for example, the second external device icon 841 representing a PC), the control unit 170 displays the image signal 860, which inputted from an external device (for example, the PC) related to the first external device icon 840 having the pointer 850 thereon, on the full screen 810 of the image display device. In this state, when an input is received to select the second external device icon 841 in operation S730, as shown in FIG. 16, a popup window 870 that asks whether to select an input switch to a PC (i.e., a second external device) is displayed on the full screen of the image display device 100. Then, if the input switch to the external device is selected through the popup window 870, the input is switched to the PC (i.e., the second external device) in operation S740. Accordingly, as shown in FIG. 17, an image signal 880 of the PC (i.e., the selected second external device) is displayed on the full screen 810 of the image display device 100. Furthermore, the remote control device 200 that controls the image display device 100 may control the input-switched external device. This will be described in more detail. The remote control device 200 transmits a control command for controlling an external device to the input-switched external device through the image display device 100 in operation S750. In response to the transmitted control command, a control command result of the external device is displayed on the full screen 810 of the image display device 100. For example, as shown in FIG. 17, while the image signal 880 of the second external device is displayed on the display unit 180, in case that a control command of the remote control device 200 is transmitted to a corresponding external device, the pointer 850 displayed on the image signal 880 of the second external device may be manipulated in response to the control command. By doing so, the remote control device 200 that controls the image display device 100 may identically control the input-switched external device, so that the user's convenience may be improved. According to embodiments, since an image signal inputted from an external device is provided in advance before input switching, ease of use and service efficiency may be improved. The method of providing an external device list according to the present invention may be programmed to be executed in a computer and may be stored on a computer readable recording medium. Examples of the computer readable recording medium include read-only memory (ROM), random-access memory (RAM), CD-ROMs, magnetic tapes, floppy disks, and optical data storage devices. The computer readable recording medium can also be distributed over network coupled computer systems so that the computer readable code is stored and executed in a distributed fashion. Also, functional programs, codes, and code segments for accomplishing the present invention can be easily construed by programmers skilled in the art to which the present invention pertains. Moreover, although the preferred embodiments of the present invention are described above, the present invention is not limited the above-mentioned specific embodiments. It will be understood by those skilled in the art that various changes in forms and details may be made therein without departing from the spirit and scope of the invention. Also, these modified embodiments should be understood without departing from the technical scope or prospect of the present invention. | <SOH> BACKGROUND <EOH>The present invention relates to an image display device, and more particularly, to a method for providing a list of external devices thereof. Recently, digital TV services using a wire or wireless communication network are becoming more common. The digital TV services provide various services that typical analog broadcasting services cannot provide. For example, an Internet Protocol Television (IPTV) service (i.e., one type of the digital TV services) provides interaction through which a user may actively select kinds of watching programs and watching time. The IPTV service may provide various additional services such as internet search, home shopping, and online game on the basis of the interaction. | <SOH> SUMMARY <EOH>Embodiments provide a method of providing an external device list, which allows a user to recognize an input switch in advance before an image signal of an external device, which is applied to an image display device, is switched for input, and an image display device thereof. In one embodiment, a method of providing an external device list to an image display device includes: displaying a plurality of external device icons connectible to the image display device; positioning a pointer on a first external device icon among the plurality of external device icons; and displaying on a screen of the image display device an image signal of an external device corresponding to the first external device icon having the pointer thereon. In another embodiment, an image display device includes: a display unit displaying a plurality of external device icons connectible to the image display device; and a control unit performing a control to display an image signal of an external device corresponding to a first external device icon having a pointer thereon when the pointer is positioned on the first external device icon among the plurality of external device icons. The details of one or more embodiments are set forth in the accompanying drawings and the description below. Other features will be apparent from the description and drawings, and from the claims. | H04N2143615 | 20171019 | 20180208 | 61886.0 | H04N21436 | 2 | KHALID, OMER | METHOD OF PROVIDING EXTERNAL DEVICE LIST AND IMAGE DISPLAY DEVICE | UNDISCOUNTED | 1 | CONT-ACCEPTED | H04N | 2,017 |
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15,789,331 | PENDING | ELECTRONIC DISPLAY WITH COOLING | An electronic display including an electronic image assembly and a cooling system for an electronic image assembly. A closed loop gas circulation path and an open loop ambient air flow path are provided to effectuate cooling. A common heat exchanger is located in gaseous communication with both the closed loop gas circulation path and the open loop ambient air flow path. The open loop ambient air flow path facilitates removal of heat from gas circulating within the closed loop gas circulation path. A cooling channel may be located behind a rear portion of the electronic image assembly to further enhance cooling via the circulation of ambient air therein. | 1. An electronic display comprising: an electronic image assembly having a front portion and a rear portion; an open loop ambient air flow path behind the rear portion of the electronic image assembly; a closed loop gas circulation path about the electronic image assembly; a common heat exchanger located in the pathway of both the closed loop gas circulation path and the open loop ambient air flow path; a gas circulation device positioned to force circulating gas through the common heat exchanger; and an air circulation device positioned to force ambient air through the common heat exchanger. 2. The electronic display of claim 1, further comprising: a substantially planar surface located behind and spaced apart from the rear portion of the electronic image assembly; and a space defined between the rear portion of the electronic image assembly and the substantially planar surface; wherein the space is in gaseous communication with the open loop ambient air flow path. 3. The electronic display of claim 2, wherein the substantially planar surface is a plate. 4. The electronic display of claim 2, wherein the substantially planar surface is a portion of the heat exchanger. 5. The electronic display of claim 1, further comprising: a front display surface spaced apart from the front portion of the electronic image assembly; and a front channel defined by the space between the front display surface and the front portion of the electronic image assembly, the front channel forming part of the closed loop gas circulation path. 6. The electronic display of claim 1, further comprising at least one electronic component located in the pathway of the closed loop gas circulation path, the at least one electronic component selected from the group consisting of transformers, circuit boards, resistors, capacitors, batteries, power modules, motors, inductors, illumination devices, wiring, wiring harnesses, lights, thermo-electric devices, and switches. 7. The electronic display of claim 1, further comprising a cooling device placed near an entrance to the open loop ambient air flow path for reducing the temperature of ambient air entering the open loop ambient air flow path. 8. An electronic display comprising: an electronic image assembly having a front portion and a rear portion; a closed loop gas circulation path encircling the electronic image assembly; an open loop ambient air flow path behind the rear portion of the electronic image assembly; a substantially planar surface located behind and spaced apart from the rear portion of the electronic image assembly, the space between the substantially planar surface and the rear portion of the electronic image assembly defining a rear channel; a common heat exchanger in gaseous communication with both the closed loop gas circulation path and the open loop ambient air flow path; at least one fan positioned to force circulating gas through the closed loop gas circulation path; at least one fan positioned to force ambient air through the open loop ambient air flow path. 9. The electronic display of claim 8, wherein the open loop ambient air flow path is also in gaseous communication with the rear channel. 10. The electronic display of claim 8, further comprising a second open loop ambient air flow path in gaseous communication with the rear channel. 11. The electronic display of claim 8, wherein: the common heat exchanger includes first and second gas pathways, the first and second gas pathways being isolated from each other; where the first gas pathway is in gaseous communication with the open loop ambient air flow path; and where the second gas pathway is in gaseous communication with the closed loop gas circulation path. 12. The electronic display of claim 11, wherein the first gas pathway is also in gaseous communication with the rear channel. 13. The electronic display of claim 8, wherein the substantially planar surface is a plate. 14. The electronic display of claim 8, wherein the substantially planar surface is a portion of the heat exchanger. 15. The electronic display of claim 8, further comprising: a front display surface spaced apart from the front portion of the electronic image assembly; and a front channel defined by a space between the front display surface and the front portion of the electronic image assembly, the front channel forming part of the closed loop gas circulation path. 16. The electronic display of claim 8, further comprising at least one electronic component located in the pathway of the closed loop gas circulation path, the at least one electronic component selected from the group consisting of transformers, circuit boards, resistors, capacitors, batteries, power modules, motors, inductors, illumination devices, wiring, wiring harnesses, lights, thermo-electric devices, and switches. 17. A cooling system for an electronic image assembly, comprising: an open loop ambient air flow path at a rear portion of the electronic image assembly; a closed loop gas circulation path encircling the electronic image assembly; a common heat exchanger in gaseous communication with both the closed loop gas circulation path and the open loop ambient air flow path; a front channel defined by a space between a front portion of the electronic image assembly and a front display surface located forward of and spaced apart from the front portion of the electronic image assembly, the front channel forming a part of the closed loop gas circulation path; a rear channel defined by a space between the rear portion of the electronic image assembly and a substantially planar surface located behind and spaced apart from the rear portion of the electronic image assembly, the rear channel forming a part of the open loop ambient air flow path; at least one fan positioned to force circulating gas through the closed loop gas circulation path and the common heat exchanger; and at least one fan positioned to force ambient air through the open loop ambient air flow path and the common heat exchanger. 18. The cooling system of claim 17, wherein the substantially planar surface is a plate. 19. The cooling system of claim 17, wherein the substantially planar surface is a portion of the common heat exchanger. 20. The cooling system of claim 17, further comprising at least one electronic component located in the pathway of the closed loop gas circulation path, the at least one electronic component selected from the group consisting of transformers, circuit boards, resistors, capacitors, batteries, power modules, motors, inductors, illumination devices, wiring, wiring harnesses, lights, thermo-electric devices, and switches. | CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. application Ser. No. 14/834,034 filed on Aug. 24, 2015. U.S. application Ser. No. 14/834,034 is a continuation of U.S. application Ser. No. 14/050,464 filed on Oct. 10, 2013, now U.S. Pat. No. 9,119,325 issued on Aug. 25, 2015. U.S. application Ser. No. 14/050,464 is a continuation of U.S. application Ser. No. 12/641,468 filed Dec. 18, 2009, now U.S. Pat. No. 8,654,302 issued on Feb. 18, 2014, which is a non-provisional of U.S. Application No. 61/138,736 filed Dec. 18, 2008. U.S. application Ser. No. 12/641,468 is a continuation-in-part of U.S. application Ser. No. 12/411,925 filed Mar. 26, 2009, now U.S. Pat. No. 8,854,595 issued on Oct. 7, 2014, which is a non-provisional application of U.S. Application No. 61/039,454 filed Mar. 26, 2008. U.S. application Ser. No. 12/641,468 is a continuation-in-part of U.S. application Ser. No. 12/556,029 filed Sep. 9, 2009, now U.S. Pat. No. 8,373,841 issued on Feb. 12, 2013, which is a non-provisional application of U.S. Application No. 61/095,615 filed Sep. 9, 2008. U.S. application Ser. No. 12/641,468 is a continuation-in-part of U.S. application Ser. No. 12/234,307 filed Sep. 19, 2008, now U.S. Pat. No. 8,767,165 issued on Jul. 1, 2014, which is a non-provisional application of U.S. Application No. 61/033,064 filed Mar. 3, 2008. U.S. application Ser. No. 12/641,468 is a continuation-in-part of U.S. application Ser. No. 12/234,360 filed Sep. 19, 2008, which is a non-provisional application of U.S. Application No. 61/053,713 filed May 16,2008. U.S. application Ser. No. 12/641,468 is a continuation-in-part of U.S. application Ser. No. 12/237,365 filed Sep. 24, 2008, now U.S. Pat. No. 8,879,042 issued Nov. 4, 2014, which is a non-provisional application of U.S. Application No. 61/057,599 filed May 30, 2008. U.S. application Ser. No. 12/641,468 is a continuation-in-part of U.S. application No. 12/235,200 filed Sep. 22, 2008, which is a non-provisional of U.S. Application No. 61/076,126 filed Jun. 26, 2008. U.S. application Ser. No. 12/641,468 is a continuation-in-part of U.S. application Ser. No. 12/620,330 filed Nov. 17, 2009, now U.S. Pat. No. 8,274,622 issued Sep. 25, 2012, which is a non-provisional of U.S. Application No. 61/115,333 filed Nov. 17, 2008. U.S. application Ser. No. 12/641,468 is a continuation-in-part of U.S. application Ser. No. 12/556,209 filed Sep. 9, 2009, now U.S. Pat. No. 8,379,182 issued Feb. 19, 2013, which is a non-provisional of U.S. provisional application No. 61/095,616 filed Sep. 9, 2008. All of said aforementioned applications are hereby incorporated by reference in their entirety as if fully recited herein. TECHNICAL FIELD The exemplary embodiments described herein generally relate to cooling systems and in particular to cooling systems for electronic displays. BACKGROUND Conductive and convective heat transfer systems for electronic displays generally attempt to remove heat from the electronic components in a display through the sidewalls of the display. In order to do this, the systems of the past have relied primarily on fans for moving internal air (or ingested ambient air) within the housing past the components to be cooled and out of the display. These components are typically power supplies. In some cases, the heated air is moved into convectively thermal communication with fins. While such heat transfer systems have enjoyed a measure of success in the past, improvements to displays and new display applications require even greater cooling capabilities. Electronic displays are now being used in outdoor environments and other applications where they may be exposed to high ambient temperatures and even direct sunlight. In particular, cooling devices for electronic displays of the past have generally used convective heat dissipation systems that function to cool only the rear interior portion of the display. By itself, this is not adequate in many climates, especially when radiative heat transfer from the sun through a display window becomes a major factor. In many applications and locations 200 Watts or more of power through such a display window is common. Furthermore, the market is demanding larger screen sizes for displays. With increased electronic display screen size and corresponding display window size more heat will be generated and more heat will be transmitted into the displays. Also, when displays are used in outdoor environments the ambient air may contain contaminates (dust, dirt, pollen, water vapor, smoke, etc.) which, if ingested into the display for cooling the interior can cause damage to the interior components of the display. A large fluctuation in temperature is common in the devices of the past. Such temperature fluctuation adversely affects the electronic components in these devices; both performance and lifetime may be severely affected. Thus, there exists a need for a cooling system for electronic displays which are placed within environments having high ambient temperatures, possibly contaminates present within the ambient air, and even placed in direct sunlight. SUMMARY Exemplary embodiments may comprise two separate flow paths for gas through an electronic display. A first flow path may be a closed loop and a second flow path may be an open loop. The closed loop path travels across the front surface of the image assembly, continues to the rear of the display where it may enter a heat exchanger, finally returning to the front surface of the image assembly. The open loop path may draw ambient gas (ex. ambient air) through the rear of the display (sometimes through a heat exchanger, behind an image assembly, or both) and then exhausts it out of the display housing. A heat exchanger may be used to transfer heat from the circulating gas to the ambient gas. In alternative embodiments, the ambient gas may also be forced behind the image assembly (sometimes a backlight), in order to cool the image assembly and/or backlight assembly (if a backlight is necessary for the particular type of display being used). A cross-flow heat exchanger may be used in an exemplary embodiment. The foregoing and other features and advantages of the exemplary embodiments will be apparent from the following more detailed description of the particular embodiments of the invention, as illustrated in the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS A better understanding of an exemplary embodiment will be obtained from a reading of the following detailed description and the accompanying drawings wherein identical reference characters refer to identical parts and in which: FIG. 1 is a rear perspective view of an embodiment where the rear cover of the display has been removed. FIG. 2A is a perspective section view of another embodiment showing the closed loop and open loop channels. FIG. 2B is a perspective section view similar to the view shown in FIG. 2A where the rear and side covers have been removed. FIG. 3 is a perspective section of another embodiment where ambient gas is ingested only into the heat exchanger and not into optional additional channels. FIG. 4 is a perspective section view of an exemplary embodiment where a cross-flow heat exchanger is used to separate high power and low power electrical assemblies. DETAILED DESCRIPTION OF THE EXEMPLARY EMBODIMENTS FIG. 1 shows the rear of an embodiment for an electronic display 100, where the rear cover for the display housing has been removed in order to show the internal components. In this embodiment, the fan assemblies 102 and 103 for the closed loop may be placed along two opposing edges of a heat exchanger 101. Preferably, fan assembly 102 is the inlet for the heat exchanger and fan assembly 103 is the exit for the heat exchanger 101. These assemblies can optionally be reversed however, where fan assembly 103 is the inlet and fan assembly 102 is the exit. Further, both assemblies 102 and 103 are not required. Some embodiments may use only one fan assembly for the closed loop. If only one fan assembly is used, it may be preferable to place the fan assembly at the inlet of the heat exchanger 101, so that the circulating gas is ‘pulled’ across the front of the image assembly and pushed through the heat exchanger 101. This is not required however; other embodiments may pull the isolated gas through the heat exchanger 101. Other embodiments may push the isolated gas across the front of the image assembly. Fan assemblies 104 and 105 for the open loop may be placed along two opposing edges of the display housing. Again, both assemblies 104 and 105 are not required as some embodiments may use only one assembly and may use the open loop fan assemblies in a push or pull design. Because the various fan assemblies described herein can be placed in multiple orientations, when referring to the placement of the various fan assemblies, the terms ‘push’, ‘pull’, ‘force’, and ‘draw’ will be used interchangeably and any orientation may be used with the various embodiments herein. The circulating gas which is being forced by the closed loop fan assemblies is primarily circulating around the display. For example, the gas travels in a loop where it passes through a channel, contacting the front surface of the image assembly (see FIGS. 2A-2B) and absorbs heat from the image assembly. The circulating gas is then preferably directed (or forced) into the heat exchanger 101 in order to transfer heat from the circulating gas to the ambient gas. Afterwards, the circulating gas exits the heat exchanger 101 and may eventually return to the channel and contact the front surface of the image assembly. The circulating gas may also pass over several electronic components 110 in order to extract heat from these devices as well. The electronic components 110 may be any components or assemblies used to operate the display including, but not limited to: transformers, circuit boards, resistors, capacitors, batteries, power modules, motors, inductors, illumination devices, wiring and wiring harnesses, lights, thermo-electric devices, and switches. In some embodiments, the electrical components 110 may also include heaters, when the display assembly might be used in cold-weather environments. In order to cool the circulating gas (as well as optionally cooling a backlight assembly or image assembly) ambient gas is ingested into the display housing by the open loop fan assembly 104 and/or 105. The ambient gas may simply be ambient air which is surrounding the display. In some embodiments, the ambient gas may be air conditioned (or otherwise cooled) prior to being drawn into the display. Once the ambient gas is ingested into the display, it may be directed (or forced) through the heat exchanger 101 and optionally also across the rear surface of the backlight assembly or image assembly (see FIGS. 2A-2B). By using the heat exchanger 101, heat may be transferred from the circulating gas to the ambient gas. The heated ambient gas may then be expelled out of the display housing. Although not required, it is preferable that the circulating gas and ambient gas do not mix. This may prevent any contaminates and/or particulate that is present within the ambient gas from harming the interior of the display. In a preferred embodiment, the heat exchanger 101 would be a cross-flow heat exchanger. However, many types of heat exchangers are known and can be used with any of the embodiments herein. The heat exchanger 101 may be a cross-flow, parallel flow, or counter-flow heat exchanger. In an exemplary embodiment, the heat exchanger 101 would be comprised of a plurality of stacked layers of thin plates. The plates may have a corrugated, honeycomb, or tubular design, where a plurality of channels/pathways/tubes travel down the plate length-wise. The plates may be stacked such that the directions of the pathways are alternated with each adjacent plate, so that each plate's pathways are substantially perpendicular to the pathways of the adjacent plates. Thus, gas may enter the heat exchanger only through plates whose channels or pathways travel parallel to the path of the gas. Because the plates are alternated, the closed loop and ambient gases may travel in plates which are adjacent to one another and heat may be transferred between the two gases without mixing the gases themselves (if the heat exchanger is adequately sealed, which is preferable but not required). In an alternative design, an open channel may be placed in between a pair of corrugated, honeycomb, or tubular plates. The open channel may travel in a direction which is perpendicular to the pathways of the adjacent plates. This open channel may be created by running two strips of material or tape (esp. very high bond (VHB) tape) between two opposite edges of the plates in a direction that is perpendicular to the direction of the pathways in the adjacent plates. Thus, gas entering the heat exchanger in a first direction may travel through the open channel (parallel to the strips or tape). Gas which is entering in a second direction (substantially perpendicular to the first direction) would travel through the pathways of the adjacent plates). Other types of cross-flow heat exchangers could include a plurality of tubes which contain the first gas and travel perpendicular to the path of the second gas. As the second gas flows over the tubes containing the first gas, heat is exchanged between the two gases. Obviously, there are many types of cross-flow heat exchangers and any type would work with the embodiments herein. An exemplary heat exchanger may have plates where the sidewalls have a relatively low thermal resistance so that heat can easily be exchanged between the two paths of gas. A number of materials can be used to create the heat exchanger. Preferably, the material used should be corrosion resistant, rot resistant, light weight, and inexpensive. Metals are typically used for heat exchangers because of their high thermal conductivity and would work with these embodiments. However, it has been discovered that plastics and composites can also satisfy the thermal conditions for electronic displays. An exemplary embodiment would utilize polypropylene as the material for constructing the plates for the heat exchanger. It has been found that although polypropylene may seem like a poor thermal conductor, the large amount of surface area relative to the small material thickness, results in an overall thermal resistance that is very low. Thus, an exemplary heat exchanger would be made of plastic and would thus produce a display assembly that is thin and lightweight. Specifically, corrugated plastic may be used for each plate layer. As mentioned above, both inlet and exit fan assemblies are not required for the embodiments. Alternatively, only a single fan assembly may be used for each loop. Thus, only an inlet fan assembly may be used with the closed loop and only an exhaust fan assembly may be used with the open loop. Alternatively, one of the loops may have both inlet and exit fan assemblies while the other loop only has either an inlet or exit assembly. The gas used in both loops can be any number of gaseous matters. In some embodiments, air may be used as the gas for both loops. Preferably, the gas which travels through the closed loop should be substantially clear, so that when it passes in front of the image assembly it will not affect the appearance of the image to a viewer. The gas which travels through the closed loop would also preferably be substantially free of contaminates and/or particulate (ex. dust, dirt, pollen, water vapor, smoke, etc.) in order to prevent an adverse effect on the image quality and damage to the internal electronic components. It may also be preferable to keep the gas within the open loop from having contaminates. An optional filter may be used to ensure that the air (either in the closed or open loop) stays free of contaminates. However, in an exemplary embodiment the open loop may be designed so that contaminates could possibly be present within the ambient gas but this will not harm the display. In these embodiments, the heat exchanger (and the optional path behind the image assembly or backlight) is properly sealed so that any contaminates in the ambient gas would not enter sensitive portions of the display. Thus, in these exemplary embodiments, ingesting ambient air for the ambient gas, even if the ambient air contains contaminates, will not harm the display. This can be particularly beneficial when the display is used in outdoor environments or indoor environments where contaminates are present in the ambient air. FIG. 2A shows a cross-section of another embodiment of a display 200. In this figure, the rear cover 250 and side covers 251 and 252 are shown to illustrate one method for sealing the overall display 200. The image assembly 220 is shown near the front of the display 200. As discussed above, the image assembly 220 may comprise any form of electronic assembly for generating an image, including but not limited to: LCD, light emitting diode (LED), organic light emitting diode (OLED), field emitting displays (FED), light-emitting polymers (LEP), plasma displays, and any other flat/thin panel displays. The front display surface 221 is placed in front of the image assembly 220, defining a channel 290 through which the circulating gas may flow. The front display surface 221 may be any transparent material (glass, plastic, or composite) and may optionally comprise several layers for polarizing light, reducing glare or reflections, and protecting the internal display components. In an exemplary embodiment, the front display surface 221 would comprise two panes of glass which are laminated together with index-matching optical adhesive. Further, a polarizing layer may be attached to one of the panes of glass in order to reduce the internal reflections and solar loading on the image assembly 220. It is most preferable that the polarizing layer be attached to the inner surface of the front display surface 221 (the one facing the closed loop channel 290) and also contain an anti-reflective (AR) coating. The front display surface may be a durable display panel as disclosed in co-pending U.S. application Ser. No. 12/330,041 filed on Dec. 8, 2008, herein incorporated by reference in its entirety. For the embodiment shown in FIG. 2A, the image assembly 220 may be an LCD stack with a backlight assembly 222. Some backlights may use cold cathode fluorescent lamps (CCFLs) to produce the illumination necessary for generating an image. In an exemplary embodiment, the backlight assembly 222 would comprise a printed circuit board (PCB) with a plurality of LEDs (light emitting diodes) on the front surface. An exemplary embodiment would have a low level of thermal resistance between the front surface of the backlight assembly 222 and the rear surface 223 of the backlight. A metallic PCB may be used for this purpose. The rear surface 223 of the backlight may contain a thermally conductive material, such as a metal. Aluminum may be an exemplary material for the rear surface 223. A second surface 224 may be placed behind the rear surface 223 of the backlight assembly 222. The space between the rear surface 223 of the backlight and the second surface 224 may define an additional optional open loop channel 225 through which ambient gas may travel in order to cool the backlight assembly 222 (or image assembly 220 if no backlight is used). FIG. 2B shows the same cross section from FIG. 2A with the rear cover 250 and side covers 251 and 252 removed and the closed and open loop air flows shown for explanatory purposes. The closed loop fan assembly 202 may be used to propel the circulating gas 210 around the closed loop. A first open loop fan assembly 203 may be used to draw ambient gas 211 through the heat exchanger 201. Optionally, a second open loop fan assembly 204 may be used to draw ambient gas 212 through the additional optional channel 225 for cooling the backlight assembly 222 (or image assembly 220 if no backlight is used). The optional second open loop fan assembly 204 can also be used to exhaust ambient gas which has traveled through the heat exchanger 201 and through the channel 225. If a second open loop fan assembly 204 is not used (perhaps because the additional optional channel 225 is not used), the first open loop fan assembly 203 may be used to exhaust the ambient gas 211 that has traveled through the heat exchanger 201. As noted above, in an exemplary embodiment the ambient gas 211 and 212 does not mix with the circulating gas 210. It may be important for the image quality that the circulating gas remains free of particulate and contaminates as this gas travels in front of the image assembly 220. Since gas for the open loop may contain various contaminates, a preferable embodiment should be adequately sealed to prevent the gas from the two loops from mixing. This is not necessary however, as filters (either removable or permanent) may be used to minimize the effect of particulate for both the open and closed loops. FIG. 3 is a perspective section view of another embodiment of a display assembly 10 showing inlet 60 and exhaust 65 apertures for the ambient gas 20. The inlet aperture 60 may contain a screen or filter (removable or permanent) to remove any particulate (although this may not be necessary). One or more fans 50 may be positioned so as to draw the ambient gas 20 into the inlet aperture 60 and through the heat exchanger 201. In this embodiment, the ambient gas 20 is only drawn through the heat exchanger 201 and not through any additional optional channels. This embodiment may be used when the image assembly 80 (or backlight assembly) does not require the additional cooling of an additional channel. For example, and not by way of limitation, this embodiment 10 may be used when an OLED is used as the image assembly 80. Further, this embodiment 10 may be used when the LCD backlight is not generating large amounts of heat because it is not required to be extremely bright (perhaps because it is not used in direct sunlight). Still further, this embodiment may be used when the ambient gas 20 contains particulate or contaminates which may damage the display. In these situations, it may be desirable to limit the exposure of the display to the ambient gas 20. Thus, in these situations it may be desirable to only ingest ambient gas 20 into the heat exchanger 201 and not through any additional cooling channels. In some embodiments, the ambient gas 20 may be air conditioned (or otherwise cooled) before it is directed into the heat exchanger 201. A front display surface 221 may be used to create an anterior (front) wall of the channel 290 and/or protect the image assembly 80 from damage. An exemplary front display surface 221 may be glass. Another embodiment for the front display surface 221 may be two panes of glass which are laminated together using optical adhesive. Solar loading (radiative heat transfer from the sun through the front display surface 221 may result in a heat buildup on the image assembly 80 (ex. OLED or LCD assembly). This heat may be transferred to the circulating gas as it passes through the channel between the front display surface 221 and the image assembly 80, where this heat may then be transferred to the ambient gas 20 and expelled from the display. The image assembly could be any one of the following: LCD, plasma display assembly, OLED, light emitting polymer (LEP) assembly, organic electro luminescence (OEL) assembly, LED display assembly, or any other flat/thin panel electronic display. FIG. 4 shows another embodiment where a circulating gas 400 is forced between a front display surface 221 and an image assembly 80 and then through a heat exchanger 201 in order to remove at least a portion of the heat absorbed from the image assembly 80 and front display surface 221. Here, the circulating gas 400 may be propelled by a closed loop fan assembly 410. The heat exchanger 201 may accept circulating gas 400 in one direction while accepting ambient gas 310 in a substantially perpendicular direction such that heat may transfer between the two gases. In this embodiment, an optional additional flow of ambient gas 300 is accepted through the inlet aperture 350 and directed along channel 225 in order to cool the rear portion of the image assembly 80 (possibly a backlight). When this optional additional flow of ambient gas 300 is used, it is preferable that the anterior (front) surface 500 of the channel 225 be thermally conductive and preferably in thermal communication with at least a portion of the image assembly 80. In this arrangement, the ambient gas 300 may also be used to absorb heat from the image assembly 80. In some embodiments, the image assembly may be an LCD with an LED backlight. Here, the LED backlight may be in thermal communication with surface 500 so that heat can be transferred form the LED backlight to the ambient gas 300. Alternatively, the image assembly 80 may be an OLED assembly and the surface 500 may be in thermal communication with the OLED assembly. Inlet aperture 350 may accept both ambient gas 310 and 300, or there may be separate inlet apertures for each flow of gas 310 and 300. For the embodiment shown in FIG. 4, a plurality of ribs are shown placed within channel 225. These ribs may be thermally conductive and in thermal communication with surface 500. Thus, heat from surface 500 may be distributed throughout the ribs and removed by the ambient gas 300. It has been found, that this arrangement can provide improved cooling abilities for the image assembly 80 and/or backlight (if necessary). It can also provide greater structural rigidity to the overall assembly. It has been found that some image assemblies (especially LEDs and OLEDs) may have performance properties which vary depending on temperature. Thus, as the temperature of the image assembly increases, the luminance, color temperature, and other optical properties can vary. When ‘hot spots’ are present within a backlight or illumination assembly, these hot spots can result in irregularities in the resulting image which might be visible to the end user. Thus, with some of the embodiments described herein, the heat which may be generated by the backlight assembly or image assembly can be distributed throughout the ribs and thermally-conductive surfaces to remove hot spots and cool the backlight or image assembly. The ribs shown in this embodiment contain a hollow rectangular cross-section, but this is not required. Other embodiments may contain ribs with I-beam cross-sections, hollow square cross-sections, solid rectangular or solid square cross-sections, ‘T’ cross-sections, ‘Z’ cross-sections, corrugated or honeycomb cross-section, or any combination or mixture of these. Metal may be used to produce the ribs in some embodiments. In other embodiments, additional heat-producing electronic assemblies may be placed in thermal communication with the ribs so that heat can be removed from these assemblies as well. In an exemplary embodiment, power modules may be placed in thermal communication with the ribs so that the heat from the power modules can be distributed throughout the ribs and removed by the ambient gas 300. The circulating gas 400 may also pass over electronic assemblies in order to accept heat from these electronic assemblies. In this exemplary embodiment, the electronic assemblies have been separated by the heat exchanger 201 into two groups. The first group of electronic assemblies 9 may be considered the high power assemblies and may include but are not limited to: power modules, inductors, transformers, and other power-related devices. The second group of electronic assemblies 7 may be considered the low power assemblies and may include but are not limited to: timing and control boards, hard drives and other storage devices, video cards, software drivers, microprocessors, and other control devices. It is known to those skilled in the art that some high power electronic assemblies can cause electrical interference with other electronic assemblies that may be sensitive to electrical interference. Thus, in the exemplary embodiment shown, the heat exchanger 201 is used to separate the lower power electronic assemblies 7 from the high power electronic assemblies 9 to ensure a minimum amount of interference between the two. Further, some high power electronic assemblies 9 are known to also generate heat. This heat may be transferred to the circulating gas 400 prior to introducing this gas into the heat exchanger 201. In the exemplary embodiment shown, ambient air can be ingested as the ambient gas 310 and there is little risk of damage to the electrical assemblies 7 and 9 because the ambient gas 310 would preferably never contact these electrical assemblies. However, the electrical assemblies 7 and 9 will remain cool (as well as clean and dry) because of the cross-flow from the circulating gas 400. The cooling system described herein may run continuously. However, if desired, temperature sensing devices (not shown) may be incorporated within the electronic display to detect when temperatures have reached a predetermined threshold value. In such a case, the various cooling fans may be selectively engaged when the temperature in the display reaches a predetermined value. Predetermined thresholds may be selected and the system may be configured to advantageously keep the display within an acceptable temperature range. Typical thermostat assemblies can be used to accomplish this task. Thermocouples may be used as the temperature sensing devices. The speed of the various fan assemblies can also be varied depending on the temperature within the display. It should be particularly noted that the spirit and scope of the disclosed embodiments provides for the cooling of any type of electronic display. By way of example and not by way of limitation, embodiments may be used in conjunction with any of the following: LCD (all types), light emitting diode (LED), organic light emitting diode (OLED), field emitting display (FED), light emitting polymer (LEP), organic electro luminescence (OEL), plasma displays, and any other type of thin/flat panel display. Furthermore, embodiments may be used with displays of other types including those not yet discovered. In particular, it is contemplated that the system may be well suited for use with large (55 inches or more) LED backlit, high definition (1080i or 1080p or greater) liquid crystal displays (LCD). While the embodiments described herein are well suited for outdoor environments, they may also be appropriate for indoor applications (e.g., factory/industrial environments, spas, locker rooms, kitchens, bathrooms) where thermal stability of the display may be at risk. It should also be noted that the variety of open and closed cooling loops that are shown in the figures may be shown in a horizontal or vertical arrangement but it is clearly contemplated that this can be reversed or changed depending on the particular embodiment. Thus, the closed loop may run horizontally or vertically and in a clock-wise or counter-clockwise direction. Further, the open loop may also be horizontal or vertical and can run left to right, right to left, and top to bottom, or bottom to top. Having shown and described various exemplary embodiments, those skilled in the art will realize that many variations and modifications may be made thereto without departing from the scope of the inventive concept. Additionally, many of the elements indicated above may be altered or replaced by different elements that will provide a like result and fall within the spirit of the inventive concept. It is the intention, therefore, to limit the inventive concept only as indicated by the scope of the claims. | <SOH> BACKGROUND <EOH>Conductive and convective heat transfer systems for electronic displays generally attempt to remove heat from the electronic components in a display through the sidewalls of the display. In order to do this, the systems of the past have relied primarily on fans for moving internal air (or ingested ambient air) within the housing past the components to be cooled and out of the display. These components are typically power supplies. In some cases, the heated air is moved into convectively thermal communication with fins. While such heat transfer systems have enjoyed a measure of success in the past, improvements to displays and new display applications require even greater cooling capabilities. Electronic displays are now being used in outdoor environments and other applications where they may be exposed to high ambient temperatures and even direct sunlight. In particular, cooling devices for electronic displays of the past have generally used convective heat dissipation systems that function to cool only the rear interior portion of the display. By itself, this is not adequate in many climates, especially when radiative heat transfer from the sun through a display window becomes a major factor. In many applications and locations 200 Watts or more of power through such a display window is common. Furthermore, the market is demanding larger screen sizes for displays. With increased electronic display screen size and corresponding display window size more heat will be generated and more heat will be transmitted into the displays. Also, when displays are used in outdoor environments the ambient air may contain contaminates (dust, dirt, pollen, water vapor, smoke, etc.) which, if ingested into the display for cooling the interior can cause damage to the interior components of the display. A large fluctuation in temperature is common in the devices of the past. Such temperature fluctuation adversely affects the electronic components in these devices; both performance and lifetime may be severely affected. Thus, there exists a need for a cooling system for electronic displays which are placed within environments having high ambient temperatures, possibly contaminates present within the ambient air, and even placed in direct sunlight. | <SOH> SUMMARY <EOH>Exemplary embodiments may comprise two separate flow paths for gas through an electronic display. A first flow path may be a closed loop and a second flow path may be an open loop. The closed loop path travels across the front surface of the image assembly, continues to the rear of the display where it may enter a heat exchanger, finally returning to the front surface of the image assembly. The open loop path may draw ambient gas (ex. ambient air) through the rear of the display (sometimes through a heat exchanger, behind an image assembly, or both) and then exhausts it out of the display housing. A heat exchanger may be used to transfer heat from the circulating gas to the ambient gas. In alternative embodiments, the ambient gas may also be forced behind the image assembly (sometimes a backlight), in order to cool the image assembly and/or backlight assembly (if a backlight is necessary for the particular type of display being used). A cross-flow heat exchanger may be used in an exemplary embodiment. The foregoing and other features and advantages of the exemplary embodiments will be apparent from the following more detailed description of the particular embodiments of the invention, as illustrated in the accompanying drawings. | H05K7202 | 20171020 | 20180208 | 67422.0 | H05K720 | 1 | MATEY, MICHAEL A | ELECTRONIC DISPLAY WITH COOLING | UNDISCOUNTED | 1 | CONT-ACCEPTED | H05K | 2,017 |
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15,789,547 | PENDING | SYSTEM AND METHOD FOR OPTIMIZED APPLIANCE CONTROL | In response to a detected presence of an intended target appliance within a logical topography of controllable appliances identity information associated with the intended target appliance is used to automatically add to a graphical user interface of a controlling device an icon representative of the intended target appliance and to create at a Universal Control Engine a listing of communication methods for use in controlling corresponding functional operations of the intended target appliance. When the icon is later activated, the controlling device is placed into an operating state appropriate for controlling functional operations of the intended target appliance while the Universal Control Engine uses at least one of the communication methods to transmit at least one command to place the intended target appliance into a predetermined operating state. | 1. A method for configuring a user interface that is caused to be presented by a smart device in a display device associated with the smart device, comprising: receiving at the smart device from a controllable appliance data that functions to identify a controllable feature of the controllable appliance; automatically adding by the smart device to the user interface an icon representative of the controllable feature of the controllable appliance as identified by the data; in response to the smart device receiving from a controlling device a first command transmission that is indicative of a selection of the added icon from the user interface when the user interface is displayed in the display device associated with the smart device, causing the smart device to modify the user interface as displayed in the display device associated with the smart device whereby at least one user interface element for use in controlling at least one controllable function of the controllable appliance is caused to be newly displayed in the display device associated with the smart device, wherein the at least one user interface element that is caused to be newly displayed in the display device of the smart device in response to the added icon being selected is predetermined as a function of the controllable feature of the controllable appliance; and in response to the smart device receiving from a controlling device a second command transmission that is indicative of a selection of the at least one user interface element that was caused to be newly displayed in the display device associated with the smart device, causing the smart device to issue a command to at least the controllable appliance to control the at least one controllable function of the controllable feature of the controllable appliance. 2. The method as recited in claim 1, wherein the first and second command transmissions are received from the controlling device via use of an infrared communications protocol. 3. The method as recited in claim 1, wherein the first and second command transmission are received from the controlling device via use of a radio frequency communications protocol. 4. The method as recited in claim 1, wherein the first and second command transmission are received from the controlling device via use of a wired communications protocol. 5. The method as recited in claim 1, wherein the display device comprises a television screen. 6. The method as recited in claim 1, wherein the smart device comprises a television. 7. The method as recited in claim 1, wherein the smart device comprises a set-top box. 8. The method as recited in claim 1, wherein the smart device comprises an A/V receiver. 9. The method as recited in claim 1, wherein the smart device issues the command to the controllable appliance via use of a wired communications protocol. 10. The method as recited in claim 1, wherein the smart device receives the controllable function support capability data for the controllable appliance from the controllable device. 11. The method as recited in claim 1, wherein the controllable function support capability data for the controllable appliance is retrieved from a memory device of the smart device. 12. The method as recited in claim 1, wherein the smart device receives the controllable function support capability data for the controllable appliance from a remotely located server device in communication with the smart device. 13. The method as recited in claim 1, wherein the controllable feature of the controllable appliance comprises a controllable media rendering feature that is provided via use of the controllable appliance. | RELATED APPLICATION INFORMATION This application claims the benefit of and is a continuation of U.S. application Ser. No. 15/259,847, filed on Sep. 8, 2016, which application claims the benefit of and is a continuation of U.S. application Ser. No. 14/136,023, filed on Dec. 20, 2013, which application claims the benefit of and is a continuation-in-part of U.S. application Ser. No. 13/899,671, filed on May 22, 2013, which application claims the benefit of and is a continuation of U.S. application Ser. No. 13/657,176, filed on Dec. 22, 2012, which application claims the benefit of U.S. Provisional Application No. 61/552,857, filed Oct. 28, 2011, and U.S. Provisional Application No. 61/680,876, filed Aug. 8, 2012, the disclosures of which are incorporated herein by reference in their entirety. This application is also related to U.S. patent application Ser. No. 12/621,277, filed on Nov. 18, 2009 and entitled “System and Method for Reconfiguration of an Entertainment System Controlling Device,” which in turn is a continuation-in-part of U.S. patent application Ser. No. 12/569,121 (now U.S. Pat. No. 8,243,207), filed on Sep. 29, 2009 and entitled “System and Method for Activity Based Configuration of an Entertainment System,” the disclosures of which are incorporated herein by reference in their entirety. This application is also related to U.S. patent application Ser. No. 13/198,072, filed on Aug. 4, 2011 and entitled “System and Method for Configuring the Remote Control Functionality of a Portable Device,” the disclosure of which is incorporated herein by reference in its entirety. This application is also related to U.S. patent application Ser. No. 13/240,604, filed on Sep. 22, 2011 and entitled “System and Method for Configuring Controlling Device Functionality,” the disclosure of which is incorporated herein by reference in its entirety. BACKGROUND Controlling devices, for example remote controls, for use in issuing commands to entertainment and other appliances, and the features and functionality provided by such controlling devices are well known in the art. In order to facilitate such functionality, various communication protocols, command formats, and interface methods have been implemented by appliance manufacturers to enable operational control of entertainment and other appliances, also as well known in the art. In particular, the recent proliferation of wireless and wired communication and/or digital interconnection methods such as WiFi, Bluetooth, HDMI, etc., amongst and between appliances has resulted in a corresponding proliferation of such communication protocols and command formats. While many of these newer methods may offer improved performance and/or reliability when compared to previous control protocols, appliance manufacturer adoption of such newer methods remains inconsistent and fragmented. This, together with the large installed base of prior generation appliances, may cause confusion, mis-operation, or other problems when a user or manufacturer of a controlling device, such as a remote control, attempts to take advantage of the enhanced features and functionalities of these new control methods. SUMMARY OF THE INVENTION This invention relates generally to enhanced methods for appliance control via use of a controlling device, such as a remote control, smart phone, tablet computer, etc., and in particular to methods for taking advantage of improved appliance control communication methods and/or command formats in a reliable manner which is largely transparent to a user and/or seamlessly integrated with legacy appliance control technology. To this end, the instant invention comprises a modular hardware and software solution, hereafter referred to as a Universal Control Engine (UCE), which is adapted to provide device control across a variety of available control methodologies and communication media, such as for example various infrared (IR) remote control protocols; Consumer Electronic Control (CEC) as may be implemented over a wired HDMI connection; internet protocol (IP), wired or wireless; RF4CE wireless; Bluetooth (BT) wireless personal area network(s); UPnP protocol utilizing wired USB connections; or any other available standard or proprietary appliance command methodology. Since each individual control paradigm may have its own strengths and weaknesses, the UCE may be adapted to combine various control methods in order to realize the best control option for each individual command for each individual device. The UCE itself may be adapted to receive commands from a controlling device, for example, a conventional remote control or a remote control app resident on a smart device such as a phone or tablet, etc., utilizing any convenient protocol and command structure (IR, RF4CE, BT, proprietary RF, etc.) As will become apparent, the controlling device may range from a very simple unidirectional IR device to a fully functional WiFi enabled smart phone or the like. The UCE may receive command requests from such a controlling device and apply the optimum methodology to propagate the command function(s) to each intended target appliance, such as for example a TV, AV receiver, DVD player, etc. In this manner the UCE may enable a single controlling device to command the operation of all appliances in a home theater system while coordinating available methods of controlling each particular appliance in order to select the best and most reliable method for issuing each command to each given device. By way of example without limitation, a UCE may utilize IR commands to power on an AV receiver appliance while CEC commands or another method may be used to select inputs or power down the same AV receiver appliance; or CEC commands may be used to power on and select inputs on a TV appliance while IR commands may be used to control the volume on the same TV appliance. As will become apparent, a UCE may comprise modular hardware and software which may be embodied in a standalone device suitable for use in an existing home theater equipment configuration, or may be incorporated into any one of the appliances such as a STB, TV, AV receiver, HDMI switch etc. Further, when incorporated into an appliance, UCE functionality may be provisioned as a separate hardware module or may be incorporated together with other hardware functionality, e.g., as part of an HDMI interface IC or chip set, etc. A better understanding of the objects, advantages, features, properties and relationships of the invention will be obtained from the following detailed description and accompanying drawings which set forth illustrative embodiments and which are indicative of the various ways in which the principles of the invention may be employed. BRIEF DESCRIPTION OF THE DRAWINGS For a better understanding of the various aspects of the invention, reference may be had to preferred embodiments shown in the attached drawings in which: FIGS. 1 and 2 illustrate exemplary systems in which a standalone UEC device may be utilized to command operation of several appliances; FIGS. 3 and 4 illustrate exemplary systems in which UEC functionality may be incorporated into an appliance which is part of a home entertainment system; FIG. 5 illustrates a block diagram of an exemplary UEC device; FIG. 6 illustrates a graphical representation of an exemplary UCE-based control environment; FIG. 7 illustrates an exemplary preferred command matrix for use in a UCE-based control environment, for example as illustrated in FIG. 6; FIG. 8 illustrates a block diagram of an exemplary smart device which may support a remote control app and a setup method for use in configuring a UCE; FIG. 9 illustrates an exemplary series of steps which may be performed in order to set up and configure an exemplary UCE; FIG. 10 illustrates an exemplary series of steps which may be performed in order to define to a UCE an appliance configuration which corresponds to a user activity; FIG. 11 illustrates exemplary activity configuration matrices such as may be defined during the steps of FIG. 10; FIG. 12 illustrates an exemplary current appliance state matrix which may be maintained by a UCE for use in determining the commands necessary to invoke one of the states defined by the matrix of FIG. 11; FIG. 13 illustrates an exemplary series of steps which may be performed by a UCE in issuing a function command to an appliance; FIG. 14 illustrates an exemplary series of steps which may be performed by a UCE in establishing appliance states matching a desired activity defined in one of the matrices of FIG. 11; and FIG. 15 illustrates an exemplary series of steps which may be performed by a smart device to setup command control macros. DETAILED DESCRIPTION With reference to FIG. 1, there is illustrated an exemplary system in which a UCE device 100 may be used to issue commands to control various controllable appliances, such as a television 106, a cable set top box combined with a digital video recorder (“STB/DVR”) 110, a DVD player 108, and an AV receiver 120. While illustrated in the context of a television 106, STB/DVR 110, a DVD player 108, and an AV receiver 120, it is to be understood that controllable appliances may include, but need not be limited to, televisions, VCRs, DVRs, DVD players, cable or satellite converter set-top boxes (“STBs”), amplifiers, CD players, game consoles, home lighting, drapery, fans, HVAC systems, thermostats, personal computers, etc. In the illustrative example of FIG. 1, appliance commands may be issued by UCE 100 in response to infrared (“IR”) request signals 116 received from a remote control device 102, radio frequency (“RF”) request signals 118 received from an app 124 resident on a smart device 104, or any other device from which UCE 100 may be adapted to receive requests, using any appropriate communication method. As illustrated, transmission of the requested appliance commands from the UCE to appliances 106,108,112,120 may take the form of wireless IR signals 114 or CEC commands issued over a wired HDMI interface 112, as appropriate to the capabilities of the particular appliance to which each command may be directed. In particular, in the exemplary system illustrated, AV receiver 120 may not support HDMI inputs, being connected to audio source appliances 108,110 via, for example S/PDIF interfaces 122. Accordingly UCE 100 may be constrained to transmit all commands destined for AV receiver 120 exclusively as IR signals, while commands destined for the other appliances 106 through 110 may take the form of either CEC or IR signals as appropriate for each command. By way of example without limitation, certain TV manufacturers may elect not to support volume adjustment via CEC. If the illustrative TV 106 is of such manufacture, UCE 100 may relay volume adjustment requests to TV 106 as IR signals 114, while other requests such as power on/off or input selections may be relayed in the form of CEC commands over HDMI connection 112. It will however be appreciated that while illustrated in the context of IR, RF, and wired CEC signal transmissions, in general, transmissions to and from UCE device 100 may take the form of any convenient IR, RF, hardwired, point-to-point, or networked protocol, as necessary for a particular embodiment. Further, while wireless communications 116, 118, etc., between exemplary devices are illustrated herein as direct links, it should be appreciated that in some instances such communication may take place via a local area network or personal area network, and as such may involve various intermediary devices such as routers, bridges, access points, etc. Since these items are not necessary for an understanding of the instant invention, they are omitted from this and subsequent Figures for the sake of clarity. Since smart device remote control apps such as that contemplated in the illustrative device 104 are well known, for the sake of brevity the operation, features, and functions thereof will not be described in detail herein. Nevertheless, if a more complete understanding of the nature of such apps is desired, the interested reader may turn to, for example, the before mentioned U.S. patent application Ser. No. 12/406,601 or U.S. patent application Ser. No. 13/329,940, (now U.S. Pat. No. 8,243,207). Turning now to FIG. 2, in a further illustrative embodiment, UCE 100 may receive wireless request signals from a remote control 200 and/or an app resident on a tablet computer 202. As before, command transmissions to appliances 106,108,110 may take the form of wired CEC commands or wireless IR commands. However, in this example remote control 200 may be in bi-directional communication 208 with UCE 100 and accordingly the UCE may delegate the transmission of IR commands 210 to the remote control device 200, i.e., use remote control 200 as a relay device for those commands determined to be best executed via IR transmissions. As also generally illustrated in FIG. 2, a setup app 214 executing on a smart device such as tablet computer 202 may be utilized in conjunction with an Internet (212,204) accessible or cloud based server 206 and associated database 207 to initially configure UCE 100 for operation with the specific group of appliances to be controlled, i.e., to communicate to UCE 100 a matching command code set and capability profile for each particular appliance to be controlled, for example based on type, manufacture, model number, etc., as will be described in greater detail hereafter. With reference to FIG. 3, in a further illustrative embodiment UCE functionality 100′ may be embedded in an appliance, for example STB/DVR 310. In this example, remote control 102 and/or smart device 104 may transmit wireless request signals directly to STB/DVR 310 for action by the built-in UCE function 100′, which actions may, as before, comprise CEC command transmissions via HDMI connection 112 or IR command transmissions 114, originating in this instance from an IR blaster provisioned to the STB/DVR appliance 310. In this configuration, a set up application resident in STB/DVR 310 may be utilized to configure UEC 100′, using for example an Internet connection 304 accessible through a cable modem and/or cable distribution system headend. In the further illustrative embodiment of FIG. 4, UCE functionality 100′ may be embedded in an AV receiver 420 which may serve as an HDMI switch between various content sources such as a STB/DVR 110 or a DVD player 108 and a rendering device such as TV 106. In addition to HDMI inputs, AV receiver 420 may also support various other input formats, for example analog inputs such as the illustrative 404 from CD player 408; composite or component video; S/PDIF coaxial or fiberoptic; etc. In this embodiment, request signals 406 may be directed to AV receiver 420, for example from remote control 402, for action by UCE function 100′. As before, resulting appliance commands may be transmitted using CEC signals transmitted over HDMI connections 112, or via IR signals 114 transmitted from an associated IR blaster. As appropriate for a particular embodiment, initial configuration of UCE 100′ to match the equipment to be controlled may be performed by an Internet-connected app resident in AV receiver 420, or by an app resident in tablet computer 202 or other smart device, as mentioned previously in conjunction with FIG. 2. As will be appreciated, various other configurations are also possible without departing from the underlying UCE concept, for example UCE function 100′ may be incorporated into an Internet-capable TV, an HDMI switch, a game console, etc.; appliance command set and capability database 207 may be located at an internet cloud or a cable system headend, may be stored locally (in all or in part), which local storage may take the form of internal memory within the UCE itself or in an appliance such as a TV, STB or AV receiver, or may take the form of a memory stick or the like attachable to a smart device or appliance; etc. With reference to FIG. 5, an exemplary UCE device 100 (whether stand alone or in an appliance supporting UCE functionality) may include, as needed for a particular application, a processor 500 coupled to a memory 502 which memory may comprise a combination of ROM memory, RAM memory, and/or non-volatile read/write memory and may take the form of a chip, a hard disk, a magnetic disk, an optical disk, a memory stick, etc., or any combination thereof. It will also be appreciated that some or all of the illustrated memory may be physically incorporated within the same IC chip as the processor 500 (a so called “microcontroller”) and, as such, it is shown separately in FIG. 5 only for the sake of clarity. Interface hardware provisioned as part of the exemplary UCE platform may include IR receiver circuitry 504 and IR transmitter circuitry 506; an HDMI interface 508; a WiFi transceiver and interface 510; an Ethernet interface 512; and any other wired or wireless I/O interface(s) 514 as appropriate for a particular embodiment, by way of example without limitation Bluetooth, RF4CE, USB, Zigbee, Zensys, X10/Insteon, HomePlug, HomePNA, etc. The electronic components comprising the exemplary UCE device 100 may be powered by an external power source 516. In the case of a standalone UCE device such as illustrated in FIG. 1 or 2, this may comprise for example a compact AC adapter “wall wart,” while integrated UCE devices such as illustrated in FIG. 3 or 4 may draw operating power from the appliance into which they are integrated. It will also be appreciated that in the latter case, in certain embodiments processor 500 and/or memory 502 and/or certain portions of interface hardware items 504 through 514 may be shared with other functionalities of the host appliance. As will be understood by those skilled in the art, some or all of the memory 502 may include executable instructions that are intended to be executed by the processor 500 to control the operation of the UCE device 100 (collectively, the UCE programming) as well as data which serves to define the necessary control protocols and command values for use in transmitting command signals to controllable appliances (collectively, the command data). In this manner, the processor 500 may be programmed to control the various electronic components within the exemplary UCE device 100, e.g., to monitor the communication means 504,510 for incoming request messages from controlling devices, to cause the transmission of appliance command signals, etc. To cause the UCE device 100 to perform an action, the UCE device 100 may be adapted to be responsive to events, such as a received request message from remote control 102 or smart device 104, changes in connected appliance status reported over HDMI interface 508, WiFi interface 510, or Ethernet interface 512, etc. In response to an event, appropriate instructions within the UCE programming may be executed. For example, when a command request is received from a smart phone 104, the UCE device 100 may retrieve from the command data stored in memory 502 a preferred command transmission medium (e.g., IR, CEC over HDMI, IP over WiFi, etc.) and a corresponding command value and control protocol to be used in transmitting that command to an intended target appliance, e.g., TV 106, in a format recognizable by that appliance to thereby control one or more functional operations of that appliance. By way of further example, the status of connected appliances, e.g., powered or not powered, currently selected input, playing or paused, etc., as may be discerned from interfaces 508 through 514, may be monitored and/or tabulated by the UCE programming in order to facilitate adjustment of appliance settings to match user-defined activity profiles, e.g. “Watch TV”, “View a movie”, etc. An overview of an exemplary UCE control environment is presented in FIG. 6. The UCE programming of an exemplary UCE device 100 may comprise a universal control engine core 650 together with a series of scalable software modules 652 through 660, each module supporting a particular appliance command protocol or method and provisioned as appropriate for a particular embodiment. By way of example, the illustrative embodiment of FIG. 6 may include an internet protocol (IP) module 652, a CEC over HDMI module 654, a Bluetooth module 656, an IR module 660, and other modules(s) 658, as appropriate for the particular application. The appliances to be controlled may include an IP enabled AV receiver 620, an IP enabled STB/DVR 610, TV 106, DVD player 108, and CD player 408. As illustrated, certain of these devices may be interconnected via HDMI 112 and/or Ethernet 670 interfaces. (In this regard, it should be appreciated that the illustrative interconnections 112 and 670 of FIG. 6 are intended to depict logical topography only, and accordingly details of exact physical cabling structure and/or the presence of any necessary switches, routers, hubs, repeaters, interconnections, etc., are omitted for the sake of clarity.) The preferred method/protocol/medium for issuance of commands to the exemplary appliances of FIG. 6 may vary by both appliance and by the function to be performed. By way of example, volume control and analog input selection commands 622 targeted to AV receiver 620 may be required to be issued via IR transmissions, while power on/off and HDMI input selection functionality commands 624 may be better communicated via CEC commands and advanced functionality commands 626 such as sound field configuration may be best communicated via an Ethernet connection. In a similar manner, the various operational functions of the other appliances may best commanded via a mixture of mediums, methods, and protocols, as illustrated. As will be appreciated, in some instances a particular appliance may support receipt of an operational command via more than one path, for example the power on/off function of AV receiver 620 may be available not only as a CEC command, but also via an IR command. In such instances, the UCE preferred command format may be that which has been determined to offer the greatest reliability, for example in the above instance the CEC command may be preferred since this form of command is not dependent on line-of-sight and also permits confirmation that the action has been performed by the target appliance. In order to determine the optimum method for each configured appliance type and command, the exemplary UCE core program 650 may be provisioned with a preferred command matrix 700, as illustrated in FIG. 7. Exemplary preferred command matrix 700 may comprise a series of data cells or elements, e.g. cells 712, each corresponding to a specific command 702 and a specific one of the appliances to be controlled 704. The data content of such a cell or element may comprise identification of a form of command/transmission to be used and a pointer to the required data value and formatting information for the specific command. By way of example, the data element 712 corresponding to the “Input 2” command 706 for the configured TV appliance 708, may comprise an indicator that a CEC command is to be used, i.e., an indicator of the transmission device that is to be used to communicate the command to the intended target appliance, together with a pointer to the appropriate command data value and HDMI-CEC bus address; while data element 714 corresponding to the same command function for the configured AV receiver 710 may comprise an indicator that an IR command is to be used, together with a pointer to appropriate command data and formatting information within an IR code library stored elsewhere in UCE memory 502. In certain embodiments one or more secondary command matrices 716 may also be provisioned, allowing for the use of alternate command methods in the event it is determined by the UCE programming that a preferred command was unsuccessful. Command matrix 700 may also contain null entries, for example 718, where a particular function is not available on or not supported by a specific appliance. In an exemplary embodiment, command matrix 700 may be created and loaded into the memory 502 of UCE 100 during an initialization and set-up process, as will now be described in further detail. In order to perform initial configuration of a UCE device, a setup application may be provided. In some embodiments, such a set up application may take the form of programming to be executed on any convenient device with a suitable user interface and capable of establishing communication with the UCE, such as without limitation a smart phone, tablet computer, personal computer, set top box, TV, etc., as appropriate for a particular embodiment. In other embodiments such a set up application may be incorporated into the UCE programming itself, utilizing for example a connected TV screen and an associated controlling device as the user interface. Regardless of the exact form and location of the programming and user interface means, the series of steps which may be performed by a UCE set up application when configuring a UCE device for operation with a specific set of appliances remains similar. Accordingly, it will be appreciated that the methods comprising the illustrative UCE set up application presented below in conjunction with FIGS. 8 and 9 may be generally applied, mutatis mutandis, to various alternative set up application embodiments. With reference to FIG. 8, as known in the art a tablet computer such as the exemplary device 202 of FIG. 2 may comprise, as needed for a particular application, a processor 800 memory 802 which memory may comprise a combination of ROM memory, RAM memory, and/or non-volatile read/write memory and may take the form of a chip, a hard disk, a magnetic disk, an optical disk, a memory stick, etc., or any combination thereof. In some embodiments, provision may also be made for attachment of external memory 804 which may take the form of an SD card, memory stick, or the like. Hardware provisioned as part of an exemplary tablet computer platform may include an LCD touchscreen 810 with associated display driver 806 and touch interface 808; hard keys 812 such as for example a power on/off key; a USB port 816; WiFi transceiver and interface 818; a Bluetooth transceiver and interface 820; a camera 822; and various other features 824 as appropriate for a particular embodiment, for example an accelerometer, GPS, ambient light sensor, near field communicator; etc. The electronic components comprising the exemplary tablet computer device 202 may be powered by a battery-based internal power source 814, rechargeable for example via USB interface 816. Memory 802 may include executable instructions that are intended to be executed by the processor 800 to control the operation of the tablet computer device 202 and to implement various functionalities such as Web browsing, game playing, video streaming, etc. As is known in the art, programming comprising additional functionalities (referred to as “apps”) may be downloaded into tablet computer 202 via, for example, WiFi interface 818, USB 816, external memory 804, or any other convenient method. As discussed previously, one such app may comprise a remote control app, for example as that described in co-pending U.S. patent application Ser. No. 13/329,940 of like assignee and incorporated herein by reference in its entirety, which app may be for use in commanding the operation of appliances 106, 108, 110 and/or 120 via UCE device 100. In order to initially configure UCE device 100 to match the appliances to be controlled and to establish an appropriate command matrix, tablet computer 202 may also be provisioned with a setup app 214, either as part of a remote control app or as separately downloadable item. With reference now to FIG. 9 such a setup app, upon being invoked at step 902 may initially request that the user place all of the appliances to be controlled into a known state, e.g., powered on, in order to enable the appliance detection and/or testing steps which follow. Next, at step 904 the setup app may determine the identity of those appliances which are CEC-enabled. This may be accomplished by communicating a request to the associated UCE, which at step 906 which may cause the UCE programming to scan connected HDMI devices for appliances which are CEC-enabled and/or identifiable via interaction over the HDMI interface, for example as described in co-pending U.S. patent application Ser. No. 13/198,072, of like assignee and incorporated herein by reference in its entirety, and communicate such appliance identities to the setup application. Thereafter, at step 904 the setup application may determine if additional non-CEC appliances are connected to the UCE device via the HDMI interface. This may be accomplished by requesting the UCE programming to scan for any further HDMI connections at step 910 and communicate the findings back to the setup application. Though not illustrated, it will be appreciated that where appropriate for a particular embodiment the UCE programming may conduct similar scans to in order to discover appliances connected via Ethernet, USB, Bluetooth, RF4CE, WiFi etc., where such interfaces may be provisioned to a UCE. Thereafter, at step 912 the setup application may display a listing of detected appliances (both identified and not yet identified) to the user. At step 914, the user may be prompted to enter appliance identifying information for those HDMI or otherwise connected appliances which were detected but not identified, as well as identifying information regarding any additional appliances which may form part of the system to be controlled but are not discoverable as described above (for example appliances such as AV receiver 120 or CD player 408 which may be responsive only to unidirectional IR commands). Without limitation, such identifying information may take the form of user-entered data such as an appliance type, brand and model number, or a setup code from a listing in a user guide; or may take the form of scanned or electronic information such as a digital picture of the appliance itself or of a bar code, QR code, or the like associated with appliance; near field acquisition of RFID tag data; etc.; or any combination thereof as appropriate for a particular embodiment. Once appropriate identifying information has been acquired, at step 916 the setup app may communicate that information to a database server, for example server 206, for performance of step 918, comprising identification of and retrieval of command codeset and capability data corresponding to the identified appliances from a database 207, and provision of this data to the setup application for processing and ultimate transfer to the UCE device. As will be appreciated, the transferred codeset data may comprise complete command data values and formatting information, may comprise pointers to command data values and formatting information already stored in the memories 502 and/or 802/804 of the UCE or the device upon which the setup application is currently resident, or a combination thereof. Where necessary, for example when database 207 may contain alternate codesets for an identified appliance, or where uncertainty exists regarding a particular appliance model number, etc., at steps 920, 922, and 924 various control paradigms and/or command data sets may be tested against the appliances to be controlled. Such testing may take the form of soliciting user response to effects observable commands, monitoring of HDMI interface status changes as described for example in U.S. patent application Ser. No. 13/240,604, of like assignee and incorporated herein by reference in its entirety, or any other method as convenient for a particular application. Once appropriate codesets have been fully determined, at steps 926,928 and 930 a suitable preferred command matrix, for example as illustrated in FIG. 7, may be constructed and stored into the memory 502 of exemplary UCE device 100, the matrix being constructed by considering the communication capabilities and functionalities of the devices identified via the above-described processes. In order to select the optimum command method for each function of each configured appliance any suitable method may be utilized, for example a system-wide prioritization of command media and methods by desirability (e.g. apply IP, CEC, IR in descending order); appliance-specific command maps by brand and/or model; function-specific preference and/or priority maps (e.g. all volume function commands via IR where available); etc.; or any combination thereof. The exact selection of command method priorities or mapping may take into account factors such connection reliability, e.g. wired versus wireless, bidirectional versus unidirectional communication, etc.; speed of command transmission or execution; internal priorities within an appliance, e.g. received IP received packets processed before CEC packets, etc.; type of protocol support (e.g. error correction versus error detection; ack/nak, etc.); or any other factors which may applied in order to achieve optimum performance of a particular embodiment. As will be appreciated, the construction of said preferred command matrix may be performed at the database server or within the setup application, or a combination thereof, depending on the particular embodiment. Once a preferred command matrix has been finalized and stored in the UCE device, at step 932 a series of desired appliance configurations associated with specific user activities may be configured and stored into the UCE device, as will be now be described. Upon completion and storage of a preferred command matrix, an exemplary setup application may subsequently guide a user through a series of steps in order to establish the desired appliance configurations for a series of possible activities. With reference to FIG. 10, at step 1002, the user may be presented with a list of possible activities, e.g., “Watch TV”, “Watch a movie”, “Listen to music”, etc. In some embodiments, the user may also be able to edit activity titles and/or create additional user defined activities. At step 1004 a user may select a particular activity for configuration, for example “Watch TV”. At step 1006, the user may be prompted to identify the content source for the activity being configured, for example cable STB/DVR 110 for the exemplary “Watch TV” activity. Such a prompt may take the form of a listing of eligible appliances as determined during the foregoing appliance set up steps; explicit user entry of an appliance type; etc. Next, at steps 1008 the user may be prompted in a similar manner to select video and audio rendering appliances for use in this activity, for example TV 106 and AVR receiver 120 respectively. Depending upon the system topography and the interfaces in use (i.e. HDMI/CEC, IP, analog, etc.) the set up application in concert with UCE programming may be able to ascertain which input port of each rendering appliance is attached to the content source appliance identified for this activity and/or if any intermediate switching appliance is in use (for example AV receiver 420 of the system illustrated in FIG. 4). Where such information is obtainable, the set up application may automatically create all or part of an appropriate rendering device input selection for the activity being configured. If not, at steps 1008 and 1010, the user may be additionally requested to identify the applicable content route(s) to the rendering appliances, e.g., input port numbers, presence of intermediate switches, etc. During or upon conclusion of steps 1004 through 1010, the set up application may construct an activity matrix, for example as illustrated in FIG. 11. By way of example, activity matrix 1100 for a “Watch TV” activity may comprise a series of cells, for example 1110 or 1112, each corresponding to a desired configuration of a particular state 1106 or function 1108 of a specific appliance 1104 during the specified activity. By way of example, cell 1110 may indicate that the input of AV receiver 120 is to be set to “S/PDIF2”, while cells 1112 and 1114 may indicate that transport function commands (e.g., “play”, “pause”, “fast forward” etc.) are to be directed to STB/DVR 110 and not to DVD 114. In this regard, it will be appreciated that while in some embodiments the assignment of functions such as, for example, volume control, to specific appliances during a particular activity may be performed within an individual controlling device, i.e., the controlling device may determine the appliance to which volume control commands are to be directed, in a preferred embodiment this assignment may be performed within the UCE, thereby ensuring consistency across each activity when multiple controlling devices are present in an environment, for example devices 102 and 104 of the environment illustrated in FIG. 1. Returning now to FIG. 10, at steps 1014 and 1016 the newly-constructed activity matrix 1100 may be tested by causing the UCE programming, utilizing preferred command matrix 700, to issue the commands necessary to place the identified appliances into the desired state and thereafter receiving verification at step 1018 that the desired activity was successfully initiated. It will be appreciated that such verification may comprise, for example, detection and reporting of HDMI or other content streams and/or appliance status by UCE programming by directly monitoring CEC status or by using methods such as described for example in U.S. patent application Ser. No. 13/240,604; solicitation of user input confirming correct operation; monitoring for presence or absence of analog input signals; recording of appliance status or error messages; etc.; or any combination thereof as appropriate for a particular embodiment. If testing is unsuccessful, at step 1018 the set up application may return to step 1002 to allow reconfiguration of that activity and/or definition of alternative activities. If testing was successful, at steps 1020 and 1022 the completed activity matrix, for example 1100 as illustrated in FIG. 11, may be transferred to the UCE 100 for storage in UCE memory 502. Thereafter, at step 1024 the user may be offered the opportunity to return to step 1002 to define additional activity configurations, for example 1101,1102 as illustrated in FIG. 11, or to exit the activity configuration process. With reference now to FIG. 13, the series of steps performed by the UCE programming in order to convey a function command to an appliance in accordance with a command request 1300 received from a controlling device such as remote control 102 or 200, smart device 104 or 202, etc., or in accordance with an internally generated requirement resulting from receipt of an activity request (as will be described hereafter) may initially comprise retrieval from a preferred command matrix that data element which corresponds to the requested command and target appliance. By way of specific example, receipt of a “TV power on” request from remote control 102 or the like at a UEC provisioned with the preferred command matrices illustrated in FIG. 7 may cause retrieval of data element 720, indicating that the command is to be communicated to the TV appliance, e.g., television 106, using an HDMI CEC command. At step 1304, the UCE programming may determine if the retrieved value constitutes a null element. If so, the referenced appliance does not support the requested command and accordingly at step 1314 an error message may be generated and the process thereafter terminated. As will be appreciated, the exact nature of such an error message may depend upon the particular embodiment and/or the requesting controlling device: for example, if the request originated from a controlling device which is in bidirectional communication with the UCE the error may be communicated back to the requesting device for action, i.e., display to the user, illuminate a LED, activate a buzzer, etc. as appropriate. Alternatively, in those embodiments where a UCE is incorporated into an appliance, that appliance's front panel display may be utilized. If the retrieved preferred command matrix element data is valid, at step 1306 the UCE may communicate the corresponding function command to the target appliance using the indicated command value and transmission method, e.g., for the exemplary data element 720 this may comprise issuing a CEC “power on” command to CEC logical device address zero (TV) via the UCE HDMI interface 508. Once the command has been issued, at step 1308 the UCE programming may determine if the communication interface and protocol used in issuing the command provides for any confirmation mechanism, i.e., explicit acknowledgement of receipt, monitoring of HDMI status on an interface, detection of a media stream or HDCP handshake, etc. If not, for example the command was issued using a unidirectional IR signal and no other confirmation means such as power or input signal monitoring is available, the UCE programming may simply assume that the command was successful and processing is complete. If however confirmation means exists, at step 1310 the UCE programming may wait to determine if the command was successfully executed. Once positive confirmation is received, processing is complete. If no confirmation or a negative confirmation is received, at step 1312 the UCE programming may determine if an alternative method is available to communicate the command to the target appliance. Returning to the specific example presented above this may comprise accessing a secondary command matrix 716 in order to determine if an alternative communication method is available for the specific function, e.g., “TV power on.” If an alternative does exist, at step 1316 the substitute command value and transmission method may be retrieved and processing may return to step 1306 to initiate an alternative attempt. Returning again to the specific example, if the CEC “power on” command corresponding to data element 720 of matrix 700 issued to TV 106 cannot be confirmed, an IR “power on” command encoded according to SIRCS (Sony Infrared Control System) in correspondence with the equivalent data element in secondary matrix 716 may be attempted as a substitute. In addition to relaying individual command requests as described above, an exemplary UCE may also support activity selection, whereby receipt of a single user request from a controlling device may cause a series of commands to be issued to various appliances in order to configure a system appropriately for a particular user activity, such as for example, watching television. To this end a set of matrices defining desired equipment states suitable to various activities, for example as illustrated at 1100 through 1102 of FIG. 11, may be stored in UCE memory 502 for access by UCE programming when executing such a request. As illustrated in FIG. 12, in some embodiments the programming of an exemplary UCE may maintain an additional matrix 1200 representative of the current state of the controlled appliances, arranged for example by appliance 1202 and by operational state 1204. By way of example, data elements 1206 and 1208 in the illustrative table 1200 may indicate that TV 106 is currently powered on (1208) with HDMI port number 2 selected as the input (1206). The data contents of the elements in such a table may be maintained in any convenient manner as appropriate to a particular embodiment, for example without limitation retrieval of HDMI/CEC status; monitoring input media streams and/or HDCP status; measuring power consumption; construction of a simulated appliance state such as described for example in U.S. Pat. No. 6,784,805; etc.; or any combination thereof. In the case of certain appliances, such as for example AV receiver 120 which may be controllable only via unidirectional IR, the current state of the appliance may not be discernible. In such cases, a null data element 1210 maybe entered into exemplary matrix 1200 to indicate that this appliance may require configuration using discrete commands only and/or user interaction. As will be appreciated, in some embodiments the data contents of the illustrative table may be maintained in memory 502 on an ongoing basis by UCE programming, while in other embodiments this data may be gathered “on the fly” at the time the activity request is being processed. Combinations of these methods may also be used, for example “on the fly” gathering for appliances connected via an HDMI bus combined with maintenance of a simulated state for appliances controlled via IR signals. In order to configure a group of appliances for a desired activity, UCE programming may compare a desired state matrix, for example 1100, to a current state matrix, for example 1200, element by element, issuing commands as necessary to bring appliances to the desired state. By way of example, an exemplary series of steps which may be performed by the programming of a UCE in order to effect a “Watch TV” activity configuration will now be presented in conjunction with FIG. 14. For the purposes of this example, the reader may also wish to reference the equipment configuration of FIG. 1 and the activity and current state matrices 1100 and 1200 of FIGS. 11 and 12. Upon receipt of a “Watch TV” request 1400, at step 1402 the exemplary UCE programming may access an applicable appliance state matrix 1100. Next, at step 1404 it may be determined by the UCE programming whether the present “power” state of TV 106 as indicated by current state matrix 1200 matches the desired state stored in the corresponding data element of matrix 1100. If the states match, processing may continue at step 1408. If the states do not match, at step 1406 a “power on” command may be communicated to TV 106. As will be appreciated from the earlier discussion in conjunction with FIG. 13 and inspection of exemplary preferred command matrix 700, in the illustrative system communication of the “power on” command to TV 106 may comprise a CEC command issued over HDMI connection 112. Next, at step 1408 a “mute” command may be communicated to TV 106, since element 1116 of illustrative matrix 1100 indicates that TV 106 is not the primary audio rendering appliance. In accordance with preferred command matrix 700, communication of the “mute” command to TV 106 may comprise an IR transmission 114. Thereafter, at steps 1410,1412 the active input of TV 106 may be set to “HDMI1” via a CEC command, and at steps 1414,1416 a CEC “power on” command may be communicated to STB/DVR 110 if that appliance is not already powered on. At step 1418, the exemplary UCE programming may set an internal status to indicate that future transport command requests (e.g., play, pause, FF, etc.) should be routed to STB/DVR 110, as indicated by element 1112 of matrix 1100. Thereafter, at steps 1420,1422 a CEC “power off” command may be communicated to STB/DVR 108 if that appliance is not already powered off. Thereafter, at steps 1424 and 1426 “power on” and “input S/PDIF2” commands may be communicated to AV receiver 120 via IR signals. As will be appreciated, it may not be possible to determine the current status of AV receiver 120, as indicated for example by elements 1210 and 1220 of matrix 1200, and accordingly so-called “discrete,” or explicit, function commands may be issued which may establish the desired status regardless of the current state of the appliance. Finally, at step 1428 the exemplary UCE programming may set an internal status to indicate that future volume control command requests (e.g. volume up/down, mute) should be routed to AV receiver 120, as indicated by element 1118 of matrix 1100, where after processing of the activity request is complete. As noted above, the exemplary UCE may also support activity selection, whereby receipt of a single user request from a smart device may cause a series of commands to be issued to various appliances in order to configure a system appropriately for one or more user activities, such as “watch TV,” “watch movie,” “listen to music,” etc. To setup the user interface of the smart device to support such macro command functionality, an exemplary method is illustrated in FIG. 15. More particularly, with reference to FIG. 15, upon invocation of a setup app at step 1502 a user may be requested to place all of the appliances to be controlled into a known state, e.g., powered on or already joined in a wireless network, in order to enable the appliance detection and/or testing steps which follow. Next, at step 1504 the setup app may determine the identity of those appliances which are CEC-enabled or IP enabled. This may be accomplished by communicating a request to the associated UCE, which at step 1506 may cause the UCE programming to scan connected HDMI devices for appliances which are CEC-enabled and/or identifiable via interaction over the HDMI interface, for example as described in co-pending U.S. patent application Ser. No. 13/198,072, of like assignee and incorporated herein by reference in its entirety, and communicate such appliance identities to the setup application. Next, at step 1508 the setup app may also determine if the appliances has any associated icon information (for example stored as metadata on the appliance, available from a remote server, or the like) as well as information related to interface connection types, e.g., WI-FI, HDMI input/output, for use in the creation of supported macros. If the icon information is available, the icon information may be sent to the smart device by the appliance and/or retrieved by the smart device using other information provided by the appliance as appropriate as shown in step 1526. An icon corresponding to the icon information may then be automatically added to the user interface of the smart device whereupon an activation of the added icon may be used to provide access to command and control functionalities associated with the corresponding controllable device, including commands in the form of a listing of automatically generated macros available for that controllable device as described below. Thus, icon information provided to the smart device may be used in connection with information stored on the smart device, stored in the internet cloud and/or at a remote server to automatically add an icon to the user interface of the smart device where the icon can be in the form of a logo for the controllable appliance, icons in the form of logos for content (e.g., television station logos) that can be accessed via the controllable appliance, etc. In a further illustrative embodiment, icons may function as soft keys which may be selected to cause the performance of a further action for example, to display a device control page (e.g., to present television control soft keys such as channel up, channel down, etc.), cause the transmission of commands, etc. as described for example in U.S. patent application Ser. No. 10/288,727, (now U.S. Pat. No. 7,831,930) of like assignee and incorporated herein by reference in its entirety, or any other method as convenient for a particular application. The setup application then continues to step 1510 (after scanning for CEC connected appliances as discussed above) whereat the setup application may next determine if additional non-CEC appliances are connected to the UCE device via the HDMI interface. This may be accomplished by requesting the UCE programming to scan for any further HDMI connections at step 1512 and communicate the findings back to the setup application. Though not illustrated, it will be appreciated that, where appropriate for a particular embodiment, the UCE programming may conduct similar scans in order to discover appliances connected via Ethernet, USB, Bluetooth, RF4CE, WiFi etc., where such interfaces may be provisioned to a UCE. Thereafter, at step 1514 the setup application may display a listing of detected appliances (both identified and not yet identified) to the user. At step 1516, the user may then be prompted to enter appliance identifying information for those HDMI or otherwise connected appliances which were detected but not identified, as well as identifying information regarding any additional appliances which may form part of the system to be controlled but which were not discoverable as described above (for example appliances such as AV receiver 120 or CD player 408 which may be responsive only to unidirectional IR commands). Without limitation, such identifying information may take the form of user-entered data such as an appliance type, brand and model number, or a setup code from a listing in a user guide; or may take the form of scanned or electronic information such as a digital picture of the appliance itself or of a bar code, QR code, or the like associated with appliance; near field acquisition of RFID tag data; MAC address; etc.; or any combination thereof as appropriate for a particular embodiment. Once appropriate identifying information has been acquired, at step 1518 the setup app may communicate that information to a database server, for example server 206, for performance of step 1520 in which the database server uses the identification information to retrieve icon information as needed (e.g., when such data was not obtainable from the appliance), command information as discussed previously, and in step 1522, to automatically generate macros which correspond to the appliance or a plurality of appliances considering their capability data as maintained in a database 207 and/or as retrieved from the appliances. Any such data gathered from and/or created by the server 206 will then be provisioned to the setup application for processing and ultimate transfer to the smart device and/or UCE as required. As will be appreciated, the transferred information and/or metadata may comprise complete command data values, appliance input/output data and current status, formatting information, pointers to command data values and formatting information already stored in the memories 502 and/or 802/804 of the UCE or the device upon which the setup application is currently resident, etc. Where necessary, for example when database 207 may contain alternate codesets, icon metadata, or macro information for an identified appliance, or where uncertainty exists regarding a particular appliance model number, etc., at steps 1528, 1530, and 1522 various control paradigms and/or command data sets may be tested against the appliances to be controlled. Such testing may take the form of soliciting user response to effects observable commands, monitoring of HDMI interface status changes as described for example in U.S. patent application Ser. No. 13/240,604, of like assignee and incorporated herein by reference in its entirety, or any other method as convenient for a particular application. Once appropriate codesets and macro operations have been fully determined, at steps 1528 and 1530 a suitable preferred user profile 1524, may be constructed and stored into the memory 502 of exemplary UCE device 100, the user profile 1524 being constructed by considering the communication capabilities and functionalities of the devices identified via the above-described processes. In order to select the optimum command method for each function of each configured appliance any suitable method may be utilized, for example a system-wide prioritization of command media and methods by desirability (e.g. apply IP, CEC, IR in descending order); appliance-specific command maps by brand and/or model; function-specific preference and/or priority maps (e.g. all volume function commands via IR where available); etc.; or any combination thereof. The exact selection of command method priorities or mapping may take into account factors such connection reliability, e.g. wired versus wireless, bidirectional versus unidirectional communication, etc.; speed of command transmission or execution; internal priorities within an appliance, e.g. received IP received packets processed before CEC packets, etc.; type of protocol support (e.g. error correction versus error detection; ack/nak, etc.); or any other factors which may applied in order to achieve optimum performance of a particular embodiment. As will be appreciated, the construction of said user profile 1524 may be performed at the database server or within the setup application, or a combination thereof, depending on the particular embodiment. While various concepts have been described in detail, it will be appreciated by those skilled in the art that various modifications and alternatives to those concepts could be developed in light of the overall teachings of the disclosure. For example, in an alternate embodiment of UCE functionality, in place of a preferred command matrix such as illustrated in FIG. 7, the programming of an exemplary UCE may utilize a command prioritization list, for example a prioritization list “IP, CEC, IR” may cause the UCE programming to first determine if the requested command can be issued using Internet Protocol, only if not, then determine if the requested command can be issued using a CEC command over the HDMI interface, and only if not, then attempt to issue the requested command via an infrared signal. Such a prioritization reflects an exemplary preference of using bi-directional communication protocols over uni-directional communication protocols over line of sight communication protocols, e.g., IR, when supported by the intended target appliance. Further, while described in the context of functional modules and illustrated using block diagram format, it is to be understood that, unless otherwise stated to the contrary, one or more of the described functions and/or features may be integrated in a single physical device and/or a software module, or one or more functions and/or features may be implemented in separate physical devices or software modules. It will also be appreciated that a detailed discussion of the actual implementation of each module is not necessary for an enabling understanding of the invention. Rather, the actual implementation of such modules would be well within the routine skill of an engineer, given the disclosure herein of the attributes, functionality, and inter-relationship of the various functional modules in the system. Therefore, a person skilled in the art, applying ordinary skill, will be able to practice the invention set forth in the claims without undue experimentation. It will be additionally appreciated that the particular concepts disclosed are meant to be illustrative only and not limiting as to the scope of the invention which is to be given the full breadth of the appended claims and any equivalents thereof. All patents cited within this document are hereby incorporated by reference in their entirety. | <SOH> BACKGROUND <EOH>Controlling devices, for example remote controls, for use in issuing commands to entertainment and other appliances, and the features and functionality provided by such controlling devices are well known in the art. In order to facilitate such functionality, various communication protocols, command formats, and interface methods have been implemented by appliance manufacturers to enable operational control of entertainment and other appliances, also as well known in the art. In particular, the recent proliferation of wireless and wired communication and/or digital interconnection methods such as WiFi, Bluetooth, HDMI, etc., amongst and between appliances has resulted in a corresponding proliferation of such communication protocols and command formats. While many of these newer methods may offer improved performance and/or reliability when compared to previous control protocols, appliance manufacturer adoption of such newer methods remains inconsistent and fragmented. This, together with the large installed base of prior generation appliances, may cause confusion, mis-operation, or other problems when a user or manufacturer of a controlling device, such as a remote control, attempts to take advantage of the enhanced features and functionalities of these new control methods. | <SOH> SUMMARY OF THE INVENTION <EOH>This invention relates generally to enhanced methods for appliance control via use of a controlling device, such as a remote control, smart phone, tablet computer, etc., and in particular to methods for taking advantage of improved appliance control communication methods and/or command formats in a reliable manner which is largely transparent to a user and/or seamlessly integrated with legacy appliance control technology. To this end, the instant invention comprises a modular hardware and software solution, hereafter referred to as a Universal Control Engine (UCE), which is adapted to provide device control across a variety of available control methodologies and communication media, such as for example various infrared (IR) remote control protocols; Consumer Electronic Control (CEC) as may be implemented over a wired HDMI connection; internet protocol (IP), wired or wireless; RF4CE wireless; Bluetooth (BT) wireless personal area network(s); UPnP protocol utilizing wired USB connections; or any other available standard or proprietary appliance command methodology. Since each individual control paradigm may have its own strengths and weaknesses, the UCE may be adapted to combine various control methods in order to realize the best control option for each individual command for each individual device. The UCE itself may be adapted to receive commands from a controlling device, for example, a conventional remote control or a remote control app resident on a smart device such as a phone or tablet, etc., utilizing any convenient protocol and command structure (IR, RF4CE, BT, proprietary RF, etc.) As will become apparent, the controlling device may range from a very simple unidirectional IR device to a fully functional WiFi enabled smart phone or the like. The UCE may receive command requests from such a controlling device and apply the optimum methodology to propagate the command function(s) to each intended target appliance, such as for example a TV, AV receiver, DVD player, etc. In this manner the UCE may enable a single controlling device to command the operation of all appliances in a home theater system while coordinating available methods of controlling each particular appliance in order to select the best and most reliable method for issuing each command to each given device. By way of example without limitation, a UCE may utilize IR commands to power on an AV receiver appliance while CEC commands or another method may be used to select inputs or power down the same AV receiver appliance; or CEC commands may be used to power on and select inputs on a TV appliance while IR commands may be used to control the volume on the same TV appliance. As will become apparent, a UCE may comprise modular hardware and software which may be embodied in a standalone device suitable for use in an existing home theater equipment configuration, or may be incorporated into any one of the appliances such as a STB, TV, AV receiver, HDMI switch etc. Further, when incorporated into an appliance, UCE functionality may be provisioned as a separate hardware module or may be incorporated together with other hardware functionality, e.g., as part of an HDMI interface IC or chip set, etc. A better understanding of the objects, advantages, features, properties and relationships of the invention will be obtained from the following detailed description and accompanying drawings which set forth illustrative embodiments and which are indicative of the various ways in which the principles of the invention may be employed. | G08C1702 | 20171020 | 20180208 | 94348.0 | G08C1702 | 5 | AZIZ, ADNAN | SYSTEM AND METHOD FOR OPTIMIZED APPLIANCE CONTROL | UNDISCOUNTED | 1 | CONT-ACCEPTED | G08C | 2,017 |
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15,789,942 | PENDING | Continuous Analyte Measurement Systems and Systems and Methods for Implanting Them | Low profile continuous analyte measurement systems and systems and methods for implantation within the skin of a patient are provided. | 1. A continuous analyte measurement system, comprising: a base unit configured for mounting on a skin surface; an analyte sensor comprising two functional sides, a proximal portion configured for positioning within the base unit and a distal portion configured for insertion into the skin surface; and a conductive member positionable within the base unit and in electrical contact with the two functional sides of analyte sensor. | RELATED APPLICATION The present application is a continuation of U.S. patent application Ser. No. 12/842,013 filed Jul. 22, 2010, now U.S. Pat. No. 9,795,326, which claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 61/227,967 filed Jul. 23, 2009, entitled “Continuous Analyte Measurement Systems and Systems and Methods for Implanting Them”, the disclosures of each of which are incorporated herein by reference for all purposes. BACKGROUND There are a number of instances when it is desirable or necessary to monitor the concentration of an analyte, such as glucose, lactate, or oxygen, for example, in bodily fluid of a body. For example, it may be desirable to monitor high or low levels of glucose in blood or other bodily fluid that may be detrimental to a human. In a healthy human, the concentration of glucose in the blood is maintained between about 0.8 and about 1.2 mg/mL by a variety of hormones, such as insulin and glucagons, for example. If the blood glucose level is raised above its normal level, hyperglycemia develops and attendant symptoms may result. If the blood glucose concentration falls below its normal level, hypoglycemia develops and attendant symptoms, such as neurological and other symptoms, may result. Both hyperglycemia and hypoglycemia may result in death if untreated. Maintaining blood glucose at an appropriate concentration is thus a desirable or necessary part of treating a person who is physiologically unable to do so unaided, such as a person who is afflicted with diabetes mellitus. Certain compounds may be administered to increase or decrease the concentration of blood glucose in a body. By way of example, insulin can be administered to a person in a variety of ways, such as through injection, for example, to decrease that person's blood glucose concentration. Further by way of example, glucose may be administered to a person in a variety of ways, such as directly, through injection or administration of an intravenous solution, for example, or indirectly, through ingestion of certain foods or drinks, for example, to increase that person's blood glucose level. Regardless of the type of adjustment used, it is typically desirable or necessary to determine a person's blood glucose concentration before making an appropriate adjustment. Typically, blood glucose concentration is monitored by a person or sometimes by a physician using an in vitro test that requires a blood sample. The person may obtain the blood sample by withdrawing blood from a blood source in his or her body, such as a vein, using a needle and syringe, for example, or by lancing a portion of his or her skin, using a lancing device, for example, to make blood available external to the skin, to obtain the necessary sample volume for in vitro testing. The fresh blood sample is then applied to an in vitro testing device such as an analyte test strip, whereupon suitable detection methods, such as colorimetric, electrochemical, or photometric detection methods, for example, may be used to determine the person's actual blood glucose level. The foregoing procedure provides a blood glucose concentration for a particular or discrete point in time, and thus, must be repeated periodically, in order to monitor blood glucose over a longer period. Conventionally, a “finger stick” is generally performed to extract an adequate volume of blood from a finger for in vitro glucose testing since the tissue of the fingertip is highly perfused with blood vessels. These tests monitor glucose at discrete periods of time when an individual affirmatively initiates a test at a given point in time, and therefore may be characterized as “discrete” tests. Unfortunately, the fingertip is also densely supplied with pain receptors, which can lead to significant discomfort during the blood extraction process. Unfortunately, the consistency with which the level of glucose is checked varies widely among individuals. Many diabetics find the periodic testing inconvenient and they sometimes forget to test their glucose level or do not have time for a proper test. Further, as the fingertip is densely supplied with pain receptors which causes significant discomfort during the blood extraction process, some individuals will not be inclined to test their glucose levels as frequently as they should. These situations may result in hyperglycemic or hypoglycemic episodes. Glucose monitoring systems that allow for sample extraction from sites other than the finger and/or that can operate using small samples of blood, have been developed. (See, e.g., U.S. Pat. Nos. 6,120,676, 6,591,125 and 7,299,082, the disclosures of each of which are incorporated herein by reference for all purposes). Typically, about one μL or less of sample may be required for the proper operation of these devices, which enables glucose testing with a sample of blood obtained from the surface of a palm, a hand, an arm, a thigh, a leg, the torso, or the abdomen. Even though less painful than the finger stick approach, these other sample extraction methods are still inconvenient and may also be somewhat painful. In addition to the discrete, in vitro, blood glucose monitoring systems described above, at least partially implantable, or in vivo, blood glucose monitoring systems, which are designed to provide continuous or semi-continuous in vivo measurement of an individual's glucose concentration, have been described. See, e.g., U.S. Pat. Nos. 6,175,752, 6,284,478, 6,134,461, 6,560,471, 6,746,582, 6,579,690, 6,932,892 and 7,299,082, the disclosures of each of which are incorporated herein by reference for all purposes. A number of these in vivo systems are based on “enzyme electrode” technology, whereby an enzymatic reaction involving an enzyme such as glucose oxidase, glucose dehydrogenase, or the like, is combined with an electrochemical sensor for the determination of an individual's glucose level in a sample of the individual's biological fluid. By way of example, the electrochemical sensor may be placed in substantially continuous contact with a blood source, e.g., may be inserted into a blood source, such as a vein or other blood vessel, for example, such that the sensor is in continuous contact with blood and can effectively monitor blood glucose levels. Further by way of example, the electrochemical sensor may be placed in substantially continuous contact with bodily fluid other than blood, such as dermal or subcutaneous fluid, for example, for effective monitoring of glucose levels in such bodily fluid, such as interstitial fluid. Relative to discrete or periodic monitoring using analyte test strips, continuous monitoring is generally more desirable in that it may provide a more comprehensive assessment of glucose levels and more useful information, including predictive trend information, for example. Subcutaneous continuous glucose monitoring is also desirable as it is typically less invasive than continuous glucose monitoring in blood accessed from a blood vessel. Regardless of the type of implantable analyte monitoring device employed, it has been observed that transient, low sensor readings which result in clinically significant sensor related errors may occur for a period of time. For example, it has been found that during the initial 12-24 hours of sensor operation (after implantation), a glucose sensor's sensitivity (defined as the ratio between the analyte sensor current level and the blood glucose level) may be relatively low—a phenomenon sometimes referred to as “early signal attenuation” (ESA). Additionally, low sensor readings may be more likely to occur at certain predictable times such as during night time use—commonly referred to as “night time drop outs”. An in vivo analyte sensor with lower than normal sensitivity may report blood glucose values lower than the actual values, thus potentially underestimating hyperglycemia, and triggering false hypoglycemia alarms. While these transient, low readings are infrequent and, in many instances, resolve after a period of time, the negative deviations in sensor readings impose constraints upon analyte monitoring during the period in which the deviations are observed. One manner of addressing this problem is to configure the analyte monitoring system so as to delay reporting readings to the user until after this period of negative deviations passes. However, this leaves the user vulnerable and relying on alternate means of analyte measuring, e.g., in vitro testing, during this time. Another way of addressing negative deviations in sensor sensitivity is to require frequent calibration of the sensor during the time period in which the sensor is used. This is often accomplished in the context of continuous glucose monitoring devices by using a reference value after the sensor has been positioned in the body, where the reference value most often employed is obtained by a finger stick and use of a blood glucose test strip. However, these multiple calibrations are not desirable for at least the reasons that they are inconvenient and painful, as described above. One cause of spurious low readings or drop outs by these implantable sensors is thought to be the presence of blood clots, also known as “thrombi”, formed as a result of insertion of the sensor in vivo. Such clots exist in close proximity to a subcutaneous glucose sensor and have a tendency to “consume” glucose at a high rate, thereby lowering the local glucose concentration. It may also be that the implanted sensor constricts adjacent blood vessels thereby restricting glucose delivery to the sensor site. One approach to addressing the problem of drop outs is to reduce the size of the sensor, thereby reducing the likelihood of thrombus formation upon implantation and impingement of the sensor structure on adjacent blood vessels, and thus, maximizing fluid flow to the sensor. One manner of reducing the size or surface area of at least the implantable portion of a sensor is to provide a sensor in which the sensor's electrodes and other sensing components and/or layers are distributed over both sides of the sensor, thereby necessitating a narrow sensor profile. Examples of such double-sided sensors are disclosed in U.S. Pat. No. 6,175,752, U.S. Patent Application Publication No. 2007/0203407, now U.S. Pat. No. 7,826,879, and U.S. Provisional Application No. 61/165,499 filed Mar. 31, 2009, the disclosures of each of which are incorporated herein by reference for all purposes. It would also be desirable to provide sensors for use in a continuous analyte monitoring system that have negligible variations in sensitivity, including no variations or at least no statistically significant and/or clinically significant variations, from sensor to sensor. Such sensors would have to lend themselves to being highly reproducible and would necessarily involve the use of extremely accurate fabrication processes. It would also be highly advantageous to provide continuous analyte monitoring systems that are substantially impervious to, or at least minimize, spurious low readings due to the in vivo environmental effects of subcutaneous implantation, such as ESA and night-time dropouts. Of particular interest are analyte monitoring devices and systems that are capable of substantially immediate and accurate analyte reporting to the user so that spurious low readings, or frequent calibrations, are minimized or are non existent. It would also be highly advantageous if such sensors had a construct which makes them even less invasive than currently available sensors and which further minimizes pain and discomfort to the user. SUMMARY Embodiments of the present disclosure include continuous analyte monitoring systems utilizing implantable or partially implantable analyte sensors which have a relatively small profile (as compared to currently available implantable sensors). The relatively small size of the subject sensors reduce the likelihood of bleeding and, therefore, minimize thrombus formation upon implantation and the impingement of the sensor structure on adjacent blood vessels, and thus, maximizing fluid flow to the sensor and reducing the probability of ESA or low sensor readings. In certain embodiments, the sensors are double-sided, meaning that both sides of the sensor's substrate are electrochemically functional, i.e., each side provides at least one electrode, thereby reducing the necessary surface area of the sensor. This enables the sensors to have a relatively smaller insertable distal or tail portion which reduces the in vivo environmental effects to which they are subjected. Further, the non-insertable proximal or external portion of the sensor may also have a relatively reduced size. The subject continuous analyte monitoring systems include a skin-mounted portion or assembly and a remote portion or assembly. The skin-mounted portion includes at least the data transmitter, the transmitter battery, a portion of the sensor electronics, and electrical contacts for electrically coupling the implanted sensor with the transmitter. The remote portion of the system includes at least a data receiver and a user interface which may also be configured for test strip-based glucose monitoring. The skin-mounted portion of the system has a housing or base which is constructed to externally mount to the patient's skin and to mechanically and electrically couple the implanted sensor with the transmitter. Removably held or positioned within the housing/base structure is a connector piece having an electrical contact configuration which, when used with a double-sided sensor, enables coupling of the sensor to the transmitter in a low-profile, space-efficient manner. The skin-mounted components of the system, including the associated mounting/coupling structure, have complementary diminutive structures which, along with the very small sensor, which maximize patient usability and comfort. Embodiments further include systems and devices for implanting the subject analyte sensors within a patient's skin and simultaneously coupling the analyte monitoring system's external, skin-mounted unit to the implanted sensor. Certain insertion systems include at least a manually-held and/or manually-operated inserter device and an insertion needle which is carried by and removably coupled to the inserter. In certain of these embodiments, only the insertion needle is disposable with the inserter or insertion gun being reusable, reducing the overall cost of the system and providing environmental advantages. In other embodiments, the skin-mounted unit and sensor are inserted manually without the use of an insertion device. Embodiments of the subject continuous analyte monitoring systems may include additional features and advantages. For example, certain embodiments do not require individual-specific calibration by the user, and, in certain of these embodiments, require no factory-based calibration as well. Certain other embodiments of the continuous analyte monitoring systems are capable of substantially immediate and accurate analyte reporting to the user so that spurious low readings, or frequent calibrations, are minimized or are non-existent. The subject analyte sensors usable with the subject continuous analyte monitoring systems are highly reproducible with negligible or virtually non-existent sensor-to-sensor variations with respect to sensitivity to the analyte, eliminating the need for user-based calibration. Furthermore, in certain embodiments, the analyte sensors have a predictable sensitivity drift on the shelf and/or during in vivo use are provided. Computer programmable products including devices and/or systems that include programming for a given sensor drift profile may also be provided. The programming may use the drift profile to apply a correction factor to the system to eliminate the need for user-based calibration. These and other features, objects and advantages of the present disclosure will become apparent to those persons skilled in the art upon reading the details of the present disclosure as more fully described below. INCORPORATION BY REFERENCE The following patents, applications and/or publications are incorporated herein by reference for all purposes: U.S. Pat. Nos. 4,545,382; 4,711,245; 5,262,035; 5,262,305; 5,264,104; 5,320,715; 5,356,786; 5,509,410; 5,543,326; 5,593,852; 5,601,435; 5,628,890; 5,820,551; 5,822,715; 5,899,855; 5,918,603; 6,071,391; 6,103,033; 6,120,676; 6,121,009; 6,134,461; 6,143,164; 6,144,837; 6,161,095; 6,175,752; 6,270,455; 6,284,478; 6,299,757; 6,338,790; 6,377,894; 6,461,496; 6,503,381; 6,514,460; 6,514,718; 6,540,891; 6,560,471; 6,579,690; 6,591,125; 6,592,745; 6,600,997; 6,605,200; 6,605,201; 6,616,819; 6,618,934; 6,650,471; 6,654,625; 6,676,816; 6,730,200; 6,736,957; 6,746,582; 6,749,740; 6,764,581; 6,773,671; 6,881,551; 6,893,545; 6,932,892; 6,932,894; 6,942,518; 7,041,468; 7,167,818; and 7,299,082; U.S. Published Application Nos. 2004/0186365, now U.S. Pat. No. 7,811,231; 2005/0182306, now U.S. Pat. No. 8,771,183; 2006/0025662, now U.S. Pat. No. 7,740,581; 2006/0091006; 2007/0056858, now U.S. Pat. No. 8,298,389; 2007/0068807, now U.S. Pat. No. 7,846,311; 2007/0095661; 2007/0108048, now U.S. Pat. No. 7,918,975; 2007/0199818, now U.S. Pat. No. 7,811,430; 2007/0227911, now U.S. Pat. No. 7,887,682; 2007/0233013; 2008/0066305, now U.S. Pat. No. 7,895,740; 2008/0081977, now U.S. Pat. No. 7,618,369; 2008/0102441, now U.S. Pat. No. 7,822,557; 2008/0148873, now U.S. Pat. No. 7,802,467; 2008/0161666; 2008/0267823; and 2009/0054748, now U.S. Pat. No. 7,885,698; U.S. patent application Ser. No. 11/461,725, now U.S. Pat. No. 7,866,026; Ser. No. 12/131,012; 12/242,823, now U.S. Pat. No. 8,219,173; Ser. No. 12/363,712, now U.S. Pat. No. 8,346,335; Ser. No. 12/495,709; 12/698,124; and Ser. No. 12/714,439; U.S. Provisional Application Ser. Nos. 61/184,234; 61/230,686; and 61/347,754. BRIEF DESCRIPTION OF THE DRAWINGS A detailed description of various aspects, features and embodiments of the present disclosure is provided herein with reference to the accompanying drawings, which are briefly described below. The drawings are illustrative and are not necessarily drawn to scale, with some components and features being exaggerated for clarity. The drawings illustrate various aspects and features of the present disclosure and may illustrate one or more embodiment(s) or example(s) of the present disclosure in whole or in part. A reference numeral, letter, and/or symbol that is used in one drawing to refer to a particular element or feature maybe used in another drawing to refer to a like element or feature. Included in the drawings are the following: FIG. 1 shows a block diagram of an embodiment of a data monitoring and management system usable with the continuous analyte monitoring systems of the present disclosure; FIG. 2 shows a block diagram of an embodiment of a transmitter unit of the data monitoring and management system of FIG. 1; FIG. 3 shows a block diagram of an embodiment of the receiver/monitor unit of the data monitoring and management system of FIG. 1; FIG. 4 shows a schematic diagram of an embodiment of an analyte sensor usable with the present disclosure; FIGS. 5A and 5B show perspective and cross sectional views, respectively, of an embodiment of an analyte sensor usable with the present disclosure; FIGS. 6A, 6B and 6C show top, bottom and cross-sectional side views, respectively, of an embodiment of a two-sided analyte sensor usable with the present disclosure; FIGS. 7A, 7B and 7C show top, bottom and cross-sectional side views, respectively, of another embodiment of a two-sided analyte sensor usable with the present disclosure; FIGS. 8A and 8B show perspective and top views, respectively, of one embodiment of a continuous analyte monitoring system of the present disclosure utilizing a double-sided analyte sensor; FIGS. 9A-9E show various views of another embodiment of a continuous analyte monitoring system of the present disclosure utilizing a different double-sided analyte sensor; specifically, FIG. 9A is a cross-sectional view of the system's control unit, including the transmitter, on-skin mounting structure, and an electrical/mechanical connector with an analyte sensor operatively attached thereto; FIG. 9B is an exploded view of the connector and analyte sensor; FIG. 9C is an exploded, partial cutaway view of the mechanical/electrical connector and the analyte sensor; FIG. 9D is a lengthwise cross-sectional view of the cutaway portion of the connector taken along lines D-D of FIG. 9C; FIG. 9E is a cross-sectional view of the coupling core, taken along lines E-E of FIG. 9C, and associated pins of the system's transmitter; FIGS. 10A-10F are schematic representations illustrating use of an insertion system of the present disclosure to insert the continuous analyte monitoring system of FIGS. 9A-9E on/in the skin of a patient; FIGS. 11A and 11B show side and top views, respectively, of an insertion needle of the insertion system of FIGS. 10A-10F having the double-sided analyte sensor of FIGS. 9A-9E operatively nested therein; and FIGS. 12A and 12B are top and bottom perspective views of another continuous analyte monitoring system of the present disclosure. DETAILED DESCRIPTION Before the embodiments of the present disclosure are described, it is to be understood that the present disclosure is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims. Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within embodiments of the present disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges as also encompassed within embodiments of the present disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the present disclosure. Generally, embodiments of the present disclosure relate to methods and devices for detecting at least one analyte, such as glucose, in body fluid. Embodiments relate to the continuous and/or automatic in vivo monitoring of the level of one or more analytes using a continuous analyte monitoring system that includes an analyte sensor for the in vivo detection, of an analyte, such as glucose, lactate, and the like, in a body fluid. Embodiments include wholly implantable analyte sensors and analyte sensors in which only a portion of the sensor is positioned under the skin and a portion of the sensor resides above the skin, e.g., for contact to a control unit, transmitter, receiver, transceiver, processor, etc. At least a portion of a sensor may be, for example, subcutaneously positionable in a patient for the continuous or semi-continuous monitoring of a level of an analyte in a patient's interstitial fluid. For the purposes of this description, semi-continuous monitoring and continuous monitoring will be used interchangeably, unless noted otherwise. The sensor response may be correlated and/or converted to analyte levels in blood or other fluids. In certain embodiments, an analyte sensor may be positioned in contact with interstitial fluid to detect the level of glucose, which detected glucose may be used to infer the glucose level in the patient's bloodstream. Analyte sensors may be insertable into a vein, artery, or other portion of the body containing fluid. Embodiments of the analyte sensors of the subject disclosure may be configured for monitoring the level of the analyte over a time period which may range from minutes, hours, days, weeks, or longer. FIG. 1 shows a data monitoring and management system such as, for example, an analyte (e.g., glucose) monitoring system 100 in accordance with certain embodiments. Embodiments of the subject disclosure are further described primarily with respect to glucose monitoring devices and systems, and methods of glucose detection, for convenience only and such description is in no way intended to limit the scope of the present disclosure. It is to be understood that the analyte monitoring system may be configured to monitor a variety of analytes instead of or in addition to glucose, e.g., at the same time or at different times. Analytes that may be monitored include, but are not limited to, acetyl choline, amylase, bilirubin, cholesterol, chorionic gonadotropin, creatine kinase (e.g., CK-MB), creatine, creatinine, DNA, fructosamine, glucose, glutamine, growth hormones, hormones, ketone bodies, lactate, oxygen, peroxide, prostate-specific antigen, prothrombin, RNA, thyroid stimulating hormone, and troponin. The concentration of drugs, such as, for example, antibiotics (e.g., gentamicin, vancomycin, and the like), digitoxin, digoxin, drugs of abuse, theophylline, and warfarin, may also be monitored. In those embodiments that monitor more than one analyte, the analytes may be monitored at the same or different times. The analyte monitoring system 100 includes a sensor 101, a data processing unit 102 connectable to the sensor 101, and a primary receiver unit 104 which is configured to communicate with the data processing unit 102 via a communication link 103. In certain embodiments, the primary receiver unit 104 may be further configured to transmit data to a data processing terminal 105 to evaluate or otherwise process or format data received by the primary receiver unit 104. The data processing terminal 105 may be configured to receive data directly from the data processing unit 102 via a communication link which may optionally be configured for bi-directional communication. Further, the data processing unit 102 may include a transmitter or a transceiver to transmit and/or receive data to and/or from the primary receiver unit 104 and/or the data processing terminal 105 and/or optionally the secondary receiver unit 106. Also shown in FIG. 1 is an optional secondary receiver unit 106 which is operatively coupled to the communication link 103 and configured to receive data transmitted from the data processing unit 102. The secondary receiver unit 106 may be configured to communicate with the primary receiver unit 104, as well as the data processing terminal 105. The secondary receiver unit 106 may be configured for bi-directional wireless communication with each of the primary receiver unit 104 and the data processing terminal 105. As discussed in further detail below, in certain embodiments the secondary receiver unit 106 may be a de-featured receiver as compared to the primary receiver, i.e., the secondary receiver may include a limited or minimal number of functions and features as compared with the primary receiver unit 104. As such, the secondary receiver unit 106 may include a smaller (in one or more, including all, dimensions), compact housing or embodied in a device such as a wrist watch, arm band, etc., for example. Alternatively, the secondary receiver unit 106 may be configured with the same or substantially similar functions and features as the primary receiver unit 104. The secondary receiver unit 106 may include a docking portion to be mated with a docking cradle unit for placement by, e.g., the bedside for nighttime monitoring, and/or a bi-directional communication device. A docking cradle may recharge a powers supply. Only one sensor 101, data processing unit 102 and data processing terminal 105 are shown in the embodiment of the analyte monitoring system 100 illustrated in FIG. 1. However, it will be appreciated by one of ordinary skill in the art that the analyte monitoring system 100 may include more than one sensor 101 and/or more than one data processing unit 102, and/or more than one data processing terminal 105. Multiple sensors may be positioned in a patient for analyte monitoring at the same or different times. In certain embodiments, analyte information obtained by a first positioned sensor may be employed as a comparison to analyte information obtained by a second sensor. This may be useful to confirm or validate analyte information obtained from one or both of the sensors. Such redundancy may be useful if analyte information is contemplated in critical therapy-related decisions. The analyte monitoring system 100 may be a continuous monitoring system or semi-continuous. In a multi-component environment, each component may be configured to be uniquely identified by one or more of the other components in the system so that communication conflict may be readily resolved between the various components within the analyte monitoring system 100. For example, unique IDs, communication channels, and the like, may be used. In certain embodiments, the sensor 101 is physically positioned in and/or on the body of a user whose analyte level is being monitored. The sensor 101 may be configured to continuously or semi-continuously sample the analyte level of the user automatically (without the user initiating the sampling), based on a programmed intervals such as, for example, but not limited to, once every minute, once every five minutes and so on, and convert the sampled analyte level into a corresponding signal for transmission by the data processing unit 102. The data processing unit 102 is coupleable to the sensor 101 so that both devices are positioned in or on the user's body, with at least a portion of the analyte sensor 101 positioned transcutaneously. The data processing unit 102 may include a fixation element such as adhesive or the like to secure it to the user's body. A mount (not shown) attachable to the user and mateable with the unit 102 may be used. For example, a mount may include an adhesive surface. The data processing unit 102 performs data processing functions, where such functions may include, but are not limited to, filtering and encoding of data signals, each of which corresponds to a sampled analyte level of the user, for transmission to the primary receiver unit 104 via the communication link 103. In one embodiment, the sensor 101 or the data processing unit 102 or a combined sensor/data processing unit may be wholly implantable under the skin layer of the user. In certain embodiments, the primary receiver unit 104 may include a signal interface section including an radio frequency (RF) receiver and an antenna that is configured to communicate with the data processing unit 102 via the communication link 103, and a data processing section for processing the received data from the data processing unit 102 such as data decoding, error detection and correction, data clock generation, data bit recovery, etc., or any combination thereof. In operation, the primary receiver unit 104 in certain embodiments is configured to synchronize with the data processing unit 102 to uniquely identify the data processing unit 102, based on, for example, an identification information of the data processing unit 102, and thereafter, to continuously or semi-continuously receive signals transmitted from the data processing unit 102 associated with the monitored analyte levels detected by the sensor 101. Referring again to FIG. 1, the data processing terminal 105 may include a personal computer, a portable computer such as a laptop or a handheld device (e.g., personal digital assistants (PDAs), telephone such as a cellular phone (e.g., a multimedia and Internet-enabled mobile phone such as an iPhone or similar phone), mp3 player, pager, and the like), drug delivery device, each of which may be configured for data communication with the receiver via a wired or a wireless connection. Additionally, the data processing terminal 105 may further be connected to a data network (not shown) for storing, retrieving, updating, and/or analyzing data corresponding to the detected analyte level of the user. The data processing terminal 105 may include an infusion device such as an insulin infusion pump or the like, which may be configured to administer insulin to patients, and which may be configured to communicate with the primary receiver unit 104 for receiving, among others, the measured analyte level. Alternatively, the primary receiver unit 104 may be configured to integrate an infusion device therein so that the primary receiver unit 104 is configured to administer insulin (or other appropriate drug) therapy to patients, for example, for administering and modifying basal profiles, as well as for determining appropriate boluses for administration based on, among others, the detected analyte levels received from the data processing unit 102. An infusion device may be an external device or an internal device (wholly implantable in a user). In certain embodiments, the data processing terminal 105, which may include an insulin pump, may be configured to receive the analyte signals from the data processing unit 102, and thus, incorporate the functions of the primary receiver unit 104 including data processing for managing the patient's insulin therapy and analyte monitoring. In certain embodiments, the communication link 103 as well as one or more of the other communication interfaces shown in FIG. 1, may use one or more of: an RF communication protocol, an infrared communication protocol, a Bluetooth® enabled communication protocol, an 802.11x wireless communication protocol, or an equivalent wireless communication protocol which would allow secure, wireless communication of several units (for example, per HIPAA requirements), while avoiding potential data collision and interference. FIG. 2 shows a block diagram of an embodiment of a data processing unit of the data monitoring and detection system shown in FIG. 1. User input and/or interface components may be included or a data processing unit may be free of user input and/or interface components. Referring to the Figure, the transmitter unit 102 in one embodiment includes an analog interface 201 configured to communicate with the sensor 101 (FIG. 1), a user input 202, and a temperature detection section 203, each of which is operatively coupled to a transmitter processor 204 such as a central processing unit (CPU). In certain embodiments, one or more application-specific integrated circuits (ASIC) may be used to implement one or more functions or routines associated with the operations of the data processing unit (and/or receiver unit) using for example one or more state machines and buffers. As can be seen in the embodiment of FIG. 2, the sensor 101 (FIG. 1) includes four contacts, three of which are electrodes—work electrode (W) 210, reference electrode (R) 212, and counter electrode (C) 213, each operatively coupled to the analog interface 201 of the data processing unit 102. This embodiment also shows optional guard contact (G) 211. Fewer or greater electrodes may be employed. For example, the counter and reference electrode functions may be served by a single counter/reference electrode, there may be more than one working electrode and/or reference electrode and/or counter electrode, etc. Also shown is a leak detection circuit 214 coupled to the guard contact (G) 211 and the processor 204 in the transmitter unit 102 of the analyte monitoring system 100. The leak detection circuit 214 in accordance with one embodiment of the present disclosure may be configured to detect leakage current in the sensor 101 to determine whether the measured sensor data is corrupt or whether the measured data from the sensor 101 is accurate. Further shown in FIG. 2 are a transmitter serial communication section 205 and an RF transmitter 206, each of which is also operatively coupled to the transmitter processor 204. Moreover, a power supply 207 such as a battery is also provided in the transmitter unit 102 to provide the necessary power for the transmitter unit 102. Additionally, as can be seen from the Figure, clock 208 is provided to, among others, supply real time information to the transmitter processor 204. In one embodiment, a unidirectional input path is established from the sensor 101 (FIG. 1) and/or manufacturing and testing equipment to the analog interface 201 of the transmitter unit 102, while a unidirectional output is established from the output of the RF transmitter 206 of the transmitter unit 102 for transmission to the primary receiver unit 104. In this manner, a data path is shown in FIG. 2 between the aforementioned unidirectional input and output via a dedicated link 209 from the analog interface 201 to serial communication section 205, thereafter to the processor 204, and then to the RF transmitter 206. FIG. 3 is a block diagram of an embodiment of a receiver/monitor unit such as the primary receiver unit 104 of the data monitoring and management system shown in FIG. 1. The primary receiver unit 104 may include one or more of: a blood glucose test strip interface 301 for in vitro testing, an RF receiver 302, an input 303, a temperature monitor section 304, and a clock 305, each of which is operatively coupled to a processing and storage section 307. The primary receiver unit 104 also includes a power supply 306 operatively coupled to a power conversion and monitoring section 308. Further, the power conversion and monitoring section 308 is also coupled to the receiver processor 307. Moreover, also shown are a receiver serial communication section 309, and an output 310, each operatively coupled to the processing and storage unit 307. The receiver may include user input and/or interface components or may be free of user input and/or interface components. In certain embodiments having a test strip interface 301, the interface includes a glucose level testing portion to receive a blood (or other body fluid sample) glucose test or information related thereto. For example, the interface may include a test strip port to receive a glucose test strip. The device may determine the glucose level of the test strip, and optionally display (or otherwise notice) the glucose level on the output 310 of the primary receiver unit 104. Any suitable test strip may be employed, e.g., test strips that only require a very small amount (e.g., one microliter or less, e.g., 0.5 microliter or less, e.g., 0.1 microliter or less), of applied sample to the strip in order to obtain accurate glucose information, e.g. Freestyle® and Precision® blood glucose test strips from Abbott Diabetes Care Inc. Glucose information obtained by the in vitro glucose testing device may be used for a variety of purposes, computations, etc. For example, the information may be used to calibrate sensor 101 (however, calibration of the subject sensors may not be necessary), confirm results of the sensor 101 to increase the confidence thereof (e.g., in instances in which information obtained by sensor 101 is employed in therapy related decisions), etc. Exemplary blood glucose monitoring systems are described, e.g., in U.S. Pat. Nos. 6,071,391, 6,120,676, 6,338,790 and 6,616,819, and in U.S. application Ser. No. 11/282,001, now U.S. Pat. No. 7,918,975 and Ser. No. 11/225,659, now U.S. Pat. No. 8,298,389, the disclosures of each of which are incorporated herein by reference for all purposes. In further embodiments, the data processing unit 102 and/or the primary receiver unit 104 and/or the secondary receiver unit 106, and/or the data processing terminal/infusion section 105 may be configured to receive the blood glucose value from a wired connection or wirelessly over a communication link from, for example, a blood glucose meter. In further embodiments, a user manipulating or using the analyte monitoring system 100 (FIG. 1) may manually input the blood glucose value using, for example, a user interface (for example, a keyboard, keypad, voice commands, and the like) incorporated in the one or more of the data processing unit 102, the primary receiver unit 104, secondary receiver unit 106, or the data processing terminal/infusion section 105. Additional detailed descriptions are provided in U.S. Pat. Nos. 5,262,035, 5,262,305, 5,264,104, 5,320,715, 5,593,852, 6,103,033, 6,134,461, 6,175,752, 6,560,471, 6,579,690, 6,605,200, 6,654,625, 6,746,582 and 6,932,894, and in U.S. Published Patent Application Nos. 2004/0186365, now U.S. Pat. No. 7,811,231 and 2005/0182306, now U.S. Pat. No. 8,771,183, the disclosures of each of which are incorporated herein by reference for all purposes. FIG. 4 schematically shows an embodiment of an analyte sensor usable in the continuous analyte monitoring systems just described. This sensor embodiment includes electrodes 401, 402 and 403 on a base 404. Electrodes (and/or other features) may be applied or otherwise processed using any suitable technology, e.g., chemical vapor deposition (CVD), physical vapor deposition, sputtering, reactive sputtering, printing, coating, ablating (e.g., laser ablation), painting, dip coating, etching and the like. Suitable conductive materials include but are not limited to aluminum, carbon (such as graphite), cobalt, copper, gallium, gold, indium, iridium, iron, lead, magnesium, mercury (as an amalgam), nickel, niobium, osmium, palladium, platinum, rhenium, rhodium, selenium, silicon (e.g., doped polycrystalline silicon), silver, tantalum, tin, titanium, tungsten, uranium, vanadium, zinc, zirconium, mixtures thereof, and alloys, oxides, or metallic compounds of these elements. The sensor may be wholly implantable in a user or may be configured so that only a portion is positioned within (internal) a user and another portion outside (external) a user. For example, the sensor 400 may include a portion positionable above a surface of the skin 410, and a portion positioned below the skin. In such embodiments, the external portion may include contacts (connected to respective electrodes of the second portion by traces) to connect to another device also external to the user such as a transmitter unit. While the embodiment of FIG. 4 shows three electrodes side-by-side on the same surface of base 404, other configurations are contemplated, e.g., fewer or greater electrodes, some or all electrodes on different surfaces of the base or present on another base, some or all electrodes stacked together, some or all electrodes twisted together (e.g., an electrode twisted around or about another or electrodes twisted together), electrodes of differing materials and dimensions, etc. FIG. 5A shows a perspective view of an embodiment of an electrochemical analyte sensor 500 of the present disclosure having a first portion (which in this embodiment may be characterized as a major or body portion) positionable above a surface of the skin 510, and a second portion (which in this embodiment may be characterized as a minor or tail portion) that includes an insertion tip 530 positionable below the skin, e.g., penetrating through the skin and into, e.g., the dermal space 520, in contact with the user's biofluid such as interstitial fluid. Contact portions of a working electrode 501, a reference electrode 502, and a counter electrode 503 are positioned on the portion of the sensor 500 situated above the skin surface 510. Working electrode 501, a reference electrode 502, and a counter electrode 503 are shown at the second section and particularly at the insertion tip 530. Traces may be provided from the electrode at the tip to the contact, as shown in FIG. 5A. It is to be understood that greater or fewer electrodes may be provided on a sensor. For example, a sensor may include more than one working electrode and/or the counter and reference electrodes may be a single counter/reference electrode, etc. FIG. 5B shows a cross sectional view of a portion of the sensor 500 of FIG. 5A. The electrodes 501, 502 and 503 of the sensor 500 as well as the substrate and the dielectric layers are provided in a layered configuration or construction. For example, as shown in FIG. 5B, in one aspect, the sensor 500 (such as the sensor 101 FIG. 1), includes a substrate layer 504, and a first conducting layer 501 such as carbon, gold, etc., disposed on at least a portion of the substrate layer 504, and which may provide the working electrode. Also shown disposed on at least a portion of the first conducting layer 501 is a sensing component or layer 508, discussed in greater detail below. The area of the conducting layer covered by the sensing layer is herein referred to as the active area. A first insulation layer such as a first dielectric layer 505 is disposed or layered on at least a portion of the first conducting layer 501, and further, a second conducting layer 502 may be disposed or stacked on top of at least a portion of the first insulation layer (or dielectric layer) 505, and which may provide the reference electrode. In one aspect, conducting layer 502 may include a layer of silver/silver chloride (Ag/AgCl), gold, etc. A second insulation layer 506 such as a dielectric layer in one embodiment may be disposed or layered on at least a portion of the second conducting layer 509. Further, a third conducting layer 503 may provide the counter electrode 503. It may be disposed on at least a portion of the second insulation layer 506. Finally, a third insulation layer 507 may be disposed or layered on at least a portion of the third conducting layer 503. In this manner, the sensor 500 may be layered such that at least a portion of each of the conducting layers is separated by a respective insulation layer (for example, a dielectric layer). The embodiment of FIGS. 5A and 5B show the layers having different lengths. Some or all of the layers may have the same or different lengths and/or widths. In addition to the electrodes, sensing layer and dielectric layers, sensor 500 may also include a temperature probe, a mass transport limiting layer, a biocompatible layer, and/or other optional components (none of which are illustrated). Each of these components enhances the functioning of and/or results from the sensor. Substrate 504 may be formed using a variety of non-conducting materials, including, for example, polymeric or plastic materials and ceramic materials. (It is to be understood that substrate includes any dielectric material of a sensor, e.g., around and/or in between electrodes of a sensor such as a sensor in the form of a wire wherein the electrodes of the sensor are wires that are spaced-apart by a substrate). In some embodiments, the substrate is flexible. For example, if the sensor is configured for implantation into a patient, then the sensor may be made flexible (although rigid sensors may also be used for implantable sensors) to reduce pain to the patient and damage to the tissue caused by the implantation of and/or the wearing of the sensor. A flexible substrate often increases the patient's comfort and allows a wider range of activities. Suitable materials for a flexible substrate include, for example, non-conducting plastic or polymeric materials and other non-conducting, flexible, deformable materials. Examples of useful plastic or polymeric materials include thermoplastics such as polycarbonates, polyesters (e.g., Mylar and polyethylene terephthalate (PET)), polyvinyl chloride (PVC), polyurethanes, polyethers, polyamides, polyimides, or copolymers of these thermoplastics, such as PETG (glycol-modified polyethylene terephthalate). In other embodiments, the sensors, or at least a portion of the sensors, are made using a relatively rigid substrate, for example, to provide structural support against bending or breaking. Examples of rigid materials that may be used as the substrate include poorly conducting ceramics, such as aluminum oxide and silicon dioxide. One advantage of an implantable sensor having a rigid substrate is that the sensor 500 may have a sharp point and/or a sharp edge to aid in implantation of a sensor without an additional insertion device. It will be appreciated that for many sensors and sensor applications, both rigid and flexible sensors will operate adequately. The flexibility of the sensor may also be controlled and varied along a continuum by changing, for example, the composition and/or thickness and/or width of the substrate (and/or the composition and/or thickness and/or width of one or more electrodes or other material of a sensor). In addition to considerations regarding flexibility, it is often desirable that implantable sensors should have a substrate which is non-toxic. For example, the substrate may be approved by one or more appropriate governmental agencies or private groups for in vivo use. Although the sensor substrate, in at least some embodiments, has uniform dimensions along the entire length of the sensor, in other embodiments, the substrate has a distal end or tail portion and a proximal end or body portion with different widths, respectively, as illustrated in FIG. 5A. In these embodiments, the distal end 530 of the sensor may have a relatively narrow width. For in vivo sensors which are implantable into the subcutaneous tissue or another portion of a patient's body, the narrow width of the distal end of the substrate may facilitate the implantation of the sensor. Often, the narrower the width of the sensor, the less pain the patient will feel during implantation of the sensor and afterwards. For subcutaneously implantable sensors which are designed for continuous or semi-continuous monitoring of the analyte during normal activities of the patient, a tail portion or distal end of the sensor which is to be implanted into the patient may have a width of about 2 mm or less, e.g., about 1 mm or less, e.g., about 0.5 mm or less, e.g., about 0.25 mm or less, e.g., about 0.15 mm or less. However, wider or narrower sensors may be used. The proximal end of the sensor may have a width larger than the distal end to facilitate the connection between the electrode contacts and contacts on a control unit, or the width may be substantially the same as the distal portion. The thickness of the substrate may be determined by the mechanical properties of the substrate material (e.g., the strength, modulus, and/or flexibility of the material), the desired use of the sensor including stresses on the substrate arising from that use, as well as the depth of any channels or indentations that may be formed in the substrate, as discussed below. The substrate of a subcutaneously implantable sensor for continuous or semi-continuous monitoring of the level of an analyte while the patient engages in normal activities may have a thickness that ranges from about 50 μm to about 500 μm, e.g., from about 100 μm to about 300 μm. However, thicker and thinner substrates may be used. The length of the sensor may have a wide range of values depending on a variety of factors. Factors which influence the length of an implantable sensor may include the depth of implantation into the patient and the ability of the patient to manipulate a small flexible sensor and make connections between the sensor and the sensor control unit/transmitter. A subcutaneously implantable sensor of FIG. 5A may have an overall length ranging from about 0.3 to about 5 cm, however, longer or shorter sensors may be used. The length of the tail portion of the sensor (e.g., the portion which is subcutaneously inserted into the patient) is typically from about 0.25 to about 2 cm in length. However, longer and shorter portions may be used. All or only a part of this narrow portion may be subcutaneously implanted into the patient. The lengths of other implantable sensors will vary depending, at least in part, on the portion of the patient into which the sensor is to be implanted or inserted. Electrodes 501, 502 and 503 are formed using conductive traces disposed on the substrate 504. These conductive traces may be formed over a smooth surface of the substrate or within channels formed by, for example, embossing, indenting or otherwise creating a depression in the substrate. The conductive traces may extend most of the distance along a length of the sensor, as illustrated in FIG. 5A, although this is not necessary. For implantable sensors, particularly subcutaneously implantable sensors, the conductive traces typically may extend close to the tip of the sensor to minimize the amount of the sensor that must be implanted. The conductive traces may be formed on the substrate by a variety of techniques, including, for example, photolithography, screen printing, or other impact or non-impact printing techniques. The conductive traces may also be formed by carbonizing conductive traces in an organic (e.g., polymeric or plastic) substrate using a laser. A description of some exemplary methods for forming the sensor is provided in U.S. patents and applications noted herein, including U.S. Pat. Nos. 5,262,035, 6,103,033, 6,175,752 and 6,284,478, the disclosures of each of which are incorporated herein by reference for all purposes. Another method for disposing the conductive traces on the substrate includes the formation of recessed channels in one or more surfaces of the substrate and the subsequent filling of these recessed channels with a conductive material. The recessed channels may be formed by indenting, embossing, or otherwise creating a depression in the surface of the substrate. Exemplary methods for forming channels and electrodes in a surface of a substrate can be found in U.S. Pat. No. 6,103,033, the disclosure of which is incorporated herein by reference for all purposes. The depth of the channels is typically related to the thickness of the substrate. In one embodiment, the channels have depths in the range of about 12.5 μm to about 75 μm, e.g., about 25 μm to about 50 μm. The conductive traces are typically formed using a conductive material such as carbon (e.g., graphite), a conductive polymer, a metal or alloy (e.g., gold or gold alloy), or a metallic compound (e.g., ruthenium dioxide or titanium dioxide). The formation of films of carbon, conductive polymer, metal, alloy, or metallic compound are well-known and include, for example, chemical vapor deposition (CVD), physical vapor deposition, sputtering, reactive sputtering, printing, coating, and painting. In embodiments in which the conductive material is filled into channels formed in the substrate, the conductive material is often formed using a precursor material, such as a conductive ink or paste. In these embodiments, the conductive material is deposited on the substrate using methods such as coating, painting, or applying the material using a spreading instrument, such as a coating blade. Excess conductive material between the channels is then removed by, for example, running a blade along the substrate surface. In certain embodiments, some or all of the electrodes 501, 502, 503 may be provided on the same side of the substrate 504 in the layered construction as described above, or alternatively, may be provided in a co-planar manner such that two or more electrodes may be positioned on the same plane (e.g., side-by side (e.g., parallel) or angled relative to each other) on the substrate 504. For example, co-planar electrodes may include a suitable spacing there between and/or include dielectric material or insulation material disposed between the conducting layers/electrodes. Furthermore, in certain embodiments, one or more of the electrodes 501, 502, 503 may be disposed on opposing sides of the substrate 504. Variations of such double-sided sensors are illustrated in FIGS. 6 and 7, discussed and described in detail below. In such double-sided sensor embodiments, the corresponding electrode contacts may be on the same or different sides of the substrate. For example, an electrode may be on a first side and its respective contact may be on a second side, e.g., a trace connecting the electrode and the contact may traverse through the substrate. As noted above, analyte sensors include an analyte-responsive enzyme to provide a sensing component or sensing layer 508 proximate to or on a surface of a working electrode in order to electrooxidize or electroreduce the target analyte on the working electrode. Some analytes, such as oxygen, can be directly electrooxidized or electroreduced, while other analytes, such as glucose and lactate, require the presence of at least one component designed to facilitate the electrochemical oxidation or reduction of the analyte. The sensing layer may include, for example, a catalyst to catalyze a reaction of the analyte and produce a response at the working electrode, an electron transfer agent to transfer electrons between the analyte and the working electrode (or other component), or both. In certain embodiments, the sensing layer includes one or more electron transfer agents. Electron transfer agents that may be employed are electroreducible and electrooxidizable ions or molecules having redox potentials that are a few hundred millivolts above or below the redox potential of the standard calomel electrode (SCE). The electron transfer agent may be organic, organometallic, or inorganic. Examples of organic redox species are quinones and species that in their oxidized state have quinoid structures, such as Nile blue and indophenol. Examples of organometallic redox species are metallocenes such as ferrocene. Examples of inorganic redox species are hexacyanoferrate (III), ruthenium hexamine etc. In certain embodiments, electron transfer agents have structures or charges which prevent or substantially reduce the diffusional loss of the electron transfer agent during the period of time that the sample is being analyzed. For example, electron transfer agents include, but are not limited to, a redox species, e.g., bound to a polymer which can in turn be disposed on or near the working electrode. The bond between the redox species and the polymer may be covalent, coordinative, or ionic. Although any organic, organometallic or inorganic redox species may be bound to a polymer and used as an electron transfer agent, in certain embodiments the redox species is a transition metal compound or complex, e.g., osmium, ruthenium, iron, and cobalt compounds or complexes. It will be recognized that many redox species described for use with a polymeric component may also be used, without a polymeric component. One type of polymeric electron transfer agent contains a redox species covalently bound in a polymeric composition. An example of this type of mediator is poly(vinylferrocene). Another type of electron transfer agent contains an ionically-bound redox species. This type of mediator may include a charged polymer coupled to an oppositely charged redox species. Examples of this type of mediator include a negatively charged polymer coupled to a positively charged redox species such as an osmium or ruthenium polypyridyl cation. Another example of an ionically-bound mediator is a positively charged polymer such as quaternized poly(4-vinyl pyridine) or poly(l-vinyl imidazole) coupled to a negatively charged redox species such as ferricyanide or ferrocyanide. In other embodiments, electron transfer agents include a redox species coordinatively bound to a polymer. For example, the mediator may be formed by coordination of an osmium or cobalt 2,2′-bipyridyl complex to poly(l-vinyl imidazole) or poly(4-vinyl pyridine). Suitable electron transfer agents are osmium transition metal complexes with one or more ligands, each ligand having a nitrogen-containing heterocycle such as 2,2′-bipyridine, 1,10-phenanthroline, 1-methyl, 2-pyridyl biimidazole, or derivatives thereof. The electron transfer agents may also have one or more ligands covalently bound in a polymer, each ligand having at least one nitrogen-containing heterocycle, such as pyridine, imidazole, or derivatives thereof. One example of an electron transfer agent includes (a) a polymer or copolymer having pyridine or imidazole functional groups and (b) osmium cations complexed with two ligands, each ligand containing 2,2′-bipyridine, 1,10-phenanthroline, or derivatives thereof, the two ligands not necessarily being the same. Some derivatives of 2,2′-bipyridine for complexation with the osmium cation include, but are not limited to, 4,4′-dimethyl-2,2′-bipyridine and mono-, di-, and polyalkoxy-2,2′-bipyridines, such as 4,4′-dimethoxy-2,2′-bipyridine. Derivatives of 1,10-phenanthroline for complexation with the osmium cation include, but are not limited to, 4,7-dimethyl-1,10-phenanthroline and mono, di-, and polyalkoxy-1,10-phenanthrolines, such as 4,7-dimethoxy-1,10-phenanthroline. Polymers for complexation with the osmium cation include, but are not limited to, polymers and copolymers of poly(l-vinyl imidazole) (referred to as “PVI”) and poly(4-vinyl pyridine) (referred to as “PVP”). Suitable copolymer substituents of poly(l-vinyl imidazole) include acrylonitrile, acrylamide, and substituted or quaternized N-vinyl imidazole, e.g., electron transfer agents with osmium complexed to a polymer or copolymer of poly(l-vinyl imidazole). Embodiments may employ electron transfer agents having a redox potential ranging from about −200 mV to about +200 mV versus the standard calomel electrode (SCE). As mentioned above, the sensing layer may also include a catalyst which is capable of catalyzing a reaction of the analyte. The catalyst may also, in some embodiments, act as an electron transfer agent. When the analyte of interest is glucose, a catalyst such as a glucose oxidase, glucose dehydrogenase (e.g., pyrroloquinoline quinone (PQQ), dependent glucose dehydrogenase or oligosaccharide dehydrogenase, flavine adenine dinucleotide (FAD) dependent glucose dehydrogenase, or nicotinamide adenine dinucleotide (NAD) dependent glucose dehydrogenase) may be used. A lactate oxidase or lactate dehydrogenase may be used when the analyte of interest is lactate. Laccase may be used when the analyte of interest is oxygen or when oxygen is generated or consumed in response to a reaction of the analyte. In certain embodiments, a catalyst may be attached to a polymer, cross linking the catalyst with another electron transfer agent which, as described above, may be polymeric. A second catalyst may also be used in certain embodiments. This second catalyst may be used to catalyze a reaction of a product compound resulting from the catalyzed reaction of the analyte. The second catalyst may operate with an electron transfer agent to electrolyze the product compound to generate a signal at the working electrode. Alternatively, a second catalyst may be provided in an interferent-eliminating layer to catalyze reactions that remove interferents. Certain embodiments include a Wired Enzyme™ sensing layer (such as used in the FreeStyle Navigator® continuous glucose monitoring system by Abbott Diabetes Care Inc.) that works at a gentle oxidizing potential, e.g., a potential of about +40 mV. This sensing layer uses an osmium (Os)-based mediator designed for low potential operation and is stably anchored in a polymeric layer. Accordingly, in certain embodiments the sensing element is redox active component that includes (1) Osmium-based mediator molecules attached by stable (bidente) ligands anchored to a polymeric backbone, and (2) glucose oxidase enzyme molecules. These two constituents are crosslinked together. In certain embodiments, the sensing system detects hydrogen peroxide to infer glucose levels. For example, a hydrogen peroxide-detecting sensor may be constructed in which a sensing layer includes enzymes such as glucose oxidase, glucose dehydrogenase, or the like, and is positioned proximate to the working electrode. The sensing layer may be covered by one or more layers, e.g., a membrane that is selectively permeable to glucose. Once the glucose passes through the membrane, it may be oxidized by the enzyme and reduced glucose oxidase can then be oxidized by reacting with molecular oxygen to produce hydrogen peroxide. Certain embodiments include a hydrogen peroxide-detecting sensor constructed from a sensing layer prepared by crosslinking two components together, for example: (1) a redox compound such as a redox polymer containing pendent Os polypyridyl complexes with oxidation potentials of about +200 mV vs. SCE, and (2) periodate oxidized horseradish peroxidase (HRP). Such a sensor functions in a reductive mode; the working electrode is controlled at a potential negative to that of the Os complex, resulting in mediated reduction of hydrogen peroxide through the HRP catalyst. In another example, a potentiometric sensor can be constructed as follows. A glucose-sensing layer is constructed by crosslinking together (1) a redox polymer containing pendent Os polypyridyl complexes with oxidation potentials from about −200 mV to +200 mV vs. SCE, and (2) glucose oxidase. This sensor can then be used in a potentiometric mode, by exposing the sensor to a glucose containing solution, under conditions of zero current flow, and allowing the ratio of reduced/oxidized Os to reach an equilibrium value. The reduced/oxidized Os ratio varies in a reproducible way with the glucose concentration, and will cause the electrode's potential to vary in a similar way. The components of the sensing layer may be in a fluid or gel that is proximate to or in contact with the working electrode. Alternatively, the components of the sensing layer may be disposed in a polymeric or sol-gel matrix that is proximate to or on the working electrode. Preferably, the components of the sensing layer are non-leachably disposed within the sensor. More preferably, the components of the sensor are immobilized within the sensor. Examples of sensing layers that may be employed are described in U.S. patents and applications noted herein, including, e.g., in U.S. Pat. Nos. 5,262,035, 5,264,104, 5,543,326, 6,605,200, 6,605,201, 6,676,819 and 7,299,082, the disclosures of each of which are incorporated herein by reference for all purposes. Regardless of the particular components that make up a given sensing layer, a variety of different sensing layer configurations may be used. In certain embodiments, the sensing layer covers the entire working electrode surface, e.g., the entire width of the working electrode surface. In other embodiments, only a portion of the working electrode surface is covered by the sensing layer, e.g., only a portion of the width of the working electrode surface. Alternatively, the sensing layer may extend beyond the conductive material of the working electrode. In some cases, the sensing layer may also extend over other electrodes, e.g., over the counter electrode and/or reference electrode (or counter/reference is provided), and may cover all or only a portion thereof. In other embodiments the sensing layer is not deposited directly on the working electrode. Instead, the sensing layer may be spaced apart from the working electrode, and separated from the working electrode, e.g., by a separation layer. A separation layer may include one or more membranes or films or a physical distance. In addition to separating the working electrode from the sensing layer the separation layer may also act as a mass transport limiting layer, and/or an interferent eliminating layer, and/or a biocompatible layer. In certain embodiments which include more than one working electrode, one or more of the working electrodes may not have a corresponding sensing layer, or may have a sensing layer which does not contain one or more components (e.g., an electron transfer agent and/or catalyst) needed to electrolyze the analyte. Thus, the signal at this working electrode may correspond to background signal which may be removed from the analyte signal obtained from one or more other working electrodes that are associated with fully-functional sensing layers by, for example, subtracting the signal. Whichever configuration of the sensing component or layer is employed, at least one factor in minimizing variations in sensor sensitivity, at least within the same sensor batch or lot (or all sensors made according to the same specification), is by strictly maintaining the dimensions (width, length, diameter and thickness) of the active area, i.e., the area of the working electrode in contact with the sensing component or layer, from sensor to sensor. Optimizing sensitivity, including reproducing substantially the same sensitivity for sensors within a lot or batch of sensors, reduces and in certain embodiments eliminates the need for sensor calibration, by the user. Accordingly, sensors that do not require a user to calibrate, using for example an in vitro test strip or the like after insertion of the sensor into the body for testing, are achieved. Examples of sensors for use in one or more embodiments of the present disclosure can be found in, among others, U.S. patent application Ser. No. 12/714,439, the disclosure of which is incorporated herein by reference for all purposes. Calibration, when an electrochemical glucose sensor is used, generally involves converting the raw current signal (nA) into a glucose concentration (mg/dL). One way in which this conversion is done is by relating or equating the raw analyte signal with a calibration measurement (i.e., with a reference measurement), and obtaining a conversion factor (raw analyte signal/reference measurement value). This relationship is often referred to as the sensitivity of the sensor, which, once determined, may then be used to convert sensor signals to calibrated analyte concentration values, e.g., via simple division (raw analyte signal/sensitivity=calibrated analyte concentration). For example, a raw analyte signal of 10 nA could be associated with a calibration analyte concentration of 100 mg/dL, and thus, a subsequent raw analyte signal of 20 nA could be converted to an analyte concentration of 200 mg/dL, as may be appropriate for a given analyte, such as glucose, for example. There are many ways in which the conversion factor may be obtained. For example, the sensitivity factor can be derived from a simple average of multiple analyte signal/calibration measurement data pairs, or from a weighted average of multiple analyte signal/calibration measurement data pairs. Further by way of example, the sensitivity may be modified based on an empirically derived weighting factor, or the sensitivity may be modified based on the value of another measurement, such as temperature. It will be appreciated that any combination of such approaches, and/or other suitable approaches, is contemplated herein. For subcutaneous glucose sensors, calibration at the site of manufacture, that may be relied upon to calibrate sensor signal for the useful life of a sensor, presents numerous challenges to the feasibility. This infeasibility may be based on any of a number of factors. For example, variations in the within-lot sensitivity of the analyte sensors and/or variations in sensor drift may be too great. The present disclosure provides sensor embodiments which attempt to address both the in vivo environmental effects and the manufacturing-based inconsistencies which can lead to variation in sensor sensitivity, and/or which obviate the need for any form of calibration, whether at the factory or by the user, at anytime prior to or during operative use of the sensor. Certain of these sensor embodiments are double-sided, i.e., both sides of the sensor's substrate are electrochemically functional, with each side providing at least one electrode. Because both sides of the sensor are utilized, the smaller the necessary surface area required per side to host the electrodes. This space-efficient construct allows the sensor to be miniaturized and much smaller than conventional sensors, and, in particular, have a relatively narrower tail portion, i.e., at least the portion of a sensor that is constructed to be positioned beneath a skin surface of a user is miniaturized. A narrower structure reduces trauma to tissue at the implantation site, thereby reducing bleeding and the production of thrombi around the sensor. The smaller structure also minimizes impingement upon adjacent blood vessels. The smaller width of the sensor allows, in addition to perpendicular diffusion of the analyte (e.g., glucose), for the lateral diffusion of analyte molecules towards the active sensing area. These effects substantially if not completely eliminate spurious low readings. In addition to providing micro tail sections, these double-sided sensors are designed and configured to be highly reproducible. Further, they may be fabricated by methods, techniques and equipment which minimize inconsistencies in the registration, deposition and resolution of the sensor components, as described herein. Referring now to FIGS. 6A-6C, an example of such a double-sided sensor in which an implantable portion of the sensor 600, e.g., the distal portion of the sensor's tail section, is illustrated. In particular, FIGS. 6A and 6B provide top and bottom views, respectively, of tail section 600 and FIG. 6C provides a cross-sectional side view of the same taken along lines C-C in FIG. 6A. Sensor tail portion 600 includes a substrate 602 (see FIG. 6C) having a top conductive layer 604a which substantially covers the entirety of the top surface area of substrate 602, i.e., the conductive layer substantially extends the entire length of the substrate to distal edge 612 and across the entire width of the substrate from side edge 614a to side edge 614b. Similarly, the bottom conductive layer 604b substantially covers the entirety of the bottom side of the substrate of tail portion 600. However, one or both of the conductive layers may terminate proximally of distal edge 612 and/or may have a width which is less than that of substrate 602 where the width ends a selected distance from the side edges 614a, 614b of the substrate, which distance may be equidistant or vary from each of the side edges. One of the top or bottom conductive layers, here, top conductive layer 604a, serves as the sensor's working electrode. The opposing conductive layer, here, bottom conductive layer 604b, serves as a reference and/or counter electrode. Where conductive layer 604b serves as either a reference or counter electrode, but not both, a third electrode may optionally be provided on a surface area of the proximal portion of the sensor (not shown). For example, conductive layer 604b may serve as reference electrode and a third conductive trace (not shown), present only on the non-implantable proximal portion of the sensor, may serve as the sensor's counter electrode. Disposed over a distal portion of the length of conducting layer/working electrode 604a is sensing component or layer 606. Providing the sensing layer closer to the distal tip of the sensor places the sensing material in the best position for contact with the analyte-containing fluid. As only a small amount of sensing material is required to facilitate electrooxidization or electroreduction of the analyte, positioning the sensing layer 606 at or near the distal tip of the sensor tail reduces the amount of material needed. Sensing layer 606 may be provided in a continuous stripe/band between and substantially orthogonal to the substrate's side edges 614a, 614b with the overlap or intersection of working electrode 604a and the sensing layer 606 defining the sensor's active area. Due to the orthogonal relationship between sensing layer 606 and conductive layer 604a, the active area has a rectilinear polygon configuration; however, any suitable shape may be provided. The dimensions of the active area may be varied by varying either or both of the respective width dimensions of the sensing and conducting layers. The width WS of the sensing layer 606 may cover the entire length of the working electrode or only a portion thereof. As the width WC of the conductive layer is dictated by the width of the tail portion's substrate in this embodiment, any registration or resolution inconsistencies between the conductive layer and the substrate are obviated. In certain embodiments, the width of the sensing layer WS is in the range from about 0.05 mm to about 5 mm, e.g., from about 0.1 mm to about 3 mm; the width of the conductive layer WC is in the range from about 0.05 mm to about 0.6 mm, e.g., from about 0.1 mm to about 0.3 mm, with the resulting active area in the range from about 0.0025 mm2 to about 3 mm2, e.g., from about 0.01 mm2 to about 0.9 mm2. Referring again to the electrodes, the same materials and methods may be used to make the top and bottom electrodes, although different materials and methods may also be used. With the working and reference electrodes positioned on opposing sides of the substrate as in the illustrated embodiment of FIGS. 6A-6C, it is not additionally inconvenient to use two or more different types of conductive material to form the respective electrodes as only one type of conductive material would need to be applied to each side of the substrate, thereby reducing the number of steps in the manufacturing process. Selection of the conductive materials for the respective electrodes is based in part on the desired rate of reaction of the sensing layer's mediator at an electrode. In some instances the rate of reaction for the redox mediator at the counter/reference electrode is controlled by, for example, choosing a material for the counter/reference electrode that would require an overpotential or a potential higher than the applied potential to increase the reaction rate at the counter/reference electrode. For example, some redox mediators may react faster at a carbon electrode than at a silver/silver chloride (Ag/AgCl) or gold electrode. However, as Ag/AgCl and gold are more expensive than carbon, it may be desirous to use the former materials judiciously. The sensor embodiment of FIGS. 6A-6C provides such a construct in which the full-length conductive layers 604a, 604b may be of a material such as carbon with a secondary layer of conductive layer 610 of a material such as Ag/AgCl disposed over a distal portion of bottom conductive layer 604b to collectively form the sensor's reference electrode. As with sensing layer 606, conductive material 610 may be provided in a continuous stripe/band between and substantially orthogonal to the substrate's side edges 614a, 614b. While layer 610 is shown positioned on substrate 602 proximally of sensing layer 606 (but on the opposite side of the substrate), layer 610 may be positioned at any suitable location on the tail portion 600 of the reference electrode 604b. For example, as illustrated in FIGS. 7A-7C, the secondary conductive material 710 of reference electrode 708b may be aligned with and/or distal to sensing layer 706 with dimensions WS and WC. Referring again to sensor 600, an insulation/dielectric layer 608a, 608b is disposed on each side 600a, 600b of the sensor, over at least the sensor's body portion (not shown), to insulate the proximal portion of the electrodes, i.e., the portion of the electrodes which in part remains external to the skin upon implantation. The top dielectric layer 608a disposed on the working electrode 604a may extend distally to but preferably not over any portion of sensing layer 606. Alternatively, as illustrated in FIGS. 7A-7C, dielectric layer 708a on the working electrode side of the sensor 700 may be provided prior to sensing layer 706 whereby the dielectric layer 708a has at least two portions spaced apart from each other on conductive layer 704a, best illustrated in FIG. 7C. FIG. 7C provides a cross-sectional side view taken along lines C-C in FIG. 7A. The sensing material 706 is then provided in the spacing between the two portions. As for the dielectric layer on the bottom/reference electrode side of the sensor, it may extend any suitable length of the sensor's tail section, i.e., it may extend the entire length of both of the primary and secondary conductive layers or portions thereof. For example, as illustrated in FIGS. 6A-6C, bottom dielectric layer 608b extends over the entire bottom surface area of secondary conductive material 610 but terminates proximally of the distal edge 612 of the length of the primary conductive layer 604b. It is noted that at least the ends of the secondary conductive material 610 which extend along the side edges 614a, 614b of the substrate 602 are not covered by dielectric layer 608b and, as such, are exposed to the in vivo environment when in operative use. In contrast, as illustrated in FIGS. 7A-7C, bottom dielectric layer 708b has a length which terminates proximally of secondary conductive layer 710 on bottom primary conductive layer 704b along substrate 702. Additional conducting and dielectric layers may be provided on either or both sides of the sensors, as described above. Finally, one or more membranes, which may function as one or more of an analyte flux modulating layer and/or an interferent-eliminating layer and/or biocompatible layer, discussed in greater detail below, may be provided about the sensor, e.g., as one or more of the outermost layer(s). In certain embodiments, as illustrated in FIG. 6C, a first membrane layer 616 may be provided solely over the sensing component or sensing layer 606 on the working electrode 604a to modulate the rate of diffusion or flux of the analyte to the sensing layer. For embodiments in which a membrane layer is provided over a single component/material, it may be suitable to do so with the same striping configuration and method as used for the other materials/components. Here, the stripe/band of membrane material 616 preferably has a width greater than that of sensing stripe/band 606. As it acts to limit the flux of the analyte to the sensor's active area, and thus contributes to the sensitivity of the sensor, controlling the thickness of membrane 616 is important. Providing membrane 616 in the form of a stripe/band facilitates control of its thickness. A second membrane layer 618, which coats the remaining surface area of the sensor tail, may also be provided to serve as a biocompatible conformal coating and provide smooth edges over the entirety of the sensor. In other sensor embodiments, as illustrated in FIG. 7C, a single, homogenous membrane 718 may be coated over the entire sensor surface area, or at least over both sides of the distal tail portion. It is noted that to coat the distal and side edges of the sensor, the membrane material would have to be applied subsequent to singulation of the sensor precursors. Based on current sensor fabrication techniques, provision of the sensor's conductive layers can be accomplished more accurately than provision of the sensing layers. As such, improving upon the accuracy of providing the sensing component on the sensor, and thus, the accuracy of the resulting active area, may significantly decrease any sensor to sensor sensitivity variability and obviate the need for calibration of the sensor. Accordingly, the present disclosure also includes methods for fabricating such analyte sensors having accurately defined active areas. Additionally, the methods provide finished sensors which are smaller than currently available sensors with micro-dimensioned tail portions which are far less susceptible to the in situ environmental conditions which can cause spurious low readings. In one variation of the subject methods, web-based manufacturing techniques are used to perform one or more steps in fabricating the subject sensors, many of the steps of which are disclosed in U.S. Pat. No. 6,103,033. To initiate the fabrication process, a continuous film or web of substrate material is provided and heat treated as necessary. The web may have precuts or perforations defining the individual sensor precursors. The various conductive layers are then formed on the substrate web by one or more of a variety of techniques as described above, with the working and reference (or counter/reference) electrode traces provided on opposite sides of the web. As mentioned previously, the electrode traces may be provided in channels formed in the surface of the substrate material; however, with the desire to provide a sensor having a tail portion that has the smallest functional profile possible, and particularly with the sensor tail having two functional sides, the use of channels may not be optimal as it requires a thicker substrate material. Also, as mentioned previously, a third, optional electrode trace (which may function as a counter electrode, for example) may be provided on the proximal body portion of the sensor precursors. The “primary” conductive traces provided on the area of the tail portions of the precursor sensors have a width dimension greater than the intended width dimension of the tail portions of the finalized sensors. The precursor widths of these conductive traces may range from about 0.3 mm to about 10 mm including widths in range from about 0.5 mm to about 3 mm, or may be even narrower. The primary conductive layers are formed extending distally along the tail section of the sensor precursors to any suitable length, but preferably extend at least to the intended distal edge of the finalized sensors to minimize the necessary sensor tail length. Next, the sensing layer and secondary conductive layers, if employed, are formed on the primary conductive layers on the respective sides of the substrates or substrate web. As discussed, each of these layers is preferably formed in a stripe or band of the respective material disposed orthogonally to the length of the primary conductive layer/sensor tail. With a single, continuous deposition process, the mean width of the sensing strip is substantially constant along the substrate webbing, and ultimately, from sensor to sensor. The secondary conductive layer (e.g., Ag/AgCl on the reference electrode), if provided, may also be formed in a continuous orthogonal stripe/band with similar techniques. One particular method of providing the various stripes/band of material on the sensors is by depositing, printing or coating the sensing component/material by means of an inkjet printing process (e.g., piezoelectric inkjet as manufactured by Scienion Inc. and distributed by BioDot Inc.). Another way of applying these materials is by means of a high precision pump (e.g., those which are piston driven or driven by peristaltic motion) and/or footed needle. The respective stripes/bands may be provided over a webbing of sequentially aligned sensor precursors prior to singulation of the sensors or over a plurality of sensors/electrodes where the sensors have been singulated from each other prior to provision of the one or more stripes/bands. With both the sensing and conductive layers/strips having substantially constant widths and provided substantially orthogonal to each other, the active area which their intersection forms is also substantially constant along both the length and width of the sensor. In such embodiments, the active area (as well as the intersecting area of the primary and secondary conductive layers which form the reference electrode) has a rectilinear polygonal shape which may be easier to provide in a reproducible manner from sensor to sensor; however, any relative arrangement of the layers resulting in any suitable active area geometry may be employed. The sensor precursors, i.e., the template of substrate material (as well as the conductive and sensing materials if provided on the substrate at the time of singulation), may be singulated from each other using any convenient cutting or separation protocol, including slitting, shearing, punching, laser singulation, etc. These cutting methods are also very precise, further ensuring that the sensor's active area, when dependent in part on the width of the sensor (i.e., the tail portion of the substrate), has very accurate dimensions from sensor to sensor. Moreover, with each of the materials (i.e., the primary and secondary conductive materials, sensing component, dielectric material, membrane, etc.) provided with width and/or length dimensions extending beyond the intended dimensions or boundaries of the final sensors, issues with resolution and registration of the materials is minimized if not obviated altogether. The final, singulated, double-sided sensor structures have dimensions in the following ranges: widths from about 500 μm to about 100 including widths in range from about 300 μm to about 150 μm; tail lengths from about 10 mm to about 3 mm, including lengths in range from about 6 mm to about 4 mm; and thicknesses from about 500 μm to about 100 including thicknesses in range from about 300 μm to about 150 μm. As such, the implantable portions of the sensors are reduced in size from conventional sensors by approximately 20% to about 80% in width as well as in cross-section. The reduced size minimizes bleeding and thrombus formation upon implantation of the sensor and impingement on adjacent tissue and vessels, thereby minimizing impediment to lateral diffusion of the analyte to the sensor's sensing component or sensing layer. The substrate web may have precuts or perforations that provide guidance for the final cut employed to singulate the precursors. Depending on the layout and orientation of the sensor precursors, the singulation lines may be at fixed or varying intervals. For example, if the orientation and spacing of the sensor precursors are serial and constant over the area of the substrate material, the singulation lines will typically be at fixed intervals in all directions. However, where the sensors having irregular or asymmetrical shapes (e.g., as illustrated in FIG. 5A) it may be preferential to orient the sensor precursors in an alternating (e.g., head to toe) or in mirroring (e.g., back to back) arrangements to minimize the unused substrate material and any of the sensor materials deposited thereon. Where the orientation of the sensor precursors is alternating or in a mirroring arrangement, the singulation lines may not be at fixed intervals. Embodiments include sensor lots having very low variations in sensitivity of sensors within the lot. Low sensitivity variation enables sensors that do not require calibration by a user after a sensor is positioned in the body. Accordingly, in certain embodiments, sensor lots are provided that have a coefficient of variation (CV) of about 5% or less, e.g., about 4.5% or less, e.g., about 4% or less, e.g., about 3% or less. Sensors having predictable sensor in vivo sensitivity and signal are provided. For example, sensors having predictable shelf life sensitivity drift (the period of time between manufacture and use) and predictable in vivo sensitivity drift, including substantially no shelf and in vivo sensitivity drift, are also provided. In embodiments in which sensors have drift (e.g., where the sensor sensitivity drifts an expected percentage over a certain time), a drift profile is contemplated. This drift profile may be contemplated by an algorithm of the monitoring system to determine a drift correction factor that may be applied to sensor signal to obtain a glucose measurement (mg/dL). Due, at least in part, to the high reproducibility of the manufacturing process that results in low manufacturing coefficient of variation (CV), a single drift correction factor may be used for all sensors of a given sensor manufacturing lot or batch. In certain embodiments, sensor sensitivity may be determined post-fabrication by the manufacturer at the site of manufacture. This “factory-determined” sensitivity may then be used in an algorithm to calibrate sensor signal for the useable lifetime of the sensor, negating the need for a user to obtain a reference value, e.g., from a test strip, for calibration. Sensitivity may include determining the relationship of sensor signal to a reference such as an in vitro reference (a known glucose level to which one or more sensors of a sensor lot may be compared). Sensitivity may include determining a conversion factor as described herein. In certain embodiments, the determined sensitivity may be further augmented. For example, one or more additional factors (e.g., to account for the relationship of blood to subcutaneous tissue glucose, effect of oxygen, temperature, etc.) may be contemplated. In any event, a sensitivity value is determined. Exemplary calibration protocols are described, e.g., in U.S. Pat. No. 7,299,082, the disclosure of which is incorporated herein by reference for all purposes. Because the sensitivities of each sensor of a given manufacturing lot are substantially the same according to the embodiments herein, the factory-determined sensitivity may be applied to all sensors of such a lot, i.e., a single calibration algorithm may be used for all the sensors of a given lot. In one embodiment, the information is programmed or is programmable into software of the monitoring system, e.g., into one or more processors. For example, the factory-determined sensitivity may be provided to a user with a sensor(s) and uploaded to a calibration algorithm manually or automatically (e.g., via bar code and reader, or the like). Calibration of sensor signal may then be implemented using suitable hardware/software of the system. A mass transport limiting layer or membrane, e.g., an analyte flux modulating layer, may be included with the sensor to act as a diffusion-limiting barrier to reduce the rate of mass transport of the analyte, for example, glucose or lactate, into the region around the working electrodes. The mass transport limiting layers are useful in limiting the flux of an analyte to a working electrode in an electrochemical sensor so that the sensor is linearly responsive over a large range of analyte concentrations. Mass transport limiting layers may include polymers and may be biocompatible. A mass transport limiting layer may provide many functions, e.g., biocompatibility and/or interferent-eliminating, etc. A membrane may be formed by crosslinking in situ a polymer, modified with a zwitterionic moiety and a non-pyridine copolymer component. The modified polymer may be made from a precursor polymer containing heterocyclic nitrogen groups. For example, a precursor polymer may be polyvinylpyridine or polyvinylimidazole. Embodiments also include membranes that are made of a polyurethane, or polyether urethane, or chemically related material, or membranes that are made of silicone, and the like. Optionally, another moiety or modifier that is either hydrophilic or hydrophobic, and/or has other desirable properties, may be used to “fine-tune” the permeability of the resulting membrane to an analyte of interest. Optional hydrophilic modifiers, such as poly(ethylene glycol), hydroxyl or polyhydroxyl modifiers, may be used to enhance the biocompatibility of the polymer or the resulting membrane. The membrane may also be formed in situ by applying an alcohol-buffer solution of a crosslinker and a modified polymer over an enzyme-containing sensing layer and allowing the solution to cure for about one to two days or other appropriate time period. The crosslinker-polymer solution may be applied to the sensing layer by placing a droplet or droplets of the solution on the sensor, by dipping the sensor into the solution, or the like. Generally, the thickness of the membrane is controlled by the concentration of the solution, by the number of droplets of the solution applied, by the number of times the sensor is dipped in the solution, or by any combination of these factors. A membrane applied in this manner may have any combination of the following functions: (1) mass transport limitation, i.e., reduction of the flux of analyte that can reach the sensing layer, (2) biocompatibility enhancement, or (3) interferent reduction. Exemplary mass transport layers are described in U.S. patents and applications noted herein, including, e.g., in U.S. Pat. Nos. 5,593,852, 6,881,551 and 6,932,894, the disclosures of each of which are incorporated herein by reference for all purposes. A sensor may also include an active agent such as an anticlotting and/or antiglycolytic agent(s) disposed on at least a portion a sensor that is positioned in a user. An anticlotting agent may reduce or eliminate the clotting of blood or other body fluid around the sensor, particularly after insertion of the sensor. Examples of useful anticlotting agents include heparin and tissue plasminogen activator (TPA), as well as other known anticlotting agents. Embodiments may include an antiglycolytic agent or precursor thereof. Examples of antiglycolytic agents are glyceraldehyde, fluoride ion, and mannose. The electrochemical sensors of the present disclosure may employ any suitable measurement technique, e.g., may detect current, may employ potentiometry, etc. Techniques may include, but are not limited to, amperometry, coulometry, and voltammetry. In some embodiments, sensing systems may be optical, colorimetric, and the like. The subject analyte measurement systems may include an optional alarm system that, e.g., based on information from a processor, warns the patient of a potentially detrimental condition of the analyte. For example, if glucose is the analyte, an alarm system may warn a user of conditions such as hypoglycemia and/or hyperglycemia and/or impending hypoglycemia, and/or impending hyperglycemia. An alarm system may be triggered when analyte levels approach, reach or exceed a threshold value. An alarm system may also, or alternatively, be activated when the rate of change, or acceleration of the rate of change, in analyte level increase or decrease approaches, reaches or exceeds a threshold rate or acceleration. A system may also include system alarms that notify a user of system information such as battery condition, calibration, sensor dislodgment, sensor malfunction, etc. Alarms may be, for example, auditory and/or visual. Other sensory-stimulating alarm systems may be used including alarm systems which heat, cool, vibrate, or produce a mild electrical shock when activated. The subject disclosure also includes sensors used in sensor-based drug delivery systems. The system may provide a drug to counteract the high or low level of the analyte in response to the signals from one or more sensors. Alternatively, the system may monitor the drug concentration to ensure that the drug remains within a desired therapeutic range. The drug delivery system may include one or more (e.g., two or more) sensors, a processing unit such as a transmitter, a receiver/display unit, and a drug administration system. In some cases, some or all components may be integrated in a single unit. A sensor-based drug delivery system may use data from the one or more sensors to provide necessary input for a control algorithm/mechanism to adjust the administration of drugs, e.g., automatically or semi-automatically. As an example, a glucose sensor may be used to control and adjust the administration of insulin from an external or implanted insulin pump. Referring now to FIGS. 8A-12B, the continuous analyte measurement systems illustrated therein are particularly suitable for use with the double-sided analyte sensors disclosed herein. These systems include a skin-mounted portion or assembly and a remote portion or assembly. The skin-mounted portion includes at least the data transmitter, the transmitter battery and electrical contacts for electrically coupling the implanted sensor with the transmitter, and has a housing or base which is constructed to externally mount to the patient's skin and to mechanically and electrically couple the implanted sensor with the transmitter. Removably held or positioned within the housing/base structure is a connector piece having an electrical contact configuration which, when used with a double-sided sensor, enables coupling of the sensor to the transmitter in a low-profile, space-efficient manner. The remote portion of the system includes at least a data receiver and a user interface which may also be configured for test strip-based glucose monitoring. Various embodiments of these systems and methods of using them are now described in greater detail. FIGS. 8A and 8B illustrate one embodiment of the skin-mounted portion or assembly 800 of a continuous analyte monitoring system of the present disclosure. Assembly 800 includes a connector or base 802 and a transmitter 804 both having rectangular or square constructs which, when operatively coupled together, are mounted side-by-side in the same plane on the skin. The underside of both components has an adhesive layer for securing to the skin surface. Connector 802 encases a conductive core or elongated member 806 extending along its length. Conductive core 806 is shown having a cylindrical configuration but may have any suitable shape. The connector body and conductive core may be made of any suitable non-conductive and conductive materials, respectively. To provide a non-rigid or semi-flexible embodiment, connector body 802 or the portion of it about the conductive core 806 may be made of a flexible or compressible material such as silicone, etc., and connector core 806 may be made of a conductive polymeric material, e.g., carbon-doped silicone. The connector 802 and its connector core 806 may be provided in two parts or halves 802a and 802b, whereby the system's analyte sensor 808, here, having two functional sides 808a and 808b, may be sandwiched therebetween. Each of the inner ends of core 806 abuts a respective electrode 814a, 814b of sensor 808. A bracket or fixture 816 may be employed to clamp together or apply pressure on opposing ends of the two connector body 802/connector core 806 pieces to ensure a sufficient, continuous electrical contact between connector core 806 and sensor electrodes 814a, 814b. The body of the connector 802 has hollowed holes or receptacles 810a, 810b within a side thereof which extend to or within conductive core 806. Holes 810a, 810b are dimensioned and spaced for receiving corresponding conductive pins 812a, 812b extending from an end 815 of transmitter 804. When the connector 802 and transmitter 804 are operatively coupled, as illustrated in FIG. 8B, pins 812a, 812b extend within and are in electrical communication with conductive core 806, and thus, with sensor 808. The compressible, non-conductive material of connector 802 provides a substantially hermetic seal between transmitter 804 and sensor 808. The transmitter housing may house a battery (not shown) for powering the transmitter 804, the sensor 808, and at least a portion of the system's control electronics, e.g., the data processing unit, etc. FIGS. 9A-9E illustrate another embodiment of the skin-mounted portion or assembly 900 of a continuous analyte monitoring system of the present disclosure. With reference to FIG. 9A, assembly 900 includes a transmitter 902 mounted atop a mounting structure or base 904, the underside of which has an adhesive layer for securing to the skin surface. Here, transmitter 902 has a round foot print and a convex, low-profile top surface. The transmitter housing may house a battery (not shown) for powering the transmitter 902, the sensor 906, and at least a portion of the system's control electronics, e.g., the data processing unit, etc. A raised rim 916 or similar feature on the top surface 912 of base 904 is shaped and dimensioned to securely hold transmitter 902 in a snap-fit configuration. Base 904 also has a centrally disposed cradle 908 on its top surface 912 for receiving and snugly holding a connector 910. As best shown in FIG. 9B, a sidewall of the base 904 has an outwardly extending portion 914 which defines a slit or keyhole therein to receive a sensor 906 (as well as an insertion needle, as will be explained below) when operatively held by connector 910. An aperture (not shown) within the bottom of cradle 908 allows passage of sensor tail 906b upon placement of connector 910 within the cradle 908. Cradle 908 may be sized to compress the ends of the connector 910 toward each other so as to ensure a constant electrical connection between the connector 910 and sensor 906. As illustrated in FIGS. 9C-9E, connector 910 has a cylindrical configuration having several concentric layers or materials: a non-conductive inner member 910a, a conductive intermediate layer 910b, and an outer dielectric cover or shell 910c. In one embodiment, the cylindrical connector is compliant, with each of its layers made of compliant material(s) as described with respect to the embodiment of FIGS. 8A and 8B. The optional inner member 910a is made of a non-conductive compliant or substantially rigid material which extends through a hole 906c at the proximal end 906a of sensor 906 and, thus, acts as an alignment pin. The terminal ends of the working and reference electrodes of double-sided sensor 906 form a conductive area or ring 906d about hole 906c. Conductive ring 906d may be made of gold or another highly conductive material. The connector's intermediate layer 910b is made of a compliant conductive material, such as a conductive polymeric material as described with respect to the embodiment of FIGS. 8A and 8B, which abuts against both sides of conductive area 906d of the sensor. The outer shell 910c of the connector, which extends over and insulates each of the conductive ends of the intermediate layer 910b, is made of a compliant dielectric material, such as silicone, which ensures that the interconnection between the transmitter, connector and sensor is hermetically sealed. On a top surface of outer shell 910c are a pair of bores or holes 918 for receiving a corresponding pair of pins or plugs 920 extending from the bottom side of transmitter 902. The bores and pins may have respective mating configurations to ensure a snug fit and hermetically seal between transmitter 902 and connector 910. For example, as illustrated in FIG. 9E, bores 918 may have a stepped configuration and pins 920 may have a conical configuration. At least the distal tip 922 of each pin 920 is made of a conductive material, such as gold, to establish electrical communication between transmitter 902 and sensor 906. FIGS. 10A-10F illustrate various steps in a method of the present disclosure for mounting the continuous analyte monitoring system's on-skin assembly 900, including implanting sensor 906 within the skin, utilizing an insertion device 1000 of the present disclosure. However, the sensor/connector may be configured to be manually inserted/mounted without the use of an insertion device. Insertion device 1000 comprises a body 1002 having a distal base portion 1008 having a bottom surface configured for placement on the skin surface 1005. It is noted that the figures show, with solid drawing lines, components of the insertion device and the analyte monitoring system that would otherwise not be visible when positioned or housed within device body 1002 for purposes of illustration and ease of description. For example, in FIGS. 10A-10C, mounting base 904 of assembly 900 (FIG. 9A) is shown releasably held within an opening in the bottom surface of device body 1002. Insertion device 1000 further includes a plunger mechanism 1004 positioned within the housing 1002 and movable in a direction perpendicular to the skin surface 1005. The distal end of the plunger mechanism 1004 carries an insertion needle 1006. The components of insertion device 1000 are typically formed using structurally rigid materials, such as metal or rigid plastic. Preferred materials include stainless steel and ABS (acrylonitrile-butadiene-styrene) plastic. With reference to FIGS. 11A and 11B, the shaft of insertion needle 1006 may include a longitudinal opening, having a cross-sectional shape for releasably carrying the forward edge 906e of the analyte sensor (see FIG. 11B). In particular, the needle shaft 1006 may be C-, U- or V-shaped to support the sensor and limit the amount that the sensor may bend or bow during insertion. The cross-sectional width and height of insertion needle 1006 are appropriately sized to hold the sensor being inserted. In the illustrated embodiment, insertion needle 1006 is pointed and/or sharp at the tip 1012 to facilitate penetration of the skin of the patient. A sharp, thin insertion needle may reduce pain felt by the patient upon insertion of the sensor. In other embodiments, the tip of the insertion needle has other shapes, including a blunt or flat shape. These embodiments may be particularly useful when the insertion needle is not intended to penetrate the skin but rather serves as a structural support for the sensor as the sensor is pushed into the skin. As such, the sensor itself may include optional features to facilitate insertion. For example, sensor 906 may have a pointed tail portion 906b to ease insertion. In addition, the sensor may include a barb (not shown) which helps retain the sensor in the subcutaneous tissue upon insertion. The sensor may also include a notch (not shown) that can be used in cooperation with a corresponding structure (not shown) in the insertion needle to apply pressure against the sensor during insertion, but disengage as the insertion needle is removed. To commence the sensor insertion/transmitter mounting procedure, the front edge 906e (see FIGS. 11A and 11B) of sensor 906, which is operatively held within connector 910 (as shown in FIG. 9B but not evident in the side views provided in FIGS. 10A-10F), is slid into placed within insertion needle 1006. In turn, the pre-loaded insertion needle 1006 is operatively loaded onto the distal end of plunger 1004. Mounting base 904 with the attached connector cradle 908 is then coupled to the bottom end of insertion body 1002, such as by a snap-fit arrangement that is releasable upon complete downward displacement of plunger 1004. The collective assembly is then placed on the target skin surface 1005, as shown in FIG. 10A. The user 1010 then applies a downward force on plunger 1004, as shown in FIG. 10B, which force is transferred against insertion needle 1006 and/or sensor 906 to carry the sensor 906 into the skin 1005 of the patient. The plunger 1004 may be biased to require a certain amount of force to avoid accidental depression and to provide for very fast penetration and removal of the insertion needle from the skin. For example, a cocked or wound spring, a burst of compressed gas, an electromagnet repelled by a second magnet, or the like, may be used to provide the biasing force on plunger 1004. In one embodiment (as shown), the plunger force is applied to insertion needle 1006, and optionally to sensor 906, to push a portion of both the sensor 906 and the insertion needle 1006 through the skin 1005 of the patient and into the subcutaneous tissue. Alternatively, the force may be applied only to the sensor 906, pushing it into the skin 1005, while the insertion needle 1006 remains stationary and provides structural support to the sensor 906. In either embodiment, a hard stop to the sensor's continued penetration into the skin 1005 is provided when the connector 910 is seated within cradle 908. Once fully depressed, plunger 1004 is then released by the user 1010, as illustrated in FIG. 10C. With the upward spring biased placed on the plunger, the insertion needle is quickly retracted from the skin 1005 with sensor 906 remaining in the subcutaneous tissue due to frictional forces between the sensor and the patient's tissue. If the sensor includes the optional barb, then this structure may also facilitate the retention of the sensor within the interstitial tissue as the barb catches in the tissue. Release of plunger 1004 may also automatically decouple mounting base 904 from insertion body 1002, or a separate trigger mechanism (not shown) may be provided on the device to perform such function. The adhesive on the skin-contacting surface of base 904 retains it in place when the insertion device 1000 is removed from the skin, as illustrated in FIG. 10D. The insertion device 1000 is typically manufactured to be disposable to avoid the possibility of contamination. Alternatively, the insertion device 1000 may be sterilized and reused with only the insertion needle being disposable. After removal of the insertion device 1000 from the skin 1005, the transmitter 902 may then be manually coupled onto the mounting base 904, as shown in FIG. 10E. Specifically, the conductive pins 920 of transmitter 902 are positioned within the corresponding holes 918 within connector 910 (see FIG. 9E). In an alternate embodiment, the insertion device may be configured to mechanically mount the transmitter 902 which would be pre-mounted to the mounting base 904. In either variation, control electronics (not shown) housed within transmitter 902 enables monitoring of glucose (or other target analytes) by sensor 906 and transmission of such analyte data by transmitter 902 to the remote receiver unit (not shown) according to the pre-programmed protocols. As mentioned previously, a battery may be provided within the transmitter housing to power the transmitter 902 as well as to provide the necessary electrical signals to sensor 906. The battery may be rechargeable/replaceable through a door (not shown) provided in the transmitter housing. To minimize the size of the on-skin unit, the battery may be relatively small, having only a moderately-lasting charge, e.g., about 3-14 days more or less. In another variation, the battery is not rechargeable or replaceable, but is disposed of along with the transmitter upon expiration of the battery charge. As this arrangement is more expensive, having a battery/transmitter that has a longer-lasting charge, e.g., about 6 months to a year may be necessary; of course, the tradeoff being a larger unit. Still yet, the transmitter may be extensively reusable with the battery being disposable along with the sensor upon expiration of the sensor's useful life, typically, between about 3 to about 14 days, in which case, the battery may be very small to last only as long as the sensor. FIGS. 12A and 12B illustrate top and bottom views, respectively, of an on-skin mounting unit or base 1050 of another continuous analyte monitoring system of the present disclosure in which the battery is provided in the mounting base rather than in the transmitter. The conductive proximal portion 1054a (i.e., the electrodes) of an analyte sensor 1054 is positionable or positioned within a slot or slit 1066 within a side wall of base 1050 with the tail portion 1054b extending transversely from the base. The proximal sensor portion 1054a lies between a two-piece electrical core or connector 1056 which is permanently housed within mounting unit 1050. The connector has contacts 1056a (see FIG. 12A) which extend to a top surface 1052 of base 1050 for receiving corresponding conductive pins of the transmitter (not shown). The entire base 1050 may be fabricated of a compressible, insulating material, such as silicone. Features 1064 on opposing sidewalls of the base aligned with the ends of connector 1056 are compressible to ensure that connector 1056 maintains continuous electrical contact with sensor 1054. Such compression features 1064 may comprise a flexure such as a living hinge or the like. To prevent any movement of sensor 1054 upon placement within skin tissue, an optional alignment pin 1058 may be provided through a hole within proximal sensor portion 1054a. The opposing ends of the alignment pin 1058 may extend beyond the sidewalls of the base to physically engage with corresponding features of the transmitter (not shown) upon coupling with the base unit 1050. Also housed within base unit 1050 is a battery 1060 having high (+) and ground (−) connector contacts 1060a, 1060b, respectively. As seen in FIG. 12A, the connector contacts 1056a and battery contacts 1060a, 1060b have receptacle configurations to matingly receiving corresponding pin contacts of a transmitter (not shown) when mounted atop mounting base 1050. As such, electrical communication is established between sensor 1054 and the transmitter, and power is supplied to the transmitter and to the on-skin unit as a whole. The coupling between the transmitter and mounting base may be by way of a snap-fit arrangement between the pins and receptacles, which also allows for easy removal when replacing the base unit 1050 upon expiration of the battery 1060 and/or useful life of the sensor 1054 with the more expensive transmitter component being reusable. All of the on-skin portions of the subject continuous monitoring systems have a very low-profile configuration. While certain embodiments have at least one dimension that is extremely small, other dimensions may be slightly greater to provide the necessary volume to house the various components of the on-skin units. For example, an on-skin unit may have a very low height dimension, but have relatively greater width and length dimensions. On the other hand, the width/length dimensions may be very small with the height being relatively greater. The optimal dimensions of a particular on-skin unit may depend on where on the body the unit is intended to be mounted. One exemplary set of dimensions for an on-skin unit of the present disclosure includes a width from about 7.5 to about 8.5 mm, a length from about 10 to about 11 mm, and a height from about 2.5 to about 3.3 mm. Exemplary analyte monitoring systems are described in, for example, U.S. patent application Ser. No. 12/698,124 entitled “Compact On-Body Physiological Monitoring Devices and Methods Thereof” and in U.S. patent application Ser. No. 12/730,193 entitled “Methods of Treatment and Monitoring Systems for Same”, the disclosures of each of which are incorporated herein by reference for all purposes. Exemplary methods and systems for inserting a an analyte sensor are described in, for example, U.S. Pat. No. 6,990,366, U.S. patent application Ser. Nos. 12/698,124, 12/698,129, now U.S. Pat. No. 9,402,544, and U.S. Provisional Application Nos. 61/238,159, 61/238,483 and 61/249,535, the disclosures of each of which are incorporated herein by reference for all purposes. Although the subject sensors may be inserted anywhere in the body, it is often desirable that the insertion site be positioned so that the on-skin sensor control unit can be concealed. In addition, it is often desirable that the insertion site be at a place on the body with a low density of nerve endings to reduce the pain to the patient. Examples of preferred sites for insertion of the sensor and positioning of the on-skin sensor control unit include the abdomen, thigh, leg, upper arm, and shoulder. In one embodiment, the subject sensors are injected between 2 to 12 mm into the interstitial tissue of the patient for subcutaneous implantation. Preferably, the sensor is injected 3 to 9 mm, and more preferably 5 to 7 mm, into the interstitial tissue. Other embodiments of the present disclosure may include sensors implanted in other portions of the patient, including, for example, in an artery, vein, or organ. The depth of implantation varies depending on the desired implantation target. Sensor insertion angles usually range from about 10° to about 90°, typically from about 15° to about 60°, and often from about 30° to about 45°. The construct of the insertion device, of course, will vary depending on the desired angle of insertion. In one embodiment, a continuous analyte measurement system may include a base unit configured for mounting on a skin surface, an analyte sensor comprising two functional sides, a proximal portion configured for positioning within the base unit and a distal portion configured for insertion into the skin surface, and a conductive member positionable within the base unit and in electrical contact with the two functional sides of analyte sensor. The proximal portion of the analyte sensor may have a planar configuration and the conductive member may be mechanically and electrically coupled to the two functional sides of the proximal portion of the analyte sensor. The base unit may be compressible on opposing sides at least about the conductive member. Furthermore, the system may include a component for compressing the opposing ends of the conductive member. In one aspect, the component for compressing may be flexures on opposing sides of the base unit about the conductive member. In another aspect, the component for compressing may be a clamping fixture positionable on opposing sides of the base unit about the conductive member. In one aspect, the system may include an alignment pin extending through the proximal portion of the analyte sensor. The base unit may be a non-conductive compressible material. The non-conductive compressible material may be silicone. The conductive connector may be a conductive compressible material. The conductive compressible material may be carbon-doped silicone. In a further aspect, the system may include a transmitter configured for mounting to the base unit in a low-profile manner, wherein the base unit includes a pair of receptacles for receiving a corresponding pair of conductive pins of the transmitter, and the conductive pins contact the conductive member when the transmitter is operatively mounted to the base unit. The transmitter may mount with the base unit in a side-by-side configuration. The transmitter may mount atop the base unit. The transmitter may house a battery. The base unit may house a battery. Moreover, the base unit may include a second pair of receptacles for receiving a corresponding second pair of conductive pins of the transmitter, wherein the conductive pins contact the battery when the transmitter is operatively mounted to the base unit. The base unit may include a cradle therein for receiving and holding the conductive member. The cradle may compress opposing ends of the conductive member when held within the cradle. The conductive member may include a conductive core and an insulating shell covering the conductive core. In one aspect, the conductive member may include a non-conductive inner member within the conductive core, wherein the non-conductive inner member extends through an opening in the analyte sensor. The base unit may include an adhesive bottom for adhering to the skin surface. The base unit may include an opening therein through which the distal end of the analyte sensor extends. The distal end of the analyte sensor may extend along a sidewall of the base unit. Regarding methodology, the subject methods may include each of the mechanical and/or activities associated with use of the devices described. As such, methodology implicit to the use of the devices described forms part of the present disclosure. Other methods may focus on fabrication of such devices. The methods that may be performed according to embodiments herein and that may have been described above and/or claimed below, the operations have been described in selected typographical sequences. However, the sequences have been selected and so ordered for typographical convenience and are not intended to imply any particular order for performing the operations. As for other details of the present disclosure, materials and alternate related configurations may be employed as within the level of those with skill in the relevant art. The same may hold true with respect to method-based aspects of the present disclosure in terms of additional acts as commonly or logically employed. In addition, though embodiments of the present disclosure have been described in reference to several examples, optionally incorporating various features, the present disclosure is not to be limited to that which is described or indicated as contemplated with respect to each variation of the present embodiments. Various changes may be made to the embodiments described and equivalents (whether recited herein or not included for the sake of some brevity) may be substituted without departing from the true spirit and scope of the present disclosure. Any number of the individual parts or subassemblies shown may be integrated in their design. Such changes or others may be undertaken or guided by the principles of design for assembly. Also, it is contemplated that any optional feature of the inventive variations described may be set forth and claimed independently, or in combination with any one or more of the features described herein. Reference to a singular item, includes the possibility that there are plural of the same items present. More specifically, as used herein and in the appended claims, the singular forms “a,” “an,” “said,” and “the” include plural referents unless the specifically stated otherwise. In other words, use of the articles allow for “at least one” of the subject item in the description above as well as the claims below. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation. Without the use of such exclusive terminology, the term “comprising” in the claims shall allow for the inclusion of any additional element—irrespective of whether a given number of elements are enumerated in the claim, or the addition of a feature could be regarded as transforming the nature of an element set forth in the claims. Stated otherwise, unless specifically defined herein, all technical and scientific terms used herein are to be given as broad a commonly understood meaning as possible while maintaining claim validity. In all, the breadth of the present disclosure is not to be limited by the examples provided. | <SOH> BACKGROUND <EOH>There are a number of instances when it is desirable or necessary to monitor the concentration of an analyte, such as glucose, lactate, or oxygen, for example, in bodily fluid of a body. For example, it may be desirable to monitor high or low levels of glucose in blood or other bodily fluid that may be detrimental to a human. In a healthy human, the concentration of glucose in the blood is maintained between about 0.8 and about 1.2 mg/mL by a variety of hormones, such as insulin and glucagons, for example. If the blood glucose level is raised above its normal level, hyperglycemia develops and attendant symptoms may result. If the blood glucose concentration falls below its normal level, hypoglycemia develops and attendant symptoms, such as neurological and other symptoms, may result. Both hyperglycemia and hypoglycemia may result in death if untreated. Maintaining blood glucose at an appropriate concentration is thus a desirable or necessary part of treating a person who is physiologically unable to do so unaided, such as a person who is afflicted with diabetes mellitus. Certain compounds may be administered to increase or decrease the concentration of blood glucose in a body. By way of example, insulin can be administered to a person in a variety of ways, such as through injection, for example, to decrease that person's blood glucose concentration. Further by way of example, glucose may be administered to a person in a variety of ways, such as directly, through injection or administration of an intravenous solution, for example, or indirectly, through ingestion of certain foods or drinks, for example, to increase that person's blood glucose level. Regardless of the type of adjustment used, it is typically desirable or necessary to determine a person's blood glucose concentration before making an appropriate adjustment. Typically, blood glucose concentration is monitored by a person or sometimes by a physician using an in vitro test that requires a blood sample. The person may obtain the blood sample by withdrawing blood from a blood source in his or her body, such as a vein, using a needle and syringe, for example, or by lancing a portion of his or her skin, using a lancing device, for example, to make blood available external to the skin, to obtain the necessary sample volume for in vitro testing. The fresh blood sample is then applied to an in vitro testing device such as an analyte test strip, whereupon suitable detection methods, such as colorimetric, electrochemical, or photometric detection methods, for example, may be used to determine the person's actual blood glucose level. The foregoing procedure provides a blood glucose concentration for a particular or discrete point in time, and thus, must be repeated periodically, in order to monitor blood glucose over a longer period. Conventionally, a “finger stick” is generally performed to extract an adequate volume of blood from a finger for in vitro glucose testing since the tissue of the fingertip is highly perfused with blood vessels. These tests monitor glucose at discrete periods of time when an individual affirmatively initiates a test at a given point in time, and therefore may be characterized as “discrete” tests. Unfortunately, the fingertip is also densely supplied with pain receptors, which can lead to significant discomfort during the blood extraction process. Unfortunately, the consistency with which the level of glucose is checked varies widely among individuals. Many diabetics find the periodic testing inconvenient and they sometimes forget to test their glucose level or do not have time for a proper test. Further, as the fingertip is densely supplied with pain receptors which causes significant discomfort during the blood extraction process, some individuals will not be inclined to test their glucose levels as frequently as they should. These situations may result in hyperglycemic or hypoglycemic episodes. Glucose monitoring systems that allow for sample extraction from sites other than the finger and/or that can operate using small samples of blood, have been developed. (See, e.g., U.S. Pat. Nos. 6,120,676, 6,591,125 and 7,299,082, the disclosures of each of which are incorporated herein by reference for all purposes). Typically, about one μL or less of sample may be required for the proper operation of these devices, which enables glucose testing with a sample of blood obtained from the surface of a palm, a hand, an arm, a thigh, a leg, the torso, or the abdomen. Even though less painful than the finger stick approach, these other sample extraction methods are still inconvenient and may also be somewhat painful. In addition to the discrete, in vitro, blood glucose monitoring systems described above, at least partially implantable, or in vivo, blood glucose monitoring systems, which are designed to provide continuous or semi-continuous in vivo measurement of an individual's glucose concentration, have been described. See, e.g., U.S. Pat. Nos. 6,175,752, 6,284,478, 6,134,461, 6,560,471, 6,746,582, 6,579,690, 6,932,892 and 7,299,082, the disclosures of each of which are incorporated herein by reference for all purposes. A number of these in vivo systems are based on “enzyme electrode” technology, whereby an enzymatic reaction involving an enzyme such as glucose oxidase, glucose dehydrogenase, or the like, is combined with an electrochemical sensor for the determination of an individual's glucose level in a sample of the individual's biological fluid. By way of example, the electrochemical sensor may be placed in substantially continuous contact with a blood source, e.g., may be inserted into a blood source, such as a vein or other blood vessel, for example, such that the sensor is in continuous contact with blood and can effectively monitor blood glucose levels. Further by way of example, the electrochemical sensor may be placed in substantially continuous contact with bodily fluid other than blood, such as dermal or subcutaneous fluid, for example, for effective monitoring of glucose levels in such bodily fluid, such as interstitial fluid. Relative to discrete or periodic monitoring using analyte test strips, continuous monitoring is generally more desirable in that it may provide a more comprehensive assessment of glucose levels and more useful information, including predictive trend information, for example. Subcutaneous continuous glucose monitoring is also desirable as it is typically less invasive than continuous glucose monitoring in blood accessed from a blood vessel. Regardless of the type of implantable analyte monitoring device employed, it has been observed that transient, low sensor readings which result in clinically significant sensor related errors may occur for a period of time. For example, it has been found that during the initial 12-24 hours of sensor operation (after implantation), a glucose sensor's sensitivity (defined as the ratio between the analyte sensor current level and the blood glucose level) may be relatively low—a phenomenon sometimes referred to as “early signal attenuation” (ESA). Additionally, low sensor readings may be more likely to occur at certain predictable times such as during night time use—commonly referred to as “night time drop outs”. An in vivo analyte sensor with lower than normal sensitivity may report blood glucose values lower than the actual values, thus potentially underestimating hyperglycemia, and triggering false hypoglycemia alarms. While these transient, low readings are infrequent and, in many instances, resolve after a period of time, the negative deviations in sensor readings impose constraints upon analyte monitoring during the period in which the deviations are observed. One manner of addressing this problem is to configure the analyte monitoring system so as to delay reporting readings to the user until after this period of negative deviations passes. However, this leaves the user vulnerable and relying on alternate means of analyte measuring, e.g., in vitro testing, during this time. Another way of addressing negative deviations in sensor sensitivity is to require frequent calibration of the sensor during the time period in which the sensor is used. This is often accomplished in the context of continuous glucose monitoring devices by using a reference value after the sensor has been positioned in the body, where the reference value most often employed is obtained by a finger stick and use of a blood glucose test strip. However, these multiple calibrations are not desirable for at least the reasons that they are inconvenient and painful, as described above. One cause of spurious low readings or drop outs by these implantable sensors is thought to be the presence of blood clots, also known as “thrombi”, formed as a result of insertion of the sensor in vivo. Such clots exist in close proximity to a subcutaneous glucose sensor and have a tendency to “consume” glucose at a high rate, thereby lowering the local glucose concentration. It may also be that the implanted sensor constricts adjacent blood vessels thereby restricting glucose delivery to the sensor site. One approach to addressing the problem of drop outs is to reduce the size of the sensor, thereby reducing the likelihood of thrombus formation upon implantation and impingement of the sensor structure on adjacent blood vessels, and thus, maximizing fluid flow to the sensor. One manner of reducing the size or surface area of at least the implantable portion of a sensor is to provide a sensor in which the sensor's electrodes and other sensing components and/or layers are distributed over both sides of the sensor, thereby necessitating a narrow sensor profile. Examples of such double-sided sensors are disclosed in U.S. Pat. No. 6,175,752, U.S. Patent Application Publication No. 2007/0203407, now U.S. Pat. No. 7,826,879, and U.S. Provisional Application No. 61/165,499 filed Mar. 31, 2009, the disclosures of each of which are incorporated herein by reference for all purposes. It would also be desirable to provide sensors for use in a continuous analyte monitoring system that have negligible variations in sensitivity, including no variations or at least no statistically significant and/or clinically significant variations, from sensor to sensor. Such sensors would have to lend themselves to being highly reproducible and would necessarily involve the use of extremely accurate fabrication processes. It would also be highly advantageous to provide continuous analyte monitoring systems that are substantially impervious to, or at least minimize, spurious low readings due to the in vivo environmental effects of subcutaneous implantation, such as ESA and night-time dropouts. Of particular interest are analyte monitoring devices and systems that are capable of substantially immediate and accurate analyte reporting to the user so that spurious low readings, or frequent calibrations, are minimized or are non existent. It would also be highly advantageous if such sensors had a construct which makes them even less invasive than currently available sensors and which further minimizes pain and discomfort to the user. | <SOH> SUMMARY <EOH>Embodiments of the present disclosure include continuous analyte monitoring systems utilizing implantable or partially implantable analyte sensors which have a relatively small profile (as compared to currently available implantable sensors). The relatively small size of the subject sensors reduce the likelihood of bleeding and, therefore, minimize thrombus formation upon implantation and the impingement of the sensor structure on adjacent blood vessels, and thus, maximizing fluid flow to the sensor and reducing the probability of ESA or low sensor readings. In certain embodiments, the sensors are double-sided, meaning that both sides of the sensor's substrate are electrochemically functional, i.e., each side provides at least one electrode, thereby reducing the necessary surface area of the sensor. This enables the sensors to have a relatively smaller insertable distal or tail portion which reduces the in vivo environmental effects to which they are subjected. Further, the non-insertable proximal or external portion of the sensor may also have a relatively reduced size. The subject continuous analyte monitoring systems include a skin-mounted portion or assembly and a remote portion or assembly. The skin-mounted portion includes at least the data transmitter, the transmitter battery, a portion of the sensor electronics, and electrical contacts for electrically coupling the implanted sensor with the transmitter. The remote portion of the system includes at least a data receiver and a user interface which may also be configured for test strip-based glucose monitoring. The skin-mounted portion of the system has a housing or base which is constructed to externally mount to the patient's skin and to mechanically and electrically couple the implanted sensor with the transmitter. Removably held or positioned within the housing/base structure is a connector piece having an electrical contact configuration which, when used with a double-sided sensor, enables coupling of the sensor to the transmitter in a low-profile, space-efficient manner. The skin-mounted components of the system, including the associated mounting/coupling structure, have complementary diminutive structures which, along with the very small sensor, which maximize patient usability and comfort. Embodiments further include systems and devices for implanting the subject analyte sensors within a patient's skin and simultaneously coupling the analyte monitoring system's external, skin-mounted unit to the implanted sensor. Certain insertion systems include at least a manually-held and/or manually-operated inserter device and an insertion needle which is carried by and removably coupled to the inserter. In certain of these embodiments, only the insertion needle is disposable with the inserter or insertion gun being reusable, reducing the overall cost of the system and providing environmental advantages. In other embodiments, the skin-mounted unit and sensor are inserted manually without the use of an insertion device. Embodiments of the subject continuous analyte monitoring systems may include additional features and advantages. For example, certain embodiments do not require individual-specific calibration by the user, and, in certain of these embodiments, require no factory-based calibration as well. Certain other embodiments of the continuous analyte monitoring systems are capable of substantially immediate and accurate analyte reporting to the user so that spurious low readings, or frequent calibrations, are minimized or are non-existent. The subject analyte sensors usable with the subject continuous analyte monitoring systems are highly reproducible with negligible or virtually non-existent sensor-to-sensor variations with respect to sensitivity to the analyte, eliminating the need for user-based calibration. Furthermore, in certain embodiments, the analyte sensors have a predictable sensitivity drift on the shelf and/or during in vivo use are provided. Computer programmable products including devices and/or systems that include programming for a given sensor drift profile may also be provided. The programming may use the drift profile to apply a correction factor to the system to eliminate the need for user-based calibration. These and other features, objects and advantages of the present disclosure will become apparent to those persons skilled in the art upon reading the details of the present disclosure as more fully described below. | A61B514532 | 20171020 | 20180208 | 69622.0 | A61B5145 | 1 | JANG, CHRISTIAN YONGKYUN | Continuous Analyte Measurement Systems and Systems and Methods for Implanting Them | UNDISCOUNTED | 1 | CONT-ACCEPTED | A61B | 2,017 |
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15,790,003 | PENDING | Coordination of Acoustic Sources Based on Location | An audio/video (A/V) hub that calculates an estimated location is described. In particular, the A/V hub may calculate an estimated location of a listener relative to electronic devices (such as electronic devices that include speakers) in an environment that includes the A/V hub and the electronic devices based on: communication with another electronic device; sound measurements in the environment; and/or time-of-flight measurements. Then, the A/V hub may transmit, to the electronic devices, one or more frames that include audio content and playback timing information, which may specify playback times when the electronic devices are to playback the audio content based on the estimated location. Moreover, the playback times of the electronic devices may have a temporal relationship so that the playback of the audio content by the electronic devices is coordinated. | 1. A coordination device, comprising: one or more nodes configured to communicatively couple to one or more antennas; an interface circuit communicatively coupled to the one or more nodes, wherein the coordination device is configured to: calculate an estimated location of a listener relative to electronic devices in an environment; and transmit, to the one or more nodes, one or more frames that include audio content and playback timing information for the electronic devices, wherein the playback timing information specifies playback times when the electronic devices are to playback the audio content based on the estimated location, and wherein the playback times of the electronic devices have a temporal relationship so that the playback of the audio content by the electronic devices is coordinated. 2. The coordination device of claim 1, wherein the estimated location of the listener is calculated based on the communication with another electronic device. 3. The coordination device of claim 1, wherein the coordination device further comprises an acoustic transducer configured to perform sound measurements in the environment; and wherein the estimated location of the listener is calculated based on the sound measurements. 4. The coordination device of claim 1, wherein the interface circuit is further configured to receive, from the one or more nodes, additional sound measurements of the environment associated with other electronic devices; and wherein the estimated location of the listener is calculated based on the additional sound measurements. 5. The coordination device of claim 1, wherein the interface circuit is configured to: perform time-of-flight measurements; and wherein the estimated location of the listener is calculated based on the time-of-flight measurements. 6. The coordination device of claim 1, wherein the playback times are based on current time offsets between clocks in the electronic devices and a clock in the coordination device. 7. The coordination device of claim 1, wherein the coordination device is configured to calculate additional estimated locations of additional listeners relative to the electronic devices in the environment; and wherein the playback times are based on the estimated location and the additional estimated locations. 8. The coordination device of claim 7, wherein the playback times are based on an average of the estimated location and the additional estimated locations. 9. The coordination device of claim 7, wherein the playback times are based on a weighted average of the estimated location and the additional estimated locations. 10. The coordination device of claim 1, wherein the temporal relationship has a non-zero value, so that at least some of the electronic devices are instructed to playback the audio content with a phase relative to each other by using different values of the playback times. 11. The coordination device of claim 10, wherein the different playback times are based on acoustic characterization of the environment. 12. The coordination device of claim 10, wherein the different playback times are based on a desired acoustic characteristic in the environment. 13. A non-transitory computer-readable storage medium for use with a coordination device, the computer-readable storage medium storing a program module that, when executed by the coordination device, causes the coordination device to calculate an estimated location by carrying out one or more operations that comprise: calculating the estimated location of a listener relative to electronic devices in an environment; and transmitting, to one or more nodes in the coordination device that are communicatively coupled to one or more antennas, one or more frames that include audio content and playback timing information for the electronic devices, wherein the playback timing information specifies playback times when the electronic devices are to playback the audio content based on the estimated location, and wherein the playback times of the electronic devices have a temporal relationship so that the playback of the audio content by the electronic devices is coordinated. 14. The computer-readable storage medium of claim 13, wherein the one or more operations comprise communicating, to or from the one or more nodes, one or more frames associated with another electronic device; and wherein the estimated location of the listener is calculated based on the one or more frames. 15. The computer-readable storage medium of claim 13, wherein the one or more operations comprise performing sound measurements in the environment using an acoustic transducer; and wherein the estimated location of the listener is calculated based on the sound measurements. 16. The computer-readable storage medium of claim 13, wherein the one or more operations comprise communicating, to or from the one or more nodes, frames that are associated with other electronic devices in the environment and to receive, from the one or more nodes, additional sound measurements of the environment that are associated with the other electronic devices; and wherein the estimated location of the listener is calculated based on the additional sound measurements. 17. The computer-readable storage medium of claim 13, wherein the one or more operations comprise performing time-of-flight measurements; and wherein the estimated location of the listener is calculated based on the time-of-flight measurements. 18. The computer-readable storage medium of claim 13, wherein the playback times are based on current time offsets between clocks in the electronic devices and a clock in the coordination device. 19. The computer-readable storage medium of claim 13, wherein the one or more operations comprise calculating additional estimated locations of additional listeners relative to the electronic devices in the environment; and wherein the playback times are based on the estimated location and the additional estimated locations. 20. A method for calculating an estimated location, wherein the method comprises: by a coordination device: calculating the estimated location of a listener relative to electronic devices in an environment; and transmitting, to one or more nodes in the coordination device that are communicatively coupled to one or more antennas, one or more frames that include audio content and playback timing information for the electronic devices, wherein the playback timing information specifies playback times when the electronic devices are to playback the audio content based on the estimated location, and wherein the playback times of the electronic devices have a temporal relationship so that the playback of the audio content by the electronic devices is coordinated. | CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. 119(e) to U.S. Provisional Application Ser. No. 62/433,237, “Wireless Coordination of Audio Sources,” by Gaylord Yu, filed on Dec. 13, 2016, the contents of which are herein incorporated by reference. BACKGROUND Field The described embodiments relate to a communication technique. More specifically, the described embodiments include a communication technique that coordinates playback times of electronic devices that output sound based on dynamic estimates of a location of a user. Related Art Music often has a significant impact on an individual's emotions and perceptions. This is thought to be a result of connections or relationships between the areas of the brain that decipher, learn, and remember music with those that produce emotional responses, such as the frontal lobes and limbic system. Indeed, emotions are thought to be involved in the process of interpreting music, and concurrently are very important in the effect of music on the brain. Given this ability of music to ‘move’ a listener, audio quality is often an important factor in user satisfaction when listening to audio content and, more generally, when viewing and listening to audio/video (A/V) content. However, it is often challenging to achieve high audio quality in an environment. For example, the acoustic sources (such as loudspeakers) may not be properly placed in the environment. Alternatively or additionally, a listener may not be located at an ideal position in the environment. In particular, in a stereo playback system, the so-called ‘sweet spot,’ where the amplitude differences and arrival time differences are small enough that an apparent image and localization of an original sound source are both maintained, is usually limited to a fairly small area between the loudspeakers. When the listener is outside that area, the apparent image collapses and only one or the other independent audio channel output by the loudspeakers may be heard. Furthermore, achieving high audio quality in the environment typically places strong constraints on synchronization of the loudspeakers. Consequently, when one or more of these factors is sub-optimal, the acoustic quality in the environment may be degraded. In turn, this may adversely impact listener satisfaction and the overall user experience when listening to audio content and/or A/V content. SUMMARY A first group of described embodiments includes an audio/video (A/V) hub. This A/V hub includes: one or more antennas; and an interface circuit that, during operation, communicates with electronic devices using wireless communication. During operation, the A/V hub receives, via the wireless communication, frames from the electronic devices, where a given frame includes a transmit time when a given electronic device transmitted the given frame. Then, the A/V hub stores receive times when the frames were received, where the receive times are based on a clock in the A/V hub. Moreover, the A/V hub calculates current time offsets between clocks in the electronic devices and the clock in the A/V hub based on the receive times and transmit times of the frames. Next, the A/V hub transmits one or more frames that include audio content and playback timing information to the electronic devices, where the playback timing information specifies playback times when the electronic devices are to playback the audio content based on the current time offsets. Furthermore, the playback times of the electronic devices have a temporal relationship so that the playback of the audio content by the electronic devices is coordinated. Note that the temporal relationship may have a non-zero value, so that at least some of the electronic devices are instructed to playback the audio content with a phase relative to each other by using different values of the playback times. For example, the different playback times may be based on acoustic characterization of an environment that includes the electronic devices and the A/V hub. Alternatively or additionally, the different playback times may be based on a desired acoustic characteristic in the environment. In some embodiments, the electronic devices are located at vector distances from the A/V hub, and the interface circuit determines magnitudes of the vector distances based on the transmit times and the receive times using wireless ranging. Moreover, the interface circuit may determine angles of the vector distances based on the angle of arrival of wireless signals associated with the frames that are received by the one or more antennas during the wireless communication. Furthermore, the different playback times may be based on the determined vector distances. Alternatively or additionally, the different playback times are based on an estimated location of a listener relative to the electronic devices. For example, the interface circuit may: communicate with another electronic device; and calculate the estimated location of the listener based on the communication with the other electronic device. Moreover, the A/V hub may include an acoustic transducer that performs sound measurements of the environment that includes the A/V hub, and the A/V hub may calculate the estimated location of the listener based on the sound measurements. Furthermore, the interface circuit may communicate with other electronic devices in the environment and may receive additional sound measurements of the environment from the other electronic devices. In these embodiments, the A/V hub calculates the estimated location of the listener based on the additional sound measurements. In some embodiments, the interface circuit: performs time-of-flight measurements; and calculates the estimated location of the listener based on the time-of-flight measurements. Note that the electronic devices may be located at non-zero distances from the A/V hub, and the current time offsets may be calculated based on the transmit times and the receive times using wireless ranging by ignoring the distances. Moreover, the current time offsets may be based on models of clock drift in the electronic devices. Another embodiment provides a computer-readable storage medium for use with the A/V hub. This computer-readable storage medium includes a program module that, when executed by the A/V hub, cause the A/V hub to perform at least some of the aforementioned operations. Another embodiment provides a method for coordinating playback of audio content. This method includes at least some of the operations performed by the A/V hub. Another embodiment provides one or more of the electronic devices. A second group of described embodiments includes an audio/video (A/V) hub. This A/V hub includes: memory that, during operation, stores characterization information of an environment that includes the A/V hub; one or more antennas; and an interface circuit that, during operation, communicates with an electronic device using wireless communication. During operation, the A/V hub detects, using the wireless communication, the electronic device in the environment. Then, the A/V hub determines a change condition, where the change condition includes: that the electronic device was not previously detected in the environment; and/or a change in a location of the electronic device. When the change condition is determined, the A/V hub transitions into a characterization mode. During the characterization mode, the A/V hub: provides instructions to the electronic device to playback audio content at a specified playback time; determines one or more acoustic characteristics of the environment based on acoustic measurements in the environment; and stores the characterization information in the memory, where the characterization information includes the one or more acoustic characteristics. Moreover, the characterization information may include: an identifier of the electronic device; and the location of the electronic device. For example, the location may include a distance between the A/V hub and the electronic device, and an angle of arrival of wireless signals during the wireless communication. Consequently, the change in the location may include a change in: the distance, the angle of arrival, or both. In some embodiments, the distance is determined using wireless ranging. Note that the one or more acoustic characteristics may include information specifying: an acoustic transfer function in at least a first band of frequencies, acoustic loss, acoustic delay, acoustic noise in the environment, ambient sound in the environment, a reverberation time of the environment, and/or a spectral response in at least a second band of frequencies. Furthermore, the A/V hub may calculate the location of the electronic device in the environment based on the wireless communication. Additionally, the interface circuit may communicate with other electronic devices in the environment using the wireless communication, and the acoustic measurements may be received from the other electronic devices. In these embodiments, the one or more acoustic characteristics may be determined based on locations of the other electronic devices in the environment. Note that the A/V hub may: receive the locations of the other electronic devices from the other electronic devices; access predetermined locations of the other electronic devices stored in the memory; and determine the locations of the other electronic devices based on the wireless communication. In some embodiments, the A/V hub includes one or more acoustic transducers, and the A/V hub performs the acoustic measurements using the one or more acoustic transducers. Moreover, the A/V hub may: receive a user input; and transition into the characterization mode based on the user input. Furthermore, the A/V hub may transmit one or more frames that include additional audio content and playback timing information to the electronic device, where the playback timing information may specify a playback time when the electronic device is to playback the additional audio content based on the one or more acoustic characteristics. Another embodiment provides a computer-readable storage medium for use with the A/V hub. This computer-readable storage medium includes a program module that, when executed by the A/V hub, cause the A/V hub to perform at least some of the aforementioned operations. Another embodiment provides a method for selectively determining one or more acoustic characteristics of the environment that includes the A/V hub. This method includes at least some of the operations performed by the A/V hub. Another embodiment provides the electronic device. A third group of described embodiments includes an audio/video (A/V) hub. This A/V hub includes: one or more acoustic transducers that, during operation, measure sound output by electronic devices in an environment that includes the A/V hub and the electronic devices; one or more antennas; and an interface circuit that, during operation, communicates with the electronic devices using wireless communication. During operation, the A/V hub measures the sound output by the electronic devices using the one or more acoustic transducers, where the sound corresponds to one or more acoustic-characterization patterns. Then, the A/V hub calculates current time offsets between clocks in the electronic devices and a clock in the A/V hub based on the measured sound, one or more times when the electronic devices output the sound and the one or more acoustic-characterization patterns. Next, the A/V hub transmits, using wireless communication, one or more frames that include audio content and playback timing information to the electronic devices, where the playback timing information specifies playback times when the electronic devices are to playback the audio content based on the current time offsets. Moreover, the playback times of the electronic devices have a temporal relationship so that the playback of the audio content by the electronic devices is coordinated. Note that the measured sound may include information that specifies the one or more times when the electronic devices output the sound, and the one or more times may correspond to the clocks in the electronic devices. Moreover, the A/V hub may provide to the electronic devices, via the wireless communication, one or more times when the electronic devices are to output the sound, and the one or more times may correspond to the clock in the A/V hub. Furthermore, a given electronic device may output the sound at a different time in the one or more times than those used by a remainder of the electronic devices. Alternatively or additionally, the sound output by a given electronic device may correspond to a given acoustic-characterization patterns, which may be different from those used by the remainder of the electronic devices. Note that the acoustic-characterization patterns may include pulses. Moreover, the sound may be in a range of frequencies outside of human hearing. In some embodiments, the A/V hub modifies the measured sound based on an acoustic transfer function of the environment in at least a band of frequencies. Moreover, the temporal relationship may have a non-zero value, so that at least some of the electronic devices are instructed to playback the audio content with a phase relative to each other by using different values of the playback times. For example, the different playback times may be based on: acoustic characterization of the environment; a desired acoustic characteristic in the environment; and/or an estimated location of a listener relative to the electronic devices. Another embodiment provides a computer-readable storage medium for use with the A/V hub. This computer-readable storage medium includes a program module that, when executed by the A/V hub, cause the A/V hub to perform at least some of the aforementioned operations. Another embodiment provides a method for coordinating playback of audio content. This method includes at least some of the operations performed by the A/V hub. Another embodiment provides one or more of the electronic devices. A fourth group of described embodiments includes an audio/video (A/V) hub. This A/V hub includes: one or more antennas; and an interface circuit that, during operation, communicates with electronic devices using wireless communication. During operation, the A/V hub calculates an estimated location of a listener relative to the electronic devices in an environment that includes the A/V hub and the electronic devices. Then, the A/V hub transmits one or more frames that include audio content and playback timing information to the electronic devices, where the playback timing information specifies playback times when the electronic devices are to playback the audio content based on the estimated location. Note that the playback times of the electronic devices have a temporal relationship so that the playback of the audio content by the electronic devices is coordinated. Moreover, the interface circuit may communicate with another electronic device, and the estimated location of the listener may be calculated based on the communication with the other electronic device. Furthermore, the A/V hub may include an acoustic transducer that performs sound measurements in the environment, and the estimated location of the listener may be calculated based on the sound measurements. Alternatively or additionally, the interface circuit may communicate with other electronic devices in the environment and may receive additional sound measurements of the environment from the other electronic devices, and the estimated location of the listener may be calculated based on the additional sound measurements. In some embodiments, the interface circuit performs time-of-flight measurements, and the estimated location of the listener is calculated based on the time-of-flight measurements. Note that the playback times may be based on current time offsets between clocks in the electronic devices and a clock in the A/V hub. Moreover, the A/V hub may calculate additional estimated locations of additional listeners relative to the electronic devices in the environment, and the playback times may be based on the estimated location and the additional estimated locations. For example, the playback times may be based on an average of the estimated location and the additional estimated locations. Alternatively, the playback times may be based on a weighted average of the estimated location and the additional estimated locations. Furthermore, the temporal relationship may have a non-zero value, so that at least some of the electronic devices are instructed to playback the audio content with a phase relative to each other by using different values of the playback times. In some embodiments, the different playback times are based on: acoustic characterization of the environment; and/or a desired acoustic characteristic in the environment. Another embodiment provides a computer-readable storage medium for use with the A/V hub. This computer-readable storage medium includes a program module that, when executed by the A/V hub, cause the A/V hub to perform at least some of the aforementioned operations. Another embodiment provides a method for calculating an estimated location. This method includes at least some of the operations performed by the A/V hub. Another embodiment provides one or more of the electronic devices. A fifth group of described embodiments includes an audio/video (A/V) hub. This A/V hub includes: one or more acoustic transducers that, during operation, measure sound output by electronic devices in an environment that includes the A/V hub and the electronic devices; one or more antennas; and an interface circuit that, during operation, communicates with the electronic devices using wireless communication. During operation, the A/V hub measures the sound output by the electronic devices using the one or more acoustic transducers, where the sound corresponds to audio content. Then, the A/V hub aggregates the electronic devices into two or more subsets based on the measured sound. Moreover, the A/V hub determines playback timing information for the subsets, where the playback timing information specifies playback times when the electronic devices in a given subset are to playback the audio content. Next, the A/V hub transmits, using wireless communication, one or more frames that include the audio content and playback timing information to the electronic devices, where the playback times of the electronic devices in at least the given subset have a temporal relationship so that the playback of the audio content by the electronic devices in the given subset is coordinated. Note that the different subsets may be located in different rooms in the environment. Moreover, at least one of the subsets may playback different audio content than a remainder of the subsets. Furthermore, the aggregation of the electronic devices into the two or more subsets may be based on: the different audio content; an acoustic delay of the measured sound; and/or a desired acoustic characteristic in the environment. Additionally, the A/V hub may calculate an estimated location of a listener relative to the electronic devices, and the aggregation of the electronic devices into the two or more subsets may be based on the estimated location of the listener. In some embodiments, the A/V hub modifies the measured sound based on an acoustic transfer function of the environment in at least a band of frequencies. Moreover, the A/V hub may determine playback volumes for the subsets that are used when the subsets playback the audio content, and the one or more frames may include information that specifies the playback volumes. For example, a playback volume for at least one of the subsets may be different than the playback volumes of a remainder of the subsets. Alternatively or additionally, the playback volumes may reduce acoustic cross-talk among the two or more subsets. Another embodiment provides a computer-readable storage medium for use with the A/V hub. This computer-readable storage medium includes a program module that, when executed by the A/V hub, cause the A/V hub to perform at least some of the aforementioned operations. Another embodiment provides a method for aggregating electronic devices. This method includes at least some of the operations performed by the A/V hub. Another embodiment provides one or more of the electronic devices. A sixth group of described embodiments includes an audio/video (A/V) hub. This A/V hub includes: one or more acoustic transducers that, during operation, measure sound output by electronic devices in an environment that includes the A/V hub and the electronic devices; one or more antennas; and an interface circuit that, during operation, communicates with the electronic devices using wireless communication. During operation, the A/V hub measures the sound output by the electronic devices using the one or more acoustic transducers, where the sound corresponds to audio content. Then, the A/V hub compares the measured sound to a desired acoustic characteristic at a first location in the environment based on the first location, a second location of the A/V hub, and an acoustic transfer function of the environment in at least a band of frequencies, where the comparison involves calculating the acoustic transfer function at the first location based on the acoustic transfer function at other locations in the environment and correcting the measured sound based on the calculated the acoustic transfer function at the first location. Moreover, the A/V hub determines equalized audio content based on the comparison and the audio content. Next, the A/V hub transmits, using wireless communication, one or more frames that include the equalized audio content to the electronic devices to facilitate output by the electronic devices of additional sound, which corresponds to the equalized audio content. Note that the first location may include an estimated location of a listener relative to the electronic devices, and the A/V hub may calculate the estimated location of the listener. For example, the A/V hub may calculate the estimated location of the listener based on the sound measurements. Alternatively or additionally, the interface circuit may: communicate with another electronic device; and may calculate the estimated location of the listener based on the communication with the other electronic device. In particular, the communication with the other electronic device may include wireless ranging, and the estimated location may be calculated based on the wireless ranging and an angle of arrival of wireless signals from the other electronic device. In some embodiments, the interface circuit: performs time-of-flight measurements; and calculates the estimated location of the listener based on the time-of-flight measurements. Moreover, the interface circuit may communicate with other electronic devices in the environment and may receive additional sound measurements of the environment from the other electronic devices. Then, the A/V hub may perform one or more additional comparisons of the additional sound measurements to the desired acoustic characteristic at the first location in the environment based on one or more third locations of the other electronic devices and the acoustic transfer function of the environment in at least a band of frequencies, and the equalized audio content is further determined based on the one or more additional comparisons. Furthermore, the interface circuit may determine the one or more third locations based on the communication with the other electronic devices. For example, the communication with the other electronic devices may include wireless ranging, and the one or more third locations may be calculated based on the wireless ranging and angles of arrival of wireless signals from the other electronic devices. Alternatively or additionally, the interface circuit may receive information specifying the third locations from the other electronic devices. In some embodiments, the desired acoustic characteristic is based on a type of audio playback, which may include: monophonic, stereophonic and/or multichannel. Moreover, the A/V hub may determine playback timing information that specifies playback times when the electronic devices playback the equalized audio content, the one or more frames further may include the playback timing information, and the playback times of the electronic devices have a temporal relationship so that the playback of the audio content by the electronic devices is coordinated. Another embodiment provides a computer-readable storage medium for use with the A/V hub. This computer-readable storage medium includes a program module that, when executed by the A/V hub, cause the A/V hub to perform at least some of the aforementioned operations. Another embodiment provides a method for determining the equalized audio content. This method includes at least some of the operations performed by the A/V hub. Another embodiment provides one or more of the electronic devices. A seventh group of described embodiments includes an audio/video (A/V) hub. This A/V hub includes: one or more antennas; and an interface circuit that, during operation, communicates with electronic devices using wireless communication. During operation, the A/V hub receives, via the wireless communication, frames from the electronic devices. Then, the A/V hub stores receive times when the frames were received, where the receive times are based on a clock in the A/V hub. Moreover, the A/V hub calculates current time offsets between clocks in the electronic devices and the clock in the A/V hub based on the receive times and expected transmit times of the frames, where the expected transmit times are based on coordination of the clocks in the electronic devices and the clock in the A/V hub at a previous time and a predefined transmit schedule of the frames. Next, the A/V hub transmits one or more frames that include audio content and playback timing information to the electronic devices, where the playback timing information specifies playback times when the electronic devices are to playback the audio content based on the current time offsets. Furthermore, the playback times of the electronic devices have a temporal relationship so that the playback of the audio content by the electronic devices is coordinated. Note that the temporal relationship may have a non-zero value, so that at least some of the electronic devices are instructed to playback the audio content with a phase relative to each other by using different values of the playback times. For example, the different playback times may be based on acoustic characterization of an environment that includes the electronic devices and the A/V hub. Alternatively or additionally, the different playback times may be based on a desired acoustic characteristic in the environment. In some embodiments, the electronic devices are located at vector distances from the A/V hub, and the interface circuit determines magnitudes of the vector distances based on transmit times of the frames and the receive times using wireless ranging. Moreover, the interface circuit may determine angles of the vector distances based on the angle of arrival of wireless signals associated with the frames that are received by the one or more antennas during the wireless communication. Furthermore, the different playback times may be based on the determined vector distances. Alternatively or additionally, the different playback times are based on an estimated location of a listener relative to the electronic devices. For example, the interface circuit may: communicate with another electronic device; and calculate the estimated location of the listener based on the communication with the other electronic device. Moreover, the A/V hub may include an acoustic transducer that performs sound measurements of the environment that includes the A/V hub, and the A/V hub may calculate the estimated location of the listener based on the sound measurements. Furthermore, the interface circuit may communicate with other electronic devices in the environment and may receive additional sound measurements of the environment from the other electronic devices. In these embodiments, the A/V hub calculates the estimated location of the listener based on the additional sound measurements. In some embodiments, the interface circuit: performs time-of-flight measurements; and calculates the estimated location of the listener based on the time-of-flight measurements. Note that the coordination of the clocks in the electronic devices and the clock in the A/V hub may have occurred during an initialization mode of operation. Moreover, the current time offsets may be based on models of clock drift in the electronic devices. Another embodiment provides a computer-readable storage medium for use with the A/V hub. This computer-readable storage medium includes a program module that, when executed by the A/V hub, cause the A/V hub to perform at least some of the aforementioned operations. Another embodiment provides a method for coordinating playback of audio content. This method includes at least some of the operations performed by the A/V hub. Another embodiment provides one or more of the electronic devices. This Summary is only provided for purposes of illustrating some exemplary embodiments, so as to provide a basic understanding of some aspects of the subject matter described herein. Accordingly, it will be appreciated that the above-described features are only examples and should not be construed to narrow the scope or spirit of the subject matter described herein in any way. Other features, aspects, and advantages of the subject matter described herein will become apparent from the following Detailed Description, Figures, and Claims. BRIEF DESCRIPTION OF THE FIGURES FIG. 1 is a block diagram illustrating a system with electronic devices in accordance with an embodiment of the present disclosure. FIG. 2 is a flow diagram illustrating a method for coordinating playback of audio content in accordance with an embodiment of the present disclosure. FIG. 3 is a drawing illustrating communication among the electronic devices in FIG. 1 in accordance with an embodiment of the present disclosure. FIG. 4 is a drawing illustrating coordinating playback of audio content by the electronic devices in FIG. 1 in accordance with an embodiment of the present disclosure. FIG. 5 is a flow diagram illustrating a method for coordinating playback of audio content in accordance with an embodiment of the present disclosure. FIG. 6 is a drawing illustrating communication among the electronic devices in FIG. 1 in accordance with an embodiment of the present disclosure. FIG. 7 is a drawing illustrating coordinating playback of audio content by the electronic devices in FIG. 1 in accordance with an embodiment of the present disclosure. FIG. 8 is a flow diagram illustrating a method for coordinating playback of audio content in accordance with an embodiment of the present disclosure. FIG. 9 is a drawing illustrating communication among the electronic devices in FIG. 1 in accordance with an embodiment of the present disclosure. FIG. 10 is a drawing illustrating coordinating playback of audio content by the electronic devices in FIG. 1 in accordance with an embodiment of the present disclosure. FIG. 11 is a flow diagram illustrating a method for selectively determining one or more acoustic characteristics of an environment in accordance with an embodiment of the present disclosure. FIG. 12 is a drawing illustrating communication among the electronic devices in FIG. 1 in accordance with an embodiment of the present disclosure. FIG. 13 is a drawing illustrating selective acoustic characterization of an environment that includes the electronic devices in FIG. 1 in accordance with an embodiment of the present disclosure. FIG. 14 is a flow diagram illustrating a method for calculating an estimated location in accordance with an embodiment of the present disclosure. FIG. 15 is a drawing illustrating communication among the electronic devices in FIG. 1 in accordance with an embodiment of the present disclosure. FIG. 16 is a drawing illustrating calculating an estimated location of one or more listeners relative to the electronic devices in FIG. 1 in accordance with an embodiment of the present disclosure. FIG. 17 is a flow diagram illustrating a method for aggregating electronic devices in accordance with an embodiment of the present disclosure. FIG. 18 is a drawing illustrating communication among the electronic devices in FIG. 1 in accordance with an embodiment of the present disclosure. FIG. 19 is a drawing illustrating aggregating the electronic devices in FIG. 1 in accordance with an embodiment of the present disclosure. FIG. 20 is a flow diagram illustrating a method for determining equalized audio content in accordance with an embodiment of the present disclosure. FIG. 21 is a drawing illustrating communication among the electronic devices in FIG. 1 in accordance with an embodiment of the present disclosure. FIG. 22 is a drawing illustrating determining equalized audio content using the electronic devices in FIG. 1 in accordance with an embodiment of the present disclosure. FIG. 23 is a block diagram illustrating one of the electronic devices of FIG. 1 in accordance with an embodiment of the present disclosure. Note that like reference numerals refer to corresponding parts throughout the drawings. Moreover, multiple instances of the same part are designated by a common prefix separated from an instance number by a dash. DETAILED DESCRIPTION In a first group of embodiments, an audio/video (A/V) hub that coordinates playback of audio content is described. In particular, the A/V hub may calculate current time offsets between clocks in electronic devices (such as electronic devices that include speakers) and a clock in the A/V hub based on differences between transmit times of frames from the electronic devices and receive times when the frames were received. For example, the current time offsets may be calculated using wireless ranging by ignoring distances between the A/V hub and the electronic devices. Then, the A/V hub may transmit, to the electronic devices, one or more frames that include audio content and playback timing information, which may specify playback times when the electronic devices are to playback the audio content based on the current time offsets. Furthermore, the playback times of the electronic devices may have a temporal relationship so that the playback of the audio content by the electronic devices is coordinated. By coordinating the playback of the audio content by the electronic devices, this coordination technique may provide an improved acoustic experience in an environment that includes the A/V hub and the electronic devices. For example, the coordination technique may correct for clock drift between the A/V hub and the electronic devices. Alternatively or additionally, the coordination technique may correct or adapt for acoustic characteristics of the environment and/or based on a desired acoustic characteristic in the environment. In addition, the coordination technique may correct the playback times based on an estimated location of a listener relative to the electronic devices. In these ways, the coordination technique may improve the acoustic quality and, more generally, the user experience when using the A/V hub and the electronic devices. Consequently, the coordination technique may increase customer loyalty and revenue of a provider of the A/V hub and the electronic devices. In a second group of embodiments, an audio/video (A/V) hub that selectively determines one or more acoustic characteristics of an environment that includes the A/V hub is described. In particular, the A/V hub may detect, using wireless communication, an electronic device (such as an electronic device that includes a speaker) in the environment. Then, the A/V hub may determine a change condition, such as when the electronic device was not previously detected in the environment and/or a change in a location of the electronic device. In response to determining the change condition, the A/V hub may transition into a characterization mode. During the characterization mode, the A/V hub may: provide instructions to the electronic device to playback audio content at a specified playback time; determine one or more acoustic characteristics of the environment based on acoustic measurements in the environment; and store the one or more acoustic characteristics and/or a location of the electronic device in memory. By selectively determining the one or more acoustic characteristics, this characterization technique may facilitate an improved acoustic experience in the environment that includes the A/V hub and the electronic device. For example, the characterization technique may identify the changes and characterize the modified environment, which may be subsequently used to correct for the impact of the change during playback of audio content by one or more electronic devices (including the electronic device). In these ways, the characterization technique may improve acoustic quality and, more generally, the user experience when using the A/V hub and the electronic devices. Consequently, the characterization technique may increase customer loyalty and revenue of a provider of the A/V hub and the electronic devices. In a third group of embodiments, an audio/video (A/V) hub that coordinates playback of audio content is described. In particular, the A/V hub may calculate current time offsets between clocks in electronic devices (such as electronic devices that include speakers) and a clock in the A/V hub based on measured sound corresponding to one or more acoustic-characterization patterns, one or more times when the electronic devices output the sound and the one or more acoustic-characterization patterns. Then, the A/V hub may transmit, to the electronic devices, one or more frames that include audio content and playback timing information, which may specify playback times when the electronic devices are to playback the audio content based on the current time offsets. Moreover, the playback times of the electronic devices may have a temporal relationship so that the playback of the audio content by the electronic devices is coordinated. By coordinating the playback of the audio content by the electronic devices, this coordination technique may provide an improved acoustic experience in an environment that includes the A/V hub and the electronic devices. For example, the coordination technique may correct for clock drift between the A/V hub and the electronic devices. Alternatively or additionally, the coordination technique may correct or adapt for acoustic characteristics of the environment and/or based on a desired acoustic characteristic in the environment. In addition, the coordination technique may correct the playback times based on an estimated location of a listener relative to the electronic devices. In these ways, the coordination technique may improve the acoustic quality and, more generally, the user experience when using the A/V hub and the electronic devices. Consequently, the coordination technique may increase customer loyalty and revenue of a provider of the A/V hub and the electronic devices. In a fourth group of embodiments, an audio/video (A/V) hub that calculates an estimated location is described. In particular, the A/V hub may calculate an estimated location of a listener relative to electronic devices (such as electronic devices that include speakers) in an environment that includes the A/V hub and the electronic devices based on: communication with another electronic device; sound measurements in the environment; and/or time-of-flight measurements. Then, the A/V hub may transmit, to the electronic devices, one or more frames that include audio content and playback timing information, which may specify playback times when the electronic devices are to playback the audio content based on the estimated location. Moreover, the playback times of the electronic devices may have a temporal relationship so that the playback of the audio content by the electronic devices is coordinated. By calculating the estimated location of the listener, this characterization technique may facilitate an improved acoustic experience in the environment that includes the A/V hub and the electronic devices. For example, the characterization technique may track changes in the location of the listener in the environment, which may be subsequently used to correct or adapt playback of audio content by one or more electronic devices. In these ways, the characterization technique may improve the acoustic quality and, more generally, the user experience when using the A/V hub and the electronic devices. Consequently, the characterization technique may increase customer loyalty and revenue of a provider of the A/V hub and the electronic devices. In a fifth group of embodiments, an audio/video (A/V) hub that aggregates electronic devices is described. In particular, the A/V hub may measure sound, corresponding to audio content, output by electronic devices (such as electronic devices that include speakers). Then, the A/V hub may aggregate the electronic devices into two or more subsets based on the measured sound. Moreover, the A/V hub may determine, for the subsets, playback timing information, which may specify playback times when the electronic devices in a given subset are to playback the audio content. Next, the A/V hub may transmit, to the electronic devices, one or more frames that include the audio content and playback timing information, where the playback times of the electronic devices in at least the given subset have a temporal relationship so that the playback of the audio content by the electronic devices in the given subset is coordinated. By aggregating the electronic devices, this characterization technique may facilitate an improved acoustic experience in the environment that includes the A/V hub and the electronic devices. For example, the characterization technique may aggregate the electronic devices based on: different audio content; an acoustic delay of the measured sound; and/or a desired acoustic characteristic in the environment. In addition, the A/V hub may determine playback volumes for the subsets that are used when the subsets playback the audio content in order to reduce acoustic cross-talk among the two or more subsets. In these ways, the characterization technique may improve the acoustic quality and, more generally, the user experience when using the A/V hub and the electronic devices. Consequently, the characterization technique may increase customer loyalty and revenue of a provider of the A/V hub and the electronic devices. In a sixth group of embodiments, an audio/video (A/V) hub that determines equalized audio content is described. In particular, the A/V hub may measure the sound, corresponding to audio content, output by electronic devices (such as electronic devices that include speakers). Then, the A/V hub may compare the measured sound to a desired acoustic characteristic at a first location in the environment based on the first location, a second location of the A/V hub, and an acoustic transfer function of the environment in at least a band of frequencies. For example, the comparison may involve calculating the acoustic transfer function at the first location based on the acoustic transfer function at other locations in the environment and correcting the measured sound based on the calculated the acoustic transfer function at the first location. Moreover, the A/V hub may determine the equalized audio content based on the comparison and the audio content. Next, the A/V hub may transmit, to the electronic devices, one or more frames that include the equalized audio content to facilitate output by the electronic devices of additional sound, which corresponds to the equalized audio content. By determining the equalized audio content, this signal-processing technique may facilitate an improved acoustic experience in the environment that includes the A/V hub and the electronic devices. For example, the signal-processing may dynamically modify the audio content based on an estimated location of a listener relative to locations of the electronic devices and the acoustic transfer function of the environment in at least the band of frequencies. This may allow a desired acoustic characteristic or a type of audio playback (such as monophonic, stereophonic or multichannel) to be achieved at the estimated location in the environment. In these ways, the signal-processing technique may improve the acoustic quality and, more generally, the user experience when using the A/V hub and the electronic devices. Consequently, the signal-processing technique may increase customer loyalty and revenue of a provider of the A/V hub and the electronic devices. In a seventh group of embodiments, an audio/video (A/V) hub that coordinates playback of audio content is described. In particular, the A/V hub may calculate current time offsets between clocks in electronic devices (such as electronic devices that include speakers) and a clock in the A/V hub based on differences between receive times when frames are received from electronic devices and expected transmit times of the frames. For example, the expected transmit times may be based on coordination of clocks in the electronic devices and a clock in the A/V hub at a previous time and a predefined transmit schedule of the frames. Then, the A/V hub may transmit, to the electronic devices, one or more frames that include audio content and playback timing information, which may specify playback times when the electronic devices are to playback the audio content based on the current time offsets. Furthermore, the playback times of the electronic devices may have a temporal relationship so that the playback of the audio content by the electronic devices is coordinated. By coordinating the playback of the audio content by the electronic devices, this coordination technique may provide an improved acoustic experience in an environment that includes the A/V hub and the electronic devices. For example, the coordination technique may correct for clock drift between the A/V hub and the electronic devices. Alternatively or additionally, the coordination technique may correct or adapt for acoustic characteristics of the environment and/or based on a desired (or target) acoustic characteristic in the environment. In addition, the coordination technique may correct the playback times based on an estimated location of a listener relative to the electronic devices. In these ways, the coordination technique may improve the acoustic quality and, more generally, the user experience when using the A/V hub and the electronic devices. Consequently, the coordination technique may increase customer loyalty and revenue of a provider of the A/V hub and the electronic devices. In the discussion that follows, the A/V hub (which is sometimes referred to as ‘a coordination device’), an A/V display device, a portable electronic device, one or more receiver devices, and/or one or more electronic devices (such as a speaker and, more generally, a consumer-electronic device) may include radios that communicate packets or frames in accordance with one or more communication protocols, such as: an Institute of Electrical and Electronics Engineers (IEEE) 802.11 standard (which is sometimes referred to as ‘Wi-Fi®,’ from the Wi-Fi® Alliance of Austin, Tex.), Bluetooth® (from the Bluetooth Special Interest Group of Kirkland, Wash.), a cellular-telephone communication protocol, a near-field-communication standard or specification (from the NFC Forum of Wakefield, Mass.), and/or another type of wireless interface. For example, the cellular-telephone communication protocol may include or may be compatible with: a 2nd generation of mobile telecommunication technology, a 3rd generation of mobile telecommunications technology (such as a communication protocol that complies with the International Mobile Telecommunications-2000 specifications by the International Telecommunication Union of Geneva, Switzerland), a 4th generation of mobile telecommunications technology (such as a communication protocol that complies with the International Mobile Telecommunications Advanced specification by the International Telecommunication Union of Geneva, Switzerland), and/or another cellular-telephone communication technique. In some embodiments, the communication protocol includes Long Term Evolution or LTE. However, a wide variety of communication protocols may be used (such as Ethernet). In addition, the communication may occur via a wide variety of frequency bands. Note that the portable electronic device, the A/V hub, the A/V display device, and/or the one or more electronic devices may communicate using infra-red communication that is compatible with an infra-red communication standard (including unidirectional or bidirectional infra-red communication). Moreover, A/V content in following discussion may include video and associated audio (such as music, sound, dialog, etc.), video only or audio only. Communication among electronic devices is shown in FIG. 1, which presents a block diagram illustrating a system 100 with a portable electronic device 110 (such as a remote control or a cellular telephone), one or more A/V hubs (such as A/V hub 112), one or more A/V display devices 114 (such as a television, a monitor, a computer and, more generally, a display associated with an electronic device), one or more receiver devices (such as receiver device 116, e.g., a local wireless receiver associated with a proximate A/V display device 114-1 that can receive frame-by-frame transcoded A/V content from A/V hub 112 for display on A/V display device 114-1), one or more speakers 118 (and, more generally, one or more electronic devices that include one or more speakers) and/or one or more content sources 120 associated with one or more content providers (e.g., a radio receiver, a video player, a satellite receiver, an access point that provides a connection to a wired network such as the Internet, a media or a content source, a consumer-electronic device, an entertainment device, a set-top box, over-the-top content delivered over the Internet or a network without involvement of a cable, satellite or multiple-system operator, a security camera, a monitoring camera, etc.). Note that A/V hub 112, A/V display devices 114, receiver device 116 and speakers 118 are sometimes collectively referred to as ‘components’ in system 100. However, A/V hub 112, A/V display devices 114, receiver device 116 and/or speakers 118 are sometimes referred to as ‘electronic devices.’ In particular, portable electronic device 110 and A/V hub 112 may communicate with each other using wireless communication, and one or more other components in system 100 (such as at least: one of A/V display devices 114, receiver device 116, one of speakers 118 and/or one of content sources 120) may communicate using wireless and/or wired communication. During the wireless communication, these electronic devices may wirelessly communicate while: transmitting advertising frames on wireless channels, detecting one another by scanning wireless channels, establishing connections (for example, by transmitting association requests), and/or transmitting and receiving packets or frames (which may include the association requests and/or additional information as payloads, such as information specifying communication performance, data, a user interface, A/V content, etc.). As described further below with reference to FIG. 23, portable electronic device 110, A/V hub 112, A/V display devices 114, receiver device 116, speakers 118 and content sources 120 may include subsystems, such as: a networking subsystem, a memory subsystem and a processor subsystem. In addition, portable electronic device 110, A/V hub 112, receiver device 116, and/or speakers 118, and optionally one or more of A/V display devices 114 and/or content sources 120, may include radios 122 in the networking subsystems. For example, a radio or receiver device may be in an A/V display device, e.g., radio 122-5 is included in A/V display device 114-2.) Moreover, note that radios 122 may be instances of the same radio or may be different from each other. More generally, portable electronic device 110, A/V hub 112, receiver device 116 and/or speakers 118 (and optionally A/V display devices 114 and/or content sources 120) can include (or can be included within) any electronic devices with the networking subsystems that enable portable electronic device 110, A/V hub 112 receiver device 116 and/or speakers 118 (and optionally A/V display devices 114 and/or content sources 120) to wirelessly communicate with each other. This wireless communication can comprise transmitting advertisements on wireless channels to enable electronic devices to make initial contact or detect each other, followed by exchanging subsequent data/management frames (such as association requests and responses) to establish a connection, configure security options (e.g., Internet Protocol Security), transmit and receive packets or frames via the connection, etc. As can be seen in FIG. 1, wireless signals 124 (represented by a jagged line) are transmitted from radio 122-1 in portable electronic device 110. These wireless signals may be received by at least one of: A/V hub 112, receiver device 116 and/or at least one of speakers 118 (and, optionally, one or more of A/V display devices 114 and/or content sources 120). For example, portable electronic device 110 may transmit packets. In turn, these packets may be received by a radio 122-2 in A/V hub 112. This may allow portable electronic device 110 to communicate information to A/V hub 112. While FIG. 1 illustrates portable electronic device 110 transmitting packets, note that portable electronic device 110 may also receive packets from A/V hub 112 and/or one or more other components in system 100. More generally, wireless signals may be transmitted and/or received by one or more of the components in system 100. In the described embodiments, processing of a packet or frame in portable electronic device 110, A/V hub 112, receiver device 116 and/or speakers 118 (and optionally one or more of A/V display devices 114 and/or content sources 120) includes: receiving wireless signals 124 with the packet or frame; decoding/extracting the packet or frame from received wireless signals 124 to acquire the packet or frame; and processing the packet or frame to determine information contained in the packet or frame (such as the information associated with a data stream). For example, the information from portable electronic device 110 may include user-interface activity information associated with a user interface displayed on touch-sensitive display (TSD) 128 in portable electronic device 110, which a user of portable electronic device 110 uses to control at least: A/V hub 112, at least one of A/V display devices 114, at least one of speakers 118 and/or at least one of content sources 120. (In some embodiments, instead of or in additional to touch-sensitive display 128, portable electronic device 110 includes a user interface with physical knobs and/or buttons that a user can use to control at least: A/V hub 112 one of A/V display devices 114, at least one of speakers 118 and/or one of content sources 120.) Alternatively, the information from portable electronic device 110, A/V hub 112, one or more of A/V display devices 114, receiver device 116, one or more of speakers 118 and/or one or more of content sources 120 may specify communication performance about the communication between portable electronic device 110 and one or more other components in system 100. Moreover, the information from A/V hub 112 may include device-state information about a current device state of at least one of A/V display devices 114, at least one of speakers 118 and/or one of content sources 120 (such as on, off, play, rewind, fast forward, a selected channel, selected A/V content, a content source, etc.), or may include user-interface information for the user interface (which may be dynamically updated based on the device-state information and/or the user-interface activity information). Furthermore, the information from at least A/V hub 112 and/or one of content sources 120 may include audio and/or video (which is sometimes denoted as ‘audio/video’ or ‘A/V’ content) that are displayed or presented on one or more of A/V display devices 114, as well as display instructions that specify how the audio and/or video are to be displayed or presented. However, as noted previously, the audio and/or video may be communicated between components in system 100 via wired communication. Therefore, as shown in FIG. 1, there may be a wired cable or link, such as a high-definition multimedia-interface (HDMI) cable 126, such as between A/V hub 112 and A/V display device 114-3. While the audio and/or video may be included in or associated with HDMI content, in other embodiments the audio content may be included in or associated with A/V content that is compatible with another format or standard is used in the embodiments of the disclosed communication technique. For example, the A/V content may include or may be compatible with: H.264, MPEG-2, a QuickTime video format, MPEG-4, MP4, and/or TCP/IP. Moreover, the video mode of the A/V content may be 720p, 1080i, 1080p, 1440p, 2000, 2160p, 2540p, 4000p and/or 4320p. Note that A/V hub 112 may determine display instructions (with a display layout) for the A/V content based on a format of a display in one of A/V display devices 114, such as A/V display device 114-1. Alternatively, A/V hub 112 can use pre-determined display instructions or A/V hub 112 can modify or transform the A/V content based on the display layout so that the modified or transformed A/V content has an appropriate format for display on the display. Moreover, the display instructions may specify information to be displayed on the display in A/V display device 114-1, including where A/V content is displayed (such as in a central window, in a tiled window, etc.). Consequently, the information to be displayed (i.e., an instance of the display instructions) may be based on a format of the display, such as: a display size, display resolution, display aspect ratio, display contrast ratio, a display type, etc. Furthermore, note that when A/V hub 112 receives the A/V content from one of content sources 120, A/V hub 112 may provide the A/V content and display instructions to A/V display device 114-1 as frames with the A/V content are received from one of content sources 120 (e.g., in real time), so that the A/V content is displayed on the display in A/V display device 114-1. For example, A/V hub 112 may collect the A/V content in a buffer until a frame is received, and then A/V hub 112 may provide the complete frame to A/V display device 114-1. Alternatively, A/V hub 112 may provide packets with portions of a frame to A/V display device 114-1 as they are received. In some embodiments, the display instructions may be provided to A/V display device 114-1 differentially (such as when the display instructions change), regularly or periodically (such as in one of every N packets or in a packet in each frame) or in each packet. Moreover, note that the communication between portable electronic device 110, A/V hub 112, one or more of A/V display devices 114, receiver device 116, one or more of speakers 118 and/or one or more content sources 120 may be characterized by a variety of performance metrics, such as: a received signal strength indicator (RSSI), a data rate, a data rate discounting radio protocol overhead (which is sometimes referred to as a ‘throughput’), an error rate (such as a packet error rate, or a retry or resend rate), a mean-square error of equalized signals relative to an equalization target, intersymbol interference, multipath interference, a signal-to-noise ratio, a width of an eye pattern, a ratio of number of bytes successfully communicated during a time interval (such as 1-10 s) to an estimated maximum number of bytes that can be communicated in the time interval (the latter of which is sometimes referred to as the ‘capacity’ of a channel or link), and/or a ratio of an actual data rate to an estimated maximum data rate (which is sometimes referred to as ‘utilization’). Moreover, the performance during the communication associated with different channels may be monitored individually or jointly (e.g., to identify dropped packets). The communication between portable electronic device 110, A/V hub 112, one of A/V display devices 114, receiver device 116 one of speakers 118 and/or one or more of content sources 120 in FIG. 1 may involve one or more independent, concurrent data streams in different wireless channels (or even different communication protocols, such as different Wi-Fi communication protocols) in one or more connections or links, which may be communicated using multiple radios. Note that the one or more connections or links may each have a separate or different identifier (such as a different service set identifier) on a wireless network in system 100 (which may be a proprietary network or a public network). Moreover, the one or more concurrent data streams may, on a dynamic or packet-by-packet basis, be partially or completely redundant to improve or maintain the performance metrics even when there are transient changes (such as interference, changes in the amount of information that needs to be communicated, movement of portable electronic device 110, etc.), and to facilitate services (while remaining compatible with the communication protocol, e.g., a Wi-Fi communication protocol) such as: channel calibration, determining of one or more performance metrics, performing quality-of-service characterization without disrupting the communication (such as performing channel estimation, determining link quality, performing channel calibration and/or performing spectral analysis associated with at least one channel), seamless handoff between different wireless channels, coordinated communication between components, etc. These features may reduce the number of packets that are resent, and, thus, may decrease the latency and avoid disruption of the communication and may enhance the experience of one or more users that are viewing A/V content on one or more of A/V display devices 114 and/or listening to audio output by one or more of speakers 118. As noted previously, a user may control at least A/V hub 112, at least one of A/V display devices 114, at least one of speakers 118 and/or at least one of content sources 120 via the user interface displayed on touch-sensitive display 128 on portable electronic device 110. In particular, at a given time, the user interface may include one or more virtual icons that allow the user to activate, deactivate or change functionality or capabilities of at least: A/V hub 112, at least one of A/V display devices 114, at least one of speakers 118 and/or at least one of content sources 120. For example, a given virtual icon in the user interface may have an associated strike area on a surface of touch-sensitive display 128. If the user makes and then breaks contact with the surface (e.g., using one or more fingers or digits, or using a stylus) within the strike area, portable electronic device 110 (such as a processor executing a program module) may receive user-interface activity information indicating activation of this command or instruction from a touch-screen input/output (I/O) controller, which is coupled to touch-sensitive display 128. (Alternatively, touch-sensitive display 128 may be responsive to pressure. In these embodiments, the user may maintain contact with touch-sensitive display 128 with an average contact pressure that is usually less than a threshold value, such as 10-20 kPa, and may activate a given virtual icon by increase the average contact pressure with touch-sensitive display 128 above the threshold value.) In response, the program module may instruct an interface circuit in portable electronic device 110 to wirelessly communicate the user-interface activity information indicating the command or instruction to A/V hub 112, and A/V hub 112 may communicate the command or the instruction to the target component in system 100 (such as A/V display device 114-1). This instruction or command may result in A/V display device 114-1 turning on or off, displaying A/V content from a particular content source, performing a trick mode of operation (such as fast forward, reverse, fast reverse or skip), etc. For example, A/V hub 112 may request the A/V content from content source 120-1, and then may provide the A/V content along with display instructions to A/V display device 114-1, so that A/V display device 114-1 displays the A/V content. Alternatively or additionally, A/V hub 112 may provide audio content associated with video content from content source 120-1 to one or more of speakers 118. As noted previously, it is often challenging to achieve high audio quality in an environment (such as a room, a building, a vehicle, etc.). In particular, achieving high audio quality in the environment typically places strong constraints on coordination of the loudspeakers, such as speakers 118. For example, the coordination may need to be maintained to 1-5 μs accuracy (which are nonlimiting exemplary values). In some embodiments, the coordination includes synchronization in the time domain within a temporal or phase accuracy and/or the frequency domain within a frequency accuracy. In the absence of suitable coordination, the acoustic quality in the environment may be degraded, with a commensurate impact on listener satisfaction and the overall user experience when listening to audio content and/or A/V content. This challenge may be addressed in a coordination technique by directly or indirectly coordinating speakers 118 with A/V hub 112. As described below with reference to FIGS. 2-4, in some embodiments coordinated playback of audio content by speakers 118 may be facilitated using wireless communication. In particular, because the speed of light is almost six orders of magnitude faster than the speed of sound, the propagation delay of wireless signals in an environment (such as a room) is negligible relative to the desired coordination accuracy of speakers 118. For example, the desired coordination accuracy of speakers 118 may be on the order of a microsecond, while the propagation delay in a typical room (e.g., over distances of at most 10-30 m) may be one or two orders of magnitude smaller. Consequently, techniques such as wireless ranging or radio-based distance measurements may be used to coordinate speakers 118. In particular, during wireless ranging A/V hub 112 may transmit a frame or a packet that includes a transmission time and an identifier of A/V hub 112 based on a clock in A/V hub 112, and a given one of speakers 118 (such as speaker 118-1) may determine an arrival or a reception time of the frame or packet based on a clock in speaker 118-1. Alternatively, speaker 118-1 may transmit a frame or a packet (which is sometimes referred to as an ‘input frame’) that includes a transmission time and an identifier of speaker 118-1 based on the clock in speaker 118-1, and/V hub 112 may determine an arrival or a reception time of the frame or packet based on the clock in/V hub 112. Typically, the distance between A/V hub 112 and speaker 118-1 is determined based on the product of the time of fight (the difference of the arrival time and the transmission time) and the speed of propagation. However, by ignoring the physical distance between A/V hub 112 and speaker 118-1, i.e., by assuming instantaneous propagation (which for stationary devices in the same room or environment introduces a negligible static offset), the difference of the arrival time and the transmission time may dynamically track the drift or the current time offset in the coordination of the clocks in A/V hub 112 and speaker 118-1 (as well as the negligible static offset). The current time offset may be determined by A/V hub 112 or may be provided to A/V hub 112 by speaker 118-1. Then, A/V hub 112 may transmit, to speaker 118-1, one or more frames (which are sometimes referred to as ‘output frames’) that include audio content and playback timing information, which may specify playback times when speaker 118-1 is to playback the audio content based on the current time offset. This may be repeated for other speakers 118. Furthermore, the playback times of speakers 118 may have a temporal relationship so that the playback of the audio content by speakers 118 is coordinated. In addition to correcting for drift in the clocks, this coordination technique (as well as the other embodiments of the coordination technique described below) may provide an improved acoustic experience in an environment that includes A/V hub 112 and speakers 118. For example, the coordination technique may correct or adapt for predetermined or dynamically determined acoustic characteristics of the environment (as described further below with reference to FIGS. 11-13), based on a desired acoustic characteristic in the environment (such as a type of playback, e.g., monophonic, stereophonic and/or multichannel, an acoustic radiation pattern, such as directed or diffuse, intelligibility, etc.) and/or based on dynamically estimated locations of one or more listeners relative to speakers 118 (as described further below with reference to FIGS. 14-16). In addition, the coordination technique may be used in conjunction with dynamic aggregation of speakers 118 into groups (as described further below with reference to FIGS. 17-19) and/or with dynamically equalized audio content based audio content being played and differences between an acoustic characteristic and the desired acoustic characteristic in the environment (as described further below with reference to FIGS. 20-22). Note that the wireless ranging (as well as the wireless communication in general) may be performed at or in one or more bands of frequencies, such as at or in: a 2 GHz wireless band, a 5 GHz wireless band, an ISM band, a 60 GHz wireless band, ultra-wide band, etc. In some embodiments, one or more additional communication techniques may be used to identify and/or exclude multi-path wireless signals during the coordination of speakers 118. For example, A/V hub 112 and/or speakers 118 may determine the angle of arrival (including non-line-of-sight reception) using: a directional antenna, the differential time of arrival at an array of antennas with known location(s), and/or the angle of arrival at two receivers having known location (i.e., trilateration or multilateration). As described further below with reference to FIGS. 5-7, another approach for coordinating speakers 118 may use scheduled transmission times. In particular, during a calibration mode, clocks in A/V hub 112 and speakers 118 may be coordinated. Subsequently, in a normal operating mode, A/V hub 112 may transmit frames or packets with an identifier of A/V hub 112 at predefined transmission times based on the clock in A/V hub 112. However, because of the relative drift in the clock in A/V hub 112, these packets or frames will arrive or be received at speakers 118 at different times than the expected predefined transmission times based on the clocks in speakers 118. Thus, by once again ignoring the propagation delay, the difference of the arrival time and the predefined transmission time of a given frame at a given one of speakers 118 (such as speaker 118-1) may dynamically track the drift or the current time offset in the coordination of the clocks in A/V hub 112 and speaker 118-1 (as well as the negligible static offset associated with the propagation delay). Alternatively or additionally, after the calibration mode, speakers 118 may transmit frames or packets with identifiers of speakers 118 at predefined transmission times based on the clock in speakers 118. However, because of drift in the clocks in speakers 118, these packets or frames will arrive or be received by A/V hub 112 at different times than the expected predefined transmission times based on the clock in A/V hub 112. Thus, by once again ignoring the propagation delay, the difference of the arrival time and the predefined transmission time of a given frame from a given one of speakers 118 (such as speaker 118-1) may dynamically track the drift or the current time offset in the coordination of the clocks in A/V hub 112 and speaker 118-1 (as well as the negligible static offset associated with the propagation delay). Once again, the current time offset may be determined by A/V hub 112 or may be provided to A/V hub 112 by one or more of speakers 118 (such as speaker 118-1). Note that in some embodiments the current time offset is further based on models of clock drift in A/V hub 112 and speakers 118. Then, A/V hub 112 may transmit, to speaker 118-1, one or more frames that include audio content and playback timing information, which may specify playback times when speaker 118-1 is to playback the audio content based on the current time offset. This may be repeated for other speakers 118. Furthermore, the playback times of speakers 118 may have a temporal relationship so that the playback of the audio content by speakers 118 is coordinated. Moreover, note that the one or more additional communication techniques may also be used in these embodiments to identify and/or exclude multi-path wireless signals during the coordination of speakers 118. As described further below with reference to FIGS. 8-10, another approach for coordinating speakers 118 may use acoustic measurements. In particular, during a calibration mode, clocks in A/V hub 112 and speakers 118 may be coordinated. Subsequently, A/V hub 112 may output sound that corresponds to an acoustic-characterization pattern that uniquely identifies A/V hub 112 (such as a sequence of pulses, different frequencies, etc.) at predefined transmission times. This acoustic-characterization pattern may be output at frequencies outside of the range of human hearing (such as at ultrasonic frequencies). However, because of the relative drift in the clock in A/V hub 112, the sound corresponding to the acoustic-characterization pattern will be measured at speakers 118 (i.e., will arrive or be received) at different times than the expected predefined transmission times based on the clocks in speakers 118. In these embodiments, the different times need to be corrected for the contributions associated with acoustic propagation delays based on the predetermined or known locations of A/V hub 112 and speakers 118 and/or using wireless ranging. For example, the locations may be determined using a triangulation and/or trilateration in a local positioning system, a global positioning system, and/or a wireless network (such as a cellular-telephone network or a WLAN). Thus, after correcting for the acoustic propagation delay, the difference of the arrival time and the predefined transmission time of a given frame at a given one of speakers 118 (such as speaker 118-1) may dynamically track the drift or the current time offset in the coordination of the clocks in A/V hub 112 and speaker 118-1. Alternatively or additionally, after the calibration mode, speakers 118 may output sound that corresponds to acoustic-characterization patterns that uniquely identify speakers 118 (such as different sequences of pulses, different frequencies, etc.) at predefined transmission times. However, because of the relative drift in the clocks in speakers 118, the sound corresponding to the acoustic-characterization patterns will be measured at A/V hub 112 (i.e., will arrive or be received) at different times than the expected predefined transmission times based on the clock in A/V hub 112. In these embodiments, the different times need to be corrected for the contributions associated with acoustic propagation delays based on the predetermined or known locations of A/V hub 112 and speakers 118 and/or using wireless ranging. Thus, after correcting for the acoustic propagation delay, the difference of the arrival time and the predefined transmission time of a given frame from a given one of speakers 118 (such as speaker 118-1) may dynamically track the drift or the current time offset in the coordination of the clocks in A/V hub 112 and speaker 118-1. Once again, the current time offset may be determined by A/V hub 112 or may be provided to A/V hub 112 by speaker 118-1. Then, A/V hub 112 may transmit, to speaker 118-1, one or more frames that include audio content and playback timing information, which may specify playback times when speaker 118-1 is to playback the audio content based on the current time offset. This may be repeated for other speakers 118. Furthermore, the playback times of speakers 118 may have a temporal relationship so that the playback of the audio content by speakers 118 is coordinated. Although we describe the network environment shown in FIG. 1 as an example, in alternative embodiments, different numbers or types of electronic devices may be present. For example, some embodiments include more or fewer electronic devices. As another example, in another embodiment, different electronic devices are transmitting and/or receiving packets or frames. While portable electronic device 110 and A/V hub 112 are illustrated with a single instance of radios 122, in other embodiments portable electronic device 110 and A/V hub 112 (and optionally A/V display devices 114, receiver device 116, speakers 118 and/or content sources 120) may include multiple radios. We now describe embodiments of the communication technique. FIG. 2 presents a flow diagram illustrating a method 200 for coordinating playback of audio content, which may be performed by an A/V hub, such as A/V hub 112 (FIG. 1). During operation, the A/V hub (such as a control circuit or control logic, e.g., a processor executing a program module, in the A/V hub) may receive, via wireless communication, frames (operation 210) or packets from one or more electronic devices, where a given frame or packet includes a transmit time when a given electronic device transmitted the given frame or packet. Then, the A/V hub may store receive times (operation 212) when the frames or packets were received, where the receive times are based on a clock in the A/V hub. For example, a receive time may be may be added to an instance of a packet or a frame or packet received from one of the electronic devices by a physical layer and/or a media access control (MAC) layer in or associated with an interface circuit in the A/V hub. Note that the receive time may be associated with the leading edge or the trailing edge of the packet or frame or packet, such as with a receive time signal which is associated with the leading edge or with a receive clear signal which is associated with the trailing edge. Similarly, the transmit time may be added to an instance of a frame or a packet transmitted by one of the electronic devices by a physical layer and/or a MAC layer in or associated with an interface circuit in the electronic device. In some embodiments, the transmit and receive times are determined and added to the frames or packets by wireless-ranging capability in a physical layer and/or a MAC layer in or associated with the interface circuits. Moreover, the A/V hub may calculate current time offsets (operation 214) between clocks in the electronic devices and the clock in the A/V hub based on the receive times and transmit times of the frames or packets. Furthermore, the current time offsets may be calculated by the A/V hub based on models of clock drift in the electronic devices, such as an electrical circuit model of a clock circuit and/or a look-up table of clock drift as a function of time. Note that the electronic devices may be located at non-zero distances from the A/V hub, and the current time offsets may be calculated based on the transmit times and the receive times using wireless ranging by ignoring the distances. Next, the A/V hub may transmit one or more frames (operation 216) or packets that include audio content and playback timing information to the electronic devices, where the playback timing information specifies playback times when the electronic devices are to playback the audio content based on the current time offsets. Furthermore, the playback times of the electronic devices may have a temporal relationship so that the playback of the audio content by the electronic devices is coordinated. Note that the temporal relationship may have a non-zero value, so that at least some of the electronic devices are instructed to playback the audio content with a phase relative to each other by using different values of the playback times. For example, the different playback times may be based on predetermined or dynamically determined acoustic characteristics of an environment that includes the electronic devices and the A/V hub. Alternatively or additionally, the different playback times may be based on a desired acoustic characteristic in the environment. In some embodiments, the A/V hub optionally performs one or more additional operations (operation 218). For example, the electronic devices may be located at vector distances from the A/V hub, and the interface circuit may determine magnitudes of the vector distances based on the transmit times and the receive times using wireless ranging. Moreover, the interface circuit may determine angles of the vector distances based on the angle of arrival of wireless signals associated with the frames or packets that are received by the one or more antennas during the wireless communication. Furthermore, the different playback times may be based on the determined vector distances. For example, the playback times may correspond to the determined vector distances such that the sound associated with the audio content from different electronic devices at different locations in the environment may arrive at a location in the environment (e.g., a location of the A/V hub, in the middle of the environment, at a preferred listening location of a user, etc.) with a desired phase relationship or to achieve a desired acoustic characteristic at the location. Alternatively or additionally, the different playback times are based on an estimated location of a listener relative to the electronic devices, such that the sound associated with the audio content from different electronic devices at different locations in the environment may arrive at the estimated location of the listener with a desired phase relationship or to achieve a desired acoustic characteristic at the estimated location. Techniques that can be used to determine the location of the listener are described further below with reference to FIGS. 14-16. Note that while the wireless ranging capability in the interface circuits may involve coordinated clocks in the A/V hub and the electronic devices, in other embodiments the clocks are not coordinated. Thus, a variety of radiolocation techniques may be used. In some embodiments, the wireless-ranging capability includes the use of transmissions over GHz or multi-GHz bandwidths to create pulses of short duration (such as, e.g., approximately 1 ns). FIG. 3 is a drawing illustrating between A/V hub 112, and speaker 118-1. In particular, interface circuit 310 in speaker 118-1 may transmit one or more frames or packets (such as packet 312) to A/V hub 112. Packet 312 may include corresponding transmit time 314, based on an interface clock 316 provided by an interface clock circuit 318 in or associated with an interface circuit 310 in speaker 118-1, when speaker 118-1 transmitted packets 312. When an interface circuit 320 in A/V hub 112 receives packet 312, it may include receive time 322 in packet 312 (or it may store receive time 322 in memory 324), where for each packet the corresponding receive time may be based on an interface clock 326 provided by an interface clock circuit 328 in or associated with interface circuit 318. Then, interface circuit 320 may calculate, based on differences between transmit times 314 and receive times 322, a current time offset 330 between interface clock 316 and interface clock 326. Moreover, interface circuit 320 may provide current time offset 330 to processor 332. (Alternatively, processor 332 may calculate the current time offset 330.) Furthermore, processor 332 may provide playback timing information 334 and audio content 336 to interface circuit 320, where the playback timing information 334 specifies a playback time when speaker 118-1 is to playback audio content 336 based on the current time offset 330. In response, interface circuit 330 may transmit one or more frames or packets 338 that includes the playback timing information 334 and audio content 336 to speaker 118-1. (However, in some embodiments, playback timing information 334 and audio content 336 are transmitted using separate or different frames or packets.) After interface circuit 310 receives the one or more frames or packets 338, it may provide the playback timing information 334 and audio content 336 to processor 340. Processor 340 may execute software that performs a playback operation 342. For example, processor 340 may store audio content 336 in a queue in memory. In these embodiments, playback operation 350 includes outputting audio content 336 from the queue, including driving an electrical-to-acoustic transducer in speaker 118-1 based on audio content 336 so speaker 118-1 outputs sound at a time specified by the playback timing information 334. In an exemplary embodiment, the communication technique is used to coordinate the playback of audio content by speakers 118. This is illustrated in FIG. 4, which presents a drawing illustrating coordinating playback of audio content by speakers 118. In particular, when frames or packets (such as packet 410-1) are transmitted by speakers 118 they may include information specifying transmit times (such as transmit time 412-1). For example, the physical layer in the interface circuits in speakers 118 may include the transmit times in packets 410. In FIG. 4 and the other embodiments below, note that information in frames or packets may be included at an arbitrary position (such the beginning, the middle and/or the end). When packets 410 are received by A/V hub 112, additional information specifying receive times (such as receive time 414-1 of packet 410-1) may be included in packets 410. For example, the physical layer in the interface circuit in A/V hub 112 may include the receive times in packets 410. Moreover, the transmit times and the receive times may be used to track the drift of clocks in A/V hub 112 and speakers 118. Using the transmit times and receive times, A/V hub 112 may calculate current time offsets between the clocks in speakers 118 and the clock in A/V hub 112. Furthermore, the current time offsets may be calculated by A/V hub 112 based on models in A/V hub 112 of the clock drift in speakers 118. For example, a model of the relative or absolute clock drift may include a polynomial or a cubic spline expression (and, more generally, a function) with parameters that specify or estimate the clock drift in a given speaker as a function of time based on historical time offsets. Subsequently, A/V hub 112 may transmit one or more packets or frames or packets that include audio content 420 and playback timing information (such as playback timing information 418-1 in packet 416-1) to speakers 118, where the playback timing information specifies playback times when speakers 118 devices are to playback audio content 420 based on the current time offsets. The playback times of speakers 118 may have a temporal relationship so that the playback of audio content 420 by speakers 118 is coordinated, e.g., so that the associated sound or wavefronts arrive at a location 422 in an environment with a desired phase relationship. Another embodiment of the coordination in the communication technique is shown in FIG. 5, which presents a flow diagram illustrating a method 500 for coordinating playback of audio content. Note that method 500 may be performed by an A/V hub, such as A/V hub 112 (FIG. 1). During operation, the A/V hub (such as a control circuit or control logic, e.g., a processor executing a program module, in the A/V hub) may receive, via wireless communication, frames (operation 510) or packets from electronic devices. Then, the A/V hub may store receive times (operation 512) when the frames or packets were received, where the receive times are based on a clock in the A/V hub. For example, a receive time may be may be added to an instance of a frame or a packet received from one of the electronic devices by a physical layer and/or a MAC layer in or associated with an interface circuit in the A/V hub. Note that the receive time may be associated with the leading edge or the trailing edge of the frame or a packet, such as with a receive time signal which is associated with the leading edge or with a receive clear signal which is associated with the trailing edge. Moreover, the A/V hub may calculate current time offsets (operation 514) between clocks in the electronic devices and the clock in the A/V hub based on the receive times and expected transmit times of the frames or packets, where the expected transmit times are based on coordination of the clocks in the electronic devices and the clock in the A/V hub at a previous time and a predefined transmit schedule of the frames or packets (such as every 10 or 100 ms, which are nonlimiting examples). For example, during an initialization mode, time offsets between the clocks in the electronic devices and the clock in the A/V hub may be eliminated (i.e., coordination may be established). Note that the predefined transmit times in the transmit schedule may include or may be other than beacon transmit times in a WLAN. Subsequently, the clocks and the clock may have relative drift, which can be tracked based on differences between the receive times and expected transmit times of the frames or packets. In some embodiments, the current time offsets are calculated by the A/V hub based on models of clock drift in the electronic devices. Next, the A/V hub may transmit one or more frames (operation 516) or packets that include audio content and playback timing information to the electronic devices, where the playback timing information specifies playback times when the electronic devices are to playback the audio content based on the current time offsets. Furthermore, the playback times of the electronic devices may have a temporal relationship so that the playback of the audio content by the electronic devices is coordinated. Note that the temporal relationship may have a non-zero value, so that at least some of the electronic devices are instructed to playback the audio content with a phase relative to each other by using different values of the playback times. For example, the different playback times may be based on predetermined or dynamically determined acoustic characteristics of an environment that includes the electronic devices and the A/V hub. Alternatively or additionally, the different playback times may be based on a desired acoustic characteristic in the environment. In some embodiments, the A/V hub optionally performs one or more additional operations (operation 518). For example, the electronic devices may be located at vector distances from the A/V hub, and the interface circuit may determine magnitudes of the vector distances based on the transmit times and the receive times using wireless ranging. Moreover, the interface circuit may determine angles of the vector distances based on the angle of arrival of wireless signals associated with the frames or packets that are received by the one or more antennas during the wireless communication. Furthermore, the different playback times may be based on the determined vector distances. For example, the playback times may correspond to the determined vector distances such that the sound associated with the audio content from different electronic devices at different locations in the environment may arrive at a location in the environment (e.g., a location of the A/V hub, in the middle of the environment, at a preferred listening location of a user, etc.) with a desired phase relationship or to achieve a desired acoustic characteristic at the location. Alternatively or additionally, the different playback times are based on an estimated location of a listener relative to the electronic devices, such that the sound associated with the audio content from different electronic devices at different locations in the environment may arrive at the estimated location of the listener with a desired phase relationship or to achieve a desired acoustic characteristic at the estimated location. Techniques that can be used to determine the location of the listener are described further below with reference to FIGS. 14-16. FIG. 6 is a drawing illustrating communication among portable electronic device 110, A/V hub 112, and speaker 118-1. In particular, during an initialization mode, interface circuit 610 in A/V hub 112 may transmit a frame or packet 612 to interface circuit 614 in speaker 118-1. This packet may include information 608 that coordinates clocks 628 and 606 provided, respectively, by interface clock circuits 616 and 618. For example, the information may eliminate a time offset between interface clock circuits 616 and 618 and/or may set interface clock circuits 616 and 618 to the same clock frequency. Subsequently, interface circuit 614 may transmit one or more frames or packets (such as packet 620) to A/V hub 112 at predefined transmit times 622. When an interface circuit 610 in A/V hub 112 receives packet 620, it may include receive time 624 in packet 620 (or it may store receive time 624 in memory 626), where for each packet the corresponding receive time may be based on interface clock 628 provided by an interface clock circuit 616 in or associated with interface circuit 610. Then, interface circuit 610 may calculate, based on differences between transmit times 622 and receive times 624, a current time offset 630 between interface clock 628 and interface clock 606. Moreover, interface circuit 610 may provide current time offset 630 to processor 632. (Alternatively, processor 632 may calculate the current time offset 630.) Furthermore, processor 632 may provide playback timing information 634 and audio content 636 to interface circuit 610, where the playback timing information 634 specifies a playback time when speaker 118-1 is to playback audio content 636 based on the current time offset 630. In response, interface circuit 610 may transmit one or more frames or packets 638 that includes the playback timing information 634 and audio content 636 to speaker 118-1. (However, in some embodiments, playback timing information 634 and audio content 636 are transmitted using separate or different frames or packets.) After interface circuit 614 receives the one or more frames or packets 638, it may provide the playback timing information 634 and audio content 636 to processor 640. Processor 640 may execute software that performs a playback operation 642. For example, processor 640 may store audio content 636 in a queue in memory. In these embodiments, playback operation 650 includes outputting audio content 636 from the queue, including driving an electrical-to-acoustic transducer in speaker 118-1 based on audio content 636 so speaker 118-1 outputs sound at a time specified by the playback timing information 634. In an exemplary embodiment, the communication technique is used to coordinate the playback of audio content by speakers 118. This is illustrated in FIG. 7, which presents a drawing illustrating coordinating playback of audio content by speakers 118. In particular, A/V hub 112 may transmit frames or packets 710 to speakers 118 with information (such as information 708 in packet 710-1) that coordinates clocks, provided by clock circuits, in A/V hub 112 and speakers 118. Subsequently, speakers 118 may transmit frames or packets 712 to A/V hub 112 at predefined transmit times. When these frames or packets are received by A/V hub 112, information specifying receive times may be included in packets 712 (such as receive time 714-1 in packet 712-1). The predefined transmit times and the receive times may be used to track the drift of the clocks in A/V hub 112 and speakers 118. Using the predefined transmit times and the receive times, A/V hub 112 may calculate current time offsets between the clocks in speakers 118 and the clock in A/V hub 112. Furthermore, the current time offsets may be calculated by A/V hub 112 based on models in A/V hub 112 of the clock drift in speakers 118. For example, a model of the relative or absolute clock drift may include a polynomial or a cubic spline expression (and, more generally, a function) with parameters that specify or estimate the clock drift in a given speaker as a function of time based on historical time offsets. Subsequently, A/V hub 112 may transmit one or more frames or packets that include audio content 720 and playback timing information (such as playback timing information 718-1 in packet 716-1) to speakers 118, where the playback timing information specifies playback times when speakers 118 devices are to playback audio content 720 based on the current time offsets. The playback times of speakers 118 may have a temporal relationship so that the playback of audio content 720 by speakers 118 is coordinated, e.g., so that the associated sound or wavefronts arrive at a location 722 in an environment with a desired phase relationship. Another embodiment of the coordination in the communication technique is shown in FIG. 8, which presents a flow diagram illustrating a method 800 for coordinating playback of audio content. Note that method 800 may be performed by an A/V hub, such as A/V hub 112 (FIG. 1). During operation, the A/V hub (such as a control circuit or control logic, e.g., a processor executing a program module, in the A/V hub) may measure sound (operation 810) output by electronic devices in an environment that includes the A/V hub using one or more acoustic transducers in the A/V hub, where the sound corresponds to one or more acoustic-characterization patterns. For example, the measured sound may include the sound pressure. Note that the acoustic-characterization patterns may include pulses. Moreover, the sound may be in a range of frequencies outside of human hearing, such as ultrasound. Furthermore, a given electronic device may output the sound at a different time in the one or more times than those used by a remainder of the electronic devices, so that the sound from the given electronic device can be identified or distinguished from the sound output by the remainder of the electronic devices. Alternatively or additionally, the sound output by a given electronic device may correspond to a given acoustic-characterization pattern, which may be different from those used by the remainder of the electronic devices. Thus, the acoustic-characterization patterns may uniquely identify the electronic devices. Then, the A/V hub may calculate current time offsets (operation 812) between clocks in the electronic devices and a clock in the A/V hub based on the measured sound, one or more times when the electronic devices output the sound and the one or more acoustic-characterization patterns. For example, the A/V hub may correct the measured sound based on an acoustic characteristic of the environment, such as an acoustic delay associated with at least a particular frequency or a predetermined (or dynamically determined) acoustic transfer function of the environment in at least a band of frequencies (such as 100-20,000 Hz, which is a nonlimiting example), and the output times may be compared to triggered output times or predefined output times. This may allow the A/V hub to determine the original output sound without the spectral filtering or distortions associated with the environment, which may allow the A/V hub to more accurately determine the current time offsets. Note that the measured sound may include information that specifies the one or more times when the electronic devices output the sound (e.g., the pulses in the acoustic-characterization patterns may specify the times), and the one or more times may correspond to the clocks in the electronic devices. Alternatively or additionally, the A/V hub may optionally provide to the electronic devices, via the wireless communication, one or more times (operation 808) when the electronic devices are to output the sound, and the one or more times may correspond to the clock in the A/V hub. For example, the A/V hub may transmit one or more frames or packets to the electronic devices with the one or more times. Thus, the A/V hub may trigger the output of the sound or the sound may be output at predefined output times. Next, the A/V hub may transmit, using wireless communication, one or more frames (operation 814) or packets that include audio content and playback timing information to the electronic devices, where the playback timing information specifies playback times when the electronic devices are to playback the audio content based on the current time offsets. Moreover, the playback times of the electronic devices have a temporal relationship so that the playback of the audio content by the electronic devices is coordinated. Note that the temporal relationship may have a non-zero value, so that at least some of the electronic devices are instructed to playback the audio content with a phase relative to each other by using different values of the playback times. For example, the different playback times may be based on predetermined or dynamically determined acoustic characteristics of an environment that includes the electronic devices and the A/V hub. Alternatively or additionally, the different playback times may be based on a desired acoustic characteristic in the environment and/or an estimated location of a listener relative to the electronic devices. In some embodiments, the A/V hub optionally performs one or more additional operations (operation 816). For example, the A/V hub may modify the measured sound based on an acoustic transfer function of the environment in at least a band of frequencies that includes the spectral content in acoustic-characterization patterns. Note that the acoustic transfer function may be predetermined and accessed by the A/V hub or dynamically determined by the A/V hub. This correction for the filtering associated with the environment may be necessary because, while the time delay and dispersion associated with the propagation of sound in the environment may be much larger than the desired coordination of the clocks in the electronic devices and the clock in the A/V hub, the leading edge of the modified direct sound may be determined with sufficient accuracy that the current time offset between the clocks in the electronic devices and the clock in the A/V hub can be determined. For example, the desired coordination accuracy of speakers 118 may be as small as on the order of a microsecond, while the propagation delay of sound in a typical room (e.g., over distances of at most 10-30 m) may be five orders of magnitude larger. Nonetheless, the modified measured sound may allow the leading edges of the direct sound associated with pulses in the sound output from a given electronic device to be measured with as little as microsecond accuracy, which can facilitate coordination of the clocks in the electronic devices and the clock in the A/V hub. In some embodiments, the A/V hub determines the temperature in the environment, and the calculations of the current time offset may be corrected for changes in the temperature (which impact the speed of sound in the environment). FIG. 9 is a drawing illustrating communication among portable electronic device 110, A/V hub 112, and speaker 118-1. In particular, processor 910 in speaker 118-1 may instruct 912 one or more acoustic transducers 914 in speaker 118-1 to output sound at an output time, where the sound corresponds to an acoustic-characterization pattern. For example, the output time may be predefined (such as based on a pattern or sequence of pulses in the acoustic-characterization pattern, a predefined output schedule with scheduled output times or a predefined interval between output times) and thus may be known to A/V hub 112 and the speaker 118-1. Alternatively, interface circuit 916 in A/V hub 112 may provide a trigger frame or packet 918. After interface circuit 920 receives trigger packet 918, it may forward an instruction 922 to processor 910 in speaker 118-1, which triggers the sound output from the one or more acoustic transducers 914 based on instruction 922. Subsequently, the one or more acoustic transducers 924 in A/V hub 112 may measure 926 the sound, and may provide information 928 that specifies the measurements to processor 930 in A/V hub 112. Next, processor 930 may calculate a current time offset 932 between a clock from a clock circuit in speaker 118-1 (such as an interface clock circuit) and a clock from a clock circuit (such as an interface clock circuit) in A/V hub 112 based on the information 928, one or more times when speaker 118-1 output the sound and an acoustic-characterization pattern associated with speaker 118-1. For example, processor 930 may determine the current time offset 932 based on at least two times in the acoustic-characterization pattern when the one or more acoustic transducers 914 in speaker 118-1 output sound corresponding to the acoustic-characterization pattern. Moreover, processor 930 may provide playback timing information 934 and audio content 936 to interface circuit 916, where the playback timing information 934 specifies a playback time when speaker 118-1 is to playback audio content 936 based on the current time offset 932. Note that processor 930 may access audio content 936 in memory 938. In response, interface circuit 916 may transmit one or more frames or packets 940 that includes the playback timing information 934 and audio content 936 to speaker 118-1. (However, in some embodiments, playback timing information 934 and audio content 936 are transmitted using separate or different frames or packets.) After interface circuit 920 receives the one or more frames or packets 940, it may provide the playback timing information 934 and audio content 936 to processor 924. Processor 924 may execute software that performs a playback operation 942. For example, processor 924 may store audio content 936 in a queue in memory. In these embodiments, playback operation 942 includes outputting audio content 936 from the queue, including driving one or more of acoustic transducers 914 based on audio content 936 so speaker 118-1 outputs sound at a time specified by the playback timing information 934. In an exemplary embodiment, the communication technique is used to coordinate the playback of audio content by speakers 118. This is illustrated in FIG. 10, which presents a drawing illustrating coordinating playback of audio content by speakers 118. In particular, speakers 118 may output sound 1010 corresponding to acoustic-characterization patterns. For example, an acoustic-characterization pattern associated with speaker 118-1 may include two or more pulses 1012, where a time interval 1014 between pulses 1012 may correspond to a clock provided by a clock circuit in speaker 118-1. In some embodiments, a pattern or sequence of pulses in the acoustic-characterization patterns may also uniquely identify speakers 118. While pulses 1012 are used to illustrated the acoustic-characterization patterns in FIG. 10, in other embodiments a variety of temporal, frequency and/or modulation techniques may be used, including: amplitude modulation, frequency modulation, phase modulation, etc. Note that A/V hub 112 may optional trigger the output of sound 1010 by transmitting one or more frames or packets 1016 with information 1018 specifying times to speakers 118 when speakers 118 are to output sound 1010 corresponding to the acoustic-characterization patterns. Then, A/V hub 112 may measure sound 1010 output by the electronic devices using one or more acoustic transducers, where the sound corresponds to one or more of the acoustic-characterization patterns. After measuring sound 1010, A/V hub 112 may calculate current time offsets between clocks in speakers 118 and a clock in A/V hub 112 based on the measured sound 1010, one or more times when the speakers 118 output the sound and the one or more acoustic-characterization patterns. In some embodiments, the current time offsets may be calculated by A/V hub 112 based on models in A/V hub 112 of clock drift in speakers 118. For example, a model of the relative or absolute clock drift may include a polynomial or a cubic spline expression (and, more generally, a function) with parameters that specify or estimate the clock drift in a given speaker as a function of time based on historical time offsets. Next, A/V hub 112 may transmit one or more frames or packets that include audio content 1022 and playback timing information to speakers 118 (such as playback timing information 1024-1 in packet 1020-1), where the playback timing information specifies playback times when speakers 118 devices are to playback audio content 1022 based on the current time offsets. The playback times of speakers 118 may have a temporal relationship so that the playback of audio content 1022 by speakers 118 is coordinated, e.g., so that the associated sound or wavefronts arrive at a location 1026 in an environment with a desired phase relationship. The communication technique may include operations that are used to adapt the coordination to improve the acoustic experience of listeners. One approach is shown in FIG. 11, which presents a flow diagram illustrating a method 1100 for selectively determining one or more acoustic characteristics of an environment (such as a room). Method 1100 may be performed by an A/V hub, such as A/V hub 112 (FIG. 1). During operation, the A/V hub (such as a control circuit or control logic, e.g., a processor executing a program module, in the A/V hub) may optionally detect, using wireless communication, an electronic device (operation 1110) in an environment. Alternatively or additionally, the A/V hub may determine a change condition (operation 1112), where the change condition includes: that the electronic device was not previously detected in the environment; and/or a change in a location of the electronic device (including a change in the location that occurs long after the electronic device was first detected in the environment). When the change condition is determined (operation 1112), the A/V hub may transition into a characterization mode (operation 1114). During the characterization mode, the A/V hub may: provide instructions (operation 1116) to the electronic device to playback audio content at a specified playback time; determine one or more acoustic characteristics (operation 1118) of the environment based on acoustic measurements in the environment; and store the characterization information (operation 1120) in memory, where the characterization information includes the one or more acoustic characteristics. Moreover, the A/V hub may transmit one or more frames (operation 1122) or packets that include additional audio content and playback timing information to the electronic device, where the playback timing information may specify a playback time when the electronic device is to playback the additional audio content based on the one or more acoustic characteristics. In some embodiments, the A/V hub optionally performs one or more additional operations (operation 1124). For example, the A/V hub may calculate the location of the electronic device in the environment, such as based on wireless communication. Moreover, the characterization information may include an identifier of the electronic device, which may be received from the electronic device by the A/V hub using wireless communication. Furthermore, the A/V hub may determine the one or more acoustic characteristics based, at least in part, on acoustic measurements performed by other electronic devices. Thus, the A/V hub may communicate with the other electronic devices in the environment using the wireless communication, and may receive the acoustic measurements from the other electronic devices. In these embodiments, the one or more acoustic characteristics may be determined based on locations of the other electronic devices in the environment. Note that the A/V hub may: receive the locations of the other electronic devices from the other electronic devices; access predetermined locations of the other electronic devices stored in memory; and determine the locations of the other electronic devices, e.g., based on the wireless communication. In some embodiments, the A/V hub includes one or more acoustic transducers, and the A/V hub performs the acoustic measurements using the one or more acoustic transducers. Therefore, the one or more acoustic characteristics may be determined by the A/V hub alone or in conjunction with the acoustic measurements performed by the other electronic devices. However, in some embodiments, instead of determining the one or more acoustic characteristics, the A/V hub receives the determined one or more acoustic characteristics from one of the other electronic devices. While the acoustic characterization may be fully automated based on the change condition, in some embodiments a user may manually initiate the characterization mode or may manually approve the characterization mode when the change condition is detected. For example, the A/V hub may: receive a user input; and transition into the characterization mode based on the user input. FIG. 12 is a drawing illustrating communication between A/V hub 112 and speaker 118-1. In particular, interface circuit 1210 in A/V hub 112 may detect speaker 118-1 by wireless communication of frames or packets 1212 with interface circuit 1214 in speaker 118-1. Note that this communication may be unilateral or bilateral. Interface circuit 1210 may provide information 1216 to processor 1218. This information may indicate the presence of speaker 118-1 in an environment. Alternatively or additionally, information 1216 may specify a location of speaker 118-1. Then, processor 1218 may determine whether a change condition 1220 has occurred. For example, processor 1218 may determine the presence of speaker 118-1 in the environment when it was not present previously or that the location of previously detected speaker 118-1 has changed. When change condition 1220 is determined, processor 1218 may transition to a characterization mode 1222. During characterization mode 1222, processor 1218 may provide instruction 1224 to interface circuit 1210. In response, interface circuit 1210 may transmit instruction 1224 to interface circuit 1214 in frame or packet 1226. After receiving packet 1226, interface circuit 1214 may provide instruction 1224 to processor 1228, when then instructs one or more acoustic transducers 1230 to playback audio content 1232 at a specified playback time. Note that processor 1228 may access audio content 1232 in memory 1208 or audio content 1232 may be included in packet 1226. Next, one or more acoustic transducers 1234 in A/V hub 112 may perform acoustic measurements 1236 of sound corresponding to audio content 1232 output by the one or more acoustic transducers 1230. Based on acoustic measurements 1236 (and/or additional acoustic measurements received from other speakers by interface circuit 1210), processor 1218 may determine one or more acoustic characteristics 1238 of the environment, which are then stored in memory 1240. Moreover, processor 1218 may provide playback timing information 1242 and audio content 1244 to interface circuit 1210, where the playback timing information 1242 specifies a playback time when speaker 118-1 is to playback audio content 1244 based, at least in part, on the one or more acoustic characteristics 1238. In response, interface circuit 1210 may transmit one or more frames or packets 1246 that includes the playback timing information 1242 and audio content 1244 to speaker 118-1. (However, in some embodiments, playback timing information 1242 and audio content 1244 are transmitted using separate or different frames or packets.) After interface circuit 1214 receives the one or more frames or packets 1246, it may provide the playback timing information 1242 and audio content 1244 to processor 1228. Processor 1228 may execute software that performs a playback operation 1248. For example, processor 1228 may store audio content 1244 in a queue in memory. In these embodiments, playback operation 1248 includes outputting audio content 1244 from the queue, including driving one or more of acoustic transducers 1230 based on audio content 1244 so speaker 118-1 outputs sound at a time specified by the playback timing information 1242. In an exemplary embodiment, the communication technique is used to selectively determine one or more acoustic characteristics of an environment (such as a room) that includes A/V hub 112 when a change is detected. FIG. 13 presents a drawing illustrating selective acoustic characterization of an environment that includes speakers 118. In particular, A/V hub 112 may detect speaker 118-1 in the environment. For example, A/V hub 112 may detect speaker 118-1 based on wireless communication of one or more frames or packets 1310 with speaker 118-1. Note that the wireless communication may be unilateral or bilateral. When a change condition is determined (such as when the presence of speaker 118-1 is first detected, i.e., when speaker 118-1 was not previously detected in the environment, and/or when there is a change in a location 1312 of previously detected speaker 118-1 in the environment), A/V hub 112 may transition into a characterization mode. For example, A/V hub 112 may transition into the characterization mode when a magnitude change in location 1312 on the order of the wavelength at the upper limit of human hearing, e.g., a change of 0.0085, 0.017 or 0.305 m (which are nonlimiting examples), in location 1312 of speaker 118-1 is detected. During the characterization mode, A/V hub 112 may: provide instructions in frame or packet 1314 to speaker 118-1 to playback audio content at a specified playback time (i.e., to output sound 1316); determine one or more acoustic characteristics of the environment based on acoustic measurements of sound 1316 output by speaker 118-1; and store the one or more acoustic characteristics, which may include location 1312 of speaker 118-1, in memory. For example, the audio content may include a pseudorandom frequency pattern or white noise over a range of frequencies (such as between 100 and 10,000 or 20,000 Hz, or two or more sub-frequency bands in the range of human hearing, e.g., at 500, 1000 and 2000 Hz, which are nonlimiting examples), an acoustic pattern having a carrier frequency that varies as a function of time over a range of frequencies, an acoustic pattern having spectral content in a range of frequencies, and/or one or more types of music (such as symphony music, classical music, chamber music, opera, rock or pop music, etc.). In some embodiments, the audio content uniquely identifies speaker 118-1, such as a particular temporal pattern, spectral content and/or one or more frequency tones. Alternatively or additionally, A/V hub 112 may receive, via wireless communication with speaker 118-1, an identifier of speaker 118-1, such as an alphanumeric code. However, in some embodiments, the acoustic characterization is performed without speaker 118-1 playing the audio content. For example, the acoustic characterization may be based on the acoustic energy associated with a person's voice or by measuring 1-2 min. of percussive background noise in the environment. Thus, in some embodiments the acoustic characterization includes passive characterization (instead of active measurements when the audio content is playing). Moreover, the acoustic characteristics may include: an acoustic spectral response of the environment over a range of frequencies (i.e., information that specifies an amplitude response as a function of frequency), an acoustic transfer function or impulse response over a range of frequencies (i.e., information that specifies an amplitude and a phase response as a function of frequency), room resonances or low-frequency room modes (which have nodes and antinodes as a function of position or location in the environment, and which may be determined by measuring sound in the environment in different directions at 90° from each other), location 1312 of speaker 118-1, reflections (including early reflections within 50-60 ms of the arrival of direct sound from speaker 118-1, and late reflections or echoes that occur on longer time scales, which can impact clarity), an acoustic delay of the direct sound, an average reverberation time over a range of frequencies (or the persistence of acoustic sound in the environment over a range of frequencies after the audio content has discontinued), a volume of the environment (such as a size and/or a geometry of room, which may be determined optically), background noise in the environment, ambient sound in the environment, a temperature of the environment, a number of people in the environment (and, more generally, absorption or acoustic loss over a range of frequencies in the environment), a metric of how acoustically lively, bright or dull the environment is and/or information that specifies a type of the environment (such as an auditorium, a general-purpose room, a concert hall, a size of a room, types of furnishing in a room, etc.). For example, the reverberation time may be defined as the time for the sound pressure associated with an impulse at a frequency to decay to a particular level, such as −60 dB. In some embodiments, the reverberation time is a function of the frequency. Note that the range of frequencies in the preceding examples of the acoustic characteristics may be the same or different from each other. Thus, in some embodiments, different ranges of frequencies may be used for different acoustic characteristics. In addition, note that an ‘acoustic transfer function’ in some embodiments may include a magnitude of the acoustic transfer function (which is sometimes referred to as an ‘acoustic spectral response’), a phase of the acoustic transfer function, or both. As noted previously, the acoustic characteristics may include location 1312 of speaker 118-1. The location 1312 of speaker 118-1 (including distance and direction) may be determined by A/V hub 112 and/or in conjunction with other electronic devices in the environment (such as speakers 118) using techniques such as: triangulation, trilateration, time of flight, wireless ranging, the angle of arrival, etc. Moreover, location 1312 may be determined by A/V hub 112 using: wireless communication (such as communication with a wireless local area network or with a cellular-telephone network), acoustic measurements, a local positioning system, a global positioning system, etc. While the acoustic characteristics may be determined by A/V hub 112 based on measurements performed by A/V hub 112, in some embodiments the acoustic characteristics are determined by or in conjunction with other electronic devices in the environment. In particular, one or more other electronic devices (such as one or more other speakers 118) may perform acoustic measurements, which are then wirelessly communicated to A/V hub 112 in frames or packets 1318. (Thus, acoustic transducers that perform the acoustic measurements may be included in A/V hub 112 and/or in the one or more other speakers 118.) Consequently, A/V hub 112 may compute the acoustic characteristics based, at least in part, on the acoustic measurements performed by A/V hub 112 and/or the one or more other speakers 118. Note that the computations may also be based on location(s) 1320 of the one or more other speakers 118 in the environment. These locations may be: received from the one or more other speakers 118 in frames or packets 1318, calculated using one of the aforementioned techniques (such as using wireless ranging), and/or accessed in memory (i.e., locations 1320 may be predetermined). Moreover, while the acoustic characterization may occur when the change condition is detected, alternatively or additionally A/V hub 112 may transition to the characterization mode based on a user input. For example, the user may activate a virtual command icon in a user interface on portable electronic device 110. Thus, the acoustic characterization may be automatically, manually initiated and/or semi-automatically initiated (in which a user interface is used to ask the user for approval before the transition to the characterization mode). After determining the acoustic characteristics, A/V hub 112 may transition back to a normal operating mode. In this operating mode, A/V hub 112 may transmit one or more frames or packets (such as packet 1322) that include additional audio content 1324 (such as music) and playback timing information 1326 to speaker 118-1, where the playback timing information 1326 may specify a playback time when speaker 118-1 is to playback the additional audio content 1324 based on the one or more acoustic characteristics. Thus, the acoustic characterization may be used to correct for or adapt to the changes (direct or indirect) in the one or more acoustic characteristics that are associated with a change in location 1312 of speaker 118-1, thereby improving the user experience. Another approach for improving the acoustic experience is to adapt the coordination based on dynamically tracked locations of one or more listeners. This is shown in FIG. 14, which presents a flow diagram illustrating a method 1400 for calculating an estimated location. Note that method 1400 may be performed by an A/V hub, such as A/V hub 112 (FIG. 1). During operation, the A/V hub (such as a control circuit or control logic, e.g., a processor executing a program module, in the A/V hub) may calculate an estimated location of a listener (operation 1410) (or an electronic device associated with the listener, such as portable electronic device 110 in FIG. 1) relative to the electronic devices in an environment that includes the A/V hub and the electronic devices. Then, the A/V hub may transmit one or more frames (operation 1412) or packets that include audio content and playback timing information to the electronic devices, where the playback timing information specifies playback times when the electronic devices are to playback the audio content based on the estimated location. Furthermore, the playback times of the electronic devices have a temporal relationship so that the playback of the audio content by the electronic devices is coordinated. Note that the temporal relationship may have a non-zero value, so that at least some of the electronic devices are instructed to playback the audio content with a phase relative to each other by using different values of the playback times. For example, the different playback times may be based on predetermined or dynamically determined acoustic characteristics of the environment that includes the electronic devices and the A/V hub. Alternatively or additionally, the different playback times may be based on a desired acoustic characteristic in the environment. Additionally, the playback times may be based on current time offsets between clocks in the electronic devices and a clock in the A/V hub. In some embodiments, the A/V hub optionally performs one or more additional operations (operation 1414). For example, the A/V hub may communicate with another electronic device, and the estimated location of the listener may be calculated based on the communication with the other electronic device. Moreover, the A/V hub may include an acoustic transducer that performs sound measurements in the environment, and the estimated location of the listener may be calculated based on the sound measurements. Alternatively or additionally, the A/V hub may communicate with other electronic devices in the environment and may receive additional sound measurements of the environment from the other electronic devices, and the estimated location of the listener may be calculated based on the additional sound measurements. In some embodiments, the A/V hub performs time-of-flight measurements, and the estimated location of the listener is calculated based on the time-of-flight measurements. Furthermore, the A/V hub may calculate additional estimated locations of additional listeners relative to the electronic devices in the environment, and the playback times may be based on the estimated location and the additional estimated locations. For example, the playback times may be based on an average of the estimated location and the additional estimated locations. Alternatively, the playback times may be based on a weighted average of the estimated location and the additional estimated locations. FIG. 15 is a drawing illustrating communication among portable electronic device 110, A/V hub 112, and speakers 118, such as speaker 118-1. In particular, interface circuit 1510 in A/V hub 112 may receive one or more frames or packets 1512 from interface circuit 1514 in portable electronic device 110. Note that the communication between A/V hub 112 and portable electronic device 110 may be unidirectional or bidirectional. Then, based on the one or more frames or packets 1512, interface circuit 1510 and/or processor 1516 in A/V hub 112 may estimate location 1518 of a listener associated with portable electronic device 110. For example, interface circuit 1510 may provide information 1508 based on packets 1512, which is used by processor 1516 to estimate location 1518. Alternatively or additionally, one or more acoustic transducers 1520 in A/V hub 112 and/or one or more acoustic transducers 1506 in speakers 118 may performs measures 1522 of sound associated with listener. If speakers 118 perform measurements 1522-2 of the sound, interface circuits 1524 in one or more of speakers 118 (such as speaker 118-1) may transmit one or more frames or packets 1526 to interface circuit 1510 with information 1528 that specifies measurements 1522-2 of the sound based on instructions 1530 from processor 1532. Then, interface circuit 1514 and/or processor 1516 may estimate location 1518 based on the measured sound 1522. Next, processor 1516 may instruct interface circuit 1510 to transmit one or more frames or packets 1536 to speaker 118-1 with playback timing information 1538 and audio content 1540, where the playback timing information 1538 specifies a playback time when speaker 118-1 is to playback audio content 1540 based, at least in part, on location 1518. (However, in some embodiments, playback timing information 1538 and audio content 1540 are transmitted using separate or different frames or packets.) Note that processor 1516 may access audio content 1540 in memory 1534. After receiving the one or more frames or packets 1536, interface circuit 1524 may provide playback timing information 1538 and audio content 1540 to processor 1532. Processor 1532 may execute software that performs a playback operation 1542. For example, processor 1532 may store audio content 1540 in a queue in memory. In these embodiments, playback operation 1542 includes outputting audio content 1540 from the queue, including driving one or more of acoustic transducers 1506 based on audio content 1540 so speaker 118-1 outputs sound at a time specified by the playback timing information 1538. In an exemplary embodiment, the communication technique is used to dynamically track the locations of one or more listeners in an environment. FIG. 16 presents a drawing illustrating calculating an estimated location of one or more listeners relative to speakers 118. In particular, A/V hub 112 may calculate estimated location(s) of one or more listeners, such as location 1610 of listener 1612 relative to such as speakers 118 in an environment that includes A/V hub 112 and speakers 118. For example, location 1610 may be determined coarsely (e.g., to the nearest room, 3-10 m accuracy, etc.) or finely (e.g., 0.1-3 m accuracy), which are nonlimiting numerical examples. In general, location 1610 may be determined by A/V hub 112 and/or in conjunction with other electronic devices (such as speakers 118) in the environment using techniques such as: triangulation, trilateration, time of flight, wireless ranging, the angle of arrival, etc. Moreover, location 1610 may be determined by A/V hub 112 using: wireless communication (such as communication with a wireless local area network or with a cellular-telephone network), acoustic measurements, a local positioning system, a global positioning system, etc. For example, location 1610 of at least listener 1612 may be estimated by A/V hub 112 based on wireless communication (such as using wireless ranging, time-of-flight measurements, the angle of arrival, RSSI, etc.) of one or more frames or packets 1614 with another electronic device, such as portable electronic device 110, which may be proximate to listener 1612 or on their person. In some embodiments, the wireless communication with the other electronic device (such as a MAC address in frames or packets received from portable electronic device 110) is used as a signature or an electronic thumbprint that identifies listener 1612. Note that the communication between portable electronic device 110 and A/V hub 112 may be unidirectional or bidirectional. During wireless ranging, A/V hub 112 may transmit a frame or a packet that includes a transmission time to, e.g., portable electronic device 110. When this frame or packet is received by portable electronic device 110, the arrival time may be determined. Based on the product of the time of flight (the difference of the arrival time and the transmission time) and the speed of propagation, the distance between A/V hub 112 and portable electronic device 110 can be calculated. Then, this distance may be communicated in a subsequent transmission of a frame or a packet from portable electronic device 110 to A/V hub 112 along with an identifier of portable electronic device 110. Alternatively, portable electronic device 110 may transmit a frame or a packet that includes a transmission time and an identifier of portable electronic device 110, and A/V hub 112 may determine the distance between portable electronic device 110 and A/V hub 112 based on the product of the time of flight (the difference of a arrival time and the transmission time) and the speed of propagation. In a variation on this approach, A/V hub 112 may transmit frames or packets 1614 that are reflected at portable electronic device 110, and the reflected frames or packets 1614 may be used to dynamically determine the distance between portable electronic device 110 and A/V hub 112. While the preceding example illustrated wireless ranging with coordinated clocks in portable electronic device 110 and A/V hub 112, in other embodiments the clocks are not coordinated. For example, the position of portable electronic device 110 may be estimated based on the speed of propagation and the time of arrival data of wireless signals at several receivers at different known locations in the environment (which is sometimes referred to as ‘differential time of arrival’) even when the transmission time is unknown or unavailable. For example, the receivers may be at least some of the other speakers 118 at locations 1616, which may be predefined or predetermined. More generally, a variety of radiolocation techniques may be used, such as: determining distance based on a difference in the power of the RSSI relative to the original transmitted signal strength (which may include corrections for absorption, refraction, shadowing and/or reflection); determining the angle of arrival at a receiver (including non-line-of-sight reception) using a directional antenna or based on the differential time of arrival at an array of antennas with known location(s) in the environment; determining the distance based on backscattered wireless signals; and/or determining the angle of arrival at two receivers having known location in the environment (i.e., trilateration or multilateration). Note that the wireless signals may include transmissions over GHz or multi-GHz bandwidths to create pulses of short duration (such as, e.g., approximately 1 ns), which may allow the distance to be determined within 0.305 m (e.g., 1 ft), and which are nonlimiting examples. In some embodiments, the wireless ranging is facilitated using location information, such as a location of one or more of electronic devices in the environment (such as locations 1616) that are determined or specified by a local positioning system, a global positioning system and/or a wireless network. Alternatively or additionally, location 1610 may be estimated by A/V hub 112 based on sound measurements in the environment, such as acoustic tracking of listener 1612, e.g., based on sounds 1618 they make as they move about, talk and/or breathe. The sound measurements may be performed by A/V hub 112 (such as using two or more acoustic transducers, e.g., microphones, which may be arranged as a phased array). However, in some embodiments sound measurements may be performed separately or additionally by one or more electronic devices in the environment, such as speakers 118, and these sound measurements may be wireless communicated to A/V hub 112 in frames or packets 1618, which then uses the sound measurements to estimate location 1610. In some embodiments, listener 1612 is identified using a voice-recognition technique. In some embodiments, location 1610 is estimated by A/V hub 112 based on sound measurements in the environment and a predetermined acoustic characteristic of the environment, such as a spectral response or an acoustic transfer function. For example, variation in the excitation of predetermined room modes as listener 1612 moves in the environment may be used to estimate location 1610. Moreover, one or more other techniques may be used to track or estimate location 1610 of listener 1612. For example, location 1610 may be estimated based on optical imaging of listener 1612 in a band of wavelengths (such as visible light or infrared light), time-of-flight measurements (such as laser ranging), and/or a grid of optical beams (such as infrared beams) that localize listener 1612 in a grid (and, thus, coarsely determine location 1610) based on a pattern of beam-line crossings. In some embodiments, the identity of listener 1612 is determined in optical images using a facial-recognition and/or a gate-recognition technique. For example, in some embodiments the location of the listener in the environment is tracked based on wireless communication with a cellular telephone that is carried with the listener. Based on the pattern of the locations in the environment, the locations of furniture in the environment and/or a geometry of the environment (such as a size or dimensions of a room) may be determined. This information may be used to determine an acoustic characteristic of the environment. Moreover, the historical locations of the listener may be used to constrain an estimated location of the listener in the environment. In particular, historical information about the location of the listener in the environment at different times of day may be used to assist in estimating the current location of the listener at a particular time of day. Thus, in general, the location of the listener may be estimated using a combination of optical measurements, acoustic measurements, acoustic characteristics, wireless communication and/or machine learning. After determining location 1610, A/V hub 112 may transmit at least one or more frames or packets to speakers 118 that include additional audio content 1622 (such as music) and playback timing information (such as playback timing information 1624-1 in packet 1620-1 to speaker 118-1), where the playback timing information 1624-1 may specify a playback time when speaker 118-1 is to playback the additional audio content 1622 based on location 1610. Thus, the communication technique may be used to correct for or adapt to the changes in location 1610, thereby improving the user experience. As noted previously, the different playback times may be based on a desired acoustic characteristic in the environment. For example, the desired acoustic characteristic may include a type of playback, such as: monophonic, stereophonic and/or multichannel sound. Monophonic sound may include one or more audio signals that contain no amplitude (or level) and arrival time/phase information that replicates or simulates directional cues. Moreover, stereophonic sound may include two independent audio-signal channels, and the audio signals may have a specific amplitude and phase relationship with each other so that, during the playback operation, there is an apparent image of the original sound source. In general, the audio signals for both channels may provide coverage over most or all of the environment. By adjusting the relative amplitudes and/or phases of the audio channels, the sweet spot may be moved to follow the determined location of at least the listener. However, the amplitude differences and arrival time differences (the directional cues) may need to be small enough that the stereo image and localization are both maintained. Otherwise, the image may collapse and only one or the other audio channel is heard. Note that the audio channels in stereophonic sound may need to have the correct absolute phase response. This means that an audio signal with a positive pressure waveform at the input to the system may need to have the same positive pressure waveform at the output from one of speakers 118. Therefore, a drum, which, when struck, produces a positive pressure waveform at a microphone may need to produce a positive pressure waveform in the environment. Alternatively, if the absolute polarity is flipped the wrong way, the audio image may not be stable. In particular, the listener may not find or perceive a stable audio image. Instead, the audio image may wander and may localize at speakers 118. Furthermore, multichannel sound may include left, center and right audio channels. For example, these channels may allow monophonic speech reinforcement and music or sound effect cues to be localized or mixed with a particular perspective, with stereo or stereo-like imaging. Thus, the three audio channels may provide coverage over most or all of the entire environment while maintaining amplitude and directional cues, as was the case for monophonic or stereophonic sound. Alternatively or additionally, the desired acoustic characteristic may include an acoustic radiation pattern. The desired acoustic radiation pattern may be a function of the reverberation time in the environment. For example, the reverberation time may change depending on the number of people in the environment, the type and amount of furniture in the environment, whether or not the curtains are open or closed, whether or not a window is open or closed, etc. When the reverberation time is longer or is increased, the desired acoustic radiation pattern may be more directed, so that the sound is steered or beamed to a listener (thereby reducing the reverberation). In some embodiments, the desired acoustic characteristic includes intelligibility of words. While the preceding discussion illustrated techniques that can be used to dynamically track location 1610 of listener 1612 (or portable electronic device 110), these techniques may be used to determine the location of an electronic device (such as a speaker 118-1) in the environment. Another approach for improving the acoustic experience is to dynamically aggregate electronic devices into groups and/or to adapt the coordination based on the groups. This is shown in FIG. 17, which presents a flow diagram illustrating a method 1700 for aggregating electronic devices. Note that method 1700 may be performed by an A/V hub, such as A/V hub 112 (FIG. 1). During operation, the A/V hub (such as a control circuit or control logic, e.g., a processor executing a program module, in the A/V hub) may measure sound (operation 1710) output by electronic devices (such as speakers 118) in an environment using one or more acoustic transducers, where the sound corresponds to audio content. For example, the measured sound may include the sound pressure. Then, the A/V hub may aggregate the electronic devices (operation 1712) into two or more subsets based on the measured sound. Note that the different subsets may be located in different rooms in the environment. Moreover, at least one of the subsets may playback different audio content than a remainder of the subsets. Furthermore, the aggregation of the electronic devices into the two or more subsets may be based on: the different audio content; an acoustic delay of the measured sound; and/or a desired acoustic characteristic in the environment. In some embodiments, electronic devices in the subsets and/or geographic locations or regions associated with the subsets are not predefined. Instead, the A/V hub may dynamically aggregate the subsets. Moreover, the A/V hub may determine playback timing information (operation 1714) for the subsets, where the playback timing information specifies playback times when the electronic devices in a given subset are to playback the audio content. Next, the A/V hub may transmit, using wireless communication, one or more frames (operation 1716) or packets that include the audio content and playback timing information to the electronic devices, where the playback times of the electronic devices in at least the given subset have a temporal relationship so that the playback of the audio content by the electronic devices in the given subset is coordinated. In some embodiments, the A/V hub optionally performs one or more additional operations (operation 1718). For example, the A/V hub may calculate an estimated location of at least a listener relative to the electronic devices, and the aggregation of the electronic devices into the two or more subsets may be based on the estimated location of at least the listener. This may help ensure that the listener has an improved acoustic experience, with reduced acoustic cross-talk from the other subset(s). Moreover, the A/V hub may modify the measured sound based on a predetermined (or dynamically determined) acoustic transfer function of the environment in at least a band of frequencies (such as 100-20,000 Hz, which is a nonlimiting example). This may allow the A/V hub to determine the original output sound without the spectral filtering or distortions associated with the environment, which may allow the A/V hub to make better decisions when aggregating the subsets. Furthermore, the A/V hub may determine playback volumes for the subsets that are used when the subsets playback the audio content, and the one or more frames or packets may include information that specifies the playback volumes. For example, a playback volume for at least one of the subsets may be different than the playback volumes of a remainder of the subsets. Alternatively or additionally, the playback volumes may reduce acoustic cross-talk among the two or more subsets so that listeners are more likely to hear the sound output by the subset to which they are proximate or closest. FIG. 18 is a drawing illustrating communication among portable electronic device 110, A/V hub 112, and speakers 118. In particular, processor 1810 may instruct 1812 one or more acoustic transducers 1814 in A/V hub 112 to perform measurements 1816 of sound associated with speakers 118. Then, based on measurements 1816, processor 1810 may aggregate speakers 118 into two or more subsets 1818. Moreover, processor 1810 may determine playback timing information 1820 for subsets 1818, wherein the playback timing information 1820 specifies playback times when speakers 118 in a given subset are to playback audio content 1822. Note that processor 1810 may access audio content 1822 in memory 1824. Next, processor 1810 may instruct interface circuit 1826 to transmit frames or packets 1828 to speakers 118 with playback timing information 1820 and audio content 1822. (However, in some embodiments, playback timing information 1820 and audio content 1822 are transmitted using separate or different frames or packets.) After receiving the one or more frames or packets 1826, an interface circuit in speaker 118-3 may provide playback timing information 1820 and audio content 1822 to a processor. This processor may execute software that performs a playback operation 1830. For example, the processor may store audio content 1822 in a queue in memory. In these embodiments, playback operation 1830 includes outputting audio content 1822 from the queue, including driving one or more of acoustic transducers based on audio content 1822 so speaker 118-3 outputs sound at a time specified by the playback timing information 1820. Note that the playback times of speakers 118 in at least the given subset have a temporal relationship so that the playback of audio content 1822 by the speakers 118 in the given subset is coordinated. In an exemplary embodiment, the communication technique is used to aggregate speakers 118 into subsets. FIG. 19 presents a drawing illustrating aggregating speakers 118, which may be in the same or different rooms in an environment. A/V hub 112 may measure sound 1910 output by speakers 118. Based on these measurements, A/V hub 112 may aggregate speakers 118 into subsets 1912. For example, the subsets 1912 may be aggregated based on sound intensity and/or acoustic delay, so that proximate speakers are aggregated together. In particular, speakers that have the highest acoustic intensity or similar acoustic delay may be aggregated together. In order to facilitate the aggregation, speakers 118 may wirelessly transmit and/or acoustically output identification information or acoustic-characterization patterns outside of the range of human hearing. For example, the acoustic-characterization patterns may include pulses. However, a variety of temporal, frequency and/or modulation techniques may be used, including: amplitude modulation, frequency modulation, phase modulation, etc. Alternatively or additionally, A/V hub 112 may instruct each of speakers 118 to, one at a time, dither the playback times or phase of their output sound, so that A/V hub 112 can associate the measured sound with particular speakers. Moreover, the measured sound 1910 may be corrected using an acoustic transfer function of an environment, so that the impact of reflections and filtering (or distortion) is removed prior to aggregating speakers 118. In some embodiments, the speakers 118 are aggregated based, at least in part, on locations 1914 of speakers 118, which may be determined using one or more of the aforementioned techniques (such as using wireless ranging). In this way, subsets 1912 may be dynamically modified as one or more listeners repositions speakers 118 in the environment. Then, A/V hub 112 may transmit one or more frames or packets (such as packet 1916) that include additional audio content 1918 (such as music) and playback timing information 1920 to speakers 118 in at least one of subsets 1912 (such as subset 1912-1), where the playback timing information 1920 may specify playback times when speakers 118 in subset 1912-1 are to playback the additional audio content 1918. Thus, the communication technique may be used to dynamically select subsets 1912, e.g., based on a location of a listener and/or a desired acoustic characteristic in an environment that includes A/V hub 112 and speakers 118. Another approach for improving the acoustic experience is to dynamically equalize audio based on acoustic monitoring in an environment. FIG. 20 presents a flow diagram illustrating a method 2000 for determining equalized audio content, which may be performed by an A/V hub, such as A/V hub 112 (FIG. 1). During operation, the A/V hub (such as a control circuit or control logic, e.g., a processor executing a program module, in the A/V hub) may measure sound (operation 2010) output by electronic devices (such as speakers 118) in the environment using one or more acoustic transducers, where the sound corresponds to audio content. For example, the measured sound may include the sound pressure. Then, the A/V hub may compare the measured sound to a desired acoustic characteristic (operation 2012) at a first location in the environment based on the first location, a second location of the A/V hub, and a predetermined or dynamically determined acoustic transfer function of the environment in at least a band of frequencies (such as 100-20,000 kHz, which is a nonlimiting example). Note that the comparison may be performed in the time domain and/or in the frequency domain. In order to perform the comparison, the A/V hub may calculate the acoustic characteristic (such as an acoustic transfer function or a modal response) at the first location and/or the second location, and may correct the measured sound for filtering or distortions in the environment using the calculated acoustic characteristic. Using the acoustic transfer function as an example, this calculation may involve the use of a Green's function technique to compute the acoustic response of the environment as a function of location with one or more point or distributed acoustic sources at predefined or known location(s) in the environment. Note that the acoustic transfer function at the first location and the correction may depend on the integrated acoustic behavior of the environment (and, thus, the second location and/or locations of acoustic sources, such as speakers 118, in the environment). Therefore, the acoustic transfer function may include information specifying the location(s) in the environment where the acoustic transfer function was determined (e.g., the second location) and/or the location(s) of an acoustic source in the environment (such as the location of at least one of the electronic devices). Moreover, the A/V hub may determine equalized audio content (operation 2014) based on the comparison and the audio content. Note that the desired acoustic characteristic may be based on a type of audio playback, such as: monophonic, stereophonic and/or multichannel. Alternatively or additionally, the desired acoustic characteristic may include an acoustic radiation pattern. The desired acoustic radiation pattern may be a function of the reverberation time in the environment. For example, the reverberation time may change depending on the number of people in the environment, the type and amount of furniture in the environment, whether or not the curtains are open or closed, whether or not a window is open or closed, etc. When the reverberation time is longer or is increased, the desired acoustic radiation pattern may be more directed, so that the sound associated with the equalized audio content is steered or beamed to a listener (thereby reducing the reverberation). Consequently, in some embodiments the equalization is a complex function that modifies the amplitude and/or phase in the audio content. Moreover, the desired acoustic characteristic may include reducing room resonances or room modes by reducing the energy in the associated low frequencies in the acoustic content. Note that in some embodiments, the desired acoustic characteristic includes intelligibility of words. Thus, the target (the desired acoustic characteristic) may be used to adapt the equalization of the audio content. Next, the A/V hub may transmit, using wireless communication, one or more frames (operation 2016) or packets that include the equalized audio content to the electronic devices to facilitate output by the electronic devices of additional sound, which corresponds to the equalized audio content. In some embodiments, the A/V hub optionally performs one or more additional operations (operation 2018). For example, the first location may include an estimated location of a listener relative to the electronic devices, and the A/V hub may calculate the estimated location of the listener. In particular, the estimated location of the listener may use one or more of the aforementioned techniques for dynamically determining the location of the listener. Thus, the A/V hub may calculate the estimated location of the listener based on the sound measurements. Alternatively or additionally, the A/V hub may: communicate with another electronic device; and may calculate the estimated location of the listener based on the communication with the other electronic device. In some embodiments, the communication with the other electronic device includes wireless ranging, and the estimated location may be calculated based on the wireless ranging and an angle of arrival of wireless signals from the other electronic device. Furthermore, the A/V hub may perform time-of-flight measurements, and may calculate the estimated location of the listener based on the time-of-flight measurements. In some embodiments, the dynamic equalization allows the ‘sweet spot’ in the environment to be adapted based on the location of the listener. Note that the A/V hub may determine the number of listeners in the environment and/or the locations of the listeners, and the dynamic equalization may adapt the sound so that the listeners (or a majority of the listeners) have the desired acoustic characteristic when listening to the equalized audio content. Moreover, the A/V hub may communicate with other electronic devices in the environment and may receive (separately from or in conjunction with the sound measurements) additional sound measurements of the environment from the other electronic devices. Then, the A/V hub may perform one or more additional comparisons of the additional sound measurements to the desired acoustic characteristic at the first location in the environment based on one or more third locations of the other electronic devices (such as the locations of speakers 118) and the predetermined or dynamically determined acoustic transfer function of the environment in at least the band of frequencies, and the equalized audio content is further determined based on the one or more additional comparisons. In some embodiments, the A/V hub determines the one or more third locations based on the communication with the other electronic devices. For example, the communication with the other electronic devices may include wireless ranging, and the one or more third locations may be calculated based on the wireless ranging and angles of arrival of wireless signals from the other electronic devices. Alternatively or additionally, the A/V hub may receive information specifying the third locations from the other electronic devices. Thus, the locations of the other electronic devices may be determined using one or more of the aforementioned techniques for determining the location of an electronic device in the environment. Furthermore, the A/V hub may determine playback timing information that specifies playback times when the electronic devices playback the equalized audio content, and the one or more frames or packets may include the playback timing information. In these embodiments, the playback times of the electronic devices have a temporal relationship so that the playback of the audio content by the electronic devices is coordinated. FIG. 21 is a drawing illustrating communication among portable electronic device 110, A/V hub 112, and speakers 118. In particular, processor 2110 may instruct 2112 one or more acoustic transducers 2114 in A/V hub 112 to measure sound 2116 associated with speakers 118 and corresponding to audio content 2118. Then, processor 21110 may compare 2120 the measured sound 2116 to a desired acoustic characteristic 2122 at a first location in the environment based on the first location, a second location of A/V hub 112, and a predetermined or dynamically determined acoustic transfer 2124 function of the environment in at least a band of frequencies (which may be accessed in memory 2128). Moreover, processor 2110 may determine equalized audio content 2126 based on comparison 2120 and audio content 2118, which may be accessed in memory 2128. Note that processor 2110 may know, in advance, audio content 2118 being output by speakers 118. Next, processor 2110 may determine playback timing information 2130, wherein the playback timing information 2130 specifies playback times when speakers 118 are to playback equalized audio content 2126. Furthermore, processor 2110 may instruct interface circuit 2132 to transmit one or more frames or packets 2134 to speakers 118 with playback timing information 2130 and equalized audio content 2126. (However, in some embodiments, playback timing information 2130 and audio content 2126 are transmitted using separate or different frames or packets.) After receiving the one or more frames or packets 2134, an interface circuit in one of speakers 118 (such as speaker 118-1) may provide playback timing information 2130 and equalized audio content 2126 to a processor. This processor may execute software that performs a playback operation. For example, the processor may store equalized audio content 2126 in a queue in memory. In these embodiments, the playback operation includes outputting equalized audio content 2126 from the queue, including driving one or more of acoustic transducers based on equalized audio content 2126 so speaker 118-1 outputs sound at a time specified by the playback timing information 2130. Note that the playback times of speakers 118 have a temporal relationship so that the playback of equalized audio content 2126 by the speakers 118 is coordinated. In an exemplary embodiment, the communication technique is used to dynamically equalize audio content. FIG. 22 presents a drawing illustrating determining equalized audio content using speakers 118. In particular, A/V hub 112 may measure sound 2210, corresponding to audio content, which is output by speakers 118. Alternatively or additionally, portable electronic device 110 and/or at least some of speakers 118 may measure sound 2210 and may provide information specifying the measurements to A/V hub 112 in frames or packets 2212. Then, A/V hub 112 may compare the measured sound 2210 to a desired acoustic characteristic at a location 2214 in the environment (such as a dynamic location of one or more listeners, which may also be the location of portable electronic device 110) based on location 2214, location 2216 of A/V hub 112, locations 2218 of speakers 118, and/or a predetermined or dynamically determined acoustic transfer function (or, more generally, an acoustic characteristic) of the environment in at least a band of frequencies. For example, A/V hub 112 may calculate the acoustic transfer function at location 2214, 2216 and/or 2218. As noted previously, this calculation may involve the use of a Green's function technique to compute the acoustic response at locations 2214, 2216 and/or 2218. Alternatively or additionally, the calculation may involve interpolation (such as minimum bandwidth interpolation) of a predetermined acoustic transfer function at different locations in the environment that locations 2214, 2216 and/or 2218. Then, A/V hub 112 may correct the measured sound 2210 based on the computed and/or interpolated acoustic transfer function (and, more generally, the acoustic characteristic). In this way, the communication technique may be used to compensate for sparse sampling when the acoustic transfer function was originally determined. Moreover, A/V hub 112 may determine equalized audio content based on the comparison and the audio content. For example, A/V hub 112 may modify the spectral content and/or phase of the audio content as a function of frequency in a range of frequencies (such as 100-10,000 or 20,000 Hz) to achieve the desired acoustic characteristic. Next, A/V hub 112 may transmit one or more frames or packets that include the equalized audio content (such as music) and playback timing information to speakers 118 (such as packet 2220 with equalized audio content 2222 and playback timing information 2224), where the playback timing information may specify playback times when speakers 118 are to playback the equalized audio content. In this way, the communication technique may allow the sound output by speakers 118 to adapt to changes in location 2214 of one or more listeners (such as an average or mean location, a location corresponding to a majority of the listeners, an average location of a largest subset of the listeners for which the desired acoustic characteristic can be achieved given the audio content and the acoustic transfer function or the acoustic characteristics of the environment, etc.). This may allow the sweet spot in stereophonic sound to track motion of the one or more listeners and/or changes in the number of listeners in the environment (which may be determined by A/V hub 112 using one or more of the aforementioned techniques). Alternatively or additionally, the communication technique may allow the sound output by speakers 118 to adapt to changes in the audio content and/or in the desired acoustic characteristic. For example, depending on the type of audio content (such as a type of music), the one or more listeners may want or desire a big or broad sound (with diverging sound waves corresponding to an apparently physically extended acoustic source) or an apparently narrow or point source. Thus, the communication technique may allow the audio content to be equalized according to a desired psychoacoustic experience of the one or more listeners. Note that the desired acoustic characteristic or the desired psychoacoustic experience may be explicitly specified by one or more of the listeners (such by using a user interface on portable electronic device 110) or may be determined or inferred indirectly without user action (such as based on the type of music or prior acoustic preferences of the one or more listeners that are stored in a listening history). In some embodiments of methods 200 (FIG. 2), 500 (FIG. 5), 800 (FIG. 8), 1100 (FIG. 11), 1400 (FIG. 14), 1700 (FIG. 17) and/or 2000 (FIG. 20) there are additional or fewer operations. Moreover, the order of the operations may be changed, and/or two or more operations may be combined into a single operation. Furthermore, one or more operations may be modified. We now describe embodiments of an electronic device. FIG. 23 presents a block diagram illustrating an electronic device 2300, such as portable electronic device 110, A/V hub 112, one of A/V display devices 114, receiver device 116 or one of speakers 118 in FIG. 1. This electronic device includes processing subsystem 2310, memory subsystem 2312, networking subsystem 2314, optional feedback subsystem 2334, and optional monitoring subsystem 2336. Processing subsystem 2310 includes one or more devices configured to perform computational operations. For example, processing subsystem 2310 can include one or more microprocessors, application-specific integrated circuits (ASICs), microcontrollers, programmable-logic devices, and/or one or more digital signal processors (DSPs). One or more of these components in processing subsystem are sometimes referred to as a ‘control circuit.’ In some embodiments, processing subsystem 2310 includes a ‘control mechanism’ or a ‘means for processing’ that perform at least some of the operations in the communication technique. Memory subsystem 2312 includes one or more devices for storing data and/or instructions for processing subsystem 2310 and networking subsystem 2314. For example, memory subsystem 2312 can include dynamic random access memory (DRAM), static random access memory (SRAM), and/or other types of memory. In some embodiments, instructions for processing subsystem 2310 in memory subsystem 2312 include: one or more program modules or sets of instructions (such as program module 2322 or operating system 2324), which may be executed by processing subsystem 2310. Note that the one or more computer programs or program modules may constitute a computer-program mechanism. Moreover, instructions in the various modules in memory subsystem 2312 may be implemented in: a high-level procedural language, an object-oriented programming language, and/or in an assembly or machine language. Furthermore, the programming language may be compiled or interpreted, e.g., configurable or configured (which may be used interchangeably in this discussion), to be executed by processing subsystem 2310. In addition, memory subsystem 2312 can include mechanisms for controlling access to the memory. In some embodiments, memory subsystem 2312 includes a memory hierarchy that comprises one or more caches coupled to a memory in electronic device 2300. In some of these embodiments, one or more of the caches is located in processing subsystem 2310. In some embodiments, memory subsystem 2312 is coupled to one or more high-capacity mass-storage devices (not shown). For example, memory subsystem 2312 can be coupled to a magnetic or optical drive, a solid-state drive, or another type of mass-storage device. In these embodiments, memory subsystem 2312 can be used by electronic device 2300 as fast-access storage for often-used data, while the mass-storage device is used to store less frequently used data. Networking subsystem 2314 includes one or more devices configured to couple to and communicate on a wired and/or wireless network (i.e., to perform network operations), including: control logic 2316, interface circuits 2318 and associated antennas 2320. (While FIG. 23 includes antennas 2320, in some embodiments electronic device 2300 includes one or more nodes, such as nodes 2308, e.g., pads, which can be coupled to antennas 2320. Thus, electronic device 2300 may or may not include antennas 2320.) For example, networking subsystem 2314 can include a Bluetooth networking system, a cellular networking system (e.g., a 3G/4G network such as UMTS, LTE, etc.), a universal serial bus (USB) networking system, a networking system based on the standards described in IEEE 802.11 (e.g., a Wi-Fi networking system), an Ethernet networking system, and/or another networking system. Note that the combination of a given one of interface circuits 2318 and at least one of antennas 2320 may constitute a radio. In some embodiments, networking subsystem 2314 includes a wired interface, such as HDMI interface 2330. Networking subsystem 2314 includes processors, controllers, radios/antennas, sockets/plugs, and/or other devices used for coupling to, communicating on, and handling data and events for each supported networking system. Note that mechanisms used for coupling to, communicating on, and handling data and events on the network for each network system are sometimes collectively referred to as a ‘network interface’ for the network system. Moreover, in some embodiments a ‘network’ between the electronic devices does not yet exist. Therefore, electronic device 2300 may use the mechanisms in networking subsystem 2314 for performing simple wireless communication between the electronic devices, e.g., transmitting advertising or beacon frames or packets and/or scanning for advertising frames or packets transmitted by other electronic devices as described previously. Within electronic device 2300, processing subsystem 2310, memory subsystem 2312, networking subsystem 2314, optional feedback subsystem 2334 and optional monitoring subsystem 2336 are coupled together using bus 2328. Bus 2328 may include an electrical, optical, and/or electro-optical connection that the subsystems can use to communicate commands and data among one another. Although only one bus 2328 is shown for clarity, different embodiments can include a different number or configuration of electrical, optical, and/or electro-optical connections among the subsystems. In some embodiments, electronic device 2300 includes a display subsystem 2326 for displaying information on a display (such as a request to clarify an identified environment), which may include a display driver, an I/O controller and the display. Note that a wide variety of display types may be used in display subsystem 2326, including: a two-dimensional display, a three-dimensional display (such as a holographic display or a volumetric display), a head-mounted display, a retinal-image projector, a heads-up display, a cathode ray tube, a liquid-crystal display, a projection display, an electroluminescent display, a display based on electronic paper, a thin-film transistor display, a high-performance addressing display, an organic light-emitting diode display, a surface-conduction electronic-emitter display, a laser display, a carbon-nanotube display, a quantum-dot display, an interferometric modulator display, a multi-touch touchscreen (which is sometimes referred to as a touch-sensitive display), and/or a display based on another type of display technology or physical phenomenon. Furthermore, optional feedback subsystem 2334 may include one or more sensor-feedback mechanisms or devices, such as: a vibration mechanism or a vibration actuator (e.g., an eccentric-rotating-mass actuator or a linear-resonant actuator), a light, one or more speakers, etc., which can be used to provide feedback to a user of electronic device 2300 (such as sensory feedback). Alternatively or additionally, optional feedback subsystem 2334 may be used to provide a sensory input to the user. For example, the one or more speakers may output sound, such as audio. Note that the one or more speakers may include an array of transducers that can be modified to adjust a characteristic of the sound output by the one or more speakers, such as a phased-array of acoustic transducers. This capability may allow the one or more speakers to modify the sound in an environment to achieve a desired acoustic experience for a user, such as by changing equalization or spectral content, phase and/or a direction of the propagating sound waves. In some embodiments, optional monitoring subsystem 2336 includes one or more acoustic transducers 2338 (such as one or more microphones, a phased-array, etc.) that monitor sound in the environment that includes electronic device 2300. The acoustic monitoring may allow electronic device 2300 to acoustically characterize the environment, acoustically characterize sound output by speakers in the environment (such as sound corresponding to audio content), determine a location of a listener, determine a location of a speaker in the environment and/or measure sound from one or more speakers that correspond to one or more acoustic-characterization patterns (which may be used to coordinate playback of audio content). Additionally, optional monitoring subsystem 2336 may include location transducers 2340 that can be used to determine a location of a listener or an electronic device (such as a speaker) in the environment. Electronic device 2300 can be (or can be included in) any electronic device with at least one network interface. For example, electronic device 2300 can be (or can be included in): a desktop computer, a laptop computer, a subnotebook/netbook, a server, a tablet computer, a smartphone, a cellular telephone, a smartwatch, a consumer-electronic device (such as a television, a set-top box, audio equipment, a speaker, video equipment, etc.), a remote control, a portable computing device, an access point, a router, a switch, communication equipment, test equipment, and/or another electronic device. Although specific components are used to describe electronic device 2300, in alternative embodiments, different components and/or subsystems may be present in electronic device 2300. For example, electronic device 2300 may include one or more additional processing subsystems, memory subsystems, networking subsystems, and/or display subsystems. Moreover, while one of antennas 2320 is shown coupled to a given one of interface circuits 2318, there may be multiple antennas coupled to the given one of interface circuits 2318. For example, an instance of a 3×3 radio may include three antennas. Additionally, one or more of the subsystems may not be present in electronic device 2300. Furthermore, in some embodiments, electronic device 2300 may include one or more additional subsystems that are not shown in FIG. 23. Also, although separate subsystems are shown in FIG. 23, in some embodiments, some or all of a given subsystem or component can be integrated into one or more of the other subsystems or component(s) in electronic device 2300. For example, in some embodiments program module 2322 is included in operating system 2324. Moreover, the circuits and components in electronic device 2300 may be implemented using any combination of analog and/or digital circuitry, including: bipolar, PMOS and/or NMOS gates or transistors. Furthermore, signals in these embodiments may include digital signals that have approximately discrete values and/or analog signals that have continuous values. Additionally, components and circuits may be single-ended or differential, and power supplies may be unipolar or bipolar. An integrated circuit may implement some or all of the functionality of networking subsystem 2314, such as one or more radios. Moreover, the integrated circuit may include hardware and/or software mechanisms that are used for transmitting wireless signals from electronic device 2300 and receiving signals at electronic device 2300 from other electronic devices. Aside from the mechanisms herein described, radios are generally known in the art and hence are not described in detail. In general, networking subsystem 2314 and/or the integrated circuit can include any number of radios. In some embodiments, networking subsystem 2314 and/or the integrated circuit include a configuration mechanism (such as one or more hardware and/or software mechanisms) that configures the radios to transmit and/or receive on a given channel (e.g., a given carrier frequency). For example, in some embodiments, the configuration mechanism can be used to switch the radio from monitoring and/or transmitting on a given channel to monitoring and/or transmitting on a different channel. (Note that ‘monitoring’ as used herein comprises receiving signals from other electronic devices and possibly performing one or more processing operations on the received signals, e.g., determining if the received signal comprises an advertising frame or packet, calculating a performance metric, performing spectral analysis, etc.) Furthermore, networking subsystem 2314 may include at least one port (such as an HDMI port 2332) to receive and/or provide the information in the data stream to at least one of A/V display devices 114 (FIG. 1), at least one of speakers 118 (FIG. 1) and/or at least one of content sources 120 (FIG. 1). While a communication protocol compatible with Wi-Fi was used as an illustrative example, the described embodiments may be used in a variety of network interfaces. Furthermore, while some of the operations in the preceding embodiments were implemented in hardware or software, in general the operations in the preceding embodiments can be implemented in a wide variety of configurations and architectures. Therefore, some or all of the operations in the preceding embodiments may be performed in hardware, in software or both. For example, at least some of the operations in the communication technique may be implemented using program module 2322, operating system 2324 (such as drivers for interface circuits 2318) and/or in firmware in interface circuits 2318. Alternatively or additionally, at least some of the operations in the communication technique may be implemented in a physical layer, such as hardware in interface circuits 2318. Moreover, while the preceding embodiments included a touch-sensitive display in the portable electronic device that the user touches (e.g., with a finger or digit, or a stylus), in other embodiments the user interface is display on a display in the portable electronic device and the user interacts with the user interface without making contact or touching the surface of the display. For example, the user's interact(s) with the user interface may be determined using time-of-flight measurements, motion sensing (such as a Doppler measurement) or another non-contact measurement that allows the position, direction of motion and/or speed of the user's finger or digit (or a stylus) relative to position(s) of one or more virtual command icons to be determined. In these embodiments, note that the user may activate a given virtual command icon by performing a gesture (such as ‘tapping’ their finger in the air without making contact with the surface of the display). In some embodiments, the user navigates through the user interface and/or activates/deactivates functions of one of the components in system 100 (FIG. 1) using spoken commands or instructions (i.e., via voice recognition) and/or based on where they are looking at one a display in portable electronic device 110 or on one of A/V display devices 114 in FIG. 1 (e.g., by tracking the user's gaze or where the user is looking). Furthermore, while A/V hub 112 (FIG. 1) were illustrated as separate components from A/V display devices 114 (FIG. 1), in some embodiments an A/V hub and an A/V display device are combined into a single component or a single electronic device. While the preceding embodiments illustrated the communication technique with audio and/or video content (such as HDMI content), in other embodiments the communication technique is used in the context of an arbitrary type of data or information. For example, the communication technique may be used with home-automation data. In these embodiments, A/V hub 112 (FIG. 1) may facilitate communication among and control of a wide variety of electronic devices. Thus, A/V hub 112 (FIG. 1) and the communication technique may be used to facilitate or implement services in the so-called Internet of things. In the preceding description, we refer to ‘some embodiments.’ Note that ‘some embodiments’ describes a subset of all of the possible embodiments, but does not always specify the same subset of embodiments. The foregoing description is intended to enable any person skilled in the art to make and use the disclosure, and is provided in the context of a particular application and its requirements. Moreover, the foregoing descriptions of embodiments of the present disclosure have been presented for purposes of illustration and description only. They are not intended to be exhaustive or to limit the present disclosure to the forms disclosed. Accordingly, many modifications and variations will be apparent to practitioners skilled in the art, and the general principles defined herein may be applied to other embodiments and applications without departing from the spirit and scope of the present disclosure. Additionally, the discussion of the preceding embodiments is not intended to limit the present disclosure. Thus, the present disclosure is not intended to be limited to the embodiments shown, but is to be accorded the widest scope consistent with the principles and features disclosed herein. | <SOH> BACKGROUND <EOH> | <SOH> SUMMARY <EOH>A first group of described embodiments includes an audio/video (A/V) hub. This A/V hub includes: one or more antennas; and an interface circuit that, during operation, communicates with electronic devices using wireless communication. During operation, the A/V hub receives, via the wireless communication, frames from the electronic devices, where a given frame includes a transmit time when a given electronic device transmitted the given frame. Then, the A/V hub stores receive times when the frames were received, where the receive times are based on a clock in the A/V hub. Moreover, the A/V hub calculates current time offsets between clocks in the electronic devices and the clock in the A/V hub based on the receive times and transmit times of the frames. Next, the A/V hub transmits one or more frames that include audio content and playback timing information to the electronic devices, where the playback timing information specifies playback times when the electronic devices are to playback the audio content based on the current time offsets. Furthermore, the playback times of the electronic devices have a temporal relationship so that the playback of the audio content by the electronic devices is coordinated. Note that the temporal relationship may have a non-zero value, so that at least some of the electronic devices are instructed to playback the audio content with a phase relative to each other by using different values of the playback times. For example, the different playback times may be based on acoustic characterization of an environment that includes the electronic devices and the A/V hub. Alternatively or additionally, the different playback times may be based on a desired acoustic characteristic in the environment. In some embodiments, the electronic devices are located at vector distances from the A/V hub, and the interface circuit determines magnitudes of the vector distances based on the transmit times and the receive times using wireless ranging. Moreover, the interface circuit may determine angles of the vector distances based on the angle of arrival of wireless signals associated with the frames that are received by the one or more antennas during the wireless communication. Furthermore, the different playback times may be based on the determined vector distances. Alternatively or additionally, the different playback times are based on an estimated location of a listener relative to the electronic devices. For example, the interface circuit may: communicate with another electronic device; and calculate the estimated location of the listener based on the communication with the other electronic device. Moreover, the A/V hub may include an acoustic transducer that performs sound measurements of the environment that includes the A/V hub, and the A/V hub may calculate the estimated location of the listener based on the sound measurements. Furthermore, the interface circuit may communicate with other electronic devices in the environment and may receive additional sound measurements of the environment from the other electronic devices. In these embodiments, the A/V hub calculates the estimated location of the listener based on the additional sound measurements. In some embodiments, the interface circuit: performs time-of-flight measurements; and calculates the estimated location of the listener based on the time-of-flight measurements. Note that the electronic devices may be located at non-zero distances from the A/V hub, and the current time offsets may be calculated based on the transmit times and the receive times using wireless ranging by ignoring the distances. Moreover, the current time offsets may be based on models of clock drift in the electronic devices. Another embodiment provides a computer-readable storage medium for use with the A/V hub. This computer-readable storage medium includes a program module that, when executed by the A/V hub, cause the A/V hub to perform at least some of the aforementioned operations. Another embodiment provides a method for coordinating playback of audio content. This method includes at least some of the operations performed by the A/V hub. Another embodiment provides one or more of the electronic devices. A second group of described embodiments includes an audio/video (A/V) hub. This A/V hub includes: memory that, during operation, stores characterization information of an environment that includes the A/V hub; one or more antennas; and an interface circuit that, during operation, communicates with an electronic device using wireless communication. During operation, the A/V hub detects, using the wireless communication, the electronic device in the environment. Then, the A/V hub determines a change condition, where the change condition includes: that the electronic device was not previously detected in the environment; and/or a change in a location of the electronic device. When the change condition is determined, the A/V hub transitions into a characterization mode. During the characterization mode, the A/V hub: provides instructions to the electronic device to playback audio content at a specified playback time; determines one or more acoustic characteristics of the environment based on acoustic measurements in the environment; and stores the characterization information in the memory, where the characterization information includes the one or more acoustic characteristics. Moreover, the characterization information may include: an identifier of the electronic device; and the location of the electronic device. For example, the location may include a distance between the A/V hub and the electronic device, and an angle of arrival of wireless signals during the wireless communication. Consequently, the change in the location may include a change in: the distance, the angle of arrival, or both. In some embodiments, the distance is determined using wireless ranging. Note that the one or more acoustic characteristics may include information specifying: an acoustic transfer function in at least a first band of frequencies, acoustic loss, acoustic delay, acoustic noise in the environment, ambient sound in the environment, a reverberation time of the environment, and/or a spectral response in at least a second band of frequencies. Furthermore, the A/V hub may calculate the location of the electronic device in the environment based on the wireless communication. Additionally, the interface circuit may communicate with other electronic devices in the environment using the wireless communication, and the acoustic measurements may be received from the other electronic devices. In these embodiments, the one or more acoustic characteristics may be determined based on locations of the other electronic devices in the environment. Note that the A/V hub may: receive the locations of the other electronic devices from the other electronic devices; access predetermined locations of the other electronic devices stored in the memory; and determine the locations of the other electronic devices based on the wireless communication. In some embodiments, the A/V hub includes one or more acoustic transducers, and the A/V hub performs the acoustic measurements using the one or more acoustic transducers. Moreover, the A/V hub may: receive a user input; and transition into the characterization mode based on the user input. Furthermore, the A/V hub may transmit one or more frames that include additional audio content and playback timing information to the electronic device, where the playback timing information may specify a playback time when the electronic device is to playback the additional audio content based on the one or more acoustic characteristics. Another embodiment provides a computer-readable storage medium for use with the A/V hub. This computer-readable storage medium includes a program module that, when executed by the A/V hub, cause the A/V hub to perform at least some of the aforementioned operations. Another embodiment provides a method for selectively determining one or more acoustic characteristics of the environment that includes the A/V hub. This method includes at least some of the operations performed by the A/V hub. Another embodiment provides the electronic device. A third group of described embodiments includes an audio/video (A/V) hub. This A/V hub includes: one or more acoustic transducers that, during operation, measure sound output by electronic devices in an environment that includes the A/V hub and the electronic devices; one or more antennas; and an interface circuit that, during operation, communicates with the electronic devices using wireless communication. During operation, the A/V hub measures the sound output by the electronic devices using the one or more acoustic transducers, where the sound corresponds to one or more acoustic-characterization patterns. Then, the A/V hub calculates current time offsets between clocks in the electronic devices and a clock in the A/V hub based on the measured sound, one or more times when the electronic devices output the sound and the one or more acoustic-characterization patterns. Next, the A/V hub transmits, using wireless communication, one or more frames that include audio content and playback timing information to the electronic devices, where the playback timing information specifies playback times when the electronic devices are to playback the audio content based on the current time offsets. Moreover, the playback times of the electronic devices have a temporal relationship so that the playback of the audio content by the electronic devices is coordinated. Note that the measured sound may include information that specifies the one or more times when the electronic devices output the sound, and the one or more times may correspond to the clocks in the electronic devices. Moreover, the A/V hub may provide to the electronic devices, via the wireless communication, one or more times when the electronic devices are to output the sound, and the one or more times may correspond to the clock in the A/V hub. Furthermore, a given electronic device may output the sound at a different time in the one or more times than those used by a remainder of the electronic devices. Alternatively or additionally, the sound output by a given electronic device may correspond to a given acoustic-characterization patterns, which may be different from those used by the remainder of the electronic devices. Note that the acoustic-characterization patterns may include pulses. Moreover, the sound may be in a range of frequencies outside of human hearing. In some embodiments, the A/V hub modifies the measured sound based on an acoustic transfer function of the environment in at least a band of frequencies. Moreover, the temporal relationship may have a non-zero value, so that at least some of the electronic devices are instructed to playback the audio content with a phase relative to each other by using different values of the playback times. For example, the different playback times may be based on: acoustic characterization of the environment; a desired acoustic characteristic in the environment; and/or an estimated location of a listener relative to the electronic devices. Another embodiment provides a computer-readable storage medium for use with the A/V hub. This computer-readable storage medium includes a program module that, when executed by the A/V hub, cause the A/V hub to perform at least some of the aforementioned operations. Another embodiment provides a method for coordinating playback of audio content. This method includes at least some of the operations performed by the A/V hub. Another embodiment provides one or more of the electronic devices. A fourth group of described embodiments includes an audio/video (A/V) hub. This A/V hub includes: one or more antennas; and an interface circuit that, during operation, communicates with electronic devices using wireless communication. During operation, the A/V hub calculates an estimated location of a listener relative to the electronic devices in an environment that includes the A/V hub and the electronic devices. Then, the A/V hub transmits one or more frames that include audio content and playback timing information to the electronic devices, where the playback timing information specifies playback times when the electronic devices are to playback the audio content based on the estimated location. Note that the playback times of the electronic devices have a temporal relationship so that the playback of the audio content by the electronic devices is coordinated. Moreover, the interface circuit may communicate with another electronic device, and the estimated location of the listener may be calculated based on the communication with the other electronic device. Furthermore, the A/V hub may include an acoustic transducer that performs sound measurements in the environment, and the estimated location of the listener may be calculated based on the sound measurements. Alternatively or additionally, the interface circuit may communicate with other electronic devices in the environment and may receive additional sound measurements of the environment from the other electronic devices, and the estimated location of the listener may be calculated based on the additional sound measurements. In some embodiments, the interface circuit performs time-of-flight measurements, and the estimated location of the listener is calculated based on the time-of-flight measurements. Note that the playback times may be based on current time offsets between clocks in the electronic devices and a clock in the A/V hub. Moreover, the A/V hub may calculate additional estimated locations of additional listeners relative to the electronic devices in the environment, and the playback times may be based on the estimated location and the additional estimated locations. For example, the playback times may be based on an average of the estimated location and the additional estimated locations. Alternatively, the playback times may be based on a weighted average of the estimated location and the additional estimated locations. Furthermore, the temporal relationship may have a non-zero value, so that at least some of the electronic devices are instructed to playback the audio content with a phase relative to each other by using different values of the playback times. In some embodiments, the different playback times are based on: acoustic characterization of the environment; and/or a desired acoustic characteristic in the environment. Another embodiment provides a computer-readable storage medium for use with the A/V hub. This computer-readable storage medium includes a program module that, when executed by the A/V hub, cause the A/V hub to perform at least some of the aforementioned operations. Another embodiment provides a method for calculating an estimated location. This method includes at least some of the operations performed by the A/V hub. Another embodiment provides one or more of the electronic devices. A fifth group of described embodiments includes an audio/video (A/V) hub. This A/V hub includes: one or more acoustic transducers that, during operation, measure sound output by electronic devices in an environment that includes the A/V hub and the electronic devices; one or more antennas; and an interface circuit that, during operation, communicates with the electronic devices using wireless communication. During operation, the A/V hub measures the sound output by the electronic devices using the one or more acoustic transducers, where the sound corresponds to audio content. Then, the A/V hub aggregates the electronic devices into two or more subsets based on the measured sound. Moreover, the A/V hub determines playback timing information for the subsets, where the playback timing information specifies playback times when the electronic devices in a given subset are to playback the audio content. Next, the A/V hub transmits, using wireless communication, one or more frames that include the audio content and playback timing information to the electronic devices, where the playback times of the electronic devices in at least the given subset have a temporal relationship so that the playback of the audio content by the electronic devices in the given subset is coordinated. Note that the different subsets may be located in different rooms in the environment. Moreover, at least one of the subsets may playback different audio content than a remainder of the subsets. Furthermore, the aggregation of the electronic devices into the two or more subsets may be based on: the different audio content; an acoustic delay of the measured sound; and/or a desired acoustic characteristic in the environment. Additionally, the A/V hub may calculate an estimated location of a listener relative to the electronic devices, and the aggregation of the electronic devices into the two or more subsets may be based on the estimated location of the listener. In some embodiments, the A/V hub modifies the measured sound based on an acoustic transfer function of the environment in at least a band of frequencies. Moreover, the A/V hub may determine playback volumes for the subsets that are used when the subsets playback the audio content, and the one or more frames may include information that specifies the playback volumes. For example, a playback volume for at least one of the subsets may be different than the playback volumes of a remainder of the subsets. Alternatively or additionally, the playback volumes may reduce acoustic cross-talk among the two or more subsets. Another embodiment provides a computer-readable storage medium for use with the A/V hub. This computer-readable storage medium includes a program module that, when executed by the A/V hub, cause the A/V hub to perform at least some of the aforementioned operations. Another embodiment provides a method for aggregating electronic devices. This method includes at least some of the operations performed by the A/V hub. Another embodiment provides one or more of the electronic devices. A sixth group of described embodiments includes an audio/video (A/V) hub. This A/V hub includes: one or more acoustic transducers that, during operation, measure sound output by electronic devices in an environment that includes the A/V hub and the electronic devices; one or more antennas; and an interface circuit that, during operation, communicates with the electronic devices using wireless communication. During operation, the A/V hub measures the sound output by the electronic devices using the one or more acoustic transducers, where the sound corresponds to audio content. Then, the A/V hub compares the measured sound to a desired acoustic characteristic at a first location in the environment based on the first location, a second location of the A/V hub, and an acoustic transfer function of the environment in at least a band of frequencies, where the comparison involves calculating the acoustic transfer function at the first location based on the acoustic transfer function at other locations in the environment and correcting the measured sound based on the calculated the acoustic transfer function at the first location. Moreover, the A/V hub determines equalized audio content based on the comparison and the audio content. Next, the A/V hub transmits, using wireless communication, one or more frames that include the equalized audio content to the electronic devices to facilitate output by the electronic devices of additional sound, which corresponds to the equalized audio content. Note that the first location may include an estimated location of a listener relative to the electronic devices, and the A/V hub may calculate the estimated location of the listener. For example, the A/V hub may calculate the estimated location of the listener based on the sound measurements. Alternatively or additionally, the interface circuit may: communicate with another electronic device; and may calculate the estimated location of the listener based on the communication with the other electronic device. In particular, the communication with the other electronic device may include wireless ranging, and the estimated location may be calculated based on the wireless ranging and an angle of arrival of wireless signals from the other electronic device. In some embodiments, the interface circuit: performs time-of-flight measurements; and calculates the estimated location of the listener based on the time-of-flight measurements. Moreover, the interface circuit may communicate with other electronic devices in the environment and may receive additional sound measurements of the environment from the other electronic devices. Then, the A/V hub may perform one or more additional comparisons of the additional sound measurements to the desired acoustic characteristic at the first location in the environment based on one or more third locations of the other electronic devices and the acoustic transfer function of the environment in at least a band of frequencies, and the equalized audio content is further determined based on the one or more additional comparisons. Furthermore, the interface circuit may determine the one or more third locations based on the communication with the other electronic devices. For example, the communication with the other electronic devices may include wireless ranging, and the one or more third locations may be calculated based on the wireless ranging and angles of arrival of wireless signals from the other electronic devices. Alternatively or additionally, the interface circuit may receive information specifying the third locations from the other electronic devices. In some embodiments, the desired acoustic characteristic is based on a type of audio playback, which may include: monophonic, stereophonic and/or multichannel. Moreover, the A/V hub may determine playback timing information that specifies playback times when the electronic devices playback the equalized audio content, the one or more frames further may include the playback timing information, and the playback times of the electronic devices have a temporal relationship so that the playback of the audio content by the electronic devices is coordinated. Another embodiment provides a computer-readable storage medium for use with the A/V hub. This computer-readable storage medium includes a program module that, when executed by the A/V hub, cause the A/V hub to perform at least some of the aforementioned operations. Another embodiment provides a method for determining the equalized audio content. This method includes at least some of the operations performed by the A/V hub. Another embodiment provides one or more of the electronic devices. A seventh group of described embodiments includes an audio/video (A/V) hub. This A/V hub includes: one or more antennas; and an interface circuit that, during operation, communicates with electronic devices using wireless communication. During operation, the A/V hub receives, via the wireless communication, frames from the electronic devices. Then, the A/V hub stores receive times when the frames were received, where the receive times are based on a clock in the A/V hub. Moreover, the A/V hub calculates current time offsets between clocks in the electronic devices and the clock in the A/V hub based on the receive times and expected transmit times of the frames, where the expected transmit times are based on coordination of the clocks in the electronic devices and the clock in the A/V hub at a previous time and a predefined transmit schedule of the frames. Next, the A/V hub transmits one or more frames that include audio content and playback timing information to the electronic devices, where the playback timing information specifies playback times when the electronic devices are to playback the audio content based on the current time offsets. Furthermore, the playback times of the electronic devices have a temporal relationship so that the playback of the audio content by the electronic devices is coordinated. Note that the temporal relationship may have a non-zero value, so that at least some of the electronic devices are instructed to playback the audio content with a phase relative to each other by using different values of the playback times. For example, the different playback times may be based on acoustic characterization of an environment that includes the electronic devices and the A/V hub. Alternatively or additionally, the different playback times may be based on a desired acoustic characteristic in the environment. In some embodiments, the electronic devices are located at vector distances from the A/V hub, and the interface circuit determines magnitudes of the vector distances based on transmit times of the frames and the receive times using wireless ranging. Moreover, the interface circuit may determine angles of the vector distances based on the angle of arrival of wireless signals associated with the frames that are received by the one or more antennas during the wireless communication. Furthermore, the different playback times may be based on the determined vector distances. Alternatively or additionally, the different playback times are based on an estimated location of a listener relative to the electronic devices. For example, the interface circuit may: communicate with another electronic device; and calculate the estimated location of the listener based on the communication with the other electronic device. Moreover, the A/V hub may include an acoustic transducer that performs sound measurements of the environment that includes the A/V hub, and the A/V hub may calculate the estimated location of the listener based on the sound measurements. Furthermore, the interface circuit may communicate with other electronic devices in the environment and may receive additional sound measurements of the environment from the other electronic devices. In these embodiments, the A/V hub calculates the estimated location of the listener based on the additional sound measurements. In some embodiments, the interface circuit: performs time-of-flight measurements; and calculates the estimated location of the listener based on the time-of-flight measurements. Note that the coordination of the clocks in the electronic devices and the clock in the A/V hub may have occurred during an initialization mode of operation. Moreover, the current time offsets may be based on models of clock drift in the electronic devices. Another embodiment provides a computer-readable storage medium for use with the A/V hub. This computer-readable storage medium includes a program module that, when executed by the A/V hub, cause the A/V hub to perform at least some of the aforementioned operations. Another embodiment provides a method for coordinating playback of audio content. This method includes at least some of the operations performed by the A/V hub. Another embodiment provides one or more of the electronic devices. This Summary is only provided for purposes of illustrating some exemplary embodiments, so as to provide a basic understanding of some aspects of the subject matter described herein. Accordingly, it will be appreciated that the above-described features are only examples and should not be construed to narrow the scope or spirit of the subject matter described herein in any way. Other features, aspects, and advantages of the subject matter described herein will become apparent from the following Detailed Description, Figures, and Claims. | H04S7303 | 20171022 | 20180614 | 59334.0 | H04S700 | 0 | MAUNG, THOMAS H | COORDINATION OF ACOUSTIC SOURCES BASED ON LOCATION | UNDISCOUNTED | 0 | ACCEPTED | H04S | 2,017 |
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15,790,926 | PENDING | Insulating Container | An insulating device can include an aperture having a waterproof closure which allows access to the chamber within the insulating device. The closure can help prevent any fluid leakage into and out of the insulating device if the insulating device is overturned or in any configuration other than upright. The closure also prevents any fluid from permeating into the chamber if the insulating device is exposed to precipitation, other fluid, or submersed under water. This construction results in an insulating chamber impervious to water and other liquids when the closure is sealed. | 1. A method of forming an insulating device comprising: forming an inner liner first portion and an outer shell first portion; securing the inner liner first portion and the outer shell first portion to a sealable closure to form a cap assembly; forming an inner liner second portion and securing the inner liner second portion to the inner liner first portion to form an inner liner; forming an outer shell second portion; rolling a rectangular foam portion to form a first cylindrical foam portion and securing a foam base portion to the first cylindrical foam portion to form a foam assembly; inserting the foam assembly into the outer shell second portion; and inserting the inner liner into the foam assembly; securing the outer shell first portion to the outer shell second portion to form the outer shell. 2. The method of claim 1 wherein the closure is provided with at least one flange and wherein the flange is secured to a bottom surface of the outer shell first portion and a top surface of the inner liner first portion. 3. The method of claim 1 wherein the foam freely floats between the outer shell second portion and the inner liner second portion. 4. The method of claim 1 wherein the closure is configured to be a barrier against fluid penetration in and out of the inner vessel. 5. The method of claim 1 wherein the outer shell and inner shell are only connected to the closure and not to the insulating layer. 6. The method of claim 1 further comprising forming waterproof polymer welds between the closure and the inner shell and the closure and the outer shell when the closure, the outer shell, and the inner liner are lying in a flat plane. 7. The method of claim 1 wherein the outer shell is formed of a TPU nylon material. 8. The method of claim 1 wherein the closure has a first flange and a second flange wherein the outer liner is secured to top surfaces of the first flange and the second flange and the inner liner is secured to bottom surfaces of the first flange and the second flange. 9. The method of claim 1 wherein the inner liner is formed from a TPU nylon material. 10. The method of claim 1 wherein the top of the insulating layer has a first perimeter circumference, wherein the bottom of the insulating layer has a second perimeter circumference; and wherein the first perimeter circumference is equal to the second perimeter circumference. | This application is a continuation application of U.S. application Ser. No. 14/831,641, filed Aug. 20, 2015 which is a divisional of U.S. application Ser. No. 14/479,607, filed on Sep. 8, 2014 (now U.S. Pat. No. 9,139,352, issued Sep. 22, 2015, which claims priority to U.S. Application No. 61/937,310 filed on Feb. 7, 2014, which is incorporated fully herein by reference. FIELD The present disclosure relates generally to non-rigid, portable, insulated devices or containers useful for keeping food and beverages cool or warm, and, more particularly, an insulating device with a waterproof closure. BACKGROUND Coolers are designed to keep food and beverages at lower temperatures. Containers may be composed of rigid materials such as metal or plastics or flexible materials such as fabric or foams. Coolers can be designed to promote portability. For example, rigid containers can be designed to incorporate wheels that facilitate ease of transport or coolers can be designed in smaller shapes to allow individuals to carry the entire device. Non-rigid containers can be provided with straps and/or handles and may in certain instances be made of lighter weight materials to facilitate mobility. Non-rigid coolers that maximize portability can be designed with an aperture on the top that allows access to the interior contents of the cooler. The aperture can also be provided with a closure. SUMMARY This Summary provides an introduction to some general concepts relating to this invention in a simplified form that are further described below in the Detailed Description. This Summary is not intended to identify key features or essential features of the invention. Aspects of the disclosure herein may relate to insulating devices having one or more of (1) a waterproof closure (2) an outer shell, (3) an inner liner, (4) an insulating layer floating freely in between the outer shell and the inner liner, or (5) a waterproof storage compartment. BRIEF DESCRIPTION OF THE DRAWINGS The foregoing Summary, as well as the following Detailed Description, will be better understood when considered in conjunction with the accompanying drawings in which like reference numerals refer to the same or similar elements in all of the various views in which that reference number appears. FIG. 1A shows a left front perspective view of an example insulating device in accordance with an aspect of the disclosure; FIG. 1B shows a frontside perspective view of the example insulating device of FIG. 1A without the shoulder strap; FIG. 2 shows a backside perspective view of the example insulating device of FIG. 1A without the shoulder strap; FIG. 3A shows a top perspective view of the example insulating device of FIG. 1A without the shoulder strap; FIG. 3B shows a top view of a portion of the example insulating device of FIG. 1A; FIG. 3C shows a portion of an alternate top perspective view of the example insulating device of FIG. 1A; FIG. 4 shows a bottom perspective view of the example insulating device of FIG. 1A; FIG. 5A illustrates a schematic of a cross-sectional view of the example insulating device of FIG. 1A; FIG. 5B illustrates another schematic of an enlarged portion of a cross-sectional view of the example insulating device of FIG. 1A; FIG. 6 illustrates an exemplary process flow diagram for forming an insulating device; FIGS. 7A-7J illustrate exemplary methods of forming an insulating device; FIGS. 8A and 8B depict perspective views of an alternative example insulating device. FIG. 9 depicts an example test method for determining if an insulating device maintains the contents therein. FIG. 10 depicts an example test for determining the strength of an insulating device. DETAILED DESCRIPTION In the following description of the various examples and components of this disclosure, reference is made to the accompanying drawings, which form a part hereof, and in which are shown by way of illustration various example structures and environments in which aspects of the disclosure may be practiced. It is to be understood that other structures and environments may be utilized and that structural and functional modifications may be made from the specifically described structures and methods without departing from the scope of the present disclosure. Also, while the terms “frontside,” “backside,” “top,” “base,” “bottom,” “side,” “forward,” and “rearward” and the like may be used in this specification to describe various example features and elements, these terms are used herein as a matter of convenience, e.g., based on the example orientations shown in the figures and/or the orientations in typical use. Nothing in this specification should be construed as requiring a specific three dimensional or spatial orientation of structures in order to fall within the scope of the claims. FIGS. 1-4 depict an exemplary insulating device 10 that can be configured to keep desired contents stored cool or warm for an extended period of time. The insulating device can generally include an outer shell 501, a closure 301, an insulating layer 502, and an inner liner 500. As shown in FIG. 3C, the inner liner 500 forms a chamber or receptacle 504 for receiving the desired contents therein. As shown in FIG. 1A, various handles, straps, and webs (e.g. 210, 212, 218, 224) can also be included on the insulating device 10 for carrying, holding, or securing the insulating device 10. The insulating device 10 can be configured to keep desired contents stored in the receptacle 504 cool or warm for an extended period of time. In one example, the insulating device 10 can also be designed to maintain water inside the inner chamber or receptacle 504, and the insulating device 10 can be configured to be water “resistant” from the outside in. In other words, insulating device 10 can be formed “water tight” inside the inner liner 500, and water cannot leak into the inner liner 500 from the outside or out from the inside of the inner liner 500 when the closure 301 is in the closed position. FIG. 4 depicts a bottom view of the insulating device 10. As shown in FIG. 4 the insulating device 10 may include a base 215 and a base support ridge 400. The base support ridge 400 can provide structural integrity and support to the insulating device 10 when the insulating device 10 is placed onto a surface. In one example, as shown in FIGS. 3A and 4, the top of the outer shell 501 has a first perimeter circumference (Tcir) and the bottom of the outer shell 501 has a second perimeter circumference or a base perimeter 401 (Bcir). The circumference of the top of the outer shell 501 can be equal to the circumference on the bottom when folded into a cylinder, and Bcir can be equal to Tcir. In one example, the first circumference and the second circumference can both have an oval shape to form an elongated or elliptical cylinder. In one example, the top outer layer 501a can have a length of 23.5 inches and a width of 5.5 inches. Therefore, the length to width ratio of the top outer layer 501a can be approximately 4.3. Additionally, the base 215 can have a length of 20.0 inches and a width of 12.25 inches. Therefore, the length to width ratio of the base 215 is approximately 1.6. In this example, the length to width ratio of the upper wall can be greater than the length to width ratio of the base. In one example, as shown in FIG. 5A the inner layer or inner liner 500 can be formed of a top inner liner portion or first portion 500a, an inner layer mid portion or second portion 500b, and an inner layer bottom portion 500c. The top inner liner portion 500a, the inner layer mid portion 500b, and the inner layer bottom portion 500c are secured together, by for example welding, to form the chamber 504. The chamber 504 can be a “dry bag,” or vessel for storing contents. In one example, after the top inner liner portion 500a, the inner layer mid portion 500b, and the inner layer bottom portion 500c are secured or joined together, a tape, such as a TPU tape can be place over the seams joining the sections of the chamber 504. The inner liner 500 can, thus, either maintain liquid in the chamber 504 of the insulating device 10 or prevent liquid contents from entering into the chamber 504 of the insulating device 10. In one example, as will be described in further detail below, the inner liner 500 can be suspended in the insulating device 10 by only the closure 301. The insulating layer 502 can be located between the inner liner 500 and the outer shell 501, and can be formed as a foam insulator to assist in maintaining the internal temperature of the receptacle 504. In one example, the insulating layer 502 can be a free floating layer that is not attached directly to the outer shell 501 or the inner liner 500. The insulating layer 502 can be formed of a first portion 502a and a second portion or base portion 502b. The first portion 502a and the second portion 502b can be formed of an insulating foam material as will be described in further detail below. The first portion 502a can have a rectangular shape that maintains its form when folded into a cylinder and placed in between the inner liner 500 and the outer shell 501 and when encased from above by the outer shell 501. The insulating layer 502 maintains its shape which results in the basic oval-cylindrical shape of the insulating device 10. Therefore, similar to the outer shell 501, the top of the insulating layer 502 has a first perimeter circumference, and the bottom of the insulating layer 502 has a second perimeter circumference. The first perimeter circumference of the insulating layer 502 can be equal to the second perimeter circumference of the insulating layer 502. The base portion 502b can be included to provide additional insulation along the insulating device 10 at base 215. The base portion 502b can be formed as an oval shape to close off a lower opening 506 formed by the cylindrical shape of the insulating layer 502. Additionally, the bottom portion of the insulating device 10 can include an additional base-support layer 505, which adds to the insulation and the structural integrity of the insulating device 10. The base support layer 505 may also provide additional protection around the bottom of the insulating device 10. In one example, the base support layer 505 can be formed from EVA foam. The base support layer 505 may include a certain design such as a logo or name that can be molded or embossed directly into the material. The base support ridge 400, which provides structural integrity and support to the insulating device 10 can also be molded or embossed directly into the base support layer 505. In one example, the base support layer 505 and the base portion 502b can be detached for ease of assembly. The outer shell 501 can be formed of a top outer layer portion or first shell portion 501a, an outer layer or second outer shell portion 501b, and a bottom or third shell portion 501c. The outer shell 501 provides a covering for the insulating device 10. In one example, the insulating layer 502 can be suspended freely within the outer shell 501. However, it is contemplated that any of the layers could be secured or formed as a one-piece integral structure. The outer shell 501 can be configured to support one or more optional handles or straps (e.g. 210, 212, 218). In this regard, the outer shell 501 can also include multiple reinforcement areas or patches 220 that are configured to assist in structurally supporting the optional handles or straps (e.g. 210, 212, 218). The handles or straps (e.g. 210, 212, 218) and other attachments can be stitched using threads 222, however these threads 222 do not, in one example, extend through the outer shell 501 into the insulating layer 502. Rather, the threads are sewn to the patches 220, and the patches 220 can be RF welded to the outer shell 501 or by any other method disclosed herein. As shown in FIG. 5A, the first outer shell portion 501a may be attached to the second shell portion 501b by stitching 510. However, the first outer shell portion 501a can be attached to the second shell portion 501b using any known method, e.g., polymer welding, or other adhesive around the entire perimeter of the second shell portion 501b. Additionally, in one example, the base-support layer 505 formed from EVA foam can be secured to bottom or third shell portion 501c by lamination. The second shell portion 501b can be secured to the third shell portion 501c and the base-support layer 505 by polymer welding (e.g. RF welding), stitching, or adhesives. The insulating device 10 can include two carry handles 210 that are connected to the frontside 216 of the insulating device 10 and the backside 217 of the insulating device 10. In one particular example, a shoulder strap 218 can be attached via plastic or metal clip to the ring 214 attached to side handles 212 to facilitate carrying insulating device 10 over the shoulder. The insulating device 10 may also include side handles 212 on each end of the cooler. The side handles 212 provide the user with another option for grasping and carrying the insulating device. Carry handles 210 may also form a slot for receiving rings 214 near the bottom of the attachment point of the carry handles to the insulating device 10. The rings 214 can be secured to the carry handles 210 and the attachment points 213 by stitching, adhesive, or polymer welding and can be used to help secure or tie down the insulating device 10 to another structure such as a vehicle, vessel, camping equipment, and the like or various objects such as keys, water bottle bottles, additional straps, bottle openers, tools, other personal items, and the like. Additionally, as shown in FIG. 2, webbing formed as loops 224 can be sewn onto the straps forming the handles 210 on the back of the insulating device 10. The loops 224 can be used to attach items (e.g., carabineers, dry bags) to the insulating device 10. The side handles 212 can also provide the user with another option for securing the insulating device 10 to a structure. In one example, the carry handles 210, side handles 212, shoulder strap 218 and attachment points 213 can be constructed of nylon webbing. Other materials may include polypropylene, neoprene, polyester, Dyneema, Kevlar, cotton fabric, leather, plastics, rubber, or rope. The carry handles 210 and side handles 212 can be attached to the outer shell by stitching, adhesive, or polymer welding. The shoulder strap 218 can be attached to the insulating device 10 at attachment points 213. The attachment points 213 can be straps that also form a slot for receiving rings 214. The rings 214 can provide for the attachment of the shoulder strap 218. In one example, the rings 214 can be Acetal D-rings. Rings 214 in can be plastic, metal, ceramic, glass, alloy, polypropylene, neoprene, polyester, Dyneema, and Kevlar, cotton fabric, leather, plastics, rubber, or rope. Rings 214 can include other shapes, sizes, and configurations other than a “D” shape. Examples include round, square, rectangular, triangular, or rings with multiple attachment points. Additionally, pockets or other storage spaces can be attached to the outside of the insulating device 10 in addition to the carry handles 210 and side handles 212. In one example, the closure 301 can be substantially waterproof or a barrier to prevent liquid contents from either entering or exiting the insulating device. Additionally, the closure 301 can be impervious to liquid such that insulating device 10 liquid penetration is prevented at any orientation of the insulating device 10. Also maintaining the closure 301 in flat plane can assist in providing a water tight seal. FIGS. 3A-3C depicts top views of the insulating device 10, and depicts the top outer layer or the first outer shell portion 501a and the closure 301. The top outer layer 501a depicted in FIG. 3A can be secured to the closure 301. In one example, the closure 301 can be a waterproof zipper assembly and can be watertight up to 7 psi above atmospheric pressure during testing with compressed air. However, in other examples, the water tightness of the closure 301 can be from 5 psi to 9 psi above atmospheric pressure and in other examples, the water tightness of the closure 301 can be from 2 psi to 14 psi above atmospheric pressure. The waterproof zipper assembly can include a slider body 303 and pull-tab 302. FIG. 3B shows a magnified view of the closure 301 that includes bottom stop 304 and teeth or a chain 305. In one particular example, the waterproof zipper assembly can be constructed with plastic or other non-metallic teeth 305 to prevent injury when retrieving food or beverages from the inner chamber 504. As shown in FIG. 3C, the closure 301 is open or unzipped and an aperture 512 formed in the outer shell 501 and the inner liner 500 is open and reveals the inner liner 500 and the inner chamber 504. It is contemplated that the closure or seal 301 can include various sealing devices in addition to the depicted waterproof zipper assembly in FIGS. 3A-3C. For example, Velcro, snaps, buckles, zippers, excess material that is folded multiple times to form a seal such as a roll-down seal, seals, metal or plastic clamps and combinations thereof could be used to seal the inner liner 500 and the outer shell 501. FIG. 8 depicts another exemplary insulating device 1010, which has similar features and functions as the example discussed above in relation to FIGS. 1A-5B in which like reference numerals refer to the same or similar elements. However, in this example, a loop patch 1015 can be provided on the front of the bag. The loop patch 1015 can be configured to receive many types of items or a corresponding group of hooks, which can be placed onto the surface anywhere on various items, such as fishing lures, keys, bottle openers, card holders, tools, other personal items, and the like. The loop patch 1015 can include a logo, company name, personalization, or other customization. The loop patch 1015 can be formed of by needle loops and can have a high cycle life of over 10,000 closures. In addition, the loop patch can be washable and UV resistant to prevent discoloration. The loop patch can be selected based on a desired sheer and peel strength depending on the types of materials that are to be secured to the insulating device 1010. In the example shown in FIG. 8, additionally, a strip 1013 can be provided along the bottom of the bag, which can provide additional strength and reinforcement to the outer shell 1501, and may enhance the aesthesis of the insulating device 1010. Example methods of forming the insulating device 10 will now be described. A general overview of an exemplary assembly process of the insulating device 10 is depicted schematically in FIG. 6. The various steps, however, need not necessarily be performed in the order described. As shown in step 602 first the portions used to form the inner liner 500, the outer shell 501, and the insulating layer 502 can be formed or cut to size. In step 604, a top cap assembly 300 can be assembled to the closure 301. In step 606, the inner liner 500 can be formed, and in step 608, the top cap assembly 300 can be welded to the inner liner 500. In step 610, the outer shell 501 can be formed. In step 612, the insulation layer 502 can be assembled, and in step 616, the insulation layer 502 can be placed into the inner liner. Finally, in step 618, the top cap assembly 300 can be secured to the outer shell 501. Referring to step 602, as shown in FIGS. 7A and 7B, inner liner top portions or first inner liner portions 500a and outer layer top portion 501a that form the top cap assembly 300 can be formed or cut to size. FIG. 7C shows a second portion or base portion 502b of the insulating layer 502 being cut or formed to size from stock foam. In this example, the base portion 502b is cut from the stock foam 530, by cutting tool 700. In one example, the cutting tool 700 can be formed in the shape of the base portion 502b. Referring now to step 604 and FIG. 7D, the top outer layer 501a and the top inner liner 500a can be secured to the closure 301 to form the top cap assembly 300, and the top outer layer 501a and the top inner liner 500a can be secured to the closure 301 in a flat, horizontal plane. Referring to FIGS. 5A-5B the top outer layer 501a can be attached by polymer welding or adhesive to closure 301. In particular as shown schematically in FIG. 5B, the closure 301 can be provided with a first flange 301a and a second flange 301b, which can form waterproof zipper tape 306. The top outer layer 501a can be attached directly to the top surfaces of the first flange 301a and the second flange 301b of the closure 301. In one example, the first flange 301a and the second flange 301b, can be RF welded to the underside of the top outer layer 501a. In another example, as shown in FIG. 7E, the top inner liner portion 500a can be provided with tabs 515. Tabs 515 can assist in the assembly process to keep the outer strips of the top inner liner portion 500a in place during assembly and can be removed after the top cap assembly 300 is formed. In one example, the top inner liner portion 500a can be attached to the structure of the insulating device 10 as shown schematically in FIG. 5B. In particular, the top inner liner portion 500a can be attached to the bottom of the closure 301. For example, as shown in FIG. 5B, and a first end 540a and a second end 540b of the top inner liner portion 500a can be attached to undersides of the first flange 301a and the second flange 301b. The top inner liner portion 500a and the top outer layer 501a can be attached to the closure 301 by polymer welding or adhesive. Polymer welding includes both external and internal methods. External or thermal methods can include hot gas welding, hot wedge welding, hot plate welding, infrared welding and laser welding. Internal methods may include mechanical and electromagnetical welds. Mechanical methods may include spine welding, stir welding, vibration welding, and ultrasonic welding. Electromagnetical methods may include resistance, implant, electrofusion welding, induction welding, dielectric welding, RF (Radio Frequency) welding, and microwave welding. The welding can be conducted in a flat or horizontal plane to maximize the effectiveness of the polymer welding to the construction materials. As a result, a rugged watertight seam can be created that prevents water or fluids from escaping from or into the inner chamber 504. In a particular example, the polymer welding technique to connect the top inner liner portion 500a to the bottom of the closure 301 can include RF welding. The RF welding technique provides a waterproof seam that prevents water or any other fluid from penetrating the seam at pressure up to 7 psi above atmospheric pressure. The insulating device 10, therefore, can be inverted or submerged in water and leakage is prevented both into and out of the internal chamber 504 formed by inner liner 500. In one example, the insulating device 10 can be submerged under water to a depth of about 16 feet before water leakage occurs. However, it is contemplated that this depth could range from about 11 feet to 21 feet or 5 feet to 32 feet before any leakage occurs. Next referring to step 606 and FIG. 7F, the inner layer mid-portion 500b can be formed by RF welding. As shown in FIG. 7F, the inner layer mid-portion 500b can be formed of a rectangular sheet of material. The inner layer mid-portion 500b can also be secured to the inner layer bottom portion 500c in a subsequent step not shown. Referring to step 608 and FIGS. 7G and 7H, the inner layer mid portion 500b and the inner layer bottom portion 500c can be secured to the top cap assembly 300 using an RF welding operation. Referring to step 610, the second shell portion 501b and the bottom outer shell 501c, which supports the base support layer 505, can be RF welded to construct the outer shell 501 for the insulating device 10. In one example, as shown schematically in FIG. 5A, the top outer layer 501a can be sewed to the perimeter of the second shell portion 501b to form the outer shell 501 of the insulating device. A fabric binding can be used to cover the stitched seam edges of the second shell portion 501b and the top outer layer 501a. This assists in closing or joining the outer shell 501 around the insulating layer 502. Referring to step 612 and FIG. 71, the insulating layer 502 can be constructed. In one example the first portion 502a of the insulating layer 502 can be formed into a rectangular shape and can be secured at the smaller sides of the rectangular shape using double sided tape to form the cylindrical shape. The second portion or base portion 502b can be formed into an oval shape that can have a smaller circumference than the circumference of the cylindrical shape of the first portion 502a. The second portion 502b can be secured to the first portion 502a also using a double-sided tape to form the insulating layer 502. In one example, double sided tape can be placed either around the inner perimeter of the first portion 502a cylinder or around the outer perimeter of the base portion 502b, and the base portion 502b can be adhered to the first portion 502a. Other methods of securing the base portion 502b to the first portion 502a to form the insulating layer 502 are contemplated, such adhesives or polymer welding. Referring to step 614, the assembled insulating layer 502 can be placed into the outer shell 501. In step 616, the formed inner liner 500 and top cap assembly 300 can be placed into the insulating layer 502. Finally in step 618 the top cap assembly 300 can be sewed to the outer shell 501 to form seams 520 as depicted schematically in FIG. 5A. In this way, neither the inner liner 500 nor the outer shell 501 need to be bound to the insulating layer 502. Also the inner liner 500 is only connected to the closure 301 and the closure 301 holds the inner liner and the outer shell 501 together, which results in a simpler manufacturing process. After sewing the top cap assembly 300 to the outer shell 501, a fabric binding is added to cover the raw edges adjacent the seams 520. Thus, the top seams 520 can be the only primary seams on the insulating device 10 that are created by stitching. In one particular example, the inner liner 500 and the outer shell 501 can be constructed from double laminated TPU nylon fabric. Nylon fabric can be used as a base material for the inner liner 500 and the outer shell 501 and can be coated with a TPU laminate on each side of the fabric. The TPU nylon fabric used in one particular example is 0.6 millimeters thick, is waterproof, and has an antimicrobial additive that meets all Food and Drug Administration requirements. Alternative materials used to manufacture the inner shell or chamber 504 and outer shell 501 include PVC, TPU coated nylon, coated fabrics, and other weldable and waterproof fabrics. A closed cell foam can be used to form the insulating layer 502 that is situated in between the inner liner 500 and the outer shell 501. In one example, the insulating layer 502 is 1.0 inches thick. In one example, the insulating layer 502 can be formed of NBR/PVC blend or any other suitable blend. The thermal conductivity of an example insulating layer 502 can be in the range of 0.16-0.32 BTU.in/(hr·sqft·° F.), and the density of the insulating layer 502 can be in the range of 0.9 to 5 lbs/ft3. In one example, the thermal conductivity of the insulating layer 502 can be in the range of 0.25 BTU.in/(hr·sqft·° F.), and the density of the insulating layer 502 can be 3.5 lbs/ft3. The foam base can be manufactured from an NBR/PVC blend or any other suitable blend. In addition to the base portion 502b of the insulating layer 502, the insulating device 10 may also include an outer base support layer 505 constructed of foam, plastic, metal or other material. In one example, the base portion 502b can be detached from the base support layer. In one example, the base portion 502b is 1.5 inches thick. Additionally as shown in FIG. 5A, the EVA foam base support layer 505 can be 0.2 inches thick. Although the base support layer 505 is laminated to the base outer layer 501c, in an alternative example, the base support layer 505 can be attached to the bottom of the base portion 502b by co-molding, polymer welding, adhesive, or any known methods. A heat gain test was conducted on the exemplary insulating device 10. The purpose of a heat gain test is to determine how long the insulating device can keep temperature below 50° F. at an ambient of 106° F.±4 with the amount of ice based on its internal capacity. The procedure is as follows: 1. Turn on the oven and set to 106° F.±4. Allow the oven to stabilize for at least one hour. 2. Turn on the chart recorder. The recorder shall have three J-thermocouples connected to it to chart the following temperatures: (1) Test unit, (2) Oven, and (3) Room ambient. 3. Stabilize the test unit by filling it to half its capacity with ice water, and allowing it to sit for 5 minutes at room temperature (72° F.±2). 4. After 5 minutes, pour out the contents, and immediately connect the J-thermocouple end to the inside bottom center of the unit. The thermocouple wire end must be flush to the inside bottom surface and secured with an adhesive masking tape. 5. Pour the correct amount of ice ensuring the thermocouple wire is not moved. Amount of ice is based on 4 lbs. per cubic feet of the internal capacity of the unit. 6. Close the lid and position the test unit inside the oven. 7. Close the oven making sure the thermocouple wires are functioning. 8. Mark the start of the chart recorder. Apparatus: 1. Oven. 2. Ice. 3. Chart Recorder. 4. J-Thermocouples (3). Results: 1. Cold Retention Time: Elapsed time from <32° F. to 50° F. in decimal hours. 2. Heat Gain Rate (° F./Hr): (50° F.−32° F.)÷Elapsed Time=18° F.÷Elapsed Time In one test of the example insulating device, the heat gain rate equaled 1.4 degF/hr assuming 26.5 quarts capacity and used 3.542 lbs of ice for the test. The ability of the insulating device 10 to withstand interior leaks can also be tested to see how well the insulating device maintains the contents stored in the storage compartment or receptacle 504. In one example test, the insulating device 10 can be filled with a liquid, such as water, and then can be inverted for a predetermined time period to test for any moisture leaks. In this example, the insulating device 10 is filled with a liquid until approximately half of a volume of the receptacle 504 is filled, e.g. 3 gallons of water, and the closure 301 is then closed fully to ensure that the slider body 303 is completely sealed into the horseshoe-shaped portion 308. The entire insulating device 10 is then inverted and held inverted for a time period of 30 minutes. The insulating device 10 is then reviewed for any leaks. The insulating device 10 can be configured to withstand being held inverted for 30 minutes without any water escaping or leaving the receptacle 504. In alternative examples, the insulating device can be configured to withstand being held inverted for 15 minutes to 120 minutes without any water escaping or leaving the receptacle 504. To perform this test, it may be helpful to lubricate the closure to ensure that the closure is adequately sealed. For example, as shown in FIG. 9, a horseshoe-shaped portion 308 of the closure 301 is provided with lubricant 309. The strength and durability of the fabric forming the outer shell 501, inner liner 500 and the insulating layer 502 of the insulating device 10 may also be tested. In one example, the test can be devised as a puncture test. In particular, this test can be designed as an ASTM D751-06 Sec. 22-25 screwdriver puncture test. In one example, the insulating device 10 can withstand 35 lbs to 100 lbs of puncture force. The handle strength and durability of the insulating device 10 can also be tested. One such example test is depicted in FIG. 10. As depicted in FIG. 10, the closure 310 can be fully closed, one of the carry handles 210 can hooked to an overhead crane 600, and the opposite carry handle 210 is hooked to a platform 650, which can hold weight. In one example, the platform 650 can be configured to hold 200 lbs. of weight. During the test, the crane 600 is slowly raised, which suspends the insulating device 10 in a position where the bottom plane of the insulating device 10 is perpendicular with the floor. In one example, the insulating device 10 can be configured to hold 200 lbs. of weight for a minimum of 3 minutes without showing any signs of failure. In alternative examples, the insulating device can be configured to hold 100 lbs. to 300 lbs. of weight for 1 to 10 minutes without showing signs of failure. An exemplary insulating device may include an outer shell, an inner liner, an insulating layer floating freely in between the outer shell and the inner liner, and a waterproof closure. The top of the shell has first perimeter circumference, and the bottom of the shell has a second perimeter circumference. The first perimeter circumference can be equal to the second perimeter circumference. The closure can be a zipper assembly comprising a plurality of zipper teeth, and the zipper teeth can be formed of plastic or metal. The outer shell can be made of a double laminated TPU nylon fabric. The inner liner can be made of a double laminated TPU nylon fabric. The insulating layer can be formed of a closed cell foam. The insulating layer can be made of a NBR and a PVC blend, and at least a portion of the insulating layer can be constructed with an EVA foam layer. The outer shell further can include at least one of a strap or handle. The outer shell further can include at least one ring for securing the insulating device. An exemplary insulating device can include an outer shell, an inner liner, a closure adapted to seal at least one of the outer shell or the inner liner, and an insulating layer between the outer shell and the inner liner. The closure can have a first flange and a second flange, and the outer liner can be secured to top surfaces of the first flange and the second flange and the inner liner can be secured to bottom surfaces of the first flange and the second flange. The outer liner and the inner liner can be connected to the closure by a polymer weld. The outer shell can have a first circumference and a second circumference, the first circumference and the second circumference both having an oval shape. The closure can be adapted to be a barrier against fluid. The closure can be a zipper apparatus that is watertight up to 7 psi above atmospheric pressure. An exemplary method of assembling a insulating device may include forming an inner liner having an inner vessel, forming an outer shell, forming an insulating layer between the inner liner and the outer shell, and securing a closure configured to be a barrier against fluid penetration in and out of the inner vessel wherein the closure is secured in a flat plane and is secured to the outer shell and the inner shell. The outer shell and inner shell may only be connected to the closure and not to the insulating layer between the outer shell and inner liner. A waterproof polymer weld can be formed between the closure and the inner shell and the closure and the outer shell when the closure, the outer shell, and the inner liner are lying in a horizontal plane. The outer shell and the inner layer can be formed of a TPU nylon material. The closure can have a first flange and a second flange. The outer liner can be secured to top surfaces of the first flange and the second flange and the inner liner can be secured to bottom surfaces of the first flange and the second flange. The method can also include forming the insulating layer from a rectangular shape, and rolling the rectangular shape into a cylindrical shape. The top of the insulating layer has a first perimeter circumference and the bottom of the insulating layer has a second perimeter circumference. The first perimeter circumference can be equal to the second perimeter circumference. Another example insulating device can include an outer shell, an inner liner forming a storage compartment, a foam layer floating freely in between the outer and inner liner, the foam layer providing insulation, an opening extending through the outer layer and the inner layer, and a closure adapted to substantially seal the opening. The closure can be substantially waterproof so as to resist liquid from exiting the opening. The insulating device can also include an upper wall and a base, the upper wall defining an upper wall circumference, an upper wall length and an upper wall width, and the base defining a base circumference, a base length and a base width. The upper wall circumference can be equal to the base circumference and the ratio of the upper wall length to the upper wall width can be greater than the ratio of the base length to the base width. In one example, a heat gain rate of the insulating device can be approximately 1.0-1.5 degF/hr. Another example method of forming an insulating device may include forming an inner liner first portion and an outer shell first portion, securing the inner liner first portion and the outer shell first portion to a sealable closure to form a cap assembly, forming an inner liner second portion and securing the inner liner second portion to the inner liner first portion to form an inner liner, forming an outer shell second portion, rolling a rectangular foam portion to form a first cylindrical foam portion and securing a foam base portion to the first cylindrical portion to form a foam assembly, inserting the foam assembly into the outer shell second portion, inserting the inner liner into the foam assembly, and stitching the outer shell first portion to the outer shell second portion. The inner liner first portion and the outer shell first portion can be welded to the closure. The closure can be provided with at least one flange and the flange can be secured to a bottom surface of the outer shell first portion and a top surface of the inner liner first portion. The foam can float between the outer shell second portion and the inner liner second portion. An example portable insulating device may include an outer liner, an inner liner forming a storage compartment, a foam layer in between the outer and inner liner. The foam layer can be adapted to provide insulation. The example portable insulating device may also include an opening extending through one of the outer layer and the inner layer and a closing means for substantially sealing the opening. The closure can be substantially waterproof. In one example, a portable cooler may include an aperture on the top of the cooler that is opened and closed by a zipper apparatus which allows access to a chamber within the cooler. The aperture prevents any fluid leakage out of the cooler if the cooler is overturned or in any configuration other than upright. The zipper assembly also prevents any fluid from permeating into the cooler chamber if the cooler is exposed to precipitation, other fluid, or submersed under water. An example method of assembling a zipper apparatus and aperture configured to be impervious to water or other liquids and fluids can include attachment of a waterproof zipper via material welding to both an outer shell and an inner liner. This method may result in a chamber impervious to water and other liquids when the zipper apparatus on the aperture is sealed. In one example, an insulating device may include an outer shell, an inner liner forming a storage compartment, a foam layer floating formed in between the outer and inner liner, the foam layer providing insulation, an opening extending through the outer layer and the inner layer, a closure adapted to substantially seal the opening, the closure being substantially waterproof so as to resist liquid from exiting the opening when the insulating device is in any orientation. In one example, the top portion of the outer shell can have a first perimeter circumference in a first configuration. The outer shell may include a bottom portion, the bottom portion of the outer shell can have a second perimeter circumference in a second configuration that is different from the first configuration, and the first perimeter circumference can be equal to the second perimeter circumference. The first configuration and the second configuration can be both oval shaped. In one example, the insulating device may include an upper wall and a base, the upper wall can define an upper wall circumference, an upper wall length and an upper wall width, and the base can define a base circumference, a base length and a base width. The upper wall circumference can be equal to the base circumference and the ratio of the upper wall length to the upper wall width can be greater than the ratio of the base length to the base width. The cold retention time of the insulating device can be approximately 11 to 20 hours. However, in one example the cold retention time can be 11 to 15 hours. In another example the cold retention time can be approximately 12.24 hours. The heat gain rate of the insulating device can be approximately 1 to 1.5 degF/hr, and, in one particular example, the heat gain rate can be approximately 1.4 degF/hr. The storage compartment can be configured to maintain a liquid therein while inverted for greater than 15 minutes. In one particular example, the storage compartment can be configured to maintain the liquid for a period of greater than 30 minutes therein when inverted and a half of a volume of the storage compartment is filled with the liquid. In one example, the insulating layer can be floating freely in between the outer shell and the inner liner. The insulating layer can be formed of closed cell foam, and the insulating layer can be made of a NBR and a PVC blend. In one example least a portion of the insulating layer can be constructed with an EVA foam layer. The closure can be a zipper assembly comprising a plurality of zipper teeth, and the zipper teeth can be formed of plastic. In one example, the outer shell and the inner liner can be made of a double laminated TPU nylon fabric. The outer shell further can include at least one of a strap or handle. The outer shell can include at least one ring for securing the insulating device. The insulating layer can be configured to maintain an internal temperature of the insulating device below 50 degrees Fahrenheit for 65 to 85 hours. The closure can be formed with a first flange and a second flange and the outer liner can be secured to top surfaces of the first flange and the second flange. The inner liner can be secured to bottom surfaces of the first flange and the second flange. The outer liner and the inner liner can be connected to the closure by a polymer weld. In one example, the closure can be watertight up to 2 to 14 psi above atmospheric pressure. A loop patch may also be provided on the insulating device. In another example, an insulating device may include an outer shell, an inner liner forming a storage compartment, a foam layer floating in between the outer and inner liner, which provides insulation, an opening extending through the outer layer and the inner layer, a closure adapted to substantially seal the opening. The closure can be substantially waterproof so as to prevent liquid from exiting the opening when the insulating device is inverted for a period of greater than 15 minutes. The heat gain rate of the insulating device can be approximately 1.0 to 1.5 degF/hr. The insulting device can include at least one handle. The at least one handle can be configured to support 100 lbs. to 300 lbs. of weight for 1 to 10 minutes without showing signs of failure. In one example, the insulating device can be configured to withstand 35 lbs. to 100 lbs. of puncture force. An example method of forming an insulating device can include forming an inner liner first portion and an outer shell first portion, securing the inner liner first portion and the outer shell first portion to a sealable closure to form a cap assembly, forming an inner liner second portion and securing the inner liner second portion to the inner liner first portion to form an inner liner, forming an outer shell second portion, rolling a rectangular foam portion to form a first cylindrical foam portion and securing a foam base portion to the first cylindrical foam portion to form a foam assembly, inserting the foam assembly into the outer shell second portion, inserting the inner liner into the foam assembly, and securing the outer shell first portion to the outer shell second portion to form the outer shell. The method may also include securing a closure configured to be a barrier against fluid penetration in and out of the inner vessel and forming a waterproof polymer weld between the closure and the inner shell and the closure and the outer shell when the closure, the outer shell, and the inner liner are lying in a flat plane. In an example, the inner liner first portion and the outer shell first portion can be secured to the closure. The closure can be provided with at least one flange, and the flange can be secured to a bottom surface of the outer shell first portion and a top surface of the inner liner first portion. The foam can freely float between the outer shell second portion and the inner liner second portion. The outer shell and inner shell are only connected to the closure and not to the insulating layer between the outer shell and inner liner. The outer shell can be formed of a TPU nylon material, and the inner liner can be formed from a TPU nylon material. The closure can include a first flange and a second flange. The outer liner can be secured to top surfaces of the first flange and the second flange, and the inner liner can be secured to bottom surfaces of the first flange and the second flange. The top of the insulating layer can have a first perimeter circumference. The bottom of the insulating layer can have a second perimeter circumference. The first perimeter circumference can be equal to the second perimeter circumference. The present invention is disclosed above and in the accompanying drawings with reference to a variety of examples. The purpose served by the disclosure, however, is to provide examples of the various features and concepts related to the invention, not to limit the scope of the invention. One skilled in the relevant art will recognize that numerous variations and modifications may be made to the examples described above without departing from the scope of the present invention. | <SOH> BACKGROUND <EOH>Coolers are designed to keep food and beverages at lower temperatures. Containers may be composed of rigid materials such as metal or plastics or flexible materials such as fabric or foams. Coolers can be designed to promote portability. For example, rigid containers can be designed to incorporate wheels that facilitate ease of transport or coolers can be designed in smaller shapes to allow individuals to carry the entire device. Non-rigid containers can be provided with straps and/or handles and may in certain instances be made of lighter weight materials to facilitate mobility. Non-rigid coolers that maximize portability can be designed with an aperture on the top that allows access to the interior contents of the cooler. The aperture can also be provided with a closure. | <SOH> SUMMARY <EOH>This Summary provides an introduction to some general concepts relating to this invention in a simplified form that are further described below in the Detailed Description. This Summary is not intended to identify key features or essential features of the invention. Aspects of the disclosure herein may relate to insulating devices having one or more of (1) a waterproof closure (2) an outer shell, (3) an inner liner, (4) an insulating layer floating freely in between the outer shell and the inner liner, or (5) a waterproof storage compartment. | B65D81389 | 20171023 | 20180215 | 70917.0 | B65D8138 | 1 | SLAWSKI, BRIAN R | Insulating Container | UNDISCOUNTED | 1 | CONT-ACCEPTED | B65D | 2,017 |
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15,791,094 | ACCEPTED | LIGHTING CONTROL DEVICE, LIGHTING SYSTEM, LIGHTING CONTROL METHOD | The lighting control device includes a controller. The controller generates a second dimming signal corresponding to a measurement result of brightness of surroundings in the first mode and generates a second dimming signal corresponding to a first dimming signal in the second mode. The controller selects the first mode and start operating in the first mode when receiving the first dimming signal having a third duty cycle not falling within a range from a first duty cycle corresponding to an upper limit of the dimming level to a second duty cycle corresponding to a lower limit of the dimming level. The controller selects the second mode and start operating in the second mode when receiving the first dimming signal having a duty cycle falling within the range. | 1. A lighting control device comprising: an input circuit configured to receive from outside a first dimming signal having a duty cycle corresponding to a dimming level designating brightness of a lighting fixture; an output circuit configured to output a second dimming signal to the lighting fixture; a detector configured to measure brightness of surroundings; and a controller configured to select one operation mode from two operation modes including a first mode and a second mode, and operate in a selected operation mode, wherein: the first dimming signal has a duty cycle falling within a range from a first duty cycle corresponding to an upper limit of the dimming level of the lighting fixture to a second duty cycle corresponding to a lower limit of the dimming level of the lighting fixture; the controller is configured to, while operating in the first mode, generate a second dimming signal corresponding to a measurement result of the detector; the controller is configured to, while operating in the second mode, generate a second dimming signal corresponding to the first dimming signal; the controller is configured to select the first mode and start operating in the first mode when the input circuit receives the first dimming signal having a third duty cycle not falling within the range while operating in the second mode; and the controller is configured to select the second mode and start operating in the second mode when the input circuit receives the first dimming signal having a duty cycle falling within the range while operating in the first mode. 2. The lighting control device according to claim 1, wherein: the detector is configured to measure brightness of a space to be illuminated by the lighting fixture and output a measurement signal indicative of a measurement value of the brightness of the space to the controller; and the controller is configured to, while operating in the first mode, determine a dimming level enabling decreasing a difference between the measurement value indicated by the measurement signal and a desired value for the brightness of the space, and generate the second dimming signal including a duty cycle corresponding to the dimming level determined. 3. The lighting control device according to claim 1, wherein the controller is configured to, while operating in the second mode, generate the second dimming signal including a duty cycle corresponding to a dimming level equal to a dimming level indicated by the first dimming signal received by the input circuit. 4. The lighting control device according to claim 1, wherein the output circuit is configured to output the second dimming signal using an electromagnetic wave as a communication medium. 5. The lighting control device according to claim 1, wherein the output circuit is configured to output the second dimming signal using an electric conductor as a communication medium. 6. A lighting system comprising: the lighting control device according to claim 1; and a manual control device configured to output the first dimming signal having a duty cycle corresponding to the dimming level to the input circuit of the lighting control device, wherein the manual control device includes a manual control interface for allowing manual control by hand, and a signal output circuit configured to output the first dimming signal having a duty cycle corresponding to manual control of the manual control interface. 7. The lighting system according to claim 6, wherein: the manual control interface is a push button and the signal output circuit is configured to output the first dimming signal having a duty cycle falling within the range from the first duty cycle to the second duty cycle each time the manual control interface is pushed, and output the first dimming signal having the third duty cycle when a period of time when the manual control interface is pressed continuously is longer than a predetermined period of time. 8. The lighting system according to claim 6, wherein: the manual control interface includes a manual control knob to be rotated or slid; and the signal output circuit is configured to output the first dimming signal having a duty cycle falling within the range from the first duty cycle to the second duty cycle in accordance with a manual control position of the manual control knob rotated or slid, and output the first dimming signal having the third duty cycle when the manual control knob reaches a predetermined position by being rotated or slid. 9. The lighting system according to claim 6, wherein: the manual control device further includes an indicator; and the indicator is configured to make indication while the signal output circuit is outputting the first dimming signal having the third duty cycle. 10. A lighting system comprising: the lighting control device according to claim 1; and at least one lighting fixture, wherein the at least one lighting fixture is configured to, when receiving the second dimming signal outputted from the output circuit of the lighting control device, allow light output thereof to correspond to a dimming level indicated by the second dimming signal received. 11. The lighting system according to claim 10, further comprising a manual control device configured to output the first dimming signal to the lighting control device, wherein the manual control device includes a manual control interface for allowing manual control by hand, and a signal output circuit configured to output the first dimming signal having a duty cycle corresponding to manual control of the manual control interface. 12. The lighting system according to claim 11, wherein: the manual control interface is a push button; and the signal output circuit is configured to output the first dimming signal having a duty cycle falling within the range from the first duty cycle to the second duty cycle each time the manual control interface is pushed, and output the first dimming signal having the third duty cycle when a period of time when the manual control interface is pressed continuously is longer than a predetermined period of time. 13. The lighting system according to claim 11, wherein: the manual control interface includes a manual control knob to be rotated or slid; and the signal output circuit is configured to output the first dimming signal having a duty cycle falling within the range from the first duty cycle to the second duty cycle in accordance with a manual control position of the manual control knob rotated or slid, and output the first dimming signal having the third duty cycle when the manual control knob reaches a predetermined position by being rotated or slid. 14. The lighting system according to claim 11, wherein: the manual control device further includes an indicator; and the indicator is configured to make indication while the signal output circuit is outputting the first dimming signal having the third duty cycle. 15. A lighting control method comprising: selecting one control method from two control methods including a first control method and a second control method; and performing a selected control method to achieve dimming control of at least one lighting fixture, wherein: the first control method is a control method of generating a second dimming signal corresponding to a measurement result of brightness of surroundings; the second control method is a control method of generating a second dimming signal corresponding to a first dimming signal having a duty cycle corresponding to a dimming level designating brightness of the at least one lighting fixture; the first control method is selected and performed when the first dimming signal having a third duty cycle not falling within a range from a first duty cycle corresponding to an upper limit of the dimming level to a second duty cycle corresponding to a lower limit of the dimming level is inputted while the second control method is performed; and the second control method is selected and performed when the first dimming signal having a duty cycle falling within the range is inputted while the first control method is performed. | CROSS-REFERENCE TO RELATED APPLICATION The present application is based upon and claims the benefit of priority of Japanese Patent Application No. 2016-209772, filed on Oct. 26, 2016, the entire contents of which are incorporated herein by reference. TECHNICAL FIELD The present disclosure relates to lighting control devices, lighting systems, and lighting control methods, and particularly to a lighting control device for dimming control of a lighting fixture, a lighting system including the lighting control device and a lighting fixture, and a lighting control method for dimming control of a lighting fixture. BACKGROUND ART Document 1 (JP 2013-235776 A) discloses a lighting system including at least one lighting fixture, a dimmer for outputting a dimming signal, and a dimming signal conversion device for converting the dimming signal (duty signal) outputted from the dimmer into a phase control signal and outputting the phase control signal to the lighting fixture. The dimmer includes a dimmer body with a rectangular box shape to be attached to a wall surface. The dimmer body is provided at its front face with a rotary manual control knob for selecting a dimming level of the lighting fixture. The manual control knob is provided to the dimmer body and is rotatable within a range of manual control positions including a manual control position corresponding to a lower limit value of the dimming level and a manual control position corresponding to an upper limit value of the dimming level. The dimmer generates a rectangular wave signal (duty signal) with a duty cycle corresponding to a manual control position of the manual control knob, and outputs to a dimming signal line the dimming signal being the rectangular wave signal. Note that, in such lighting systems, there are demands to realize dimming control of changing the dimming level of the lighting fixture automatically depending on brightness of surroundings, in addition to dimming control responding to human manual control, for example. However, it is considered difficult to satisfy the above demands by configurations of the lighting system and the dimming signal conversion device (lighting control device) disclosed in document 1. SUMMARY An object according to the present disclosure would be to propose a lighting control device, a lighting system, and a lighting control method which can increase types of dimming control and improve usability. A lighting control device according to one aspect of the present disclosure includes: an input circuit configured to receive from outside a first dimming signal having a duty cycle corresponding to a dimming level designating brightness of a lighting fixture; and an output circuit configured to output a second dimming signal to the lighting fixture. The lighting control device further includes: a detector configured to measure brightness of surroundings; and a controller configured to select one operation mode from two operation modes including a first mode and a second mode, and operate in a selected operation mode. The first dimming signal has a duty cycle falling within a range from a first duty cycle corresponding to an upper limit of the dimming level of the lighting fixture to a second duty cycle corresponding to a lower limit of the dimming level of the lighting fixture. The controller is configured to, while operating in the first mode, generate a second dimming signal corresponding to a measurement result of the detector. The controller is configured to, while operating in the second mode, generate a second dimming signal corresponding to the first dimming signal. The controller is configured to select the first mode and start operating in the first mode when the input circuit receives the first dimming signal having a third duty cycle not falling within the range while operating in the second mode. The controller is configured to select the second mode and start operating in the second mode when the input circuit receives the first dimming signal having a duty cycle falling within the range while operating in the first mode. A lighting system according to another aspect of the present disclosure includes: the lighting control device; and a manual control device configured to output the first dimming signal having a duty cycle corresponding to the dimming level to the input circuit of the lighting control device. The manual control device includes: a manual control interface for allowing manual control by hand; and a signal output circuit configured to output the first dimming signal having a duty cycle corresponding to manual control of the manual control interface. A lighting system according to another aspect of the present disclosure includes: the lighting control device; and at least one lighting fixture. The at least one lighting fixture is configured to, when receiving the second dimming signal outputted from the output circuit of the lighting control device, allow light output thereof to correspond to a dimming level indicated by the second dimming signal received. A lighting control method according to another aspect of the present disclosure includes: selecting one control method from two control methods including a first control method and a second control method; and performing a selected control method to achieve dimming control of at least one lighting fixture. The first control method is a control method of generating a second dimming signal corresponding to a measurement result of brightness of surroundings. The second control method is a control method of generating a second dimming signal corresponding to a first dimming signal having a duty cycle corresponding to a dimming level designating brightness of the at least one lighting fixture. The first control method is selected and performed when the first dimming signal having a third duty cycle not falling within a range from a first duty cycle corresponding to an upper limit of the dimming level to a second duty cycle corresponding to a lower limit of the dimming level is inputted while the second control method is performed. The second control method is selected and performed when the first dimming signal having a duty cycle falling within the range is inputted while the first control method is performed. BRIEF DESCRIPTION OF THE DRAWINGS The figures depict one or more implementations in accordance with the present teaching, by way of example only, not by way of limitations. In the figures, like reference numerals refer to the same or similar elements. FIG. 1 is a diagram for illustration of system configuration of a lighting system according to one embodiment of the present disclosure and a circuit block of a lighting control device according to one embodiment of the present disclosure. FIG. 2 is a diagram for illustration of a relationship between a duty cycle of a first dimming signal and a dimming level in the lighting control device and the lighting system of the above. FIG. 3A is a front view of a manual control device in the above lighting system. FIG. 3B is a circuit block diagram of the above manual control device. FIG. 3C is a circuit diagram of an output circuit of the above manual control device. FIG. 3D is a waveform chart of the above first dimming signal. FIG. 4 is a front view of modification 1 of a manual control device in the above lighting system. DETAILED DESCRIPTION The following detail descriptions referring to attached drawings are made to embodiments of lighting control devices according to the present disclosure and embodiments of lighting systems according to the present disclosure. Note that the configurations described in the following embodiments are merely examples of possible embodiments of the present disclosure. Embodiments of the present disclosure may not be limited to the following embodiments, and the following embodiments can be modified in various ways in accordance with design or the like as long as they can achieve technical effects given by the present disclosure. As shown in FIG. 1, a lighting system 7 of the present embodiment includes a lighting control device 1 and at least one lighting fixture 2. Additionally, the lighting system 7 may preferably include a manual control device 3. The lighting system 7 may include one lighting fixture 2 only, or may include a plurality of lighting fixtures 2, the lighting control device 1 and the at least one lighting fixture 2 are electrically connected to an external power supply 4 through a power supply line 5 which is a two-wire electric cable in a power transferring manner. Examples of the external power supply 4 may include a commercial AC power supply. Note that, the power supply line 5 may be a three-wire electric cable including a grounding line. All the lighting fixtures 2 have the same configurations. For this reason, FIG. 1 shows a circuit block for only one of the lighting fixtures 2. The lighting fixture 2 includes a light source 20, a lighting controller 21, a receiver 22, and a fixture controller 23. The light source 20 is an LED module including a substrate and a plurality of illumination-use white LEDs (Light Emitting Diodes). The lighting controller 21 is configured to light (turn on) the light source 20 by converting AC power supplied from the external power supply 4 through the power supply line 5 into DC power and supplying converted DC power to the light source 20. The lighting controller 21 may preferably be constituted by, for example, a full-wave rectifier, a power factor correction circuit (step-up chopper circuit), and a step-down chopper circuit. In accordance with instructions from the fixture controller 23, the lighting controller 21 may turn off the light source 20 by stopping the step-down chopper circuit, and may control brightness of the light source 20 by increasing or decreasing a DC current outputted from the step-down chopper circuit. Note that, the lighting controller 21 operating in such a manner is well-known and therefore detail circuit configuration thereof are not shown and described herein. The receiver 22 is configured to obtain an original signal (a second dimming signal S2) by demodulating radio waves (wireless signals) received by an antenna, and obtain data (including a duty cycle) included in the thus-obtained second dimming signal S2 and provide the data to the fixture controller 23. Radio waves to be received by the receiver 22 are radio waves (for example radio waves in a 920 MHz band) for specified small power radio stations stipulated in Japanese Radio Act. The receiver 22 operating in such a manner can be realized by a wireless module including one or more integrated circuits, or an RF (Radio Frequency) receiver, and therefore detail circuit configuration thereof are not shown and described herein. The fixture controller 23 may be preferably realized by one or more microcontrollers. The fixture controller 23 is configured to convert the data (duty cycle) received from the receiver 22 into a dimming level. Note that, the dimming level designates an amount of light from the light source 20 (brightness of the lighting fixture 2). In more detail, the dimming level is defined as a percentage of a desired output current of the lighting controller 21 to an output current of the lighting controller 21 which enables rated lighting of the light source 20. The fixture controller 23 controls the lighting controller 21 so that a current flowing through the lighting controller 21 has magnitude corresponding to the dimming level converted from the duty cycle. For example, when the dimming level is assumed to be 80%, the fixture controller 23 controls the lighting controller 21 so that the current flowing through the lighting controller 21 has magnitude corresponding to 80% of the output current enabling the rated lighting. Accordingly, adjustment (dimming) of light output of the light source 20 is made. The lighting fixture 2 is a lighting fixture to be mounted on/in a ceiling of a gymnasium or a hall to illuminate a floor of the gymnasium or audience seats of the hall from a height, which is a so-called high-ceiling-mounted lighting fixture. Note that, the lighting fixture 2 may not be limited to such a high-ceiling-mounted lighting fixture but may be a lighting fixture to be mounted on/in a ceiling or a wall of an office or a store. The lighting control device 1 includes a controller 10, an input circuit 11, an output circuit 12, a detector 13, and a power supply 14 (see FIG. 1). The power supply 14 is electrically connected to the external power supply 4 through the power supply line 5 in a power transferring manner. The power supply 14 converts an AC voltage (for example, an AC voltage with an effective value of 100 V) supplied from the external power supply 4 into a low DC voltage of about 5 V or 3.3 V. The power supply 14 supplies the converted DC voltage as an operation power supply voltage Vcc to the controller 10, the input circuit 11, the output circuit 12, and the detector 13. The input circuit 11 is electrically connected to the manual control device 3 through a two-wire dimming signal line 6. The input circuit 11 receives a dimming signal (a first dimming signal S1) from the manual control device 3 through the dimming signal line 6. The dimming signal (the first dimming signal S1) is, as shown in FIG. 3D, a rectangular wave signal with a constant period T1 and has a duty cycle corresponding to a dimming level. The duty cycle is, as shown in FIG. 3D, a ratio of an on width T2 to the period T1 of the first dimming signal S1 (given by T2/T1×100 [%]). The input circuit 11 outputs to the controller 10 a DC voltage with a voltage value in proportion to a duty cycle (dimming level) of the first dimming signal S1 by integrating it. The output circuit 12 sends the second dimming signal S2 through wireless signals using as communication media radio waves (for example radio waves in a 920 MHz band) for specified small power radio stations, in a similar manner to the receiver 22 of the lighting fixture 2. Note that, the output circuit 12 operating in such a manner can be realized by a wireless module including one or more integrated circuits like the receiver 22 of the lighting fixture 2, for example, and therefore detail circuit configuration thereof are not shown and described herein. The detector 13 may include a photoelectric conversion element such as a photodiode and a solar cell, and an analog-digital conversion circuit for converting an analog electric signal outputted from the photoelectric conversion element into a digital measurement signal. An analog amount of the electric signal outputted from the photoelectric conversion element may be proportional to an amount of light received by the photoelectric conversion element, that is, illuminance. The controller 10 may be constituted by hardware including one or more microcontrollers, and software executed by the one or more microcontrollers. The software includes a first program and a second program. Note that, in the following description, operation of the controller 10 realized by the one or more microcontrollers executing the first program may be referred to as a first mode, and operation of the controller 10 realized by the one or more microcontrollers executing the second program may be referred to as a second mode. While operating in the first mode, the controller 10 obtains the measurement signal outputted from the detector 13 and compares the amount of light indicated by the measurement signal with a desired value of brightness. When the amount of light indicated by the measurement signal is lower than the desired value, the controller 10 generates the second dimming signal S2 including data (duty cycle) corresponding to a dimming level higher than the current dimming level, and provides it to the output circuit 12. In contrast, when the amount of light indicated by the measurement signal is higher than the desired value, the controller 10 generates the second dimming signal S2 including data (duty cycle) corresponding to a dimming level lower than the current dimming level, and provides it to the output circuit 12. The second dimming signal S2 provided to the output circuit 12 is outputted (transmitted) to the individual lighting fixtures 2 through wireless signals using radio waves as communication media. In short, while operating in the first mode, the controller 10 controls luminance of the individual lighting fixtures 2 in order to keep constant the brightness (illuminance) of the floor of the gymnasium, the audience seats of the hall, or the like, for example. While operating in the second mode, the controller 10 generates the second dimming signal S2 with a dimming level equal to a dimming level of the first dimming signal S1 inputted into the input circuit 11, and provides it to the output circuit 12. The second dimming signal S2 provided to the output circuit 12 is outputted (transmitted) to the individual lighting fixtures 2 through wireless signals using radio waves as communication media. In short, while operating in the second mode, the controller 10 relays the first dimming signal S1 received from the manual control device 3 through the dimming signal line 6 to the individual lighting fixtures 2. The manual control device 3 includes a manual control interface 31 for allowing manual control by hand, and a signal output circuit 30 configured to output the first dimming signal 51 having a duty cycle corresponding to manual control of the manual control interface 31. Additionally, the manual control device 3 may preferably include, as shown in FIG. 3B, a manual controller 32, an output circuit 33, and an indicator 34. The manual control interface 31 may preferably be a push button for allowing push by human hand(s) (finger(s)). For example, the manual controller 32 may preferably include a push button switch configured to: be on while the manual control interface 31 (push button) is pushed; and be off while the manual control interface 31 (push button) is not pushed. The manual controller 32 outputs a manual control signal to the signal output circuit 30 while the push button switch is on. The signal output circuit 30 may be preferably constituted by a microcontroller. When acknowledging reception of the manual control signal from the manual controller 32, the signal output circuit 30 determines that the push button switch (that is the manual control interface 31) is pushed. The indicator 34 includes a plurality of indicating devices, and a drive circuit for operating (lighting) the plurality of indicating devices individually. As to the indicator 34, the drive circuit is controlled by the signal output circuit 30 to light at least one of the plurality of indicating devices. Note that, each indicating device may be preferably an indication-use light emitting diode. The output circuit 33 may be preferably constituted by, as shown in FIG. 3C, a switch device Q1 and a resistor R1. The switch device Q1 is a pnp bipolar transistor. The switch device Q1 has an emitter receiving a constant voltage Vd. The switch device Q1 has a collector electrically connected to the ground via the resistor R1. The switch device Q1 has a base electrically connected to an output port of the microcontroller constituting the signal output circuit 30. A junction between the collector of the switch device Q1 and the resistor R1 is electrically connected to the dimming signal line 6. Accordingly, when the output port of the signal output circuit 30 has a low level, the output circuit 33 turns on the switch device Q1 to cause a flow of current through the resistor R1, thereby allowing the first dimming signal S1 to have a high level. In contrast, when the output port of the signal output circuit 30 has a high level, the output circuit 33 turns off the switch device Q1 not to cause a flow of current through the resistor R1, thereby allowing the first dimming signal S1 to have a low level. For example, as shown in FIG. 3A, the manual control device 3 includes a housing 35 which has an elongated rectangular box shape of synthetic resin. The housing 35 has a front face provided with four first push buttons 310 and four second push buttons 311. The four first push buttons 310 are arranged in one line along a lengthwise direction (horizontal direction) of the housing 35. Further, the four second push buttons 311 are arranged in one line along the lengthwise direction (horizontal direction) of the housing 35, and each of the four second push buttons 311 and a corresponding one of the first push button 310 are arranged in one line along a width direction (vertical direction) of the housing 35. The four first push buttons 310 are associated with the four second push buttons 311 one by one. Stated differently, the manual control interface 31 includes four sets of a first push button 310 and a second push button 311 which are arranged in one line along the vertical direction of the housing 35. The signal output circuit 30 is configured to allow electrical connection with dimming signal lines 6 of four systems. The dimming signal line 6 of each system is electrically connected to a corresponding one of the lighting control devices 1. Note that, FIG. 1 shows system configurations where a dimming signal line 6 of only one system is electrically connected to a lighting control device 1. However, in other system configurations, dimming signal lines 6 of four systems may be electrically connected to lighting control devices 1 individually. In this regard, the front face of the housing 35 is provided with a plurality (for example, seven) of through holes 350 are arranged: in one line along the vertical direction; and in immediate left of a corresponding one of the four sets of the first push button 310 and the second push button 311. These through holes 350 allows light (for example, green light, blue light, or red light) emitted from the plurality of indicating devices of the indicator 34, to pass toward a front side of the housing 35. The manual controller 32 outputs a first manual control signal while a push button switch corresponding to a first push button 310 is on. The manual controller 32 outputs a second manual control signal while a push button switch corresponding to a second push button 311 is on. The signal output circuit 30 increases the dimming level when receiving the first manual control signal from the manual controller 32. The signal output circuit 30 decreases the dimming level when receiving the second manual control signal from the manual controller 32. Additionally, the signal output circuit 30 controls the indicator 34 to increase or decrease the number of indicating devices to be lit in accordance with the dimming level, thereby allowing the indicator 34 to indicate the dimming level. In this regard, the signal output circuit 30 has a function of changing a duty cycle of the first dimming signal S1 within a range X1 from a first duty cycle D1 corresponding to an upper limit of the dimming level to a second duty cycle D2 corresponding to a lower limit of the dimming level (see FIG. 2). Note that, the upper limit of the dimming level is, for example, 100% of a rated value. The lower limit of the dimming level is, for example, 5% of the rated value. Additionally, the first duty cycle D1 is, for example, 5%, and the second duty cycle D2 is, for example, 95% (see FIG. 2). The signal output circuit 30 converts a dimming level designated in response to manual control of the manual control interface 31 into a duty cycle, and outputs a first dimming signal S1 with a converted duty cycle from the output circuit 33 to the lighting control device 1 through the dimming signal line 6 (see FIG. 3D). Note that, the fixture controller 23 of the lighting fixture 2 may preferably control the lighting controller 21 to turn off the light source 20 when a duty cycle of the first dimming signal 51 is a value (for example, 99%) higher than 95%. Note that, the signal output circuit 30 outputs a first dimming signal S1 having a third duty cycle D3 when a period of time when the manual control interface 31 is pressed continuously is longer than a predetermined period of time (for example, 5 seconds). In more detail, the signal output circuit 30 may preferably output the first dimming signal S1 with its duty cycle being set to the third duty cycle D3, from the output circuit 33, when input of the first manual control signal continues for more than 5 seconds while the dimming level is set to 100%. The third duty cycle D3 may be any of duty cycles not falling within the range Xl. For example, the third duty cycle D3 may preferably be equal to or smaller than 2.5%±0.5%. The controller 10 of the lighting control device 1 is configured to, in response to reception of the first dimming signal 51 with the third duty cycle D3 from the input circuit 11 while operating in the second mode, select the first mode and start operating in the first mode. Additionally, the controller 10 is configured to, in response to reception of the first dimming signal 51 with a third duty cycle within the range X1 while operating in the first mode, select the second mode and start operating in the second mode. In short, the controller 10 is configured to select either the first mode or the second mode and operate in a selected mode in response to a duty cycle (any of duty cycles within the range X1 or the third duty cycle D3) of the first dimming signal 51 inputted into the input circuit 11. Accordingly, by operating by hand the manual control interface 31 of the manual control device 3, a user can change the dimming level and additionally switch the operation mode of (the controller 10 of) the lighting control device 1. Note that, it is preferable that, while outputting the first dimming signal 51 with the third duty cycle D3, the signal output circuit 30 instruct the indicator 34 to indicate that the operation mode of the lighting control device 1 is the first mode. For example, the signal output circuit 30 may control the drive circuit of the indicator 34 to blink an indicating device (an indicating device corresponding to the uppermost through hole 350 in FIG. 3A) which is of indicating devices on opposite ends in the vertical direction and adjacent to the first push button 310. Therefore, by blinking one or more indicating devices of the indicator 34, the manual control device 3 can notify a user that (the controller 10 of) the lighting control device 1 is operating in the first mode. Note that, the manual control interface 31 of the manual control device 3 may not be limited to a push button. For example, FIG. 4 shows a manual control device 3A of Modification 1 which includes a housing 36 with a cuboidal shape and a manual control interface (a manual control knob 312) rotatably attached to a front face of the housing 36. The manual control knob 312 is constituted by a molded product of synthetic resin with a hollow cylindrical shape. The manual control knob 312 has a front face (bottom) provided with a straight marking 313. In contrast, in a surrounding of the manual control knob 312 in the front face of the housing 36, a first mark 360, a second mark 361, and a third mark 362 are provided. When viewed from front of the housing 36, the manual control knob 312 is rotatable continuously and bidirectionally between a position (lower limit position) where the marking 313 is aligned with the first mark 360 and another position (upper limit position) where the marking 313 is aligned with the second mark 361. Further, the manual control knob 312 is rotatable bidirectionally between the upper limit position and a position (switching position) where the marking 313 is aligned with the third mark 362. A manual controller 32 in the manual control device 3A of Modification 1 may preferably include a variable resistor which varies its resistance depending on a manual control position (a position of the marking 313 relative to the housing 36) of the manual control knob 312. The manual controller 32 may be preferably configured to output a manual control signal having voltage in proportion to a current resistance of the variable resistor to a signal output circuit 30. The signal output circuit 30 is configured to, when receiving the manual control signal corresponding to the lower limit position of the manual control knob 312 from the manual controller 32, output the first dimming signal S1 with the second duty cycle D2 corresponding to the lower limit of the dimming level. And, the signal output circuit 30 is configured to, when receiving the manual control signal corresponding to the upper limit position of the manual control knob 312 from the manual controller 32, output the first dimming signal S1 with the first duty cycle D1 corresponding to the upper limit of the dimming level. Additionally, the signal output circuit 30 is configured to, when receiving the manual control signal corresponding to the switching position of the manual control knob 312 from the manual controller 32, output the first dimming signal S1 with the third duty cycle D3. Accordingly, by operating (rotating) the manual control knob 312 of the manual control device 3, a user can change the dimming level and additionally switch the operation mode of (the controller 10 of) the lighting control device 1. Note that, the housing 36 of the manual control device 3 may be preferably designed to give click feeling to a hand of a user manually controlling the manual control knob 312 when the manual control knob 312 is moved (rotated) between the upper limit position and the switching position. For example, as to the manual control device 3, both the manual control knob 312 and the housing 36 may be provided with protrusions so that click feeling is made when a protrusion provided to the manual control knob 312 goes across a protrusion provided to the housing 36. Note that, the output circuit 12 of the lighting control device 1 may be configured to output the second dimming signal S2 using an electromagnetic wave other than a radio wave, that is, infrared light, as a communication medium. Alternatively, the output circuit 12 may be configured to output the second dimming signal S2 using an electric conductor (an electric conductor of a clad cable) instead of an electromagnetic wave. The manual control interface 31 of the manual control device 3 may be a slidable manual control knob instead of a push button or the rotary manual control knob 312. As apparently derived from the above descriptions, the lighting control device (1) of the first aspect includes: an input circuit (11) configured to receive from outside a first dimming signal (Si) having a duty cycle corresponding to a dimming level designating brightness of a lighting fixture (2); and an output circuit (12) configured to output a second dimming signal (S2) to the lighting fixture (2). The lighting control device (1) further includes: a detector (13) configured to measure brightness of surroundings; and a controller (10) configured to select one operation mode from two operation modes including a first mode and a second mode, and operate in a selected operation mode. The first dimming signal (S1) has a duty cycle falling within a range (X1) from a first duty cycle (D1) corresponding to an upper limit of the dimming level of the lighting fixture (2) to a second duty cycle (D2) corresponding to a lower limit of the dimming level of the lighting fixture (2). The controller (10) is configured to, while operating in the first mode, generate a second dimming signal (S2) corresponding to a measurement result of the detector (13). The controller (10) is configured to, while operating in the second mode, generate a second dimming signal (S2) corresponding to the first dimming signal (Si). The controller (10) is configured to select the first mode and start operating in the first mode when the input circuit (11) receives the first dimming signal (Si) having a third duty cycle (D3) not falling within the range (X1) while operating in the second mode. The controller (10) is configured to select the second mode and start operating in the second mode when the input circuit (11) receives the first dimming signal (S1) having a duty cycle falling within the range (X1) while operating in the first mode. The lighting control device (1) of the first aspect enables dimming control according to brightness of surroundings measured by the detector (13), and additionally dimming control according to the first dimming signal (S1) inputted into the input circuit (11) from an external device. Therefore, the lighting control device (1) of the first aspect can increase types of dimming control and improve usability. The lighting control device (1) of the second aspect would be realized in combination with the first aspect. In the lighting control device (1) of the second aspect, the detector (13) is configured to measure brightness of a space to be illuminated by the lighting fixture (2) and output a measurement signal indicative of a measurement value of the brightness of the space to the controller (10). The controller (10) is configured to, while operating in the first mode, determine a dimming level enabling decreasing a difference between the measurement value indicated by the measurement signal and a desired value for the brightness of the space, and generate the second dimming signal (S2) including a duty cycle corresponding to the dimming level determined. The lighting control device (1) of the second aspect can control the brightness of the space to be illuminated by the lighting fixture (2) to correspond to the desired value. The lighting control device (1) of the third aspect would be realized in combination with the first or second aspect. In the lighting control device (1) of the third aspect, the controller (10) is configured to, while operating in the second mode, generate the second dimming signal (S2) including a duty cycle corresponding to a dimming level equal to a dimming level indicated by the first dimming signal (S1) received by the input circuit (11). The lighting control device (1) of the third aspect can control the brightness of the space to be illuminated by the lighting fixture (2) to correspond to desired brightness. The lighting control device (1) of the fourth aspect would be realized in combination with any one of the first to third aspects. In the lighting control device (1) of the fourth aspect, the output circuit (12) is configured to output the second dimming signal (S2) using an electromagnetic wave as a communication medium. Note that, the electromagnetic wave may be a radio wave or another electromagnetic wave, such as the infrared light, other than a radio wave. The lighting control device (1) of the fourth aspect can omit electric cables for electrically interconnecting the output circuit (12) and the lighting fixture (2) to allow transmission of the second dimming signal (S2), and accordingly, installation can be simplified. The lighting control device (1) of the fifth aspect would be realized in combination with any one of the first to third aspects. In the lighting control device (1) of the fifth aspect, the output circuit (12) is configured to output the second dimming signal (S2) using an electric conductor as a communication medium. The lighting control device (1) of the fifth aspect can reduce influence of possible noises received on the second dimming signal (S2). As apparently derived from the above descriptions, the lighting system (7) of the sixth aspect includes: the lighting control device (1) according to any one of the first to fifth aspects; and a manual control device (3; 3A) configured to output the first dimming signal (51) having a duty cycle corresponding to the dimming level to the input circuit (11) of the lighting control device (1). The manual control device (3; 3A) includes: a manual control interface (31) for allowing manual control by hand; and a signal output circuit (30) configured to output the first dimming signal (S1) having a duty cycle corresponding to manual control of the manual control interface (31). The lighting system (7) of the sixth aspect allows output of the first dimming signal (S1) to the lighting control device (1) from the manual control device (3; 3A) including the manual control interface (31) to be manually operated by hand. Therefore, usability can be improved. The lighting system (7) of the seventh aspect would be realized in combination with the sixth aspect. In the lighting system (7) of the seventh aspect, the manual control interface (31) is a push button (the first push button 310; the second push button 311). The signal output circuit (30) is configured to output the first dimming signal (S1) having a duty cycle falling within the range (X1) from the first duty cycle (D1) to the second duty cycle (D2) each time the manual control interface (31) is pushed. And, the signal output circuit (30) is configured to output the first dimming signal (S1) having the third duty cycle (D3) when a period of time when the manual control interface (31) is pressed continuously is longer than a predetermined period of time. According to the lighting system (7) of the seventh aspect, there is no need to provide a dedicated manual control interface to the manual control device (3) in order to allow the manual control device (3) to output the first dimming signal (S1) with the third duty cycle (D3). Therefore, configurations of the manual control device (3) can be simplified. The lighting system (7) of the eighth aspect would be realized in combination with the sixth aspect. In the lighting system (7) of the eighth aspect, the manual control interface includes a manual control knob (312) to be rotated or slid. The signal output circuit (30) is configured to output the first dimming signal (S1) having a duty cycle falling within the range (X1) from the first duty cycle (D1) to the second duty cycle (D2) in accordance with a manual control position of the manual control knob (312) rotated or slid. And, the signal output circuit (30) is configured to output the first dimming signal (S1) having the third duty cycle (D3) when the manual control knob (312) reaches a predetermined position by being rotated or slid. According to the lighting system (7) of the eighth aspect, there is no need to provide a dedicated manual control interface to the manual control device (3A) in order to allow the manual control device (3A) to output the first dimming signal (Si) with the third duty cycle (D3). Therefore, configurations of the manual control device (3A) can be simplified. The lighting system (7) of the ninth aspect would be realized in combination with any one of the sixth to eighth aspects. In the lighting system (7) of the ninth aspect, the manual control device (3) further includes an indicator (34). The indicator (34) is configured to make indication while the signal output circuit (30) is outputting the first dimming signal (S1) having the third duty cycle (D3). The lighting system (7) of the ninth aspect can inform a user by indication of the indicator (34), that the controller (10) of the lighting control device (1) is in operation in the first mode. As apparently derived from the above descriptions, the lighting system (7) of the tenth aspect includes: the lighting control device (1) according to any one of the first to fifth aspects; and at least one lighting fixture (2). The at least one lighting fixture (2) is configured to, when receiving the second dimming signal (S2) outputted from the output circuit (12) of the lighting control device (1), allow light output thereof to correspond to a dimming level indicated by the second dimming signal (S2) received. The lighting system (7) of the tenth aspect enables dimming control according to brightness of surroundings measured by the detector (13), and additionally dimming control according to the first dimming signal (Si) inputted into the input circuit (11) from an external device. Therefore, the lighting system (7) of the tenth aspect can increase types of dimming control and improve usability. The lighting system (7) of the eleventh aspect would be realized in combination with the tenth aspect. The lighting system (7) of the eleventh aspect includes a manual control device (3; 3A) configured to output the first dimming signal (S1) to the lighting control device (1). The manual control device (3; 3A) includes: a manual control interface (31) for allowing manual control by hand, and a signal output circuit (30) configured to output the first dimming signal (S1) having a duty cycle corresponding to manual control of the manual control interface (31). The lighting system (7) of the eleventh aspect allows output of the first dimming signal (S1) to the lighting control device (1) from the manual control device (3; 3A) including the manual control interface (31) to be manually operated by hand. Therefore, usability can be improved. The lighting system (7) of the twelfth aspect would be realized in combination with the eleventh aspect. In the lighting system (7) of the twelfth aspect, the manual control interface (31) is a push button (the first push button 310; the second push button 311). The signal output circuit (30) is configured to output the first dimming signal (S1) having a duty cycle falling within the range (X1) from the first duty cycle (D1) to the second duty cycle (D2) each time the manual control interface (31) is pushed. And, the signal output circuit (30) is configured to output the first dimming signal (Si) having the third duty cycle (D3) when a period of time when the manual control interface (31) is pressed continuously is longer than a predetermined period of time. According to the lighting system (7) of the twelfth aspect, there is no need to provide a dedicated manual control interface to the manual control device (3) in order to allow the manual control device (3) to output the first dimming signal (S1) with the third duty cycle (D3). Therefore, configurations of the manual control device (3) can be simplified. The lighting system (7) of the thirteenth aspect would be realized in combination with the eleventh aspect. In the lighting system (7) of the thirteenth aspect, the manual control interface includes a manual control knob (312) to be rotated or slid. The signal output circuit (30) is configured to output the first dimming signal (S1) having a duty cycle falling within the range (X1) from the first duty cycle (D1) to the second duty cycle (D2) in accordance with a manual control position of the manual control knob (312) rotated or slid. And, the signal output circuit (30) is configured to output the first dimming signal (S1) having the third duty cycle (D3) when the manual control knob (312) reaches a predetermined position by being rotated or slid. According to the lighting system (7) of the thirteenth aspect, there is no need to provide a dedicated manual control interface to the manual control device (3A) in order to allow the manual control device (3A) to output the first dimming signal (Si) with the third duty cycle (D3). Therefore, configurations of the manual control device (3A) can be simplified. The lighting system (7) of the fourteenth aspect would be realized in combination with any one of the eleventh to thirteenth aspects. In the lighting system (7) of the fourteenth aspect, the manual control device (3) further includes an indicator (34). The indicator (34) is configured to make indication while the signal output circuit (30) is outputting the first dimming signal (Si) having the third duty cycle (D3). The lighting system (7) of the fourteenth aspect can inform a user by indication of the indicator (34), that the controller (10) of the lighting control device (1) is in operation in the first mode. The lighting control method of the fifteenth aspect includes: selecting one control method from two control methods including a first control method and a second control method; and performing a selected control method to achieve dimming control of at least one lighting fixture (2). The first control method is a control method of generating a second dimming signal (S2) corresponding to a measurement result of brightness of surroundings. The second control method is a control method of generating a second dimming signal (S2) corresponding to a first dimming signal (S1) having a duty cycle corresponding to a dimming level designating brightness of the at least one lighting fixture (2). The first control method is selected and performed when the first dimming signal (S1) having a third duty cycle (D3) not falling within a range (X1) from a first duty cycle (D1) corresponding to an upper limit of the dimming level to a second duty cycle (D2) corresponding to a lower limit of the dimming level is inputted while the second control method is performed. The second control method is selected and performed when the first dimming signal (S1) having a duty cycle falling within the range (X1) is inputted while the first control method is performed. The lighting control method of the fifteenth aspect enables dimming control according to brightness of surroundings, and additionally dimming control according to the first dimming signal (S1) inputted from an external device. Therefore, it is possible to increase types of dimming control and improve usability. While the foregoing has described what are considered to be the best mode and/or other examples, it is understood that various modifications may be made therein and that the subject matter disclosed herein may be implemented in various forms and examples, and that they may be applied in numerous applications, only some of which have been described herein. It is intended by the following claims to claim any and all modifications and variations that fall within the true scope of the present teachings. | <SOH> BACKGROUND ART <EOH>Document 1 (JP 2013-235776 A) discloses a lighting system including at least one lighting fixture, a dimmer for outputting a dimming signal, and a dimming signal conversion device for converting the dimming signal (duty signal) outputted from the dimmer into a phase control signal and outputting the phase control signal to the lighting fixture. The dimmer includes a dimmer body with a rectangular box shape to be attached to a wall surface. The dimmer body is provided at its front face with a rotary manual control knob for selecting a dimming level of the lighting fixture. The manual control knob is provided to the dimmer body and is rotatable within a range of manual control positions including a manual control position corresponding to a lower limit value of the dimming level and a manual control position corresponding to an upper limit value of the dimming level. The dimmer generates a rectangular wave signal (duty signal) with a duty cycle corresponding to a manual control position of the manual control knob, and outputs to a dimming signal line the dimming signal being the rectangular wave signal. Note that, in such lighting systems, there are demands to realize dimming control of changing the dimming level of the lighting fixture automatically depending on brightness of surroundings, in addition to dimming control responding to human manual control, for example. However, it is considered difficult to satisfy the above demands by configurations of the lighting system and the dimming signal conversion device (lighting control device) disclosed in document 1. | <SOH> SUMMARY <EOH>An object according to the present disclosure would be to propose a lighting control device, a lighting system, and a lighting control method which can increase types of dimming control and improve usability. A lighting control device according to one aspect of the present disclosure includes: an input circuit configured to receive from outside a first dimming signal having a duty cycle corresponding to a dimming level designating brightness of a lighting fixture; and an output circuit configured to output a second dimming signal to the lighting fixture. The lighting control device further includes: a detector configured to measure brightness of surroundings; and a controller configured to select one operation mode from two operation modes including a first mode and a second mode, and operate in a selected operation mode. The first dimming signal has a duty cycle falling within a range from a first duty cycle corresponding to an upper limit of the dimming level of the lighting fixture to a second duty cycle corresponding to a lower limit of the dimming level of the lighting fixture. The controller is configured to, while operating in the first mode, generate a second dimming signal corresponding to a measurement result of the detector. The controller is configured to, while operating in the second mode, generate a second dimming signal corresponding to the first dimming signal. The controller is configured to select the first mode and start operating in the first mode when the input circuit receives the first dimming signal having a third duty cycle not falling within the range while operating in the second mode. The controller is configured to select the second mode and start operating in the second mode when the input circuit receives the first dimming signal having a duty cycle falling within the range while operating in the first mode. A lighting system according to another aspect of the present disclosure includes: the lighting control device; and a manual control device configured to output the first dimming signal having a duty cycle corresponding to the dimming level to the input circuit of the lighting control device. The manual control device includes: a manual control interface for allowing manual control by hand; and a signal output circuit configured to output the first dimming signal having a duty cycle corresponding to manual control of the manual control interface. A lighting system according to another aspect of the present disclosure includes: the lighting control device; and at least one lighting fixture. The at least one lighting fixture is configured to, when receiving the second dimming signal outputted from the output circuit of the lighting control device, allow light output thereof to correspond to a dimming level indicated by the second dimming signal received. A lighting control method according to another aspect of the present disclosure includes: selecting one control method from two control methods including a first control method and a second control method; and performing a selected control method to achieve dimming control of at least one lighting fixture. The first control method is a control method of generating a second dimming signal corresponding to a measurement result of brightness of surroundings. The second control method is a control method of generating a second dimming signal corresponding to a first dimming signal having a duty cycle corresponding to a dimming level designating brightness of the at least one lighting fixture. The first control method is selected and performed when the first dimming signal having a third duty cycle not falling within a range from a first duty cycle corresponding to an upper limit of the dimming level to a second duty cycle corresponding to a lower limit of the dimming level is inputted while the second control method is performed. The second control method is selected and performed when the first dimming signal having a duty cycle falling within the range is inputted while the first control method is performed. | H05B330845 | 20171023 | 20180529 | 20180426 | 94315.0 | H05B3308 | 0 | A, MINH D | LIGHTING CONTROL DEVICE, LIGHTING SYSTEM, LIGHTING CONTROL METHOD | UNDISCOUNTED | 0 | ACCEPTED | H05B | 2,017 |
15,791,097 | PENDING | Crystalline Form Of Nicotinamide Riboside | Provided are crystalline forms of nicotinamide riboside, including a Form I of nicotinamide riboside chloride according to formula (I). Also disclosed are pharmaceutical compositions comprising the crystalline Form I of nicotinamide riboside chloride, and methods of producing such pharmaceutical compositions. In other aspects, the present disclosure pertains to methods comprising administering to a subject the crystalline Form I of nicotinamide riboside chloride. The present disclosure also provides methods of preparing the crystalline Form I of nicotinamide riboside chloride. Also provided are a crystalline Form I of nicotinamide riboside chloride that is prepared according to any of the disclosed methods for preparing the crystalline Form I. | 1. A crystalline Form I of nicotinamide riboside chloride according to formula I that is characterized by a powder X-ray diffraction pattern having peaks at 5.1, 15.7, and 21.7 degrees two theta±0.2 degrees two theta. 2.-4. (canceled) 5. The crystalline Form I according to claim 1 that is characterized by a powder X-ray diffraction pattern substantially as shown in FIG. 1. 6. The crystalline Form I according to claim 1 that is characterized by a powder X-ray diffraction pattern having peaks substantially as shown in Table 1±0.2 degrees two theta. 7. The crystalline Form I according to claim 1 that is characterized by an IR spectrum having peaks at 671.7, 1035.6, and 1061.8 cm−1±0.2 cm−1. 8. The crystalline Form I according to claim 1 that is characterized by an IR spectrum substantially as shown in FIG. 2. 9. The crystalline Form I according to claim 1 that is characterized by an IR spectrum having peaks substantially as shown in Table 2±0.2 cm−1. 10. The crystalline Form I according to claim 1 that is further characterized by a DSC thermogram substantially as shown in FIG. 4. 11. The crystalline Form I according to claim 1 that is further characterized by a DSC thermogram obtained using a heating rate of 10 K/min comprising an endothermic event with an onset temperature of 119° C.±2° C., an endothermic event with a peak temperature of 123° C.±2° C., or both. 12. The crystalline Form I according to claim 1 that is further characterized by a DSC thermogram obtained using a heating rate of 1 K/min comprising an endothermic event with an onset temperature of 104° C.±2° C., a peak temperature of 108° C.±2° C., or both. 13. The crystalline Form I according to claim 1 that is further characterized by a DSC thermogram obtained using a heating rate of 2 K/min comprising an endothermic event with an onset temperature of 109° C.±2° C., a peak temperature of 113° C.±2° C., or both. 14. The crystalline Form I according to claim 1 that is further characterized by a DSC thermogram obtained using a heating rate of 5 K/min comprising an endothermic event with an onset temperature of 114° C.±2° C., a peak temperature of 118° C.±2° C., or both. 15. The crystalline Form I according to claim 1 that is further characterized by a DSC thermogram obtained using a heating rate of 20 K/min comprising an endothermic event with an onset temperature of 122° C.±2° C., a peak temperature of 128° C.±2° C., or both. 16. The crystalline Form I according to claim 1 that is further characterized by a TGA/SDTA thermogram substantially as shown in FIG. 7A. 17. The crystalline Form I according to claim 1 that is further characterized by a TGA/SDTA thermogram comprising an endothermic event at 116° C.±2° C. and a mass loss of about 0.4%. 18. The crystalline Form I according to claim 1 that is further characterized by a DVS change in mass plot substantially as shown in FIG. 8A. 19. The crystalline Form I according to claim 1 that is further characterized by a DVS isotherm plot substantially as shown in FIG. 8B. 20. The crystalline Form I according to claim 1 that is further characterized by a water vapor sorption isotherm showing a water uptake of not more than about 0.5 wt % at a relative humidity of up to 60%. 21. The crystalline Form I according to claim 1 that is further characterized by a water vapor sorption isotherm showing a water uptake of not more than about 1.0 wt %, at a relative humidity of up to 70%. 22. The crystalline Form I according to claim 1 wherein said crystalline Form I is anhydrous. 23.-24. (canceled) 25. A method comprising administering to a subject the crystalline Form I according to claim 1. 26. The method according to claim 25 wherein said crystalline Form I is administered to said subject in a composition that further comprises a pharmaceutically acceptable excipient. 27.-32. (canceled) | CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. Ser. No. 15/328,664, filed Jan. 24, 2017, which is a National Stage Application filed under 35 U.S.C. 371 of International Application No. PCT/US2015/041956 filed Jul. 24, 2015, which claims the benefit of U.S. Provisional Patent Application No. 62/028,702, filed on Jul. 24, 2014, the entire contents of which are incorporated herein by reference. TECHNICAL FIELD The present disclosure relates to crystalline forms of nicotinamide riboside, and in particular, nicotinamide riboside chloride, as well as compositions containing the crystalline form and methods for using the crystalline form. BACKGROUND Crystalline forms of useful molecules can have advantageous properties relative to the amorphous form of such molecules. For example, crystal forms are often easier to handle and process, for example, when preparing compositions that include the crystal form. Crystalline forms typically have greater storage stability and are more amenable to purification. The use of a crystalline form of a pharmaceutically useful compound can also improve the performance characteristics of a pharmaceutical product that includes the compound. Obtaining the crystalline form also serves to enlarge the repertoire of materials that formulation scientists have available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life. Nicotinamide riboside (CAS Number 1341-23-7) is a precursor to nicotinamide adenine dinucleotide (NAD) and represents a source of vitamin B3. Recent studies have indicated that novel health benefits may result from ingesting nicotinamide riboside in larger quantities than is found naturally in foods. For example, nicotinamide riboside has been implicated in raising tissue NAD concentrations and in eliciting insulin sensitivity and enhancement of sirtuin functions. See Chi Y, et al., Curr Opin Clin Nutr Metab Care. 2013 November; 16(6):657-61. Its ability to increase NAD production indicates that nicotinamide riboside can also increase mitochondrial health, stimulate mitochondrial function, and induce creation of new mitochondria. Additional studies with nicotinamide riboside in models of Alzheimer's disease have suggested that the molecule is bioavailable to the brain and provides neuroprotective effects, likely by stimulation of brain NAD synthesis. Id. Furthermore, a 2012 study observed that mice on a high-fat diet that was supplemented with nicotinamide riboside gained 60% less weight than mice eating the same high-fat diet without nicotinamide riboside. Nicotinamide riboside chloride (3-carbamoyl-1-[(2R,3R,4S5R)-3,4-dihydroxy-5-(hydroxymethypoxolan-2-yl]-pyrin-1-ylium chloride; also referred to as 1-((3-D-Ribofuranosyl)nicotinamide chloride) is a known salt form of nicotinamide riboside and has the structure depicted below: Despite the useful attributes of nicotinamide riboside and its chloride salt, for example, for use in pharmaceuticals or nutritional supplements, and the benefits of providing such molecules in an ordered form, improvements are generally desired. SUMMARY The present disclosure pertains to crystalline forms of nicotinamide riboside, including a Form I of nicotinamide riboside chloride according to formula I Also disclosed are pharmaceutical compositions comprising the crystalline Form I of nicotinamide riboside chloride, and methods of producing such pharmaceutical compositions. In other aspects, the present disclosure pertains to methods comprising administering to a subject the crystalline Form I of nicotinamide riboside chloride. The present disclosure also provides methods of preparing the crystalline Form I of nicotinamide riboside chloride. Also provided are a crystalline Form I of nicotinamide riboside chloride that is prepared according to any of the disclosed methods for preparing the crystalline Form I. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 provides an X-ray powder diffraction pattern for crystalline nicotinamide riboside chloride. FIG. 2 shows a solid state IR spectrum of crystalline nicotinamide riboside chloride. FIG. 3A is a rendering of a Scanning Electron Microscopy (SEM) image of a first morphology of crystalline nicotinamide riboside chloride, and FIG. 3B is a rendering of an SEM image of a second morphology of crystalline nicotinamide riboside chloride. FIG. 4 provides DSC thermograms for crystalline Form I of nicotinamide riboside chloride as measured for each of the tested heating rates. FIG. 5 provides DSC thermogram for a sample of crystalline Form I of nicotinamide riboside chloride that was heated at a rate of 10 K/min. FIG. 6 provides the DSC thermogram for the amorphous form of nicotinamide riboside. FIG. 7A shows a TGA/SDTA thermogram for crystalline Form I of nicotinamide riboside chloride, and FIG. 7B shows a TGA/SDTA thermogram for the amorphous form of nicotinamide riboside. FIG. 8A provides a DVS change in mass plot for a sample of the crystalline Form I of nicotinamide riboside chloride, and FIG. 8B provides a DVS isotherm plot for a sample of the crystalline Form I of nicotinamide riboside chloride. FIG. 9A provides a DVS change in mass plot for a sample of the amorphous form of nicotinamide riboside chloride, and FIG. 9B provides a DVS isotherm plot for a sample of the amorphous form of nicotinamide riboside chloride. FIG. 10 provides a comparison of the sorption curve for crystalline Form I of nicotinamide riboside chloride with the sorption curve for an amorphous sample of nicotinamide riboside chloride. DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS The present invention may be understood more readily by reference to the following detailed description taken in connection with the accompanying figures and examples, which form a part this disclosure. It is to be understood that this invention is not limited to the specific products, methods, conditions or parameters described and/or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed invention. The entire disclosures of each patent, patent application, and publication cited or described in this document are hereby incorporated herein by reference. As employed above and throughout the disclosure, the following terms and abbreviations, unless otherwise indicated, shall be understood to have the following meanings. In the present disclosure the singular forms “a,” “an,” and “the” include the plural reference, and reference to a particular numerical value includes at least that particular value, unless the context clearly indicates otherwise. Thus, for example, a reference to “a solvent” is a reference to one or more of such solvents and equivalents thereof known to those skilled in the art, and so forth. Furthermore, when indicating that a certain element “may be” X, Y, or Z, it is not intended by such usage to exclude in all instances other choices for the element. When values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. As used herein, “about X” (where X is a numerical value) preferably refers to ±10% of the recited value, inclusive. For example, the phrase “about 8” refers to a value of 7.2 to 8.8, inclusive; as another example, the phrase “about 8%” refers to a value of 7.2% to 8.8%, inclusive. Where present, all ranges are inclusive and combinable. For example, when a range of “1 to 5” is recited, the recited range should be construed as including ranges “1 to 4”, “1 to 3”, “1-2”, “1-2 & 4-5”, “1-3 & 5”, and the like. In addition, when a list of alternatives is positively provided, such a listing can also include embodiments where any of the alternatives may be excluded. For example, when a range of “1 to 5” is described, such a description can support situations whereby any of 1, 2, 3, 4, or 5 are excluded; thus, a recitation of “1 to 5” may support “1 and 3-5, but not 2”, or simply “wherein 2 is not included.” As used herein, the terms “treatment” or “therapy” (as well as different word forms thereof) includes preventative (e.g., prophylactic), curative, or palliative treatment. Such preventative, curative, or palliative treatment may be full or partial. For example, complete elimination of unwanted symptoms, or partial elimination of one or more unwanted symptoms would represent “treatment” as contemplated herein. As employed above and throughout the disclosure the term “effective amount” refers to an amount effective, at dosages, and for periods of time necessary, to achieve the desired result with respect to the treatment of the relevant disorder, condition, or side effect. It will be appreciated that the effective amount of components of the present invention will vary from patient to patient not only with the particular compound, component or composition selected, the route of administration, and the ability of the components to elicit a desired response in the individual, but also with factors such as the disease state or severity of the condition to be alleviated, hormone levels, age, sex, weight of the individual, the state of being of the patient, and the severity of the condition being treated, concurrent medication or special diets then being followed by the particular patient, and other factors which those skilled in the art will recognize, with the appropriate dosage ultimately being at the discretion of the attendant physician. Dosage regimens may be adjusted to provide the improved therapeutic response. An effective amount is also one in which any toxic or detrimental effects of the components are outweighed by the therapeutically beneficial effects. As an example, the compounds useful in the methods of the present invention are administered at a dosage and for a time such that the level of activation and adhesion activity of platelets is reduced as compared to the level of activity before the start of treatment. “Pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem complications commensurate with a reasonable benefit/risk ratio. Provided herein are crystalline forms of nicotinamide riboside chloride. Although nicotinamide riboside and its chloride salt are well known among those of ordinary skill in the art in their amorphous forms and have numerous uses deriving, for example, from the ability of such molecules to increase NAD production, the present disclosure is directed to these molecules in a crystalline form. Crystalline forms of nicotinamide riboside have advantageous properties, including chemical purity, flowability, solubility, morphology or crystal habit, and stability (such as storage stability, stability to dehydration, stability to polymorphic conversion, low hygroscopicity, and low content of residual solvents). A crystal form may be referred to herein as being characterized by graphical data substantially “as depicted in” a Figure. Such data include, for example, powder X-ray diffractograms and solid state IR spectra. The skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to factors such as variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirm whether the two sets of graphical data are characterizing the same crystal form or two different crystal forms. The present disclosure pertains to crystalline forms of nicotinamide riboside, including a Form I of nicotinamide riboside chloride according to formula I The crystalline Form I may be characterized by a powder X-ray diffraction pattern having peaks at 5.1, 15.7, and 21.7 degrees two theta±0.2 degrees two theta. The crystalline Form I may also or alternatively be characterized by a powder X-ray diffraction pattern having peaks at 5.1, 15.7, 21.7, 23.5, and 26.4 degrees two theta±0.2 degrees two theta. The crystalline Form I may also or alternatively be characterized by a powder X-ray diffraction pattern having peaks at 5.1, 15.7, 18.6, 21.7, 23.5, 26.4, and 28.0 degrees two theta±0.2 degrees two theta. In other embodiments, the crystalline Form I may be characterized by a powder X-ray diffraction pattern substantially as shown in FIG. 1. The crystalline Form I may also or alternatively be characterized by a powder X-ray diffraction pattern having peaks substantially as provided in Table 1, below, ±0.2 degrees two theta. TABLE 1 No. Pos. [° 2Th.] d-spacing [Å] Height [cts] I/Imax 1 5.0847 17.36541 29562 87% 2 10.09 8.75955 158 0% 3 12.194 7.25232 4234 12% 4 14.141 6.25817 2433 7% 5 15.662 5.65364 19978 59% 6 17.4 5.09227 576 2% 7 18.573 4.77348 9176 27% 8 19.415 4.56839 2563 8% 9 20.35 4.36098 831 2% 10 21.685 4.09491 33878 100% 11 21.919 4.05175 4369 13% 12 22.148 4.01031 5971 18% 13 22.842 3.89009 4521 13% 14 23.519 3.77954 10585 31% 15 23.825 3.73181 8674 26% 16 24.103 3.68936 4752 14% 17 24.47 3.63519 434 1% 18 25.05 3.55221 5408 16% 19 25.149 3.53825 107 0% 20 25.244 3.52517 8758 26% 21 25.438 3.4987 4768 14% 22 25.836 3.44564 2741 8% 23 26.035 3.41975 2662 8% 24 26.43 3.36953 18356 54% 25 28.016 3.1823 9628 28% 26 28.164 3.16597 3910 12% 27 29.13 3.06327 552 2% 28 29.7 3.00557 799 2% 29 30.02 2.97428 2725 8% 30 30.628 2.91661 3400 10% 31 30.996 2.88284 2421 7% 32 31.576 2.8312 2259 7% 33 32.658 2.73983 850 3% 34 32.95 2.71631 431 1% 35 33.295 2.6888 1887 6% 36 33.8 2.64976 2964 9% 37 35.06 2.55763 1199 4% 38 35.426 2.53179 3426 10% 39 35.586 2.5208 4384 13% 40 35.92 2.49794 500 1% 41 36.534 2.45752 2679 8% 42 37.074 2.42298 1143 3% 43 37.616 2.3893 536 2% 44 38.13 2.35799 1057 3% 45 38.56 2.33306 1731 5% 46 39.218 2.29527 980 3% 47 39.729 2.26696 1467 4% 48 40.624 2.21904 2257 7% 49 41.32 2.18334 890 3% 50 42.2 2.13986 1389 4% 51 42.76 2.11298 1812 5% 52 43.79 2.06588 681 2% 53 44.58 2.03105 1628 5% 54 44.68 2.02661 1483 4% 55 45.083 2.00939 363 1% 56 45.857 1.97724 2012 6% 57 46.63 1.9463 858 3% 58 46.95 1.93366 455 1% 59 47.67 1.90628 518 2% 60 48.08 1.89074 630 2% 61 49.69 1.83344 442 1% 62 49.96 1.82422 354 1% 63 50.3 1.81235 222 1% The crystalline Form I of nicotinamide riboside chloride may also or alternatively be characterized by a solid-state IR spectrum having peaks at 671.7, 1035.6, and, 1061.8 cm−1±0.2 cm−1. The crystalline Form I of nicotinamide riboside chloride may also or alternatively be characterized by a solid-state IR spectrum having peaks at 671.7, 1035.6, 1061.8, 1398.9, and 1649.3 cm−1±0.2 cm−1. In certain embodiments, the crystalline Form I of nicotinamide riboside chloride may be characterized by a solid-state IR spectrum substantially as shown in FIG. 2. In further embodiments, the crystalline Form I of nicotinamide riboside chloride may be characterized by a solid-state IR spectrum having peaks substantially as provided in Table 2, below, ±0.2 cm−1. TABLE 2 IR (cm−1) 3307.91 3236.09 3150.27 2967.14 1702.35 1667.56 1649.34 1611.33 1582.94 1468.53 1436.77 1398.92 1324.43 1291.92 1263.29 1215.24 1179.00 1148.84 1135.31 1110.95 1101.18 1061.82 1035.62 986.71 926.55 899.63 852.33 830.75 779.75 760.46 734.93 705.48 671.72 3307.91 3236.09 3150.27 2967.14 1702.35 1667.56 1649.34 1611.33 1582.94 1468.53 1436.77 1398.92 1324.43 1291.92 1263.29 1215.24 1179.00 1148.84 1135.31 1110.95 1101.18 1061.82 1035.62 986.71 926.55 899.63 852.33 830.75 779.75 760.46 734.93 705.48 671.72 Another embodiment relates to a crystalline Form I of nicotinamide riboside chloride that has a DSC thermogram substantially as shown in FIG. 4. In another embodiment, crystalline Form I of nicotinamide riboside chloride is characterized by a DSC thermogram obtained using a heating rate of 10 K/min comprising an endothermic event with an onset temperature of 119° C.±2° C. In certain instances, the crystalline Form I of nicotinamide riboside chloride is characterized by a DSC thermogram obtained using a heating rate of 10 K/min comprising an endothermic event with an onset temperature of 118.8° C.±2° C. In other embodiments, crystalline Form I of nicotinamide riboside chloride is characterized by a DSC thermogram obtained using a heating rate of 1 K/min comprising an endothermic event with an onset temperature of 104° C.±2° C., a peak temperature of 108° C.±2° C., or both. In other embodiments, crystalline Form I of nicotinamide riboside chloride is characterized by a DSC thermogram obtained using a heating rate of 2 K/min comprising an endothermic event with an onset temperature of 109° C.±2° C., a peak temperature of 113° C.±2° C., or both. In other embodiments, crystalline Form I of nicotinamide riboside chloride is characterized by a DSC thermogram obtained using a heating rate of 5 K/min comprising an endothermic event with an onset temperature of 114° C.±2° C., a peak temperature of 118° C.±2° C., or both. In still another embodiment, the crystalline Form I of nicotinamide riboside chloride is characterized by a DSC thermogram obtained using a heating rate of 10 K/min comprising an endothermic event with a peak temperature of 123° C.±2° C. In a further embodiment, the crystalline Form I of nicotinamide riboside chloride is characterized by a DSC thermogram obtained using a heating rate of 10 K/min comprising an onset temperature of 119° C.±2° C., an endothermic event with a peak temperature of 123° C.±2° C., or both. In other embodiments, crystalline Form I of nicotinamide riboside chloride is characterized by a DSC thermogram obtained using a heating rate of 20 K/min comprising an endothermic event with an onset temperature of 122° C.±2° C., a peak temperature of 128° C.±2° C., or both. It is well known that the DSC onset and peak temperatures as well as energy values may vary due to, for example, the purity of the sample and sample size and due to instrumental parameters, especially the temperature scan rate. Hence the DSC data presented are not to be taken as absolute values. A person skilled in the art can set up instrumental parameters for a Differential scanning calorimeter so that data comparable to the data presented here can be collected according to standard methods, for example those described in Milne, G. W. H. et al (1996), Differential Scanning calorimetry, Springer, Berlin. One embodiment of the present invention pertains to a crystalline Form I of nicotinamide riboside chloride that has a TGA/SDTA thermogram substantially as shown in FIG. 7A. The present disclosure also provides a crystalline Form I of nicotinamide riboside chloride that is characterized by a TGA/SDTA thermogram comprising an endothermic event at 116° C.±2° C. and a mass loss of about 0.4%. The present disclosure also provides a crystalline Form I of nicotinamide riboside chloride that is characterized by a TGA/SDTA thermogram comprising an endothermic event at 116.3° C.±2° C. and a mass loss of 0.36%. Also disclosed are a crystalline Form I of nicotinamide riboside chloride that is characterized by a DVS change in mass plot substantially as shown in FIG. 8A. In another embodiment, the crystalline Form I of nicotinamide riboside chloride that is characterized by a DVS isotherm plot substantially as shown in FIG. 8B. In another aspect, the present disclosure provides a crystalline Form I of nicotinamide riboside chloride that is characterized by a water vapor sorption isotherm showing a water uptake of not more than about 0.5 wt % at a relative humidity of up to 60%. In another embodiment, the crystalline Form I of nicotinamide riboside chloride is characterized by a water vapor sorption isotherm showing a water uptake of not more than about 0.5 wt %, preferably not more than about 1.0 wt %, at a relative humidity of up to 70%. The instant crystalline Form I of nicotinamide riboside chloride may be provided in one of several different morphologies. For example, the crystalline material may exist in a morphology having a bulk density of about 0.25 to about 0.4 g/mL, or may exist in a morphology having a bulk density of about 0.40 to about 0.65 g/mL. The present disclosure also relates to mixtures of at least these two morphologies in any proportion. FIG. 3A depicts a Scanning Electron Microscopy (SEM) image of the inventive crystalline nicotinamide riboside chloride in a morphology having a bulk density of about 0.25 to about 0.4 g/mL, and FIG. 3B depicts a Scanning Electron Microscopy (SEM) image of the inventive crystalline nicotinamide riboside chloride in a morphology having a bulk density of about 0.40 to about 0.65 g/mL. The present inventors have discovered that the morphology of crystalline nicotinamide chloride having a bulk density of about 0.25 to about 0.4 g/mL is more stable to degradation via oxygen or water absorption. This morphology also appears to provide the product with a slightly higher purity as well. Because of the purity, stability, and color variations in the other morphology (the morphology having a bulk density of about 0.40 to about 0.65 g/mL), in at least some instances a preference exists for the crystalline nicotinamide chloride having a bulk density of about 0.25 to about 0.4 g/mL as it appears to produce higher quality product with more consistency. In some embodiments, the crystalline Form I of nicotinamide riboside chloride is at least partially hydrated, and in other embodiments, the crystalline Form I of nicotinamide riboside chloride is anhydrous. The present disclosure also pertains to pharmaceutical compositions comprising the crystalline Form I of nicotinamide riboside chloride. The pharmaceutical composition may comprise the crystalline Form I of nicotinamide riboside chloride in any of the embodiments described above, and a pharmaceutically acceptable excipient. The pharmaceutical composition should include a therapeutically effective amount of the crystalline Form I of nicotinamide riboside chloride. As used herein, the phrase “therapeutically effective amount” refers to the amount of active compound that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) preventing the disease or condition; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease; (2) inhibiting the disease or condition; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., including arresting further development of the pathology and/or symptomatology); and (3) ameliorating the disease or condition; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., including reversing the pathology and/or symptomatology). The present compositions may be formulated for any type of administration. For example, the compositions may be formulated for administration orally, topically, parenterally, enterally, or by inhalation. The crystalline Form I may be formulated for neat administration, or in combination with conventional pharmaceutical carriers, diluents, or excipients, which may be liquid or solid. The applicable solid carrier, diluent, or excipient may function as, among other things, a binder, disintegrant, filler, lubricant, glidant, compression aid, processing aid, color, sweetener, preservative, suspensing/dispersing agent, tablet-disintegrating agent, encapsulating material, film former or coating, flavoring agent, or printing ink. Any material used in preparing any dosage unit form is preferably pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the crystalline Form I may be incorporated into sustained-release preparations and formulations. Administration in this respect includes administration by, inter alia, the following routes: intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, transepithelial including transdermal, ophthalmic, sublingual and buccal; topically including ophthalmic, dermal, ocular, rectal and nasal inhalation via insufflation, aerosol, and rectal systemic. In powders, the carrier, diluent, or excipient may be a finely divided solid that is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier, diluent or excipient having the necessary compression properties in suitable proportions and compacted in the shape and size desired. For oral therapeutic administration, the active compound may be incorporated with the carrier, diluent, or excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. The amount of active compound(s) in such therapeutically useful compositions is preferably such that a suitable dosage will be obtained. Liquid carriers, diluents, or excipients may be used in preparing solutions, suspensions, emulsions, syrups, elixirs, and the like. The active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid such as water, an organic solvent, a mixture of both, or pharmaceutically acceptable oils or fat. The liquid carrier, excipient, or diluent can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, or osmo-regulators. Suitable solid carriers, diluents, and excipients may include, for example, calcium phosphate, silicon dioxide, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, ethylcellulose, sodium carboxymethyl cellulose, microcrystalline cellulose, polyvinylpyrrolidine, low melting waxes, ion exchange resins, croscarmellose carbon, acacia, pregelatinized starch, crospovidone, HPMC, povidone, titanium dioxide, polycrystalline cellulose, aluminum methahydroxide, agar-agar, tragacanth, or mixtures thereof. Suitable examples of liquid carriers, diluents and excipients, for example, for oral, topical, or parenteral administration, include water (particularly containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil), or mixtures thereof. For parenteral administration, the carrier, diluent, or excipient can also be an oily ester such as ethyl oleate and isopropyl myristate. Also contemplated are sterile liquid carriers, diluents, or excipients, which are used in sterile liquid form compositions for parenteral administration. Solutions of the active compounds as free bases or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. A dispersion can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms. The pharmaceutical forms suitable for injectable use include, for example, sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form is preferably sterile and fluid to provide easy syringability. It is preferably stable under the conditions of manufacture and storage and is preferably preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier, diluent, or excipient may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of a dispersion, and by the use of surfactants. The prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions may be achieved by the use of agents delaying absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions may be prepared by incorporating the crystalline Form I of nicotinamide riboside chloride in the pharmaceutically appropriate amounts, in the appropriate solvent, with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions may be prepared by incorporating the sterilized active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation may include vacuum drying and freeze drying techniques that yield a powder of the active ingredient or ingredients, plus any additional desired ingredient from the previously sterile-filtered solution thereof. Thus, the crystalline Form I of nicotinamide riboside chloride may be administered in an effective amount by any of the conventional techniques well-established in the medical field. For example, the administration may be in the amount of about 50 mg/day to about 50,000 mg per day. In some embodiments, the administration may be in the amount of about 250 mg/kg/day. Thus, administration may be in the amount of about 50 mg/day, about 100 mg/day, about 200 mg/day, about 250 mg/day, about 300 mg/day, about 500 mg/day, about 700 mg/day, about 800 mg/day, about 1000 mg/day, about 2000 mg/day, about 4000 mg/day, about 5000 mg/day, about 10,000 mg/day, about 20,000 mg/day, about 30,000 mg/day, about 40,000 mg/day, or about 50,000 mg/day. Also disclosed are methods of producing such pharmaceutical compositions comprising combining any of the previously disclosed embodiments of the crystalline Form I of nicotinamide riboside chloride with a pharmaceutically acceptable excipient. Any acceptable method of combining an active agent with a pharmaceutically acceptable excipient may be used in accordance with the present methods, and those of ordinary skill in the art can readily appreciate appropriate techniques of combination. In some embodiments, the step of combination may be as simple as adding a desired quantity of the crystalline Form I of nicotinamide riboside chloride to an existing substance, such as a liquid beverage or a powdered beverage mixture. In other embodiments, the step of combination includes any technique that is conventionally used to mix active agents with excipients pursuant to preparing a pharmaceutical dosage form (for example, solid, semi-solid, liquid, or in a form suitable for inhalation), a cosmetic item (such as a powder, cream, lotion, or emollient), or a food item (for example, solid, semi-solid, or liquid). In other aspects, the present disclosure pertains to methods comprising administering to a subject the crystalline Form I of nicotinamide riboside chloride. The administration of the crystalline Form I of nicotinamide riboside chloride may be by any of the routes described above in connection with the present pharmaceutical compositions. For example, the crystalline Form I of nicotinamide riboside chloride may be administered orally, topically, parenterally, enterally, or by inhalation. In view of the exceptional stability of the presently disclosed crystalline Form I of nicotinamide riboside chloride, the active agent may be used or otherwise prepared for any known route of administration, and any known route of administration may be used pursuant to the present methods. The crystalline Form I of nicotinamide riboside chloride may be administered in combination with a pharmaceutically acceptable excipient. A subject or patient in whom administration of the therapeutic compound is an effective therapeutic regimen for a disease or disorder is preferably a human, but can be any animal, including a laboratory animal in the context of a clinical trial or screening or activity experiment. Thus, as can be readily appreciated by one of ordinary skill in the art, the methods, compounds and compositions of the present invention are particularly suited to administration to any animal, particularly a mammal, and including, but by no means limited to, humans, domestic animals, such as feline or canine subjects, farm animals, such as but not limited to bovine, equine, caprine, ovine, and porcine subjects, wild animals (whether in the wild or in a zoological garden), research animals, such as mice, rats, rabbits, goats, sheep, pigs, dogs, cats, and the like, avian species, such as chickens, turkeys, songbirds, and the like, i.e., for veterinary medical use. The present disclosure also provides methods of preparing the crystalline Form I of nicotinamide riboside chloride. The methods may include the steps of forming a solution comprising nicotinamide riboside chloride and a polar solvent with hydrogen bonding, and cooling the combination. In some embodiments, the polar solvent with hydrogen bonding may be a polar alcohol. Exemplary polar alcohols include methanol, 1-butanol, 2-butanol, t-butyl alcohol, diethylene glycol, ethanol, ethylene glycol, glycerin, 1-propanol, 2-propanol. The polar solvent with hydrogen bonding may have high water solubility. For example, the polar solvent with hydrogen bonding may be acetone, acetonitrile, diglyme (diethylene glycol dimethyl ether), 1,2-dimethoxy-ethane (DME), dimethyl-formamide (DMF), dimethyl sulfoxide (DMSO), dioxane, hexamethylphosphoramide (HMPA), hexamethylphosphorous triamide (HMPT), N-methyl-2-pyrrolidinone (NMP), or pyridine. The polar solvent with hydrogen bonding may be combined with water. The solution may otherwise comprise a source of water. In some embodiments, the formation of the solution comprises combining crude nicotinamide riboside chloride with the polar solvent with hydrogen bonding. In other embodiments, the solution is formed by making nicotinamide riboside chloride in situ in the presence of the polar solvent with hydrogen bonding. Following the formation of the solution comprising nicotinamide riboside chloride and the polar solvent with hydrogen bonding, the cooling of the mixture may be at a temperature of about 15° C., about 10° C., about 0° C., about −10° C., about −15° C., about −20° C., or about −25° C. The cooling of the mixture may be for about 12 hours, about 18 hours, about 20 hours, about 24 hours, about 30 hours, about 36 hours, or about 40 hours. Following the cooling step, the method may further comprise adding an anti-solvent to the cooled composition, which will now include some crystallized product. As used herein, an “anti-solvent” is any material that assists with pushing the crystalline product out of solution. An exemplary anti-solvent is methyl tert-butyl ether (MTBE). Following the addition of the anti-solvent to the cooled composition, the reaction mixture may be cooled for an additional period of time. The additional cooling period may be for about 4 hours, about 6 hours, about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, or about 24 hours, and the cooling temperature may be about 15° C., about 10° C., about 0° C., about −10° C., about −15° C., about −20° C., or about −25° C. Following the additional cooling period, the solids that result from the preceding steps may be filtered and/or rinsed, for example, with an anti-solvent, such as MTBE. Also disclosed is crystalline Form I of nicotinamide riboside chloride that is prepared according to the above-described process. The crystalline Form I of nicotinamide riboside chloride may be prepared according to any embodiment of the process for forming the crystalline form that is disclosed herein. The present invention is further defined in the following Examples. It should be understood that these examples, while indicating preferred embodiments of the invention, are given by way of illustration only, and should not be construed as limiting the appended claims. From the above discussion and these examples, one skilled in the art can ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Examples Synthesis of Crude Nicotinamide Riboside Chloride Numerous routes for the synthesis of crude nicotinamide riboside and its chloride salt have been published. Any known route, or any other acceptable route may be used in order to prepare the non-crystalline form of the relevant compound. Exemplary routes for the synthesis of nicotinamide riboside or its chloride salt are disclosed in the following publications: Jarman, et al., J. Chem. Soc. (1969), (2), 199-203 (chloride salt); Yang, et al. J. Med. Chem. 2007, 50, 6458-6461; U.S. Pub. No. 2007/0117765; Franchetti, et al., Bioorg Med Chem Lett. 2004 Sep. 20; 14(18):4655-8; Saunders P P, et al., Cancer Res. 1989 Dec. 1; 49(23):6593-9; Dowden J, et al., Nucleosides Nucleotides Nucleic Acids. 2005; 24(5-7):513-8; Schlenk, F., Archives of Biochemistry (1943), 3, 93-103; Freyne, et al., Carbohydr. Res., 78:235-242 (1980); Tanimori, et al., Bioorg. Med. Chem. Lett., 12:1135-1137 (2002); WO 2010/017374; Davies L C, Nucleosides & Nucleotides 14(3-5), 311-312 1995; Kam B L, et al., Carbohydrate Research, 77 (1979) 275-280; Viscontini M, et al., Volumen XXXIX, Fasciculus VI (1956)—No. 195, 1620-1631. The entire disclosures of each of the references listed above are incorporated herein by reference. Nicotinamide riboside may be initially synthesized with a different anion than Cl−, for example, triflate or trifluoromethanesulfonate. Following synthesis of this alternative form of nicotinamide riboside, the initial ion may be “exchanged” out, with a chloride anion, or other anion with a higher affinity, taking its place, by means of ion-exchange chromatography. Those of ordinary skill in the art can readily appreciate how to perform ion-exchange chromatography. Alternatively, amorphous nicotinamide riboside chloride may be acquired from commercial sources. Preparation of Crystalline Nicotinamide Riboside Chloride A solution was formed comprising methanol and nicotinamide riboside chloride. Following formation of the solution, the solution was cooled to −10° C. and maintained at that temperature. Over the course of the next 12-24 hours the product began to crystallize. The rate at which the crystallization occurs can be increased by seeding the solution, for example, using known techniques. Following this period, the mixture was confirmed to be a slurry, and 3 parts (this volume may be varied, for example, from 1-5 parts, depending on the amount of methanol) methyl t-butyl ether was added slowly over 6-12 hours. The MTBE functioned as an anti-solvent in order to push the majority of product out of solution. The reaction mixture was then held at −10° C. for an additional 12 hours. The solids were then filtered and rinsed with MTBE. The preceding reaction/cooling times were based on plant production of hundreds of kilograms. Many of the times may be reduced when performing the reaction on a smaller scale, without a dramatic effect on the morphology and physical form. Preparation of Amorphous Nicotinamide Riboside Chloride Experiments were performed to identify an appropriate method for preparing substantially pure samples of amorphous nicotinamide riboside chloride for use in comparison studies against crystalline Form I of that compound. In Table 3, below, QSA1, QSA2, and QSA3 were conducted to identify a solvent system for producing the amorphous sample. TABLE 3 Experiment Solvent XRPD QSA1 Water Amorphous QSA2 Dioxane/water (2:1) Amorphous QSA3 Ethanol/water (2:1) Oil QSA4 Water Amorphous QSA5 Dioxane/water (2:1) Amorphous SAS11 Dioxane/water (2:1) Amorphous Pursuant to QSA1-QSA3, the compound (nicotinamide riboside chloride) was dissolved in the selected solvent system (see Table 3). The vial was exposed to liquid nitrogen and the frozen solution was then freeze dried under vacuum. The ethanol/water solvent system yielded an oil, and this sample was not used further. QSA4, QSA5 and SAS11 represent scaled up freeze drying experiments. The amorphous material of NR-Cl obtained pursuant to QSA5 and SAS11 (dioxane/water solvent system) what somewhat easier to handle (less sticky) than the amorphous material from water (QSA4). Accordingly, all experiments involving amorphous material were performed using the sample resulting from QSA5. However, SEM images were obtained using the sample obtained using the conditions described for SAS11. Instrumentation X-Ray Powder Diffraction. The X-ray powder diffraction information concerning the crystalline nicotinamide riboside chloride was obtained using PANalytical X-PertPRO Multi-Purpose Diffractometer, model # PY3040. No special sample preparation was required. SEM. Scanning Electron Microscopy images were obtained using Hitachi FE-SEM model #S-4500. No special sample preparation was required. Infrared Spectroscopy. Fourier Transform Infrared Spectroscopy (FTIR) spectra were obtained using a Spectrum One™ FTIR instrument with universal Attenuated Total Reflection (Perkin-Elmer, Inc., Waltham, Mass.). Differential Scanning calorimetry (DSC) DSC analysis was conducted on both crystalline Form I of nicotinamide riboside chloride and also amorphous nicotinamide riboside chloride, using a Model DSC822e Differential Scanning calorimeter (Mettler-Toledo GmbH, Switzerland). Various heating rates were used pursuant to the measurement of melting points of the crystalline Form I of nicotinamide riboside chloride, the results of which are shown in Table 4, below: TABLE 4 Heating Rate Endothermic Peak (° C.) 1K/min 108.01 2K/mmn 112.53 5K/mmn 118.43 10K/min 123.25 20K/min 127.82 FIG. 4 provides the DSC thermograms for crystalline Form I of nicotinamide riboside chloride as measured for each of the tested heating rates. FIG. 5 provides the DSC thermagram for the sample of crystalline Form I of nicotinamide riboside chloride that was heated at a rate of 10 K/min. FIG. 6 provides the DSC thermogram for the amorphous sample. As expected, DSC analysis of the amorphous form of nicotinamide riboside chloride yielded no melting point. Thermal Gravametric Mass Spectral Analysis Mass loss due to solvent or water loss from the crystalline Form I of nicotinamide riboside chloride and from the amorphous form was determined by TGA/SDTA. Monitoring the sample weight, during heating in a Thermogravimetric Analysis/Simultaneous Differential Thermal Analysis (TGA/SDTA) instrument, Model 851e (Mettler-Toledo GmbH, Switzerland), resulted in respective mass vs. temperature curves. The TGA/SDTA851e was calibrated for temperature with indium and aluminum. Samples were weighed into 100 μl aluminum crucibles and sealed. The seals were pin-holed and the crucibles heated in the TGA from 25 to 300° C. at a heating rate of 10° C. min−1. Dry N2 gas was used for purging. The gases evolved from the TGA samples were analyzed by a mass spectrometer Omnistar GSD 301 T2 (Pfeiffer Vacuum GmbH, Germany). The latter is a quadrupole mass spectrometer, which analyses masses in the range of 0-200 amu. The TGA/SDTA thermagrams for crystalline Form I of nicotinamide riboside chloride and for the amorphous form of nicotinamide riboside chloride are shown in FIGS. 7A and 7B, respectively. In FIG. 7A, the SDTA measurement for the crystalline Form I shows an endothermic event at 116.3° C., and the TGA measurement shows a mass loss of 0.36%. These results permit the conclusion that the compound is not solvated and contains a minor amount of residual solvent. In FIG. 7B, the SDTA measurement for the amorphous sample shows an exothermic event at 118.6° C., and the TGA measurement shows a mass loss of 1.59%. These results permit the conclusion that the compound is not solvated and contains some residual solvent. Hygroscopicity/Dynamic Vapor Sorbtion (DVS) Moisture sorption isotherms were collected on a DVS-1 system from Surface Measurement Systems UK Ltd. (London, UK) for both crystalline Form I of nicotinamide riboside chloride and for the amorphous form of nicotinamide riboside chloride. Sample sizes were between 9.7 and 14.3 mg of solid material. The relative humidity was started with an initial drying step going from 40% RH to 0% RH. Subsequently, the relative humidity was increased to 95% (sorption), decreased to 0% RH (desorption) and increased again to 95% RH (sorption). Weight equilibration was set per step with a holding time of 1 hour (10% relative humidity step). Individual samples sizes were 12.6568 mg for crystalline Form I and 9.6799 mg for the amorphous sample. FIG. 8A provides a DVS change in mass plot for a sample of the crystalline Form I of nicotinamide riboside chloride, and FIG. 8B provides a DVS isotherm plot for a sample of the crystalline Form I of nicotinamide riboside chloride. FIG. 9A provides a DVS change in mass plot for a sample of the amorphous form of nicotinamide riboside chloride, and FIG. 9B provides a DVS isotherm plot for a sample of the amorphous form of nicotinamide riboside chloride. FIG. 10 provides a comparison of the sorption curve for crystalline Form I of nicotinamide riboside chloride with the sorption curve for the amorphous sample. The comparison reveals that although both forms absorbed water, there was a clear difference at the rate of absorbtion from 0% to 60% relative humidity—the crystalline Form I was much less prone to absorption at lower relative humidities than the amorphous material. Even at 70% relative humidity, the weight of the crystalline sample had not increased by more than about 1.0%. These characteristics of the crystalline Form I are advantageous for the handling of the material overall and represent the ability to remain stable over a greater range of working conditions relative to the amorphous form. | <SOH> BACKGROUND <EOH>Crystalline forms of useful molecules can have advantageous properties relative to the amorphous form of such molecules. For example, crystal forms are often easier to handle and process, for example, when preparing compositions that include the crystal form. Crystalline forms typically have greater storage stability and are more amenable to purification. The use of a crystalline form of a pharmaceutically useful compound can also improve the performance characteristics of a pharmaceutical product that includes the compound. Obtaining the crystalline form also serves to enlarge the repertoire of materials that formulation scientists have available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life. Nicotinamide riboside (CAS Number 1341-23-7) is a precursor to nicotinamide adenine dinucleotide (NAD) and represents a source of vitamin B3. Recent studies have indicated that novel health benefits may result from ingesting nicotinamide riboside in larger quantities than is found naturally in foods. For example, nicotinamide riboside has been implicated in raising tissue NAD concentrations and in eliciting insulin sensitivity and enhancement of sirtuin functions. See Chi Y, et al., Curr Opin Clin Nutr Metab Care. 2013 November; 16(6):657-61. Its ability to increase NAD production indicates that nicotinamide riboside can also increase mitochondrial health, stimulate mitochondrial function, and induce creation of new mitochondria. Additional studies with nicotinamide riboside in models of Alzheimer's disease have suggested that the molecule is bioavailable to the brain and provides neuroprotective effects, likely by stimulation of brain NAD synthesis. Id. Furthermore, a 2012 study observed that mice on a high-fat diet that was supplemented with nicotinamide riboside gained 60% less weight than mice eating the same high-fat diet without nicotinamide riboside. Nicotinamide riboside chloride (3-carbamoyl-1-[(2R,3R,4S5R)-3,4-dihydroxy-5-(hydroxymethypoxolan-2-yl]-pyrin-1-ylium chloride; also referred to as 1-((3-D-Ribofuranosyl)nicotinamide chloride) is a known salt form of nicotinamide riboside and has the structure depicted below: Despite the useful attributes of nicotinamide riboside and its chloride salt, for example, for use in pharmaceuticals or nutritional supplements, and the benefits of providing such molecules in an ordered form, improvements are generally desired. | <SOH> SUMMARY <EOH>The present disclosure pertains to crystalline forms of nicotinamide riboside, including a Form I of nicotinamide riboside chloride according to formula I Also disclosed are pharmaceutical compositions comprising the crystalline Form I of nicotinamide riboside chloride, and methods of producing such pharmaceutical compositions. In other aspects, the present disclosure pertains to methods comprising administering to a subject the crystalline Form I of nicotinamide riboside chloride. The present disclosure also provides methods of preparing the crystalline Form I of nicotinamide riboside chloride. Also provided are a crystalline Form I of nicotinamide riboside chloride that is prepared according to any of the disclosed methods for preparing the crystalline Form I. | C07H19048 | 20171023 | 20180329 | 96712.0 | C07H19048 | 1 | BERRY, LAYLA D | Crystalline Form Of Nicotinamide Riboside | UNDISCOUNTED | 1 | CONT-ACCEPTED | C07H | 2,017 |
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15,793,031 | PENDING | MERCHANDISE SECURITY SYSTEM INCLUDING RETRACTABLE ALARMING POWER CORD | A merchandise security system for an electronic item of merchandise is provided. In one example, the merchandise security system includes a continuous alarming power cord comprising at least one electrical conductor. The alarming power cord has a first end adapted to be electrically connected to the electronic item of merchandise and a second end. The merchandise security system also includes a reel for receiving the second end of the alarming power cord and adapted for storing at least a portion of the alarming power cord thereon. In addition, the merchandise security system includes monitoring circuitry in electrical communication with the alarming power cord and configured to detect an interruption in an electrical signal provided to the alarming power cord. | 1. A merchandise security system for an electronic item of merchandise comprising: a reel configured to store at least a portion of a cord thereon, the reel comprising at least one electrical coupling on an outer surface thereof; and a housing defining an interior for receiving the reel therein, the reel configured to be removably inserted within the housing, the housing comprising at least one electrical coupling configured to engage with and electrically connect to the at least one electrical coupling of the reel when the reel is received within the housing. 2. The merchandise security system of claim 1, further comprising a cord configured to be coupled to the electronic item of merchandise. 3. The merchandise security system of claim 2, further comprising a connector coupled to the cord and adapted to engage a power input port of the electronic item of merchandise. 4. The merchandise security system of claim 2, further comprising monitoring electronics configured to detect an interruption in a signal provided to the cord. 5. The merchandise security system of claim 1, wherein the at least one electrical coupling of the reel comprises an electrical trace. 6. The merchandise security system of claim 1, wherein the at least one electrical coupling of the housing comprises an electrical terminal. 7. The merchandise security system of claim 1, wherein the at least one electrical coupling of the housing comprises an electrical terminal coupled to an interior surface of the interior of the housing. 8. The merchandise security system of claim 1, wherein the at least one electrical coupling of the housing comprises an electrical terminal engaged with an interior surface of the interior of the housing. 9. The merchandise security system of claim 1, wherein the at least one electrical coupling of the housing is configured to extend between an interior surface of the interior of the housing and the at least one electrical coupling of the reel when the at least one electrical coupling of the housing is engaged with and electrically connected to the at least one electrical coupling of the reel. 10. The merchandise security system of claim 1, wherein the at least one electrical coupling of the housing is engaged with an interior surface of the interior of the housing. 11. The merchandise security system of claim 1, wherein the at least one electrical coupling of the housing is engaged with an interior surface of the interior of the housing and the at least one electrical coupling of the reel when the at least one electrical coupling of the housing is engaged with and electrically connected to the at least one electrical coupling of the reel. 12. The merchandise security system of claim 1, wherein the at least one electrical coupling of the housing comprises an electrical terminal and an electrical lead electrically connected to a printed circuit board disposed within the interior of the housing. 13. The merchandise security system of claim 1, wherein the at least one electrical coupling of the housing is electrically connected to a printed circuit board disposed within the interior of the housing. 14. The merchandise security system of claim 1, wherein the housing is a display stand configured to removably secure the electronic item of merchandise thereon. 15. The merchandise security system of claim 1, wherein the housing further comprises means for retracting the cord onto the reel. 16. The merchandise security system of claim 1, wherein the reel is rotatable for dispensing and collecting a predetermined portion of the cord. 17. The merchandise security system of claim 1, further comprising monitoring electronics configured to detect decoupling of the at least one electrical coupling of the reel from the at least one electrical coupling of the housing. 18. The merchandise security system of claim 17, wherein the monitoring electronics is configured to activate an audible and/or a visible alarm in response to decoupling of the at least one electrical coupling of the reel from the at least one electrical coupling of the housing. 19. The merchandise security system of claim 1, wherein the housing comprises a barrier configured to cover an opening to the interior of the housing for containing the reel therein and to be removed from the opening for inserting and removing the reel though the opening. 20. The merchandise security system of claim 19, wherein the barrier comprises a door. 21. The merchandise security system of claim 19, wherein the at least one electrical coupling of the housing is coupled to an interior surface of the barrier. 22. The merchandise security system of claim 1, wherein the at least one electrical coupling of the housing is coupled to an interior surface of the interior of the housing. 23. The merchandise security system of claim 1, wherein the at least one electrical coupling of the reel is circular in shape. 24. A method for securing an electronic item of merchandise from theft, the method comprising: inserting a reel within an interior of a housing such that at least one electrical coupling of the housing engages with and electrically connects to at least one electrical coupling on an outer surface of the reel, wherein the reel is configured to store at least a portion of a cord thereon; and covering the interior of the housing for retaining the reel therein. 25. The method of claim 24, further comprising coupling the cord to the electronic item of merchandise. 26. The method of claim 24, further comprising accessing the interior of the housing for removing the reel from the housing. 27. The method of claim 24, wherein covering comprises covering the interior of the housing with a barrier for enclosing the reel within the interior of the housing. 28. The method of claim 24, wherein inserting comprises inserting the reel within the interior of the housing such that the at least one electrical coupling of the reel is engaged with the at least one electrical coupling of the housing and an interior surface of the interior of the housing. 29. The method of claim 24, wherein inserting comprises inserting the reel within the interior of the housing such that the at least one electrical coupling of the housing extends between an interior surface of the interior of the housing and the at least one electrical coupling of the reel. 30. A merchandise security system for an electronic item of merchandise comprising: a reel configured to store at least a portion of a cord thereon, the reel comprising at least one electrical coupling on an outer surface thereof; and a housing defining an interior for receiving the reel therein, the reel configured to be removably inserted within the housing, the housing comprising at least one electrical coupling configured to engage with and electrically connect to the at least one electrical coupling of the reel when the reel is received within the housing, wherein the at least one electrical coupling of the housing is configured to extend between the interior surface of the interior of the housing and the at least one electrical coupling of the reel when the at least one electrical coupling of the housing is engaged with and electrically connected to the at least one electrical coupling of the reel, wherein the housing comprises a barrier configured to cover an opening to the interior of the housing for containing the reel therein and to be removed from the opening for inserting and removing the reel though the opening; a printed circuit board disposed within the interior of the housing and electrically connected to the at least one electrical coupling of the housing; and a power cable electrically coupled to the printed circuit board for providing electrical power to the electronic item of merchandise. | CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. application Ser. No. 15/248,105, filed on Aug. 26, 2016, which is a continuation of U.S. application Ser. No. 14/793,051 filed on Jul. 7, 2015, and now U.S. Pat. No. 9,430,922, which is a continuation of U.S. application Ser. No. 13/965,525 filed on Aug. 13, 2013, and now U.S. Pat. No. 9,105,167, which claims the benefit of priority of U.S. Provisional Application No. 61/695,107, filed on Aug. 30, 2012, each of which is hereby incorporated by reference in its entirety. FIELD OF THE INVENTION Embodiments of the present invention relate generally to merchandise systems that provide power and security for an item of merchandise. BACKGROUND OF THE INVENTION U.S. Pat. No. 6,799,994 assigned to Telefonix, Inc. of Waukegan, Ill. discloses an apparatus and a method for the convenient management of cords associated with the retail display of an electronic item of merchandise, such as a video camera. The apparatus includes a multi-conductor power cable and a reel for dispensing and retracting the power cable. The apparatus further comprises an adapter cord selected from a plurality of adapter cords for electrically connecting the power cable to a variety of items of merchandise having different power and connection requirements. The power cable is directly coupled to an alarm module that activates an alarm in response to an electronic circuit being opened in the event that the power cable is cut or disconnected. U.S. Patent Application Publication No. 2012/0043936 A1 assigned to RTF Research & Technologies, Inc. of Caledon, Ontario Canada discloses a charging and monitoring system for handheld electronic items of merchandise, such as cell phones, Blackberry's, PDAs, cameras and the like. The system includes a coaxial security and power cable having a conductive core. A portion of one end of the coaxial power cable is accumulated on a reel of a recoiler assembly, while the other end of the coaxial power cable is adapted to mechanically and electrically engage a preferred mounting pad for a handheld electronic item of merchandise. The end of the coaxial cable accumulated on the reel is electrically coupled to a power and alarm cable through an electrical connector, such as a conventional registered jack (RJ) plug and socket. The free end of the power and alarm cable is electrically coupled to a power and alarm router having multiple ports for electrical connection to multiple power and alarm cables. The mounting pad is adapted to provide power to a power input port of the handheld electronic item of merchandise by means of a conventional electrical connection, such as a standard USB cable extending from the mounting pad. BRIEF SUMMARY OF THE INVENTION Embodiments of the present invention are directed to merchandise security systems for an electronic item of merchandise. In one embodiment, the merchandise security system includes a continuous alarming power cord comprising at least one electrical conductor. The alarming power cord has a first end adapted to be electrically connected to the electronic item of merchandise. The merchandise security system also includes a reel for receiving a second end of the alarming power cord that is adapted for storing at least a portion of the alarming power cord thereon. The merchandise security system further includes monitoring circuitry in electrical communication with the alarming power cord and configured to detect an interruption in an electrical signal provided to the alarming power cord. Thus, the alarming power cord may not require a second cable selected from a plurality of adapter cables to provide an appropriate operating voltage and/or current to the electronic item of merchandise. In one embodiment, the merchandise security system includes an alarm module comprising the monitoring circuitry and a power cable having a first end electrically coupled to the second end of the alarming power cord and a second end electrically connected to the alarm module. The second end of the alarming power cord and the first end of the power cable may each terminate in a transformer comprising a coiled spool of wire configured to electrically connect the alarming power cord and the power cable. Thus, the alarming power cord and the power cable may not be in direct wire-to-wire electrical communication. According to one example, the reel comprises a central hub portion for receiving the second end of the alarming power cord, wherein the first end of the power cable is electrically coupled to the second end of the alarming power cord at the central hub portion of the reel. The alarm module may be configured to generate an audible and/or a visible alarm in response to interruption of the electrical signal. Moreover, the second end of the alarming power cord may include a connector and the first end of the power cable may include a socket or plug configured to mate with the connector. According to one embodiment, the merchandise security system further comprises a display stand for housing the reel and providing electrical power to the alarming power cord. The electronic item of merchandise may be configured to be removably secured on the display stand. Each of the reel and the display stand may include electrical traces configured to electrically couple with one another for providing electrical power through the alarming power cable to the electronic item of merchandise. In other embodiments, the merchandise security system further comprises means for retracting the alarming power cord onto the reel, wherein the reel and the portion of the alarming power cord stored thereon are detachable from the means for retracting. The means for retracting the alarming power cord onto the reel may be biased by a biasing force to automatically retract the portion of the alarming power cord in the absence of a tensile pulling force that exceeds the biasing force. In one embodiment, the reel is rotatable for dispensing and collecting a predetermined portion of the alarming power cord. In addition, the first end of the alarming power cord may include a connector adapted to engage a power input port of the electronic item of merchandise. In one embodiment, the merchandise security system further comprises a strain relief block configured to be attached to the electronic item of merchandise, wherein a portion of the alarming power cord is configured to be routed through the strain relief block. In one embodiment, a merchandise security system for an electronic item of merchandise is provided. The merchandise security system includes a continuous alarming power cord comprising at least one electrical conductor, wherein the alarming power cord has a first end including a connector adapted to engage a power input port of the electronic item of merchandise. The merchandise security system also includes a rotatable reel connected to a second end of the alarming power cord that is adapted for dispensing and collecting at least a portion of the alarming power cord thereon. The merchandise security system further includes monitoring circuitry in electrical communication with the alarming power cord. According to another embodiment, a method for securing an electronic item of merchandise from theft is provided. The method may include electrically connecting a first end of a continuous alarming power cord to the electronic item of merchandise, wherein a second end of the alarming power cord is connected to a reel for storing at least a portion of the alarming power cord thereon. The method may also include electrically coupling the second end of the alarming power cord to a power source such that an electrical signal is provided to the alarming power cord, wherein an interruption in the electrical signal is detectable by monitoring electronics. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is an environmental perspective view of a merchandise security system including a retractable alarming power cord and a rotatable reel according to the invention. FIG. 2 is an exploded perspective view of a merchandise security system according to another embodiment of the present invention. DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS The accompanying drawing figures, wherein like reference numerals denote like elements throughout the various views, illustrate embodiments of a merchandise security system for providing power and/or security to an item of merchandise. By way of example and not limitation, the item of merchandise may be an electronic device, such as a mobile (e.g. cellular) telephone, media player, handheld game console, personal data assistant (PDA), global positioning satellite (GPS) device, handheld digital camera or video recorder, tablet computer, e-reader and the like, that requires electrical power for a potential purchaser to operate before making a decision whether to purchase the merchandise while the item is being displayed in a display area of a retail store and protected from theft by the merchandise security system. Embodiments of the present invention are directed to a merchandise security system for protecting an electronic item of merchandise from theft, while providing power to the merchandise. In one embodiment, the merchandise security system includes an alarming power cord adapted for electrical connection to a power input port of the item of merchandise and a reel for retractably storing at least a portion of the alarming power cord. The alarming power cord may be electrically coupled to a power cable extending between a powered alarm module and a core portion of the reel. Power from the alarm module may be transferred to the alarming power cord by a conventional electrical connector (e.g. RJ type plug and socket), or alternatively, by induction via, for example, a transformer. FIG. 1 shows a merchandise security system 10 according to one embodiment of the invention including an alarming power cord (also commonly referred to as an “alarming pigtail”) 12 that is retractably wound on a rotatable reel 14, such that at least a portion of the alarming power cord is retractable onto the reel. The rotatable reel 14 is configured to dispense and collect a predetermined portion of the alarming power cord 12 and is biased to automatically retract the alarming power cord onto the reel in a known manner when a potential purchaser returns an item of merchandise M to a display support S, such as a stand, counter or the like. As such, the rotatable reel functions in the same or similar manner as a conventional recoiler or retractor of the type commonly employed with a retail merchandise display system. As shown in FIG. 1, the rotatable reel 14 and the means for retracting R the alarming power cord 12 on the reel may be separate such that the reel and the alarming power cord are detachable from the means for retracting to remove and replace the alarming power cord with a different alarming power cord configured for use with a different item of merchandise M. In one embodiment, the alarming power cord 12 comprises at least one conductor (e.g., two conductors) for providing power at an appropriate current and/or voltage to the electronic item of merchandise M. As such, the alarming power cord 12 has a relatively small platform and is flexible relative to a mechanical security cable or a multi-conductor electrical power cable of the type disclosed in U.S. Pat. No. 6,799,994. The free end of the alarming power cord 12 may comprise an electrical connector 13, such a conventional micro-USB type power connector or a 30-pin Apple type power connector, adapted to engage a power input port P of the electronic item of merchandise M. If desired, a portion of the alarming power cord 12 adjacent the free end may be routed through an appropriately sized channel formed in a strain relief block 16 adapted to be attached to a surface of the electronic item of merchandise M, for example by a pressure sensitive adhesive (PSA). The strain relief block 16 prevents the electrical connector 13 of the alarming power cord 12 from being removed, disconnected or dislodged from the power input port P of the electronic item of merchandise M when tension is applied to the alarming power cord during extension and retraction of the alarming power cord from the reel 14 by a potential purchaser examining and/or operating the item of merchandise. The other end of the alarming power cord 12 may terminate adjacent a central hub 15 of the rotatable reel 14. In one embodiment, the alarming power cord 12 terminates in an electrical transformer 17 comprising a coiled spool of wire. Alternatively, the alarming power cord 12 may terminate in a conventional electrical connector, such as a registered jack (RJ) type plug or socket. The merchandise security system 10 may further comprise a power cable 20 that extends between an alarm/power module 30 and the central hub 15 of the rotatable reel 14 to electrically connect the alarm/power module to the alarming power cord 12. Likewise, the end of the power cable 20 adjacent the hub 15 of the reel 14 may terminate in an electrical transformer 27 comprising a coiled spool of wire. Alternatively, the end of the power cable 20 may terminate in an electrical connector that is adapted to electrically couple the power cable 20 to the alarming power cord 12, such as a compatible registered jack (RJ) socket or plug. Regardless, the power cable 20 provides an electrical signal, including a power signal, to the alarming power cord 12 for charging and/or powering the electronic item of merchandise M via the electrical connector 13 and the power input port P of the item of merchandise. The alarm/power module 30 comprises monitoring electronics 32 that monitor the electrical signal in the power cable 20 and the alarming power cord 12 to determine whether the electrical signal has been interrupted, for example, by disconnecting the alarming power cord from the power input port P of the item of merchandise M, or by electrically decoupling the alarming power cord 12 from the power cable 20 at the central hub 15 of the rotatable reel 14, or by cutting/severing the alarming power cord 12 or the power cable 20 at any point between the alarm/power module 30 and the item of merchandise M. In the event that the electrical signal is interrupted, the alarm/power module 30 may activate an audible and/or a visible alarm 34 to alert store personnel to a potential theft of the electronic item of merchandise M. The alarm/power module 30 may be electrically connected to an external power supply (not shown), such as a standard 110 Volt Alternating Current (AC) outlet, or alternatively, may include an internal power supply, such as a conventional rechargeable battery 36, for providing power to the electronic item of merchandise M through the power cable 20 and the alarming power cord 12. Furthermore, the alarm/power module 30 may comprise voltage regulating electronics 38 adapted to convert the voltage and/or current provided by the power supply to an appropriate voltage and/or current for operating the electronic item of merchandise M. It is important to note that the merchandise security system 10 comprises an alarming power cord 12 that extends continuously from the power input port P of the electronic item of merchandise M to an electrical coupling (e.g. 17, 27) disposed at the central hub 15 of the rotatable reel 14. Accordingly, the alarming power cord 12 does not comprise a first cable configured for electrical connection to a second cable selected from a plurality of adapter cables to provide an appropriate operating voltage and/or current to the electronic item of merchandise M. Furthermore, the alarming power cord 12 may not be in direct wire-to-wire electrical communication with the power cable 20 since the alarming power cord and the power cable may each comprise a corresponding electrical transformer 17, 27 formed by a coiled spool of wire. In addition, the merchandise security system 10 of the present invention further comprises a strain relief block 16 for preventing the electrical connector 13 at the free end of the alarming power cord 12 from being removed, disconnected or dislodged from the power input port P of the electronic item of merchandise M. FIG. 2 shows another embodiment of a merchandise security system 40 according to the invention including an alarming power cord (also commonly referred to as an “alarming pigtail”) 42 that is retractably wound on a rotatable reel 44, such that at least a portion of the alarming power cord is retractable onto the reel. The rotatable reel 44 is configured to dispense and collect a predetermined portion of the alarming power cord 42 and is biased to automatically retract the alarming power cord in a known manner when a potential purchaser returns an item of merchandise M to a display support, such as a stand, counter or the like. As such, the rotatable reel functions in the same or similar manner as a conventional recoiler or retractor of the type commonly employed with a retail merchandise display system. As shown in FIG. 2, the merchandise security system 40 further comprises a generally hollow display stand 50 configured for housing the rotatable reel 44 and for providing electrical power to the alarming power cord 42, and consequently, to the item of merchandise M. The display stand 50 comprises means for retracting the alarming power cord 42 onto the reel 44 in the form of a torsion spring 52 fixed at one end to the display stand and attached at the other end to a hub 54. Hub 54 has an exterior shape (e.g. rectangular, square, polygonal, etc.) that corresponds to a center sprocket 45 on the rotatable reel 44 such that the hub of the display stand 50 engages the center sprocket of the reel when the reel is inserted into the hollow interior of the display stand with the extensible and retractable portion of the alarming power cord 42 wound onto the reel 44. The free end of the alarming power cord 42 may comprise an electrical connector 43, such a conventional micro-USB type power connector or a 30-pin Apple type power connector, adapted to engage a power input port P of an electronic item of merchandise M. If desired, a portion of the alarming power cord 42 adjacent the free end may be routed through an appropriately sized channel formed in a strain relief block 46 adapted to be attached to an exterior surface of the electronic item of merchandise M, for example, by a pressure sensitive adhesive (PSA) such as double sided tape. The strain relief block 46 prevents the electrical connector 43 of the alarming power cord 42 from being removed, disconnected or dislodged from the power input port P of the electronic item of merchandise M when tension is applied to the alarming power cord during extension and retraction of the alarming power cord from the reel 44 by a potential purchaser examining and/or operating the item of merchandise. An opening or recess 56 is formed in display stand 50 for permitting the portion of the alarming power cord 42 to be extended and retracted from the reel 44 within the hollow interior of the display stand 50. When a potential purchaser picks up the item of merchandise M, reel 44 rotates on hub 54 and torsion spring 52 is wound (i.e. tightened) as the alarming power cord 42 is unwound from the reel. As a result, reel 44 is biased by the wound torsion spring 52 to automatically retract the portion of the power alarming cord onto the reel as the potential purchaser returns the item of merchandise M to the display stand 50. As shown, the strain relief block 46 may optionally comprise one or more magnets 48 for engaging corresponding magnets 58 provided on the display stand 50 to position the item of merchandise M in a desired orientation on the display stand 50. The merchandise security system 40 further comprises a power cable 60 that extends between a power source, such as a power strip, terminal or the like, that is electrically connected to a conventional 110 Volt Alternating Current (AC) power outlet. Alternatively, the power cable 60 may be directly connected to the power outlet. Regardless, the power cable 60 is electrically coupled to an electrical circuit, for example a printed circuit board (PCB), 62 disposed within the hollow interior of the display stand 50. As shown, PCB 62 may have electrical leads 64 that terminate in electrical terminals 66 configured to engage and electrically couple with electrical traces 67 formed on the interior surface of a door 51 of the display stand 50. Door 51 is adapted to be opened to receive reel 44 within the hollow interior of the display stand 50 and to be closed to retain the reel within the interior of the display stand. Electrical traces 67 are configured to electrically couple with corresponding electrical traces 47 provided on an exterior surface of reel 44. In turn, the electrical traces 47 of the reel 44 electrically couple with the electrical conductors disposed within the alarming power cord 42. As such, the power cable 60 is operable to provide electrical power to the item of merchandise M. As illustrated, the electrical traces 67 may be circular in configuration to facilitate electrical communication as the reel 44 rotates. As previously described, the power cable 60 provides an electrical signal, including a power signal, to the alarming power cord 42 for charging and/or powering the electronic item of merchandise M via the electrical connector 43 and the power input port P of the item of merchandise. The merchandise security system 40 comprises monitoring electronics on the PCB 62 that monitor the electrical signal in the power cable 60 and the alarming power cord 42 to determine whether the electrical signal has been interrupted, for example, by disconnecting the alarming power cord from the power input port P of the item of merchandise M, or by electrically decoupling the alarming power cord 42 from the power cable 60 at the electrical traces 47, 67 of the rotatable reel 44 and the display stand 50, respectively, by opening the door 51, or by cutting/severing the alarming power cord 42 or the power cable 60 at any point between the power source and the item of merchandise M. In the event that the electrical signal is interrupted, PCB 62 may activate an audible and/or a visible alarm to alert store personnel to a potential theft of the electronic item of merchandise M, as previously described. It is important to note that the merchandise security system 40 comprises an alarming power cord 42 that extends continuously from the power input port P of the electronic item of merchandise M to an electrical coupling (e.g. electrical traces 47, 67) disposed adjacent the central socket 45 of the rotatable reel 44 and the hub 54 of the display stand 50. Accordingly, the alarming power cord 42 does not comprise a first cable configured for electrical connection to a second cable selected from a plurality of adapter cables to provide an appropriate operating voltage and/or current to the electronic item of merchandise M. Furthermore, the alarming power cord 42 is not in direct wire-to-wire electrical communication with the power cable 60 since the alarming power cord and the power cable are separated by PCB 62, electrical leads 64, electrical terminals 66 and electrical traces 67, 47. In addition, the merchandise security system 40 of the present invention further comprises a strain relief block 46 for preventing the electrical connector 43 at the free end of the alarming power cord 42 from being removed, disconnected or dislodged from the power input port P of the electronic item of merchandise M. The foregoing has described one or more embodiments of a merchandise security system. Embodiments according to the invention have been shown and described herein for purposes of illustrating and enabling the best mode of the invention. Those of ordinary skill in the art, however, will readily understand and appreciate that numerous variations and modifications of the invention may be made without departing from the spirit and scope of the invention. Accordingly, all such variations and modifications are intended to be encompassed by the appended claims. | <SOH> BACKGROUND OF THE INVENTION <EOH>U.S. Pat. No. 6,799,994 assigned to Telefonix, Inc. of Waukegan, Ill. discloses an apparatus and a method for the convenient management of cords associated with the retail display of an electronic item of merchandise, such as a video camera. The apparatus includes a multi-conductor power cable and a reel for dispensing and retracting the power cable. The apparatus further comprises an adapter cord selected from a plurality of adapter cords for electrically connecting the power cable to a variety of items of merchandise having different power and connection requirements. The power cable is directly coupled to an alarm module that activates an alarm in response to an electronic circuit being opened in the event that the power cable is cut or disconnected. U.S. Patent Application Publication No. 2012/0043936 A1 assigned to RTF Research & Technologies, Inc. of Caledon, Ontario Canada discloses a charging and monitoring system for handheld electronic items of merchandise, such as cell phones, Blackberry's, PDAs, cameras and the like. The system includes a coaxial security and power cable having a conductive core. A portion of one end of the coaxial power cable is accumulated on a reel of a recoiler assembly, while the other end of the coaxial power cable is adapted to mechanically and electrically engage a preferred mounting pad for a handheld electronic item of merchandise. The end of the coaxial cable accumulated on the reel is electrically coupled to a power and alarm cable through an electrical connector, such as a conventional registered jack (RJ) plug and socket. The free end of the power and alarm cable is electrically coupled to a power and alarm router having multiple ports for electrical connection to multiple power and alarm cables. The mounting pad is adapted to provide power to a power input port of the handheld electronic item of merchandise by means of a conventional electrical connection, such as a standard USB cable extending from the mounting pad. | <SOH> BRIEF SUMMARY OF THE INVENTION <EOH>Embodiments of the present invention are directed to merchandise security systems for an electronic item of merchandise. In one embodiment, the merchandise security system includes a continuous alarming power cord comprising at least one electrical conductor. The alarming power cord has a first end adapted to be electrically connected to the electronic item of merchandise. The merchandise security system also includes a reel for receiving a second end of the alarming power cord that is adapted for storing at least a portion of the alarming power cord thereon. The merchandise security system further includes monitoring circuitry in electrical communication with the alarming power cord and configured to detect an interruption in an electrical signal provided to the alarming power cord. Thus, the alarming power cord may not require a second cable selected from a plurality of adapter cables to provide an appropriate operating voltage and/or current to the electronic item of merchandise. In one embodiment, the merchandise security system includes an alarm module comprising the monitoring circuitry and a power cable having a first end electrically coupled to the second end of the alarming power cord and a second end electrically connected to the alarm module. The second end of the alarming power cord and the first end of the power cable may each terminate in a transformer comprising a coiled spool of wire configured to electrically connect the alarming power cord and the power cable. Thus, the alarming power cord and the power cable may not be in direct wire-to-wire electrical communication. According to one example, the reel comprises a central hub portion for receiving the second end of the alarming power cord, wherein the first end of the power cable is electrically coupled to the second end of the alarming power cord at the central hub portion of the reel. The alarm module may be configured to generate an audible and/or a visible alarm in response to interruption of the electrical signal. Moreover, the second end of the alarming power cord may include a connector and the first end of the power cable may include a socket or plug configured to mate with the connector. According to one embodiment, the merchandise security system further comprises a display stand for housing the reel and providing electrical power to the alarming power cord. The electronic item of merchandise may be configured to be removably secured on the display stand. Each of the reel and the display stand may include electrical traces configured to electrically couple with one another for providing electrical power through the alarming power cable to the electronic item of merchandise. In other embodiments, the merchandise security system further comprises means for retracting the alarming power cord onto the reel, wherein the reel and the portion of the alarming power cord stored thereon are detachable from the means for retracting. The means for retracting the alarming power cord onto the reel may be biased by a biasing force to automatically retract the portion of the alarming power cord in the absence of a tensile pulling force that exceeds the biasing force. In one embodiment, the reel is rotatable for dispensing and collecting a predetermined portion of the alarming power cord. In addition, the first end of the alarming power cord may include a connector adapted to engage a power input port of the electronic item of merchandise. In one embodiment, the merchandise security system further comprises a strain relief block configured to be attached to the electronic item of merchandise, wherein a portion of the alarming power cord is configured to be routed through the strain relief block. In one embodiment, a merchandise security system for an electronic item of merchandise is provided. The merchandise security system includes a continuous alarming power cord comprising at least one electrical conductor, wherein the alarming power cord has a first end including a connector adapted to engage a power input port of the electronic item of merchandise. The merchandise security system also includes a rotatable reel connected to a second end of the alarming power cord that is adapted for dispensing and collecting at least a portion of the alarming power cord thereon. The merchandise security system further includes monitoring circuitry in electrical communication with the alarming power cord. According to another embodiment, a method for securing an electronic item of merchandise from theft is provided. The method may include electrically connecting a first end of a continuous alarming power cord to the electronic item of merchandise, wherein a second end of the alarming power cord is connected to a reel for storing at least a portion of the alarming power cord thereon. The method may also include electrically coupling the second end of the alarming power cord to a power source such that an electrical signal is provided to the alarming power cord, wherein an interruption in the electrical signal is detectable by monitoring electronics. | G08B131418 | 20171025 | 20180215 | 69902.0 | G08B1314 | 1 | TWEEL JR, JOHN ALEXANDER | MERCHANDISE SECURITY SYSTEM INCLUDING RETRACTABLE ALARMING POWER CORD | SMALL | 1 | CONT-ACCEPTED | G08B | 2,017 |
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15,793,326 | PENDING | Liquid Formulations of Urease Inhibitors for Fertilizers | An improved solvent system for the formulation and application of N-alkyl thiophosphoric triamide urease inhibitors. These formulations provide safety and performance benefits relative to existing alternatives and enable storage, transport and subsequent coating or blending with urea based or organic based fertilizers. These formulations are comprised primarily of environmentally friendly aprotic and protic solvents (particularly dimethyl sulfoxide and alcohols/polyols) to stabilize the urease inhibitor. | 1. A composition comprising: a. urea, b. a liquid solution comprised of urease inhibitor(s) that have been solubilized within an aprotic solvent wherein said aprotic solvent comprises dimethyl sulfoxide wherein the liquid additive composition comprises 45-5% of said urease inhibitor(s) and 55-95% of dimethyl sulfoxide. 2. The composition of claim 1, wherein the composition comprises one or more urease inhibitors selected from the group consisting of aliphatic phosphoric triamide, phosphoramides, and N-alkyl thiophosphoric triamides. 3. The composition of claim 1, wherein the composition comprises the urease inhibitor N-(n-butyl) thiophosphoric triamide. 4. The composition of claim 1, wherein the composition further comprises aprotic solvents and protic solvents wherein said aprotic solvents are one or more members selected from the group consisting of: a) one or more alkylene carbonates selected from the group consisting of propylene carbonate, ethylene carbonate, and butylene carbonate, b) 2-methoxyethyl ether, c) cyclohexylpyrrolidone, d) 1,3 dimethyl-2-imidazolidinone, e) dimethyloxyethane, and f) the organo phosphorous liquid hexamethyl phosphoramides, and wherein said protic solvents are one or more members selected from the group consisting of: a) glycerine, b) ethyl lactate, and c) one or more alcohols selected from the group consisting of n-propyl alcohol, isopropyl alcohol, cyclohexanol, isobutyl alcohol, and tert-amyl alcohol. 5. The composition of claim 1, wherein the composition further comprises one or more members selected from the group consisting of buffers, flow aides, silicas, surfactants, and dyes/colorants. 6. The composition of claim 1, wherein the composition comprises at least 2 quarts of liquid solution per ton of urea. 7. The composition of claim 1, wherein the composition further comprises water thereby resulting in a liquid urea fertilizer. 8. The composition of claim 1, wherein urea is combined with said liquid solution to make fertilizer more effective when applied to soil for plant growth, wherein the composition reduces hydrolysis of the urea to ammonia, thereby reducing ammonia losses to an atmosphere resulting in improved nitrogen retention in the soil. 9. A composition comprising: a. urea, b. a liquid fertilizer additive comprised of urease inhibitor(s) that have been solubilized within polar aprotic solvents and one or more solvents selected from the group consisting of aprotic and protic solvents wherein said polar aprotic solvents comprise one or more members selected from the group consisting of: i. dimethyl sulfoxide, and ii. one or more sulfoxide(s) selected from the group consisting of dialkyl, diaryl, or alkylaryl sulfoxide(s) selected from the formula structure: R9S(O)xR10 wherein 1. R9 and R10 are each independently a C1-C6alkylene group, an aryl group or C1-C3 alkylenearyl group, 2. or R9 and R10 with the sulfur to which they are attached form a 4 to 8 membered ring wherein R9 and R10 together are a C1-C6alkylene group which optionally contains one or more atoms selected from the group consisting of O, S, Se, Te, N, and P in the ring, 3. x=1 or 2 such that said composition comprises at least 2 quarts of the liquid fertilizer additive per ton of urea, wherein the liquid fertilizer additive composition comprises 75-5% of said urease inhibitors and 25-95% of said polar aprotic, aprotic and protic solvents. 10. The composition of claim 9, wherein the composition comprises one or more urease inhibitors selected from the group consisting of aliphatic phosphoric triamide, phosphoramides, and N-alkyl thiophosphoric triamides. 11. The composition of claim 9, wherein the composition comprises the urease inhibitor N-(n-butyl) thiophosphoric triamide. 12. The composition of claim 9, wherein the composition comprises the polar aprotic solvent dimethyl sulfoxide. 13. The composition of claim 9, wherein the composition comprises one or more aprotic solvents selected from the group consisting of: a) one or more alkylene carbonates selected from the group consisting of propylene carbonate, ethylene carbonate, and butylene carbonate, b) 2-methoxyethyl ether, c) cyclohexylpyrrolidone, d) 1,3 dimethyl-2-imidazolidinone, and e) organo phosphorous liquid hexamethyl phosphoramides. 14. The composition of claim 9, wherein the composition comprises one or more protic solvents selected from the group consisting of: a) one or more C1 to C6 alcohols, b) one or more polyols selected from the group consisting of alkylene and poly(alkylene) glycols, c) glycerin, d) one or more alkanolamines selected from the group consisting of ethanolamine, diethanolamine, dipropanolamine, methyl diethanolamine, monoisopropanolamine, and triethanolamine, and e) one or more alkyl lactate selected from the group consisting of ethyl lactate, propyl lactate, or butyl lactate. 15. The composition of claim 9, wherein the composition comprises one or more polyalkylene glycols selected from the group consisting of: polymethylene glycols, polyethylene glycols, polypropylene glycols, and polybutylene glycols. 16. The composition of claim 9, wherein the composition comprises one or more alkylene glycols selected from the group consisting of ethylene glycol, propylene glycol, and butylene glycol. 17. The composition of claim 9, wherein the composition further comprises one or more members selected from the group consisting of buffers, flow aides, silicas, surfactants and, dyes/colorants. 18. The composition of claim 9, wherein the composition further comprises water thereby resulting in a liquid urea fertilizer. 19. The composition of claim 9, wherein urea is combined with said fertilizer additive to make fertilizer more effective when applied to soil for plant growth, wherein said fertilizer additive reduces hydrolysis of urea to ammonia, thereby reducing ammonia losses to an atmosphere improving nitrogen retention in the soil. | The present application is a continuation and claims priority under 35 §USC 120 to U.S. application Ser. No. 15/636,211 filed Jun. 28, 2017, which in turn is a continuation and claims priority to U.S. application Ser. No. 13/890,082 filed May 8, 2013, which in turn claims priority under 35 §USC 119(e) to U.S. Provisional Application 61/708,105 filed Oct. 1, 2012, the entire contents of all of which are hereby incorporated by reference in their entireties. FIELD OF THE INVENTION In embodiments, the present invention relates to improved solvent formulations for the urease inhibitor N-(n-butyl) thiophosphoric triamide, hereafter referred to by its acronym NBPT. NBPT is a solid chemical substance, which is dissolved in a suitable solvent to allow application at low levels in the field. Additionally, solutions of NBPT are desirable when it is to be incorporated as a component of a granular mixed fertilizer, such that it can be deposited as a coating in a controlled and homogenous layer. In one embodiment, this invention proposes formulations of mixtures containing aprotic and protic solvents which are more environmentally friendly and are safer for workers to handle than known NBPT solutions. Moreover, performance advantages relative to NBPT solution stability, solution handling, and loading levels are disclosed for these new formulations. BACKGROUND OF THE INVENTION Description of the Prior Art Nitrogen is an essential plant nutrient and is thought to be important for the adequate and strong foliage. Urea provides a large nitrogen content and is one of the best of all nitrogenous fertilizer materials, which consequently makes it an efficient fertilizer compound. In the presence of soil moisture, natural or synthetic ureas are converted to ammonium ion, which is then available for plant uptake. When applied as a fertilizer material, native soil bacteria enzymatically convert urea to two molar equivalents of ammonium ion for each mole of urea as demonstrated by the following two reactions: CO(NH2)2+2H2O→(NH4)2CO3 (NH4)2CO3+2H+→2NH4++CO2+H2O In the presence of water, the ammonium thus produced is in equilibrium with ammonia. The equilibrium between NH4+ and NH3 is pH dependent, in accordance with the following equilibrium: NH4++OH−NH3(solution)+H2O As such, gaseous ammonia losses are higher at higher pH values. The flux of NH3 from soil is primarily dependent on the NH3 concentration, pH, and temperature. In the presence of oxygen, ammonium can also be converted to nitrate (NO3−). Nitrogen in both its ammonium and nitrate forms may then be taken up as nutrient substances by growing plants. The ammonium ion can also ultimately be converted to ammonia gas, which escapes to the air. The concentrations of NH3 in the air and in solution are governed by Henry's law constant (H), which is a function of temperature: └NH3(air)┘=H└NH3(solution)┘ Urea fertilizer is often just applied once at the beginning of the growing season. A weakness in this nitrogen delivery system involves the different rates at which ammonium and nitrate are produced in the soil, and the rate at which ammonium and nitrate are required by the plant during its growing season. The generation of ammonium and nitrate is fast relative to its uptake by plants, allowing a considerable amount of the fertilizer nitrogen to go unutilized or to be lost to the atmosphere as ammonia gas, where it is no longer available to the plant. Thus, there is a desire to control the hydrolysis of urea to ammonium and ammonia gas, thereby making the urea fertilizer more effective for plant growth. Numerous methods have been developed for making urea fertilizers more effective, and for controlling the volatilization of ammonia from urea. Weston et al. (U.S. Pat. No. 5,352,265) details a method for controlling urea fertilizer losses, including: (1) multiple fertilizer treatments in the field, staged across the growing season, (2) the development of ‘controlled release’ granular fertilizer products, using protective coatings which erode slowly to introduce the urea to the soil in a controlled fashion, and (3) the discovery of simple chemical compounds (urease inhibitors) which inhibit the rate at which urea is metabolized by soil bacteria and converted to the ammonium ion. Use of various urea coatings to provide urea in a controlled fashion to the plant has been widely demonstrated. Phosphate coatings for urea have been described by Barry et al. (U.S. Pat. No. 3,425,819) wherein the coating is applied to urea as an aqueous phosphate mixture. Miller (U.S. Pat. No. 3,961,932) describes the use of chelated micronutrients to coat fertilizer materials. Polymer coatings have also been disclosed which control the delivery of fertilizer materials (see, for example, U.S. Pat. Nos. 6,262,183 and 5,435,821). Whitehurst et al. (U.S. Pat. No. 6,830,603) teach the use of borate salts to produce coated urea fertilizer, as a means of controlling ammonia losses during the growth cycle. Whitehurst summarizes numerous examples of this coating strategy to inhibit the loss of ammonia nitrogen in the soil. Accordingly, the prior art considers the merits of coated fertilizer products as one means of inhibiting the loss of ammonia nitrogen in the soil. Urease inhibiting materials other than NBPT have been disclosed. Some examples include the use of polysulfide and thiosulfate salts as taught by Hojjatie et al (US 2006/0185411 A1) and the use of dicyandiamide (DCD) and nitrapyrin. Kolc at al. (U.S. Pat. No. 4,530,714) teach the use of aliphatic phosphoric triamide urease inhibitors, including the use of NBPT for this purpose. Kolc mentions the use of aqueous and organic carrier media, but specifies volatile (and flammable) solvents from the group including acetone, diisobutylketone, methanol, ethanol, diethyl ether, toluene, methylene chloride, chlorobenzene, and petroleum distillates. The principle reason for the use of these solvents was to assure that negligible amounts of solvent residue be retained on the crop. Improved carrier systems for NBPT have been described subsequent to the Kolc. NBPT is both a hydrolytically and thermally unstable substance and several solvent systems have been developed to overcome these and other weaknesses. Unfortunately, the existing formulations are problematic in their own right due to thermal stability concerns and the toxicity of key formulation components. Generally, it is desirable that solvents being used in conjunction with fertilizers be water soluble in all proportions which allows for facile dispersion at the point of use as well as a relatively high flashpoint (so that it has a reduced chances of explosions and/or fires at elevated temperatures). Many of the formulation solvents disclosed in U.S. Pat. No. 4,530,714 do not possess these desirable properties. Examples of such problematic solvents from this patent include the use of toluene, a flammable and water immiscible solvent. Weston et al. (U.S. Pat. No. 5,352,265) disclose the use of pyrrolidone solvents, such as N-Methyl pyrrolidone (NMP), as does Narayanan et al. (U.S. Pat. Nos. 5,160,528 and 5,071,463). It is shown that a solvents of this type can dissolve high levels of NBPT to produce product concentrates and that the resulting concentrates have good temperature stability. These features are useful in that they allow commercial products to be stored, pumped, and transported in conventional ways. In U.S. Pat. No. 5,698,003, Omilinsky and coworkers also disclose the use of ‘liquid amides” such as NMP in NBPT formulations. Omilinsky further speaks to the importance of solution stability and develops glycol-type solvents as desirable base solvents for NBPT delivery mixtures. The dominant role played by a liquid amide co-solvent is to depress the pour point of the mixture, which is insufficiently high as a consequence of the natural viscosity of glycols at reduced temperatures. NMP plays several roles in NBPT-based agrichemical formulations. As taught in '265, '528, and '463, NMP is a useful solvent capable of producing concentrated NBPT product formulations which have good temperature stability. It may also be used as an additive to depress the pour point of viscous base solvents, such as propylene glycol. Omilinsky discloses the use of NMP as a co-solvent to depress the pour point of propylene glycol in '003. In mixtures such as those described in U.S. Pat. No. 5,698,003, the requirement for an additive to depress the pour point of glycol-type NBPT solvent formulations is described. Solvents such as propylene glycol have the attractive feature of being essentially nontoxic and are thus an attractive mixture component in agrichemical and pharmaceutical products. One drawback of some glycols is a relatively high viscosity level, which can make these materials resistant to flow and difficult to pour. Indeed, the dynamic viscosity at 25° C. of propylene glycol is 48.8 centipoise, almost 50 times that of water at the same temperature. Viscosity data for propylene glycol can be found in Glycols (Curme and Johnston, Reinhold Publishing Corp., New York, 1952). Omilinsky '003 describes the use of NMP as an additive capable of depressing the pour point of NBPT mixtures. Although NMP and other liquid amide solvents play useful roles in the described NBPT formulations, concerns about the safety of these solvents has increased greatly in recent years. In particular, European Directives 67/548/EEC and/or 99/45/EC have recently classified N-methylpyrrolidone (NMP) as a reproductive toxin (R61) in amounts exceeding 5% of the product formulation. It is scheduled for listing on the European Union's ‘Solvent of Very High Concern’ list, which would preclude its use in industrial and agrichemical formulations. In the US, NMP is subject to California Proposition 65 (The Safe Drinking Water and Toxic Enforcement Act of 1986) requirements, which regulate substances known by the US State of California to cause cancer or reproductive harm. Nothing in the prior art addresses the suitability of NMP in these formulations from the standpoint of safety, or proposes appropriate alternatives from the perspectives of both safety and performance. Indeed, guidelines for the use of reaction solvents in the pharmaceutical industry also speak to the relatively poor safety profile of NMP. As reaction solvents may be present at residual levels in finished drug products such considerations are warranted. The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) classifies NMP as a ‘solvent to be limited (Class 2)’ in its document Impurities: Guideline for Residual Solvents Q3C (R3). NMP is potentially toxic if it is given directly to humans and/or animals. Moreover, it is possible that NMP may be toxic when it is ingested by higher order animals after passage through the food chain. For example, often times, fertilizers are not completely absorbed/used by fields/crops/plants on which they are used and the fertilizers end up in water-ways (such as fresh water, brackish water or salt water bodies). In those situations where at least a part of the fertilizer ends up in these bodies of water, they may be absorbed, ingested or otherwise taken in by organisms that are either directly or indirectly consumed by higher animals (such as humans). In these instances, it is possible that the fertilizer and/or compounds that are associated with said fertilizer may be directly and/or indirectly ingested by humans or higher animals and lead to toxicity to said humans. It is also possible that the fertilizers that end up in water ways may be directly ingested by higher animals/humans that drink the water. Moreover, when toxic compounds that are associated with various fertilizers are used, not only may they be toxic to the higher animals but they also may be toxic to the animals lower in the food chain. At higher doses, this may mean die-off of the animals lower in the food chain, which consequently means that there may be economic consequences such as crop and/or animal die-off, which means lower profit margins and less food available. In light of the above, it is desirable to develop formulations/fertilizers that are less toxic to the environment and to animals and humans. An important feature of NBPT-based agrichemical formulation is their chemical stability in solution. Although such products are diluted with water at the point of use, NBPT undergoes hydrolysis in the presence of water. Aqueous solutions or emulsions of NBPT are therefore not practical from a commercial perspective and organic solvents are preferred as vehicles to deliver concentrated NBPT products. But NBPT is not chemically inert to all solvents, and its stability must be assessed in order to develop a product suitable to the needs of agrichemical users. The stability of NBPT to NMP has been previously established in U.S. Pat. No. 5,352,265 (Weston et al.) and by Narayanan et al. (U.S. Pat. Nos. 5,160,528 and 5,071,463). Beyond the consideration of NBPT chemical stability in the presence of formulation solvents is the inherent stability of the solvents themselves to hydrolysis. As NBPT products are often ultimately dispersed into water, the hydrolytic stability of liquid amide solvents like NMP is a consideration. At elevated temperatures and pH levels, NMP hydrolysis can be significant (“M-Pyrrol” product bulletin, International Specialty Products, p. 48). SUMMARY OF THE INVENTION In one embodiment, the present invention relates to liquid formulations containing N-(n-butyl) thiophosphoric triamide (NBPT). In an embodiment, the formulations can be made by dissolving the NBPT into an aprotic solvent consisting of a) dimethyl sulfoxide, b) dialkyl, diaryl, or alkylaryl sulfoxide having the formula R1—SO—R2, when R1 is methyl, ethyl, n-propyl, phenyl or benzyl and R2 is ethyl, n-propyl, phenyl or benzyl, c) sulfolane, d) ethylene carbonate, propylene carbonate, or mixtures thereof. In an embodiment, these formulations can be mixed with a protic component consisting of 1) an alcohol or polyol from the family of alkylene and poly(alkylene) glycols (PG), 2) an alkylene glycol from the group comprised of ethylene, propylene, or butylene glycol, 3) glycerin, 4) an alkanolamine from the group comprising ethanolamine, diethanolamine, dipropanolamine, methyl diethanolamine, monoisopropanolamine and triethanolamine, and/or 5) ethyl, propyl, or butyl lactate. In one embodiment, we propose the use of dimethyl sulfoxide (DMSO) as a replacement in NBPT-based agrichemical products for more toxic solvents such as, for N-methyl pyrrolidone. BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS FIG. 1 shows accelerated chemical stability of NBPT solutions comparing the test product (50% PG, 25% DMSO, 25% NBPT) vs. the commercial product containing N-methyl pyrrolidone. The stability testing was conducted at 50° C., and concentrations were assayed by HPLC. FIG. 2 shows accelerated chemical stability of NBPT solutions comparing the test product (35% PG, 40% DMSO, 25% NBPT) vs. the commercial product containing N-methyl pyrrolidone. The stability testing was conducted at 50° C., and concentrations were assayed by HPLC. FIG. 3 shows accelerated chemical stability of NBPT solutions comparing the test product (20% PG, 40% DMSO, 40% NBPT) vs. the commercial product containing N-methyl pyrrolidone. The stability testing was conducted at 50° C., and concentrations were assayed by HPLC. FIG. 4 shows accelerated chemical stability of NBPT solutions comparing the test product (48.5% glycerine, 1.5% methanol, 25% DMSO, 25% NBPT) vs. the commercial product containing N-methyl pyrrolidone. The stability testing was conducted at 50° C., and concentrations were assayed by FIG. 5 shows accelerated chemical stability of NBPT solutions comparing the test product (48.5% glycerine, 1.5% methanol, 25% DMSO, 25% NBPT) vs. the commercial product containing N-methyl pyrrolidone. The stability testing was conducted at 50° C., and concentrations were assayed by HPLC. FIG. 6 shows accelerated chemical stability of four NBPT solutions: Mix A; 75.0% N-methyl pyrrolidone, 25% NBPT. Mix B; 75 PG, 25% NBPT. Mix C; 75.0% Buffered mix, 25.0% NBPT. Mix D; 75% DMSO, 25.0% NBPT. The stability testing was conducted at 50° C., and concentrations were assayed by HPLC. FIG. 7 shows viscosity testing results comparing mixtures of propylene glycol with varying percentages of co-solvents DMSO vs. NMP. Viscosities were measured using a Brookfield LVDV-E digital rotational viscometer with LVDV-E spindle set. Also shown is the viscosity of the commercial NBPT product, which contains NMP and PG, of example 2. FIG. 8 shows viscosity testing results comparing mixtures of glycerol with varying percentages of co-solvents DMSO vs. NMP. Viscosities were measured using a Brookfield LVDV-E digital rotational viscometer with LVDV-E spindle set. Also shown is the viscosity of the commercial NBPT product, which contains NMP and PG, of example 2. FIG. 9 shows viscosity testing results comparing mixtures of monoisopropanolamine (MIPA) with varying percentages of co-solvents DMSO vs. NMP. Viscosities were measured using a Brookfield LVDV-E digital rotational viscometer with LVDV-E spindle set. Also shown is the viscosity of the commercial NBPT product, which contains NMP and PG, of example 2. FIG. 10 shows ammonia emissions testing results from soil which had been applied commercial urea fertilizer vs. commercial urea fertilizer coated with an NBPT solution containing 50.0% PG, 30.0% DMSO, and 20.0% NBPT by weight. The testing was conducted for 7 days at 22° C. using a commercially available potting soil blend, and was analyzed using a chemiluminescence ammonia analyzer. DETAILED DESCRIPTION OF THE INVENTION In an embodiment, the present invention relates to formulations containing N-(n-butyl) thiophosphoric triamide (NBPT). In an embodiment, these formulations are prepared by dissolving NBPT into an aprotic solvent consisting of a) dimethyl sulfoxide, b) dialkyl, diaryl, or alkylaryl sulfoxide having the formula R1—SO—R2, when R1 is methyl, ethyl, n-propyl, phenyl or benzyl and R2 is ethyl, n-propyl, phenyl or benzyl, c) sulfolane, d) ethylene carbonate, propylene carbonate, or mixtures thereof. In an embodiment, these formulations can be mixed with a protic component consisting of 1) an alcohol or polyol from the family of alkylene and poly(alkylene) glycols (PG), 2) an alkylene glycol from the group comprised of ethylene, propylene, or butylene glycol, 3) glycerin, 4) an alkanolamine from the group comprising ethanolamine, diethanolamine, dipropanolamine, methyl diethanolamine, monoisopropanolamine and triethanolamine, and/or 5) ethyl, propyl, or butyl lactate. In one embodiment, dimethyl sulfoxide (DMSO) is used as a replacement in NBPT-based agrichemical products for more toxic solvents such as, for N-methyl pyrrolidone (NMP). In one embodiment, the solution is either combined with a dry granular or liquid urea fertilizer and applied to cropland to make the fertilizer more effective for plant growth, and/or applied directly to urea-containing lands, surfaces, or products to reduce ammonia emissions. In one embodiment, coated granular urea products containing additional plant nutrients can be prepared from granular urea, a source or sources of the additional nutrients in powdered form and the diluted NBPT containing mixture described below. Granular urea can be first dampened with the diluted NBPT containing mixture followed by mixing to distribute the NBPT containing liquid mixture over the granular urea surface using any commonly used equipment to commingle a liquid with a granular solid. After distribution of the diluted NBPT containing mixture over the granular surface, the additional nutrients in powdered form can be added to the dampened mixture and the resulting combined ingredients can be further mixed to distribute the powdered materials. In an alternate embodiment, the powdered materials may be first mixed with the granular urea and then the NBPT containing diluted mixture can be sprayed onto a tumbling bed of the dry ingredients to agglomerate the dry materials. This latter method may be particularly suited to continuous processing. The term “urea fertilizer” as used herein refers to both natural and synthetic ureas, either used alone or mixed with other macro- and/or micronutrients and/or organic matter. Dry granular urea fertilizer contains about 46% nitrogen by weight. In one embodiment, the compounds listed in this invention as aprotic and protic solvents may be described generally as sulfoxides and alcohols, respectively. In an embodiment, the present invention relates to the use of safer and more environmentally friendly solvents to overcome the limitations of specific existing urease inhibitor formations. In an embodiment, the solvents used in the present invention are less toxic than the solvents that have been used in the prior art, for example, NMP. In an embodiment, the formulations use combinations of polar aprotic solvents (sulfoxides, sulfones, dialkyl carbonates) with protic solvents (glycols, triols, and alkanolamines) to produce NBPT formulations having acceptable viscosity levels and high NBPT loading while also being relatively non-toxic. Moreover, in an embodiment, the protic/aprotic solvent mixtures demonstrate excellent NBPT stability as demonstrated by accelerated stability testing. One aspect of the invention involves the use of dimethyl sulfoxide as a replacement for the more hazardous liquid amide component in formulations requiring such a co-solvent to modify the formulation's flow properties. In this aspect, this is a considerable improvement in light of increased regulatory scrutiny of the liquid amide solvents. In one embodiment, the present invention relates to the use of DMSO with NBPT instead of NMP. NMP has a recognized reproductive toxicity and an examination of acute toxicity data shows that NMP is considerably more hazardous than dimethyl sulfoxide, by any exposure route. A summary of basic toxicological indicators is given in Table 1. TABLE 1 Comparative acute/reproductive toxicity data for dimethyl sulfoxide and N-methyl pyrrolidone. Toxicological indicator Dimethyl sulfoxide N-methyl pyrrolidone CAS [67-68-4] [872-50-4] Oral LD-50 14,500-28,300 3,914 Dermal LD-50 40,000 8,000 Inhalation toxicity None established 3200 μg/day (MADL) Reproductive toxin no yes MADL = Maximum Allowable Dosage Level per day (California Proposition 65) As shown in the table above, it should be clear to those of ordinary skill in the art that DMSO is significantly less toxic than NMP. Furthermore, DMSO is classified as ‘a solvent with low toxic potential (Class 3)’—the most favorable rating. In one embodiment, the present invention addresses the shortcomings of solvents of the prior art by the use of specific mixtures of low toxicity polar aprotic solvents (most principally dimethyl sulfoxide) and various common protic solvents, that also tend to be relatively non-toxic. In an embodiment, the present invention relates to formulations comprising aprotic/protic solvent mixtures that are used to fluidize the specific urease inhibitor N-(n-butyl) thiophosphoric triamide such that it might be used to coat fertilizer products. In one embodiment, phosphate coatings for urea may be used wherein the coating is applied to urea as an aqueous phosphate mixture prior to adding the fertilizer additive of the present invention. In an embodiment, chelated micronutrients may be used to coat fertilizer materials. Alternatively and/or additionally, polymer coatings may be used which control the delivery of fertilizer materials. In one embodiment, the formulations of the present invention use DMSO as a solvent. DMSO has an advantage over prior art solvents such as NMP because DMSO does not undergo the hydrolysis that can be significant with NMP (see “M-Pyrrol” product bulletin, International Specialty Products, p. 48). Accordingly, when one uses DMSO, one has significantly more latitude in formulation development. Further, the solvent properties of DMSO are useful in these formulations in that NBPT concentrations containing over 50 wt. % NBPT are attainable. Such high loading of an active substance by a solvent enables the manufacture of product concentrates, which can be less expensive to store, transport and use. When the fertilizer additive product arrives at the user, the user is able to dilute the concentrate with water and use the fertilizer additive (with fertilizer) for their crops/plants or the like. In one embodiment, NBPT is dissolved into an aprotic solvent such as dimethyl sulfoxide. The NBPT-aprotic solvent solution may be used alone, or further mixed with a protic solvent to improve product handling, stability, and/or pourability of the solution. The mixing of the materials may be accomplished in any commonly used method: for example; simply tank mixing materials prior to use, using a metering system to inject materials simultaneously, or mixing via a spray injection system. In one embodiment, the NBPT/aprotic solvent/protic solvent mixture is mixed to produce a NBPT concentration of 5% to 75% by weight. Alternatively, a NBPT concentration of 5% to 60% by weight may be used. Alternatively, a NBPT concentration of 5% to 50% by weight may be used. Alternatively, a NBPT concentration of 5% to 40% by weight may be used. The initial solubilizing step in dimethyl sulfoxide can be accomplished between room temperature about 19° C. up to about 150° C. (the boiling point of DMSO at atmospheric pressure is ˜190° C.). Alternatively, the solubilizing step in dimethyl sulfoxide can be accomplished between about 22° C. and up to 60° C. The mixture can be mixed in any common mixing tank. Although the metering of NBPT, aprotic solvent, and protic solvent can be based on a weight, it may also be based on a volumetric basis. A dye or colorant can be added to the mixture to aid in visual assessment of uniform coating during the coating of granular urea. Alternatively, a dye or colorant can be added to the mixture to aid in visual assessment of uniform coating during the coating of urea in aqueous mixtures just prior to application. In one embodiment, the colorant can include any nontoxic common food dye. EXAMPLES The following examples are provided to illustrate the practice of the invention. The examples are not intended to illustrate the complete range of possible uses. All compositions are based on mass percentages unless expressly stated. Concentrations of individual components are presented before their name. For example, 20.0% NBPT refers to a mixture containing 20.0% NBPT by weight. Example 1 An NBPT solution was prepared by thoroughly mixing NBPT, DMSO, and PG to obtain the following percentages by weight: 50.0% PG, 30.0% DMSO, 20.0% NBPT. Example 2 To test for the toxicity of DMSO and compare it to the relative toxicity of NMP, a 96 hr. acute toxicity range-finding test was conducted on juvenile crayfish (Procambarus clarkii) to estimate the lethal concentration to half of the population (LC50) for the solution as described in example 1. Simultaneously, the LC50 was determined on a commercially available NBPT solution which contained 26.7% NBPT by weight (per product label), and approximately 10% N-methyl pyrrolidone (MSDS range 10-30%), and approximately 63% propylene glycol (MSDS range 40-70%). Crayfish were placed into static chambers and exposed to equal NBPT concentrations of 0, 72, 145, 290, 580, and 1160 mg/L in clean water. The LC50 of the solution of example 1 was 145 mg NBPT (as active ingredient)/L, while the LC50 of Agrotain® Ultra was 75 mg NBPT (as active ingredient)/L. Because a higher LC50 value indicates lower toxicity, the solution of example 1 was approximately half as toxic as the commercial product which contained N-methyl pyrrolidone. This test demonstrates that the formulations of the present invention are significantly less toxic than the formulations of the prior art. Example 3 NBPT solutions were prepared in DMSO and equal amounts of DMSO/PG to determine the maximum solubility at room temperature of 22° C. Following mixing and sonification, the samples were visually inspected, then filtered through a 0.45 μm filter and analyzed by near infrared reflectance spectrometry. At 22° C., the solubility of NBPT in DMSO was at least 58.9% by weight. The solubility of NBPT in equal amounts of DMSO/PG was at least 55.0% by weight. It would be expected that at increased temperatures beyond that disclosed above, one might be able to increase the solubility of NBPT above the amounts found in this example providing an avenue for concentrates. Even if the temperature is lowered during transport, instructions on the use of the fertilizer additive may instruct the user to raise the temperature of the formulation to assure complete solubilization of the product prior to use. Example 4 An NBPT solution was prepared by thoroughly mixing NBPT, DMSO, and PG to obtain the following percentages by weight: 50% PG, 25% DMSO, and 25% NBPT. The commercially available NBPT solution of example 2 was also used for comparison. Example 5 The NBPT solutions of example 4 were placed into individual vials and incubated for 45 days at 50±1° C. in a laboratory oven. Samples were periodically removed for analysis of NBPT in solution using a Waters model 1525 High Performance Liquid Chromatograph (HPLC) equipped with a Waters 2489 tunable UV/visible detector. Suitable analytical parameters (mobile phase composition, column selection, etc.) such as would occur to workers knowledgeable in the art were employed, and raw data from the HPLC analyses were calibrated against authentic standards of NBPT having a nominal purity of >99%. FIG. 1 shows the results of the accelerated stability testing. This test shows that the NBPT did not have significant deterioration at elevated temperatures meaning that the formulations of the present invention can be transported without worrying about significant degradation of the product. Example 6 An NBPT solution was prepared by thoroughly mixing NBPT, DMSO, and PG to obtain the following percentages by weight: 35% PG, 40% DMSO, and 25% NBPT. The commercially available NBPT solution of example 2 was also used for comparison. Example 7 The NBPT solutions of example 6 were placed into individual vials and incubated for 45 days at 50±1° C. in a laboratory oven. Samples were periodically removed and analyzed using the procedures of example 5. FIG. 2 shows the results of the accelerated stability testing. This test shows that the NBPT did not have significant deterioration at elevated temperatures when the relative amounts of DMSO are varied. Accordingly, the formulations of the present invention can be transported without worrying about significant degradation of the product at different DMSO levels. Example 8 An NBPT solution was prepared by thoroughly mixing NBPT, DMSO, and PG to obtain the following percentages by weight: 20% PG, 40% DMSO, and 40% NBPT. The commercially available NBPT solution of example 2 was also used for comparison. Example 9 The NBPT solutions of example 8 were placed into individual vials and incubated for 45 days at 50±1° C. in a laboratory oven. Samples were periodically removed and analyzed using the procedures of example 5. FIG. 3 shows the results of the accelerated stability testing. This test shows that the NBPT did not have significant deterioration at elevated temperatures when the relative amount of NBPT is increased. Accordingly, the formulations of the present invention can be transported without worrying about significant degradation of the product even at a relatively high NBPT concentration. Example 10 An NBPT solution was prepared by thoroughly mixing NBPT, DMSO, glycerine, and methanol to obtain the following percentages by weight: 48.5% glycerine, 1.5% methanol, 25% DMSO, and 25% NBPT. The commercially available NBPT solution of example 2 was also used for comparison. Example 11 The NBPT solutions of example 10 were placed into individual vials and incubated for 45 days at 50±1° C. in a laboratory oven. Samples were periodically removed and analyzed using the procedures of example 5. FIG. 4 shows the results of the accelerated stability testing. This test shows that the NBPT did not have significant deterioration at elevated temperatures with this formulation meaning that this formulation can be transported without worrying about significant degradation of the product. Example 12 An NBPT solution was prepared by thoroughly mixing NBPT, DMSO, glycerine, and methanol to obtain the following percentages by weight: 33.5% glycerine, 1.5% methanol, 25% DMSO, and 40% NBPT. The commercially available NBPT solution of example 2 was also used for comparison. Example 13 The NBPT solutions of example 12 were placed into individual vials and incubated for 45 days at 50±1° C. in a laboratory oven. Samples were periodically removed and analyzed using the procedures of example 5. FIG. 5 shows the results of the accelerated stability testing. This test shows that the NBPT did not have significant deterioration at elevated temperatures with this formulation meaning that this formulation can be transported without worrying about significant degradation of the product. Example 14 A buffer solution was prepared by carefully mixing monoisopropanolamine (MIPA) with glacial acetic acid (GAA) to obtain the following percentages by weight: 62.5% MIPA, 37.5% GAA. The mixing was conducted such that the temperature of the mixture remained below 50° C. Multiple NBPT solutions were prepared to obtain the following percentages by weight: Mix A: 75% N-methyl pyrrolidone, 25% NBPT; Mix B: 75% PG, 25% NBPT; Mix C: 75% Buffer Solution, 25% NBPT; Mix D: 75% DMSO, 25% NBPT. Example 15 The four NBPT solutions of example 14 were placed into individual vials and incubated for approximately 200 hrs. at 50±1° C. Samples were periodically removed and analyzed using the HPLC procedures of example 5. FIG. 6 shows the results of the accelerated stability testing. This test shows that Mix C had more sample degradation at elevated temperatures than mixtures containing DMSO (Mix D), NMP (Mix A) or PG (Mix B). It should be noted that PG does not have the pourability of DMSO and NMP is more toxic than DMSO. Example 16 Dynamic viscosity measurements were collected for propylene glycol, glycerin, and a representative alkanolamine (monoisopropanolamine, MIPA) with increasing levels of DMSO and NMP. A Brookfield LVDV-E digital rotational viscometer with LVDV-E spindle set (Brookfield Engineering Labs, Inc., Middleboro, Mass.) was employed for this work and was calibrated using Cannon N14 general purpose, synthetic base oil viscosity calibration standard solution (Cannon Instrument Company, State College, Pa.). The sampling was conducted at 21° C. FIGS. 7, 8, and 9 display the ability of DMSO to depress the viscosity of NBPT mixtures at 21° C. as a function of concentration, relative to similar NMP measurements. This test shows that there is virtually no difference between DMSO and NMP in reducing the viscosity of various viscous formulations. Example 17 A dye solution was added to the solution of example 1. 454 grams of granular urea was added to two clean, dry glass 2000 mL media bottles. Using a pipette, 1.87 mL, to represent application rate of 2 quarts product/ton urea of the dyed solution in example 1, was added to the urea in one of the bottles. Using a pipette, 1.87 mL, to represent application rate of 2 quarts product/ton urea of the commercial solution of example 2, was added to the urea in the other bottle. With the lid on, the media bottles were rotated hand over hand (1 rotation=360-degree hand over hand turn) until the urea was consistently coated. More complete coverage was observed after four turns in the dyed solution of example 1. The number of rotations required to obtain 100% visual coverage was recorded. The dyed solution of example 1 required 30 rotations for complete coverage, while the commercial product of example 2 required 35 rotations. This test shows that formulations containing DMSO and a dye can more easily cover urea than a corresponding solution containing NMP and a dye. Example 18 The NBPT solutions of examples 4, 6, 8, 10, and 12, together with the commercial NBPT solution of example 2, were placed in a −20° C. freezer for 48 hrs. The NBPT solutions of examples 4, 6, 8, and the commercial NBPT solution of example 2, were all freely flowable at −20° C. The NBPT solution of example 10 was very viscous but still flowable. The NBPT solution of example 12 was a solid at −20° C. Example 19 Commercial granulated urea was treated with the NBPT solution of example 1. Both untreated and treated urea were applied to a commercially available potting soil blend at 22° C., and ammonia concentrations in the headspace were measured for a 7-day period using a chemiluminescence analyzer. Ammonia concentrations in the treated urea were considerably less than those in the untreated urea. FIG. 10 shows the results of the ammonia emissions testing. This test shows that NBPT formulations containing DMSO are effective at reducing the hydrolysis of urea to ammonium, thereby reducing ammonia losses to the atmosphere and making the fertilizer more effective. In certain embodiments, the present invention relates to formulations, fertilizer additives, methods and processes of making and using these formulations and/or fertilizer additives. In an embodiment, the present invention relates to a formulation comprising N-(n-butyl) thiophosphoric triamide and one or more of an C1-6alkylene carbonate and R1S(O)xR2 wherein R1 and R2 are each independently a C1-6 alkylene group, an aryl group, or C1-3alkylenearyl group or R1 and R2 with the sulfur to which they are attached form a 4 to 8 membered ring wherein R1 and R2 together are a C1-6 alkylene group which optionally contains one or more atoms selected from the group consisting of O, S, Se, Te, N, and P in the ring and x is 1 or 2. In a variation, the atoms in the ring may optionally include O, S, N and P or alternatively, O, S, and N. In one embodiment, the formulation contains R1S(O)xR2, which is dimethyl sulfoxide. Alternatively, the formulation contains R1S(O)xR2, which is a dialkyl, diaryl, or alkylaryl sulfoxide. Alternatively, R1 and R2 may be the same or different and each of R1 and R2 may be C1-6 alkylene group, an aryl group, or C1-3alkylenearyl group. In an embodiment, R1 is methyl, ethyl, n-propyl, phenyl or benzyl and R2 is methyl, ethyl, n-propyl, phenyl or benzyl or mixtures thereof. In another embodiment, R1S(O)xR2 is sulfolane. In an embodiment, the formulation may contain akylene carbonate, which is ethylene carbonate, propylene carbonate, butylene carbonate or mixtures thereof. In a variation, the formulation may contain akylene carbonate, which is ethylene carbonate, propylene carbonate, or mixtures thereof. In an embodiment, the formulation may further comprise an alcohol or polyol wherein the polyol is alkylene or poly(alkylene) glycols or mixtures thereof. In an embodiment, the polyol is an alkylene glycol selected from the group consisting of ethylene, propylene, and butylene glycol, or mixtures thereof. In an embodiment, the polyol is glycerin. In an embodiment, the formulation may further comprise an alkanolamine selected from the group consisting of ethanolamine, diethanolamine, dipropanolamine, methyl diethanolamine, monoisopropanolamine and triethanolamine. The formulation(s) may contain an aqueous ethanolamine borate such as ARBORITE Binder. In one embodiment, the concentration of the secondary or tertiary amino alcohol may be kept above about 12% and alternatively, above about 20%. When the concentration of aqueous ethanolamine borate is below about a 12% concentration, a suspension of NBPT in the aqueous mixture may form which can be solved by agitation to be used to prepare other products. In an embodiment of the invention, NBPT may be dissolved by melting the compound with sufficient triethanolamine to provide a mixture with up to about 30% by weight of NBPT. The resulting NBPT mixture in triethanolamine can be used to treat urea as described herein. In another embodiment of the invention, NBPT is dissolved in diethanolamine in an amount up to 40% by weight by melting the solid into diethanolamine until a solution is obtained. The NBPT diethanolamine mixture may be used to treat urea as described herein. In another embodiment of the invention, a liquid mixture of diisopropanolamine may be prepared by gently warming the solid until it has liquefied and the mixing NBPT with the solid up to the solubility limit. The liquid NBPT containing mixture in disioproanolamine may be used to treat urea as described herein. In a variation, the formulation may further comprise ethyl, propyl, or butyl lactate. In an embodiment, the N-(n-butyl)-thiophosphoric triamide (NBPT) may be present in an amount that is between about 5-75 wt. % of the formulation. In a variation, the formulation may contain between about 10 and 75 wt. % NBPT, 10 and 50 wt. % DMSO, and 10 and 80 wt. % PG (poly glycol) or alkylene carbonate. In a variation, the formulation may contain between about 10 and 60 wt. % NBPT, 10 and 40 wt. % DMSO, and 10 and 60 wt. % PG or alkylene carbonate. In a variation, the formulation may contain between about 10 and 50 wt. % NBPT, 10 and 50 wt. % DMSO, and 10 and 50 wt. % PG or alkylene carbonate. In a variation, the formulation may contain between about 10 and 40 wt. % NBPT, 10 and 40 wt. % DMSO, and 10 and 50 wt. % PG or alkylene carbonate. In a variation, the formulation may contain between about 20 and 50 wt. % NBPT, 20 and 50 wt. % DMSO, and 10 and 50 wt. % PG or alkylene carbonate. In a variation, the formulation may be diluted with water. In an embodiment, the present invention relates to a fertilizer additive comprising N-(n-butyl) thiophosphoric triamide and one or more of an C1-6alkylene carbonate and R1S(O)xR2 wherein R1 and R2 are each independently a C1-6 alkylene group, an aryl group, or C1-3alkylenearyl group or R1 and R2 with the sulfur to which they are attached form a 4 to 8 membered ring wherein R1 and R2 together are a C1-6 alkylene group which optionally contains one or more atoms selected from the group consisting of O, S, Se, Te, N, and P in the ring and x is 1 or 2. In an embodiment, the fertilizer additive may comprise N-(n-butyl)-thiophosphoric triamide and dimethyl sulfoxide. In a variation, the fertilizer may further comprise polyalkylene glycols. In a variation, the polyalkylene glycols are selected from the group consisting of polymethylene glycols, polyethylene glycols, polypropylene glycols, polybutylene glycols, and mixtures thereof. In an embodiment, the fertilizer additive may be any of the embodiments discussed above as it relates to the formulation. In an embodiment, the present invention relates to a method of reducing the volatility of urea fertilizers comprising adding a composition that comprises N-(n-butyl)-thiophosphoric triamide and one or more of an C1-6alkylene carbonate and R1S(O)xR2 wherein R1 and R2 are each independently a C1-6 alkylene group, an aryl group, or C1-3alkylenearyl group or R1 and R2 with the sulfur to which they are attached form a 4 to 8 membered ring wherein R1 and R2 together are a C1-6 alkylene group which optionally contains one or more atoms selected from the group consisting of O, S, Se, Te, N, and P in the ring and x is 1 or 2. In an embodiment, the present invention relates to a method of making a formulation and/or fertilizer additive, wherein to N-(n-butyl)-thiophosphoric triamide is added one or more of an C1-6alkylene carbonate and R1S(O)xR2 wherein R1 and R2 are each independently a C1-6 alkylene group, an aryl group, or C1-3alkylenearyl group or R1 and R2 with the sulfur to which they are attached form a 4 to 8 membered ring wherein R1 and R2 together are a C1-6 alkylene group which optionally contains one or more atoms selected from the group consisting of O, S, Se, Te, N, and P in the ring and x is 1 or 2. In an embodiment, the methods may comprise R1S(O)xR2, which is dimethyl sulfoxide. In an embodiment, the methods may comprise C1-6alkylene carbonate, which is ethylene carbonate, propylene carbonate, butylene carbonate or mixtures thereof. In an embodiment, the methods may comprise any of the formulations and/or fertilizer additives discussed above. Every patent mentioned herein is incorporated by reference in its entirety. It should be understood that the present invention is not to be limited by the above description. Modifications can be made to the above without departing from the spirit and scope of the invention. It is contemplated and therefore within the scope of the present invention that any feature that is described above can be combined with any other feature that is described above. Moreover, it should be understood that the present invention contemplates minor modifications that can be made to the formulations, compositions, fertilizer additives and methods of the present invention. When ranges are discussed, any number that may not be explicitly disclosed but fits within the range is contemplated as an endpoint for the range. The scope of protection to be afforded is to be determined by the claims which follow and the breadth of interpretation which the law allows. | <SOH> BACKGROUND OF THE INVENTION <EOH> | <SOH> SUMMARY OF THE INVENTION <EOH>In one embodiment, the present invention relates to liquid formulations containing N-(n-butyl) thiophosphoric triamide (NBPT). In an embodiment, the formulations can be made by dissolving the NBPT into an aprotic solvent consisting of a) dimethyl sulfoxide, b) dialkyl, diaryl, or alkylaryl sulfoxide having the formula R 1 —SO—R 2 , when R 1 is methyl, ethyl, n-propyl, phenyl or benzyl and R 2 is ethyl, n-propyl, phenyl or benzyl, c) sulfolane, d) ethylene carbonate, propylene carbonate, or mixtures thereof. In an embodiment, these formulations can be mixed with a protic component consisting of 1) an alcohol or polyol from the family of alkylene and poly(alkylene) glycols (PG), 2) an alkylene glycol from the group comprised of ethylene, propylene, or butylene glycol, 3) glycerin, 4) an alkanolamine from the group comprising ethanolamine, diethanolamine, dipropanolamine, methyl diethanolamine, monoisopropanolamine and triethanolamine, and/or 5) ethyl, propyl, or butyl lactate. In one embodiment, we propose the use of dimethyl sulfoxide (DMSO) as a replacement in NBPT-based agrichemical products for more toxic solvents such as, for N-methyl pyrrolidone. | C05G308 | 20171025 | 20180215 | 63662.0 | C05G308 | 1 | LANGEL, WAYNE A | Liquid Formulations of Urease Inhibitors for Fertilizers | SMALL | 1 | CONT-ACCEPTED | C05G | 2,017 |
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15,793,845 | PENDING | PERSONALIZED GENETIC TESTING | The present disclosure provides methods and systems for personalized genetic testing of a subject. In some embodiments, a sequencing assay is performed on a biological sample from the subject, which then leads to genetic information related to the subject. Next, nucleic acid molecules are array-synthesized or selected based on the genetic information derived from data of the sequencing assay. At least some of the nucleic acid molecules may then be used in an assay which may provide additional information on one or more biological samples from the subject or a biological relative of the subject. | 1. A method for personalized genetic testing, comprising: (a) using a plurality of genetic characteristics to generate a nucleic acid configuration of an assay, which nucleic acid configuration includes nucleic acid sequences of a plurality of nucleic acid probe molecules, wherein said nucleic acid sequences are selective for genetic variants, wherein said plurality of genetic characteristics is determined by analyzing nucleic acid sequence data generated from nucleic acid molecules obtained from at least one biological sample of a subject, and wherein said plurality of genetic characteristics include said genetic variants in said nucleic acid molecules from said at least one biological sample; (b) providing said plurality of nucleic acid probe molecules by (i) synthesizing said plurality of nucleic acid probe molecules using at least one array, or (ii) selecting said plurality of nucleic acid probe molecules from a collection of nucleic acid probe molecules; and (c) using said plurality of nucleic acid probe molecules provided in (b) to perform at least said assay on one or more biological samples from said subject or at least one biological relative of said subject, to generate data indicative of a presence or absence of at least a subset of said genetic variants in said subject or said at least one biological relative. 2. The method of claim 1, further comprising generating said nucleic acid sequence data using a sequencing assay to sequence or quantify said nucleic acid molecules from said at least one biological sample. 3. The method of claim 2, further comprising analyzing said nucleic acid sequence data to determine said plurality of genetic characteristics. 4. The method of claim 2, further comprising outputting a report that is generated at least based on comparison of results from said sequencing assay with results from at least said assay of (c). 5. The method of claim 2, wherein in said sequencing assay, said at least one biological sample is obtained from said subject at a first time point, and wherein in (c), said one or more biological samples are obtained from said subject or said at least one biological relative of said subject at a second time point subsequent to said first time point. 6. The method of claim 2, wherein said sequencing assay comprises (i) exome sequencing, (ii) sequencing a panel of genes, (iii) whole genome sequencing, and/or (iv) sequencing a population of complementary deoxyribonucleic acid molecules derived from ribonucleic acid molecules. 7. The method of claim 2, wherein each of said plurality of nucleic acid probe molecules of said assay includes oligonucleotide-directed genomic content comprising (i) at least one variable portion from a result of said sequencing assay and (ii) at least one fixed portion independent of said result of said sequencing assay. 8. The method of claim 7, wherein said at least one variable portion corresponds to genes which are more highly expressed than genes that correspond to said at least one fixed portion. 9. The method of claim 7, wherein said at least one variable portion corresponds to genes with a first expression profile and said at least one fixed portion corresponds to genes with a second expression profile, wherein said first expression profile has greater sample-to-sample variability than said second expression profile. 10. The method of claim 7, wherein said at least one variable portion corresponds to potential neoantigen causing genetic variants of said subject, and wherein said at least one fixed portion corresponds to one or more of (1) cancer driver genes, (2) genes involved in the pharmacogenomics of cancer drugs, (3) genes involved in Mendelian immunological diseases, (4) genes related to inherited forms of cancer, (5) genes associated with tumor escape from a targeted or immune cancer therapy, (6) HLA typing, and (7) genetic variants common in the population and used by B-allele methods to detect structural variation. 11. The method of claim 7, wherein said at least one variable portion corresponds to genetic variants responsible for Mendelian phenotype of a proband, and wherein said at least one fixed portion corresponds to one or more of (1) additional genetic content not related to the Mendelian condition of the proband, (2) pharmacogenomics, (3) genetic sample ID by a fixed panel of genetic variants or a fixed panel of phenotype-related genetic variants, and (4) genetic variants common in the population and used by B-allele methods to detect structural variation. 12. The method of claim 1, wherein providing said plurality of nucleic acid probe molecules comprises synthesizing said plurality of nucleic acid probe molecules using at least one array. 13. The method of claim 1, further comprising outputting a report that is indicative of a presence or absence of said at least said subset of said genetic variants in said subject or said at least one biological relative. 14. The method of claim 1, wherein said one or more biological samples in (c) comprise a plurality of biological samples, and wherein (c) further comprises outputting a report that is generated at least based on comparison of results from said at least said assay from said plurality of biological samples assayed in (c) with each other. 15. The method of claim 1, further comprising providing a therapeutic intervention at least based on said presence or absence of said at least said subset of said genetic variants identified in (c). 16. The method of claim 1, wherein said at least one biological sample includes a tumor sample and said nucleic acids molecules are from cells in said tumor sample, and wherein said nucleic acid molecules are representative of a cancer genome of said subject. 17. The method of claim 1, wherein said plurality of genetic characteristics comprises one or more members selected from the group consisting of (i) single nucleotide polymorphisms, (ii) insertions and/or deletions, (iii) copy number variations, and (iv) structural variations. 18. The method of claim 1, wherein said plurality of genetic characteristics comprise genetic variants in a germline sequence of said subject. 19. The method of claim 1, wherein said plurality of genetic characteristics comprise post-zygotic variants from a germline sequence of said subject or recombination of elements from a germline sequence of said subject. 20. The method of claim 1, wherein said plurality of genetic characteristics in (a) comprises levels of gene expression and/or sequence counts or read-depth in data generated from ribonucleic acid molecules or complementary deoxyribonucleic acid molecules derived from said at least one biological sample. 21. The method of claim 1, wherein said plurality of genetic characteristics in (a) comprise levels of methylation at locations or in specific regions of a genome. 22. The method of claim 1, wherein said plurality of genetic characteristics in (a) comprise locations in or regions of a genome, and wherein said plurality of nucleic acid probe molecules of said assay enrich or deplete a nucleic acid mixture of nucleic acid molecules which include said locations or regions of said genome or portions thereof. 23. The method of claim 22, wherein said plurality of nucleic acid probe molecules of said assay enrich or deplete a nucleic acid mixture of nucleic acid molecules for target regions, by hybridization or amplification. 24. The method of claim 1, wherein (b) further comprises synthesizing said plurality of nucleic acid probe molecules on a single solid substrate. 25. The method of claim 1, wherein said assay in (c) comprises generating nucleic acid sequence data from said one or more biological samples. 26. The method of claim 1, wherein said plurality of genetic characteristics in (a) includes one or more of (i) genetic variants of said nucleic acid sequence with respect to a reference sequence(s) or germline sequence(s), (ii) alleles which match said reference sequence(s) and are correlated with a type of cancer or other disease, (iii) alleles which determine a human leukocyte antigen (HLA) type, (iv) metrics of gene expression and/or allele-specific expression, and (v) quantification of non-coding ribonucleic acid (RNA) molecules or micro-RNA molecules which are at least partially tissue-type specific or cancer-type specific. 27. The method of claim 1, wherein said at least one biological sample of (a) and said one or more biological samples of (c) include the same biological sample. 28. The method of claim 1, wherein in (a), said nucleic acid molecules from said at least one biological sample of said subject are obtained distal to their origin in a body of said subject, and said plurality of genetic characteristics include identified genomic locations of mosaic variants in said at least one biological sample. 29. The method of claim 28, wherein said plurality of nucleic acid probe molecules amplify or enrich said mosaic variants. 30. The method of claim 28, wherein in (c), said assay is performed on said one or more biological samples from one or more other locations in said body of said subject, to determine an extent to which said mosaic variants are observed in said one or more biological samples. | CROSS-REFERENCE This application is a continuation application of International Application Patent No. PCT/US2017/034823, filed May 26, 2047, which application claims priority to U.S. Provisional Patent Application No. 62/342,674, filed May 27, 2016, each of which is entirely incorporated herein by reference. BACKGROUND The history of deoxynucleic acid (DNA) sequencing and DNA synthesis has been intertwined, with advances in one often leading to advances in or applications of the other. The double helix structure of DNA was discovered by Watson and Crick in 1953. In the decades following that, chemists worked to develop methods to synthesize DNA strands (oligonucleotides) of predefined sequence. Caruthers, et al (U.S. Pat. No. 4,458,066 “Process for preparing oligonucleotides”, filed Mar. 24, 1981) introduced the phosphoramidite chemistry now widely used. It was implemented on substrates similar to chromatography columns, yielding one oligonucleotide per synthesis. At the end of this process, the synthesized molecules are cleaved from the substrates on which they have been synthesized, so they can be used in further reactions in solution. Instrument manufacturers subsequently introduced equipment implementing this process on multiple columns in parallel. On Apr. 24, 2000 for example, PE Applied Biosystems issued a press release introducing its “ABI 3900 High Throughput DNA Synthesizer” with 48 columns operating concurrently. In a system of this type, each oligo was synthesized on a separate substrate and delivered in a separate tube (or other container). Relatively large amounts of each DNA sequence can be synthesized on these machines (the ABI 3900 specification was 40 nanomoles up to 1 micro-mole per sequence). Methods for the synthesis of DNA sequences led to Polymerase Chain Reaction (PCR), which uses synthesized DNA priming sequences. Kary Mullis, who invented PCR and was later awarded the Nobel Prize for it, was working in a DNA synthesis lab at Cetus at the time. It was originally devised as a method to enable sequencing of the sickle cell anemia locus via Sanger sequencing. U.S. Pat. No. 4,683,202 “Process for amplifying nucleic acid sequences”, the original PCR patent, was filed in 1985. This was further refined in methods which integrated DNA amplification and the Sanger chain terminating reaction, e.g., Murray, V., “Improved double-stranded DNA sequencing using the linear polymerase chain reaction” Nucleic Acids Research, Vol 17, No 21 Pg 8889, Nov. 11, 1989. Still further refinement along these lines was termed “Cycle Sequencing” (e.g., U.S. Pat. No. 5,432,065 filed Mar. 30, 1993). All of these combined the use of individually synthesized DNA sequences, as primers for further DNA synthesis with polymerase enzymes. During this time, other groups developed methods for synthesis of DNA on a highly parallel microscopic scale, on a single substrate. This increased the parallelism of DNA synthesis by over a thousand-fold. Compared to the ABI 3900 instrument mentioned above for example, which can synthesize up to 48 sequences in parallel, some array-based methods can synthesize over 50,000 sequences in parallel without large manufacturing set-up costs. One method of array-based synthesis was described in Pirrung, et al (U.S. Pat. No. 5,143,854 “Large scale photolithographic solid phase synthesis of polypeptides and receptor binding screening thereof”, priority date Jun. 7, 1989). It was developed by scientists at Affymax Corporation, later spun out as Affymetrix, Inc. This early work used fixed photolithographic masks, similar to those of the semiconductor industry. This enabled production of many “DNA arrays” with the same set of DNA sequences on them. A group at the University of Wisconsin at Madison later devised a more flexible version of this using micro-mirror arrays (rather the fixed photolithographic masks) to dynamically define the spatial pattern of light in the system. This was spun out into the company Nimblegen in 1999, which was acquired by Roche in 2007. Another method for synthesis of DNA on a highly parallel microscopic scale, on a single substrate, was developed using technology from ink-jet printing. Brennan (U.S. Pat. No. 5,472,672 “Apparatus and method for polymer synthesis using arrays” filed Oct. 22, 1993) described such a system including the dispensing of microscopic droplets of synthesis reagents through an array of nozzles on a moveable print head. This technology was commercialized by Agilent, Inc. Early applications of these DNA arrays involved use of the oligonucleotides on the array substrates where they were synthesized. This typically involved hybridization of DNA (or complementary deoxyribonucleic acid (cDNA)) from a test sample to the oligonucleotides on the array. If the DNA (or cDNA) of the test sample was fluorescently labeled in advance, then imaging the array after hybridization and washing can quantify the amount of each sequence in the test sample. This was initially used to measure mRNA expression of genes and it was later used for genotyping. Application of DNA array technology to DNA sequencing largely waited until DNA sequencing itself advanced. The original methods of DNA sequencing (Sanger, Maxim & Gilbert shared a 1975 Nobel prize) used electrophoresis for separation and subsequent readout. Each such electrophoretic separation and detection was spatially separate, though companies developed instruments with several in parallel (e.g., Applied Biosystems Model 370, introduced about 1987, supported up to 24 in parallel; Applied Biosystems Model 3700, introduced in 1999 supported up to 96 in parallel, and Amersham's Molecular Dynamics unit introduced a version of its MegaBace system about 2002 with 384 in parallel.) Several groups did attempt to leverage DNA arrays for DNA sequencing (e.g., Lysov, et al, 1996, “Efficiency of sequencing by hybridization on oligonucleotide matrix supplemented by measurement of the distance between DNA segments.”). Affymetrix commercialized this approach for small applications (variants in CYP drug metabolizing genes, genotyping of HIV). These methods conduct the DNA sequencing reactions and fluorescent readout on the array and thus have been limited to one base per array spot and fairly small non-repetitive portions of genomes. Heidi Rehm, et al at the Harvard Medical School published a set of protocols for this in April 2011 “Targeted Sequencing Using Affymetrix CustomSeq Arrays” in Current Protocols in Human Genetics. In it the technology was described as suitable for re-sequencing portions of the human genome up to 300,000 bases in total length. The field moved forward with the commercialization of “Next Generation DNA Sequencing” methods, which enabled measurement of hundreds of thousands of sequences at a time. One of the first such systems was commercialized by 454, Inc (previously a division of Curagen, Inc and later acquired by Roche) in 2005 (Margulies, M. et al. “Genome sequencing in microfabricated high-density picoliter reactors” Nature 437, 376-380 (2005). This initial system can measure up to 200,000 sequences in parallel, each on average 100 bases long. Two years later, in 2007, a group at the Baylor College of Medicine used a 454 DNA sequencing instrument to sequence an exome (Albert, et al “Direct selection of human genomic loci by microarray hybridization” Nature Methods, November 2007, 4(11):903-5). The key to this work was that a DNA array was used not as a substrate for sequencing itself, but to enrich a genomic DNA sample for just the parts of the genome intended for sequencing. The original DNA sample, fragmented, was hybridized to the array. Portions of the genome which did not hybridize were washed off. Then the portions of the genome which did hybridize to the array were eluted off the array and sequenced separate from the array, using the 454 system. The DNA arrays used were from Nimblegen. Although that DNA synthesis technology had been available since 1999, it was its 2007 combination with huge parallelism of next generation DNA sequencing that made this application practical. In the work described above, DNA sequences synthesized on an array were used in-place on the array substrate. During the early 2000's though, groups began to explore technologies by which DNA molecules can be synthesized on an array but attached to the substrate of the array by a cleavable linker. This meant that after array synthesis, the linkers can be cleaved (e.g., chemically) releasing the oligonucleotides into solution, where they can be used as a pool. One example of this work is U.S. Pat. No. 7,211,654 (Xiaolian, et al, “Linkers and co-coupling agents for optimization of oligonucleotide synthesis and purification on solid supports” May 1, 2007). In 2007, a group at the Broad Institute, began to explore use of this approach to create pools of oligonucleotides in solution to capture select portions of the genome of a test sample. (See U.S. provisional application 61/063,489, Gnirke, et al, filed Feb. 4, 2008: “Selection of nucleic acids by solution hybridization to oligonucleotide baits”.) Dr. Carsten Russ of the Broad Institute described this approach at the February 2008 AGBT conference (reported by GenomeWeb). During 2008, Agilent licensed this technology. It was published on line Feb. 1, 2009 “Solution hybrid selection with ultra-long oligonucleotides for massively parallel sequencing” Nature Biotechnology 27, 182-189 (2009). In February 2009 Agilent launched this as a product line (trade name “SureSelect”) with its first human exome kit (“SureSelect All Exon”). Dr. Gnirke, et al at the Broad Institute continued to innovate and applied targeted capture, using array synthesis of DNA, to RNA transcriptomes: “Targeted next-generation sequencing of a cancer transcriptome enhances detection of sequence variants and novel fusion transcripts” Joshua Levin, et al (including Andreas Gnirke). Genome Biology 2009, 10:R115. In parallel with this, Next Generation DNA Sequencing technologies continued to advance. In June 2006, Solexa, Inc first shipped its Genome Analyzer system. This system measured 40 million DNA sequences in parallel, each initially 25 bases long. In 2008 Illumina, Inc acquired Solexa. Subsequent versions of this technology have continued to advance. The most current instrument (Illumina HiSeq-4000) can produce about 6 billion sequences in parallel, each 2×125 bases, for a total of 1.5 trillion bases, in a single run. Exome sequencing has been broadly adopted as a research tool. As an example, the Exome Aggregation Consortium based at the Broad Institute has released a dataset based on human exome sequences from over 60,000 individuals (release v0.3 Jan. 2015). Exome sequencing has also been adopted clinically. The first commercial clinical exome tests were announced by GeneDx and Ambry Genetics at the ASHG conference in October 2011. Others including the Baylor College of Medicine have also offered commercial clinical human exome-based tests, and over 8,000 have been performed. DNA synthesis technologies have continued to advance, particularly focused on gene synthesis applications requiring very long DNA sequences. Many of these advances involve the construction of long DNA molecules by strategies which combine shorter synthetic DNA molecules. This was reviewed in: “Large-scale de novo DNA synthesis: technologies and applications” Sriram Kosuri and George Church, Nature Methods, Volume 11, No 5, May 2014; 499. SUMMARY In spite of the advances described above, the clinical adoption of exome-scale sequencing has been limited by the costs involved. Health insurers, who are asked to pay for these tests, often refuse, given the scale of the expense. This problem is even worse in cancer, where the depth of deoxynucleic acid (DNA) sequencing required can be much higher (e.g., >500×) than that for inherited diseases (e.g., 30-100×). While array-based DNA synthesis is now widely used to capture whole exomes, transcriptomes, or application-specific subsets of exomes (e.g., the genes involved with a specific Mendelian disease), a limitation of the field, as recognized herein, is the potential to leverage array synthesis of DNA in a personalized manner. The field has largely used array-based synthesis to develop standard products which are broadly applicable across a whole set of human patients and/or research subjects. Even where custom array synthesis is proposed, it is to sequence regions of the genome defined independent of a specific sample. In one aspect, the disclosure provides a method for personalized genetic testing, comprising: (a) using a plurality of genetic characteristics to determine a nucleic acid configuration of an assay, which nucleic acid configuration includes nucleic acid sequences of a plurality of nucleic acid probe molecules, wherein the nucleic acid sequences are selective for genetic variants, wherein the plurality of genetic characteristics is determined by analyzing nucleic acid sequence data generated from at least one biological sample of a subject, and wherein the plurality of genetic characteristics include the genetic variants in the nucleic acid molecules from the at least one biological sample; (b) providing the plurality of nucleic acid probe molecules by (i) synthesizing the plurality of nucleic acid probe molecules using at least one array, or (ii) selecting the plurality of nucleic acid probe molecules from a collection of nucleic acid probe molecules; and (c) using the plurality of nucleic acid probe molecules provided in (b) to perform at least the assay on one or more biological samples from the subject or at least one biological relative of the subject, to generate data indicative of a presence or absence of at least a subset of the genetic variants in the subject or the at least one biological relative. Some embodiments may further comprise generating the nucleic acid sequence data using a sequencing assay to sequence or quantify nucleic acid molecules from the at least one biological sample. In some embodiments providing the plurality of nucleic acid probe molecules comprises synthesizing the plurality of nucleic acid probe molecules using at least one array. In some embodiments, in the sequencing assay, at least one biological sample is obtained from the subject at a first time point, and wherein in (c), the one or more biological samples are obtained from the subject or the at least one biological relative of the subject at a second time point subsequent to the first time point. In some embodiments, providing the plurality of nucleic acid probe molecules comprises selecting the plurality of nucleic acid probe molecules from a collection of nucleic acid probe molecules. Some embodiments comprise outputting a report that is indicative of a presence or absence of the at least the subset of the genetic variants in the subject or the at least one biological relative. In some embodiments, the nucleic acid probe molecules comprise primers for amplifying the nucleic acid sequences. Some embodiments further comprise outputting a report that is generated at least based on comparison of results from the sequencing assay with results from the second assay of (c). In some embodiments, the one or more biological samples in (c) comprise a plurality of biological samples, and wherein (c) further comprises outputting a report that is generated at least based on comparison of results from the at least the assay from the plurality of biological samples assayed in (c) with each other. In some embodiments, at least the assay comprises a plurality of the assay. In some embodiments, the plurality of the assay is performed on (i) a plurality of biological samples of the subject or (ii) a plurality of biological samples of the at least one biological relative of the subject. Some embodiments further comprise providing a therapeutic intervention at least based on the presence or absence of the at least the subset of the genetic variants identified in (c). In some embodiments, the sequencing assay comprises (i) exome sequencing, (ii) sequencing a panel of genes, (iii) whole genome sequencing, and/or (iv) sequencing a population of complementary deoxyribonucleic acid molecules derived from ribonucleic acid molecules. In some embodiments, the sequencing assay comprises sequencing the nucleic acid molecules generated in quantity or sequence by interaction with the at least one biological sample from the subject. In some embodiments, the sequencing assay comprises sequencing the nucleic acid molecules derived from antibody-oligonucleotide conjugates of the subject. In some embodiments, the nucleic acid molecules from the at least one biological sample comprise nucleic acid molecules from cells of the subject and are representative of a germline genome of the subject. In some embodiments, the nucleic acid molecules from the at least one biological sample comprise nucleic acids from (i) white blood cells or (ii) non-cancerous cells adjacent to or embedded in a tumor or metastasis of the subject. In some embodiments, the nucleic acid molecules from the at least one biological sample are cell-free nucleic acid molecules. In some embodiments, at least one biological sample includes a blood sample and the nucleic acids molecules are from blood cells in the blood sample, and wherein the subject has been diagnosed with a blood-related cancer such that the nucleic acid molecules in (a) are representative of a cancer genome of the subject. In some embodiments, the nucleic acids molecules are derived from a buccal swab, and wherein the nucleic acid molecules are representative of an ectodermal genome of the subject. In some embodiments, at least one biological sample includes a tumor sample and the nucleic acids molecules are from cells in the tumor sample, and wherein the nucleic acid molecules are representative of a cancer genome of the subject. In some embodiments, the nucleic acid molecules are derived from T-cells and/or B-cells of an adaptive immune system of the subject, representing post-zygotic V(D)J recombination. In some embodiments, the nucleic acid molecules comprise non-human nucleic acid molecules derived from the at least one biological sample, representing a genome(s) of one or more microbial organisms. In some embodiments, the sequencing assay comprises analysis of a single biological sample from the subject. In some embodiments, at least one biological sample includes a plurality of biological samples, and wherein the first assay comprises analysis of the plurality of biological samples and at least one of the plurality of genetic characteristics determined in (b) is based on comparison of the analysis. In some embodiments, at least one biological sample includes a tumor of the subject, and wherein the first assay of (a) comprises analysis of the at least one biological sample and analysis of an additional biological sample which represents a germline genome of the subject. In some embodiments, at least one biological sample includes a tumor of the subject and the nucleic acid molecules include deoxyribonucleic acid (DNA) molecules and ribonucleic acid (RNA) molecules from the tumor, and wherein the first assay comprises analysis of the DNA and RNA. In some embodiments, the plurality of genetic characteristics comprises one or more (i) single nucleotide polymorphisms, (ii) insertions and/or deletions, (iii) copy number variations, and (iv) structural variations. In some embodiments, the plurality of genetic characteristics include signatures combining multiple genetic variants. In some embodiments, the plurality of genetic characteristics comprise genetic variants in a germline sequence of the subject. In some embodiments, the plurality of genetic characteristics comprise post-zygotic variants from a germline sequence of the subject. In some embodiments, the plurality of genetic characteristics comprise post-zygotic recombination of elements from a germline sequence of the subject. In some embodiments, the plurality of genetic characteristics comprise levels of gene expression and/or sequencing read counts or read-depth in data derived from ribonucleic acid molecules or complementary deoxyribonucleic acid molecules derived from the at least one biological sample. In some embodiments, the plurality of genetic characteristics comprise levels of messenger ribonucleic acid expression of alleles from deoxyribonucleic acid molecules derived from the at least one biological sample. In some embodiments, the plurality of genetic characteristics comprise levels of methylation at specific locations or in specific regions of a genome. In some embodiments, the plurality of genetic characteristics comprise locations in or regions of a genome, and wherein the plurality of nucleic acid probe molecules of the assay enrich or deplete a nucleic acid mixture of nucleic acid molecules which include the locations or regions of the genome or portions thereof. In some embodiments, the plurality of genetic characteristics comprise numbers of sequences derived from oligo-antibody conjugates contacted with the at least one biological sample. In some embodiments, the plurality of nucleic acid probe molecules of the assay enrich or deplete a nucleic acid mixture of nucleic acid molecules for target regions, by hybridization or amplification. In some embodiments, each of the nucleic acid probe molecules of the assay includes a region targeted for a genomic locus or region. In some embodiments, each of the nucleic acid probe molecules of the second assay includes a barcode sequence. In some embodiments, each of the nucleic acid probe molecules of the assay includes a region for demultiplexing or selective amplification of at least a subset of nucleic acid molecules from the one or more biological samples, pooled across multiple genomic loci and/or across multiple subjects. In some embodiments, the plurality of nucleic acid probe molecules includes sequences selected from a library of sequences. In some embodiments, the sequences capture coding exons of a genome of the subject or the at least one biological relative. In some embodiments, each of the plurality of nucleic acid probe molecules includes a variation from a reference sequence in the first assay of the subject. Some embodiments further comprise synthesizing the plurality of nucleic acid probe molecules on a single solid substrate. Some embodiments further comprise synthesizing at least 100 nucleic acid sequences in parallel. Some embodiments further comprise synthesizing at least 1,000 nucleic acid sequences in parallel. Some embodiments further comprise synthesizing at least 10,000 nucleic acid sequences in parallel. Some embodiments further comprise synthesizing at least 50,000 nucleic acid sequences in parallel. Some embodiments further comprise synthesizing a plurality of nucleic acid sequences in spatially separate regions of the single solid substrate. In some embodiments, the assay comprises generating nucleic acid sequence data from the one or more biological samples. Some embodiments further comprise mapping the nucleic acid sequence data to a reference. In some embodiments, each of the plurality of nucleic acid probe molecules is at least 50 bases in length. In some embodiments, the assay comprises nucleic acid sequencing or gene expression analysis. In some embodiment, each of the plurality of nucleic acid probe molecules of the assay includes oligonucleotide-directed genomic content comprising (i) at least one variable portion from a result of the sequencing assay and (ii) at least one fixed portion independent of the result of the sequencing assay. In some embodiments, the oligonucleotides of the at least one fixed portion are synthesized on the same array(s) as the at least one variable portion. The method of Claim 54, wherein oligonucleotides of the at least one fixed portion are synthesized on separate array(s) as the at least one variable portion. In some embodiments, at least one variable portion corresponds to genes which are more highly expressed than genes that correspond to the at least one fixed portion. In some embodiments, at least one variable portion corresponds to genes with a first expression profile and the at least one fixed portion corresponds to genes with a second expression profile, wherein the first expression profile has greater sample-to-sample variability than the second expression profile. In some embodiments, the genomic content includes coding regions of genes. In some embodiments, the genomic content includes regions corresponding to non-coding ribonucleic acid (RNA), micro-RNA and/or intronic RNA. In some embodiments, at least one variable portion corresponds to potential neoantigen causing genetic variants of the subject, and wherein the at least one fixed portion corresponds to one or more of (1) cancer driver genes, (2) genes involved in the pharmacogenomics of cancer drugs, (3) genes involved in Mendelian immunological diseases, (4) genes related to inherited forms of cancer, (5) genes associated with tumor escape from a targeted or immune cancer therapy, (6) HLA typing, and (7) genetic variants common in the population and used by B-allele methods to detect structural variation. In some embodiments, at least one variable portion corresponds to genetic variants responsible for Mendelian phenotype of a proband, and wherein the at least one fixed portion corresponds to one or more of (1) additional genetic content not related to the Mendelian condition of the proband, (2) pharmacogenomics, (3) genetic sample ID by a fixed panel of genetic variants or a fixed panel of phenotype-related genetic variants, and (4) genetic variants common in the population and used by B-allele methods to detect structural variation. In some embodiments, the (i) the subject is a member of a family pedigree and has or is suspected of having a medical condition that is Mendelian, (ii) the plurality of genetic characteristics in (a) are genetic variants of a nucleic sequence from a reference sequence(s) or alleles which match the reference sequence(s) and are associated with a medical condition, (iii) the nucleic acid sequences in (c) are configured to capture or amplify genomic regions comprising at least a subset of the genetic variants, (iv) the assay is nucleic acid sequencing, and (vi) the one or more biological samples in (c) is from the at least one biological relative that is a member of the family pedigree. Some embodiments further comprise generating a report that identifies genetic variants shared by family members of the family pedigree, which genetic variants are responsible for the medical condition of the subject. In some embodiments, the (i) the medical condition includes neurological clinical features, (ii) at least one of the biological samples assayed is from buccal swabs or other tissue of ectodermal lineage, (iii) the report is generated based at least in part on a possibility that one or more genetic variants of the subject are mosaic and included in the ectodermal lineage of the subject. In some embodiments, at least one of the biological samples assayed includes deoxyribonucleic acid molecules from sperm of an individual in the family pedigree, and wherein the report is generated based at least in part on a possibility that one or more of the genetic variants are gonadal mosaic in a father of the subject. Some embodiments further comprise combining genetic variants from probands in multiple Mendelian pedigrees into a single list of genetic loci and/or regions. In some embodiments, the plurality of nucleic acid probe molecules are for in-solution capture of those genetic loci and/or regions, by hybridization. In some embodiments, the plurality of nucleic acid probe molecules is synthesized by inkjet printing on an array with a capacity of at least about 50,000 nucleic acid sequences, and followed by cleavage from the array. Some embodiments further comprise separating genetic variants for each Mendelian pedigree from nucleic acid data from the assay. Some embodiments further comprise filtering genetic variants that are causal or suspected of being causal. In some embodiments, the plurality of genetic characteristics includes genes derived from a clinical phenotype of the subject. In some embodiments, the subject has cancer or is suspected of having cancer, and wherein the at least one biological sample includes a tissue sample or a blood sample from the subject. In some embodiments, the nucleic acid molecules include deoxyribonucleic acid (DNA) molecules. In some embodiments, the DNA includes cell-free DNA. In some embodiments, the nucleic acid molecules include ribonucleic acid (RNA) molecules or complementary deoxyribonucleic acid (DNA) molecules derived from the RNA molecules. In some embodiments, the RNA includes cell-free RNA. In some embodiments, the plurality of genetic characteristics in (a) includes one or more of (i) genetic variants of the nucleic acid sequence with respect to a reference sequence(s) or germline sequence(s), (ii) alleles which match the reference sequence(s) and are correlated with a type of cancer or other disease, (iii) alleles which determine a human leukocyte antigen (HLA) type, (iv) metrics of gene expression and/or allele-specific expression, and (v) quantification of non-coding ribonucleic acid (RNA molecules or micro-RNA molecules which are at least partially tissue-type specific or cancer-type specific. Some embodiments further comprise filtering to select at least a subset of the genetic variants determined to be relevant for analysis of the tumor or a treatment of the subject. In some embodiments, one or more biological samples are from the subject and include one or more of (i) germline deoxyribonucleic acid (DNA), (ii) tumor ribonucleic acid (RNA) or complementary DNA derived from the tumor RNA, (iii) cell-free DNA or RNA derived from blood plasma, (iv) DNA from the subject which contains or is suspected of containing mosaic variants, and (v) tumor and/or germline DNA. Some embodiments further comprise generating a report that identifies genetic variants that are associated with a therapeutic intervention for the subject. In some embodiments, the assay comprises sequencing nucleic acid molecules from the one or more biological samples of the subject. In some embodiments, the assay comprises quantifying the nucleic acid molecules. In some embodiments, the tissue sample is a tumor sample. In some embodiments, the plurality of genetic characteristics includes expressed genetic variants observed in a tumor sample of the subject but not observed in a germline of the subject, which have been assessed to be potential neoantigens for use in a personal cancer vaccine. In some embodiments, the sequencing assay comprises sequencing the nucleic acid molecules. In some embodiments, the sequencing assay further comprises sequencing a germline nucleic acid molecule(s). In some embodiments, the sequencing assay comprises sequencing a plurality of V(D)J recombination segments, each of which specifying an antigen receptor of a T-cell and/or B-cell of the subject. In some embodiments, the plurality of genetic characteristics include identities and quantities of V(D)J sequences from the plurality of V(D)J recombination segments. In some embodiments, the plurality of nucleic acid probe molecules capture or amplify nucleic acid sequences from the one or more biological samples that lead to neoantigens, which can be recognized by T-cell receptors or B-cell receptors corresponding to a V(D)J recombination segments. In some embodiments, the data confirms presence of genetic variants in a tumor of the subject, corresponding to the V(D)J recombination segments. In some embodiments, the data quantifies the genetic variants. In some embodiments, at least one biological sample and the one or more biological samples include the same biological sample. In some embodiments, the nucleic acid sequence data has less than or equal to about five million sequence reads. In some embodiments, the nucleic acid sequence data has less than or equal to about one million sequence reads. In some embodiments, the plurality of nucleic acid probe molecules capture or amplify nucleic acid molecules in the one or more biological samples. In some embodiments, the genetic variants are with respect to a reference genome. In some embodiments, the reference genome is from the subject. In some embodiments, the at least one biological sample includes tumor tissue, and wherein the first assay comprises (i) exposing the tumor tissue to a mixture of oligonucleotide-antibody conjugates, wherein at least some of the oligonucleotide-antibody conjugates bind to proteins or peptides in the tumor tissue, and (ii) sequencing oligonucleotides released from the oligonucleotide-antibody conjugates upon binding to the proteins or peptides, which oligonucleotides correspond to the nucleic acid molecules, to yield the nucleic acid sequence data. In some embodiments, the plurality of genetic characteristics includes identities and quantities of the oligonucleotide-antibody conjugates corresponding to the oligonucleotides released from the oligonucleotide-antibody conjugates. In some embodiments, the plurality of nucleic acid probe molecules are for capturing or amplifying one or more of (i) a plurality of oligonucleotide sequences of oligonucleotide-antibody conjugates, or (ii) deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) sequences corresponding to the proteins or peptides bound to an antibody component of the oligonucleotide-antibody conjugates. In some embodiments, one or more biological samples include DNA molecules, RNA molecules, or complementary DNA molecules derived from the RNA molecules from the subject. In some embodiments, the nucleic acid molecules from the at least one biological sample of the subject are obtained distal to their origin in a body of the subject, and the plurality of genetic characteristics include identified genomic locations of mosaic variants in the at least one biological sample. In some embodiments, the plurality of nucleic acid probe molecules amplify or enrich the mosaic variants. In some embodiments, the second assay is performed on the one or more biological samples from one or more other locations in the body of the subject, to determine an extent to which the mosaic variants are observed in the one or more biological samples. Some embodiments further comprise generating a report indicative of the origin in the body of the subject. In some embodiments, the nucleic acid molecules include (i) cell-free deoxyribonucleic acid (DNA) or cell-free ribonucleic acid (RNA) from blood plasma, (ii) RNA from one or more exosomes derived from a blood sample of the subject, (iii) DNA or RNA from circulating tumor cells, or (iv) DNA or RNA from a tumor metastasis. In another aspect, the present disclosure provides a method of personalized genetic testing, comprising: (a) deriving phenotypic information from a health or medical record of a subject, which health or medical record is in one or more databases; (b) determining a plurality of genetic characteristics of the subject from the phenotypic information derived in (a), wherein the plurality of genetic characteristics include genetic variants, and wherein the plurality of genetic characteristics facilitate diagnosis, prognosis or improved health or medical treatment of the subject; (c) using the plurality of genetic characteristics from (b) to determine a nucleic acid configuration of an assay, which nucleic acid configuration includes nucleic acid sequences of a plurality of nucleic acid probe molecules, wherein the nucleic acid sequences are selective for the genetic variants; (d) providing the plurality of nucleic acid probe molecules by (i) synthesizing the plurality of nucleic acid probe molecules using at least one array, or (ii) selecting the plurality of nucleic acid probe molecules from a collection of nucleic acid probe molecules; and (e) using the plurality of nucleic acid probe molecules provided in (d) to perform at least the assay on one or more biological samples from the subject or at least one biological relative of the subject, to generate data indicative of a presence or absence of at least a subset of the genetic variants in the subject or the at least one biological relative. In some embodiments, providing the plurality of nucleic acid probe molecules comprises synthesizing the plurality of nucleic acid probe molecules using at least one array. In some embodiments, providing the plurality of nucleic acid probe molecules comprises selecting the plurality of nucleic acid probe molecules from a collection of nucleic acid molecules. In some embodiments, the biological sample is obtained from the subject at a first time point, and wherein in (e), the one or more biological samples are obtained from the subject or the at least one biological relative of the subject at a second time point subsequent to the first time point. In some embodiments, the nucleic acid probe molecules comprise primers for amplifying the nucleic acid sequences. Some embodiments further comprise outputting a report that is indicative of a presence or absence of the at least the subset of the genetic variants in the subject or the at least one biological relative. Some embodiments further comprise outputting a report that is generated at least based on comparison of results from the first assay of (a) with results from the second assay of (e). In some embodiments, one or more biological samples in (e) comprise a plurality of biological samples, and wherein (e) further comprises outputting a report that is generated at least based on comparison of results from the at least the second assay from the plurality of biological samples assayed in (e) with each other. In some embodiments, at least the second assay comprises a plurality of the second assay. In some embodiments, the plurality of the second assay is performed on (i) a plurality of biological samples of the subject or (ii) a plurality of biological samples of the at least one biological relative of the subject. Some embodiments further comprise providing a therapeutic intervention at least based on the presence or absence of the at least the subset of the genetic variants identified in (e). In yet another aspect, the disclosure provides a non-transitory computer-readable medium comprising machine executable code that, upon execution by one or more computer processors, implements a method for personalized genetic testing, comprising: (a) using a plurality of genetic characteristics to determine a nucleic acid configuration of an assay, which nucleic acid configuration includes nucleic acid sequences of a plurality of nucleic acid probe molecules, wherein the nucleic acid sequences are selective for genetic variants, wherein the plurality of genetic characteristics is determined by analyzing nucleic acid sequence data generated from at least one biological sample of a subject, and wherein the plurality of genetic characteristics include the genetic variants in the nucleic acid molecules from the at least one biological sample; (b) providing the plurality of nucleic acid probe molecules by (i) synthesizing the plurality of nucleic acid probe molecules using at least one array, or (ii) selecting the plurality of nucleic acid probe molecules from a collection of nucleic acid probe molecules; and (c) using the plurality of nucleic acid probe molecules provided in (b) to perform at least the assay on one or more biological samples from the subject or at least one biological relative of the subject, to generate data indicative of a presence or absence of at least a subset of the genetic variants in the subject or the at least one biological relative. In yet another aspect, the disclosure provides a non-transitory computer-readable medium comprising machine executable code that, upon execution by one or more computer processors, implements a method for personalized genetic testing, comprising: (a) deriving phenotypic information from a health or medical record of a subject, which health or medical record is in one or more databases; (b) determining a plurality of genetic characteristics of the subject from the phenotypic information derived in (a), wherein the plurality of genetic characteristics include genetic variants, and wherein the plurality of genetic characteristics facilitate diagnosis, prognosis or improved health or medical treatment of the subject; (c) using the plurality of genetic characteristics from (b) to determine a nucleic acid configuration of an assay, which nucleic acid configuration includes nucleic acid sequences of a plurality of nucleic acid probe molecules, wherein the nucleic acid sequences are selective for the genetic variants; (d) providing the plurality of nucleic acid probe molecules by (i) synthesizing the plurality of nucleic acid probe molecules using at least one array, or (ii) selecting the plurality of nucleic acid probe molecules from a collection of nucleic acid probe molecules; and (e) using the plurality of nucleic acid probe molecules provided in (d) to perform at least the assay on one or more biological samples from the subject or at least one biological relative of the subject, to generate data indicative of a presence or absence of at least a subset of the genetic variants in the subject or the at least one biological relative. In an additional aspect, the disclosure provides a computer system for personalized genetic testing, comprising: one or more computer processors that are individually or collectively programmed to: (i) use a plurality of genetic characteristics to determine a nucleic acid configuration of an assay, which nucleic acid configuration includes nucleic acid sequences of a plurality of nucleic acid probe molecules, wherein the nucleic acid sequences are selective for the genetic variants, wherein the plurality of genetic characteristics is determined by analyzing nucleic acid sequence data generated from at least one biological sample of a subject, and wherein the plurality of genetic characteristics include the genetic variants in the nucleic acid molecules from the at least one biological sample; (ii) provide the plurality of nucleic acid probe molecules by (1) directing synthesis of the plurality of nucleic acid probe molecules using at least one array, or (2) selecting the plurality of nucleic acid probe molecules from a collection of nucleic acid probe molecules; and (iii) direct use of the plurality of nucleic acid probe molecules provided in (ii) to perform at least the assay on one or more biological samples from the subject or at least one biological relative of the subject, to generate data indicative of a presence or absence of at least a subset of the genetic variants in the subject or the at least one biological relative; and a computer display operative coupled to the one or more computer processors, wherein the computer display comprises a user interface that displays a report indicative of a presence or absence of the at least the subset of the genetic variants in the subject or the at least one biological relative. In another aspect, the disclosure provides a computer system for personalized genetic testing, comprising: one or more computer processors that are individually or collectively programmed to: (i) derive phenotypic information from a health or medical record of a subject, which health or medical record is in one or more databases; (ii) determine a plurality of genetic characteristics of the subject from the phenotypic information derived in (i), wherein the plurality of genetic characteristics include genetic variants, and wherein the plurality of genetic characteristics facilitate diagnosis, prognosis or improved health or medical treatment of the subject; (iii) use the genetic characteristics from (ii) to determine a nucleic acid configuration of an assay, which nucleic acid configuration includes nucleic acid sequences of a plurality of nucleic acid probe molecules, wherein the nucleic acid sequences are selective for the genetic variants; (iv) provide the plurality of nucleic acid probe molecules by (1) directing synthesis of the plurality of nucleic acid probe molecules using at least one array, or (2) selecting the plurality of nucleic acid probe molecules from a collection of nucleic acid probe molecules; and (v) direct use of the plurality of nucleic acid probe molecules provided in (iv) to perform at least the assay on one or more biological samples from the subject or at least one biological relative of the subject, to generate data indicative of a presence or absence of at least a subset of the genetic variants in the subject or the at least one biological relative; and a computer display operative coupled to the one or more computer processors, wherein the computer display comprises a user interface that displays a report indicative of a presence or absence of the at least the subset of the genetic variants in the subject or the at least one biological relative. In another aspect, the present disclosure provides a method of personalized genetic testing including: (a) using a first assay design to sequence nucleic acids derived from an individual person, (b) determining multiple genetic characteristics of that person or their sample from that data; (c) using the genetic characteristics from (b) to specify the design of a second assay, and in particular the sequences of multiple additional nucleic acid molecules to be used in that second assay; (d) synthesizing the additional nucleic acid molecules on at least one array; (e) using the synthesized nucleic acids to perform a second assay, on one or more samples from the same individual person, and/or from individuals in their family. Some embodiments comprise a further additional (f) a report is generated based on analysis comparing the results from the assay of (a) with results from the assay(s) of (e), or by comparison of results from assays from a plurality of samples assayed in (e) with each other. In another aspect, the present disclosure provides a method of personalized genetic testing including: (a) deriving phenotypic information from the medical record of an individual person; (b) proposing multiple genetic characteristics which, if characterized, could lead to diagnosis, prognosis or improved medical treatment of the individual; (c) using the genetic characteristics from (b) to specify the design of an assay, and in particular the sequences of multiple nucleic acid molecules to be used in that assay; (d) synthesizing the nucleic acid molecules on at least one array; (e) using the synthesized nucleic acids to perform the assay, on one or more samples from the same individual person, and/or from individuals in their family. Some embodiments further comprise (f) generating a report based on analysis of the results from the assay(s) of (e), or by comparison of results from assays from a plurality of samples assayed in (e) with each other. In some embodiments, the first assay comprises one of (i) exome sequencing, or (ii) sequencing a panel of genes, or (iii) whole genome sequencing, or (iv) sequencing a population of cDNA molecules derived from RNA. In some embodiments, the first assay comprises sequencing a population of nucleic acid molecules modified in quantity or sequence by interaction with a sample or samples derived from the individual person. In some embodiments, the first assay comprises sequencing a population of nucleic acid molecules derived from antibody-oligonucleotide conjugates that bound to proteins of the individual person, including proteins of any tumor they may have. In some embodiments, the sequencing method of (a) comprises one of (i) sequencing by synthesis using a reversible terminator chemistry, or (ii) pyrosequencing, or (iii) nanopore sequencing, or (iv) real-time single molecule sequencing. In some embodiments, the sample type which may be used in the assay of (a) comprises nucleic acids derived from cells of the individual person, representing their germline genome. In some embodiments, the sample type which may be used in the assay of (a) comprises nucleic acids derived from one of (i) white blood cells, or (ii) non-cancerous cells adjacent to or embedded in a tumor or metastasis of the individual person. In some embodiments, the sample type which may be used in the assay of (a) comprises cell-free nucleic acids derived from blood plasma of the individual person. In some embodiments, the individual person has been diagnosed with a type of blood-related cancer such that the nucleic acids of their blood cells represent the cancer genome, not their germline genome, and wherein the nucleic acids of their blood cells are used in the assay of (a). In some embodiments, the sample type which may be used in the assay of (a) comprises nucleic acids derived from a buccal swab of the individual person, representing their ectodermal genome. In some embodiments, the sample type which may be used in the assay of (a) comprises nucleic acids derived from cells of a tumor of the individual person, representing their cancer genome. In some embodiments, the sample type which may be used in the assay of (a) comprises nucleic acids derived from T-cells and/or B-cells of the adaptive immune system of the individual person, representing post-zygotic V(D)J recombination. In some embodiments, the sample type which may be used in the assay of (a) comprises non-human nucleic acids derived from a sample of the individual person, representing the genome(s) of one or more other microbial species (bacteria or viruses). In some embodiments, the first assay of (a) comprises analysis of a single sample from the individual. In some embodiments, the first assay of (a) comprises analysis of a plurality of samples from the individual and at least one of the genetic characteristics determined in (b) is based on comparison of those analyses. In some embodiments, the first assay of (a) comprises analysis of a sample from a tumor of the individual, and analysis of a second sample which represents the germline genome of the individual. In some embodiments, the first assay of (a) comprises analysis of DNA from a sample from a tumor of the individual, and analysis of RNA from a sample from a tumor of the individual. In some embodiments, the genetic characteristics determined in (b) comprise or include one or more of (i) Single Nucleotide Polymorphisms (SNPs), or (ii) Insertions and/or Deletions (InDels), or Copy Number Variations or Structural Variations. In some embodiments, the genetic characteristics determined in (b) are or include signatures combining multiple genetic variants (e.g., the HLA type or the blood type of the individual) In some embodiments, the genetic characteristics determined in (b) comprise or include genetic variants in the germline sequence of the individual. In some embodiments, the genetic characteristics determined in (b) comprise or include post-zygotic (i.e., mosaic or somatic) variants from the germline sequence of the individual. In some embodiments, the genetic characteristics determined in (b) comprise or include post-zygotic recombination of elements from the germline sequence of the individual (e.g., V(D)J recombination). In some embodiments, the genetic characteristics determined in (b) comprise or include levels of gene expression (quantification of mRNA from individual genes and/or their splice variants) and/or sequencing read counts or read-depth in data derived from an RNA or cDNA sample. In some embodiments, the genetic characteristics determined in (b) comprise or include levels of mRNA expression (including presence/absence) of specific alleles derived from the DNA of the individual. In some embodiments, the genetic characteristics determined in (b) comprise or include levels of methylation at specific locations or in specific regions of the human genome. In some embodiments, the genetic characteristics determined in (b) comprise or include numbers of sequences derived from oligo-antibody conjugates contacted with the sample(s). In some embodiments, the genetic characteristics determined in (b) comprise or include specific locations in, or specific regions, of the human genome (e.g., the locations of SNP's); and further wherein the multiple additional nucleic acids to be used in the second assay are designed to enrich or deplete a nucleic acid mixture of those nucleic acid molecules which include those locations or regions of the human genome, or parts thereof. In some embodiments, the additional nucleic acid molecules are designed to enrich or deplete a mixture, for the desired target regions, either by hybridization to the additional nucleic acid molecules or by amplification (e.g., by polymerase chain reaction) In some embodiments, the additional nucleic acid molecules are designed as primers for single-base extension, or multiple-base extension. In some embodiments, the sequences of the multiple additional nucleic acid molecules, to be used in the second assay, are composed of at least two parts: One part specific to the genomic locus or region targeted, and at least one other part for other applications in the second assay. This may be a barcode sequence or it may be a pair of amplification primer sequences. In some embodiments, the “other applications in the second assay” include demultiplexing or selective amplification of a subset, downstream of array-based synthesis pooled across multiple genomic loci, or across multiple individuals, or both. In some embodiments, the sequences of the multiple additional nucleic acid molecules, to be used in the second assay, or portions of them, are selected from a library of sequences previously designed (e.g., to capture each of the coding exons of the human genome). In some embodiments, the library of previously designed sequences has previously itself been array synthesized and experimentally tested. In some embodiments, at least one of the sequences of the multiple additional nucleic acid molecules, to be used in the second assay, or portions of them, include a variation from the reference sequence seen in the first assay of the individual, not the reference sequence itself. In some embodiments, (d) comprises the synthesis of a plurality of nucleic acid sequences on a single solid substrate. In some embodiments, the number of nucleic acid sequences synthesized in parallel on a single solid substrate is at least 100. In some embodiments, the number of nucleic acid sequences synthesized in parallel on a single solid substrate is at least 1,000. In some embodiments, the number of nucleic acid sequences synthesized in parallel on a single solid substrate is at least 10,000. In some embodiments, the number of nucleic acid sequences synthesized in parallel on a single solid substrate is at least 50,000. In some embodiments, each of the plurality of nucleic acid sequences synthesized on a single solid substrate is synthesized in a spatially separate region of the substrate. In some embodiments, the sequence synthesized in each of the plurality of spatially separate regions of a single solid substrate is specified by light directed chemical reactions (e.g., photolithography) or by reagents dispensed in a jet from a moveable print head. In some embodiments, the common substrate can be mechanically partitioned without damaging the nucleic acids synthesized, after nucleic acid synthesis but before cleavage of the nucleic acid molecules from the substrate. In some embodiments, the nucleic acid molecules are at least 50 bases long. In some embodiments, the nucleic acid molecules are at least 130 bases long. In some embodiments, the nucleic acid molecules are at least 200 bases long. In some embodiments, the capacity of the array (i.e., the number of sequences which can be synthesized on a single solid substrate) is shared by synthesis of sequences for the testing of multiple otherwise unrelated testing cases. In some embodiments, the sequences synthesized for unrelated testing cases are synthesized in spatially separated regions of a common substrate, followed by mechanical separation of the common substrate into separate pieces each containing one of those regions (e.g., wafer dicing). In some embodiments, the sequences synthesized for unrelated testing cases are synthesized on a common substrate, but contain subsequences (barcodes) which can later be used to segregate them for independent use (e.g., by hybridization). In some embodiments, the sequences synthesized for unrelated testing cases are synthesized on a common substrate, but their results are separated bioinformatically following the second assay ((e)). In some embodiments, the second assay (e) determines nucleic acid sequences and maps them to a reference (e.g., a reference genome sequence or reference set of mRNA transcripts) such that the results needed for analysis of samples processed in (e) are positioned along the reference separate from (or partially separate from) those not needed (e.g., those captured in one sample by sequences synthesized for another sample). In some embodiments, the second assay is one of (i) DNA sequencing, or (ii) genotyping, or (iii) gene expression analysis. In some embodiments, the sequencing method of (e) comprises one of (i) sequencing by synthesis using reversible terminator chemistry or (ii) pyrosequencing, or (iii) nanopore sequencing, or (iv) real-time single molecule sequencing. In some embodiments, the genotyping method of (e) comprises single-base extension, with readout of the single base by fluorescence or mass spectroscopy. In some embodiments, the genotyping of multiple loci are demultiplexed by one of (i) hybridization to an array, using nucleic acid barcodes incorporated into the sequences synthesized in (d), or (ii) using PCR primers incorporated into the sequences, or (iii) electrophoresis (e.g., SNaPshot or SNPlex), or (iv) mass spectroscopy. In some embodiments, the oligo-directed genomic content of second assay comprises: (i) at least one variable portion, defined based on results of the first assay and (ii) at least one fixed portion, independent of the results of the first assay. In some embodiments, the oligos corresponding to the fixed portion of the genomic content are synthesized on the same array(s) as used to synthesize the variable portion of the genomic content. In some embodiments, the oligos corresponding to the fixed portion of the genomic content are synthesized on separate array(s) from those used to synthesize the variable portion of the genomic content. In some embodiments, (i) the variable content for a plurality of individuals is synthesized together on an array with the fixed content, and (ii) it is demultiplexed into oligo pools specific to each of those individuals post-synthesis, and (iii) the design of the nucleic acid sequences of the variable content contains at least two segments, one used for de-multiplexing post-synthesis, and (iv) the design of the nucleic acid sequences of the fixed content also contains at least two segments, one used for de-multiplexing post-synthesis, and (v) the de-multiplexing reaction post-synthesis uses methods which allow it to capture fixed content nucleic acid molecules along with each set of individual-specific variable content. In some embodiments, the variable portion of the oligo-directed genomic content corresponds to genes which are, or are expected to be, more highly expressed, and the fixed portion corresponds to genes with on average lower levels of gene expression. In some embodiments, the variable portion of the oligo-directed genomic content corresponds to genes whose expression is thought to vary more from sample to sample, and the fixed portion corresponds to genes with more consistent levels of gene expression from sample to sample. In some embodiments, the oligo-directed content, partitioned into fixed and variable portions as described, includes not only content from the coding regions of genes, but also other forms of transcribed RNA, including but not limited to long non-coding RNA, micro-RNA and Intronic RNA. In some embodiments, the variable portion of the oligo-directed genomic content corresponds to potential neoantigen causing variants of the individual, and the fixed portion corresponds to one or more of (a) cancer driver genes, (b) genes involved in the pharmacogenomics of cancer drugs, (c) genes involved in Mendelian immunological diseases, (d) genes related to inherited forms of cancer, (e) genes associated with tumor escape from a targeted or immune cancer therapy, (f) HLA typing, or (g) variants common in the population and used by B-allele methods to detect structural variation. In some embodiments, the variable portion of the oligo-directed genomic content corresponds to variants which may be responsible for the Mendelian phenotype of a proband, and the fixed portion corresponds to one or more of (a) additional genetic content not related to the Mendelian condition of the proband (b) pharmacogenomics, or (c) genetic sample ID by a fixed panel of variants or a fixed panel of phenotype-related variants such as gender, blood type, or (d) variants common in the population and used by B-allele methods to detect structural variation. In some embodiments, the individual of (a) is a member of a family pedigree, and is affected by a medical condition which may be Mendelian, the first assay is DNA sequencing, the genetic characteristics determined in (b) are variations of the DNA sequence so determined, from a human reference sequence, or alleles which match the human reference sequence but which are known to be correlated with a medical condition; optionally filtered to select those variants most likely to be causal, the DNA sequences designed in (c) are to capture or amplify the genomic regions of those variants, in subsequent samples, the assay of (e) is DNA sequencing, the samples sequenced in (e) are from other members of the same family pedigree, the report generated attempts to identify the genetic variants shared by the family members, which are responsible for the affliction of those pedigree members who are affected, by leveraging the rules of genetic inheritance, and data on multiple variant loci measured in multiple family members. In some embodiments, the medical condition affecting the individual of (a) includes neurological clinical features, at least one of the samples assayed, in s (a) and/or (e) are from buccal swabs or other tissue of the ectodermal lineage, the report generated considers the possibility that one or more genetic variants of the afflicted individual are mosaic, and included in the ectodermal cell lineage of the individual. In some embodiments, the at least one of the samples assayed, in s (a) and/or (e) are DNA from sperm of one of the individuals in a family pedigree, the report generated considers the possibility that one or more genetic variants of the afflicted individual are gonadal mosaic in the father of the afflicted individual. In some embodiments, the potentially causal genetic variants from probands in multiple Mendelian pedigrees are combined into a single list of genetic loci and/or regions. In some embodiments, the nucleic acid sequences are designed for in-solution capture of those genetic loci and/or regions, by hybridization, nucleic acid sequences are synthesized by inkjet printing on an array with a capacity of over 50,000 nucleic acid sequences (e.g., Agilent SureSelect), following synthesis. The nucleic acid sequences are cleaved from the substrate on which they were synthesized, for use in solution, the nucleic acid sequences thus synthesized constitute a pool which is expected to capture most or all of the genetic loci and/or regions on the list from all of the Mendelian pedigrees, and are used that way on each sample. The samples themselves may be processed in a pool (each identified by a nucleic acid barcode) or individually. Variants which matter for each Mendelian pedigree are bioinformatically separated out from the DNA sequencing-based assay data of (e). A separate report may be generated for each of the Mendelian pedigrees, even though a portion of their assays (synthesis of a shared oligo pool) was in common. In some embodiments, the “genetic characteristics” of (b) constitute a list of genes derived from the clinical phenotype of the patient, using methods described in US 20160283484. In some embodiments, (i) the original individual is among those sequenced with the personalized assay, and (ii) the sequencing depth of the personalized assay, at the loci of tentatively identified mosaic variants, is higher than in the original assay and thus can be used to make a more definitive variant call. In some embodiments, the individual of (a) is a cancer patient, the first assay is sequencing of DNA derived from their tumor, the genetic characteristics determined in (b) are one or more of (i) variations of the DNA sequence so determined, from a human reference sequence, or (ii) alleles which match the human reference sequence but which are known to be correlated with some type of cancer or other disease, or (iii) alleles which determine the HLA type; optionally filtered to select those variants most likely to be relevant for analysis of the tumor or the patient's potential treatment, the DNA sequences designed in (c) are to capture or amplify the genomic regions of those variants, in subsequent samples, the assay of (e) is sequencing of DNA (or cDNA) captured or amplified using the array-synthesized oligos, the samples sequenced in (e) are from the same patient and are one or more of (i) germline DNA, (ii) tumor RNA or cDNA derived from the tumor RNA, (iii) cell-free DNA or RNA derived from blood plasma (including from different time points in the patient's progression), (iv) DNA from elsewhere in the patient's body which may contain mosaic variants, or (v) tumor DNA again (to confirm the new assay detects the variants seen with the original assay), the report generated attempts to identify genetic variants which can inform the therapy choice for the patient. In some embodiments, the individual of (a) is a cancer patient, the first assay is sequencing of DNA derived from their tumor and also germline DNA, the genetic characteristics determined in (b) are one or more of (i) variations of the DNA sequence so determined, between the tumor sequence and the germline sequence, or (ii) alleles which determine the HLA type; optionally filtered to select those variants most likely to be relevant for analysis of the tumor or the patient's potential treatment, the DNA sequences designed in (c) are to capture or amplify the genomic regions of those variants, in subsequent samples, the assay of (e) is sequencing of DNA (or cDNA) captured or amplified using the array-synthesized oligos, the samples sequenced in (e) are from the same patient and are one or more of (i) tumor RNA or cDNA derived from the tumor RNA, (ii) cell-free DNA or RNA derived from blood plasma (including from different time points in the patient's progression), (iii) DNA from elsewhere in the patient's body which may contain mosaic variants, or (iv) tumor and/or germline DNA again (to confirm the new assay detects the variants seen with the original assay), the report generated attempts to identify genetic variants which can inform the therapy choice for the patient. In some embodiments, the individual of (a) is a cancer patient, the first assay is sequencing of RNA derived from their tumor, or cDNA derived from RNA of their tumor, the genetic characteristics determined in (b) are one or more of (i) variations of the DNA sequence so determined, from a human reference sequence, or (ii) alleles which match the human reference sequence but which are known to be correlated with some type of cancer or other disease, or (iii) alleles which determine the HLA type, or (iv) metrics of gene expression and/or allele-specific expression, or (v) quantification of long non-coding RNAs or micro-RNAs which are at least partially tissue-type specific or cancer-type specific; optionally filtered to select those variants most likely to be relevant for analysis of the tumor or the patient's potential treatment, the DNA sequences designed in (c) are to capture or amplify the genomic regions of those variants, in subsequent samples, the assay of (e) is sequencing of DNA (or cDNA) captured or amplified using the array-synthesized oligos, the samples sequenced in (e) are from the same patient and are one or more of (i) germline DNA, (ii) tumor DNA, (iii) cell-free DNA or RNA derived from blood plasma (including from different time points in the patient's progression), (iv) DNA from elsewhere in the patient's body which may contain mosaic variants, or (v) tumor RNA again (to confirm the new assay detects the variants seen with the original assay), the report generated attempts to identify genetic variants which can inform the therapy choice for the patient. In some embodiments, the individual of (a) is a cancer patient, the first assay is sequencing of cell-free DNA derived from the patient's blood plasma, the genetic characteristics determined in (b) are one or more of (i) variations of the DNA sequence so determined, from a human reference sequence, or (ii) alleles which match the human reference sequence but which are known to be correlated with some type of cancer or other disease, or (iii) alleles which determine the HLA type; optionally filtered to select those variants most likely to be relevant for analysis of the tumor or the patient's potential treatment, the DNA sequences designed in (c) are to capture or amplify the genomic regions of those variants, in subsequent samples, the assay of (e) is sequencing of DNA (or cDNA) captured or amplified using the array-synthesized oligos, the samples sequenced in (e) are from the same patient and are one or more of (i) germline DNA, (ii) cell-free DNA derived from the patient's blood plasma (but now potentially at greater sequencing depth by use of a more focused, oligo-directed assay) (including from different time points in the patient's progression), (iii) cell-free RNA derived from the patient's blood plasma (including from different time points in the patient's progression) (iv) DNA from elsewhere in the patient's body which may contain mosaic variants, or (v) cell-free DNA again (to confirm the new assay detects the variants seen with the original assay), the report generated attempts to identify genetic variants which can inform the therapy choice for the patient. In some embodiments, the individual of (a) is a cancer patient, the first assay is sequencing of cell-free RNA derived from the patient's blood plasma, or cDNA derived from that RNA, the genetic characteristics determined in (b) are one or more of (i) variations of the DNA sequence so determined, from a human reference sequence, or (ii) alleles which match the human reference sequence but which are known to be correlated with some type of cancer or other disease, or (iii) alleles which determine the HLA type, or (iv) metrics of gene expression and/or allele-specific expression, or (v) quantification of long non-coding RNAs or micro-RNAs which are at least partially tissue-type specific or cancer-type specific; optionally filtered to select those variants most likely to be relevant for analysis of the tumor or the patient's potential treatment, the DNA sequences designed in (c) are to capture or amplify the genomic regions of those variants, in subsequent samples, assay of (e) is sequencing of DNA (or cDNA) captured or amplified using the array-synthesized oligos, the samples sequenced in (e) are from the same patient and are one or more of (i) germline DNA, (ii) cell-free RNA derived from blood plasma (but now potentially at greater sequencing depth by use of a more focused, oligo-directed assay), (iii) cell-free DNA from the patient's blood plasma, or (iv) DNA from elsewhere in the patient's body which may contain mosaic variants, or (v) cell-free RNA again (to confirm the new assay detects the variants seen with the original assay), the report generated attempts to identify genetic variants which can inform the therapy choice for the patient In some embodiments, the individual of (a) is a current or potential cancer patient, the first assay is quantification of RNAs derived from the patient's white blood cells, or cDNA derived from that RNA; and/or quantification of cell-free DNA and/or RNA in the blood plasma, the genetic characteristics determined in (b) are which genes and/or non-coding RNA regions are best for cell-free tumor characterization via cell-free DNA vs cell-free RNA, the DNA sequences designed in (c) are to capture or amplify the genomic regions best for cell-free tumor characterization via cell-free DNA and/or (separately, with a different group of DNA sequences) to capture or amplify the genomic regions best for cell-free tumor characterization via cell-free RNA, in subsequent samples, the assay of (e) is sequencing of cell-free DNA and/or cell-free RNA captured or amplified using the set(s) of array-synthesized oligos, the samples sequenced in (e) are from the same patient and are one or more of (i) cell-free DNA, or (ii) cell-free RNA; either derived from blood plasma; from the same or different time points in the patient's progression, and the report generated attempts to identify genetic variants which can inform the therapy choice for the patient. In some embodiments, the individual of (a) is a current or potential cancer patient, the first assay is sequencing of DNA and/or RNA derived from the patient's tumor, optionally combined with sequencing of germline DNA, the genetic characteristics determined in (b) are a list of expressed variants seen in the tumor but not seen in the germline DNA, which have been assessed to be potential neoantigens for use in a personal cancer vaccine, the DNA sequences designed in (c) are to capture or amplify a plurality of the variants, in subsequent samples, the assay of (e) is sequencing of DNA or RNA, captured or amplified using the set(s) of array-synthesized oligos, with sufficient sequencing depth and analysis to detect mosaic variants, the sample(s) sequenced in (e) are from the same patient but from non-cancerous cells, from the same tissue as the tumor, or from other tissue elsewhere in the body; and may also include the tumor DNA (again, as a control for the new assay), the report generated attempts to discriminate which of these (apparently somatic) variants also exists in cells other than the cancer. This can occur due to mosaic variation (due to a DNA replication error or a retroviral insertion) which occurred prior to the initiation of the tumor. This can lead to variants which are in the tumor and other tissues but not the germline. These variants may be inappropriate as the basis for a personal cancer vaccine, since (i) the immune response elicited by such a vaccine might also attack non-cancer cells that express the same variant, and (ii) the patient may have been tolerized to peptides generated by the variant and thus not mount an immune response to them. In some embodiments, the individual of (a) is a current or potential cancer patient, the first assay is relative quantification of RNA by gene and/or non-coding RNA region, in a sample from the patient, using targeted or untargeted cDNA sequencing or other assay approaches, the genetic characteristics determined in (b) are one or more lists of genes, non-coding RNA regions, or RNA from gene-fusion events, whose RNA sequencing read-depth would benefit from being increased or decreased relative to a non-personalized assay, in terms of achieving more uniform RNA sequencing coverage, the DNA sequences designed in (c) are to capture or amplify RNA (or cDNA) from genes and/or non-coding RNA regions and/or gene-fusion events on the lists, in subsequent samples, the assay of (e) is sequencing of RNA, (or cDNA), captured or amplified using the set(s) of array-synthesized oligos, the sample(s) sequenced in (e) are from the same patient, and may be (i) the same sample as assayed in (a), or (ii) another sample from the same tissue as assayed in (a) (e.g., to look for tumor heterogeneity), or (iii) one or more samples from different time points in a patient's progression, or (iv) from other patients being compared, the report generated includes one or more of (i) genetic variants called from the RNA sequencing data, or (ii) relative expression levels of different samples, by gene or non-coding RNA region, or (iii) allele-specific expression, where the variants being expressed may be SNP's, InDel's and/or gene fusion events. In some embodiments, the assay of (a) is RNA sequencing of a sample, the list(s) generated as genetic characteristics in (b) are of genes, non-coding RNA regions and gene fusion events not sufficiently covered by the sequencing of (a), the sample of (e) is the same as (a), the assay of (e) is sequencing of RNA (or cDNA) captured or amplified by the oligos synthesized in (d), the data from (e) is added to that from (a), in an effort to fill in the otherwise insufficient (or suboptimal) DNA sequencing coverage from (a), in the genes and other regions identified in the lists. In some embodiments, the assay of (a) is RNA sequencing (or sequencing of cDNA derived from RNA), using next generation sequencing methods, with less than five million sequence reads. In some embodiments, the assay of (a) is RNA sequencing (or sequencing of cDNA derived from RNA), using next generation sequencing methods, with less than one million sequence reads. In some embodiments, the assay of (a) is DNA sequencing of a plurality of V(D)J recombination segments which each specify an antigen receptor of a T-cell and/or B-cell of a cancer patient's immune system, the genetic characteristics in (b) are the identities and quantities of specific V(D)J sequences, the DNA sequences designed in c, and array synthesized in (d), are to capture or amplify DNA or RNA sequences which would lead to neoantigens which can be recognized by the T-cell receptors or B-cell receptors corresponding to the V(D)J segments of s (a) and (b), the sample of (e) is from the same patient and is one of (i) tumor DNA, or (ii) tumor RNA, or (iii) cDNA derived from tumor RNA, or (iv) cell-free DNA from blood plasma, or (v) cell-free RNA from blood plasma, or (vi) cDNA derived from cell-free RNA from blood plasma, the assay of (e) is sequencing of DNA, RNA (or cDNA) captured or amplified by the oligos synthesized in (d), the data from (e) is to confirm the existence of genetic variants in the tumor of the patient, corresponding to the V(D)J segments measured in (a) and (optionally) to quantify those variants. In some embodiments, the assay of (a) is sequencing of DNA, RNA or cDNA derived from a patient's tumor, directly from the tumor or from cell-free amounts in the patient's blood plasma, the genetic characteristics in (b) are the identities of variants, relative to a human reference sequence, found in the sequence data from (a), which may lead to immunologically active neoantigens, the DNA sequences designed in c, and array synthesized in (d), are to capture or amplify DNA sequences which would lead to T-cell receptors or B-cell receptors corresponding to the potential neoantigens of s (a) and (b), the sample of (e) is from the same patient and is one or more of (i) DNA from T-cells, or (ii) DNA from B-cells, the assay of (e) is sequencing of DNA captured or amplified by the oligos synthesized in (d), the data from (e) is to confirm the existence of, and optionally to quantify, V(D)J segments which would lead to T-cell or B-cell receptors corresponding to the neoantigens identified in s (a) and (b). In some embodiments, the assay of (a) comprises (i) exposing a human tumor tissue sample to a mixture of oligo-antibody conjugates, some of which may bind to proteins or peptides in the tissue sample, (ii) subsequent release of those that bound, and (iii) sequencing of their oligo portions, the genetic characteristics of (b) are the identities and quantities of oligo-antibody conjugates corresponding to the sequences determined in (a), DNA sequences designed in c and array synthesized in (d) are to capture or amplify one or more of (i) a plurality of oligo sequences of oligo-antibody conjugates identified in (b), or (ii) DNA or RNA sequences corresponding to the proteins or peptides which were bound by the antibody component of oligo-antibody conjugates in (a), the sample(s) assayed in (e) are DNA or RNA (or cDNA derived from RNA) from the same or different tissue samples of the same person as the assay of (a), the assay of (e) is sequencing, with a report identifying the specific sequences and their quantities. In some embodiments, the nucleic acid sample of the individual, measured by the assay in (a), is obtained distal to its origin in the body, the genetic characteristics determined in (b) include identified genomic locations of mosaic variants in the initial sample, the DNA sequences designed in c are designed to amplify or enrich a plurality of those mosaic loci in subsequent samples, the assay of (e) is performed on samples from one or more other locations in the body of the same individual, to see if and/or to what extent the same mosaic variants are observed in those samples, the report of (f) uses the data to determine where in the body the DNA of the original sample came from. In some embodiments, the initial nucleic acid sample is one of (i) cell-free DNA or cell-free RNA obtained from blood plasma, or (ii) RNA obtained from one or more exosomes derived from a blood sample of the individual, or (iii) DNA or RNA obtained from circulating tumor cells, or (iv) DNA or RNA from a tumor metastasis. In some embodiments, the initial nucleic acid sample is from what is thought to be a primary tumor, tested to confirm whether it is actually from the tissue within which it has been found. Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in this art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive. INCORPORATION BY REFERENCE All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also “FIG.”, “Figure”, and “FIGS.” herein) of which: FIG. 1 shows the information flow and operations of a method of the present disclosure; FIG. 2 shows an example of a Mendelian family pedigree; FIG. 3 shows a manner in which methods and systems of the present disclosure may be used to significantly lower the cost of sequencing family (pedigree) members; FIG. 4 shows an example of how custom array-based synthesis of oligonucleotides for personal assays, for example for 32 cases, can be shared, substantially lowering the synthesis cost per case; FIG. 5 shows an example workflow for period batches of 32 Mendelian cases, each batch sharing an array-synthesis of the sequences that may be needed for personalized assays for the 32 cases; FIG. 6 shows a workflow for cancer sequencing, to detect variants potentially leading to neoantigens, with a summary of the relatively large amount of deoxynucleic acid (DNA) sequencing that may be required; FIG. 7 shows an alternative workflow for cancer sequencing, to detect variants potentially leading to neoantigens, based on the methods of the present disclosure, with a significant reduction in the amount of DNA sequencing that may be required; and FIG. 8 shows a system for implementing the methods of the disclosure. DETAILED DESCRIPTION While various embodiments of the invention(s) of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions may occur to those skilled in the art without departing from the invention(s). It should be understood that various alternatives to the embodiments of the invention(s) described herein may be employed in practicing any one of the inventions(s) set forth herein. The term “subject,” as used herein, generally refers to a subject having at least one biological sample that is undergoing analysis. The subject can be undergoing analysis to diagnose, predict or monitor a health, health condition, or well-being of the subject, such as, for example, identify or monitor a disease condition (e.g., cancer) in the subject. The subject can have a sample that is undergoing analysis by a researcher or a service provider, such as a healthcare professional or other individual or entity that employs methods and systems of the present disclosure to analyze the sample. The subject can be a patient. The subject can be a human, an animal or a plant. The term “nucleic acid,” as used herein, generally refers to a polymeric form of nucleotides of any length, for example, ribonucleotides, deoxyribonucleotides or peptide nucleic acids (PNAs). Nucleic acids comprise purine and pyrimidine bases, or other natural, chemically or biochemically modified, non-natural, or derivatized nucleotide bases. The backbone of the polynucleotide can comprise sugars and phosphate groups, as may typically be found in ribonucleic acid (RNA) or deoxynucleic acid (DNA), or modified or substituted sugar or phosphate groups. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs. The sequence of nucleotides may be interrupted by non-nucleotide components. Thus the terms nucleoside, nucleotide, deoxynucleoside and deoxynucleotide generally include analogs such as those described herein. These analogs are those molecules having some structural features in common with a naturally occurring nucleoside or nucleotide such that when incorporated into a nucleic acid or oligonucleoside sequence, they allow hybridization with a naturally occurring nucleic acid sequence in solution. Typically, these analogs are derived from naturally occurring nucleosides and nucleotides by replacing and/or modifying the base, the ribose or the phosphodiester moiety. The changes can be tailor made to stabilize or destabilize hybrid formation or enhance the specificity of hybridization with a complementary nucleic acid sequence as desired. The nucleic acid molecule may be a DNA molecule. The nucleic acid molecule may be an RNA molecule. The terms “variant or derivative of a nucleic acid molecule” and “derivative or variant of a nucleic acid molecule,” as used herein, generally refer to a nucleic acid molecule comprising a polymorphism. The terms “variant or derivative of a nucleic acid molecule” or “derivative or variant of a nucleic acid molecule” may also refer to nucleic acid product that is produced from one or more assays conducted on the nucleic acid molecule. For example, a fragmented nucleic acid molecule, hybridized nucleic acid molecule (e.g., capture probe hybridized nucleic acid molecule, bead bound nucleic acid molecule), amplified nucleic acid molecule, isolated nucleic acid molecule, eluted nucleic acid molecule, and enriched nucleic acid molecule are variants or derivatives of the nucleic acid molecule. The term “genetic variant,” as used herein, generally refers to an alteration, variant or polymorphism in a nucleic acid sample or genome of a subject. Such alteration, variant or polymorphism can be with respect to a reference genome, which may be a reference genome of the subject or other individual. Single nucleotide polymorphisms (SNPs) are a form of polymorphisms. In some examples, one or more polymorphisms comprise one or more single nucleotide variations (SNVs), insertions, deletions, repeats, small insertions, small deletions, small repeats, structural variant junctions, variable length tandem repeats, and/or flanking sequences. Copy number variants (CNVs), transversions and other rearrangements are also forms of genetic variation. A genomic alternation may be a base change, insertion, deletion, repeat, copy number variation, or transversion. The terms “detectable label” or “label,” as used herein, generally refer to any chemical moiety attached to a nucleotide, nucleotide polymer, or nucleic acid binding factor. The attachment may be covalent or non-covalent. The label can be detectable and render the nucleotide or nucleotide polymer detectable to a user or a system operated by the user. The terms “detectable label” or “label” may be used interchangeably. Detectable labels that may be used in combination with the methods disclosed herein include, for example, a fluorescent label, a chemiluminescent label, a quencher, a radioactive label, biotin, quantum dot, gold, or a combination thereof. Detectable labels include luminescent molecules, fluorochromes, fluorescent quenching agents, colored molecules, radioisotopes or scintillants. Detectable labels also include any useful linker molecule (such as biotin, avidin, streptavidin, HRP, protein A, protein G, antibodies or fragments thereof, Grb2, polyhistidine, Ni2+, FLAG tags, myc tags), heavy metals, enzymes (examples include alkaline phosphatase, peroxidase and luciferase), electron donors/acceptors, acridinium esters, dyes and calorimetric substrates. It is also envisioned that a change in mass may be considered a detectable label, as is the case of surface plasmon resonance detection. The terms “target-specific”, “targeted”, and “specific,” can be used interchangeably and generally refer to a subset of the genome that is a region of interest, or a subset of the genome that comprises specific genes or genomic regions. For example, the specific genomic regions can be a region that is guanine and cytosine (GC) rich. Targeted sequencing methods can allow one to selectively capture genomic regions of interest from a nucleic acid sample prior to sequencing. Targeted sequencing involves alternate methods of sample preparation that produce libraries that represent a desired subset of the genome or to enrich the desired subset of the genome. The terms “untargeted sequencing” or “non-targeted sequencing” can be used interchangeably and generally refer to a sequencing method that does not target or enrich a region of interest in a nucleic acid sample. The terms “untargeted sequence”, “non-targeted sequence” or “non-specific sequence,” generally refer to the nucleic acid sequences that are not in a region of interest or to sequence data that is generated by a sequencing method that does not target or enrich a region of interest in a nucleic acid sample. The terms “untargeted sequence”, “non-targeted sequence” or “non-specific sequence” can also refer to sequence that is outside of a region of interest. In some cases, sequencing data that is generated by a targeted sequencing method can comprise not only targeted sequences but also untargeted sequences. The terms “probe,” “nucleic acid probe,” “capture probe,” “bait,” as used herein, generally refer to a nucleic acid molecule comprising a single-stranded portion capable of hybridizing to a complementary nucleic acid sequence. A probe can be used for detection or enrichment of nucleic acid molecules. A probe can be target-specific such that a region of interest may be pulled-down, isolated, enriched, amplified, or labeled. A probe can be used for targeted sequencing. A probe may hybridize to a targeted sequence when attached to a solid substrate or when in-solution, e.g. as for hybrid capture. A probe may be included in a set, or plurality, of probes. A probe set can comprise probes that overlap within a specific genomic region such that they are tiled or staggered. A probe set can include probes to a genomic region or a panel comprising multiple genomic regions. Probes can be amplification based or capture hybridization-based. Non-limiting examples of probes include molecular inversion probes, amplification probes, biotinylated affinity probes, or any probe comprising a detectable label. The term “barcode,” as used herein, generally refers to a short DNA sequence segment, which is generally part of a longer DNA sequence design. A barcode is typically a tag or identifier, which corresponds to a sample. This allows the sample to be pooled with others for processing, and subsequently be demultiplexed by leveraging the barcode sequence, either physically or bioinformatically. The term “buccal swab,” as used herein, generally refers to a method of obtaining a nucleic acid sample from an individual subject, by swabbing the inside of their cheek. Some of the cells obtained using this method are ectodermal in origin, and thus share early lineage and mosaic variants with the brain and other neurological tissue. The term “cell-free DNA,” as used herein, generally refers to DNA which is found circulating in the blood plasma, not contained in a cell. It is thought to originate in cells of the body which have died. Those may include blood cells (which typically only live a few days) or cancer tumor cells, which may die by apoptosis or necrosis. Dead cells that are broken up may release RNA, which can also end up in a cell-free format in the blood. Both cell-free DNA and RNA may be cleared from the blood by the liver, with a half-life in the blood of about 20 minutes. The term “exome,” as used herein, generally refers to sequencing the DNA of the coding regions of the genes. It may be implemented by methods, such as hybrid capture, which extract those portions of a DNA sample from the rest of the genome. The term “exosome,” as used herein, generally refers to a liquid bubble, encased by a flexible lipid membrane. In the human body, exosomes may be released from cells (e.g., as fragments of nucleic acid molecules from cells) and circulate in the blood stream. They may contain several types of RNA derived from those cells. If they are derived from a cancer tumor, the RNA they contain may be reflecting the mutations of the tumor itself. Because they are found in the blood circulation, they can be more accessible than a biopsy of the tumor may be. The term “gastrulation,” as used herein, generally refers to the point in development of a human embryo, when cells start to differentiate from the undifferentiated stem cells of a human embryo, into the germ layers and later other more specific cell types which make up the organs of the body. Gastrulation typically happens when a human embryo has about 200 cells, about 7 days after fertilization/conception. The term “germ layer,” as used herein, generally refers to the first three categories of human tissue to differentiate from the undifferentiated stem cells of a human embryo. There are three germ layers: Mesoderm, ectoderm and endoderm. Neural cells including the brain come from the ectoderm. Blood cells come from the mesoderm. The term “hybrid capture,” as used herein, generally refers to the in-solution capture of selected DNA molecules from a sample, by synthetic RNA molecules mixed into the same solution. The capture is by hybridization of complementary nucleic acid sequences. After the hybridization, the DNA/RNA hybrids can be selectively extracted from the solution. The RNA molecules can be synthesized with specific sequences, to allow targeting this capture process to very specific segments of the human genome, each typically a few hundred bases long. Hybrid capture can also be applied to complementary deoxyribonucleic acid (cDNA) derived from ribonucleic acid (RNA) in a sample. The term “Mendelian,” as used herein, generally refers to a disease or medical condition, inherited based on mutation of a single gene. Most Mendelian conditions are quite rare. The term “mosaicism,” as used herein, generally refers to genetic changes which occur after an embryo has started to develop. These changes will only be found in a fraction of the cells of a human body. The term “neoantigen,” as used herein, generally refers to a peptide derived from the mutated DNA sequence of a cancer tumor, which may elicit an immune response in the subject. The term “Next Generation Sequencing” (NGS), as used herein, generally refers to technologies for massively parallel determination of the sequences of nucleic acid molecules, such as deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) molecules. NGS was developed after, and has significantly replaced Sanger sequencing, which was considered the first generation DNA sequencing technology. The term “oligo,” as used herein, generally refers to an oligonucleotide, i.e., a single stranded synthetic nucleic acid molecule. It is the synthetic physical realization of a DNA (or RNA) sequence design. The term “post-zygotic,” as used herein, generally refers to the time after conception of a fetus, and initial cell division. At conception, the egg and sperm combine to form a single cell call a “zygote”. The term “RNA sequencing,” as used herein, generally refers to (i) direct sequencing of the RNA itself, or (ii) the construction of cDNA from the RNA, followed by sequencing of the cDNA. The term “somatic,” as used herein, generally refers to a type of genetic variant in a human body which is only found in a cancer tumor, or cells derived from it. These genetic changes are thought to occur during cell divisions which lead to expansion of a tumor, but they may also have occurred in the lineage of a cancer stem cell leading up to the initiation of a tumor. Because these variants occur well after conception and growth of a fetus, they are a special form of mosaicism. The term “transcriptome,” as used herein, generally refers to sequencing many (e.g., 50 million) cDNA molecules, to determine gene expression, detect gene fusion and alternative splicing events, and detect genetic variants expressed in the RNA. The term “V(D)J recombination,” as used herein, generally refers to a rearrangement of a set of genetically inherited DNA segments, by a subject's adaptive immune system, so as to create T-cell and B-cell receptors which can bind to specific antigens. The term “zygocity,” as used herein, generally refers to the number of copies of a genetic variant in each cell. A variant is “homozygous” if all of the copies of the DNA in a cell have the variant. A variant is “heterozygous” in a cell if there are two copies of the DNA and only one contains the genetic variant. The terms “bound”, “hybridized”, “conjugated”, “attached”, “linked” can be used interchangeably and generally refer to the association of an object to another object. The association of the two objects to each other may be from a covalent or non-covalent interaction. For example, a capture probe hybridized nucleic acid molecule refers a capture probe associated with a nucleic acid molecule. The capture probe and the nucleic acid molecule are in contact with each other. In another example, a bead bound nucleic acid molecule refers to a bead associated with a nucleic acid molecule. Overview Disclosed herein are methods and systems for interactive and personalized genetic testing. In a method for interactive or personalized genetic testing, initial information gathered on an individual subject (who may be a medical patient) may be used to design and synthesize chemical reagents. The chemical reagents may be used for further testing. By using information from a first operation to synthesize chemical reagents specific to the subject being tested, the subsequent testing may be better focused on the personal characteristics of the subject. This can yield information on the subject which is either more insightful, or less expensive, or both. Methods and systems of the present disclosure may detect or determine one or more phenotypes of a subject, such as a disease, at an accuracy of at least about 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%, in some cases without retesting. Such methods and systems may detect or determine a disease in a subject at a sensitivity of at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%. In an aspect of the present disclosure, a method for personalized genetic testing comprises using a first assay, a sequencing assay, to sequence or quantify nucleic acid molecules from at least one biological sample of a subject, thereby generating nucleic acid sequence data. Next, the nucleic acid sequence data may be used to determine a plurality of genetic characteristics in the at least one biological sample of the subject. The plurality of genetic characteristics may include genetic variants in the nucleic acid molecules from the at least one biological sample. As an alternative or in addition, phenotypic information may be derived from a health or medical record of a subject. The health or medical record may be in one or more databases. Next, the plurality of genetic characteristics of the subject may be determined from the phenotypic information. The plurality of genetic characteristics may include genetic variants. The plurality of genetic characteristics may facilitate diagnosis, prognosis or improved health or medical treatment of the subject. Next, the genetic characteristics may be used to determine a nucleic acid configuration of a second assay, which nucleic acid configuration includes nucleic acid sequences of a plurality of nucleic acid probe molecules. The nucleic acid sequences are selective for the genetic variants. The plurality of nucleic acid probe molecules may then be provided by, for example, (i) synthesizing the plurality of nucleic acid probe molecules using at least one array, and/or (ii) selecting the plurality of nucleic acid probe molecules from a collection of nucleic acid probe molecules. Next, the plurality of nucleic acid probe molecules may be used to perform at least the second assay on one or more biological samples from the subject or at least one biological relative of the subject, to generate data indicative of a presence or absence of at least a subset of the genetic variants in the subject or the at least one biological relative. FIG. 1 illustrates information flow and operations of a method for personalized genetic testing. In a first operation, an affected subject is identified and information can be obtained from the individual one of two ways. A first assay, also referred to herein as a sequencing assay, may be performed to sequence or quantify the nucleic acid molecules from at least one biological sample of a subject, thereby generating nucleic acid sequence data. Alternatively, the second option is obtain the phenotypic information from a medical record. Next, in a second operation, the nucleic acid sequence data may be analyzed to determine a plurality of genetic characteristics in the at least one biological sample of the subject. The plurality of genetic characteristics may include genetic variants in the nucleic acid molecules from at least one biological sample. In a third operation, the genetic characteristics can be used to determine a nucleic acid configuration of a second assay. The nucleic acid configuration may include nucleic acid sequences of a plurality of nucleic acid probe molecules. The nucleic acid sequences can be selective for genetic variants. In operation four, a plurality of nucleic acid probe molecules may be provided by (i) synthesizing the plurality of nucleic acid probe molecules using at least one array, or (ii) selecting the plurality of nucleic acid probe molecules from a collection of nucleic acid probe molecules. In operation five, using the nucleic acid probe molecules, a second assay may be performed on one or more biological samples from the subject or at least one biological relative of the subject. This assay can generate data indicative of a presence or absence of at least a subset of the genetic variants in the subject or at least one biological relative. In operation six, a therapeutic intervention may be determined from the two assays. The therapeutic intervention may be a treatment or a report. The report can compare the results from the first and second assay. The report may also compare the results among multiple samples of the second assay. Initial information may be based on a first laboratory assay, applied to a sample obtained from the subject (e.g., a blood sample, tumor biopsy, etc). The initial information may be phenotypic, such as from a medical record of the subject. In either case, this initial information can be sufficiently specific to allow the design and synthesis of chemical reagents specific to the subject being tested. Further testing of the personalized chemical reagents may be selected from a group consisting of additional analysis of the original sample from the subject, analysis of one or more other samples from the same subject, analysis of samples from other subjects who may share some of the same personal genetic characteristics (e.g., relatives of the subject), or a combination of the above. Information from the first assay can be used to design and synthesize chemical reagents. This information may allow better and/or less expensive testing of the subsequent samples. The data from subsequent analysis may be useful on its own. The data may be useful in comparison to the initial information. Additionally, multiple samples from one or more subjects may be assayed using the personalized reagents. The results may be useful by comparison of the results between those samples and/or subjects. These uses may result in a report. The reports may be read by a physician, a researcher, and/or a regulatory authority. The interactive nature of methods and systems of the present disclosure may be facilitated by information flowing between the operations. The information may be in the form of naturally occurring or synthetic molecules, or it may be in the form of data, such as may be stored in a computer. Where the information is in the form of molecules, it may be stored in particular in the form of information-containing biological polymers such as DNA, RNA, cDNA, proteins, peptides, antibodies, and combinations of these (e.g., antibody-oligo conjugates). In an aspect of the present disclosure, the information flow may begin with data on an individual subject. It may exist in digital form in the patient's medical record, or it may be in the form of naturally occurring biological molecules in the subject's body. In the latter case, it can be converted to digital form by conducting a first assay, such as DNA sequencing. Next, specific genetic characteristics may be extracted from that data (e.g., identifying genetic variants of the subject's genome relative to a reference sequence, or predicting specific variants which they may have based on their medical records). The information flow may then proceed from digital form into molecular form. In particular, the digitally stored genetic characteristics of the subject may be used to design and synthesize a set of DNA and/or RNA sequences for use in a subsequent assay to be performed on one or more subsequent samples. The personalized reagents may be a set of DNA and/or RNA sequences. Methods of the present disclosure may be capable of handling large rich data sets. In particular, during the stage where the genetic characteristics are used to design and synthesize a set of DNA and/or RNA sequences, (i.e., the information is converted from digital to molecular form), array-based methods may be applied. Some of the array-based method can generate mixed pools of over 50,000 different individual DNA sequences. One such array can contain over five million letters of DNA sequence information, with a high degree of personalization of oligo pools. For example, a printer copy of the personalization can fill a book with at least about 400, at least about 450, at least about 500, at least about 550, at least about 600, at least about 650, or at least about 700 pages long. Since large scale data storage in DNA is a recent advance, the present disclosure can further design each “book” to be an active chemical reagent, used for innovative personally-tailored types of genetic testing. The methods can also allow this approach to be affordable, In another aspect of the presented disclosure, the methods presented may allow for cost effective use of the synthesized custom DNA array on a personal basis. These methods may be selected from a group consisting of methods to share custom array synthesis over multiple clinical cases, methods to demultiplex an oligo pool after combined synthesis, applications in which multiple samples can be beneficially analyzed using reagents designed for a subject (so as to amortize the cost of custom personal reagent synthesis over multiple assays), and others. Next, information can flow back into digital form, by using the array-synthesized DNA pools to execute assays on the second sample or set of samples. The readout of this second set of assays can inform a final report, which may be created in digital form for storage, transmission, printing and/or reading. In another aspect, a set of specific medical and research applications of this process may be disclosed. FIG. 5 illustrates an example workflow for period batches of 32 Mendelian cases. Each batch may share an array-synthesis of the sequences that may be needed for personalized assays for the 32 cases. In a first operation, an affected subject is identified. All samples may be received and quantified for batch N. The information can be obtained from the subject in two ways. 32 probands may be exome sequences as a batch, thereby generating nucleic acid sequence data. Concurrently, the phenotype-driven gene list may be obtained from a medical record. Next, the nucleic acid sequence data can be analyzed to identify an average of 200 variants/case or 6,400 probes/batch. The plurality of genetic characteristics may include genetic variants in the nucleic acid molecules. Capture probes can then be designed or selected from a pre-designed exome probe set. In the next operation, a plurality of nucleic acid probe molecules may be provided by custom nucleic acid probe synthesis for the consumer panel sequencing (e.g., 6,400 sequences). In the next operation, using the nucleic acid probe molecules, a second assay can be performed on one or more biological samples from the subject or at least one biological relative of the subject. This assay may generate data indicative of a presence or absence of at least a subset of the genetic variants in the subject or at least one biological relative. Next, all pedigree members can be panel sequenced as a batch, through bioinformatics pipelines. The therapeutic intervention may be a treatment or a report. Obtaining Initial Information on the Subject by a First Assay The information flow of the present disclosure may begin either with the medical record of the subject, or with information-containing molecules in the subject's body. These molecules may include, for example, DNA, RNA or proteins. The information revealed may be in the form of sequence data (i.e., the order of the bases or nucleic acids which make up these polymers) or the quantities of specific sequences in the sample. If the information is initially molecular, it may be extracted from a sample from the subject's body, for example, using an assay. In one example, RNA information may be converted to cDNA. In another example, proteins may be converted to DNA by the use of oligo-antibody conjugates. The antibody portion of these molecules can bind to proteins with remarkable specificity, and the oligo (i.e., short DNA fragment) part of each conjugate can be a DNA barcode corresponding uniquely to a specific antibody (and hence protein). One oligo-antibody conjugate can bind to each protein. This one-to-one correspondence can be used to convert protein sequence and quantity information into oligo sequences. The antibodies can be selective not only at the level of a protein's amino acid sequence, but also at the level of post-translational modifications of a protein, such as phosphorylation or acetylation. Using these conjugates as transducers, DNA sequencing technologies can then be used to read out the oligo-stored information. When sequencing DNA directly from a sample, one can choose whether to sequence it without discrimination, i.e., to sequence DNA molecules from the whole human genome, or to sequence a selected subset. Exome sequencing can begin by enriching a sample for a subset. The sample may be DNA molecules. The DNA molecules may originate from or overlap with coding regions of the genes. Sequencing a panel of genes may involve enrichment of a sample. When sequencing RNA, cDNA derived from the RNA may be sequenced to capture the equivalent information. In some cases, when sequencing proteins, oligo portions of oligo-antibody conjugates which bound to the sample may be sequenced. When performing DNA sequencing, there are now a number of technical approaches which can sequence with enough throughputs to be practically useful for methods provided herein. In another aspect of the present disclosure, there are numerous technical approaches to sequence with enough throughputs to be practically useful at the scale of information flow. These technical approaches may be selected from a group consisting of (i) sequencing by synthesis with a reversible terminator chemistry, or (ii) pyrosequencing, with either optical or electronic readout, or (iii) nanopore sequencing, or (iv) real-time single molecule sequencing. These are exemplified by systems commercialized by (i) Illumina, or (ii) Thermo Fischer Scientific's Ion Torrent product line, or (iii) Oxford Nanopore, or (iv) Pacific Biosciences. Types of Samples and Nucleic Acids Derived Therefrom To obtain the desired information from the subject using the first or sequencing assay, specific sample types may be chosen for specific applications. In an aspect of the present disclosure, it may be desirable to obtain a sample reflective of the germline genome of the subject, inherited from their parents, plus any de novo variants. Samples used to obtain this type of information may include nucleated blood cells such as white blood cells, non-cancerous cells embedded in or adjacent to a tumor or metastasis, or cell-free nucleic acids obtained from the blood plasma. In particular, in the case of a leukemia subject, the white blood cells may contain cancer and may be inappropriate as a sample of the germline genome. In those cases, cell-free nucleic acids in the blood plasma may contain nucleic acids which originate in other cells of the body which are non-cancerous, and can serve as germline reference relative to the cancerous white blood cells. For certain applications, it may be desirable to obtain a sample which is reflective of the germline genome of the subject plus certain mosaic variants which have occurred post-zygotically. Even more specifically, it may be desirable to obtain a sample which reflects mosaic variants which occurred post-gastrulation, and which may be more concentrated in certain germ layers (e.g., the ectoderm, endoderm or mesoderm). A sample type which is reflective of ectodermal mosaic variation can be a buccal swab. In another aspect, it may be desirable to obtain a sample which contains nucleic acids derived from a tumor (primary or metastatic), representing their cancer genome. In another aspect, it may be desirable to obtain a sample which reflects post-zygotic V(D)J recombination which has occurred in cells of the subject's immune system. In particular, these may include T-cells and/or B-cells from the blood of the subject. The T-cells and/or B-cells may have infiltrated a tumor of the subject. In certain applications, it may be desirable to obtain a sample which reflects non-human nucleic acids derived from the subject. The sample may reflect the genome(s) of one or more microbial species (bacteria or viruses), including those which may be, or which may already have been, oncogenic. Combinations of Samples and of Nucleic Acids Derived Therefrom In an aspect of the present disclosure, it may desirable in operation (a) to obtain a single sample from the subject. It also may be desirable to obtain a plurality of samples for use in operation (a). During cancer, it may be desirable to obtain one or more samples reflective of the cancer genome, and also one or more samples reflective of the germline genome. It may also be desirable to obtain DNA and separately RNA from a tumor of the subject. Lastly, it may be desirable to obtain nucleic acids from a sample of a tumor of the subject, and also nucleic acids circulating in the blood plasma of the subject. Genetic Characteristics During the second operation of the information flow, one or more specific genetic characteristics may be extracted from the data of the first operation. The genetic characteristics selected for extraction may be chosen so as to guide the later design and array-based synthesis of nucleic acids to be used in one or more assays for personalized genetic testing. The genetic characteristics of this operation may include differences between the genetic characteristics of the subject and those of a human reference sequence. Those differences (variants) may be selected from a group consisting of single base substitutions (also called Single Nucleotide Polymorphisms, or SNPs), multiple nucleotide base substitutions (Multiple Nucleotide Polymorphisms, or MNPs), Insertions or Deletions (also referred to as InDels), or Copy Number Variations (CNVs) or Structural Variations (SVs). The genetic characteristics may combine multiple genetic variants into a signature. For example, HLA type and ABO blood type, but may also include gene expression signatures and other combinations. The genetic variants may be in the germline genome of the subject (including both inherited variants and de novo variants). They may also be variants which originated post-zygotically. These may include mosaic or somatic variants, or V(D)J recombination. The genetic characteristics may include levels of RNA expression, for example at the level of whole genes, at the level of specific transcripts, at the level of specific variants (i.e., allele-specific expression), or the levels of non-coding RNAs. They may also include levels of methylation or other forms of epigenetic information determined from the sample. The genetic characteristics may also include the quantity of sequences derived from oligo-antibody conjugates bound to, or depleted by binding to, proteins or peptides in the sample(s). Where the genetic characteristics are quantitative, they may be absolute or relative. The genetic characteristics may quantitate the actual biological molecules of the sample(s) or they may quantitate one or more indirect metrics related to the biological molecules, such as the number of sequence reads of different types which result from an assay of the sample(s). Design of Nucleic Acid Sequences for Subsequent Array-Based Synthesis and Use in a Second, Personalized, Assay During the third operation of the information flow, the genetic characteristics of the subject may be used to design (e.g., generate or engineer) a second assay. The genetic characteristics may also be used to design a set of nucleic acid sequences. The DNA sequences synthesized in the fourth operation may be used in the personalized assay of the last operation. The sequences designed in the third operation, and synthesized in the fourth operation, can direct the personalized assay onto regions of the genome, which may include those guided by the subject's initially determined genetic characteristics. This is accomplished in order to obtain more detailed analysis in the same sample, and/or for corresponding analysis of other genetically related samples (from the same subject and/or genetically-related subjects). The personalized assay may be enabled by the DNA sequences. The synthesized oligonucleotides may hybridize with the nucleic acids of (or derived from) the sample. Following this hybridization, those oligonucleotides not hybridized may be washed away. The oligonucleotides that are hybridized may be pulled out of solution by mechanisms selected from the group consisting of streptavidin binding, magnetic bead pullout, and other methods. Alternatively, the personalized assay enabled by these DNA sequences may use the DNA sequences for amplification. The synthesized DNA sequences may prime enzymatic extension of the DNA. For example, a polymerase may hybridize a single-stranded synthesized nucleic acid to a complementary target in single stranded nucleic acid molecules of, or derived from, the sample. This can form a double-stranded nucleic acid segment. This segment can then be used as the starting point for enzymatic extension. The enzymatic extension may be single base extension (including extension with a labeled or otherwise distinguishable nucleotide), a multiple-base extension (as in the gap filling of a molecular inversion probe—MIP), or it can include repeated cycles of priming and extension leading to amplification. This amplification can be exponential (as in a polymerase chain reaction (PCR)), linear, or other combinations. By the methods described above or elsewhere herein, the array-synthesized nucleic acids may be used to enrich or deplete a nucleic acid mixture of those nucleic acid molecules, which can include specific locations, for example, in, or regions of, the human genome, or of microbial genomes, or of sets of oligo-antibody conjugates. The DNA sequences designed in this operation may correspond, in whole or in part, to loci and/or regions of the target genome. They may also include one or more segments which are not related to the target genome, for other purposes. In one such approach, the segment not related to the target genome may be a nucleic acid barcode, for example, a sequence designed to convey information, or to be used as an identifier. Barcode sequence segments of this type may later be used for physical (e.g., hybridization-based) used for the capture of a subset of molecules, or they may be used for bioinformatic segmentation of a data set derived from them, or for other purposes. In another example, the segments of the nucleic acid sequences, not related to the target genome, may be primers or priming sites for enzymatic extension and/or amplification, and they may contain other functional features (e.g., recognition sequences for restriction enzymes, as used in a molecular inversion probe). FIG. 3 shows a manner in which methods and systems of the present disclosure may be used to significantly lower the cost of sequencing family (pedigree) members. In the first operation, DNA from one of the affected subjects of the pedigree may be exome sequenced. The data may be analyzed to identify variants relative to the human reference sequence. At least about 1000, 10,000, 50,000, 100,000, 130,000, or 150,000 variants can be identified. This list may then be filtered bioinformatically. The list may be filtered by factors including coding, non-synonymous variants, minor allele frequency population at most about 1%, phenotype match, and inheritance. For example, the list may be filtered bioinformatically to identify which of those variants are non-synonymous (i.e., they may be expected to change the amino acid sequence of the protein expressed by this gene). This list can then be further filtered bioinformatically to identify variants which have allele frequencies in the population below a cutoff, e.g., 1% (as may be expected for a variant causing a rare disease). The variants may be narrowed to at most about 500 variants. The variants may be narrowed to at most about 600 variants, 700 variants, 800 variants, 1000 variants, 1500 variants. The number of variants assayed may require a one-to-one ratio (or more) of variants to synthesized sequences. As a non-limiting example, 500 variants may require the synthesis of at least about 500 sequences. The genomic region captured by each probe can be at least about 350 bases. Therefore, for at least about 500 sequences, the footprint of this assay may be about 175,000 bases. Compared to an exome, where the footprint of the assay is typically at least 35 million bases, this may result in 200× less sequencing. This dramatic reduction in the amount of sequencing required, per additional family pedigree member, can make it much more affordable to sequence additional pedigree members (e.g., the parents and other children of the same parents). The number of nucleic acid sequences which can be synthesized most economically on an array may be larger than the number needed for the planned subsequent personal assay of a specific subject or clinical case. In addition, the cost of the synthesis of such an array may be larger than can be justified by the value of a personalized assay of a single specific subject or clinical case. As a result, the array may have enough capacity to synthesize all of the subject-specific sequences needed for the personalized assays of a plurality of subjects. This may allow for amortizing the cost of an array-based synthesis over that plurality of subjects, thus lowering the cost per subject. When multiple nucleic acid sequences are synthesized on an array, and subsequently cleaved from that common substrate, they may become intermingled in a pool. They can be used in that form for assays (e.g., targeted next generation DNA sequencing) which beneficially multiplex a plurality of genomic targets. In this case, data from the plurality of genomic targets can be de-multiplexed downstream by alignment of the sequences to a reference sequence. FIG. 4 shows an example of how custom array-based synthesis of oligonucleotides for personal assays, for example for 32 cases, can be shared, substantially lowering the synthesis cost per case. The saving in sequencing costs may be partially or even completely offset by the cost of synthesizing an array of hybrid capture probes. To address this, the capture probes for each of several independent clinical cases can be synthesized on a single array (the arrays used in Agilent's system for example, have a capacity up to about 55,000 probes/array). If 32 clinical cases are combined in a single array one panel synthesis, at 200 probes each, the total may be 6,400 probes, still well within the capacity of the array. This amortizes the cost of array synthesis over the 32 cases. If the probes are not de-multiplexed post-synthesis, their footprints will be additive and thus be approximately 175,000 bases/case×32 cases=5.6 million bases. This is at least a 10× reduction in sequencing footprint versus performing exome sequencing on each of the other family members of each of the pedigrees. Next, all family members may be sequenced. For example, 32 cases×3=96 samples. The probands may be included to confirm that the new panel can detect all the target variants. This assay may generate data indicative of a presence or absence of at least a subset of the genetic variants in the subjects and at least one biological relative. Genotype analysis can be performed from the sample's data, at the 200 loci specific to its case. If the subject-specific sequences for multiple subjects are synthesized together on a single array, each subject subsequently assayed may generate data not only for their own genomic regions of interest, but also for the genomic regions of interest in other subjects. For each subject, the data from the genomic regions selected for other subjects may be irrelevant. Depending on the specific configuration, this unwanted data may also add to the cost of the personalized assays. If that additional cost is burdensome, it may be a barrier to the use of personalized assays based on array-synthesis of nucleic acids. If the DNA sequences are designed with two or more segments, one corresponding to the target regions of the genome and one or more not, then the segments not corresponding to the target regions of the genome can be used to physically separate, or enrich, the synthesized molecules post synthesis. Thus subject-specific sequences for a plurality of subjects can be synthesized together on an array, and be separated out post-synthesis. This post-synthesis separation can be driven by the segments of the sequences which were not related to the target regions of the genome (e.g., the barcodes or other segment designs). For example, the subject-specific nucleic acid sequences can each be designed to have one segment corresponding to the genomic regions of interest for that subject, and a second segment with a barcode sequence corresponding to that subject. That barcode sequence can then be used after array-based synthesis to capture just the nucleic acid molecules synthesized for a specific subject. Once the nucleic acid molecules synthesized for just one subject have been physically separated out from the rest of the pool, they can be used for a personalized assay specific to just that subject. This separation may not need to be absolute to address the cost problem. In another example, the subject-specific nucleic acid sequences can each be designed to have two segments not related to the genomic regions of interest to that subject. These two segments can then be used after array-based synthesis, to amplify just the sequences needed for the personalized assay for that subject. The amplification may be done separately for each of the subjects whose sequences were synthesized together on a single array. By designing sequences, each with at least one segment not corresponding to a genomic region, the pool of oligonucleotides which exists post synthesis can be partitioned for separate uses. Those uses can include different processing of different groups of genomic content, from the same person (or people related to them). Those uses can also include separate processing and subject-specific analyses of unrelated subjects. The performance of synthesized nucleic acid sequences in a personalized assay may vary depending on many conditions of the nucleic acid sequence (e.g., % GC, alignment degeneracy, primer-dimer formation) and the parameters of the assay. This assay performance uncertainty may make personal assay synthesis unattractive. However, a large set of DNA sequences may be designed, synthesized and tested in advance. Such a set can be, for example, a set of sequences to target every exon of every gene in the human genome. Data from this testing can provide validation of the sequences which worked satisfactorily, and feedback to guide the redesign and re-synthesis of sequences where the performance of the original design was not satisfactory. By this method, a library of previously designed, tested and validated sequences can be obtained. Then, when it is time to create a personalized assay for a specific subject, the DNA sequences designed for that subject can include sequences from the pre-validated library. This method can reduce the uncertainty of personalized assay performance and reduce the cost of, and time required to, design a set of sequences for a subject-specific assay. The performance of an individual synthesized DNA sequence in an assay can also depend on the extent to which the DNA sequence used in the assay matches the region targeted in the nucleic acids derived from actual sample from the subject. Because subjects vary from the human reference in some of their nucleic acid sequences, the performance of an assay targeting the genomic region of a variant may depend on the allele of the variant in the subject being tested. It can be an advantage for a personalized genetic assay to optimize for the alleles actually present in that subject. In particular, if specific variant alleles are detected in the initial assay of the subject, then the sequences designed for the subsequent personalized assay can be based on those variant alleles. This may lead to better assay performance and reduce or eliminate allele-specific assay bias which may otherwise occur. While this principle is applicable to all variant types, it may have the highest benefit in variants which include multiple bases (e.g., multiple nucleotide polymorphisms, insertions or deletions (“InDels”), gene fusions, copy number variation, splice variants, and other forms of structural variation). Array-Based Synthesis of Nucleic Acid Sequences Array-based synthesis of multiple nucleic acid sequences on a common substrate can have varying degrees of parallelism. The optimal parallelism can vary by application, and by the use of post-synthesis de-multiplexing. The optimal parallelism for an application may be at least about 100 or at least about 1,000, or at least about 10,000 or at least about 50,000 nucleic acid sequences synthesized together on a common substrate, The optimum parallelism may be changed if the nucleic acids sequences synthesized in parallel on a common substrate are in spatially distinct regions of the substrate, separated a gap. In particular, if the gap is large enough to allow physical partitioning of the substrate after nucleic acid synthesis without damaging any of the nucleic acid molecules synthesized (e.g., wafer dicing) then the nucleic acid molecules can be partitioned without post-synthesis de-multiplexing from a pool. The optimal nucleic acid length may depend on the synthesis methods used and the cost, synthesis time, sequence-purity of the synthesis method vs the length synthesized. It also may depend on whether the sequence consists of one segment (designed to be complementary to a genomic target), two segments (with the second segment being for example a barcode), three segments (with the 2nd and 3rd segments being for example primers or priming sites for amplification) or other multi-segment structures. Thus the optimum length may be at least about 50 bases, at least about 100 bases, at least about 150, at least about 200, at least about 250, or at least about 300 bases. The method of array-based nucleic acid synthesis may be photolithographic, by reagents dispensed in a jet from a moveable print head. Non-limiting examples of methods for synthesizing probes include in situ synthesis with or without photolithography and in situ synthesis using inkjet technology. Methods of synthesizing arrays or probes using photolithography may use masking and/or may use a digital micromirror device. Other examples of array synthesis are provided in U.S. Pat. No. 5,412,087; U.S. Pat. No. 6,045,996; U.S. Pat. No. 7,534,561; U.S. Pat. No. 8,415,101; U.S. Pat. No. 8,026,094, the disclosures of which are hereby incorporated by reference. Methods to Use a Single Nucleic Acid Synthesis Array for Multiple Independent Cases The capacity of an array (i.e., the number of sequences which can be synthesized on a single solid substrate) can be shared by synthesis of sequences for the testing of multiple otherwise unrelated testing cases. This can amortize the cost of array synthesis over multiple cases, thus lowering the synthesis cost per case. When sequences for multiple independent testing cases are synthesized together on a common substrate, they (or the information streams they represent) can be separated post-synthesis to the cases for which they were designed, by at least one of: (i) mechanical partitioning of the substrate post synthesis but prior to cleavage of the nucleic acids from the substrate, or (ii) using one or more segments of each of the nucleic acid sequences to represent the subject for whose case the rest of the sequence is being synthesized (i.e., a nucleic acid barcode, or primer(s) or priming site(s)) so that after the nucleic acids have been cleaved from the substrate into a common pool, they can be segregated by methods of molecular biology (e.g., hybridization, amplification or others) for use in assays related just to individual cases, or (iii) bioinformatic segregation of data from the personalized assays, either based on the barcoding mentioned above, or by alignment of the sequences resulting from the personalized assay to a reference sequence and then partitioning the data based on genomic regions corresponding to specific cases. Types of Genetic Analyses Personalized Using Array-Synthesized Nucleic Acids In an aspect of the present disclosure, the array synthesis of nucleic acid molecules may create personalized assays for the genetic analysis of subjects or individual clinical cases. The types of assays which can be personalized in this way include, but are not limited to DNA sequencing, genotyping and gene expression. DNA sequencing may be selected from a group of methods consisting of (i) DNA sequencing by synthesis using a reversible terminator chemistry, or (ii) pyrosequencing, or (iii) nanopore sequencing, or (iv) real-time single molecule sequencing. Genotyping may comprise a single base extension. In this case, the multiplexed assay may be demultiplexed using a method selected from a group consisting of (i) hybridization to a DNA array using nucleic acid barcodes incorporated into the array-synthesized sequences, or (ii) PCR using primers incorporated into the array-synthesized sequences, or (iii) electrophoresis, or (iv) mass spectroscopy. Combinations of Fixed and Variable (Personal) Genomic Content in the Array-Synthesized Nucleic Acids In an aspect of the present disclosure, some or all of the genomic content of the array-synthesized nucleic acids, may be based on the genetic characteristics originally determined for the individual subject. In some applications, it may be desirable for the oligo-directed genomic content of the personalized assay to contain both a variable portion (defined based on the genetic characteristics originally determined for the individual subject) and at least one fixed portion (which does not change from one subject to another). The fixed content may be synthesized on the same array as the variable content, or on a different array. The fixed content may participate in the personalized assay of all samples, or a subset of them. If the variable content of multiple subjects is synthesized together on a single array, along with the shared fixed content, and if the variable portion is to be de-multiplexed following synthesis (e.g., using a barcode or priming segment of the sequence design) then the system for de-multiplexing may allow for the fixed content to also be captured with each of the separate sets of variable content. This can be done by assigning a separate barcode (or equivalent) to the fixed content, and conducting each post-synthesis de-multiplexing pullout reaction with both the barcode of the subject and the barcode of the fixed content. Where the personalized assay is designed to use RNA (or cDNA derived from RNA), the fixed content may correspond to genes which are expected to be expressed at a lower level, and the variable content may correspond to genes which are expected to be expressed at a higher level. Alternatively, the fixed content may correspond to genes with relatively stable expression (subject to subject) and the variable content may correspond to genes which are expressed more variably from subject to subject. In either case, the RNA targeted may include not only expressed RNA, but also non-coding RNA. Where the personalized assay is designed for a cancer application, the variable content may correspond to potential neoantigen-causing variants of the subject. The fixed portion may be selected from a group consisting of one or more of (i) cancer driver genes, (ii) genes involved in the pharmacogenomics of cancer drugs, (iii) genes involved in Mendelian immunological diseases, (iv) genes related to inherited forms of cancer, (v) genes associated with tumor escape from a targeted or immune cancer therapy, (vi) HLA typing, or (vii) variants common in the population and used by B-allele methods to detect structural variation. Where the personalized assay is designed for a Mendelian disease application, the variable content may correspond to variants which may be responsible for the Mendelian phenotype of a proband. The fixed portion may be selected from a group consisting of one or more of (i) additional genetic content not directly related to the Mendelian condition of the proband, or (ii) pharmacogenomics, or (iii) genetic sample ID by a fixed panel of variants or a fixed panel of phenotype-related variants such as gender, blood type, or (iv) variants common in the population and used by B-allele methods to detect structural variation. Devices The methods disclosed herein may comprise one or more devices. The methods disclosed herein may comprise one or more assays comprising one or more devices. The methods disclosed herein may comprise the use of one or more devices to perform one or more operations or assays. The methods disclosed herein may comprise the use of one or more devices in one or more operations or assays. For example, conducting a sequencing reaction may comprise one or more sequencers. In another example, producing a subset of nucleic acid molecules may comprise the use of one or more magnetic separators. In yet another example, one or more processors may be used in the analysis of one or more nucleic acid samples. Exemplary devices include, but are not limited to, sequencers, thermocyclers, real-time PCR instruments, magnetic separators, transmission devices, hybridization chambers, electrophoresis apparatus, centrifuges, microscopes, imagers, fluorometers, luminometers, plate readers, computers, processors, and bioanalyzers. The methods disclosed herein may comprise one or more sequencers. The one or more sequencers may comprise one or more HiSeq, MiSeq, HiScan, Genome Analyzer IIx, SOLiD Sequencer, Ion Torrent PGM, 454 GS Junior, Pac Bio RS, or a combination thereof. The one or more sequencers may comprise one or more sequencing platforms. The one or more sequencing platforms may comprise GS FLX by 454 Life Technologies/Roche, Genome Analyzer by Solexa/Illumina, SOLiD by Applied Biosystems, CGA Platform by Complete Genomics, PacBio RS by Pacific Biosciences, or a combination thereof. The methods disclosed herein may comprise one or more thermocyclers. The one or more thermocyclers may be used to amplify one or more nucleic acid molecules. The methods disclosed herein may comprise one or more real-time PCR instruments. The one or more real-time PCR instruments may comprise a thermal cycler and a fluorimeter. The one or more thermocyclers may be used to amplify and detect one or more nucleic acid molecules. The methods disclosed herein may comprise one or more magnetic separators. The one or more magnetic separators may be used for separation of paramagnetic and ferromagnetic particles from a suspension. The one or more magnetic separators may comprise one or more LifeStep™ biomagnetic separators, SPHERO™ FlexiMag separator, SPHERO™ MicroMag separator, SPHERO™ HandiMag separator, SPHERO™ MiniTube Mag separator, SPHERO™ UltraMag separator, DynaMag™ magnet, DynaMag™-2 Magnet, or a combination thereof. The methods disclosed herein may comprise one or more bioanalyzers. Generally, a bioanalyzer is a chip-based capillary electrophoresis machine that can analyze RNA, DNA, and proteins. The one or more bioanalyzers may comprise Agilent's 2100 Bioanalyzer. The methods disclosed herein may comprise one or more processors. The one or more processors may analyze, compile, store, sort, combine, assess or otherwise process one or more data and/or results from one or more assays, one or more data and/or results based on or derived from one or more assays, one or more outputs from one or more assays, one or more outputs based on or derived from one or more assays, one or more outputs from one or data and/or results, one or more outputs based on or derived from one or more data and/or results, or a combination thereof. The one or more processors may transmit the one or more data, results, or outputs from one or more assays, one or more data, results, or outputs based on or derived from one or more assays, one or more outputs from one or more data or results, one or more outputs based on or derived from one or more data or results, or a combination thereof. The one or more processors may receive and/or store requests from a user. The one or more processors may produce or generate one or more data, results, outputs. The one or more processors may produce or generate one or more biomedical reports. The one or more processors may transmit one or more biomedical reports. The one or more processors may analyze, compile, store, sort, combine, assess or otherwise process information from one or more databases, one or more data or results, one or more outputs, or a combination thereof. The one or more processors may analyze, compile, store, sort, combine, assess or otherwise process information from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30 or more databases. The one or more processors may transmit one or more requests, data, results, outputs and/or information to one or more users, processors, computers, computer systems, memory locations, devices, databases, or a combination thereof. The one or more processors may receive one or more requests, data, results, outputs and/or information from one or more users, processors, computers, computer systems, memory locations, devices, databases or a combination thereof. The one or more processors may retrieve one or more requests, data, results, outputs and/or information from one or more users, processors, computers, computer systems, memory locations, devices, databases or a combination thereof. The methods disclosed herein may comprise one or more memory locations. The one or more memory locations may store information, data, results, outputs, requests, or a combination thereof. The one or more memory locations may receive information, data, results, outputs, requests, or a combination thereof from one or more users, processors, computers, computer systems, devices, or a combination thereof. Methods described herein can be implemented with the aid of one or more computers and/or computer systems. A computer or computer system may comprise electronic storage locations (e.g., databases, memory) with machine-executable code for implementing the methods provided herein, and one or more processors for executing the machine-executable code. FIG. 8 shows a computer system (also “system” herein) 801 programmed or otherwise configured for implementing the methods of the disclosure, such as nucleic acid processing and/or analysis, and/or data analysis. The system 801 includes a central processing unit (CPU, also “processor” and “computer processor” herein) 805, which can be a single core or multi core processor, or a plurality of processors for parallel processing. The system 801 also includes memory 810 (e.g., random-access memory, read-only memory, flash memory), electronic storage unit 815 (e.g., hard disk), communications interface 820 (e.g., network adapter) for communicating with one or more other systems, and peripheral devices 825, such as cache, other memory, data storage and/or electronic display adapters. The memory 810, storage unit 815, interface 820 and peripheral devices 825 are in communication with the CPU 805 through a communications bus (solid lines), such as a motherboard. The storage unit 815 can be a data storage unit (or data repository) for storing data. The system 801 is operatively coupled to a computer network (“network”) 830 with the aid of the communications interface 820. The network 830 can be the Internet, an internet and/or extranet, or an intranet and/or extranet that is in communication with the Internet. The network 830 in some cases is a telecommunication and/or data network. The network 830 can include one or more computer servers, which can enable distributed computing, such as cloud computing. The network 830 in some cases, with the aid of the system 801, can implement a peer-to-peer network, which may enable devices coupled to the system 801 to behave as a client or a server. The system 801 is in communication with a processing system 835. The processing system 835 can be configured to implement the methods disclosed herein. In some examples, the processing system 835 is a nucleic acid sequencing system, such as, for example, a next generation sequencing system (e.g., Illumina sequencer, Ion Torrent sequencer, Pacific Biosciences sequencer). The processing system 835 can be in communication with the system 801 through the network 830, or by direct (e.g., wired, wireless) connection. The processing system 835 can be configured for analysis, such as nucleic acid sequence analysis. Methods as described herein can be implemented by way of machine (or computer processor) executable code (or software) stored on an electronic storage location of the system 801, such as, for example, on the memory 810 or electronic storage unit 815. During use, the code can be executed by the processor 805. In some examples, the code can be retrieved from the storage unit 815 and stored on the memory 810 for ready access by the processor 805. In some situations, the electronic storage unit 815 can be precluded, and machine-executable instructions are stored on memory 810. The code can be pre-compiled and configured for use with a machine have a processor adapted to execute the code, or can be compiled during runtime. The code can be supplied in a programming language that can be selected to enable the code to execute in a pre-compiled or as-compiled fashion. Aspects of the systems and methods provided herein, such as the system 801, can be embodied in programming. Various aspects of the technology may be thought of as “products” or “articles of manufacture” typically in the form of machine (or processor) executable code and/or associated data that is carried on or embodied in a type of machine readable medium. Machine-executable code can be stored on an electronic storage unit, such memory (e.g., read-only memory, random-access memory, flash memory) or a hard disk. “Storage” type media can include any or all of the tangible memory of the computers, processors or the like, or associated modules thereof, such as various semiconductor memories, tape drives, disk drives and the like, which may provide non-transitory storage at any time for the software programming. All or portions of the software may at times be communicated through the Internet or various other telecommunication networks. Such communications, for example, may enable loading of the software from one computer or processor into another, for example, from a management server or host computer into the computer platform of an application server. Thus, another type of media that may bear the software elements includes optical, electrical and electromagnetic waves, such as used across physical interfaces between local devices, through wired and optical landline networks and over various air-links. The physical elements that carry such waves, such as wired or wireless links, optical links or the like, also may be considered as media bearing the software. As used herein, unless restricted to non-transitory, tangible “storage” media, terms such as computer or machine “readable medium” refer to any medium that participates in providing instructions to a processor for execution. Hence, a machine readable medium, such as computer-executable code, may take many forms, including but not limited to, a tangible storage medium, a carrier wave medium or physical transmission medium. Non-volatile storage media include, for example, optical or magnetic disks, such as any of the storage devices in any computer(s) or the like, such as may be used to implement the databases, etc. shown in the drawings. Volatile storage media include dynamic memory, such as main memory of such a computer platform. Tangible transmission media include coaxial cables; copper wire and fiber optics, including the wires that comprise a bus within a computer system. Carrier-wave transmission media may take the form of electric or electromagnetic signals, or acoustic or light waves such as those generated during radio frequency (RF) and infrared (IR) data communications. Common forms of computer-readable media therefore include for example: a floppy disk, a flexible disk, hard disk, magnetic tape, any other magnetic medium, a CD-ROM, DVD or DVD-ROM, any other optical medium, punch cards paper tape, any other physical storage medium with patterns of holes, a RAM, a ROM, a PROM and EPROM, a FLASH-EPROM, any other memory chip or cartridge, a carrier wave transporting data or instructions, cables or links transporting such a carrier wave, or any other medium from which a computer may read programming code and/or data. Many of these forms of computer readable media may be involved in carrying one or more sequences of one or more instructions to a processor for execution. The one or more computers and/or computer systems may analyze, compile, store, sort, combine, assess or otherwise process one or more data and/or results from one or more assays, one or more data and/or results based on or derived from one or more assays, one or more outputs from one or more assays, one or more outputs based on or derived from one or more assays, one or more outputs from one or data and/or results, one or more outputs based on or derived from one or more data and/or results, or a combination thereof. The one or more computers and/or computer systems may transmit the one or more data, results, or outputs from one or more assays, one or more data, results, or outputs based on or derived from one or more assays, one or more outputs from one or more data or results, one or more outputs based on or derived from one or more data or results, or a combination thereof. The one or more computers and/or computer systems may receive and/or store requests from a user. The one or more computers and/or computer systems may produce or generate one or more data, results, outputs. The one or more computers and/or computer systems may produce or generate one or more biomedical reports. The one or more computers and/or computer systems may transmit one or more biomedical reports. The one or more computers and/or computer systems may analyze, compile, store, sort, combine, assess or otherwise process information from one or more databases, one or more data or results, one or more outputs, or a combination thereof. The one or more computers and/or computer systems may analyze, compile, store, sort, combine, assess or otherwise process information from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30 or more databases. The one or more computers and/or computer systems may transmit one or more requests, data, results, outputs, and/or information to one or more users, processors, computers, computer systems, memory locations, devices, or a combination thereof. The one or more computers and/or computer systems may receive one or more requests, data, results, outputs, and/or information from one or more users, processors, computers, computer systems, memory locations, devices, or a combination thereof. The one or more computers and/or computer systems may retrieve one or more requests, data, results, outputs and/or information from one or more users, processors, computers, computer systems, memory locations, devices, databases or a combination thereof. The methods disclosed herein may comprise one or more transmission devices comprising an output unit transmitting one or more data, results, outputs, information, biomedical outputs, and/or biomedical reports. The output unit can take any form which transmits the data, results, requests, and/or information and may comprise a monitor, printed format, printer, computer, processor, memory location, or a combination thereof. The transmission device may comprise one or more processors, computers, and/or computer systems for transmitting information. The computer system 801 can include or be in communication with an electronic display 840 that comprises a user interface (UI) 845 for providing, for example, a report indicative of a presence or absence of at least a subset of genetic variants in a subject or at least one biological relative. Examples of UI's include, without limitation, a graphical user interface (GUI) and web-based user interface. Methods and systems of the present disclosure can be implemented by way of one or more algorithms. An algorithm can be implemented by way of software upon execution by the central processing unit 805. The algorithm can, for example, be used to process sequencing data to determine a plurality of genetic characteristics, select probes for synthesis or from a collection of nucleic acid probe molecules. Databases The methods disclosed herein may comprise one or more databases. The methods disclosed herein may comprise at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30 or more databases. The databases may comprise genomic, proteomic, pharmacogenomic, biomedical, and scientific databases. The databases may be publicly available databases. Alternatively, or additionally, the databases may comprise proprietary databases. The databases may be commercially available databases. The databases include, but are not limited to, MendelDB, PharmGKB, Varimed, Regulome, curated BreakSeq junctions, Online Mendelian Inheritance in Man (OMIM), Human Genome Mutation Database (HGMD), NCBI dbSNP, NCBI RefSeq, GENCODE, GO (gene ontology), and Kyoto Encyclopedia of Genes and Genomes (KEGG). The methods disclosed herein may comprise analyzing one or more databases. The methods disclosed herein may comprise analyzing at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30 or more databases. Analyzing the one or more databases may comprise one or more algorithms, computers, processors, memory locations, devices, or a combination thereof. The methods disclosed herein may comprise producing one or more probes based on data and/or information from one or more databases. The methods disclosed herein may comprise producing one or more probe sets based on data and/or information from one or more databases. The methods disclosed herein may comprise producing one or more probes and/or probe sets based on data and/or information from at least about 2 or more databases. The methods disclosed herein may comprise producing one or more probes and/or probe sets based on data and/or information from at least about 3 or more databases. The methods disclosed herein may comprise producing one or more probes and/or probe sets based on data and/or information from at least about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30 or more databases. The methods disclosed herein may comprise identifying one or more nucleic acid regions based on data and/or information from one or more databases. The methods disclosed herein may comprise identifying one or more sets of nucleic acid regions based on data and/or information from one or more databases. The methods disclosed herein may comprise identifying one or more nucleic acid regions and/or sets of nucleic acid regions based on data and/or information from at least about 2 or more databases. The methods disclosed herein may comprise identifying one or more nucleic acid regions and/or sets of nucleic acid regions based on data and/or information from at least about 3 or more databases. The methods disclosed herein may comprise identifying one or more nucleic acid regions and/or sets of nucleic acid regions based on data and/or information from at least about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30 or more databases. The methods disclosed herein may further comprise producing one or more probes and/or probe sets based on the identification of the one or more nucleic acid regions and/or sets of nucleic acid regions. The methods disclosed herein may comprise analyzing one or more results based on data and/or information from one or more databases. The methods disclosed herein may comprise analyzing one or more sets of results based on data and/or information from one or more databases. The methods disclosed herein may comprise analyzing one or more combined results based on data and/or information from one or more databases. The methods disclosed herein may comprise analyzing one or more results, sets of results, and/or combined results based on data and/or information from at least about 2 or more databases. The methods disclosed herein may comprise analyzing one or more results, sets of results, and/or combined results based on data and/or information from at least about 3 or more databases. The methods disclosed herein may comprise analyzing one or more results, sets of results, and/or combined results based on data and/or information from at least about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30 or more databases. The methods disclosed herein may comprise comparing one or more results based on data and/or information from one or more databases. The methods disclosed herein may comprise comparing one or more sets of results based on data and/or information from one or more databases. The methods disclosed herein may comprise comparing one or more combined results based on data and/or information from one or more databases. The methods disclosed herein may comprise comparing one or more results, sets of results, and/or combined results based on data and/or information from at least about 2 or more databases. The methods disclosed herein may comprise comparing one or more results, sets of results, and/or combined results based on data and/or information from at least about 3 or more databases. The methods disclosed herein may comprise comparing one or more results, sets of results, and/or combined results based on data and/or information from at least about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30 or more databases. The methods disclosed herein may comprise biomedical databases, genomic databases, biomedical reports, disease reports, case-control analysis, and rare variant discovery analysis based on data and/or information from one or more databases, one or more assays, one or more data or results, one or more outputs based on or derived from one or more assays, one or more outputs based on or derived from one or more data or results, or a combination thereof. Analysis The methods disclosed herein may comprise one or more data, one or more data sets, one or more combined data, one or more combined data sets, one or more results, one or more sets of results, one or more combined results, or a combination thereof. The data and/or results may be based on or derived from one or more assays, one or more databases, or a combination thereof. The methods disclosed herein may comprise analysis of the one or more data, one or more data sets, one or more combined data, one or more combined data sets, one or more results, one or more sets of results, one or more combined results, or a combination thereof. The methods disclosed herein may comprise processing of the one or more data, one or more data sets, one or more combined data, one or more combined data sets, one or more results, one or more sets of results, one or more combined results, or a combination thereof. The methods disclosed herein may comprise at least one analysis and at least one processing of the one or more data, one or more data sets, one or more combined data, one or more combined data sets, one or more results, one or more sets of results, one or more combined results, or a combination thereof. The methods disclosed herein may comprise one or more analyses and one or more processing of the one or more data, one or more data sets, one or more combined data, one or more combined data sets, one or more results, one or more sets of results, one or more combined results, or a combination thereof. The methods disclosed herein may comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000 or more distinct analyses of the one or more data, one or more data sets, one or more combined data, one or more combined data sets, one or more results, one or more sets of results, one or more combined results, or a combination thereof. The methods disclosed herein may comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000 or more distinct processing of the one or more data, one or more data sets, one or more combined data, one or more combined data sets, one or more results, one or more sets of results, one or more combined results, or a combination thereof. The one or more analyses and/or one or more processing may occur simultaneously, sequentially, or a combination thereof. The one or more analyses and/or one or more processing may occur over 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000 or time points. The time points may occur over a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60 or more hour period. The time points may occur over a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60 or more day period. The time points may occur over a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60 or more week period. The time points may occur over a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60 or more month period. The time points may occur over a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60 or more year period. The methods disclosed herein may comprise one or more data. The one or more data may comprise one or more raw data based on or derived from one or more assays. The one or more data may comprise one or more raw data based on or derived from one or more databases. The one or more data may comprise at least partially analyzed data based on or derived from one or more raw data. The one or more data may comprise at least partially processed data based on or derived from one or more raw data. The one or more data may comprise fully analyzed data based on or derived from one or more raw data. The one or more data may comprise fully processed data based on or derived from one or more raw data. The data may comprise sequencing read data or expression data. The data may comprise biomedical, scientific, pharmacological, and/or genetic information. The methods disclosed herein may comprise one or more combined data. The one or more combined data may comprise two or more data. The one or more combined data may comprise two or more data sets. The one or more combined data may comprise one or more raw data based on or derived from one or more assays. The one or more combined data may comprise one or more raw data based on or derived from one or more databases. The one or more combined data may comprise at least partially analyzed data based on or derived from one or more raw data. The one or more combined data may comprise at least partially processed data based on or derived from one or more raw data. The one or more combined data may comprise fully analyzed data based on or derived from one or more raw data. The one or more combined data may comprise fully processed data based on or derived from one or more raw data. One or more combined data may comprise sequencing read data or expression data. One or more combined data may comprise biomedical, scientific, pharmacological, and/or genetic information. The methods disclosed herein may comprise one or more data sets. The one or more data sets may comprise one or more data. The one or more data sets may comprise one or more combined data. The one or more data sets may comprise one or more raw data based on or derived from one or more assays. The one or more data sets may comprise one or more raw data based on or derived from one or more databases. The one or more data sets may comprise at least partially analyzed data based on or derived from one or more raw data. The one or more data sets may comprise at least partially processed data based on or derived from one or more raw data. The one or more data sets may comprise fully analyzed data based on or derived from one or more raw data. The one or more data sets may comprise fully processed data based on or derived from one or more raw data. The data sets may comprise sequencing read data or expression data. The data sets may comprise biomedical, scientific, pharmacological, and/or genetic information. The methods disclosed herein may comprise one or more combined data sets. The one or more combined data sets may comprise two or more data. The one or more combined data sets may comprise two or more combined data. The one or more combined data sets may comprise two or more data sets. The one or more combined data sets may comprise one or more raw data based on or derived from one or more assays. The one or more combined data sets may comprise one or more raw data based on or derived from one or more databases. The one or more combined data sets may comprise at least partially analyzed data based on or derived from one or more raw data. The one or more combined data sets may comprise at least partially processed data based on or derived from one or more raw data. The one or more combined data sets may comprise fully analyzed data based on or derived from one or more raw data. The one or more combined data sets may comprise fully processed data based on or derived from one or more raw data. The methods disclosed herein may further comprise further processing and/or analysis of the combined data sets. One or more combined data sets may comprise sequencing read data or expression data. One or more combined data sets may comprise biomedical, scientific, pharmacological, and/or genetic information. The methods disclosed herein may comprise one or more results. The one or more results may comprise one or more data, data sets, combined data, and/or combined data sets. The one or more results may be based on or derived from one or more data, data sets, combined data, and/or combined data sets. The one or more results may be produced from one or more assays. The one or more results may be based on or derived from one or more assays. The one or more results may be based on or derived from one or more databases. The one or more results may comprise at least partially analyzed results based on or derived from one or more data, data sets, combined data, and/or combined data sets. The one or more results may comprise at least partially processed results based on or derived from one or more data, data sets, combined data, and/or combined data sets. The one or more results may comprise at fully analyzed results based on or derived from one or more data, data sets, combined data, and/or combined data sets. The one or more results may comprise fully processed results based on or derived from one or more data, data sets, combined data, and/or combined data sets. The results may comprise sequencing read data or expression data. The results may comprise biomedical, scientific, pharmacological, and/or genetic information. The methods disclosed herein may comprise one or more sets of results. The one or more sets of results may comprise one or more data, data sets, combined data, and/or combined data sets. The one or more sets of results may be based on or derived from one or more data, data sets, combined data, and/or combined data sets. The one or more sets of results may be produced from one or more assays. The one or more sets of results may be based on or derived from one or more assays. The one or more sets of results may be based on or derived from one or more databases. The one or more sets of results may comprise at least partially analyzed sets of results based on or derived from one or more data, data sets, combined data, and/or combined data sets. The one or more sets of results may comprise at least partially processed sets of results based on or derived from one or more data, data sets, combined data, and/or combined data sets. The one or more sets of results may comprise at fully analyzed sets of results based on or derived from one or more data, data sets, combined data, and/or combined data sets. The one or more sets of results may comprise fully processed sets of results based on or derived from one or more data, data sets, combined data, and/or combined data sets. The sets of results may comprise sequencing read data or expression data. The sets of results may comprise biomedical, scientific, pharmacological, and/or genetic information. The methods disclosed herein may comprise one or more combined results. The combined results may comprise one or more results, sets of results, and/or combined sets of results. The combined results may be based on or derived from one or more results, sets of results, and/or combined sets of results. The one or more combined results may comprise one or more data, data sets, combined data, and/or combined data sets. The one or more combined results may be based on or derived from one or more data, data sets, combined data, and/or combined data sets. The one or more combined results may be produced from one or more assays. The one or more combined results may be based on or derived from one or more assays. The one or more combined results may be based on or derived from one or more databases. The one or more combined results may comprise at least partially analyzed combined results based on or derived from one or more data, data sets, combined data, and/or combined data sets. The one or more combined results may comprise at least partially processed combined results based on or derived from one or more data, data sets, combined data, and/or combined data sets. The one or more combined results may comprise at fully analyzed combined results based on or derived from one or more data, data sets, combined data, and/or combined data sets. The one or more combined results may comprise fully processed combined results based on or derived from one or more data, data sets, combined data, and/or combined data sets. The combined results may comprise sequencing read data or expression data. The combined results may comprise biomedical, scientific, pharmacological, and/or genetic information. The methods disclosed herein may comprise one or more combined sets of results. The combined sets of results may comprise one or more results, sets of results, and/or combined results. The combined sets of results may be based on or derived from one or more results, sets of results, and/or combined results. The one or more combined sets of results may comprise one or more data, data sets, combined data, and/or combined data sets. The one or more combined sets of results may be based on or derived from one or more data, data sets, combined data, and/or combined data sets. The one or more combined sets of results may be produced from one or more assays. The one or more combined sets of results may be based on or derived from one or more assays. The one or more combined sets of results may be based on or derived from one or more databases. The one or more combined sets of results may comprise at least partially analyzed combined sets of results based on or derived from one or more data, data sets, combined data, and/or combined data sets. The one or more combined sets of results may comprise at least partially processed combined sets of results based on or derived from one or more data, data sets, combined data, and/or combined data sets. The one or more combined sets of results may comprise at fully analyzed combined sets of results based on or derived from one or more data, data sets, combined data, and/or combined data sets. The one or more combined sets of results may comprise fully processed combined sets of results based on or derived from one or more data, data sets, combined data, and/or combined data sets. The combined sets of results may comprise sequencing read data or expression data. The combined sets of results may comprise biomedical, scientific, pharmacological, and/or genetic information. The methods disclosed herein may comprise one or more outputs, sets of outputs, combined outputs, and/or combined sets of outputs. The methods, libraries, kits and systems herein may comprise producing one or more outputs, sets of outputs, combined outputs, and/or combined sets of outputs. The sets of outputs may comprise one or more outputs, one or more combined outputs, or a combination thereof. The combined outputs may comprise one or more outputs, one or more sets of outputs, one or more combined sets of outputs, or a combination thereof. The combined sets of outputs may comprise one or more outputs, one or more sets of outputs, one or more combined outputs, or a combination thereof. The one or more outputs, sets of outputs, combined outputs, and/or combined sets of outputs may be based on or derived from one or more data, one or more data sets, one or more combined data, one or more combined data sets, one or more results, one or more sets of results, one or more combined results, or a combination thereof. The one or more outputs, sets of outputs, combined outputs, and/or combined sets of outputs may be based on or derived from one or more databases. The one or more outputs, sets of outputs, combined outputs, and/or combined sets of outputs may comprise one or more biomedical reports, biomedical outputs, rare variant outputs, pharmacogenetic outputs, population study outputs, case-control outputs, biomedical databases, genomic databases, disease databases, net content. The methods disclosed herein may comprise one or more biomedical outputs, one or more sets of biomedical outputs, one or more combined biomedical outputs, one or more combined sets of biomedical outputs. The methods, libraries, kits and systems herein may comprise producing one or more biomedical outputs, one or more sets of biomedical outputs, one or more combined biomedical outputs, one or more combined sets of biomedical outputs. The sets of biomedical outputs may comprise one or more biomedical outputs, one or more combined biomedical outputs, or a combination thereof. The combined biomedical outputs may comprise one or more biomedical outputs, one or more sets of biomedical outputs, one or more combined sets of biomedical outputs, or a combination thereof. The combined sets of biomedical outputs may comprise one or more biomedical outputs, one or more sets of biomedical outputs, one or more combined biomedical outputs, or a combination thereof. The one or more biomedical outputs, one or more sets of biomedical outputs, one or more combined biomedical outputs, one or more combined sets of biomedical outputs may be based on or derived from one or more data, one or more data sets, one or more combined data, one or more combined data sets, one or more results, one or more sets of results, one or more combined results, one or more outputs, one or more sets of outputs, one or more combined outputs, one or more sets of combined outputs, or a combination thereof. The one or more biomedical outputs may comprise biomedical biomedical information of a subject. The biomedical biomedical information of the subject may predict, diagnose, and/or prognose one or more biomedical features. The one or more biomedical features may comprise the status of a disease or condition, genetic risk of a disease or condition, reproductive risk, genetic risk to a fetus, risk of an adverse drug reaction, efficacy of a drug therapy, prediction of optimal drug dosage, transplant tolerance, or a combination thereof. The methods disclosed herein may comprise one or more biomedical reports. The methods, libraries, kits and systems herein may comprise producing one or more biomedical reports. The one or more biomedical reports may be based on or derived from one or more data, one or more data sets, one or more combined data, one or more combined data sets, one or more results, one or more sets of results, one or more combined results, one or more outputs, one or more sets of outputs, one or more combined outputs, one or more sets of combined outputs, one or more biomedical outputs, one or more sets of biomedical outputs, combined biomedical outputs, one or more sets of biomedical outputs, or a combination thereof. The biomedical report may predict, diagnose, and/or prognose one or more biomedical features. The one or more biomedical features may comprise the status of a disease or condition, genetic risk of a disease or condition, reproductive risk, genetic risk to a fetus, risk of an adverse drug reaction, efficacy of a drug therapy, prediction of optimal drug dosage, transplant tolerance, or a combination thereof. The methods disclosed herein may also comprise the transmission of one or more data, information, results, outputs, reports or a combination thereof. For example, data/information based on or derived from the one or more assays are transmitted to another device and/or instrument. In another example, the data, results, outputs, biomedical outputs, biomedical reports, or a combination thereof are transmitted to another device and/or instrument. The information obtained from an algorithm may also be transmitted to another device and/or instrument. Information based on the analysis of one or more databases may be transmitted to another device and/or instrument. Transmission of the data/information may comprise the transfer of data/information from a first source to a second source. The first and second sources may be in the same approximate location (e.g., within the same room, building, block, campus). Alternatively, first and second sources may be in multiple locations (e.g., multiple cities, states, countries, continents, etc). The data, results, outputs, biomedical outputs, biomedical reports can be transmitted to a patient and/or a healthcare provider. Transmission may be based on the analysis of one or more data, results, information, databases, outputs, reports, or a combination thereof. For example, transmission of a second report is based on the analysis of a first report. Alternatively, transmission of a report is based on the analysis of one or more data or results. Transmission may be based on receiving one or more requests. For example, transmission of a report may be based on receiving a request from a user (e.g., patient, healthcare provider, individual). Transmission of the data/information may comprise digital transmission or analog transmission. Digital transmission may comprise the physical transfer of data (a digital bit stream) over a point-to-point or point-to-multipoint communication channel. Examples of such channels are copper wires, optical fibres, wireless communication channels, and storage media. The data may be represented as an electromagnetic signal, such as an electrical voltage, radiowave, microwave, or infrared signal. Analog transmission may comprise the transfer of a continuously varying analog signal. The messages can either be represented by a sequence of pulses using a line code (baseband transmission), or by a limited set of continuously varying wave forms (passband transmission), using a digital modulation method. The passband modulation and corresponding demodulation (also known as detection) can be carried out by modem equipment. According to the most common definition of digital signal, both baseband and passband signals representing bit-streams are considered as digital transmission, while an alternative definition only considers the baseband signal as digital, and passband transmission of digital data as a form of digital-to-analog conversion. The methods disclosed herein may comprise one or more sample identifiers. The sample identifiers may comprise labels, barcodes, and other indicators which can be linked to one or more samples and/or subsets of nucleic acid molecules. The methods disclosed herein may comprise one or more processors, one or more memory locations, one or more computers, one or more monitors, one or more computer software, one or more algorithms for linking data, results, outputs, biomedical outputs, and/or biomedical reports to a sample. The methods disclosed herein may comprise a processor for correlating the expression levels of one or more nucleic acid molecules with a prognosis of disease outcome. The methods disclosed herein may comprise one or more of a variety of correlative techniques, including lookup tables, algorithms, multivariate models, and linear or nonlinear combinations of expression models or algorithms. The expression levels may be converted to one or more likelihood scores, reflecting a likelihood that the patient providing the sample may exhibit a particular disease outcome. The models and/or algorithms can be provided in machine readable format and can, in some cases, further designate a treatment modality for a patient or class of patients. Diseases or Conditions The methods disclosed herein may comprise predicting, diagnosing, and/or prognosing a status or outcome of a disease or condition in a subject based on one or more biomedical outputs. Predicting, diagnosing, and/or prognosing a status or outcome of a disease in a subject may comprise diagnosing a disease or condition, identifying a disease or condition, determining the stage of a disease or condition, assessing the risk of a disease or condition, assessing the risk of disease recurrence, assessing reproductive risk, assessing genetic risk to a fetus, assessing the efficacy of a drug, assessing risk of an adverse drug reaction, predicting optimal drug dosage, predicting drug resistance, or a combination thereof. The samples disclosed herein may be from a subject suffering from a cancer. The sample may comprise malignant tissue, benign tissue, or a mixture thereof. The cancer may be a recurrent and/or refractory cancer. Examples of cancers include, but are not limited to, sarcomas, carcinomas, lymphomas or leukemias. Sarcomas are cancers of the bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue. Sarcomas include, but are not limited to, bone cancer, fibrosarcoma, chondrosarcoma, Ewing's sarcoma, malignant hemangioendothelioma, malignant schwannoma, bilateral vestibular schwannoma, osteosarcoma, soft tissue sarcomas (e.g., alveolar soft part sarcoma, angiosarcoma, cystosarcoma phylloides, dermatofibrosarcoma, desmoid tumor, epithelioid sarcoma, extraskeletal osteosarcoma, fibrosarcoma, hemangiopericytoma, hemangiosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, lymphosarcoma, malignant fibrous histiocytoma, neurofibrosarcoma, rhabdomyosarcoma, and synovial sarcoma). Carcinomas are cancers that begin in the epithelial cells, which are cells that cover the surface of the body, produce hormones, and make up glands. By way of non-limiting example, carcinomas include breast cancer, pancreatic cancer, lung cancer, colon cancer, colorectal cancer, rectal cancer, kidney cancer, bladder cancer, stomach cancer, prostate cancer, liver cancer, ovarian cancer, brain cancer, vaginal cancer, vulvar cancer, uterine cancer, oral cancer, penile cancer, testicular cancer, esophageal cancer, skin cancer, cancer of the fallopian tubes, head and neck cancer, gastrointestinal stromal cancer, adenocarcinoma, cutaneous or intraocular melanoma, cancer of the anal region, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, cancer of the urethra, cancer of the renal pelvis, cancer of the ureter, cancer of the endometrium, cancer of the cervix, cancer of the pituitary gland, neoplasms of the central nervous system (CNS), primary CNS lymphoma, brain stem glioma, and spinal axis tumors. The cancer may be a skin cancer, such as a basal cell carcinoma, squamous, melanoma, nonmelanoma, or actinic (solar) keratosis. The cancer may be a lung cancer. Lung cancer can start in the airways that branch off the trachea to supply the lungs (bronchi) or the small air sacs of the lung (the alveoli). Lung cancers include non-small cell lung carcinoma (NSCLC), small cell lung carcinoma, and mesotheliomia. Examples of NSCLC include squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. The mesothelioma may be a cancerous tumor of the lining of the lung and chest cavity (pleura) or lining of the abdomen (peritoneum). The mesothelioma may be due to asbestos exposure. The cancer may be a brain cancer, such as a glioblastoma. Alternatively, the cancer may be a central nervous system (CNS) tumor. CNS tumors may be classified as gliomas or nongliomas. The glioma may be malignant glioma, high grade glioma, diffuse intrinsic pontine glioma. Examples of gliomas include astrocytomas, oligodendrogliomas (or mixtures of oligodendroglioma and astocytoma elements), and ependymomas. Astrocytomas include, but are not limited to, low-grade astrocytomas, anaplastic astrocytomas, glioblastoma multiforme, pilocytic astrocytoma, pleomorphic xanthoastrocytoma, and subependymal giant cell astrocytoma. Oligodendrogliomas include low-grade oligodendrogliomas (or oligoastrocytomas) and anaplastic oligodendriogliomas. Nongliomas include meningiomas, pituitary adenomas, primary CNS lymphomas, and medulloblastomas. The cancer may be a meningioma. The leukemia may be an acute lymphocytic leukemia, acute myelocytic leukemia, chronic lymphocytic leukemia, or chronic myelocytic leukemia. Additional types of leukemias include hairy cell leukemia, chronic myelomonocytic leukemia, and juvenile myelomonocytic leukemia. Lymphomas are cancers of the lymphocytes and may develop from either B or T lymphocytes. The two major types of lymphoma are Hodgkin's lymphoma, previously known as Hodgkin's disease, and non-Hodgkin's lymphoma. Hodgkin's lymphoma is marked by the presence of the Reed-Sternberg cell. Non-Hodgkin's lymphomas are all lymphomas which are not Hodgkin's lymphoma. Non-Hodgkin lymphomas may be indolent lymphomas and aggressive lymphomas. Non-Hodgkin's lymphomas include, but are not limited to, diffuse large B cell lymphoma, follicular lymphoma, mucosa-associated lymphatic tissue lymphoma (MALT), small cell lymphocytic lymphoma, mantle cell lymphoma, Burkitt's lymphoma, mediastinal large B cell lymphoma, Waldenström macroglobulinemia, nodal marginal zone B cell lymphoma (NMZL), splenic marginal zone lymphoma (SMZL), extranodal marginal zone B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, and lymphomatoid granulomatosis. Additional diseases and/or conditions include, but are not limited to, atherosclerosis, inflammatory diseases, autoimmune diseases, rheumatic heart disease. Examples of inflammatory diseases include, but are not limited to, acne vulgaris, Alzheimer's, ankylosing spondylitis, arthritis (osteoarthritis, rheumatoid arthritis (RA), psoriatic arthritis), asthma, atherosclerosis, celiac disease, chronic prostatitis, Crohn's disease, colitis, dermatitis, diverticulitis, fibromyalgia, glomerulonephritis, hepatitis, irritable bowel syndrome (IBS), systemic lupus erythematous (SLE), nephritis, Parkinson's disease, pelvic inflammatory disease, sarcoidosis, ulcerative colitis, and vasculitis. Examples of autoimmune diseases include, but are not limited to, acute disseminated encephalomyelitis (ADEM), Addison's disease, agammaglobulinemia, alopecia areata, amyotrophic Lateral Sclerosis, ankylosing spondylitis, antiphospholipid syndrome, antisynthetase syndrome, atopic allergy, atopic dermatitis, autoimmune aplastic anemia, autoimmune cardiomyopathy, autoimmune enteropathy, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome, autoimmune peripheral neuropathy, autoimmune pancreatitis, autoimmune polyendocrine syndrome, autoimmune progesterone dermatitis, autoimmune thrombocytopenic purpura, autoimmune urticaria, autoimmune uveitis, Balo disease/Balo concentric sclerosis, BehØet's disease, Berger's disease, Bickerstaffs encephalitis, Blau syndrome, bullous pemphigoid, Castleman's disease, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy, chronic recurrent multifocal osteomyelitis, chronic obstructive pulmonary disease, Churg-Strauss syndrome, cicatricial pemphigoid, Cogan syndrome, cold agglutinin disease, complement component 2 deficiency, contact dermatitis, cranial arteritis, CREST syndrome, Crohn's disease, Cushing's syndrome, cutaneous leukocytoclastic angiitis, Dego's disease, Dercum's disease, dermatitis herpetiformis, dermatomyositis, diabetes mellitus type 1, diffuse cutaneous systemic sclerosis, Dressler's syndrome, drug-induced lupus, discoid lupus erythematosus, eczema, endometriosis, enthesitis-related arthritis, eosinophilic fasciitis, eosinophilic gastroenteritisvepidermolysis bullosa acquisita, erythema nodosum, erythroblastosis fetalis, essential mixed cryoglobulinemia, Evan's syndrome, fibrodysplasia ossificans progressiva, fibrosing alveolitis (or idiopathic pulmonary fibrosis), gastritis, gastrointestinal pemphigoid, giant cell arteritis, glomerulonephritis, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's encephalopathy, Hashimoto's thyroiditis, Henoch-Schonlein purpuravherpes gestationis aka gestational pemphigoid, hidradenitis suppurativa, Hughes-Stovin syndrome, hypogammaglobulinemia, idiopathic inflammatory demyelinating diseases, idiopathic pulmonary fibrosis, IgA nephropathy, inclusion body myositis, chronic inflammatory demyelinating polyneuropathyvinterstitial cystitis, juvenile idiopathic arthritis aka juvenile rheumatoid arthritis, Kawasaki's disease, Lambert-Eaton myasthenic syndrome, leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, linear IgA disease (LAD), Lou Gehrig's disease (Also Amyotrophic lateral sclerosis), lupoid hepatitis aka autoimmune hepatitis, lupus erythematosus, Majeed syndrome, Ménière's disease, microscopic polyangiitis, mixed connective tissue disease, morphea, Mucha-Habermann disease, multiple sclerosis, myasthenia gravis, myositis, neuromyelitis optica (also Devic's disease), neuromyotonia, occular cicatricial pemphigoid, opsoclonus myoclonus syndrome, Ord's thyroiditis, palindromic rheumatism, PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcus), paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Parsonage-Turner syndrome, Pars planitis, pemphigus vulgaris, pernicious anaemia, perivenous encephalomyelitis, POEMS syndrome, polyarteritis nodosa, polymyalgia rheumatica, polymyositis, primary biliary cirrhosis, primary sclerosing cholangitis, progressive inflammatory neuropathy, psoriasis, psoriatic arthritis, pyoderma gangrenosum, pure red cell aplasia, Rasmussen's encephalitis, Raynaud phenomenon, relapsing polychondritis, Reiter's syndrome, restless leg syndrome, retroperitoneal fibrosis, rheumatoid arthritis, rheumatic fever, sarcoidosis, Schmidt syndrome another form of APS, Schnitzler syndrome, scleritis, scleroderma, serum sickness, Sjögren's syndrome, spondyloarthropathy, Stiff person syndrome, subacute bacterial endocarditis (SBE), Susac's syndrome, Sweet's syndrome, sympathetic ophthalmia, Takayasu's arteritis, temporal arteritis (also known as “giant cell arteritis”), thrombocytopenia, Tolosa-Hunt syndrome, transverse myelitis, ulcerative colitis, undifferentiated connective tissue disease different from mixed connective tissue disease, undifferentiated spondyloarthropathy, urticarial vasculitis, vasculitis, vitiligo, and Wegener's granulomatosis. The methods provided herein may also be useful for detecting, monitoring, diagnosing and/or predicting a subject's response to an implanted device. Exemplary medical devices include but are not limited to stents, replacement heart valves, implanted cerebella stimulators, hip replacement joints, breast implants, and knee implants. The methods disclosed herein may be used for monitoring the health of a fetus using whole or partial genome analysis of nucleic acids derived from a fetus, as compared to the maternal genome. For example, nucleic acids can be useful in pregnant subjects for fetal diagnostics, with fetal nucleic acids serving as a marker for gender, rhesus D status, fetal aneuploidy, and sex-linked disorders. The methods disclosed herein may identify fetal mutations or genetic abnormalities. The methods disclosed herein can enable detection of extra or missing chromosomes, particularly those typically associated with birth defects or miscarriage. The methods disclosed herein may comprise the diagnosis, prediction or monitoring of autosomal trisomies (e.g., Trisomy 13, 15, 16, 18, 21, or 22) may be based on the detection of foreign molecules. The trisomy may be associated with an increased chance of miscarriage (e.g., Trisomy 15, 16, or 22). Alternatively, the trisomy that is detected is a liveborn trisomy that may indicate that an infant will be born with birth defects (e.g., Trisomy 13 (Patau Syndrome), Trisomy 18 (Edwards Syndrome), and Trisomy 21 (Down Syndrome)). The abnormality may also be of a sex chromosome (e.g., XXY (Klinefelter's Syndrome), XYY (Jacobs Syndrome), or XXX (Trisomy X). The methods disclosed herein may comprise one or more genomic regions on the following chromosomes: 13, 18, 21, X, or Y. For example, the foreign molecule may be on chromosome 21 and/or on chromosome 18, and/or on chromosome 13. The one or more genomic regions may comprise multiple sites on multiple chromosomes. Further fetal conditions that can be determined based on the methods and systems herein include monosomy of one or more chromosomes (X chromosome monosomy, also known as Turner's syndrome), trisomy of one or more chromosomes (13, 18, 21, and X), tetrasomy and pentasomy of one or more chromosomes (which in humans is most commonly observed in the sex chromosomes, e.g., XXXX, XXYY, XXXY, XYYY, XXXXX, XXXXY, XXXYY, XYYYY and XXYYY), monoploidy, triploidy (three of every chromosome, e.g., 69 chromosomes in humans), tetraploidy (four of every chromosome, e.g., 92 chromosomes in humans), pentaploidy and multiploidy. The methods disclosed may comprise detecting, monitoring, quantitating, or evaluating one or more pathogen-derived nucleic acid molecules or one or more diseases or conditions caused by one or more pathogens. Exemplary pathogens include, but are not limited to, Bordetella, Borrelia, Brucella, Campylobacter, Chlamydia, Chlamydophila, Clostridium, Corynebacterium, Enterococcus, Escherichia, Francisella, Haemophilus, Helicobacter, Legionella, Leptospira, Listeria, Mycobacterium, Mycoplasma, Neisseria, Pseudomonas, Rickettsia, Salmonella, Shigella, Staphylococcus, Streptococcus, Treponema, Vibrio, or Yersinia. Additional pathogens include, but are not limited to, Mycobacterium tuberculosis, Streptococcus, Pseudomonas, Shigella, Campylobacter, and Salmonella. The disease or conditions caused by one or more pathogens may comprise tuberculosis, pneumonia, foodborne illnesses, tetanus, typhoid fever, diphtheria, syphilis, leprosy, bacterial vaginosis, bacterial meningitis, bacterial pneumonia, a urinary tract infection, bacterial gastroenteritis, and bacterial skin infection. Examples of bacterial skin infections include, but are not limited to, impetigo which may be caused by Staphylococcus aureus or Streptococcus pyogenes; erysipelas which may be caused by a streptococcus bacterial infection of the deep epidermis with lymphatic spread; and cellulitis which may be caused by normal skin flora or by exogenous bacteria. The pathogen may be a fungus, such as, Candida, Aspergillus, Cryptococcus, Histoplasma, Pneumocystis, and Stachybotrys. Examples of diseases or conditions caused by a fungus include, but are not limited to, jock itch, yeast infection, ringworm, and athlete's foot. The pathogen may be a virus. Examples of viruses include, but are not limited to, adenovirus, coxsackievirus, Epstein-Barr virus, Hepatitis virus (e.g., Hepatitis A, B, and C), herpes simplex virus (type 1 and 2), cytomegalovirus, herpes virus, HIV, influenza virus, measles virus, mumps virus, papillomavirus, parainfluenza virus, poliovirus, respiratory syncytial virus, rubella virus, and varicella-zoster virus. Examples of diseases or conditions caused by viruses include, but are not limited to, cold, flu, hepatitis, AIDS, chicken pox, rubella, mumps, measles, warts, and poliomyelitis. The pathogen may be a protozoan, such as Acanthamoeba (e.g., A. astronyxis, A. castellanii, A. culbertsoni, A. hatchetti, A. polyphaga, A. rhysodes, A. healyi, A. divionensis), Brachiola (e.g., B connori, B. vesicularum), Cryptosporidium (e.g., C. parvum), Cyclospora (e.g., C. cayetanensis), Encephalitozoon (e.g., E. cuniculi, E. hellem, E. intestinalis), Entamoeba (e.g., E. histolytica), Enterocytozoon (e.g., E. bieneusi), Giardia (e.g., G. lamblia), Isospora (e.g, I. belli), Microsporidium (e.g., M. africanum, M. ceylonensis), Naegleria (e.g., N. fowleri), Nosema (e.g., N. algerae, N. ocularum), Pleistophora, Trachipleistophora (e.g., T. anthropophthera, T. hominis), and Vittaforma (e.g., V. corneae). Therapeutic Interventions The methods disclosed herein may comprise providing a therapeutic intervention, such as, for example, treating and/or preventing a disease or condition in a subject based on one or more biomedical outputs. The one or more biomedical outputs may recommend one or more therapies. The one or more biomedical outputs may suggest, select, designate, recommend or otherwise determine a course of treatment and/or prevention of a disease or condition. The one or more biomedical outputs may recommend modifying or continuing one or more therapies. Modifying one or more therapies may comprise administering, initiating, reducing, increasing, and/or terminating one or more therapies. The one or more therapies comprise an anti-cancer, antiviral, antibacterial, antifungal, immunosuppressive therapy, or a combination thereof. The one or more therapies may treat, alleviate, or prevent one or more diseases or indications. Examples of anti-cancer therapies include, but are not limited to, surgery, chemotherapy, radiation therapy, immunotherapy/biological therapy, photodynamic therapy. Anti-cancer therapies may comprise chemotherapeutics, monoclonal antibodies (e.g., rituximab, trastuzumab), cancer vaccines (e.g., therapeutic vaccines, prophylactic vaccines), gene therapy, or combination thereof. The one or more therapies may comprise an antimicrobial. Generally, an antimicrobial refers to a substance that kills or inhibits the growth of microorganisms such as bacteria, fungi, virus, or protozoans. Antimicrobial drugs either kill microbes (microbicidal) or prevent the growth of microbes (microbiostatic). There are mainly two classes of antimicrobial drugs, those obtained from natural sources (e.g., antibiotics, protein synthesis inhibitors (such as aminoglycosides, macrolides, tetracyclines, chloramphenicol, polypeptides)) and synthetic agents (e.g., sulphonamides, cotrimoxazole, quinolones). In some instances, the antimicrobial drug is an antibiotic, anti-viral, anti-fungal, anti-malarial, anti-tuberculosis drug, anti-leprotic, or anti-protozoal. Antibiotics are generally used to treat bacterial infections. Antibiotics may be divided into two categories: bactericidal antibiotics and bacteriostatic antibiotics. Generally, bactericidals may kill bacteria directly where bacteriostatics may prevent them from dividing. Antibiotics may be derived from living organisms or may include synthetic antimicrobials, such as the sulfonamides. Antibiotics may include aminoglycosides, such as amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, and paromomycin. Alternatively, antibiotics may be ansamycins (e.g., geldanamycin, herbimycin), cabacephems (e.g., loracarbef), carbapenems (e.g., ertapenem, doripenem, imipenem, cilastatin, meropenem), glycopeptides (e.g., teicoplanin, vancomycin, telavancin), lincosamides (e.g., clindamycin, lincomycin, daptomycin), macrolides (e.g., azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, spectinomycin, spiramycin), nitrofurans (e.g., furazolidone, nitrofurantoin), and polypeptides (e.g., bacitracin, colistin, polymyxin B). In some instances, the antibiotic therapy includes cephalosporins such as cefadroxil, cefazolin, cefalotin, cefalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, ceftaroline fosamil, and ceftobiprole. The antibiotic therapy may also include penicillins. Examples of penicillins include amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin g, penicillin v, piperacillin, temocillin, and ticarcillin. Alternatively, quinolines may be used to treat a bacterial infection. Examples of quinilones include ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, and temafloxacin. In some instances, the antibiotic therapy comprises a combination of two or more therapies. For example, amoxicillin and clavulanate, ampicillin and sulbactam, piperacillin and tazobactam, or ticarcillin and clavulanate may be used to treat a bacterial infection. Sulfonamides may also be used to treat bacterial infections. Examples of sulfonamides include, but are not limited to, mafenide, sulfonamidochrysoidine, sulfacetamide, sulfadiazine, silver sulfadiazine, sulfamethizole, sulfamethoxazole, sulfanilimide, sulfasalazine, sulfisoxazole, trimethoprim, and trimethoprim-sulfamethoxazole (co-trimoxazole) (tmp-smx). Tetracyclines are another example of antibiotics. Tetracyclines may inhibit the binding of aminoacyl-tRNA to the mRNA-ribosome complex by binding to the 30S ribosomal subunit in the mRNA translation complex. Tetracyclines include demeclocycline, doxycycline, minocycline, oxytetracycline, and tetracycline. Additional antibiotics that may be used to treat bacterial infections include arsphenamine, chloramphenicol, fosfomycin, fusidic acid, linezolid, metronidazole, mupirocin, platensimycin, quinupristin/dalfopristin, rifaximin, thiamphenicol, tigecycline, tinidazole, clofazimine, dapsone, capreomycin, cycloserine, ethambutol, ethionamide, isoniazid, pyrazinamide, rifampicin, rifamycin, rifabutin, rifapentine, and streptomycin. Antiviral therapies are a class of medication used specifically for treating viral infections. Like antibiotics, specific antivirals are used for specific viruses. They are relatively harmless to the host, and therefore can be used to treat infections. Antiviral therapies may inhibit various stages of the viral life cycle. For example, an antiviral therapy may inhibit attachment of the virus to a cellular receptor. Such antiviral therapies may include agents that mimic the virus associated protein (VAP and bind to the cellular receptors. Other antiviral therapies may inhibit viral entry, viral uncoating (e.g., amantadine, rimantadine, pleconaril), viral synthesis, viral integration, viral transcription, or viral translation (e.g., fomivirsen). In some instances, the antiviral therapy is a morpholino antisense. Antiviral therapies should be distinguished from viricides, which actively deactivate virus particles outside the body. Many of the antiviral drugs available are designed to treat infections by retroviruses, mostly HIV. Antiretroviral drugs may include the class of protease inhibitors, reverse transcriptase inhibitors, and integrase inhibitors. Drugs to treat HIV may include a protease inhibitor (e.g., invirase, saquinavir, kaletra, lopinavir, lexiva, fosamprenavir, norvir, ritonavir, prezista, duranavir, reyataz, viracept), integrase inhibitor (e.g., raltegravir), transcriptase inhibitor (e.g., abacavir, ziagen, agenerase, amprenavir, aptivus, tipranavir, crixivan, indinavir, fortovase, saquinavir, Intelence™, etravirine, isentress, viread), reverse transcriptase inhibitor (e.g., delavirdine, efavirenz, epivir, hivid, nevirapine, retrovir, AZT, stuvadine, truvada, videx), fusion inhibitor (e.g., fuzeon, enfuvirtide), chemokine coreceptor antagonist (e.g., selzentry, emtriva, emtricitabine, epzicom, or trizivir). Alternatively, antiretroviral therarapies may be combination therapies, such as atripla (e.g., efavirenz, emtricitabine, and tenofovira disoproxil fumarate) and completer (embricitabine, rilpivirine, and tenofovir disoproxil fumarate). Herpes viruses, known for causing cold sores and genital herpes, are usually treated with the nucleoside analogue acyclovir. Viral hepatitis (A-E) are caused by five unrelated hepatotropic viruses and are also commonly treated with antiviral drugs depending on the type of infection. Influenza A and B viruses are important targets for the development of new influenza treatments to overcome the resistance to existing neuraminidase inhibitors such as oseltamivir. In some instances, the antiviral therapy may comprise a reverse transcriptase inhibitor. Reverse transcriptase inhibitors may be nucleoside reverse transcriptase inhibitors or non-nucleoside reverse transcriptase inhibitors. Nucleoside reverse transcriptase inhibitors may include, but are not limited to, combivir, emtriva, epivir, epzicom, hivid, retrovir, trizivir, truvada, videx ec, videx, viread, zerit, and ziagen. Non-nucleoside reverse transcriptase inhibitors may comprise edurant, intelence, rescriptor, sustiva, and viramune (immediate release or extended release). Protease inhibitors are another example of antiviral drugs and may include, but are not limited to, agenerase, aptivus, crixivan, fortovase, invirase, kaletra, lexiva, norvir, prezista, reyataz, and viracept. Alternatively, the antiviral therapy may comprise a fusion inhibitor (e.g., enfuviride) or an entry inhibitor (e.g., maraviroc). Additional examples of antiviral drugs include abacavir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, boceprevir, cidofovir, combivir, darunavir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, fusion inhibitors, ganciclovir, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, integrase inhibitor, interferons (e.g., interferon type I, II, III), lamivudine, lopinavir, loviride, maraviroc, moroxydine, methisazone, nelfinavir, nevirapine, nexavir, nucleoside analogues, oseltamivir, peg-interferon alfa-2a, penciclovir, peramivir, pleconaril, podophyllotoxin, protease inhibitors, raltegravir, reverse transcriptase inhibitors, ribavirin, rimantadine, ritonavir, pyramidine, saquinavir, stavudine, tea tree oil, tenofovir, tenofovir disoproxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, and zidovudine. An antifungal drug is medication that may be used to treat fungal infections such as athlete's foot, ringworm, candidiasis (thrush), serious systemic infections such as cryptococcal meningitis, and others. Antifungals work by exploiting differences between mammalian and fungal cells to kill off the fungal organism. Unlike bacteria, both fungi and humans are eukaryotes. Thus, fungal and human cells are similar at the molecular level, making it more difficult to find a target for an antifungal drug to attack that does not also exist in the infected organism. Antiparasitics are a class of medications which are indicated for the treatment of infection by parasites, such as nematodes, cestodes, trematodes, infectious protozoa, and amoebae. Like antifungals, they may kill the infecting pest without serious damage to the host. Systems, Kits, and Libraries Methods of the disclosure can be implemented by way of systems, kits, libraries, or a combination thereof. The methods of the present disclosure may comprise one or more systems. Systems of the disclosure can be implemented by way of kits, libraries, or both. A system may comprise one or more components to perform any of the methods or any of the operations of methods disclosed herein. For example, a system may comprise one or more kits, devices, libraries, or a combination thereof. A system may comprise one or more sequencers, processors, memory locations, computers, computer systems, or a combination thereof. A system may comprise a transmission device. A kit may comprise various reagents for implementing various operations disclosed herein, including sample processing and/or analysis operations. A kit may comprise instructions for implementing at least some of the operations disclosed herein. A kit may comprise one or more capture probes, one or more beads, one or more labels, one or more linkers, one or more devices, one or more reagents, one or more buffers, one or more samples, one or more databases, or a combination thereof. A library may comprise one or more capture probes. A library may comprise one or more subsets of nucleic acid molecules. A library may comprise one or more databases. A library may be produced or generated from any of the methods, kits, or systems disclosed herein. A database library may be produced from one or more databases. A method for producing one or more libraries may comprise (a) aggregating information from one or more databases to produce an aggregated data set; (b) analyzing the aggregated data set; and (c) producing one or more database libraries from the aggregated data set. EXAMPLES The following examples are provided for the purpose of illustrating various embodiments of the present disclosure and are not meant to limit the present disclosure. These examples, along with the methods described herein, are exemplary and are not intended to limit the scope of the present disclosure. Example 1. Mendelian Disease Diagnosis The following illustrates an example of Mendelian disease diagnosis utilizing the methods disclosed herein. This example involves a family pedigree, in which at least one subject is affected by a medical condition which is suspected of being a rare Mendelian disease. In the first operation, DNA from one of the affected subjects of the pedigree is exome sequenced and the data is analyzed to identify variants relative to the human reference sequence. Several tens of thousands of such variants may be identified. This list is then filtered bioinformatically to identify which of those variants are non-synonymous (i.e., they may be expected to change the amino acid sequence of the protein expressed by this gene). This list is then further filtered bioinformatically to identify variants which have allele frequencies in the population below a cutoff, e.g., 1% (as may be expected for a variant causing a rare disease). This may narrow the list to less than five hundred variants. These are the genetic characteristics we focus on because they are most likely to contain the actual causal variant. To identify which of these variants may be causal for the suspected Mendelian disease, one may need to know which of these variants exist in other members of the family pedigree, and with what zygocity. In general, the more family pedigree members included in this analysis, the better it is to narrow down the potential list. The list may also be narrowed by manual review of the list of variants, by genetic counselors or similar experts. They seek to rule out one variant at a time by using their judgment as to the phenotypic overlap between cases in the clinical literature and the clinical features of this particular case. This is a time consuming, expensive and somewhat subjective process. If genetic data can be obtained from more members of a family pedigree, the rules of genetic inheritance can be straightforwardly applied, and the list of potential variants may be narrowed less expensively and more definitively. All of the other family members can be exome sequenced, as was done with the initial (affected) family member. That may involve a considerable amount of sequencing and quite expensive. A much less expensive method, as disclosed herein, is to create a pool of RNA molecules whose sequences are designed to capture the regions containing the 500 variants (e.g., using hybrid capture such as Agilent's Custom SureSelect). This may be done with one capture probe (an RNA molecule with a sequence complimentary to the genomic target) per variant. 500 variants may require the synthesis of at least about 500 sequences. The genomic region captured by each such probe may be at least about 350 bases. Therefore, for at least about 500 sequences, the footprint of this assay may be about 175,000 bases. Compared to an exome, where the footprint of the assay is typically at least 35 million bases, this may result in 200× less sequencing. This dramatic reduction in the amount of sequencing required, per additional family pedigree member, can make it much more affordable to sequence additional pedigree members (e.g., the parents, other children of the same parents, etc). The saving in sequencing costs described above may be partially or even completely offset by the cost of synthesizing an array of hybrid capture probes. To address this, the capture probes for each of several independent clinical cases can be synthesized on a single array (the arrays used in Agilent's system for example, have a capacity up to about 55,000 probes/array). If twenty clinical cases are combined in a single array synthesis, at 500 probes each, the total may be 10,000 probes, still well within the capacity of the array. This amortizes the cost of array synthesis over the 20 cases. If the probes are not de-multiplexed post-synthesis, their footprints will be additive and thus be approximately 175,000 bases/case×20 cases=3.5 million bases. This is still at least a 10× reduction in sequencing footprint versus performing exome sequencing on each of the other family members of each of the pedigrees. If the sequences of the capture probes are designed to include a barcode or primer pair, which is different for each clinical case, then it can be used post synthesis to separate out or enrich the capture probes for each clinical case. This can reduce the footprint of each personalized sequencing assay back to approximately 175,000 bases each. Using the methods of the present disclosure, the cost of sequencing additional samples from a pedigree can be substantially reduced. This can be leveraged to sequence additional family members of the pedigree. It can also be used to sequence additional, potentially informative samples from the original affected family member or other family members. Some Mendelian disease cases are caused by mosaic variants, i.e., mutations which occurred post-zygotically and which are thus only in a fraction of the cells of the subject. These variants can be in multiple tissues, or just in a single germ layer (i.e., ectoderm, endoderm, mesoderm). Because neural tissues, including the brain, are from the ectodermal germ layer, mosaic variants underlying neurological conditions may be in a larger fraction of ectodermal cells. These may include the cheek cells which may be captured by a buccal swab. In a published study of Cornelia-de-Lange syndrome patients for example, causal variants were found in buccal swabs of a substantial fraction of cases where they were not found in the blood of the same subject. Using method provided herein, the cost of sequencing incremental samples after the first one is relatively low, so it becomes more affordable to sequence both a blood sample and a buccal swab sample from an affected subject. Moreover, some Mendelian cases, which appear to be due to de novo variants in a child, are actually the result of gonadal mosaicism in one of the parents being passed on to the child. Particularly in cases of advanced paternal age, the spermatogenic stem cells of the father will have undergone many stages of cell division. This can lead to mutations which are only in the sperm of the father, not his blood. These mutations can be passed on to a child who may then be afflicted by a Mendelian condition caused by the mutation. If testing only checks DNA from the blood of the parents and child, such a mutation may appear to be de novo in the child, making the parents feel safe to have a second child without fear that the second child inheriting the mutation. There are an unfortunately large number of cases where this has been proven incorrect and a second child inherits the same mutation from the sperm of the father as the first child did, and is similarly afflicted. Using method provided herein, the cost of sequencing incremental samples after the first one is relatively low, so it becomes more affordable to sequence DNA from both a blood sample and a sperm sample from the father of an affected subject. FIG. 2 illustrates an example of a Mendelian family pedigree. In this pedigree, at least one subject may be affected by a medical condition which is suspected of being a rare Mendelian disease. Of the 11 member Mendelian pedigree, three members are determined to be affected. Mosaic variants may exist in just a small fraction of the cells of a sample taken from a subject. As a result, they can be more difficult to detect. A variant which is mosaic at low percentage in a parent can be inherited by their child, and if that happens, the variant will be in essentially every cell of the child. Thus, a variant which is straightforward to detect by normal sequencing levels in a child, may be more difficult to detect in their parent. This is important to determine because it informs the potential that a second child of the same parents can also inherit the variant and be similarly afflicted by it. Parents of afflicted children often seek genetic testing in part for this guidance. To increase the confidence of detecting a potentially mosaic variant in the parents, they will need to be sequenced at greater depth than the child. If the assay for additional members of a family pedigree is exome sequencing, it may be cost prohibitive to sequence at that depth. Using method provided herein, the footprint of the assay for incremental family members is much smaller (e.g., 175,000 bases vs 35 million bases, as discussed above). This smaller footprint makes it affordable to sequence the incremental samples at much greater depth, thus improving the sensitivity for detection of mosaic variants in the parents. If the initial (afflicted) subject of a Mendelian pedigree is exome sequenced, the sensitivity to mosaic variants may be limited. An exome with average coverage of 80-100 fold, may have many regions with 20-fold coverage or less. If a mosaic variant is in just 10% of the cells of a sample (5% of the autosomal chromosome copies) then it may be seen in only a few raw sequence reads. To avoid false positive variant detection due to raw sequencing errors, variants are typically only called where they are seen in a number of reads which exceeds a threshold. The higher this threshold is, the lower the false positive rate, but also the lower the sensitivity to mosaic variants. Using methods described herein, the threshold for variant calls from the initial data may be set a lower, if the original sample (or another sample from the same subject) is to be among those sequenced later with the personalized assay. As has been described above, the smaller footprint of the personalized assay makes it much less expensive to sequence at high depths. This can be used to confirm the existence of mosaic variants in small percentages of cells, and to rule out false positives from the original data. Example 2. Cancer Tumor Analysis, Including Neoantigen Detection The following illustrates an example of cancer tumor analysis, utilizing the methods disclosed herein. In this example, the subject is a cancer patient and the initial assay is next generation sequencing of DNA derived from their tumor, e.g., using an Illumina HiSeq-2500 instrument. To detect driver mutations (e.g., those involved in cell-cycle control), it may be sufficient to sequence a panel of genes, but to detect variants which may form neoantigens (and thus impact the response to checkpoint inhibitor drugs, or other immune-modulatory drugs, or combination therapies, personalized cancer vaccines, or CAR-T therapies), in some cases it may be preferable to sequence an exome. The sample can be based on surgical resection of all or part of the tumor or a small sample taken by biopsy procedures, for example. Raw sequence reads may be aligned to the human reference sequence and variants called relative to it. This list of variants can be filtered bioinformatically to select hose variants most likely to be relevant for the analysis of the tumor, or the patient's potential treatment. Alleles may also be reported at loci which determine HLA type. FIG. 6 illustrates a standard workflow for cancer sequencing. Variants may be detected potentially leading to neoantigens. Not all of the variants detected in a tumor are somatic, and not all are expressed in a tumor. In the standard cancer sequencing process, a deep tumor sample can be exome sequenced (e.g., 30-75 billion bases) and a germline DNA sample can be exome sequenced (e.g., 12 billion bases). The data can be used to determine which variants are somatic. Also, a tumor RNA (e.g., 22 billion bases, e.g., 50-70 million paired-end reads) can be deep transcriptome sequenced. A total of 64-109 billion bases of DNA sequencing for neoantigens may result in a significant cost. Using methods of the present disclosure, the list of variants determined from sequencing the tumor DNA can be used to design a set of RNA sequences which can be used for hybrid capture of the regions containing the variants of this subject's tumor. These may be the basis of a personalized assay. The personalized assay can then be used to sequence RNA (or cDNA derived from RNA) in the regions of this subject's tumor variants. A tumor RNA (e.g., 22 billion bases) can be deep transcriptome sequenced. This RNA data can be used to determine which of the variants, seen in the DNA, were expressed in RNA of the subject's tumor. As in the Mendelian example described above, the footprint of the personalized assay will be much smaller than an exome or transcriptome, substantially lowering the amount of sequencing which needs to be done. The personalized assay can also be used to sequence a germline DNA sample from the subject. This data can be used to determine which variants, originally seen in the DNA or the tumor, are somatic. The variants of a tumor may change in allele frequency over time, particularly if the tumor is poly-clonal. Observing this can provide information on the progression of the tumor. Frequent biopsies however, can be expensive and medically risky. An alternative is the look for the variants in nucleic acids shed by the tumor into the blood stream, by sequencing them from the blood plasma. Tumor nucleic acids in blood plasma can be at low concentrations, diluted by other sources of nucleic acids not related to the tumor (e.g., turnover of white blood cells). Thus a clonal tumor variant which is at 50% or 100% allele frequency in a sample of pure cancer cells, may be less than 1% in cell-free nucleic acids. Detecting variants at such low allele frequencies can require very deep sequencing (e.g., at least 1,000-fold coverage), which is very expensive, particularly if it is to be repeated at regular time intervals to monitor progression of a patient's tumor. This is particularly true with a generic assay that looks at all the loci where any variant can exist in any cancer patient. Using methods of the present disclosure, a personalized assay is created with a much smaller footprint. It can be applied to sequencing of cell-free nucleic acids of the patient at one or more time points. Because personalizing the assay has dramatically lowered the footprint of the assay relative to a generic one, the costs incurred are much lower and it becomes much more affordable to monitor a patient at multiple time points. The approach described above provides a way to monitor the allele frequencies of known tumor variants of a subject over time, but it is unlikely to detect new variants that may be in a new sub-clone or metastasis. Many of these will be in cell-cycle control genes or genes which are the focus of targeted therapies. As an example, the drug erlotinib is frequently used for the treatment of late stage lung cancers in which the gene EGFR is mutated. Most of these patients eventually progress though, based on acquiring new mutations. About 50% of those involve acquisition of the T790M mutation in EGFR. A number of these genomic locations have been identified. To take advantage of this knowledge, the personal genomic content described above can be considered variable, and locations such as EGFR T790M can be considered fixed content. Thus, as discuss above, the genomic content of a personalized genetic assay may include a portion which is variable subject to subject, and another portion which is fixed. FIG. 7 shows an alternative workflow for cancer sequencing using an interactive array-based capture panel synthesis. The sequencing can detect variants potentially leading to neoantigens, with a significant reduction in the amount of DNA sequencing that may be required. The approach begins with DNA sequencing of just the tumor's DNA. Alternatively, a tumor RNA (e.g., 22 billion bases) can be deep transcriptome sequenced. Sequences may be array synthesized on a custom capture panel targeting variants seen in the RNA. In this approach, the tumor and germline exome may be sequenced later using a personalized assay based on variants detected in the tumor. In this case, the personalized assay may include variants which turn out to be germline. Metastases and cell-free DNA at multiple downstream time points may be monitored using the second assay. The custom capture panel, deep sequencing of additional samples and types becomes very inexpensive and can amortize costs over multiple samples. Another alternative is to begin by sequencing both the tumor and germline DNA samples with a generic assay (e.g., an exome), to determine which variants are somatic. This may lead to a personalized assay with a smaller footprint. That approach may be advantageous when a personalized assay is to be used subsequently with many samples or when each involves sequencing very deeply to detect variants which are only in a small percent of cells in a sample. In a cases in which variants potentially leading to neoantigens are to be used, it may be better to begin with a generic (i.e., not individualized) assay of tumor RNA (or cDNA derived from the RNA). Variants detected there will only be those which are expressed, thus excluding somatic variants which are not expressed. In at least one data set we have generated (from a Basal Cell Carcinoma) we found that only 20% of variants detected in the DNA were confirmed in the RNA of the same tumor. This does not mean that 80% of the variants detected in the DNA were false positives. It may mean that not all genes are expressed in a tumor, and even in the genes which are expressed, allelic expression and/or splice variation may prevent variants which exist in the DNA from being expressed in the RNA. After using a generic assay to find expressed variants in the RNA, the methods presently disclosed, along with that list of variants, can create a personalized assay. It can be used to look at the germline and tumor DNA, or cell free nucleic acids. The examples above are based on initial assays which sequence DNA or RNA from the subject's tumor or a germline sample. Variants identified in that data are then used as the basis for designing nucleic acid sequences to be array synthesized to create a personalized assay. Methods of the present disclosure can also be used in a similar flow, but where the start is, or includes, an assay of cell-free DNA or RNA from the patient's blood plasma. Nucleic acids in blood plasma may include molecules derived from the tumor of a patient, but they will also contain molecules from the blood itself (e.g., the regular turnover of the white blood cell population). In a subject's blood plasma, the ratio of RNA from a tumor to that from blood cells will vary by gene. Some genes, such as the globin genes, are highly expressed in blood cells, so they will create a high background signal in the population of cell-free RNA molecules in the plasma. Although these genes may also be expressed in a tumor, it may be at a lower level. The reverse can be true as well: tumors can express certain genes at a much higher level than blood cells do. This gene-specific tumor/background ratio will vary much less in cell free DNA in the plasma. Both DNA and RNA from a tumor can contain somatic variants, so either can be used to detect them. Given that the concentration ratio of tumor-derived nucleic acids will vary by gene differently for DNA vs RNA, overall sensitivity of tumor variant detection can be improved by assaying some genes in cell free DNA and other in cell free RNA. The choice of which genes to assay (e.g., sequence) in cfDNA vs cfRNA will vary by subject. It will depend on the cell type of the tumor, because different tumor cell types (e.g., lung vs breast) express different genes at different levels. It will also vary by tumor, since the genetic variation of one tumor may activate different pathways from those in another tumor, even if they are in the same type of cancer. It will also vary by the fraction of tumor nucleic acid that makes its way from the tumor to the blood plasma and the clearance rate of DNA vs RNA by the liver (this may also vary by molecule size and sequence). In addition to these factors, the genes expressed by blood cells of one subject, and their degree of expression, will be different from some other subjects. Using methods provided herein, the choice of which genes to assay in cfDNA vs cfRNA on an individual basis can be optimized. To do this, an initial generic assay may measure the expression of genes in the blood cells, thus quantifying by gene the primary background level that a cell-free RNA signal from the tumor will need to compete against. It may also measure the concentration of cell free DNA and/or RNA in the blood plasma by gene. It may also measure the RNA expression by gene in a tumor sample. Using this data, it may be determined an optimized partitioning of genes for subsequent detection in cell free DNA vs RNA. Nucleic acids can then be array synthesized to capture one or (separately) both of those in subsequent cell free assays. Searching for Potential Neoantigens as Mosaic Variants in Non-Cancer Cells: Somatic variants which appear potentially antigenic, and hence candidates for use in a personalized cancer vaccine, may not be good candidates because they are actually mosaic variants also found elsewhere in the body and thus (a) the body may have become tolerated to them and (b) if the variants are elsewhere in the body and the vaccine is effective, it may lead to T-cell attack of those other parts of the body in addition to the cancer. Thus if these variants are also detected in additional samples of non-cancer cells, they may not be good vaccine candidates. Given that there are about 1014 cells in an adult human body, almost every position in the human genome will be mosaic at some level in some cells in a human body. Quantifying that at the genomic loci to be specifically targeted by a personalized vaccine, can help assess whether the vaccine is appropriate. Tumor variants with the highest allele frequencies frequently occurred prior to the initial “driver” mutation, and thus may well exist in other cells of the surrounding tissue. If this is just a few other cells, the impact may be unimportant, but if such a variant is in substantial non-cancer tissue, then it is a poor candidate to be the basis for a personalized cancer vaccine, for the reasons discussed above. Adjacent normal tissue may be a good place to look for this possible mosaic variation, if it can be obtained uncontaminated by cancer cells. It may also be good to look in the apparent tissue of origin, in the case where the tumor DNA being sampled is from a metastasis, or is cell-free in the plasma (i.e., remote from its origin). The present disclosure provides methods to inexpensively assay multiple tissue samples from a patient, for the variants seen in the tumor, even if they exist in a small fraction of cells in those tissue samples. Once the variants are identified in an initial assay, a personal assay can be created to look for other occurrences of those variants in other samples. Example 3. RNA Analysis The following illustrates an example of RNA analysis utilizing the methods disclosed herein. Analysis of RNA from a cancer sample can be used to detect somatic variants and determine the levels at which they are expressed. The analysis can also be used to quantify the expression of genes, thus revealing the activation or suppression of specific cancer pathways. It can also be used to detect splicing variants and gene fusion events, which can both impact tumor progression. Analysis of RNA is challenging due to its huge dynamic range. One gene can be expressed over 100,000-fold more than another. When next generation DNA sequencing is used to characterize expression, large numbers of sequence reads may be needed. In our laboratory, we offer RNA analysis commercially at a level of 50 million sequence read-pairs per sample, or 70 million. This is expensive, but needed to see the signal of genes expressed at a low level. It is also inefficient, as reads which come from the most highly expressed genes consume far more of the sequencing capacity than may be needed to obtain the desired measurement of those genes. Using methods of the present disclosure, an initial low cost assessment of expression by gene from the sample of the tumor may be made. This does not need to be at a level deep enough to call variants, just enough to determine which genes may benefit from having their relative number of sequencing reads increased or decreased. This initial data can be used to design capture probe sets for genes which are in approximately the same gene expression range in the sample. Those one or more capture probe sets can then be the basis for a personalized RNA (or cDNA) sequencing assay. The initial data from the subject's sample may be based on an analog method (e.g., fluorescent imaging of a hybridization array, or real-time quantitative PCR) or it may be based on a digital method (digital PCR, or next generation DNA sequencing). If it is based on next generation DNA sequencing, the RNA (or cDNA derived from it) may be selected by hybrid capture, or it may be selected by poly-A or ribo-minus methods, or any other suitable method. If it is based on next generation DNA sequencing, it may be sufficient at a level of five million reads, or even one million reads. The initial data may be of all genes in the human genome, or it may be of a subset of genes. The subset may be those genes known to have high expression in some samples, but much lower expression in other samples. The personalized aspect of this assay (i.e., the component which varies from subject to subject) may include all of the genes, or it may include just a subset which needs additional coverage in addition to a fixed-content standard assay. (This concept of a personalized assay being comprised of a variable-genomic-content portion plus a fixed-genomic-content portion, was discussed above.) In this case, the initial assay may be designed to determine which genes will need “topping off” by the variable-genomic-content portion of the eventual personalized assay. The exact algorithms to be used and sequences to be array-synthesized in the example above will be different for an RNA analysis whose primary goal is variant detection versus one whose primary goal is the measurement of gene expression levels. Where the goal is variant detection, the approach may attempt to achieve a minimum sequencing coverage level (e.g., 200×) over the full length of a targeted set of transcripts, at the lowest sequencing cost. Thus sequencing coverage above the target (e.g., 200×) may be avoided, in favor of lower overall costs, a more uniform distribution of reads, or both. Example 4. Analysis of V(D)J Recombination The following illustrates an example of V(D)J recombination analysis utilizing the methods disclosed herein. V(D)J recombination is the mechanism by which the immune system can adapt to a wide range of antigens. Individual T-cells and B-cells of the immune system may contain individual V(D)J combinations. These sequences may lead to the creation of receptors on the outside surfaces of T-cells and B-cells which can very specifically bind to a particular antigen. V(D)J combinations are DNA sequences which can be measured individually, and a collection of these sequences are called a T-Cell repertoire (or correspondingly B-Cell repertoire). When the immune system is mounting a response to an antigen, such as an infection or a tumor, clonal amplification occurs, of the T/B-cells adapted to that antigen, leading to a higher number of copies of the corresponding V(D)J combination. Databases have been developed linking specific antigens (e.g., viruses, peptides, etc) and the V(D)J sequences of the primary T/B-cell response. Sequencing both the T/B-cell repertoire and the DNA and RNA of a tumor, in an untargeted way, is expensive. Using methods of the present disclosure, one or the other can be sequenced first, a set of sequences can then be designed to create a personalized, targeted assay for the other. Example 5. Combined Nucleic Acid and Protein/Peptide Analysis The following illustrates an example of protein/peptide analysis, in some cases combined with nucleic acid analysis utilizing the methods disclosed herein. This application uses oligo-antibody conjugates to act as transducers between the protein/peptide domains and nucleic acid domain. They are synthetic molecules which each combine an antibody physically linked to a nucleic acid sequence. If these molecules are exposed to a biological sample, their antibody segments can bind to target proteins in the sample. Conjugates which do not bind can then be washed off. As a next operation, the conjugates which did bind the sample can be eluted off and their nucleic acid segments can be sequenced. Quantifying these sequences is a measurement of the presence and quantity of the protein(s) or peptides targeted by the antibodies. This type of experiment can be conducted with a mixture of oligo-antibody conjugates, thus providing a multiplexed protein/peptide assay with nucleic acid sequencing readout. Using method of the present disclosure, proteins and/or peptides can initially be quantified in a sample using a mixture of oligo-antibody conjugates. This information can then be used to design a set of nucleic acid sequences which are then array-synthesized. Those synthesized sequences can then be used in a personalized assay to target either (i) further measurement of proteins/peptides and/or (ii) measurement of genes (in DNA, RNA or cDNA derived from RNA) corresponding to the proteins detected by the original oligo-antibody assay. Example 6. Determining Tissue of Origin, Based on Mosaic Variants The following illustrates an example of determining tissue of origin utilizing the methods disclosed herein. In the development of a subject from a single cell (the zygote, i.e., a fertilized human egg) there are many stages of cell division. Errors can occur in the DNA replication at each of these stages, leading to mosaic variants. Some of these variants will exist only in certain parts of the subject's body—those derived from the first cell in which the mutation occurred. Later in life, cells from one part of the body may move elsewhere in the body. Tumor metastasis is one such example. It can be useful in determining the optimal medical treatment for a patient, to know the tissue of origin of a sample (e.g., one taken from a metastatic tumor, particularly in cases where the primary tumor has not been identified and may no longer even exist). U.S. Patent Publication No. 2016/0122831 discloses methods for identifying a tissue of origin of a biological sample. Those methods are based on construction of a mutational map, which links mosaic variants to the tissues in which they are seen. The present disclosure provides efficient methods for identifying a tissue of origin of a biological sample. This method begins by sequencing nucleic acids from a sample of the subject, thought to be located distal to its origin (e.g., a metastatic tumor). From that sequence data we identify post-zygotic mutations (i.e., mosaic or somatic mutations not present in the subject's germline). The genomic locations of the identified post-zygotic mutations become the basis for designing a set of nucleic acid sequences, to be array-synthesized and used in a personalized assay. That personalized assay captures genomic regions of one or more of the loci and sequences or genotypes them. This provides an inexpensive method to determine whether those post-zygotic genetic variants exist in specific other tissues of the subject's body and to quantify them. By knowing where in the subject's body each variant is seen and not seen, evidence is gained narrowing the potential tissue of origin of the original sample. The original sample for this method may be obtained directly from a tumor (e.g., by a biopsy) or indirectly. If indirectly, it may be from cell-free nucleic acids in blood plasma, RNA from exosomes, or nucleic acids from circulating tumor cells. The original sample may also be from what is thought to be a primary tumor, tested to confirm whether it is actually from the tissue within which it has been found. Example 7: Synthesis of a Plurality of Probe Molecules Using an Array The following illustrates an example synthesizing a plurality of probe molecules on an array utilizing the methods disclosed herein. From a biological sample of a subject, genetic characteristics, e.g., genetic variants, will be identified in the nucleic acid molecules of the sample. Probe sequences will be selected using the methods described herein. A plurality of nucleic acid probe molecules will be synthesized for further personalized genetic testing. Probe molecules will be synthesized by “printing” or spotting probes onto a microarray surface (e.g., glass). Probe spots will be applied by either contact or non-contact printing. A noncontact printer will use the same technology as computer printers (i.e., bubble jet or inkjet) to expel small droplets of probe solution onto the glass slide. In contact printing, each print pin will directly apply the probe solution onto the microarray surface. The result in both cases is the application of a few nanoliters of probe solution per spot to create an array of 100- to 150-μm features. Multiple droplets of a biopolymer or biomonomer fluid comprising nucleic acid(s) are dispensed from a jet to form an array of droplets on a substrate. Repeated rounds of base-by-base printing will extend the length of specific probes. The final product can be more than 50-mer (e.g. 60 mer) in situ synthesis feature on a microarray containing thousands of specifically synthesized probes. An assay will be performed using the synthesized array to analyze a biological sample from the individual from whom the sample was collected or biological relative(s) of the subject. The assay will generate data indicative of a presence or absence of at least a subset of genetic variants in a subject or the subject's biological relatives. Methods of the present disclosure may be combined with methods described in U.S. Pat. Nos. 9,128,861 and 9,183,496, U.S. Patent Publication No. 2016/0122831, and PCT Patent Publication No. WO/2015/051275, each of which is entirely incorporated herein by reference. While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. It is not intended that the invention be limited by the specific examples provided within the specification. While the invention has been described with reference to the aforementioned specification, the descriptions and illustrations of the embodiments herein are not meant to be construed in a limiting sense. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. Furthermore, it shall be understood that all aspects of the invention are not limited to the specific depictions, configurations or relative proportions set forth herein which depend upon a variety of conditions and variables. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is therefore contemplated that the invention shall also cover any such alternatives, modifications, variations or equivalents. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby. | <SOH> BACKGROUND <EOH>The history of deoxynucleic acid (DNA) sequencing and DNA synthesis has been intertwined, with advances in one often leading to advances in or applications of the other. The double helix structure of DNA was discovered by Watson and Crick in 1953. In the decades following that, chemists worked to develop methods to synthesize DNA strands (oligonucleotides) of predefined sequence. Caruthers, et al (U.S. Pat. No. 4,458,066 “Process for preparing oligonucleotides”, filed Mar. 24, 1981) introduced the phosphoramidite chemistry now widely used. It was implemented on substrates similar to chromatography columns, yielding one oligonucleotide per synthesis. At the end of this process, the synthesized molecules are cleaved from the substrates on which they have been synthesized, so they can be used in further reactions in solution. Instrument manufacturers subsequently introduced equipment implementing this process on multiple columns in parallel. On Apr. 24, 2000 for example, PE Applied Biosystems issued a press release introducing its “ABI 3900 High Throughput DNA Synthesizer” with 48 columns operating concurrently. In a system of this type, each oligo was synthesized on a separate substrate and delivered in a separate tube (or other container). Relatively large amounts of each DNA sequence can be synthesized on these machines (the ABI 3900 specification was 40 nanomoles up to 1 micro-mole per sequence). Methods for the synthesis of DNA sequences led to Polymerase Chain Reaction (PCR), which uses synthesized DNA priming sequences. Kary Mullis, who invented PCR and was later awarded the Nobel Prize for it, was working in a DNA synthesis lab at Cetus at the time. It was originally devised as a method to enable sequencing of the sickle cell anemia locus via Sanger sequencing. U.S. Pat. No. 4,683,202 “Process for amplifying nucleic acid sequences”, the original PCR patent, was filed in 1985. This was further refined in methods which integrated DNA amplification and the Sanger chain terminating reaction, e.g., Murray, V., “Improved double-stranded DNA sequencing using the linear polymerase chain reaction” Nucleic Acids Research, Vol 17, No 21 Pg 8889, Nov. 11, 1989. Still further refinement along these lines was termed “Cycle Sequencing” (e.g., U.S. Pat. No. 5,432,065 filed Mar. 30, 1993). All of these combined the use of individually synthesized DNA sequences, as primers for further DNA synthesis with polymerase enzymes. During this time, other groups developed methods for synthesis of DNA on a highly parallel microscopic scale, on a single substrate. This increased the parallelism of DNA synthesis by over a thousand-fold. Compared to the ABI 3900 instrument mentioned above for example, which can synthesize up to 48 sequences in parallel, some array-based methods can synthesize over 50,000 sequences in parallel without large manufacturing set-up costs. One method of array-based synthesis was described in Pirrung, et al (U.S. Pat. No. 5,143,854 “Large scale photolithographic solid phase synthesis of polypeptides and receptor binding screening thereof”, priority date Jun. 7, 1989). It was developed by scientists at Affymax Corporation, later spun out as Affymetrix, Inc. This early work used fixed photolithographic masks, similar to those of the semiconductor industry. This enabled production of many “DNA arrays” with the same set of DNA sequences on them. A group at the University of Wisconsin at Madison later devised a more flexible version of this using micro-mirror arrays (rather the fixed photolithographic masks) to dynamically define the spatial pattern of light in the system. This was spun out into the company Nimblegen in 1999, which was acquired by Roche in 2007. Another method for synthesis of DNA on a highly parallel microscopic scale, on a single substrate, was developed using technology from ink-jet printing. Brennan (U.S. Pat. No. 5,472,672 “Apparatus and method for polymer synthesis using arrays” filed Oct. 22, 1993) described such a system including the dispensing of microscopic droplets of synthesis reagents through an array of nozzles on a moveable print head. This technology was commercialized by Agilent, Inc. Early applications of these DNA arrays involved use of the oligonucleotides on the array substrates where they were synthesized. This typically involved hybridization of DNA (or complementary deoxyribonucleic acid (cDNA)) from a test sample to the oligonucleotides on the array. If the DNA (or cDNA) of the test sample was fluorescently labeled in advance, then imaging the array after hybridization and washing can quantify the amount of each sequence in the test sample. This was initially used to measure mRNA expression of genes and it was later used for genotyping. Application of DNA array technology to DNA sequencing largely waited until DNA sequencing itself advanced. The original methods of DNA sequencing (Sanger, Maxim & Gilbert shared a 1975 Nobel prize) used electrophoresis for separation and subsequent readout. Each such electrophoretic separation and detection was spatially separate, though companies developed instruments with several in parallel (e.g., Applied Biosystems Model 370, introduced about 1987, supported up to 24 in parallel; Applied Biosystems Model 3700, introduced in 1999 supported up to 96 in parallel, and Amersham's Molecular Dynamics unit introduced a version of its MegaBace system about 2002 with 384 in parallel.) Several groups did attempt to leverage DNA arrays for DNA sequencing (e.g., Lysov, et al, 1996, “Efficiency of sequencing by hybridization on oligonucleotide matrix supplemented by measurement of the distance between DNA segments.”). Affymetrix commercialized this approach for small applications (variants in CYP drug metabolizing genes, genotyping of HIV). These methods conduct the DNA sequencing reactions and fluorescent readout on the array and thus have been limited to one base per array spot and fairly small non-repetitive portions of genomes. Heidi Rehm, et al at the Harvard Medical School published a set of protocols for this in April 2011 “Targeted Sequencing Using Affymetrix CustomSeq Arrays” in Current Protocols in Human Genetics. In it the technology was described as suitable for re-sequencing portions of the human genome up to 300,000 bases in total length. The field moved forward with the commercialization of “Next Generation DNA Sequencing” methods, which enabled measurement of hundreds of thousands of sequences at a time. One of the first such systems was commercialized by 454, Inc (previously a division of Curagen, Inc and later acquired by Roche) in 2005 (Margulies, M. et al. “Genome sequencing in microfabricated high-density picoliter reactors” Nature 437, 376-380 (2005). This initial system can measure up to 200,000 sequences in parallel, each on average 100 bases long. Two years later, in 2007, a group at the Baylor College of Medicine used a 454 DNA sequencing instrument to sequence an exome (Albert, et al “Direct selection of human genomic loci by microarray hybridization” Nature Methods, November 2007, 4(11):903-5). The key to this work was that a DNA array was used not as a substrate for sequencing itself, but to enrich a genomic DNA sample for just the parts of the genome intended for sequencing. The original DNA sample, fragmented, was hybridized to the array. Portions of the genome which did not hybridize were washed off. Then the portions of the genome which did hybridize to the array were eluted off the array and sequenced separate from the array, using the 454 system. The DNA arrays used were from Nimblegen. Although that DNA synthesis technology had been available since 1999, it was its 2007 combination with huge parallelism of next generation DNA sequencing that made this application practical. In the work described above, DNA sequences synthesized on an array were used in-place on the array substrate. During the early 2000's though, groups began to explore technologies by which DNA molecules can be synthesized on an array but attached to the substrate of the array by a cleavable linker. This meant that after array synthesis, the linkers can be cleaved (e.g., chemically) releasing the oligonucleotides into solution, where they can be used as a pool. One example of this work is U.S. Pat. No. 7,211,654 (Xiaolian, et al, “Linkers and co-coupling agents for optimization of oligonucleotide synthesis and purification on solid supports” May 1, 2007). In 2007, a group at the Broad Institute, began to explore use of this approach to create pools of oligonucleotides in solution to capture select portions of the genome of a test sample. (See U.S. provisional application 61/063,489, Gnirke, et al, filed Feb. 4, 2008: “Selection of nucleic acids by solution hybridization to oligonucleotide baits”.) Dr. Carsten Russ of the Broad Institute described this approach at the February 2008 AGBT conference (reported by GenomeWeb). During 2008, Agilent licensed this technology. It was published on line Feb. 1, 2009 “Solution hybrid selection with ultra-long oligonucleotides for massively parallel sequencing” Nature Biotechnology 27, 182-189 (2009). In February 2009 Agilent launched this as a product line (trade name “SureSelect”) with its first human exome kit (“SureSelect All Exon”). Dr. Gnirke, et al at the Broad Institute continued to innovate and applied targeted capture, using array synthesis of DNA, to RNA transcriptomes: “Targeted next-generation sequencing of a cancer transcriptome enhances detection of sequence variants and novel fusion transcripts” Joshua Levin, et al (including Andreas Gnirke). Genome Biology 2009, 10:R115. In parallel with this, Next Generation DNA Sequencing technologies continued to advance. In June 2006, Solexa, Inc first shipped its Genome Analyzer system. This system measured 40 million DNA sequences in parallel, each initially 25 bases long. In 2008 Illumina, Inc acquired Solexa. Subsequent versions of this technology have continued to advance. The most current instrument (Illumina HiSeq-4000) can produce about 6 billion sequences in parallel, each 2×125 bases, for a total of 1.5 trillion bases, in a single run. Exome sequencing has been broadly adopted as a research tool. As an example, the Exome Aggregation Consortium based at the Broad Institute has released a dataset based on human exome sequences from over 60,000 individuals (release v0.3 Jan. 2015). Exome sequencing has also been adopted clinically. The first commercial clinical exome tests were announced by GeneDx and Ambry Genetics at the ASHG conference in October 2011. Others including the Baylor College of Medicine have also offered commercial clinical human exome-based tests, and over 8,000 have been performed. DNA synthesis technologies have continued to advance, particularly focused on gene synthesis applications requiring very long DNA sequences. Many of these advances involve the construction of long DNA molecules by strategies which combine shorter synthetic DNA molecules. This was reviewed in: “Large-scale de novo DNA synthesis: technologies and applications” Sriram Kosuri and George Church, Nature Methods, Volume 11, No 5, May 2014; 499. | <SOH> SUMMARY <EOH>In spite of the advances described above, the clinical adoption of exome-scale sequencing has been limited by the costs involved. Health insurers, who are asked to pay for these tests, often refuse, given the scale of the expense. This problem is even worse in cancer, where the depth of deoxynucleic acid (DNA) sequencing required can be much higher (e.g., >500×) than that for inherited diseases (e.g., 30-100×). While array-based DNA synthesis is now widely used to capture whole exomes, transcriptomes, or application-specific subsets of exomes (e.g., the genes involved with a specific Mendelian disease), a limitation of the field, as recognized herein, is the potential to leverage array synthesis of DNA in a personalized manner. The field has largely used array-based synthesis to develop standard products which are broadly applicable across a whole set of human patients and/or research subjects. Even where custom array synthesis is proposed, it is to sequence regions of the genome defined independent of a specific sample. In one aspect, the disclosure provides a method for personalized genetic testing, comprising: (a) using a plurality of genetic characteristics to determine a nucleic acid configuration of an assay, which nucleic acid configuration includes nucleic acid sequences of a plurality of nucleic acid probe molecules, wherein the nucleic acid sequences are selective for genetic variants, wherein the plurality of genetic characteristics is determined by analyzing nucleic acid sequence data generated from at least one biological sample of a subject, and wherein the plurality of genetic characteristics include the genetic variants in the nucleic acid molecules from the at least one biological sample; (b) providing the plurality of nucleic acid probe molecules by (i) synthesizing the plurality of nucleic acid probe molecules using at least one array, or (ii) selecting the plurality of nucleic acid probe molecules from a collection of nucleic acid probe molecules; and (c) using the plurality of nucleic acid probe molecules provided in (b) to perform at least the assay on one or more biological samples from the subject or at least one biological relative of the subject, to generate data indicative of a presence or absence of at least a subset of the genetic variants in the subject or the at least one biological relative. Some embodiments may further comprise generating the nucleic acid sequence data using a sequencing assay to sequence or quantify nucleic acid molecules from the at least one biological sample. In some embodiments providing the plurality of nucleic acid probe molecules comprises synthesizing the plurality of nucleic acid probe molecules using at least one array. In some embodiments, in the sequencing assay, at least one biological sample is obtained from the subject at a first time point, and wherein in (c), the one or more biological samples are obtained from the subject or the at least one biological relative of the subject at a second time point subsequent to the first time point. In some embodiments, providing the plurality of nucleic acid probe molecules comprises selecting the plurality of nucleic acid probe molecules from a collection of nucleic acid probe molecules. Some embodiments comprise outputting a report that is indicative of a presence or absence of the at least the subset of the genetic variants in the subject or the at least one biological relative. In some embodiments, the nucleic acid probe molecules comprise primers for amplifying the nucleic acid sequences. Some embodiments further comprise outputting a report that is generated at least based on comparison of results from the sequencing assay with results from the second assay of (c). In some embodiments, the one or more biological samples in (c) comprise a plurality of biological samples, and wherein (c) further comprises outputting a report that is generated at least based on comparison of results from the at least the assay from the plurality of biological samples assayed in (c) with each other. In some embodiments, at least the assay comprises a plurality of the assay. In some embodiments, the plurality of the assay is performed on (i) a plurality of biological samples of the subject or (ii) a plurality of biological samples of the at least one biological relative of the subject. Some embodiments further comprise providing a therapeutic intervention at least based on the presence or absence of the at least the subset of the genetic variants identified in (c). In some embodiments, the sequencing assay comprises (i) exome sequencing, (ii) sequencing a panel of genes, (iii) whole genome sequencing, and/or (iv) sequencing a population of complementary deoxyribonucleic acid molecules derived from ribonucleic acid molecules. In some embodiments, the sequencing assay comprises sequencing the nucleic acid molecules generated in quantity or sequence by interaction with the at least one biological sample from the subject. In some embodiments, the sequencing assay comprises sequencing the nucleic acid molecules derived from antibody-oligonucleotide conjugates of the subject. In some embodiments, the nucleic acid molecules from the at least one biological sample comprise nucleic acid molecules from cells of the subject and are representative of a germline genome of the subject. In some embodiments, the nucleic acid molecules from the at least one biological sample comprise nucleic acids from (i) white blood cells or (ii) non-cancerous cells adjacent to or embedded in a tumor or metastasis of the subject. In some embodiments, the nucleic acid molecules from the at least one biological sample are cell-free nucleic acid molecules. In some embodiments, at least one biological sample includes a blood sample and the nucleic acids molecules are from blood cells in the blood sample, and wherein the subject has been diagnosed with a blood-related cancer such that the nucleic acid molecules in (a) are representative of a cancer genome of the subject. In some embodiments, the nucleic acids molecules are derived from a buccal swab, and wherein the nucleic acid molecules are representative of an ectodermal genome of the subject. In some embodiments, at least one biological sample includes a tumor sample and the nucleic acids molecules are from cells in the tumor sample, and wherein the nucleic acid molecules are representative of a cancer genome of the subject. In some embodiments, the nucleic acid molecules are derived from T-cells and/or B-cells of an adaptive immune system of the subject, representing post-zygotic V(D)J recombination. In some embodiments, the nucleic acid molecules comprise non-human nucleic acid molecules derived from the at least one biological sample, representing a genome(s) of one or more microbial organisms. In some embodiments, the sequencing assay comprises analysis of a single biological sample from the subject. In some embodiments, at least one biological sample includes a plurality of biological samples, and wherein the first assay comprises analysis of the plurality of biological samples and at least one of the plurality of genetic characteristics determined in (b) is based on comparison of the analysis. In some embodiments, at least one biological sample includes a tumor of the subject, and wherein the first assay of (a) comprises analysis of the at least one biological sample and analysis of an additional biological sample which represents a germline genome of the subject. In some embodiments, at least one biological sample includes a tumor of the subject and the nucleic acid molecules include deoxyribonucleic acid (DNA) molecules and ribonucleic acid (RNA) molecules from the tumor, and wherein the first assay comprises analysis of the DNA and RNA. In some embodiments, the plurality of genetic characteristics comprises one or more (i) single nucleotide polymorphisms, (ii) insertions and/or deletions, (iii) copy number variations, and (iv) structural variations. In some embodiments, the plurality of genetic characteristics include signatures combining multiple genetic variants. In some embodiments, the plurality of genetic characteristics comprise genetic variants in a germline sequence of the subject. In some embodiments, the plurality of genetic characteristics comprise post-zygotic variants from a germline sequence of the subject. In some embodiments, the plurality of genetic characteristics comprise post-zygotic recombination of elements from a germline sequence of the subject. In some embodiments, the plurality of genetic characteristics comprise levels of gene expression and/or sequencing read counts or read-depth in data derived from ribonucleic acid molecules or complementary deoxyribonucleic acid molecules derived from the at least one biological sample. In some embodiments, the plurality of genetic characteristics comprise levels of messenger ribonucleic acid expression of alleles from deoxyribonucleic acid molecules derived from the at least one biological sample. In some embodiments, the plurality of genetic characteristics comprise levels of methylation at specific locations or in specific regions of a genome. In some embodiments, the plurality of genetic characteristics comprise locations in or regions of a genome, and wherein the plurality of nucleic acid probe molecules of the assay enrich or deplete a nucleic acid mixture of nucleic acid molecules which include the locations or regions of the genome or portions thereof. In some embodiments, the plurality of genetic characteristics comprise numbers of sequences derived from oligo-antibody conjugates contacted with the at least one biological sample. In some embodiments, the plurality of nucleic acid probe molecules of the assay enrich or deplete a nucleic acid mixture of nucleic acid molecules for target regions, by hybridization or amplification. In some embodiments, each of the nucleic acid probe molecules of the assay includes a region targeted for a genomic locus or region. In some embodiments, each of the nucleic acid probe molecules of the second assay includes a barcode sequence. In some embodiments, each of the nucleic acid probe molecules of the assay includes a region for demultiplexing or selective amplification of at least a subset of nucleic acid molecules from the one or more biological samples, pooled across multiple genomic loci and/or across multiple subjects. In some embodiments, the plurality of nucleic acid probe molecules includes sequences selected from a library of sequences. In some embodiments, the sequences capture coding exons of a genome of the subject or the at least one biological relative. In some embodiments, each of the plurality of nucleic acid probe molecules includes a variation from a reference sequence in the first assay of the subject. Some embodiments further comprise synthesizing the plurality of nucleic acid probe molecules on a single solid substrate. Some embodiments further comprise synthesizing at least 100 nucleic acid sequences in parallel. Some embodiments further comprise synthesizing at least 1,000 nucleic acid sequences in parallel. Some embodiments further comprise synthesizing at least 10,000 nucleic acid sequences in parallel. Some embodiments further comprise synthesizing at least 50,000 nucleic acid sequences in parallel. Some embodiments further comprise synthesizing a plurality of nucleic acid sequences in spatially separate regions of the single solid substrate. In some embodiments, the assay comprises generating nucleic acid sequence data from the one or more biological samples. Some embodiments further comprise mapping the nucleic acid sequence data to a reference. In some embodiments, each of the plurality of nucleic acid probe molecules is at least 50 bases in length. In some embodiments, the assay comprises nucleic acid sequencing or gene expression analysis. In some embodiment, each of the plurality of nucleic acid probe molecules of the assay includes oligonucleotide-directed genomic content comprising (i) at least one variable portion from a result of the sequencing assay and (ii) at least one fixed portion independent of the result of the sequencing assay. In some embodiments, the oligonucleotides of the at least one fixed portion are synthesized on the same array(s) as the at least one variable portion. The method of Claim 54 , wherein oligonucleotides of the at least one fixed portion are synthesized on separate array(s) as the at least one variable portion. In some embodiments, at least one variable portion corresponds to genes which are more highly expressed than genes that correspond to the at least one fixed portion. In some embodiments, at least one variable portion corresponds to genes with a first expression profile and the at least one fixed portion corresponds to genes with a second expression profile, wherein the first expression profile has greater sample-to-sample variability than the second expression profile. In some embodiments, the genomic content includes coding regions of genes. In some embodiments, the genomic content includes regions corresponding to non-coding ribonucleic acid (RNA), micro-RNA and/or intronic RNA. In some embodiments, at least one variable portion corresponds to potential neoantigen causing genetic variants of the subject, and wherein the at least one fixed portion corresponds to one or more of (1) cancer driver genes, (2) genes involved in the pharmacogenomics of cancer drugs, (3) genes involved in Mendelian immunological diseases, (4) genes related to inherited forms of cancer, (5) genes associated with tumor escape from a targeted or immune cancer therapy, (6) HLA typing, and (7) genetic variants common in the population and used by B-allele methods to detect structural variation. In some embodiments, at least one variable portion corresponds to genetic variants responsible for Mendelian phenotype of a proband, and wherein the at least one fixed portion corresponds to one or more of (1) additional genetic content not related to the Mendelian condition of the proband, (2) pharmacogenomics, (3) genetic sample ID by a fixed panel of genetic variants or a fixed panel of phenotype-related genetic variants, and (4) genetic variants common in the population and used by B-allele methods to detect structural variation. In some embodiments, the (i) the subject is a member of a family pedigree and has or is suspected of having a medical condition that is Mendelian, (ii) the plurality of genetic characteristics in (a) are genetic variants of a nucleic sequence from a reference sequence(s) or alleles which match the reference sequence(s) and are associated with a medical condition, (iii) the nucleic acid sequences in (c) are configured to capture or amplify genomic regions comprising at least a subset of the genetic variants, (iv) the assay is nucleic acid sequencing, and (vi) the one or more biological samples in (c) is from the at least one biological relative that is a member of the family pedigree. Some embodiments further comprise generating a report that identifies genetic variants shared by family members of the family pedigree, which genetic variants are responsible for the medical condition of the subject. In some embodiments, the (i) the medical condition includes neurological clinical features, (ii) at least one of the biological samples assayed is from buccal swabs or other tissue of ectodermal lineage, (iii) the report is generated based at least in part on a possibility that one or more genetic variants of the subject are mosaic and included in the ectodermal lineage of the subject. In some embodiments, at least one of the biological samples assayed includes deoxyribonucleic acid molecules from sperm of an individual in the family pedigree, and wherein the report is generated based at least in part on a possibility that one or more of the genetic variants are gonadal mosaic in a father of the subject. Some embodiments further comprise combining genetic variants from probands in multiple Mendelian pedigrees into a single list of genetic loci and/or regions. In some embodiments, the plurality of nucleic acid probe molecules are for in-solution capture of those genetic loci and/or regions, by hybridization. In some embodiments, the plurality of nucleic acid probe molecules is synthesized by inkjet printing on an array with a capacity of at least about 50,000 nucleic acid sequences, and followed by cleavage from the array. Some embodiments further comprise separating genetic variants for each Mendelian pedigree from nucleic acid data from the assay. Some embodiments further comprise filtering genetic variants that are causal or suspected of being causal. In some embodiments, the plurality of genetic characteristics includes genes derived from a clinical phenotype of the subject. In some embodiments, the subject has cancer or is suspected of having cancer, and wherein the at least one biological sample includes a tissue sample or a blood sample from the subject. In some embodiments, the nucleic acid molecules include deoxyribonucleic acid (DNA) molecules. In some embodiments, the DNA includes cell-free DNA. In some embodiments, the nucleic acid molecules include ribonucleic acid (RNA) molecules or complementary deoxyribonucleic acid (DNA) molecules derived from the RNA molecules. In some embodiments, the RNA includes cell-free RNA. In some embodiments, the plurality of genetic characteristics in (a) includes one or more of (i) genetic variants of the nucleic acid sequence with respect to a reference sequence(s) or germline sequence(s), (ii) alleles which match the reference sequence(s) and are correlated with a type of cancer or other disease, (iii) alleles which determine a human leukocyte antigen (HLA) type, (iv) metrics of gene expression and/or allele-specific expression, and (v) quantification of non-coding ribonucleic acid (RNA molecules or micro-RNA molecules which are at least partially tissue-type specific or cancer-type specific. Some embodiments further comprise filtering to select at least a subset of the genetic variants determined to be relevant for analysis of the tumor or a treatment of the subject. In some embodiments, one or more biological samples are from the subject and include one or more of (i) germline deoxyribonucleic acid (DNA), (ii) tumor ribonucleic acid (RNA) or complementary DNA derived from the tumor RNA, (iii) cell-free DNA or RNA derived from blood plasma, (iv) DNA from the subject which contains or is suspected of containing mosaic variants, and (v) tumor and/or germline DNA. Some embodiments further comprise generating a report that identifies genetic variants that are associated with a therapeutic intervention for the subject. In some embodiments, the assay comprises sequencing nucleic acid molecules from the one or more biological samples of the subject. In some embodiments, the assay comprises quantifying the nucleic acid molecules. In some embodiments, the tissue sample is a tumor sample. In some embodiments, the plurality of genetic characteristics includes expressed genetic variants observed in a tumor sample of the subject but not observed in a germline of the subject, which have been assessed to be potential neoantigens for use in a personal cancer vaccine. In some embodiments, the sequencing assay comprises sequencing the nucleic acid molecules. In some embodiments, the sequencing assay further comprises sequencing a germline nucleic acid molecule(s). In some embodiments, the sequencing assay comprises sequencing a plurality of V(D)J recombination segments, each of which specifying an antigen receptor of a T-cell and/or B-cell of the subject. In some embodiments, the plurality of genetic characteristics include identities and quantities of V(D)J sequences from the plurality of V(D)J recombination segments. In some embodiments, the plurality of nucleic acid probe molecules capture or amplify nucleic acid sequences from the one or more biological samples that lead to neoantigens, which can be recognized by T-cell receptors or B-cell receptors corresponding to a V(D)J recombination segments. In some embodiments, the data confirms presence of genetic variants in a tumor of the subject, corresponding to the V(D)J recombination segments. In some embodiments, the data quantifies the genetic variants. In some embodiments, at least one biological sample and the one or more biological samples include the same biological sample. In some embodiments, the nucleic acid sequence data has less than or equal to about five million sequence reads. In some embodiments, the nucleic acid sequence data has less than or equal to about one million sequence reads. In some embodiments, the plurality of nucleic acid probe molecules capture or amplify nucleic acid molecules in the one or more biological samples. In some embodiments, the genetic variants are with respect to a reference genome. In some embodiments, the reference genome is from the subject. In some embodiments, the at least one biological sample includes tumor tissue, and wherein the first assay comprises (i) exposing the tumor tissue to a mixture of oligonucleotide-antibody conjugates, wherein at least some of the oligonucleotide-antibody conjugates bind to proteins or peptides in the tumor tissue, and (ii) sequencing oligonucleotides released from the oligonucleotide-antibody conjugates upon binding to the proteins or peptides, which oligonucleotides correspond to the nucleic acid molecules, to yield the nucleic acid sequence data. In some embodiments, the plurality of genetic characteristics includes identities and quantities of the oligonucleotide-antibody conjugates corresponding to the oligonucleotides released from the oligonucleotide-antibody conjugates. In some embodiments, the plurality of nucleic acid probe molecules are for capturing or amplifying one or more of (i) a plurality of oligonucleotide sequences of oligonucleotide-antibody conjugates, or (ii) deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) sequences corresponding to the proteins or peptides bound to an antibody component of the oligonucleotide-antibody conjugates. In some embodiments, one or more biological samples include DNA molecules, RNA molecules, or complementary DNA molecules derived from the RNA molecules from the subject. In some embodiments, the nucleic acid molecules from the at least one biological sample of the subject are obtained distal to their origin in a body of the subject, and the plurality of genetic characteristics include identified genomic locations of mosaic variants in the at least one biological sample. In some embodiments, the plurality of nucleic acid probe molecules amplify or enrich the mosaic variants. In some embodiments, the second assay is performed on the one or more biological samples from one or more other locations in the body of the subject, to determine an extent to which the mosaic variants are observed in the one or more biological samples. Some embodiments further comprise generating a report indicative of the origin in the body of the subject. In some embodiments, the nucleic acid molecules include (i) cell-free deoxyribonucleic acid (DNA) or cell-free ribonucleic acid (RNA) from blood plasma, (ii) RNA from one or more exosomes derived from a blood sample of the subject, (iii) DNA or RNA from circulating tumor cells, or (iv) DNA or RNA from a tumor metastasis. In another aspect, the present disclosure provides a method of personalized genetic testing, comprising: (a) deriving phenotypic information from a health or medical record of a subject, which health or medical record is in one or more databases; (b) determining a plurality of genetic characteristics of the subject from the phenotypic information derived in (a), wherein the plurality of genetic characteristics include genetic variants, and wherein the plurality of genetic characteristics facilitate diagnosis, prognosis or improved health or medical treatment of the subject; (c) using the plurality of genetic characteristics from (b) to determine a nucleic acid configuration of an assay, which nucleic acid configuration includes nucleic acid sequences of a plurality of nucleic acid probe molecules, wherein the nucleic acid sequences are selective for the genetic variants; (d) providing the plurality of nucleic acid probe molecules by (i) synthesizing the plurality of nucleic acid probe molecules using at least one array, or (ii) selecting the plurality of nucleic acid probe molecules from a collection of nucleic acid probe molecules; and (e) using the plurality of nucleic acid probe molecules provided in (d) to perform at least the assay on one or more biological samples from the subject or at least one biological relative of the subject, to generate data indicative of a presence or absence of at least a subset of the genetic variants in the subject or the at least one biological relative. In some embodiments, providing the plurality of nucleic acid probe molecules comprises synthesizing the plurality of nucleic acid probe molecules using at least one array. In some embodiments, providing the plurality of nucleic acid probe molecules comprises selecting the plurality of nucleic acid probe molecules from a collection of nucleic acid molecules. In some embodiments, the biological sample is obtained from the subject at a first time point, and wherein in (e), the one or more biological samples are obtained from the subject or the at least one biological relative of the subject at a second time point subsequent to the first time point. In some embodiments, the nucleic acid probe molecules comprise primers for amplifying the nucleic acid sequences. Some embodiments further comprise outputting a report that is indicative of a presence or absence of the at least the subset of the genetic variants in the subject or the at least one biological relative. Some embodiments further comprise outputting a report that is generated at least based on comparison of results from the first assay of (a) with results from the second assay of (e). In some embodiments, one or more biological samples in (e) comprise a plurality of biological samples, and wherein (e) further comprises outputting a report that is generated at least based on comparison of results from the at least the second assay from the plurality of biological samples assayed in (e) with each other. In some embodiments, at least the second assay comprises a plurality of the second assay. In some embodiments, the plurality of the second assay is performed on (i) a plurality of biological samples of the subject or (ii) a plurality of biological samples of the at least one biological relative of the subject. Some embodiments further comprise providing a therapeutic intervention at least based on the presence or absence of the at least the subset of the genetic variants identified in (e). In yet another aspect, the disclosure provides a non-transitory computer-readable medium comprising machine executable code that, upon execution by one or more computer processors, implements a method for personalized genetic testing, comprising: (a) using a plurality of genetic characteristics to determine a nucleic acid configuration of an assay, which nucleic acid configuration includes nucleic acid sequences of a plurality of nucleic acid probe molecules, wherein the nucleic acid sequences are selective for genetic variants, wherein the plurality of genetic characteristics is determined by analyzing nucleic acid sequence data generated from at least one biological sample of a subject, and wherein the plurality of genetic characteristics include the genetic variants in the nucleic acid molecules from the at least one biological sample; (b) providing the plurality of nucleic acid probe molecules by (i) synthesizing the plurality of nucleic acid probe molecules using at least one array, or (ii) selecting the plurality of nucleic acid probe molecules from a collection of nucleic acid probe molecules; and (c) using the plurality of nucleic acid probe molecules provided in (b) to perform at least the assay on one or more biological samples from the subject or at least one biological relative of the subject, to generate data indicative of a presence or absence of at least a subset of the genetic variants in the subject or the at least one biological relative. In yet another aspect, the disclosure provides a non-transitory computer-readable medium comprising machine executable code that, upon execution by one or more computer processors, implements a method for personalized genetic testing, comprising: (a) deriving phenotypic information from a health or medical record of a subject, which health or medical record is in one or more databases; (b) determining a plurality of genetic characteristics of the subject from the phenotypic information derived in (a), wherein the plurality of genetic characteristics include genetic variants, and wherein the plurality of genetic characteristics facilitate diagnosis, prognosis or improved health or medical treatment of the subject; (c) using the plurality of genetic characteristics from (b) to determine a nucleic acid configuration of an assay, which nucleic acid configuration includes nucleic acid sequences of a plurality of nucleic acid probe molecules, wherein the nucleic acid sequences are selective for the genetic variants; (d) providing the plurality of nucleic acid probe molecules by (i) synthesizing the plurality of nucleic acid probe molecules using at least one array, or (ii) selecting the plurality of nucleic acid probe molecules from a collection of nucleic acid probe molecules; and (e) using the plurality of nucleic acid probe molecules provided in (d) to perform at least the assay on one or more biological samples from the subject or at least one biological relative of the subject, to generate data indicative of a presence or absence of at least a subset of the genetic variants in the subject or the at least one biological relative. In an additional aspect, the disclosure provides a computer system for personalized genetic testing, comprising: one or more computer processors that are individually or collectively programmed to: (i) use a plurality of genetic characteristics to determine a nucleic acid configuration of an assay, which nucleic acid configuration includes nucleic acid sequences of a plurality of nucleic acid probe molecules, wherein the nucleic acid sequences are selective for the genetic variants, wherein the plurality of genetic characteristics is determined by analyzing nucleic acid sequence data generated from at least one biological sample of a subject, and wherein the plurality of genetic characteristics include the genetic variants in the nucleic acid molecules from the at least one biological sample; (ii) provide the plurality of nucleic acid probe molecules by (1) directing synthesis of the plurality of nucleic acid probe molecules using at least one array, or (2) selecting the plurality of nucleic acid probe molecules from a collection of nucleic acid probe molecules; and (iii) direct use of the plurality of nucleic acid probe molecules provided in (ii) to perform at least the assay on one or more biological samples from the subject or at least one biological relative of the subject, to generate data indicative of a presence or absence of at least a subset of the genetic variants in the subject or the at least one biological relative; and a computer display operative coupled to the one or more computer processors, wherein the computer display comprises a user interface that displays a report indicative of a presence or absence of the at least the subset of the genetic variants in the subject or the at least one biological relative. In another aspect, the disclosure provides a computer system for personalized genetic testing, comprising: one or more computer processors that are individually or collectively programmed to: (i) derive phenotypic information from a health or medical record of a subject, which health or medical record is in one or more databases; (ii) determine a plurality of genetic characteristics of the subject from the phenotypic information derived in (i), wherein the plurality of genetic characteristics include genetic variants, and wherein the plurality of genetic characteristics facilitate diagnosis, prognosis or improved health or medical treatment of the subject; (iii) use the genetic characteristics from (ii) to determine a nucleic acid configuration of an assay, which nucleic acid configuration includes nucleic acid sequences of a plurality of nucleic acid probe molecules, wherein the nucleic acid sequences are selective for the genetic variants; (iv) provide the plurality of nucleic acid probe molecules by (1) directing synthesis of the plurality of nucleic acid probe molecules using at least one array, or (2) selecting the plurality of nucleic acid probe molecules from a collection of nucleic acid probe molecules; and (v) direct use of the plurality of nucleic acid probe molecules provided in (iv) to perform at least the assay on one or more biological samples from the subject or at least one biological relative of the subject, to generate data indicative of a presence or absence of at least a subset of the genetic variants in the subject or the at least one biological relative; and a computer display operative coupled to the one or more computer processors, wherein the computer display comprises a user interface that displays a report indicative of a presence or absence of the at least the subset of the genetic variants in the subject or the at least one biological relative. In another aspect, the present disclosure provides a method of personalized genetic testing including: (a) using a first assay design to sequence nucleic acids derived from an individual person, (b) determining multiple genetic characteristics of that person or their sample from that data; (c) using the genetic characteristics from (b) to specify the design of a second assay, and in particular the sequences of multiple additional nucleic acid molecules to be used in that second assay; (d) synthesizing the additional nucleic acid molecules on at least one array; (e) using the synthesized nucleic acids to perform a second assay, on one or more samples from the same individual person, and/or from individuals in their family. Some embodiments comprise a further additional (f) a report is generated based on analysis comparing the results from the assay of (a) with results from the assay(s) of (e), or by comparison of results from assays from a plurality of samples assayed in (e) with each other. In another aspect, the present disclosure provides a method of personalized genetic testing including: (a) deriving phenotypic information from the medical record of an individual person; (b) proposing multiple genetic characteristics which, if characterized, could lead to diagnosis, prognosis or improved medical treatment of the individual; (c) using the genetic characteristics from (b) to specify the design of an assay, and in particular the sequences of multiple nucleic acid molecules to be used in that assay; (d) synthesizing the nucleic acid molecules on at least one array; (e) using the synthesized nucleic acids to perform the assay, on one or more samples from the same individual person, and/or from individuals in their family. Some embodiments further comprise (f) generating a report based on analysis of the results from the assay(s) of (e), or by comparison of results from assays from a plurality of samples assayed in (e) with each other. In some embodiments, the first assay comprises one of (i) exome sequencing, or (ii) sequencing a panel of genes, or (iii) whole genome sequencing, or (iv) sequencing a population of cDNA molecules derived from RNA. In some embodiments, the first assay comprises sequencing a population of nucleic acid molecules modified in quantity or sequence by interaction with a sample or samples derived from the individual person. In some embodiments, the first assay comprises sequencing a population of nucleic acid molecules derived from antibody-oligonucleotide conjugates that bound to proteins of the individual person, including proteins of any tumor they may have. In some embodiments, the sequencing method of (a) comprises one of (i) sequencing by synthesis using a reversible terminator chemistry, or (ii) pyrosequencing, or (iii) nanopore sequencing, or (iv) real-time single molecule sequencing. In some embodiments, the sample type which may be used in the assay of (a) comprises nucleic acids derived from cells of the individual person, representing their germline genome. In some embodiments, the sample type which may be used in the assay of (a) comprises nucleic acids derived from one of (i) white blood cells, or (ii) non-cancerous cells adjacent to or embedded in a tumor or metastasis of the individual person. In some embodiments, the sample type which may be used in the assay of (a) comprises cell-free nucleic acids derived from blood plasma of the individual person. In some embodiments, the individual person has been diagnosed with a type of blood-related cancer such that the nucleic acids of their blood cells represent the cancer genome, not their germline genome, and wherein the nucleic acids of their blood cells are used in the assay of (a). In some embodiments, the sample type which may be used in the assay of (a) comprises nucleic acids derived from a buccal swab of the individual person, representing their ectodermal genome. In some embodiments, the sample type which may be used in the assay of (a) comprises nucleic acids derived from cells of a tumor of the individual person, representing their cancer genome. In some embodiments, the sample type which may be used in the assay of (a) comprises nucleic acids derived from T-cells and/or B-cells of the adaptive immune system of the individual person, representing post-zygotic V(D)J recombination. In some embodiments, the sample type which may be used in the assay of (a) comprises non-human nucleic acids derived from a sample of the individual person, representing the genome(s) of one or more other microbial species (bacteria or viruses). In some embodiments, the first assay of (a) comprises analysis of a single sample from the individual. In some embodiments, the first assay of (a) comprises analysis of a plurality of samples from the individual and at least one of the genetic characteristics determined in (b) is based on comparison of those analyses. In some embodiments, the first assay of (a) comprises analysis of a sample from a tumor of the individual, and analysis of a second sample which represents the germline genome of the individual. In some embodiments, the first assay of (a) comprises analysis of DNA from a sample from a tumor of the individual, and analysis of RNA from a sample from a tumor of the individual. In some embodiments, the genetic characteristics determined in (b) comprise or include one or more of (i) Single Nucleotide Polymorphisms (SNPs), or (ii) Insertions and/or Deletions (InDels), or Copy Number Variations or Structural Variations. In some embodiments, the genetic characteristics determined in (b) are or include signatures combining multiple genetic variants (e.g., the HLA type or the blood type of the individual) In some embodiments, the genetic characteristics determined in (b) comprise or include genetic variants in the germline sequence of the individual. In some embodiments, the genetic characteristics determined in (b) comprise or include post-zygotic (i.e., mosaic or somatic) variants from the germline sequence of the individual. In some embodiments, the genetic characteristics determined in (b) comprise or include post-zygotic recombination of elements from the germline sequence of the individual (e.g., V(D)J recombination). In some embodiments, the genetic characteristics determined in (b) comprise or include levels of gene expression (quantification of mRNA from individual genes and/or their splice variants) and/or sequencing read counts or read-depth in data derived from an RNA or cDNA sample. In some embodiments, the genetic characteristics determined in (b) comprise or include levels of mRNA expression (including presence/absence) of specific alleles derived from the DNA of the individual. In some embodiments, the genetic characteristics determined in (b) comprise or include levels of methylation at specific locations or in specific regions of the human genome. In some embodiments, the genetic characteristics determined in (b) comprise or include numbers of sequences derived from oligo-antibody conjugates contacted with the sample(s). In some embodiments, the genetic characteristics determined in (b) comprise or include specific locations in, or specific regions, of the human genome (e.g., the locations of SNP's); and further wherein the multiple additional nucleic acids to be used in the second assay are designed to enrich or deplete a nucleic acid mixture of those nucleic acid molecules which include those locations or regions of the human genome, or parts thereof. In some embodiments, the additional nucleic acid molecules are designed to enrich or deplete a mixture, for the desired target regions, either by hybridization to the additional nucleic acid molecules or by amplification (e.g., by polymerase chain reaction) In some embodiments, the additional nucleic acid molecules are designed as primers for single-base extension, or multiple-base extension. In some embodiments, the sequences of the multiple additional nucleic acid molecules, to be used in the second assay, are composed of at least two parts: One part specific to the genomic locus or region targeted, and at least one other part for other applications in the second assay. This may be a barcode sequence or it may be a pair of amplification primer sequences. In some embodiments, the “other applications in the second assay” include demultiplexing or selective amplification of a subset, downstream of array-based synthesis pooled across multiple genomic loci, or across multiple individuals, or both. In some embodiments, the sequences of the multiple additional nucleic acid molecules, to be used in the second assay, or portions of them, are selected from a library of sequences previously designed (e.g., to capture each of the coding exons of the human genome). In some embodiments, the library of previously designed sequences has previously itself been array synthesized and experimentally tested. In some embodiments, at least one of the sequences of the multiple additional nucleic acid molecules, to be used in the second assay, or portions of them, include a variation from the reference sequence seen in the first assay of the individual, not the reference sequence itself. In some embodiments, (d) comprises the synthesis of a plurality of nucleic acid sequences on a single solid substrate. In some embodiments, the number of nucleic acid sequences synthesized in parallel on a single solid substrate is at least 100. In some embodiments, the number of nucleic acid sequences synthesized in parallel on a single solid substrate is at least 1,000. In some embodiments, the number of nucleic acid sequences synthesized in parallel on a single solid substrate is at least 10,000. In some embodiments, the number of nucleic acid sequences synthesized in parallel on a single solid substrate is at least 50,000. In some embodiments, each of the plurality of nucleic acid sequences synthesized on a single solid substrate is synthesized in a spatially separate region of the substrate. In some embodiments, the sequence synthesized in each of the plurality of spatially separate regions of a single solid substrate is specified by light directed chemical reactions (e.g., photolithography) or by reagents dispensed in a jet from a moveable print head. In some embodiments, the common substrate can be mechanically partitioned without damaging the nucleic acids synthesized, after nucleic acid synthesis but before cleavage of the nucleic acid molecules from the substrate. In some embodiments, the nucleic acid molecules are at least 50 bases long. In some embodiments, the nucleic acid molecules are at least 130 bases long. In some embodiments, the nucleic acid molecules are at least 200 bases long. In some embodiments, the capacity of the array (i.e., the number of sequences which can be synthesized on a single solid substrate) is shared by synthesis of sequences for the testing of multiple otherwise unrelated testing cases. In some embodiments, the sequences synthesized for unrelated testing cases are synthesized in spatially separated regions of a common substrate, followed by mechanical separation of the common substrate into separate pieces each containing one of those regions (e.g., wafer dicing). In some embodiments, the sequences synthesized for unrelated testing cases are synthesized on a common substrate, but contain subsequences (barcodes) which can later be used to segregate them for independent use (e.g., by hybridization). In some embodiments, the sequences synthesized for unrelated testing cases are synthesized on a common substrate, but their results are separated bioinformatically following the second assay ((e)). In some embodiments, the second assay (e) determines nucleic acid sequences and maps them to a reference (e.g., a reference genome sequence or reference set of mRNA transcripts) such that the results needed for analysis of samples processed in (e) are positioned along the reference separate from (or partially separate from) those not needed (e.g., those captured in one sample by sequences synthesized for another sample). In some embodiments, the second assay is one of (i) DNA sequencing, or (ii) genotyping, or (iii) gene expression analysis. In some embodiments, the sequencing method of (e) comprises one of (i) sequencing by synthesis using reversible terminator chemistry or (ii) pyrosequencing, or (iii) nanopore sequencing, or (iv) real-time single molecule sequencing. In some embodiments, the genotyping method of (e) comprises single-base extension, with readout of the single base by fluorescence or mass spectroscopy. In some embodiments, the genotyping of multiple loci are demultiplexed by one of (i) hybridization to an array, using nucleic acid barcodes incorporated into the sequences synthesized in (d), or (ii) using PCR primers incorporated into the sequences, or (iii) electrophoresis (e.g., SNaPshot or SNPlex), or (iv) mass spectroscopy. In some embodiments, the oligo-directed genomic content of second assay comprises: (i) at least one variable portion, defined based on results of the first assay and (ii) at least one fixed portion, independent of the results of the first assay. In some embodiments, the oligos corresponding to the fixed portion of the genomic content are synthesized on the same array(s) as used to synthesize the variable portion of the genomic content. In some embodiments, the oligos corresponding to the fixed portion of the genomic content are synthesized on separate array(s) from those used to synthesize the variable portion of the genomic content. In some embodiments, (i) the variable content for a plurality of individuals is synthesized together on an array with the fixed content, and (ii) it is demultiplexed into oligo pools specific to each of those individuals post-synthesis, and (iii) the design of the nucleic acid sequences of the variable content contains at least two segments, one used for de-multiplexing post-synthesis, and (iv) the design of the nucleic acid sequences of the fixed content also contains at least two segments, one used for de-multiplexing post-synthesis, and (v) the de-multiplexing reaction post-synthesis uses methods which allow it to capture fixed content nucleic acid molecules along with each set of individual-specific variable content. In some embodiments, the variable portion of the oligo-directed genomic content corresponds to genes which are, or are expected to be, more highly expressed, and the fixed portion corresponds to genes with on average lower levels of gene expression. In some embodiments, the variable portion of the oligo-directed genomic content corresponds to genes whose expression is thought to vary more from sample to sample, and the fixed portion corresponds to genes with more consistent levels of gene expression from sample to sample. In some embodiments, the oligo-directed content, partitioned into fixed and variable portions as described, includes not only content from the coding regions of genes, but also other forms of transcribed RNA, including but not limited to long non-coding RNA, micro-RNA and Intronic RNA. In some embodiments, the variable portion of the oligo-directed genomic content corresponds to potential neoantigen causing variants of the individual, and the fixed portion corresponds to one or more of (a) cancer driver genes, (b) genes involved in the pharmacogenomics of cancer drugs, (c) genes involved in Mendelian immunological diseases, (d) genes related to inherited forms of cancer, (e) genes associated with tumor escape from a targeted or immune cancer therapy, (f) HLA typing, or (g) variants common in the population and used by B-allele methods to detect structural variation. In some embodiments, the variable portion of the oligo-directed genomic content corresponds to variants which may be responsible for the Mendelian phenotype of a proband, and the fixed portion corresponds to one or more of (a) additional genetic content not related to the Mendelian condition of the proband (b) pharmacogenomics, or (c) genetic sample ID by a fixed panel of variants or a fixed panel of phenotype-related variants such as gender, blood type, or (d) variants common in the population and used by B-allele methods to detect structural variation. In some embodiments, the individual of (a) is a member of a family pedigree, and is affected by a medical condition which may be Mendelian, the first assay is DNA sequencing, the genetic characteristics determined in (b) are variations of the DNA sequence so determined, from a human reference sequence, or alleles which match the human reference sequence but which are known to be correlated with a medical condition; optionally filtered to select those variants most likely to be causal, the DNA sequences designed in (c) are to capture or amplify the genomic regions of those variants, in subsequent samples, the assay of (e) is DNA sequencing, the samples sequenced in (e) are from other members of the same family pedigree, the report generated attempts to identify the genetic variants shared by the family members, which are responsible for the affliction of those pedigree members who are affected, by leveraging the rules of genetic inheritance, and data on multiple variant loci measured in multiple family members. In some embodiments, the medical condition affecting the individual of (a) includes neurological clinical features, at least one of the samples assayed, in s (a) and/or (e) are from buccal swabs or other tissue of the ectodermal lineage, the report generated considers the possibility that one or more genetic variants of the afflicted individual are mosaic, and included in the ectodermal cell lineage of the individual. In some embodiments, the at least one of the samples assayed, in s (a) and/or (e) are DNA from sperm of one of the individuals in a family pedigree, the report generated considers the possibility that one or more genetic variants of the afflicted individual are gonadal mosaic in the father of the afflicted individual. In some embodiments, the potentially causal genetic variants from probands in multiple Mendelian pedigrees are combined into a single list of genetic loci and/or regions. In some embodiments, the nucleic acid sequences are designed for in-solution capture of those genetic loci and/or regions, by hybridization, nucleic acid sequences are synthesized by inkjet printing on an array with a capacity of over 50,000 nucleic acid sequences (e.g., Agilent SureSelect), following synthesis. The nucleic acid sequences are cleaved from the substrate on which they were synthesized, for use in solution, the nucleic acid sequences thus synthesized constitute a pool which is expected to capture most or all of the genetic loci and/or regions on the list from all of the Mendelian pedigrees, and are used that way on each sample. The samples themselves may be processed in a pool (each identified by a nucleic acid barcode) or individually. Variants which matter for each Mendelian pedigree are bioinformatically separated out from the DNA sequencing-based assay data of (e). A separate report may be generated for each of the Mendelian pedigrees, even though a portion of their assays (synthesis of a shared oligo pool) was in common. In some embodiments, the “genetic characteristics” of (b) constitute a list of genes derived from the clinical phenotype of the patient, using methods described in US 20160283484. In some embodiments, (i) the original individual is among those sequenced with the personalized assay, and (ii) the sequencing depth of the personalized assay, at the loci of tentatively identified mosaic variants, is higher than in the original assay and thus can be used to make a more definitive variant call. In some embodiments, the individual of (a) is a cancer patient, the first assay is sequencing of DNA derived from their tumor, the genetic characteristics determined in (b) are one or more of (i) variations of the DNA sequence so determined, from a human reference sequence, or (ii) alleles which match the human reference sequence but which are known to be correlated with some type of cancer or other disease, or (iii) alleles which determine the HLA type; optionally filtered to select those variants most likely to be relevant for analysis of the tumor or the patient's potential treatment, the DNA sequences designed in (c) are to capture or amplify the genomic regions of those variants, in subsequent samples, the assay of (e) is sequencing of DNA (or cDNA) captured or amplified using the array-synthesized oligos, the samples sequenced in (e) are from the same patient and are one or more of (i) germline DNA, (ii) tumor RNA or cDNA derived from the tumor RNA, (iii) cell-free DNA or RNA derived from blood plasma (including from different time points in the patient's progression), (iv) DNA from elsewhere in the patient's body which may contain mosaic variants, or (v) tumor DNA again (to confirm the new assay detects the variants seen with the original assay), the report generated attempts to identify genetic variants which can inform the therapy choice for the patient. In some embodiments, the individual of (a) is a cancer patient, the first assay is sequencing of DNA derived from their tumor and also germline DNA, the genetic characteristics determined in (b) are one or more of (i) variations of the DNA sequence so determined, between the tumor sequence and the germline sequence, or (ii) alleles which determine the HLA type; optionally filtered to select those variants most likely to be relevant for analysis of the tumor or the patient's potential treatment, the DNA sequences designed in (c) are to capture or amplify the genomic regions of those variants, in subsequent samples, the assay of (e) is sequencing of DNA (or cDNA) captured or amplified using the array-synthesized oligos, the samples sequenced in (e) are from the same patient and are one or more of (i) tumor RNA or cDNA derived from the tumor RNA, (ii) cell-free DNA or RNA derived from blood plasma (including from different time points in the patient's progression), (iii) DNA from elsewhere in the patient's body which may contain mosaic variants, or (iv) tumor and/or germline DNA again (to confirm the new assay detects the variants seen with the original assay), the report generated attempts to identify genetic variants which can inform the therapy choice for the patient. In some embodiments, the individual of (a) is a cancer patient, the first assay is sequencing of RNA derived from their tumor, or cDNA derived from RNA of their tumor, the genetic characteristics determined in (b) are one or more of (i) variations of the DNA sequence so determined, from a human reference sequence, or (ii) alleles which match the human reference sequence but which are known to be correlated with some type of cancer or other disease, or (iii) alleles which determine the HLA type, or (iv) metrics of gene expression and/or allele-specific expression, or (v) quantification of long non-coding RNAs or micro-RNAs which are at least partially tissue-type specific or cancer-type specific; optionally filtered to select those variants most likely to be relevant for analysis of the tumor or the patient's potential treatment, the DNA sequences designed in (c) are to capture or amplify the genomic regions of those variants, in subsequent samples, the assay of (e) is sequencing of DNA (or cDNA) captured or amplified using the array-synthesized oligos, the samples sequenced in (e) are from the same patient and are one or more of (i) germline DNA, (ii) tumor DNA, (iii) cell-free DNA or RNA derived from blood plasma (including from different time points in the patient's progression), (iv) DNA from elsewhere in the patient's body which may contain mosaic variants, or (v) tumor RNA again (to confirm the new assay detects the variants seen with the original assay), the report generated attempts to identify genetic variants which can inform the therapy choice for the patient. In some embodiments, the individual of (a) is a cancer patient, the first assay is sequencing of cell-free DNA derived from the patient's blood plasma, the genetic characteristics determined in (b) are one or more of (i) variations of the DNA sequence so determined, from a human reference sequence, or (ii) alleles which match the human reference sequence but which are known to be correlated with some type of cancer or other disease, or (iii) alleles which determine the HLA type; optionally filtered to select those variants most likely to be relevant for analysis of the tumor or the patient's potential treatment, the DNA sequences designed in (c) are to capture or amplify the genomic regions of those variants, in subsequent samples, the assay of (e) is sequencing of DNA (or cDNA) captured or amplified using the array-synthesized oligos, the samples sequenced in (e) are from the same patient and are one or more of (i) germline DNA, (ii) cell-free DNA derived from the patient's blood plasma (but now potentially at greater sequencing depth by use of a more focused, oligo-directed assay) (including from different time points in the patient's progression), (iii) cell-free RNA derived from the patient's blood plasma (including from different time points in the patient's progression) (iv) DNA from elsewhere in the patient's body which may contain mosaic variants, or (v) cell-free DNA again (to confirm the new assay detects the variants seen with the original assay), the report generated attempts to identify genetic variants which can inform the therapy choice for the patient. In some embodiments, the individual of (a) is a cancer patient, the first assay is sequencing of cell-free RNA derived from the patient's blood plasma, or cDNA derived from that RNA, the genetic characteristics determined in (b) are one or more of (i) variations of the DNA sequence so determined, from a human reference sequence, or (ii) alleles which match the human reference sequence but which are known to be correlated with some type of cancer or other disease, or (iii) alleles which determine the HLA type, or (iv) metrics of gene expression and/or allele-specific expression, or (v) quantification of long non-coding RNAs or micro-RNAs which are at least partially tissue-type specific or cancer-type specific; optionally filtered to select those variants most likely to be relevant for analysis of the tumor or the patient's potential treatment, the DNA sequences designed in (c) are to capture or amplify the genomic regions of those variants, in subsequent samples, assay of (e) is sequencing of DNA (or cDNA) captured or amplified using the array-synthesized oligos, the samples sequenced in (e) are from the same patient and are one or more of (i) germline DNA, (ii) cell-free RNA derived from blood plasma (but now potentially at greater sequencing depth by use of a more focused, oligo-directed assay), (iii) cell-free DNA from the patient's blood plasma, or (iv) DNA from elsewhere in the patient's body which may contain mosaic variants, or (v) cell-free RNA again (to confirm the new assay detects the variants seen with the original assay), the report generated attempts to identify genetic variants which can inform the therapy choice for the patient In some embodiments, the individual of (a) is a current or potential cancer patient, the first assay is quantification of RNAs derived from the patient's white blood cells, or cDNA derived from that RNA; and/or quantification of cell-free DNA and/or RNA in the blood plasma, the genetic characteristics determined in (b) are which genes and/or non-coding RNA regions are best for cell-free tumor characterization via cell-free DNA vs cell-free RNA, the DNA sequences designed in (c) are to capture or amplify the genomic regions best for cell-free tumor characterization via cell-free DNA and/or (separately, with a different group of DNA sequences) to capture or amplify the genomic regions best for cell-free tumor characterization via cell-free RNA, in subsequent samples, the assay of (e) is sequencing of cell-free DNA and/or cell-free RNA captured or amplified using the set(s) of array-synthesized oligos, the samples sequenced in (e) are from the same patient and are one or more of (i) cell-free DNA, or (ii) cell-free RNA; either derived from blood plasma; from the same or different time points in the patient's progression, and the report generated attempts to identify genetic variants which can inform the therapy choice for the patient. In some embodiments, the individual of (a) is a current or potential cancer patient, the first assay is sequencing of DNA and/or RNA derived from the patient's tumor, optionally combined with sequencing of germline DNA, the genetic characteristics determined in (b) are a list of expressed variants seen in the tumor but not seen in the germline DNA, which have been assessed to be potential neoantigens for use in a personal cancer vaccine, the DNA sequences designed in (c) are to capture or amplify a plurality of the variants, in subsequent samples, the assay of (e) is sequencing of DNA or RNA, captured or amplified using the set(s) of array-synthesized oligos, with sufficient sequencing depth and analysis to detect mosaic variants, the sample(s) sequenced in (e) are from the same patient but from non-cancerous cells, from the same tissue as the tumor, or from other tissue elsewhere in the body; and may also include the tumor DNA (again, as a control for the new assay), the report generated attempts to discriminate which of these (apparently somatic) variants also exists in cells other than the cancer. This can occur due to mosaic variation (due to a DNA replication error or a retroviral insertion) which occurred prior to the initiation of the tumor. This can lead to variants which are in the tumor and other tissues but not the germline. These variants may be inappropriate as the basis for a personal cancer vaccine, since (i) the immune response elicited by such a vaccine might also attack non-cancer cells that express the same variant, and (ii) the patient may have been tolerized to peptides generated by the variant and thus not mount an immune response to them. In some embodiments, the individual of (a) is a current or potential cancer patient, the first assay is relative quantification of RNA by gene and/or non-coding RNA region, in a sample from the patient, using targeted or untargeted cDNA sequencing or other assay approaches, the genetic characteristics determined in (b) are one or more lists of genes, non-coding RNA regions, or RNA from gene-fusion events, whose RNA sequencing read-depth would benefit from being increased or decreased relative to a non-personalized assay, in terms of achieving more uniform RNA sequencing coverage, the DNA sequences designed in (c) are to capture or amplify RNA (or cDNA) from genes and/or non-coding RNA regions and/or gene-fusion events on the lists, in subsequent samples, the assay of (e) is sequencing of RNA, (or cDNA), captured or amplified using the set(s) of array-synthesized oligos, the sample(s) sequenced in (e) are from the same patient, and may be (i) the same sample as assayed in (a), or (ii) another sample from the same tissue as assayed in (a) (e.g., to look for tumor heterogeneity), or (iii) one or more samples from different time points in a patient's progression, or (iv) from other patients being compared, the report generated includes one or more of (i) genetic variants called from the RNA sequencing data, or (ii) relative expression levels of different samples, by gene or non-coding RNA region, or (iii) allele-specific expression, where the variants being expressed may be SNP's, InDel's and/or gene fusion events. In some embodiments, the assay of (a) is RNA sequencing of a sample, the list(s) generated as genetic characteristics in (b) are of genes, non-coding RNA regions and gene fusion events not sufficiently covered by the sequencing of (a), the sample of (e) is the same as (a), the assay of (e) is sequencing of RNA (or cDNA) captured or amplified by the oligos synthesized in (d), the data from (e) is added to that from (a), in an effort to fill in the otherwise insufficient (or suboptimal) DNA sequencing coverage from (a), in the genes and other regions identified in the lists. In some embodiments, the assay of (a) is RNA sequencing (or sequencing of cDNA derived from RNA), using next generation sequencing methods, with less than five million sequence reads. In some embodiments, the assay of (a) is RNA sequencing (or sequencing of cDNA derived from RNA), using next generation sequencing methods, with less than one million sequence reads. In some embodiments, the assay of (a) is DNA sequencing of a plurality of V(D)J recombination segments which each specify an antigen receptor of a T-cell and/or B-cell of a cancer patient's immune system, the genetic characteristics in (b) are the identities and quantities of specific V(D)J sequences, the DNA sequences designed in c, and array synthesized in (d), are to capture or amplify DNA or RNA sequences which would lead to neoantigens which can be recognized by the T-cell receptors or B-cell receptors corresponding to the V(D)J segments of s (a) and (b), the sample of (e) is from the same patient and is one of (i) tumor DNA, or (ii) tumor RNA, or (iii) cDNA derived from tumor RNA, or (iv) cell-free DNA from blood plasma, or (v) cell-free RNA from blood plasma, or (vi) cDNA derived from cell-free RNA from blood plasma, the assay of (e) is sequencing of DNA, RNA (or cDNA) captured or amplified by the oligos synthesized in (d), the data from (e) is to confirm the existence of genetic variants in the tumor of the patient, corresponding to the V(D)J segments measured in (a) and (optionally) to quantify those variants. In some embodiments, the assay of (a) is sequencing of DNA, RNA or cDNA derived from a patient's tumor, directly from the tumor or from cell-free amounts in the patient's blood plasma, the genetic characteristics in (b) are the identities of variants, relative to a human reference sequence, found in the sequence data from (a), which may lead to immunologically active neoantigens, the DNA sequences designed in c, and array synthesized in (d), are to capture or amplify DNA sequences which would lead to T-cell receptors or B-cell receptors corresponding to the potential neoantigens of s (a) and (b), the sample of (e) is from the same patient and is one or more of (i) DNA from T-cells, or (ii) DNA from B-cells, the assay of (e) is sequencing of DNA captured or amplified by the oligos synthesized in (d), the data from (e) is to confirm the existence of, and optionally to quantify, V(D)J segments which would lead to T-cell or B-cell receptors corresponding to the neoantigens identified in s (a) and (b). In some embodiments, the assay of (a) comprises (i) exposing a human tumor tissue sample to a mixture of oligo-antibody conjugates, some of which may bind to proteins or peptides in the tissue sample, (ii) subsequent release of those that bound, and (iii) sequencing of their oligo portions, the genetic characteristics of (b) are the identities and quantities of oligo-antibody conjugates corresponding to the sequences determined in (a), DNA sequences designed in c and array synthesized in (d) are to capture or amplify one or more of (i) a plurality of oligo sequences of oligo-antibody conjugates identified in (b), or (ii) DNA or RNA sequences corresponding to the proteins or peptides which were bound by the antibody component of oligo-antibody conjugates in (a), the sample(s) assayed in (e) are DNA or RNA (or cDNA derived from RNA) from the same or different tissue samples of the same person as the assay of (a), the assay of (e) is sequencing, with a report identifying the specific sequences and their quantities. In some embodiments, the nucleic acid sample of the individual, measured by the assay in (a), is obtained distal to its origin in the body, the genetic characteristics determined in (b) include identified genomic locations of mosaic variants in the initial sample, the DNA sequences designed in c are designed to amplify or enrich a plurality of those mosaic loci in subsequent samples, the assay of (e) is performed on samples from one or more other locations in the body of the same individual, to see if and/or to what extent the same mosaic variants are observed in those samples, the report of (f) uses the data to determine where in the body the DNA of the original sample came from. In some embodiments, the initial nucleic acid sample is one of (i) cell-free DNA or cell-free RNA obtained from blood plasma, or (ii) RNA obtained from one or more exosomes derived from a blood sample of the individual, or (iii) DNA or RNA obtained from circulating tumor cells, or (iv) DNA or RNA from a tumor metastasis. In some embodiments, the initial nucleic acid sample is from what is thought to be a primary tumor, tested to confirm whether it is actually from the tissue within which it has been found. Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in this art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive. | C12Q16883 | 20171025 | 20180222 | 84421.0 | C12Q168 | 1 | MARTINELL, JAMES | PERSONALIZED GENETIC TESTING | SMALL | 1 | CONT-ACCEPTED | C12Q | 2,017 |
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15,795,509 | PENDING | WASTEWATER LEACHING SYSTEM | Methods, apparatus, and systems involving high aspect ratio conduits are provided. These may involve a plurality of high aspect ratio leaching channels that may be spaced a predetermined distance apart from each other. The predetermined distance can facilitate backfilling of the volumes of adjacent high aspect ratio leaching channels. The backfill may be sand as well as other materials. | 1. A wastewater treatment system comprising: a first, second, and third, infiltrative channel, each of the three infiltrative channels spaced apart from each other, each of the three infiltrative channels having an exterior geotextile and having at least two upright infiltrative surfaces, each of the three infiltrative channels having a top, a bottom, a height, a width, and a length wherein the height to width aspect ratio of each of the infiltrative channel is 3 or 96 or is between 3 and 96, each of the three infiltrative channels have sections of one foot or more along their length without an upright interconnecting infiltrative surface interconnecting any of the three infiltrative channels to a neighboring infiltrative channel; a first separation spacer, the first separation spacer having a length, the length of the first separation spacer positioned between exterior geotextile of the first infiltrative channel and exterior geotextile of the second infiltrative channel, and the first separation spacer configured to provide a spacing between the first infiltrative channel and the second infiltrative channel, the first separation spacer configured so as not to convey wastewater from the first infiltrative channel to the second infiltrative channel via the first separation spacer; a second separation spacer, the second separation spacer positioned between exterior geotextile of the second infiltrative channel and exterior geotextile of the third infiltrative channel, and the second separation spacer configured to provide a spacing between the second infiltrative channel and the third infiltrative channel, the second separation spacer configured so as not to convey wastewater from the second infiltrative channel to the third infiltrative channel via the second separation spacer; and a wastewater dosing pipe positioned to dispense wastewater directly into each of the three infiltrative channels, wherein the wastewater channel traverses no more than a portion of a lower boundary of each of the three infiltrative channels, wherein at least a portion of the length of the first separation spacer positioned between exterior geotextile of the first infiltrative channel and exterior geotextile of the second infiltrative channel is lower than the top of the first and the second infiltrative channels, wherein at least a portion of the length of the first separation spacer positioned between exterior geotextile of the first infiltrative channel and exterior geotextile of the second infiltrative channel is higher than the bottom of the first and the second infiltrative channels, wherein at least a portion of the top of each of the three infiltrative channels is not directly underlying any section of the wastewater dosing pipe. 2. The wastewater treatment system of claim 1 wherein the infiltrative channels and separation spacers are joined and movable as a unit for shipment. 3. The wastewater treatment system of claim 1 wherein at least one of the separation spacers is a line and wherein the sections of one foot or more along their length without an upright interconnecting infiltrative surface interconnecting any of the three infiltrative channels to a neighboring infiltrative channel comprise a soil, such as sand. 4. The wastewater treatment system of claim 1 wherein wastewater dosing pipe is positioned such that wastewater dosed from the wastewater dosing pipe is not first received by an intervening continuous plastic structure that covers the tops of each of the three infiltrative channels. 5. The wastewater treatment system of claim 1 wherein the first separation spacer is secured and configured so as to inhibit lateral movement between the first infiltrative channel and the second infiltrative channel. 6. The wastewater treatment system of claim 1 wherein the first separation spacer does not pass through an infiltrative surface of the third infiltrative channel. 7. The wastewater treatment system of claim 1 wherein the first separation spacer and the second separation spacer are positioned completely below the top of each of the three infiltrative channels and positioned completely above the bottom of each of the three infiltrative channels. 8. The wastewater treatment system of claim 1 wherein the first separation spacer and the second separation spacer are each secured so as to inhibit lateral movement between only two infiltrative channels. 9. The wastewater treatment system of claim 1 wherein each of the infiltrative channels extend at least one foot beyond the dosing pipe where the dosing pipe traverses each of the infiltrative channels. 10. The wastewater treatment system of claim 1 wherein the first spacing separation spacer is perpendicular to a middle portion of an infiltrative surface of the first infiltrative channel and is perpendicular to a middle portion of an infiltrative surface of the second infiltrative channel. 11. A wastewater treatment system comprising: a first, second, and third, infiltrative channel, each of the three infiltrative channels spaced apart from each other, each of the three infiltrative channels having at least two upright infiltrative surfaces, each of the three infiltrative channels having a top, a bottom, a height, a width, and a length wherein the height to width aspect ratio of each of the infiltrative channel is 3 or 96 or is between 3 and 96, each of the three infiltrative channels have sections of one foot or more along their length without an interconnecting infiltrative surface interconnecting them to a neighboring infiltrative channel; a first separation spacer positioned between the first infiltrative channel and the second infiltrative channel, the first separation spacer having a length, the first separation spacer configured to provide a spacing between the first infiltrative channel and the second infiltrative channel, the first separation spacer configured to inhibit lateral movement between the first infiltrative channel and the second infiltrative channel, a second separation spacer positioned between the second infiltrative channel and the third infiltrative channel, the second separation spacer configured to provide a spacing between the second infiltrative channel and the third infiltrative channel, the second separation spacer configured to inhibit lateral movement between the second infiltrative channel and the third infiltrative channel; and a wastewater dosing pipe positioned to dispense wastewater directly into each of the three infiltrative channels, wherein the wastewater dosing pipe traverses no more than a portion of an upper boundary or a lower boundary of each of the three infiltrative channels, wherein the first separation spacer does not extend to the third infiltrative channel and the second separation spacer does not extend to the first infiltrative channel, wherein at least a section of the length of the first separation spacer positioned between the exterior geotextile of the first infiltrative channel and the exterior geotextile of the second infiltrative channel is lower than the top of the first infiltrative channel, wherein at least a section of the length of the first separation spacer positioned between the exterior geotextile of the first infiltrative channel and the exterior geotextile of the second infiltrative channel is higher than the bottom of the first infiltrative channel, wherein at least a portion of the top of each of the three infiltrative channels is not directly underlying any section of the wastewater channel. 12. The wastewater treatment system of claim 11 wherein the infiltrative channels and separation spacers are assembled as a unit and configured for shipping. 13. The wastewater treatment system of claim 11 wherein the separation spacers are elongated and are anchored in place. 14. The wastewater treatment system of claim 11 wherein the separation spacers are collapsible. 15. The wastewater treatment system of claim 11 wherein the separation spacers are secured and configured so as to touch at least two infiltrative channels. 16. The wastewater treatment system of claim 11 wherein the first separation spacer contacts an infiltrative surface of the first infiltrative channel and an infiltrative surface of the second infiltrative channel and the second separation spacer contacts an infiltrative surface of the second infiltrative channel and an infiltrative surface of the third infiltrative channel. 17. The wastewater treatment system of claim 11 wherein the infiltrative channels each extend at least one foot beyond an external surface of the dosing pipe. 18. The wastewater treatment system of claim 11 wherein at least one separation spacer is positioned adjacent a middle portion of one of the infiltrative channels, the middle portion positioned between the top and the bottom of the infiltrative channel the at least one separation spacer is positioned adjacent to. 19. The wastewater treatment system of claim 1 further comprising: a first treatment channel, the first treatment channel positioned between the first and second infiltrative channels; and a second treatment channel, the second treatment channel positioned between the second and third infiltrative channels, wherein at least a portion of the top of each of the three infiltrative channels and a top of each of the two treatment channels is not directly underlying any section of the wastewater channel above the particular channel. 20. A method of treating wastewater comprising: generating wastewater; and flowing the generated wastewater into the wastewater treatment system of claim 11. 21. The wastewater treatment system of claim 1, wherein: the first separation spacer contacts the exterior geotextile of an upright infiltrative surface of the first infiltrative channel, the first separation spacer contacts the exterior geotextile of an upright infiltrative surface of the second infiltrative channel, the second separation spacer contacts the exterior geotextile of an upright infiltrative surface of the second infiltrative channel, and the second separation spacer contacts the exterior geotextile of an upright infiltrative surface of the third infiltrative channel. 22. The wastewater treatment system of claim 1 wherein the first separation spacer is positioned completely below the top of each of the three infiltrative channels and is positioned completely above the bottom of each of the three infiltrative channels. 23. The wastewater treatment system of claim 22 wherein the second separation spacer is positioned completely below the top of each of the three infiltrative channels and is positioned completely above the bottom of each of the three infiltrative channels. 24. The wastewater treatment system of claim 1 wherein each of the three infiltrative channels is completely wrapped in the exterior geotextile. | CROSS-REFERENCES TO RELATED APPLICATIONS This application claims benefit under 35 U.S.C. §120 and is a continuation of U.S. patent application Ser. No. 13/682,491, filed Nov. 20, 2012. The '491 application claims benefit under 35 U.S.C. §120 and is a continuation of U.S. patent application Ser. No. 12/730,817, filed on Mar. 24, 2010, and is now U.S. Pat. No. 9,656,892. The '817 application claims benefit under 35 U.S.C. §120 and is a divisional of Ser. No. 12/042,667, filed Mar. 5, 2008, which is now abandoned. The '667 application claims priority under 35 U.S.C. §119 from U.S. provisional application 60/945,398, filed Jun. 21, 2007. The '667 application claims the benefit under 35 U.S.C. §120 and is a continuation-in-part of U.S. patent application Ser. No. 11/340,917, filed Jan. 27, 2006, and is now U.S. Pat. No. 7,374,670, which issued Apr. 30, 2008. The '917 application claims the benefit under 35 U.S.C. §120 and is a continuation-in-part of U.S. patent application Ser. No. 11/144,968, filed Jun. 3, 2005, and now U.S. Pat. No. 7,465,390, which issued Nov. 25, 2008. The '968 application claims priority under 35 U.S.C. §119 to U.S. provisional application 60/576,950, filed Jun. 4, 2004. The contents of the aforementioned applications and patents are incorporated herein, in their entirety, by reference. TECHNICAL FIELD The present invention relates to leach fields and aerobic treatment of wastewater within soil, and more particularly to a high aspect ratio wastewater system and leaching conduit. BACKGROUND Known leaching conduits, such as arch shape cross section molded plastic chambers, or stone filled trenches with perforated pipe, used for domestic and commercial wastewater systems provide interior void space, based on the thinking that a buffer space or flow equalization is thus provided for variations of inflow of wastewater. The sidewalls of conduits, where they interface with the surrounding soil, are also commonly conceived as providing surface area for percolation of wastewater, in addition to the bottom surface of the conduit. A familiar crushed stone filled trench, having a modest (4 inch) diameter perforated pipe running along its length may have about 50% void space. Currently, arch shape cross-section molded plastic leaching chambers have entirely open interiors, open bottoms and sloped and perforated sidewalls. A common cross section shape for each typical conduit has a width of about 30 to 36 inches and a height of about 12 to 18 inches. Thus this conduit may have from about 12 inches to about 18 inches of water depth at any one time. It has been seen that in these prior art conduits, a biomat will often form on the bottom and sides of the conduit, thereby lessening the effectiveness of the leaching conduits to properly infiltrate the wastewater into the soil. Drip irrigation lines are usually approximately one half inch in diameter and are typically buried 12 to 6 inches below grade. Leaching conduits are typically covered with 6 to 12 inches or more of soil, for several reasons. One is to protect the conduits from damage. Another is to prevent contact of humans and animals with potentially deleterious microorganisms associated with the wastewater being treated. Still another is to prevent odors. The dimensions of the conduits discussed in the preceding paragraph would lead to the fact that the bottom surface of the conduits are typically at about 24 inches or more below the soil surface. Generally, it is an aim to have aerobic treatment of the wastewater in the soil. Current thinking with prior art systems is that there is an air-soil gas interchange, so that oxygen is continuously supplied to the soil, to enable good microbiological treatment. However, the soil depths at which prior art conduits operate are disadvantaged in this respect. Since the bottom surface of the conduits are typically about 18 to 24 inches below the soil surface, the bottom surfaces of the conduits are often in an anaerobic condition since the oxygen demand exceeds the oxygen supply. One improvement with such systems is to force air serially through the conduit and soil influence zone which surrounds the conduit, as described in U.S. Pat. No. 6,485,647 to David Potts, issued on Nov. 26, 2002, and which is incorporated herein by reference in its entirety. Therefore, a wastewater system is needed that provides for greater aerobic conditions in leaching conduits, thereby allowing for greater processing of the wastewater prior and during absorption into the soil. SUMMARY Numerous embodiments are provided herein. These include those directed to wastewater leaching processes, systems and articles of manufacture. Wastewater treatment processes may include providing pairs of upright infiltrative surfaces where the infiltrative surfaces may define a cross-section and may have a height to width aspect ratio between 3 and 96 as well as 3 and 96. Spacings between these pairs may be uniform. A wastewater dosing channel may also be provided, this dosing channel may have a portion that traverses at least one infiltrative surface of several of the pairs of infiltrative surfaces. This channel may be positioned and configured to dose wastewater downwardly into internal spacing of the pairs of infiltrative surfaces. When the dosing channel is connected to a supply of wastewater, wastewater may flow into pairs of infiltrative surfaces and may be aerobically treated in sand or other soil between neighboring pairs of infiltrative surfaces. A wastewater system may also be provided in embodiments. This system may include a plurality of infiltrative channels where each of the channel may be spaced apart from each other and have at least two upright infiltrative surfaces and have a height to width aspect ratio of 3 or 96 or between 3 and 96. The system may also include interstitial aerobic treatment channels comprising sand, where a first treatment channel is between a first infiltrative channel and a second infiltrative channel and a second treatment channel is between the second infiltrative channel and a third infiltrative channel. A wastewater channel traversing each of the infiltrative channels may also be included. In embodiments, a portion of the upper boundary of each of the three infiltrative channels and an upper boundary of each of the two treatment channels may not be directly underlying any section of the wastewater channel above that particular channel. A wastewater system of embodiments may also include a plurality of infiltrative channels where each of the channels may be spaced apart from each other, wrapped in filter fabric, and having at least two upright infiltrative surfaces. The channels may also have a height, a width, and a length where the height to width aspect ratio of each of the infiltrative channel is 3 or 96 or is between 3 and 96. This system may also include separation spacers configured to provide a spacing between the first infiltrative channel and the second infiltrative channel; and further configured to provide a spacing between the second infiltrative channel and the third infiltrative channel. A wastewater channel traversing each of the three infiltrative channels may also be provided. This channel may traverse no more than a portion of an upper boundary of each of the three infiltrative channels and where at least a portion of the upper boundary of each of the three infiltrative channels and an upper boundary of two treatment channels is not directly underlying any section of the wastewater channel above that particular channel. System embodiments may also include first, second, and third, infiltrative channels, where each of the three infiltrative channels may be spaced apart from each other, where each of the three infiltrative channels may have at least two upright infiltrative surfaces, and where each of the three infiltrative channels may have a height, a width, and a length wherein the height to width aspect ratio of each of the infiltrative channel is 3 or 96 or is between 3 and 96, Separation spacers may be employed in embodiments. These spacers may be employed such that a first separation spacer is positioned between a first and second infiltrative channel and a second separation spacer is positioned between a second and a third infiltrative channel. In this and in other system embodiments, a wastewater channel may traverse three infiltrative channels, wherein the wastewater channel traverses no more than a portion of an upper boundary of each of the three infiltrative channels and where at least a portion of the upper boundary of each of the three infiltrative channels and an upper boundary of each of two treatment channels is not directly underlying any section of the wastewater channel above that particular channel. Other configurations and combinations may also be employed where features may be modified or combined in various ways consistent with the teachings of this disclosure. BRIEF DESCRIPTION OF THE DRAWINGS The present disclosure will be better understood by those skilled in the pertinent art by referencing the accompanying drawings, where like elements are numbered alike in the several figures, in which: FIG. 1 is a cross-sectional view of a disclosed low aspect ratio leaching conduit; FIG. 2 is a perspective view of a geonet; FIG. 3 a front view of the geonet from FIG. 2; FIG. 4 is a front view of another embodiment of the disclosed geonet: FIG. 5 is a front view of another embodiment of the disclosed geonet; FIG. 6 is an exploded view of one embodiment of a dosing pipe; FIG. 7 is a side view of the dosing pipe of FIG. 6; FIG. 8 is a cross-sectional view of the dosing pipe of FIG. 7; FIG. 9 is a schematic of a disclosed low aspect ratio wastewater treatment system; FIG. 10 is a cross-sectional view of a disclosed alternative to a geonet; FIG. 11 is another embodiment of the disclosed leaching conduit; FIG. 12 is another embodiment of the disclosed leaching conduit; FIG. 13 is a perspective view of a disclosed high aspect conduit; FIG. 14 is a cross-sectional view of the disclosed high aspect conduit from FIG. 13; FIG. 15 is a cross-sectional view of another embodiment of the disclosed high aspect conduit; FIG. 16 is a perspective view of another embodiment of the disclosed high aspect conduit; FIG. 17 is a top view of the disclosed high aspect conduit from FIG. 16; FIG. 18 is a cross-sectional view of the high aspect conduit from FIG. 16; FIG. 19 is a top view of another embodiment of the high aspect conduit; FIG. 20 is a side view of the high aspect conduit from FIG. 19; FIG. 21 is a perspective view of a high aspect conduit form and cover; FIG. 22 is a top view of the high aspect conduit form from FIG. 21; FIG. 23 is a side view of the high aspect conduit form from FIG. 21; FIG. 24 is a cross-sectional view of another disclosed conduit; FIG. 25 is a top view of a multiple I embodiment of the disclosed form; FIG. 26 is a top view of an accordion embodiment of the disclosed form; FIG. 27 is a top view of a box embodiment of the disclosed form; and FIG. 28 is a flowchart showing one embodiment of the disclosed method of using a leach field form. DETAILED DESCRIPTION Low Aspect Ratio Conduit In the present invention, as illustrated by the FIGS. 1 through 12, conduit 20 has a much lower aspect ratio (height divided by width) than conduits in the prior art. Thus, the bottom of the conduit can be positioned closer to the surface of the soil. And, it is an option to install a leaching system by laying a multiplicity of conduits 20 on the soil grade and to then cover them with appropriately chosen media and/or soil. This approach is especially advantageous for leaching system sites having shallow depths of native soil, such as those which overlie a high-water table or ledge, and the like. The disclosed conduits may be installed in spaced apart rows, or in segments which are spaced apart, all interconnected by suitable distribution lines. In the following, one conduit segment or length is described. In one embodiment, shown in FIG. 1, the disclosed conduit 20 comprises a perforated dosing pipe 22 which overlies a low aspect channel 24 all of which lie beneath a soil surface 30. The low aspect channel 24 is approximately rectangular shaped in this cross-sectional view. The pipe 22 distributes the wastewater relatively evenly along the length of the channel 24. A dosing pipe will typically be of a small diameter, for instance from about ¾ to about 2 inch in diameter. The pipe has suitable small spaced apart openings along its length, which openings may be smaller near its water source and larger farther away. A geotextile shroud 26 drapes over the pipe 22, so it runs downwardly and laterally outward, onto the top surface of low aspect channel 24. The shroud extends to the outer edges of the channel 24, to keep soil from infiltrating vertically down into the voids of the channel 24. The shroud provides assurance that there will be good water flow path from the pipe perforations and underside of the pipe, to the top of the channel 24. Optionally, some crushed stone, or plastic pieces or other granular or permeable media, may be placed in the space 28 under the shroud 26, near the pipe 22. With reference to FIG. 1, in one embodiment, the top of the low aspect channel 24 may be considered essentially planar, because as shown in the end view of FIG. 1, the shroud width “wS”, that is the width of the base of the vaguely triangular cross section which comprises the region defined by the sloping surfaces of the shroud 26 is a small fraction of the channel width “wC”. Alternatively, the shroud 26 may be a preformed shape permeable material, such as perforated molded plastic. In another variation, the shroud may be impermeable when used with blower systems and since the preponderance of the top of the channel 24 will be permeable. If a blower is in fluid communication with the low aspect ratio channel, the blower may be configured to intermittently blow air and/or some other gas through the channel 24 in order to assist in drying out the adjacent soil and to prevent biological buildup. Additionally, the blower may be configured to provide oxygen to the conduit and assist in dissipating water into the soil. The blower may also be configured to keep the dosing pipe and perforations from clogging with organic matter. The blower may dissipate water from the soil such that it prevents freezing around the conduit. The entire conduit can also be made of crushed stone, or plastic pieces or other granular or permeable media in substitution for the “geonet”. This is true with both the low aspect channel and high aspect channel described below. The low aspect channel may have a geonet 40 located within it. The geonet 40 may be obtained from various manufacturers, such as, but not limited to: Enkadrain drainage system product No. 9120 from Colbond Inc., P.O. Box 1057, Enka, N.C. 28728; and the several geonets named Grasspave2, Gravelpave2, Rainstore2, Slopetame2, Draincore2, Surefoot4, Rainstore3 from Invisible Structures, Inc., 1600 Jackson Street, Suite 310, Golden, Colo. 80401, and Advanedge® flat pipe from Advanced Drainage Systems, Inc. 4640 Trueman Boulevard, Hilliard, Ohio 43026. Referring now to FIG. 2, a perspective view of a geonet 40 is shown. The geonet 40 is typically comprised of an irregularly coiled stringy structure 44 contained between one or two layers of air-permeable sheeting 48, which layers may feel to the touch like thin felt, and which is commonly and generically called geotextile. In one embodiment, the geonet 40 has only one layer and one side of the layer has the irregularly coiled string plastic structure, as shown in FIG. 2 and FIG. 3 which is a side view of the geonet 40. The low aspect channel 24, comprising the geonet 40, may have an estimated void volume of about 90%. In one embodiment, the low aspect channel 24 will have a thickness, or height “h” as shown in FIG. 1, of about ¾ inch. The channel width “wc”, or lateral dimension of the channel 24 may be about 12 to about 48 inches, and preferably about 12 to about 40 inches. Optionally, geotextile may be placed at the opposing side of the vertical edges of the channel 24, to stop potential ingress of soil. In use, wastewater introduced into the low aspect channel 24 will percolate into the soil in the downward direction primarily, to a lesser extent in the sideways directions owing to the small vertical edge dimension, and also in the upward direction, when the conduit is full. Since the top of the conduit is permeable to air, there is good microbiological functioning of the leaching system, since air from the soil between the channel 24 and the surface can diffuse into the channel 24. If a geonet is used which has both a top and a bottom layer of air and water-permeable sheeting 48, such as the geonet 52 shown in FIG. 4, the local portion of the top layer in vicinity of the pipe 22 may be removed, and the shroud 26 need only extend laterally a small distance from the pipe 22. In alternate embodiments, the low aspect channel may be deeper than a preferred geonet material. In that case, one or more geonet mats may be laid on top of the other, such as shown in FIG. 5, where two geonet mats 40 are laid on top of one another, with the irregularly coiled stringy plastic structure 44 facing each other. In another embodiment, the geonet mats may be fabricated with a greater thickness, e.g., about 2 inches, about 3 inches or about 6 inches in thickness. In embodiments with thicker geonet mats, it may be practical to omit the dosing pipe and allow the wastewater to flow through the void space of the mat, from a low aspect channel end or selected injection points. The aspect ratio of the low aspect channel 24 may be less than about 6/30 (6 units of height divided by 30 units of width, or about 0.2), preferably the aspect ratio will less than about 1/10 (1 unit of height divided by 10 unites of width, or about 0.1), and more preferably the aspect ratio will about 1/30 (1 unit of height divided by 30 unites of width, or about 0.033) to about 1/36 (1 unit of height divided by 36 unites of width, or about 0.028) or less. These ratios reflect only the dimensions of the channel 24, and not the dosing pipe 22. However, inasmuch as the preferred dosing pipe 22 is small in diameter and vertical dimension, the ratios are roughly applicable to the whole of the conduit as well. In other embodiments, the low aspect channel 24 may be much wider than shown; and, it may comprise a continuous wide layer beneath the soil surface 30. Spaced channels 24 (also called laterals or branches), following the traditional leach field layout may be utilized in another embodiment. In one embodiment, the perforated pipe 22 will be about 4 to 12 inches beneath the surface of the soil 30. Thus, in that embodiment, the bottom of the low aspect channel 24 will be about 5-17 inches deep, depending on the diameter of pipe 22 (if a pipe 22 is used in the embodiment). Thus, it is feasible in many soil areas to have the conduit wholly in the generally more permeable A-horizon of the soil. Since most wastewater will percolate downwardly into the soil beneath the low aspect channel 24, the wastewater will be better treated than if the bottom of the conduit was deeper. The soil nearer the surface has better chance of being maintained or restored to aerobic condition by natural diffusion processes within the soil. In another embodiment, there will only be one perforation in the pipe 22 about every 10 to 20 feet. In another embodiment, pipe 22 may be inside the confines of low aspect channel 24. Solid distribution pipes with a manifold may be used with or without dosing pipes 22 to get relatively even water delivery to the channel 24. Typically dosing will be carried out with a pump and thus the pipe 22 need only be of small diameter, as previously indicated. Dosing may also be accomplished with a dosing siphon or an accumulator tank with an actuated valve. In another embodiment, dosing pipe 22 may be sandwiched between two channels 24, an upper channel and a lower channel. In another embodiment, when a dosing pipe is sandwiched between two layers, the top geonet layer may have an impermeable sheeting over it to serve to dissipate the water velocity. In still another embodiment, the pipe 22 may be located between 2 approximately horizontally parallel low aspect channels 24. FIG. 6 shows another embodiment of the perforated dosing pipe 22. In this embodiment, the dosing pipe comprises a perforated tube 72, perforations 73 in the tube 72, and a slotted sleeve 76. The perforations 73 of the tube 72 lay along a length of the pipe that is approximately equal to the length of the low aspect channel 24, that length is referred to as LLAC. The sleeve length is also approximately equal to the length of the low aspect channel 24. In another embodiment, the slotted sleeve 76 may be relatively short segments located adjacent to a perforation on the tube 72. For instance, in an embodiment with one perforation about every 15 feet of tube 72, there may be a sleeve 76 of about 6 inches located adjacent to every perforation. FIG. 7 shows the sleeve 76 fitted over the tube 72. FIG. 8 shows a cross-sectional view through the tube 72 and sleeve 76 through plane 8-8. The dotted arrows show possible paths for the water leaving the perforations, and traveling between the sleeve and the tube and exiting pipe 22 at the slotted area 80. This configuration of a perforated dosing pipe 22 is advantageous in that water will not spray out of the perforations and immediately impact the soil surrounding the conduit 20. This prevents erosion of the soil around the conduit 20. Thus, in this configuration, the dosing pipe 22, allows water to be directed only towards the low aspect channel 24, rather than to the surrounding soil. In this embodiment, a geotextile shroud 26 may be omitted, and a filler medium such as, but not limited to stone, pebble may be used to prevent soil from entering the geonet. It should be obvious to one of ordinary skill that the perforations 73, may comprise multiple perforations located along the length of the tube, or there may be only one perforation per tube 72, or one perforation 73 per a certain length of tube 72. While dosing with a pump is preferred for uniformity of distribution, the pipe 22 may be configured to rely on gravity to distribute the wastewater. In such case a larger pipe, up to about 4 inches in diameter, may be used. In still another embodiment, for either a gravity or a pump system, the pipe 22 may be eliminated, and water may be delivered directly into one end of the channel 24, or into the middle of the channel 24. The disclosed conduit 20 will provide less interior storage volume, or buffering void space, than prevalent prior art chambers or prior art stone filled trenches. Therefore, depending on the particular flow handling requirements, a water handling system may be used. For example, as illustrated by FIG. 9, a flow equalization tank 56 receives discharge from a processing vessel 60, such as a septic tank. Sewage flows from a discharge source 64 to the processing vessel 60. The discharge source 64 may be, but is not limited to: a residence or a business. Periodically, a dosing device, such as, but not limited to a pump 68 will flow water from the flow equalization tank 56 to the conduit 20 located in the subsurface leach field. The conduit 20 comprises a dosing pipe 22 and a low aspect channel 24. FIG. 6 shows one embodiment of a wastewater scheme. In other embodiments, the flow equalization tank 56 may be omitted, and the processing vessel 60 may be used for flow equalization. This may be facilitated through the use of a pump to control levels in the primary processing tank. In use, the conduit 20 will be periodically dosed with wastewater according to the particular soil's hydraulic conductivity, preferably with loading rates of about 0.25 to about 3 inch per unit horizontal bottom surface area. Preferably, the time between dosing will about two times the time for a dose of water to percolate into the soil. It is conceived that that will better enable the low aspect channel 24 and recently-saturated soil near the low aspect channel to drain of water, and to refill with gas, which is in good part oxygen containing air, flowing downward through the soil and through the permeable top of the conduit. If air distribution pipes are connected to vents, the foregoing effect can be enhanced by suitable valving at the inlet end of the pipe or pipes, through the use of check valves on the vent lines, which valves will close when water is applied to the conduit. When the water percolates into the soil, it allows the check valve or similar functioning device to open and provide for the flow of air to replace an equal volume of water. When using a low aspect channel 24 as described in this patent application, the vertical dimension (h) may be about one inch. A one-inch high low aspect channel will only hold one-inch depth of water. So, the ratio of volume to area is 1 to 1. This low ratio of volume to area arises from the present invention's low aspect ratio and is advantageous in that it prevents anaerobic conditions from developing such that a biomat layer is formed on the bottom surface of the channel 24. Therefore, smaller doses of anaerobic water and organisms enter the influence zone. The influence zone is that zone where waste water is largely renovated, or biochemically converted into a more environmentally benign form, prior to re-introduction into the ground water. This prevention of anaerobic conditions encourages a stable and sustainable aerobic microbial community to be present on a continuing basis thereby providing for greater treatment of the wastewater. This also results in a greater long term acceptance rate of wastewater at a greater percolation rate. Thus for any given daily flow of water, the flow must be dosed out to the channel in an amount that does not overflow the conduit, that is, the amount of water must be no more than the volume containable by the conduit at any one time. For instance, if the conduit has 4 rows of 20 foot channels, that are each 1 inch high and 10 inches wide, and the conduit is filled either with a geonet or other medium thereby allowing a void space of about 95%, then the total instant capacity for that conduit is given by the following: 20 feet (length)×12 inches/foot×1 inch (h)×10 inches (w)×4 rows×95%=9120 in3. Thus, wastewater from the source 64 should be dosed out in increments of no more than about 9120 in3 at a time, to prevent over-flowing of the channel 24. If the conduit appears to be overflowing, despite limiting the increment of water to a proper amount, then this may be an indication that there is a malfunction such as, but not limited to a blockage in the system. In one embodiment of the disclosed conduit, the height of low aspect channel is about 3 inches or less, and preferably about 1 inch or less. Correspondingly, the ratio of volume to bottom surface area is about 3 to 1 and less, preferably about 1 to 1 and less. Other plastic products which function similarly to a geonet may be used, so long as there is a substantial void between top and bottom layers. For example, a molded plastic three dimensional grid may be used. FIG. 10 shows another alternative. The geonet may be replaced by granular media 68, such as crushed stone or pea stone, captured between two layers of air and water permeable sheeting 48, such as a geotextile. In another alternative, polystyrene aggregate incorporated into suitable netting or blanket may be used. For example, the type of polystyrene aggregate associated with the commercial product EZflow Drainage Systems may be used. EZflow drainage systems are manufactured by RING Industrial Group, LP, 65 Industrial Park, Oakland, Tenn. 38060. When soil conditions are favorable, and there is not a great risk of upwardly moving fine grained material from the underlying soil, it might be acceptable to eliminate the bottom geotextile layer in any embodiment of the invention. In addition, the geonet may be replaced by a granular media 68 that is not captured between two layers. The granular media may include, but is not limited to: crushed stone, pea stone, crushed glass, ground rubber, tire chips, and round stone. FIG. 11 shows another embodiment of the disclosed conduit. In this embodiment, the low aspect channel 24 has a width wc. However, the geonet 40 has a width that is greater than wc, such that when the geonet 40 is placed in the channel 24, two sides 84 of the geonet 40 bend up or down along the sides of the channel 24. After the channel 24 is dug, and the geonet 40 is placed in the channel, then a perforated dosing pipe 22 may be located on top of the geonet 40, with a geotextile shroud over the pipe 22. Then, soil is filled in to the soil surface 30. In this embodiment, the channel 24 is no longer mostly rectangular shaped in cross-section, but is approximately “U” shaped in cross-section. FIG. 12 shows another embodiment of the disclosed conduit. In this embodiment, the low aspect channel 88 may be curved as shown. An air and water permeable sheeting 48, such as a geotextile material, may be located on the boundaries of the channel 88 and around the dosing pipe 22. The conduit may have a geonet 40 located within it. While it is an advantage to be able to put the conduit of the invention near the surface 30 and atmospheric oxygen, in some climates freezing of the soil and water in the conduit could be a risk. There is the obvious choice to install the system deeper. Another choice, which also may involve compromise with respect to vertical gas interchange, is to place an insulation layer within the soil, above the conduit. For instance, a cellular plastic insulation board can be installed. The board may inhibit the desired vertical gas interchange, so it may be provided selectively with through holes, to enable soil gas flow. More preferably, the insulation will be air permeable media which nonetheless provides better insulation that soil. For instance, pellets of plastic or perlite may be provided, as well as polystyrene aggregate, mentioned above. If the conduit is comprised of closed cell aggregate, and not a geonet, then the aggregate itself will provide the conduit with self-insulation, which will inhibit the cooling and freezing, at least in the bottom portion. A blower can also be utilized to provide for increased drainage during subfreezing conditions. A geogrid is typically a product that is used to stabilize soil to vehicle loads, etc and is typically a square mesh that gets buried above the strata requiring stabilization. The disclosed low aspect ratio conduit may have a geogrid installed between the conduit and the soil surface to protect the conduit from wheel loads. The disclosed leaching system is more likely to have aerobic conditions due to its low aspect ratio and its low maximum volume to bottom surface ratio of the conduit, thus leading to better processing of the wastewater. The disclosed system also provides for wastewater processing near the soil surface, which provides for greater access to oxygen and a greater likelihood of aerobic conditions for the processing. Furthermore, as septic fill becomes increasingly scarce and more expensive, the low aspect ratio leaching conduit minimizes the need and quantity of fill required. Additionally, air may be flowed through the conduit to optimize aerobic conditions. High Aspect Ratio Conduit On occasion there may not be enough space to install a low aspect ratio wastewater system as described above. Therefore, this application discloses a low aspect ratio wastewater system that may be thought of as being turned on its side, thereby creating a high aspect ratio conduit, wherein the void space is relatively small, and the top of the conduit is relatively close to the surface 30 ground. Referring to FIG. 13, an embodiment of a high aspect conduit 92 is shown. A perforated dosing pipe 22 is shown under a ground surface 30. The perforations 96 are shown located intermittently on the dosing pipe. The dosing pipe 22 is shown with a cap 100 on one end. An air and water permeable sheeting 48 encloses a portion of the perforated dosing pipe 22. The generally rectangular volume beneath the dosing pipe 22, also enclosed by the air permeable sheeting 48, contains a geonet 40. The generally rectangular shaped volume 41 is also known as the channel of the conduit 92. That is the conduit 92 comprises a channel 41 where wastewater flows through, and gas infiltrates into. Additionally, since the conduit 92 has a high aspect ratio, then the channel 41 also has a high aspect ratio. It should be noted that wherever in this patent application a geonet is referenced, that geonet may be replaced by a granular material. The dosing pipe 22 is configured to deliver fluid via the perforations 96 down into the geonet 40. FIG. 14 shows a cross-sectional view of the conduit 92. The dosing pipe 22 is surrounded by an air permeable sheeting 48. Additionally, in this view, the irregularly coiled stringy structure 44 of the geonet 40 can be seen under the dosing pipe 22, and surrounded by the air and water permeable sheeting 48. The height “h” of the channel 41 is shown in FIG. 14, and the width “w” of the conduit is also shown. The aspect ratio is given by: Aspect Ratio=h/w Eq. 1 Thus it can be seen that the aspect ratio for this disclosed conduit 92 is much higher than the conduit shown in FIG. 1. However, this disclosed conduit 92 will take up less land surface area (acreage) than a low aspect ratio conduit configured to treat generally the same amount of fluid and thus will be useful when surface area is not readily available. In some embodiments, the width of the conduit is about 3 inches or less, and more particularly between about 0.5 and 2 inches wide. The height of the conduit is between about 48 inches and about 6 inches, and more particularly about 12 to about 40 inches. Thus, in this document a high aspect ratio will be about 96 to about 3, and more particularly between about 80 and 6. In other embodiments, the high aspect channels may be “Z” shaped for additional surface area. The bottom surface area of the conduit is relatively small when compared to the sides of the conduit. The heavier sludge may settle to the bottom of the conduit and leave the sides relatively free of blockages, thereby allowing for a greater infiltration along the side of the conduit as compared to the bottom of the conduit. Additionally, the sides of the conduit have more oxygen since they are closer to the surface. FIG. 15 shows a cross-sectional view of another embodiment of the disclosed high aspect conduit 104. In this conduit 104 there are a plurality of perforated dosing pipes 22, each wrapped in air and water permeable sheeting 48. Additionally, each dosing pipe has a generally rectangular volume beneath each dosing pipe 48. Each generally rectangular volume contains a geonet 40. The irregularly coiled stringy structure 44 that makes up the geonet 40 is shown in this view. Each geonet 40 is enclosed in an air and water permeable sheeting 48. Each dosing pipe 22 is configured to deliver fluid via perforations 96 (not seen in this view) into the geonet 40. FIG. 15 shows three dosing pipes 22, however, other embodiments may have as few as 1 dosing pipe and up to as many dosing pipes as practical in a given area of land. The high aspect conduits 92, 104 disclosed in FIG. 14 and FIG. 15 could be alternatively constructed by installing a dosing pipe 22, with a geonet, such as a coiled stringy structure 44 wrapped around the pipe 22, in the center of an air and water permeable sheeting 48 that is about 2 feet wide and folding the sheeting in half about the pipe. A difference in this alternative is that the core material would be wrapped around the pipe too. Also, the bottom 93 of the high aspect conduits 92 and the bottoms 105 of the high aspect conduits 104 may be constructed without an air and water permeable sheeting 48, that is the bottoms 93, 105 may be open to the surrounding soil. All the channels 41 can also be made of crushed stone, or plastic pieces or other granular or permeable media in substitution for the “geonet”. FIG. 16 shows a perspective view of another embodiment of a disclosed high aspect conduit 108. In this embodiment, three perforated dosing pipes 116, 120, 124 are shown, however it should be understood that fewer or more dosing pipes may be used as necessary to properly treat an amount of wastewater. Beneath the center dosing pipe 120, is a generally rectangular volume 112 of geonet 40. This volume 112 generally extends and runs along a plane that is collinear to the center dosing pipe 120. A volume of 128 of geonet 40 is located under dosing pipe 116 and is partially adjacent to the geonet volume 112. The geonet volume 128 may be thought of as a generally rectangular volume formed into a “U” shape, with the bottom of the “U” 132 being adjacent to the volume 112 of geonet. There are a plurality of geonet volumes 128 located under the dosing pipe 116. Similarly, there are plurality of “U” shaped volumes 128 of geonet located under the dosing pipe 124, with each volume 128 having the bottom of the “U” 132 located adjacent to the geonet volume 112. The irregularly coiled stringy structure 44 that make up the geonet 40 are not shown in this Figure in order to simplify the Figure for better understanding. The dosing pipe 116 is configured to deliver fluid to each of the geonet volumes 128 located beneath it via perforations configured to line up with each geonet volume 128. Similarly, the dosing pipe 124 is configured to deliver fluid to each of the geonet volumes 128 located beneath it via perforations configured to line up with each geonet volume 128. The dosing pipe 120 is configured to deliver fluid to the geonet volume 112. Additionally, each of the dosing pipes 116, 120, 124 are covered with an air and water permeable sheeting (not shown in this view for ease of understanding), and each of the geonet volumes 112, and 128 are enclosed in an air and water permeable sheeting (not shown in this view for ease of understanding). In one embodiment, the width (w) of the conduit 108 may be about 3 feet, and length (l) of the channel may be about 8 feet, and the height (h) of the channel may be about 1 foot. It should be noted that the figures are not necessarily proportional or to scale. The conduit may be modified to be up to 5 feet in height (h), 10 feet wide (w), and of unlimited length (l). In another embodiment, the dosing pipes 116, 120, 124 may be replaced with a low aspect ratio conduit 20, comprising a low aspect ratio channel 24, with the low aspect ratio channel 24 adjacent to each of the “U” shaped geonet volumes 128. Thus water may be applied to the dosing pipe 22, and the low aspect ratio channel 24 would provide fluid communication to all the “U” shaped geonet volumes 128. Additionally, in another embodiment, the “U” shaped volumes may be constructed out of pieces about half as long, that simply lay adjacent to the geonet 40. The conduit 108 comprises channels that are coincident with the ‘U” shaped volumes 128 and rectangular volume 112. FIG. 17 shows a top view of the high aspect conduit 108 from FIG. 16. The irregularly coiled stringy structures 44 that make up the geonet 40 are not shown in this Figure in order to simplify the Figure for better understanding. Additionally, each of the dosing pipes 116, 120, 124 are covered with an air and water permeable sheeting (not shown in this view for ease of understanding), and each of the geonet volumes 112, and 128 are enclosed in an air and water permeable sheeting (not shown in this view for ease of understanding). FIG. 18 is a front cross-sectional view of the conduit 108 from FIGS. 16 and 17, through the plane 18-18 (shown in FIG. 17). In this view, each of the perforated dosing pipes 116, 120, 124 are shown wrapped in an air and water permeable sheeting 48. The generally rectangular volume 112 is shown with the irregularly coiled stringy structure 44 that makes up the geonet 40. The “U” shaped volumes 128 are shown also with the irregularly coiled stringy structure 44 that makes up the geonet 40 visible. The volumes 112, 128, are enclosed in an air and water permeable sheeting 48. The wastewater conduits shown in FIGS. 13-18 may be easily installed if a roll of geonet is used. Geonet is often sold in rolls of various sizes, from about half a foot in width, and about half an inch in thickness, and up to lengths of about 450 feet or more. Thus, one method of installing a wastewater conduit as shown in FIG. 13, is to obtain a geonet of about one inch in thickness, and about 1 foot in width, and about 8 feet in length. The 8 foot geonet is covered in an air permeable sheeting on all sides except for the top of the geonet which will be adjacent to a perforated dosing pipe. An 8 foot in length dosing pipe of about 1″ outer diameter may then be attached to the 8 foot geonet by wrapping the pipe with an air permeable sheeting and attaching that air permeable sheeting to the sheeting around the geonet. A trench may be dug about 8-12 inches deep and 8 feet long and about 2 inches wide. The dosing pipe and geonet may then be placed in trench and the trench filled in with soil, sand, or whatever material is suitable. The dosing pipe may then be coupled to the outflow of wastewater from the residence or business. Conduits may also be about 12 inches high by about 1 inch wide, with length varying depending on the size of land available. It should be noted that “U” shaped volumes may be easily formed by simply bending the geonet into the desired shape. The dosing pipe 22 may be configured to allow fluid such as waste water to flow into the geonet in a manner similar to that described in U.S. Pat. No. 6,959,882 issued on Nov. 1, 2005 to David A. Potts and entitled “Watering and aerating soil with a drip line”, wherein instead of flowing the fluid into soil, the fluid is flowed into the geonet. U.S. Pat. No. 6,959,882 is fully incorporated in its entirety by reference herein. FIG. 19 is a top view of the disclosed high aspect ratio conduit 136. This high aspect ratio conduit 136 comprises a perforated dosing pipe 22, a geonet layer 140 laying below and in fluid communication with the pipe 22. The geonet layer 140 comprises a geonet 40 that is about 4 inches in thickness “t”, as shown in FIG. 20. It should be noted that in other embodiments, the geonet layer 140 may be replaced with pea stone, crushed stone, plastic pieces or other granular or permeable media. Laying below the geonet layer 140 are a plurality of geonet volumes 144. Each geonet volume 144 comprises a volume of geonet 40 enclosed in an air and water permeable sheeting 48. Please note that the coiled stringy structures of the geonet 40 are not visible due to the air and water permeable sheeting 48. The geonet layer 140 is shown partially cut-away to reveal the geonet volumes 144 below. The width “w” of each geonet volume may be about 1 inch. The distance “B” between each geonet volume may be about 2 inches and up to about 10 feet or more apart. In this embodiment the dosing pipe may have internal diameter of about 4 inches. The depth “D” of each geonet volume 144 may be about 12 inches, see FIG. 20. FIG. 20 shows a side view of the disclosed high aspect ratio conduit 136. The thickness “t” of the geonet layer 140, the depth “D” of each geonet volume is shown, the width “w” of each geonet volume, and the distance “B” between each geonet volume 144 are all shown. The perforations 31 in the dosing pipe 22 may be generally aligned with the geonet volumes 144. However, in other embodiments, the perforations 31 need not be aligned with the geonet volumes 144. FIG. 21 is a perspective view of a conduit form 148 and conduit form cover 152. The conduit form 148 is configured to help install a high aspect ratio conduit 136 easily and quickly in the ground. With certain soils, such as cohesive soils, simple trenching equipment may be sufficient. The top and bottom 156 of the conduit form 152 are open. FIG. 22 is top view of the form 148, and FIG. 23 is a side view of the form 148. Referring now to FIGS. 22 and 23, a volume 161 is defined by first end wall 180, a front wall 220, a rear wall 216, a first interior wall 188, an imaginary plane 184 through the top surface of the form 148, and an imaginary plane 212 through the bottom of the interior walls 188, 192, 196, 200, and 204. A volume 162 is defined by interior wall 192, the front wall 220, the rear wall 216, an interior wall 196, the imaginary plane 184 through the top surface of the form 148, and the imaginary plane 212 through the bottom of the interior walls 188, 192, 196, 200, and 204. A volume 163 is defined by interior wall 200, the front wall 220, the rear wall 216, the interior wall 204, the imaginary plane 184 through the top surface of the form 148, and the imaginary plane 212 through the bottom of the interior walls 188, 192, 196, 200, and 204. Volumes 161, 162, 163 are each configured to contain a geonet volume 140. A volume 165 is defined by the interior wall 188, the front wall 220, the rear wall 216, the interior wall 192, the imaginary plane 184 through the top surface of the form 148, and an imaginary plane 216 through the bottom surface 217 of the form 148. A volume 166 is defined by the interior wall 196, the front wall 220, the rear wall 216, the interior wall 200, the imaginary plane 184 through the top surface of the form 148, and the imaginary plane 216 through the bottom surface 217 of the form 148. A volume 167 is defined by the interior wall 204, the front wall 220, the rear wall 216, and a second end wall 208, the imaginary plane 184 through the top surface of the form 148, and the imaginary plane 216 through the bottom surface 217 of the form 148. The volumes 165, 166, and 167 are configured to hold the soil or sand or any other suitable granular material that will occupy the volumes between the geonet volumes 140. It should be noted that the geonet can be substituted with other granular material and placed in volume 165, 166 and 167. In one embodiment, the height “D1” of the volumes 165, 166 and 167 is greater than the height “D2” of the volumes 161, 162, and 163. The form 148 may have a plurality of lifting members 168. The lifting members may be lifting hoops as shown in FIG. 21, or any other lifting mechanism configured to allow one to lift the form 148 out of the ground. The volumes 161, 162, and 163 have a width that is generally “w”, which is generally the same as the width of each geonet volume described with respect to FIGS. 19 and 20. Similarly, the volumes 165, 166, and 167 have a width that is generally “B,” which is generally the same as the width of the granular material, such as soil or sand, which occupies the volumes between the geonet volumes 144. The volumes 165, 166, 167 between the geonet volumes will be referred to herein as granular volumes. Additional forms and trench shoring devices can be utilized to maintain the integrity of the excavation and to place additional sand, soil or media around the form. In other embodiments of the disclosed forms, D1 may be about equal to D2, and the interior walls 188, 192, 196, 200, 204 may extend to the imaginary plane 216. The form has a plurality of interior walls, 188, 192, 196, 200, 204, and for exterior walls: the first end wall 180, the front wall 220, the rear wall 216, and the second end wall 208. The form may be used without a cover in some instances. The disclosed may comprise several pieces that are welded or otherwise permanently attached to each other in order to make one form. However, in another embodiment, the form may comprise several pieces (e.g. the walls) that may be fitted together using a tongue and groove attaching means, or other interlocking mechanisms. In this embodiment, the forms can may be easily transported as a stack of flat walls, and fitted together at the job site. Referring back to FIG. 21, the form cover 152 has openings 172 configured to lie directly over the volumes 165, 166 and 167. The form cover 152 also has covered portions 173 configured to lie over the volumes 161, 162 and 163. Additionally, the form cover 152 has a plurality of lifting members 176. The lifting members may be lifting hoops as shown in FIG. 21, or any other lifting mechanism configured to allow one to lift the form cover 152 off of the form 148. One method of using the form 148 and cover 152 to make a high aspect ratio conduit is as follows: dig a trench in the ground that can accommodate the form 148 and cover 152, fill the volumes 165, 166, and 167 with soil, or sand. Once filled, remove the cover 152, fill the openings volumes 161, 162 and 163 with a geonet. Finally, remove the form 148. At this point, a geonet layer 140 is placed on top of the geonet volumes and the sand/soil volumes. Next a perforated dosing pipe 22 is laid on top of the geonet layer 140 and covered with a geotextile fabric or other material. In another embodiment the dosing pipe may be placed so that a portion of the dosing pipe lies within the geonet volumes and the sand/soil volumes. Then, a layer of soil or sand is placed over the high aspect ratio conduit. Although three volumes 161, 162, 163 and three granular volumes 165, 166, 167 are shown, more or fewer volumes may be used depending on how many geonet volumes 144 and granular volumes are needed for a particular high aspect ratio conduit. Of course, the form cover 152 will be configured to have openings 172 corresponding to the granular volumes. The form cover may also incorporate a funnel, hopper, etc. into the device to improve construction efficiencies. FIGS. 25 through 27 show top views of three different form shapes, each of which has an open top and open bottom. FIG. 25 shows a form 400. The form 400 is empty in the interior 410, to allow the form to be filled with the desired aggregate material. Aggregate material may include, but is not limited to: man made granular material, naturally occurring granular material, and geonet. This form may be referred to a repeating “I” form, due the form appearing to be repeating letter I's standing on each other (or it may be referred to as repeating sideways U shapes). The interior 410 may be referred to as a geonet volume. The geonet volume 410 may comprise a central volume 411 with fingers 412 extending generally perpendicularly from the central volume. FIG. 26 shows a form 420. The form 420 is also empty in the interior 430, to allow the form to be filled with the desired aggregate material. This form 420 may be referred to as an accordion shaped form. The interior 430 may be referred to as a geonet volume. FIG. 27 shows a form 440. The form 440 is empty in the interior 450, to allow the form to be filled with the desired aggregate material. The interior 450 may be referred to as a geonet volume. This form 440 may be referred to as a box shape form. The forms have a length L. The length L may vary from 4 feet to 10 long in some preferred embodiments. In other uses, the forms may be even longer. The height of the forms (the dimension that goes into the paper that FIGS. 25-27 are shown on) may vary from 12 inches to about 6 feet tall for some preferred embodiments. In other uses, the height may be even greater than 6 feet. These forms 410, 420, 440 may have form covers that will cover the interior of each of the forms 410, 420, 440. The forms may also have a lifting means attached to each of them. The form covers will allow one to dig a trench, place form with a cover into the trench, backfill the trench, thus surround the form with backfill, but since the cover is on the form, no backfill will enter the interior of the form. Once the trench is backfilled, the cover can be removed, and a geonet can be inserted into the form interior. Then, the form can be removed from the trench. The disclosed form allows one to maximize the infiltrative surface area of leach fields, without utilizing materials that compromise the hydraulic conductivity of the leaching system. This is accomplished with the use of a rigid form made of steel, aluminum, plastic, wood, etc. Steel is especially good. After an excavation is dug, a form is placed into the trench. The native soil or specified sand, etc. is backfilled and compacted to the specified values outside the form. Then the desired aggregate, typically gravel, crushed stone, tire chips, etc. is placed inside the form. Specially designed funnels and covers can also be utilized as shown in FIG. 21 (showing the cover). Once the form is filled to the desired level (varying heights equates to different treatment capacities, separation from groundwater, etc.) the form is pulled out of the ground, typically using excavation equipment. In certain cases, vibrating or shaking the form is desirable. This can be achieved by simply banging on the side of the form with a hammer or with a mechanical vibrator, such as is used on dump truck bodies. This vibration also helps to minimize settling of the materials used in construction the leach field lateral line. Once the form is pulled out, a wastewater distribution pipe (such as, but not limited to a perforated pipe) may be placed on top or connected within to the leach field. In some cases, multiple forms that interlock with tong and groove type joints are utilized to advance a longer leach field lateral line as is shown in my high aspect ratio system. In addition to having a form interlock with one or more other forms, the forms may comprise separable walls that may attach via a tongue and groove attaching means in order to make the form. If one form is being used, a shoring board may be utilized to shore up the construction materials from falling, or slumping into the excavation when the form is pulled out and moved ahead. Forms may also be utilized that butt together. Steel is a desirable construction material for these forms due to the high strength and weight, which helps prevent the form from moving when being filled inside and around the perimeter. It should be obvious to one of ordinary skill in the art, that the form must be strong enough to withstand the weight of the backfill during the installation process. Thus, the use of a form allows one to keep different materials separate, as is desirable when constructing a leach field and or trench systems in elevated sand mounds. An example would be a rectangular form to keep a discrete interface between sand and stone. This is often problematic when constructing a system in a select fill (often sand) material. The form allows trench walls that are at a 90 degree angle, as opposed to walls that match the angle of repose of the sand in which the gravel lateral is being constructed. FIG. 28 shows a flowchart describing one disclosed method of using the disclosed forms. At act 600 a user or installer digs a trench. At act 604, the user places a form in the trench. The form, may have a cover attached during this step, or the cover may be placed on the form after the form is in the trench. At act 608, the trench is backfilled, allowing backfill to fill any granular volumes in the form (some forms may not have granular volumes, see FIGS. 25-27). Because the cover is on the form, backfill will not enter the geonet volume. At act 612 the form cover is removed. At act 616 geonet is inserted into the geonet volume(s). Crushed stone, or plastic pieces or other granular or permeable media may be used as a substitute for geonet. At act 620, the form is removed from the trench, leaving behind the geonet located within the backfill. At act 624 a distribution pipe is placed over the geonet and backfill (which is now the leach field). FIG. 24 shows a cross-sectional view of another embodiment of the disclosed conduit. In this figure, the high aspect ratio conduit 224 comprise a plurality of channels 228, 232, 230. Each channel is a generally rectangular volume, within which is a geonet 40. The irregularly coiled stringy structure 44 that makes up the geonet 40 is shown in this view. Each geonet 40 is enclosed in an air and water permeable sheeting 48. One or more dosing pipes 22 will be in fluid communication with the channels. A low aspect ratio conduit can be substituted for dosing pipe 22. Additionally, there are a plurality of pairs of anchors 240, attached to the permeable sheeting on adjacent channels. Each pair of anchors 240 is attached to a line 244. The anchors 240 and lines 244 are configured to allow the channels 228, 232, 230 to be spaced a predetermined amount in the ground to facilitate the backfilling of the volumes between adjacent channels 228, 232, 230 with sand, or other backfill. However, since the lines 244 are attached to adjacent channels, the channels 228, 232, 230 may be collapsed (i.e. set close together) for shipping. The anchors 240 may be any suitable attaching device, including but not limited to staples, plastic staples, washers. The lines 244 may be any suitable line, including but not limited to nylon line, rope, twine, chain link. To install the disclosed conduit 224, the channels 228, 232, 230 are expanded to the maximum separation distance between them, given the length of the lines 244. Stakes are typically driven into the soil to prevent the conduits from moving around in the trench and to keep them at the desired distance apart as determined by the lines 244. Although three channels 228, 232, 230 are shown in the embodiment, one of ordinary skill will understand that this conduit may be modified to have fewer channels, or more channels, such as 10 or more channels. In use, the disclosed high aspect ratio channels will be periodically dosed with wastewater so as to fill conduit and displace gas. As the wastewater drains out of the high aspect ratio channels, air is pulled in “behind” the wastewater. Additionally, the system may be configured to fully drain the high aspect ratio channels between doses. This helps maintain aerobic conditions in the conduit and helps oxidize the sludge/biomat. Prior art devices are designed to provide storage volume for water in the channels. This storing or water in the conduit results in the persistence of anaerobic conditions at the soil interface and subsequent organic buildup and less favorable conditions for treatment. Thus, the current invention may be configured to fill about 25 to about 100% of the channel void space per dose and allowing the channel to largely drain before the next dose. Preferably, the time between dosing will be about two times the time for a dose of water to percolate into the soil. It is conceived that that will better enable the high aspect channel and recently-saturated soil near the high aspect channel to drain of water, and to refill with gas, which is in good part oxygen containing air, flowing downward through the soil and through the permeable top of the conduit. If air distribution pipes are connected to vents, the foregoing effect can be enhanced by suitable valving at the inlet end of the pipe or pipes, through the use of check valves on the vent lines, which valves will close when water is applied to the conduit. When the water percolates into the soil, it allows the check valve or similar functioning device to open and provide for the flow of air to replace an equal volume of water. With the high aspect ratio channels, the sidewalls will likely play more of a role in water draining than in the low aspect ratio conduits. Additionally, a larger water column due to the geometry of the channels will assist in the infiltration of gases into the channels as the water drains out of the channels. The disclosed high aspect ratio channels will have an infiltration area to storage volume ratio of about 9 or greater. The infiltration area to storage volume ratio is calculated as follows: for a channel that is 1 foot high, 3 inches (0.25 feet) wide, and 10 feet long, the maximum storage volume of that channel is given by 1 foot×0.25 feet×10 feet, which is 2.5 ft3. The infiltration area is given by adding together the surface areas of the left and right side of the conduit and the bottom of the conduit. The left side of the conduit is given by: 1 foot×10 feet which equals 10 ft2. The right side of the conduit is given by: 1 foot×10 feet which equals 10 ft2. The bottom of the conduit is given by 0.25 feet×10 feet which equals 2.5 ft2. Adding them together gives 22.5 ft2. The infiltration area to storage volume ratio is therefore 22.5 ft2÷2.5 ft3=9 ft−1. The distal ends of the volumes 128 and the interface of the volumes 128 and the volume 112 were ignored because we are omitting surfaces at opposing angles, and parallel surfaces closer than about 4 inches apart. The logic for this is that saturated soils can result in proximity to infiltrative surfaces so close together, and gas movement in these regions is inhibited, which may lead to less aerobic conditions that desired. The disclosed conduits will have widths greater than about ½ inch. It should be noted that the terms “first”, “second”, and “third”, and the like may be used herein to modify elements performing similar and/or analogous functions. These modifiers do not imply a spatial, sequential, or hierarchical order to the modified elements unless specifically stated. While the disclosure has been described with reference to several embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the disclosure. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the disclosure without departing from the essential scope thereof. Therefore, it is intended that the disclosure not be limited to the particular embodiments disclosed as the best mode contemplated for carrying out this disclosure, but that the disclosure will include all embodiments falling within the scope of the appended claims. | <SOH> BACKGROUND <EOH>Known leaching conduits, such as arch shape cross section molded plastic chambers, or stone filled trenches with perforated pipe, used for domestic and commercial wastewater systems provide interior void space, based on the thinking that a buffer space or flow equalization is thus provided for variations of inflow of wastewater. The sidewalls of conduits, where they interface with the surrounding soil, are also commonly conceived as providing surface area for percolation of wastewater, in addition to the bottom surface of the conduit. A familiar crushed stone filled trench, having a modest (4 inch) diameter perforated pipe running along its length may have about 50% void space. Currently, arch shape cross-section molded plastic leaching chambers have entirely open interiors, open bottoms and sloped and perforated sidewalls. A common cross section shape for each typical conduit has a width of about 30 to 36 inches and a height of about 12 to 18 inches. Thus this conduit may have from about 12 inches to about 18 inches of water depth at any one time. It has been seen that in these prior art conduits, a biomat will often form on the bottom and sides of the conduit, thereby lessening the effectiveness of the leaching conduits to properly infiltrate the wastewater into the soil. Drip irrigation lines are usually approximately one half inch in diameter and are typically buried 12 to 6 inches below grade. Leaching conduits are typically covered with 6 to 12 inches or more of soil, for several reasons. One is to protect the conduits from damage. Another is to prevent contact of humans and animals with potentially deleterious microorganisms associated with the wastewater being treated. Still another is to prevent odors. The dimensions of the conduits discussed in the preceding paragraph would lead to the fact that the bottom surface of the conduits are typically at about 24 inches or more below the soil surface. Generally, it is an aim to have aerobic treatment of the wastewater in the soil. Current thinking with prior art systems is that there is an air-soil gas interchange, so that oxygen is continuously supplied to the soil, to enable good microbiological treatment. However, the soil depths at which prior art conduits operate are disadvantaged in this respect. Since the bottom surface of the conduits are typically about 18 to 24 inches below the soil surface, the bottom surfaces of the conduits are often in an anaerobic condition since the oxygen demand exceeds the oxygen supply. One improvement with such systems is to force air serially through the conduit and soil influence zone which surrounds the conduit, as described in U.S. Pat. No. 6,485,647 to David Potts, issued on Nov. 26, 2002, and which is incorporated herein by reference in its entirety. Therefore, a wastewater system is needed that provides for greater aerobic conditions in leaching conduits, thereby allowing for greater processing of the wastewater prior and during absorption into the soil. | <SOH> SUMMARY <EOH>Numerous embodiments are provided herein. These include those directed to wastewater leaching processes, systems and articles of manufacture. Wastewater treatment processes may include providing pairs of upright infiltrative surfaces where the infiltrative surfaces may define a cross-section and may have a height to width aspect ratio between 3 and 96 as well as 3 and 96. Spacings between these pairs may be uniform. A wastewater dosing channel may also be provided, this dosing channel may have a portion that traverses at least one infiltrative surface of several of the pairs of infiltrative surfaces. This channel may be positioned and configured to dose wastewater downwardly into internal spacing of the pairs of infiltrative surfaces. When the dosing channel is connected to a supply of wastewater, wastewater may flow into pairs of infiltrative surfaces and may be aerobically treated in sand or other soil between neighboring pairs of infiltrative surfaces. A wastewater system may also be provided in embodiments. This system may include a plurality of infiltrative channels where each of the channel may be spaced apart from each other and have at least two upright infiltrative surfaces and have a height to width aspect ratio of 3 or 96 or between 3 and 96. The system may also include interstitial aerobic treatment channels comprising sand, where a first treatment channel is between a first infiltrative channel and a second infiltrative channel and a second treatment channel is between the second infiltrative channel and a third infiltrative channel. A wastewater channel traversing each of the infiltrative channels may also be included. In embodiments, a portion of the upper boundary of each of the three infiltrative channels and an upper boundary of each of the two treatment channels may not be directly underlying any section of the wastewater channel above that particular channel. A wastewater system of embodiments may also include a plurality of infiltrative channels where each of the channels may be spaced apart from each other, wrapped in filter fabric, and having at least two upright infiltrative surfaces. The channels may also have a height, a width, and a length where the height to width aspect ratio of each of the infiltrative channel is 3 or 96 or is between 3 and 96. This system may also include separation spacers configured to provide a spacing between the first infiltrative channel and the second infiltrative channel; and further configured to provide a spacing between the second infiltrative channel and the third infiltrative channel. A wastewater channel traversing each of the three infiltrative channels may also be provided. This channel may traverse no more than a portion of an upper boundary of each of the three infiltrative channels and where at least a portion of the upper boundary of each of the three infiltrative channels and an upper boundary of two treatment channels is not directly underlying any section of the wastewater channel above that particular channel. System embodiments may also include first, second, and third, infiltrative channels, where each of the three infiltrative channels may be spaced apart from each other, where each of the three infiltrative channels may have at least two upright infiltrative surfaces, and where each of the three infiltrative channels may have a height, a width, and a length wherein the height to width aspect ratio of each of the infiltrative channel is 3 or 96 or is between 3 and 96, Separation spacers may be employed in embodiments. These spacers may be employed such that a first separation spacer is positioned between a first and second infiltrative channel and a second separation spacer is positioned between a second and a third infiltrative channel. In this and in other system embodiments, a wastewater channel may traverse three infiltrative channels, wherein the wastewater channel traverses no more than a portion of an upper boundary of each of the three infiltrative channels and where at least a portion of the upper boundary of each of the three infiltrative channels and an upper boundary of each of two treatment channels is not directly underlying any section of the wastewater channel above that particular channel. Other configurations and combinations may also be employed where features may be modified or combined in various ways consistent with the teachings of this disclosure. | C02F3046 | 20171027 | 20180215 | 97920.0 | C02F304 | 1 | SINGH, SUNIL | WASTEWATER LEACHING SYSTEM | SMALL | 1 | CONT-ACCEPTED | C02F | 2,017 |
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15,796,225 | PENDING | METHOD AND APPARATUS FOR POSITIONING HEATING ELEMENTS | An underlayment system is provided that includes a plurality of protrusions that extend from a common base member. The protrusions and base member can include an opening therethrough that allows for subsequent layers of material, such as adhesive, to interact and bond to each other. The protrusions are arranged in such a way to contain a wire, string, or heating element, within a receiving area. The arrangement of the protrusions allow for routing of the wire, string, or heating element in a variety of angles, bends, and other routing layouts. | 1. A floor underlayment comprising: a base layer having a top side and a bottom side; a pad layer attached to the bottom side; a plurality of protrusions extending to a first height above the top side, each protrusion comprising: a top surface at the first height; an inner wall sloping from the top surface to the top side of the base layer, the inner wall sloped in a first direction; and an outer wall extending from the top surface to the top side of the base layer, at least a portion of the outer wall sloped in the first direction, wherein the sloped inner wall and the outer wall are curved in a horizontal plane. 2. The floor underlayment of claim 1, wherein the pad layer comprises a sound dampening material. 3. The floor underlayment of claim 1, wherein the pad layer comprises a heat reflective material. 4. The floor underlayment of claim 3, wherein the heat reflective material is aluminum foil. 5. The floor underlayment of claim 1, wherein the pad layer comprises an insulative material. 6. The floor underlayment of claim 5, wherein the insulative material is polystyrene. 7. The floor underlayment of claim 5, wherein the insulative material is fleece. 8. The floor underlayment of claim 5, wherein the insulative material is wool. 9. The floor underlayment of claim 1, wherein the pad layer comprises a non-woven fabric. 10. The floor underlayment of claim 1, wherein the pad layer comprises a vapor barrier. 11. The floor underlayment of claim 1, wherein the pad layer comprises a waterproof material. 12. An underlayment comprising: a plurality of routing hubs extending upward from a top side of a base, each routing hub comprising symmetrical quadrants, each symmetrical quadrant comprising: a curved outer wall; a curved inner wall; a top surface connecting the curved outer wall to the curved inner wall, the top surface having a variable width, wherein at least a portion of the curved outer wall slopes underneath the top surface; and a pad layer attached to a bottom side of the base. 13. The underlayment of claim 12, wherein the pad layer comprises a heat reflective material. 14. The underlayment of claim 13, wherein the heat reflective material is aluminum foil. 15. The underlayment of claim 12, wherein the pad layer comprises an insulative material. 16. The underlayment of claim 15, wherein the insulative material is polystyrene. 17. The underlayment of claim 15, wherein the insulative material is fleece. 18. The underlayment of claim 15, wherein the insulative material is wool. 19. The underlayment of claim 12, wherein the pad layer comprises a non-woven fabric. 20. A floor underlayment comprising: a base layer having an upper side and a lower side opposite the upper side; a pad layer attached to the lower side, the pad layer comprising a non-woven fabric; a plurality of raised features extending upwardly from the upper side, each of the plurality of raised features comprising a contact surface supported on opposite sides by an inner sidewall and an outer sidewall, the inner sidewall defining a circular shape at the base layer and at least a portion of the outer sidewall sloping underneath the contact surface, wherein the plurality of raised features are arranged on the base layer to provide a plurality of routing options for a heating element. | CROSS REFERENCE TO RELATED APPLICATIONS The present application is a continuation-in-part of U.S. patent application Ser. No. 15/648,152, filed Jul. 12, 2017, which is a continuation of U.S. patent application Ser. No. 15/260,848, filed Sep. 9, 2016, now U.S. Pat. No. 9,777,931, which is a divisional of U.S. patent application Ser. No. 14/829,108, filed Aug. 18, 2015, now U.S. Pat. No. 9,625,163, which claims the benefit of U.S. Provisional Patent Application Ser. No. 62/038,733, filed Aug. 18, 2014, all of which are fully incorporated by reference herein. FIELD OF THE INVENTION Embodiments of the present invention are generally related to underlayments associated with radiant floor or wall heating systems. BACKGROUND In-floor and in-wall heating and cooling is well known that utilizes heat conduction and radiant heat, for example, for indoor climate control rather than forced air heating that relies on convection. The heat is usually generated by a series of pipes that circulate heated water or by electric cable, mesh, or film that provide heat when a current is applied thereto. In-floor radiant heating technology is used commonly in homes and businesses today. Electrical floor heating systems have very low installation costs and are well suited for kitchens, bathrooms, or in rooms that require additional heat, such as basements. One advantage of electric floor heating is the height of installation. For example, floor buildup can be as little as about one millimeter as the electric cables are usually associated with a specialized installation board or directly onto the sub floor. Electric underfloor heating is also installed very quickly, usually taking a half a day to a day depending on the size of the area to be heated. In addition, warm up times are generally decreased because the cables are installed approximate to the finished flooring, e.g., tile, wherein direct connection is made with the heat source rather than a stored water heater as in fluid-based systems. Electric systems are offered in several different forms, such as those that utilize a long continuous length cable or those that employ a mat with embedded heating elements. In order to maximize heat transfer, a bronze screen or carbon film heating element may be also used. Carbon film systems are normally installed under the wire and onto a thin insulation underlay to reduce thermal loss to the sub floor. Vinyls, carpets, and other soft floor finishes can be heated using carbon film elements or bronze screen elements. Another type of in-floor heating system is based on the circulation of hot water, i.e., a “hydronic” system. In a hydronic system, warm water is circulated through pipes or tubes that are incorporated into the floor and generally uses pipes from about 11/16 inch to 1 inch to circulate hot water from which the heat emanates. The size of tubes generally translates into a thicker floor, which may be undesirable. One other disadvantage of a hydronic system is that a hot water storage tank must be maintained at all times, which is less efficient than an electric floor heating system. In order to facilitate even heating of a floor, the wires must preferably be spaced at specific locations. One such system is disclosed in U.S. Patent Application Publication No. 2009/0026192 to Fuhrman (“Fuhrman”), which is incorporated by reference in its entirety herein. Fuhrman discloses a mat with a plurality of studs extending therefrom that help dictate the location of the wires. The mat with associated studs is placed over a sub floor with a layer of adhesive therebetween. Another layer of adhesive is placed above of the studs. The studs also guide the finishers to form a correct floor thickness. The studs thus provide a location for interweaving the wire or wires that are used in the heating system. The wire of Fuhrman, however, is not secured between adjacent studs and still may separate therefrom, which may cause uneven heating or wire damage. Furthermore, Fuhrman discloses a continuous mat wherein subsequent layers of adhesive are not able to interact with those previously placed. SUMMARY It is with respect to the above issues and other problems that the embodiments presented herein were contemplated. In general, embodiments of the present disclosure provide methods, devices, and systems by which various elements, such as wire, heating elements, and the like, may be routed and/or contained in a flooring underlayment. In one embodiment, the underlayment may include a number of protrusions extending from a base material. The protrusions may be configured in a cluster, or array, or even as part of another protrusion, forming routing hubs. As provided herein, a wire may be routed around, through, and even around and through the routing hubs and/or protrusions. The unique shape and arrangement of the protrusions disclosed herein can provide for the efficient routing of wires in an underlayment for any shape and/or purpose. In some embodiments, the protrusion forms a geometric shape extending away from a base material surface to a contact surface (e.g., the contact surface for flooring, tile, etc.). This extension between the base material surface and the contact surface defines the overall protrusion height. The protrusion may include a number of sides extending from the base material to the contact surface. As can be appreciated, at least one of the sides of the protrusion may include a surface configured to receive a wire. This receiving surface can be concave, convex, arcuate, linear, etc., and/or combinations thereof. Additionally or alternatively, the surface may follow, or contour, the geometric shape of the protrusion. It is an aspect of the present disclosure that at least two protrusions are arranged adjacent to one another on an underlayment base material. In one embodiment, the protrusions may be arranged such that the receiving surface of a first protrusion is offset from and facing the receiving surface of a second protrusion. The distance of the offset and the receiving surfaces can form a receiving cavity configured to receive a wire, heating element, or other element. For example, an underlayment may include a number of protrusions arranged about an array axis to form a routing hub. Where four protrusions make up a routing hub, there may exist heating element receiving cavities disposed between each protrusion. Additionally or alternatively, the underlayment may include a number of routing hubs equally-spaced along a first linear direction and/or a second linear direction to form a matrix of routing hubs. In this case, additional heating element receiving cavities may be disposed between each routing hub. As can be appreciated, the matrix of routing hubs and the array of protrusions allow for heating elements to be routed in the underlayment according to any configuration of routing curves, angles, and/or lines. In some embodiments, the protrusions, base material, and/or other features of the underlayment may be formed into a shape from at least one material. Examples of forming can include, but are not limited to, thermoforming, thermo-molding, injection molding, casting, molding, rotational molding, reaction injection, blow molding, vacuum forming, twin sheet forming, compression molding, machining, 3D printing, etc., and/or combinations thereof The protrusions, base material, and/or other features of the underlayment may include a number of cutouts, or holes. In some embodiments, the cutouts can extend at least partially into the protrusion, base material, and/or the underlayment. In one embodiment, one or more of the cutouts may completely pass through the underlayment. In any event, the cutouts may be configured to receive a mating material. For instance, the cutouts may be configured to receive adhesive, epoxy, grout, cement, glue, plastic, or other material capable of flowing at least partially into the cutouts. These cutouts can provide a number of surfaces on the underlayment to which material can adhere, or key. Additionally or alternatively, these cutouts can increase the strength of the underlayment by providing a structural skeleton, around which material can flow and cure in addition to providing a pathway for airflow, thereby enabling the utilization of a modified thinset, which requires air for curing. The cutouts further provide a passageway for moisture to flow out of the subfloor. In one embodiment, the cutouts may be provided via the forming process of the underlayment. In another embodiment, the cutouts may be made via a cutting operation performed prior to the forming process. In yet another embodiment, the cutouts may be made via a cutting operation performed subsequent to the forming process. The underlayment may include areas in and/or between the routing hubs that are configured to receive material. For instance, the areas may be configured to receive adhesive, epoxy, grout, cement, glue, plastic, or other material capable of flowing at least partially into the areas. These areas can provide a number of surfaces on the underlayment to which material can adhere, or key. Additionally or alternatively, these areas can increase the strength of the underlayment by providing a structural skeleton, around which material can flow and cure. In some embodiments, the underlayment may include a pad layer. The pad layer may include a sound dampening material; a heat reflective material, such as aluminum foil; an insulative material, such as polystyrene, fleece, or wool; a porous substrate; a vapor barrier; a waterproof material; an energy reflective material; etc., and/or combinations thereof. Examples of pad layers can include, but are in no way limited to, non-woven fabrics or materials, foil, cork, rubber, plastic, concrete, wood, organic materials, inorganic materials, composites, compounds, etc., and/or combinations thereof. The pad layer may be attached to the base material via adhesive, thermal bonding, welding, mechanical attachment, etc., and/or combinations thereof. As can be appreciated, the pad layer may include adhesive on the side opposite the base material side for affixing to a surface, such as a subfloor, floor, etc. In one embodiment, the pad layer may be configured to receive adhesive for affixing to a surface. The phrases “at least one”, “one or more”, and “and/or” are open-ended expressions that are both conjunctive and disjunctive in operation. For example, each of the expressions “at least one of A, B and C”, “at least one of A, B, or C”, “one or more of A, B, and C”, “one or more of A, B, or C” and “A, B, and/or C” means A alone, B alone, C alone, A and B together, A and C together, B and C together, or A, B and C together. When each one of A, B, and C in the above expressions refers to an element, such as X, Y, and Z, or class of elements, such as X1-Xn, Y1-Ym, and Z1-Z0, the phrase is intended to refer to a single element selected from X, Y, and Z, a combination of elements selected from the same class (e.g., X1 and X2) as well as a combination of elements selected from two or more classes (e.g., Y1 and Z0). The term “a” or “an” entity refers to one or more of that entity. As such, the terms “a” (or “an”), “one or more” and “at least one” can be used interchangeably herein. It is also to be noted that the terms “comprising”, “including”, and “having” can be used interchangeably. The term “means” as used herein shall be given its broadest possible interpretation in accordance with 35 U.S.C., Section 112, Paragraph 6. Accordingly, a claim incorporating the term “means” shall cover all structures, materials, or acts set forth herein, and all of the equivalents thereof. Further, the structures, materials or acts and the equivalents thereof shall include all those described in the summary of the invention, brief description of the drawings, detailed description, abstract, and claims themselves. It should be understood that every maximum numerical limitation given throughout this disclosure is deemed to include each and every lower numerical limitation as an alternative, as if such lower numerical limitations were expressly written herein. Every minimum numerical limitation given throughout this disclosure is deemed to include each and every higher numerical limitation as an alternative, as if such higher numerical limitations were expressly written herein. Every numerical range given throughout this disclosure is deemed to include each and every narrower numerical range that falls within such broader numerical range, as if such narrower numerical ranges were all expressly written herein. The preceding is a simplified summary of the disclosure to provide an understanding of some aspects of the disclosure. This summary is neither an extensive nor exhaustive overview of the disclosure and its various aspects, embodiments, and configurations. It is intended neither to identify key or critical elements of the disclosure nor to delineate the scope of the disclosure but to present selected concepts of the disclosure in a simplified form as an introduction to the more detailed description presented below. As will be appreciated, other aspects, embodiments, and configurations of the disclosure are possible utilizing, alone or in combination, one or more of the features set forth above or described in detail below. BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings are incorporated into and form a part of the specification to illustrate several examples of the present disclosure. These drawings, together with the description, explain the principles of the disclosure. The drawings simply illustrate preferred and alternative examples of how the disclosure can be made and used and are not to be construed as limiting the disclosure to only the illustrated and described examples. Further features and advantages will become apparent from the following, more detailed, description of the various aspects, embodiments, and configurations of the disclosure, as illustrated by the drawings referenced below. FIG. 1 shows a plan view of an underlayment section in accordance with embodiments of the present disclosure; FIG. 2 shows a cross-sectional view of an area of the underlayment taken along line A-A shown in FIG. 1; FIG. 3 shows a detail cross-sectional view of an area of the underlayment in accordance with embodiments of the present disclosure; FIG. 4 shows a detail plan view of a routing hub of the underlayment in accordance with embodiments of the present disclosure; FIG. 5 shows a plan view of routing hubs of an underlayment in accordance with a first embodiment of the present disclosure; FIG. 6 shows a plan view of routing hubs of an underlayment in accordance with a second embodiment of the present disclosure; FIG. 7 shows a detail cross-sectional view of a first embodiment of the routing hubs taken along line D-D shown in FIG. 6; and FIG. 8 shows a detail cross-sectional view of a second embodiment of the routing hubs taken along line D-D shown in FIG. 6. DETAILED DESCRIPTION Before any embodiments of the disclosure are explained in detail, it is to be understood that the disclosure is not limited in its application to the details of construction and the arrangement of components set forth in the following description or illustrated in the following drawings. The disclosure is capable of other embodiments and of being practiced or of being carried out in various ways. Also, it is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of “including,” “comprising,” or “having” and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items. FIG. 1 shows a plan view of an underlayment section 1 in accordance with embodiments of the present disclosure. The underlayment section 1 includes a number of routing hubs 2, comprising four protrusions 2a arranged in an equally-spaced circular array about an array axis 2b, in a matrix configuration. The matrix is configured in the form of an eight row by twelve column matrix of routing hubs 2. The matrix provides heating element receiving cavities 3 in the X-direction, Y-direction, and in directions approximately 45 degrees to the X-direction and/or the Y-direction. A sample routing 4 of the heating element 5 is shown in FIG. 1. In particular, the heating element section 5 shown runs along the Y-direction between the first and second columns of routing hubs 2, proceeds around the routing hub 2 in the first row and second column (2, 8) and along the negative Y-direction between the second and third columns to the (3, 1) routing hub 2, proceeds along the Y-direction between the third and fourth columns until about the (3, 4) routing hub 2, and then proceeds diagonally through the heating element receiving cavities 3 in the (4, 5), (5, 6), (6, 7), and (7, 8) routing hubs 2, and so on. FIG. 2 shows a cross-sectional view of an area of the underlayment 1 taken along line A-A. In some embodiments, one or more of the protrusions 2a can extend from the base material surface 6 to a contact surface 7. The contact surface 7 may be configured to support tile, flooring, or other material. The distance from the base material 6 to the contact surface 7 is called the protrusion height 7a. The thickness of the base material 6 is called the base thickness 6a. In some embodiments, the protrusions 2a may be formed from the base material 6, and as such, may have a wall thickness approximately equal to that of the base thickness 6a. FIG. 3 shows a detail cross-sectional view of an area of the underlayment 1 in accordance with embodiments of the present disclosure. In one embodiment, the areas adjacent to each protrusion 2a can form a heating element receiving cavity 3. Each heating element receiving cavity 3 can include an interference fit 8, or contained area, to hold a heating element 5 or wire in place. In some cases, the heating element 5 may be inserted into the heating element receiving cavity 3 with a predetermined amount of force required to part (e.g., elastically deform, plastically deform, flex, and/or deflect, etc.) at least one of the receiving surfaces 9 of the cavity. In one embodiment, when the heating element 5 is inserted into the heating element receiving cavity 3 the at least one of the receiving surfaces 9 may return to an original position thereby closing the heating element receiving cavity 3 and containing the heating element 5. FIG. 4 shows a detail plan view of a routing hub 2 of the underlayment 1 in accordance with embodiments of the present disclosure. The heating element receiving cavities 3 are shown disposed between protrusions 2a and/or routing hubs 2. In some embodiments, one or more of the heating element receiving cavities 3 can be configured differently from another heating element receiving cavity 3. For instance, several heating element receiving cavities 3 may be configured to provide a frictional fit for holding a heating element 5, while other heating element receiving cavities 3 may be configured to merely contain a heating element 5. In any event, the underlayment 1 can include one or more configurations of heating element receiving cavity 3. FIG. 5 shows a plan view of routing hubs 2 of an underlayment 1 in accordance with a first embodiment of the present disclosure. As described above, the protrusions 2a, base material 6, and/or other features of the underlayment 1 may include a number of cutouts 10, or holes. In some embodiments, the cutouts 10 can extend at least partially into the protrusion 2a, base material 6, and/or the underlayment 1. In some embodiments, the cutouts 10 are shown as extending at least partially into at least one side of at least one protrusion 2a. FIG. 6 shows a plan view of routing hubs 2 of an underlayment 1 in accordance with a second embodiment of the present disclosure. The underlayment 1 section includes a number of routing hubs 2, comprising four protrusions 2a arranged in an equally-spaced circular array about an array axis 2b, in a matrix configuration. A sample routing 4 of the heating element 5 is shown in FIG. 6. In particular, the heating element section 5 shown runs along the Y-direction of the first column of routing hubs 2, proceeds around the routing hub 2 in the second row and first column (1, 2) and along the negative Y-direction between the first and second columns, and then proceeds diagonally through the heating element receiving cavity 3 in the (2, 1) routing hub 2. FIG. 7 shows a detail cross-sectional view of a first embodiment of the routing hubs 2 taken along line D-D shown in FIG. 6. As shown, the heating element receiving cavity 3 in FIG. 7 includes arcuate receiving surfaces 9. The arcuate receiving surfaces 9 may be configured as concave, curvilinear, arched, and/or other shape configured to receive the heating element 5. In some cases, at least one of the arcuate receiving surfaces 9 of the routing hubs may be configured to contact the heating element receiving cavity 3. The contact may provide a frictional force that retains the heating element 5 in the underlayment 1. In some embodiments, the arcuate receiving surfaces 9 may contain the heating elements 5 in the heating element receiving cavity 5 without frictional contact. Additionally or alternatively, the underlayment 1 may include a pad layer 11. The pad layer 11 may include a sound dampening material; a heat reflective material, such as aluminum foil; an insulative material, such as polystyrene, fleece, or wool; a porous substrate; a vapor barrier; a waterproof material; an energy reflective material; etc., and/or combinations thereof. Examples of pad layers 11 can include, but are in no way limited to, non-woven fabrics or materials, foil, cork, rubber, plastic, concrete, wood, organic materials, inorganic materials, composites, compounds, etc., and/or combinations thereof. The pad layer 11 may be attached to the base material 6 via adhesive, thermal bonding, welding, mechanical attachment, etc., and/or combinations thereof. As can be appreciated, the pad layer 11 may include adhesive on the side opposite the base material 6 side for affixing to a surface, such as a subfloor, floor, etc. In one embodiment, the pad layer 11 may be configured to receive adhesive for affixing to a surface. It should be appreciated that any of the underlayment 1 embodiments as disclosed may include such a pad layer 11. In some embodiments, there may be additional pad layers 11, one above another (e.g., a stack of two, three, four, five, or more pad layers 11) for strengthening and controlling anti-fracture. This enables isolation of cracks in a substrate from traveling to the tile layer. FIG. 8 shows a detail cross-sectional view of a second embodiment of the routing hubs 2 taken along line D-D shown in FIG. 6. As shown, the heating element receiving cavity 3 in FIG. 8 includes angular receiving surfaces 9. The angular receiving surfaces 9 may be configured as a draft angle 9a, a dovetail, a “V” shape, or other channel shape configured to receive the heating element 5. In some cases, at least one of the angular receiving surfaces 9 of the routing hubs 2 may be configured to contact the heating element receiving cavity 3. The contact may provide a frictional force that retains the heating element 5 in the underlayment 1. In some embodiments, the angular receiving surfaces 9 may contain the heating elements 5 in the heating element receiving cavity 5 without frictional contact. The exemplary systems and methods of this disclosure have been described in relation to electronic shot placement detecting systems and methods. However, to avoid unnecessarily obscuring the present disclosure, the preceding description omits a number of known structures and devices. This omission is not to be construed as a limitation of the scopes of the claims. Specific details are set forth to provide an understanding of the present disclosure. It should, however, be appreciated that the present disclosure may be practiced in a variety of ways beyond the specific detail set forth herein. While the flowcharts have been discussed and illustrated in relation to a particular sequence of events, it should be appreciated that changes, additions, and omissions to this sequence can occur without materially affecting the operation of the disclosed embodiments, configuration, and aspects. A number of variations and modifications of the disclosure can be used. It would be possible to provide for some features of the disclosure without providing others. The present disclosure, in various aspects, embodiments, and/or configurations, includes components, methods, processes, systems and/or apparatus substantially as depicted and described herein, including various aspects, embodiments, configurations embodiments, subcombinations, and/or subsets thereof. Those of skill in the art will understand how to make and use the disclosed aspects, embodiments, and/or configurations after understanding the present disclosure. The present disclosure, in various aspects, embodiments, and/or configurations, includes providing devices and processes in the absence of items not depicted and/or described herein or in various aspects, embodiments, and/or configurations hereof, including in the absence of such items as may have been used in previous devices or processes, e.g., for improving performance, achieving ease and/or reducing cost of implementation. The foregoing discussion has been presented for purposes of illustration and description. The foregoing is not intended to limit the disclosure to the form or forms disclosed herein. In the foregoing Detailed Description for example, various features of the disclosure are grouped together in one or more aspects, embodiments, and/or configurations for the purpose of streamlining the disclosure. The features of the aspects, embodiments, and/or configurations of the disclosure may be combined in alternate aspects, embodiments, and/or configurations other than those discussed above. This method of disclosure is not to be interpreted as reflecting an intention that the claims require more features than are expressly recited in each claim. Rather, as the following claims reflect, inventive aspects lie in less than all features of a single foregoing disclosed aspect, embodiment, and/or configuration. Thus, the following claims are hereby incorporated into this Detailed Description, with each claim standing on its own as a separate preferred embodiment of the disclosure. Moreover, though the description has included description of one or more aspects, embodiments, and/or configurations and certain variations and modifications, other variations, combinations, and modifications are within the scope of the disclosure, e.g., as may be within the skill and knowledge of those in the art, after understanding the present disclosure. It is intended to obtain rights which include alternative aspects, embodiments, and/or configurations to the extent permitted, including alternate, interchangeable and/or equivalent structures, functions, ranges or steps to those claimed, whether or not such alternate, interchangeable and/or equivalent structures, functions, ranges or steps are disclosed herein, and without intending to publicly dedicate any patentable subject matter. | <SOH> BACKGROUND <EOH>In-floor and in-wall heating and cooling is well known that utilizes heat conduction and radiant heat, for example, for indoor climate control rather than forced air heating that relies on convection. The heat is usually generated by a series of pipes that circulate heated water or by electric cable, mesh, or film that provide heat when a current is applied thereto. In-floor radiant heating technology is used commonly in homes and businesses today. Electrical floor heating systems have very low installation costs and are well suited for kitchens, bathrooms, or in rooms that require additional heat, such as basements. One advantage of electric floor heating is the height of installation. For example, floor buildup can be as little as about one millimeter as the electric cables are usually associated with a specialized installation board or directly onto the sub floor. Electric underfloor heating is also installed very quickly, usually taking a half a day to a day depending on the size of the area to be heated. In addition, warm up times are generally decreased because the cables are installed approximate to the finished flooring, e.g., tile, wherein direct connection is made with the heat source rather than a stored water heater as in fluid-based systems. Electric systems are offered in several different forms, such as those that utilize a long continuous length cable or those that employ a mat with embedded heating elements. In order to maximize heat transfer, a bronze screen or carbon film heating element may be also used. Carbon film systems are normally installed under the wire and onto a thin insulation underlay to reduce thermal loss to the sub floor. Vinyls, carpets, and other soft floor finishes can be heated using carbon film elements or bronze screen elements. Another type of in-floor heating system is based on the circulation of hot water, i.e., a “hydronic” system. In a hydronic system, warm water is circulated through pipes or tubes that are incorporated into the floor and generally uses pipes from about 11/16 inch to 1 inch to circulate hot water from which the heat emanates. The size of tubes generally translates into a thicker floor, which may be undesirable. One other disadvantage of a hydronic system is that a hot water storage tank must be maintained at all times, which is less efficient than an electric floor heating system. In order to facilitate even heating of a floor, the wires must preferably be spaced at specific locations. One such system is disclosed in U.S. Patent Application Publication No. 2009/0026192 to Fuhrman (“Fuhrman”), which is incorporated by reference in its entirety herein. Fuhrman discloses a mat with a plurality of studs extending therefrom that help dictate the location of the wires. The mat with associated studs is placed over a sub floor with a layer of adhesive therebetween. Another layer of adhesive is placed above of the studs. The studs also guide the finishers to form a correct floor thickness. The studs thus provide a location for interweaving the wire or wires that are used in the heating system. The wire of Fuhrman, however, is not secured between adjacent studs and still may separate therefrom, which may cause uneven heating or wire damage. Furthermore, Fuhrman discloses a continuous mat wherein subsequent layers of adhesive are not able to interact with those previously placed. | <SOH> SUMMARY <EOH>It is with respect to the above issues and other problems that the embodiments presented herein were contemplated. In general, embodiments of the present disclosure provide methods, devices, and systems by which various elements, such as wire, heating elements, and the like, may be routed and/or contained in a flooring underlayment. In one embodiment, the underlayment may include a number of protrusions extending from a base material. The protrusions may be configured in a cluster, or array, or even as part of another protrusion, forming routing hubs. As provided herein, a wire may be routed around, through, and even around and through the routing hubs and/or protrusions. The unique shape and arrangement of the protrusions disclosed herein can provide for the efficient routing of wires in an underlayment for any shape and/or purpose. In some embodiments, the protrusion forms a geometric shape extending away from a base material surface to a contact surface (e.g., the contact surface for flooring, tile, etc.). This extension between the base material surface and the contact surface defines the overall protrusion height. The protrusion may include a number of sides extending from the base material to the contact surface. As can be appreciated, at least one of the sides of the protrusion may include a surface configured to receive a wire. This receiving surface can be concave, convex, arcuate, linear, etc., and/or combinations thereof. Additionally or alternatively, the surface may follow, or contour, the geometric shape of the protrusion. It is an aspect of the present disclosure that at least two protrusions are arranged adjacent to one another on an underlayment base material. In one embodiment, the protrusions may be arranged such that the receiving surface of a first protrusion is offset from and facing the receiving surface of a second protrusion. The distance of the offset and the receiving surfaces can form a receiving cavity configured to receive a wire, heating element, or other element. For example, an underlayment may include a number of protrusions arranged about an array axis to form a routing hub. Where four protrusions make up a routing hub, there may exist heating element receiving cavities disposed between each protrusion. Additionally or alternatively, the underlayment may include a number of routing hubs equally-spaced along a first linear direction and/or a second linear direction to form a matrix of routing hubs. In this case, additional heating element receiving cavities may be disposed between each routing hub. As can be appreciated, the matrix of routing hubs and the array of protrusions allow for heating elements to be routed in the underlayment according to any configuration of routing curves, angles, and/or lines. In some embodiments, the protrusions, base material, and/or other features of the underlayment may be formed into a shape from at least one material. Examples of forming can include, but are not limited to, thermoforming, thermo-molding, injection molding, casting, molding, rotational molding, reaction injection, blow molding, vacuum forming, twin sheet forming, compression molding, machining, 3D printing, etc., and/or combinations thereof The protrusions, base material, and/or other features of the underlayment may include a number of cutouts, or holes. In some embodiments, the cutouts can extend at least partially into the protrusion, base material, and/or the underlayment. In one embodiment, one or more of the cutouts may completely pass through the underlayment. In any event, the cutouts may be configured to receive a mating material. For instance, the cutouts may be configured to receive adhesive, epoxy, grout, cement, glue, plastic, or other material capable of flowing at least partially into the cutouts. These cutouts can provide a number of surfaces on the underlayment to which material can adhere, or key. Additionally or alternatively, these cutouts can increase the strength of the underlayment by providing a structural skeleton, around which material can flow and cure in addition to providing a pathway for airflow, thereby enabling the utilization of a modified thinset, which requires air for curing. The cutouts further provide a passageway for moisture to flow out of the subfloor. In one embodiment, the cutouts may be provided via the forming process of the underlayment. In another embodiment, the cutouts may be made via a cutting operation performed prior to the forming process. In yet another embodiment, the cutouts may be made via a cutting operation performed subsequent to the forming process. The underlayment may include areas in and/or between the routing hubs that are configured to receive material. For instance, the areas may be configured to receive adhesive, epoxy, grout, cement, glue, plastic, or other material capable of flowing at least partially into the areas. These areas can provide a number of surfaces on the underlayment to which material can adhere, or key. Additionally or alternatively, these areas can increase the strength of the underlayment by providing a structural skeleton, around which material can flow and cure. In some embodiments, the underlayment may include a pad layer. The pad layer may include a sound dampening material; a heat reflective material, such as aluminum foil; an insulative material, such as polystyrene, fleece, or wool; a porous substrate; a vapor barrier; a waterproof material; an energy reflective material; etc., and/or combinations thereof. Examples of pad layers can include, but are in no way limited to, non-woven fabrics or materials, foil, cork, rubber, plastic, concrete, wood, organic materials, inorganic materials, composites, compounds, etc., and/or combinations thereof. The pad layer may be attached to the base material via adhesive, thermal bonding, welding, mechanical attachment, etc., and/or combinations thereof. As can be appreciated, the pad layer may include adhesive on the side opposite the base material side for affixing to a surface, such as a subfloor, floor, etc. In one embodiment, the pad layer may be configured to receive adhesive for affixing to a surface. The phrases “at least one”, “one or more”, and “and/or” are open-ended expressions that are both conjunctive and disjunctive in operation. For example, each of the expressions “at least one of A, B and C”, “at least one of A, B, or C”, “one or more of A, B, and C”, “one or more of A, B, or C” and “A, B, and/or C” means A alone, B alone, C alone, A and B together, A and C together, B and C together, or A, B and C together. When each one of A, B, and C in the above expressions refers to an element, such as X, Y, and Z, or class of elements, such as X 1 -X n , Y 1 -Y m , and Z 1 -Z 0 , the phrase is intended to refer to a single element selected from X, Y, and Z, a combination of elements selected from the same class (e.g., X 1 and X 2 ) as well as a combination of elements selected from two or more classes (e.g., Y 1 and Z 0 ). The term “a” or “an” entity refers to one or more of that entity. As such, the terms “a” (or “an”), “one or more” and “at least one” can be used interchangeably herein. It is also to be noted that the terms “comprising”, “including”, and “having” can be used interchangeably. The term “means” as used herein shall be given its broadest possible interpretation in accordance with 35 U.S.C., Section 112, Paragraph 6. Accordingly, a claim incorporating the term “means” shall cover all structures, materials, or acts set forth herein, and all of the equivalents thereof. Further, the structures, materials or acts and the equivalents thereof shall include all those described in the summary of the invention, brief description of the drawings, detailed description, abstract, and claims themselves. It should be understood that every maximum numerical limitation given throughout this disclosure is deemed to include each and every lower numerical limitation as an alternative, as if such lower numerical limitations were expressly written herein. Every minimum numerical limitation given throughout this disclosure is deemed to include each and every higher numerical limitation as an alternative, as if such higher numerical limitations were expressly written herein. Every numerical range given throughout this disclosure is deemed to include each and every narrower numerical range that falls within such broader numerical range, as if such narrower numerical ranges were all expressly written herein. The preceding is a simplified summary of the disclosure to provide an understanding of some aspects of the disclosure. This summary is neither an extensive nor exhaustive overview of the disclosure and its various aspects, embodiments, and configurations. It is intended neither to identify key or critical elements of the disclosure nor to delineate the scope of the disclosure but to present selected concepts of the disclosure in a simplified form as an introduction to the more detailed description presented below. As will be appreciated, other aspects, embodiments, and configurations of the disclosure are possible utilizing, alone or in combination, one or more of the features set forth above or described in detail below. | F24D1302 | 20171027 | 20180222 | 65334.0 | F24D1302 | 1 | GITLIN, MATTHEW J | METHOD AND APPARATUS FOR POSITIONING HEATING ELEMENTS | UNDISCOUNTED | 1 | CONT-ACCEPTED | F24D | 2,017 |
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15,798,909 | PENDING | Contact Configuration for Optoelectronic Device | An optoelectronic device with a multi-layer contact is described. The optoelectronic device can include an n-type semiconductor layer having a surface. A mesa can be located over a first portion of the surface of the n-type semiconductor layer and have a mesa boundary. An n-type contact region can be located over a second portion of the surface of the n-type semiconductor contact layer entirely distinct from the first portion, and be at least partially defined by the mesa boundary. A first n-type metallic contact layer can be located over at least a portion of the n-type contact region in proximity of the mesa boundary, where the first n-type metallic contact layer forms an ohmic contact with the n-type semiconductor layer. A second metallic contact layer can be located over a second portion of the n-type contact region, where the second metallic contact layer is formed of a reflective metallic material. | 1. An optoelectronic device comprising: an n-type semiconductor layer having a surface; a mesa located over a first portion of the surface of the n-type semiconductor layer and having a mesa boundary; an n-type contact region located over a second portion of the surface of the n-type semiconductor contact layer entirely distinct from the first portion, wherein the n-type contact region is at least partially defined by the mesa boundary; a first n-type metallic contact layer located over at least a portion of the n-type contact region in proximity of the mesa boundary, wherein the first n-type metallic contact layer forms an ohmic contact with the n-type semiconductor layer; and a second metallic contact layer located over a second portion of the n-type contact region, wherein the second metallic contact layer is formed of a reflective metallic material, and wherein the second metallic contact layer includes at least one target radiation scattering domain. 2. The optoelectronic device of claim 1, wherein the first n-type metallic layer and the second metallic contact layer at least partially overlap. 3. The optoelectronic device of claim 1, wherein a third metallic contact layer is located over at least a portion of the first n-type metallic contact layer and at least a portion of the second metallic contact layer. 4. The optoelectronic device of claim 1, wherein the n-type semiconductor layer comprises a group III nitride semiconductor. 5. The optoelectronic device of claim 1, wherein the first n-type metallic contact layer comprises a plurality of domains with each domain having a smallest characteristic length-scale being at least a current spreading length width of the n-type semiconductor contact layer. 6. The optoelectronic device of claim 1, further comprising a dielectric layer located between at least a portion of the n-type contact region and the first n-type metallic contact layer, wherein the dielectric layer includes a plurality of voids extending there through, and wherein the first n-type metallic contact layer penetrates the plurality of voids and directly contacts the at least the portion of the n-type contact region. 7. The optoelectronic device of claim 1, wherein the n-type semiconductor layer includes a plurality of voids, each of the plurality of voids having a depth of 0.1-50 microns and a lateral size of 0.1-20 microns. 8. The optoelectronic device of claim 7, further comprising a plurality of target radiation scattering material domains at least partially filling the voids. 9. The optoelectronic device of claim 7, wherein at least one of: the first n-type metallic contact layer or the second n-type metallic contact layer, fills at least a portion of the plurality of voids. 10. The optoelectronic device of claim 1, wherein the n-type semiconductor layer comprises a set of angled side surfaces, wherein at least a portion of each angled side surface in the set of angled side surfaces forms an angle between approximately ten and approximately eighty degrees with a normal vector to a top surface of the n-type semiconductor contact layer. 11. The optoelectronic device of claim 1, wherein the mesa comprises a set of angled side surfaces, wherein at least a portion of each angled side surface in the set of angled side surfaces forms an angle between approximately ten and approximately eighty degrees with a normal vector of a top surface of the mesa. 12. The optoelectronic device of claim 1, further comprising: a substrate; and a buffer layer located over the substrate, wherein the n-type semiconductor layer is located over the buffer layer. 13. The optoelectronic device of claim 12, wherein a surface area of a top surface of the n-type semiconductor layer is at least 5% smaller than a surface area of a top surface of the buffer layer. 14. The optoelectronic device of claim 12, wherein a surface area of a top surface of the buffer layer is at least 5% smaller than a surface area of the top surface of the substrate. 15. The optoelectronic device of claim 12, wherein the buffer layer comprises a set of angled side surfaces, wherein at least a portion of each angled side surface in the set of angled side surfaces forms an angle between approximately ten and approximately eighty degrees with a normal vector of a top surface of the buffer layer. 16. The optoelectronic device of claim 1, wherein the mesa boundary includes a plurality of interconnected fingers, and wherein the first n-type metallic contact layer extends between the plurality of interconnected fingers. 17. An optoelectronic device comprising: an n-type group III nitride semiconductor layer having a surface, wherein the n-type semiconductor layer includes a plurality of voids, each of the plurality of voids having a depth of 0.1-50 microns and a lateral size of 0.1-20 microns; a mesa located over a first portion of the surface of the n-type group III nitride semiconductor layer and having a mesa boundary, wherein the mesa boundary includes a plurality of interconnected fingers; an n-type contact region located over a second portion of the surface of the n-type group III nitride semiconductor contact layer entirely distinct from the first portion, wherein the n-type contact region is at least partially defined by the mesa boundary; a first n-type metallic contact layer located over at least a portion of the n-type contact region in proximity of the mesa boundary, wherein the first n-type metallic contact layer forms an ohmic contact with the n-type group III nitride semiconductor layer, and wherein the first n-type metallic contact layer extends between the plurality of interconnected fingers; and a second n-type metallic contact layer located over a second portion of the n-type contact region, wherein the second n-type metallic contact layer is formed of a reflective metallic material. 18. A method of fabricating an optoelectronic device comprising: forming a mesa having a mesa boundary over a first portion of an n-type semiconductor layer, wherein the mesa includes an active semiconductor layer and a p-type semiconductor contact layer located on an opposite side of the active semiconductor layer as the n-type semiconductor layer, and wherein the n-type semiconductor layer has an n-type contact region located over a second portion of the surface of the n-type semiconductor contact layer entirely distinct from the first portion, wherein the n-type contact region is at least partially defined by the mesa boundary; depositing a first n-type metallic contact layer over a first portion of the n-type contact region in proximity to the mesa boundary; and depositing a second n-type metallic contact layer over a second portion of the n-type contact region, wherein the second n-type metallic contact layer includes at least one target radiation scattering domain. 19. The method of claim 18, wherein the first n-type metallic region and the second n-type metallic contact region at least partially overlap. 20. The method of claim 18, further comprising, prior to deposition of the first and the second n-type metallic contact layers, etching the n-type contact region to form a plurality of voids, wherein the plurality of voids have a depth of 0.1-50 microns and a lateral size of 0.1-20 microns. | REFERENCE TO RELATED APPLICATIONS The current application claims the benefit of U.S. Provisional Application No. 62/415,479, filed 31 Oct. 2016, and is a continuation-in-part of U.S. patent application Ser. No. 15/283,462, filed 3 Oct. 2016, which claims the benefit of U.S. Provisional Application No. 62/236,045, filed on 1 Oct. 2015, all of which are hereby incorporated by reference. TECHNICAL FIELD The disclosure relates generally to emitting devices, and more particularly, to an optoelectronic device having a contact configuration, which can provide, for example, decreased light absorption and/or improved light extraction. BACKGROUND ART Semiconductor emitting devices, such as light emitting diodes (LEDs) and laser diodes (LDs), include solid state emitting devices composed of group III-V semiconductors. A subset of group III-V semiconductors includes group III nitride alloys, which can include binary, ternary and quaternary alloys of indium (In), aluminum (Al), gallium (Ga), and nitrogen (N). Illustrative group III nitride-based LEDs and LDs can be of the form InyAlxGa1-x-yN, where x and y indicate the molar fraction of a given element, 0≦x, y≦1, and 0≦x+y≦1. Other illustrative group III nitride based LEDs and LDs are based on boron (B) nitride (BN) and can be of the form GazInyAlxB1-x-y-zN, where 0≦x, y, z≦1, and 0≦x+y+z≦1. An LED is typically composed of semiconducting layers. During operation of the LED, an applied bias across doped layers leads to injection of electrons and holes into an active layer where electron-hole recombination leads to light generation. Light is generated with uniform angular distribution and escapes the LED die by traversing semiconductor layers in all directions. Each semiconducting layer has a particular combination of molar fractions (e.g., x, y, and z) for the various elements, which influences the optical properties of the layer. In particular, the refractive index and absorption characteristics of a layer are sensitive to the molar fractions of the semiconductor alloy. An interface between two layers is defined as a semiconductor heterojunction. At an interface, the combination of molar fractions is assumed to change by a discrete amount. A layer in which the combination of molar fractions changes continuously is said to be graded. Changes in molar fractions of semiconductor alloys can allow for band gap control, but can lead to abrupt changes in the optical properties of the materials and result in light trapping. A larger change in the index of refraction between the layers, and between the substrate and its surroundings, results in a smaller total internal reflection (TIR) angle (provided that light travels from a high refractive index material to a material with a lower refractive index). A small TIR angle results in a large fraction of light rays reflecting from the interface boundaries, thereby leading to light trapping and subsequent absorption by layers or LED metal contacts. Roughness at an interface allows for partial alleviation of the light trapping by providing additional surfaces through which light can escape without totally internally reflecting from the interface. Nevertheless, light only can be partially transmitted through the interface, even if it does not undergo TIR, due to Fresnel losses. Fresnel losses are associated with light partially reflected at the interface for all the incident light angles. Optical properties of the materials on each side of the interface determines the magnitude of Fresnel losses, which can be a significant fraction of the transmitted light. SUMMARY OF THE INVENTION Aspects of the invention provide an optoelectronic device with a multi-layer contact. The optoelectronic device can include an n-type semiconductor layer having a surface. A mesa can be located over a first portion of the surface of the n-type semiconductor layer and have a mesa boundary. An n-type contact region can be located over a second portion of the surface of the n-type semiconductor contact layer entirely distinct from the first portion, and be at least partially defined by the mesa boundary. A first n-type metallic contact layer can be located over at least a portion of the n-type contact region in proximity of the mesa boundary, where the first n-type metallic contact layer forms an ohmic contact with the n-type semiconductor layer. A second metallic contact layer can be located over a second portion of the n-type contact region, where the second metallic contact layer is formed of a reflective metallic material. A first aspect of the invention provides an optoelectronic device comprising: an n-type semiconductor layer having a surface; a mesa located over a first portion of the surface of the n-type semiconductor layer and having a mesa boundary; an n-type contact region located over a second portion of the surface of the n-type semiconductor contact layer entirely distinct from the first portion, wherein the n-type contact region is at least partially defined by the mesa boundary; a first n-type metallic contact layer located over at least a portion of the n-type contact region in proximity of the mesa boundary, wherein the first n-type metallic contact layer forms an ohmic contact with the n-type semiconductor layer; and a second metallic contact layer located over a second portion of the n-type contact region, wherein the second metallic contact layer is formed of a reflective metallic material. A second aspect of the invention provides an optoelectronic device comprising: an n-type group III nitride semiconductor layer having a surface; a mesa located over a first portion of the surface of the n-type group III nitride semiconductor layer and having a mesa boundary, wherein the mesa boundary includes a plurality of interconnected fingers; an n-type contact region located over a second portion of the surface of the n-type group III nitride semiconductor contact layer entirely distinct from the first portion, wherein the n-type contact region is at least partially defined by the mesa boundary; a first n-type metallic contact layer located over at least a portion of the n-type contact region in proximity of the mesa boundary, wherein the first n-type metallic contact layer forms an ohmic contact with the n-type group III nitride semiconductor layer, and wherein the first n-type metallic contact layer extends between the plurality of interconnected fingers; and a second metallic contact layer located over a second portion of the n-type contact region, wherein the second metallic contact layer is formed of a reflective metallic material. A third aspect of the invention provides a method of fabricating an optoelectronic device comprising: forming a mesa having a mesa boundary over a first portion of an n-type semiconductor layer, wherein the mesa includes an active semiconductor layer and a p-type semiconductor contact layer located on an opposite side of the active semiconductor layer as the n-type semiconductor layer, and wherein the n-type semiconductor layer has an n-type contact region located over a second portion of the surface of the n-type semiconductor contact layer entirely distinct from the first portion, wherein the n-type contact region is at least partially defined by the mesa boundary; depositing a first n-type metallic contact layer over a first portion of the n-type contact region in proximity to the mesa boundary; and depositing a second metallic contact layer over a second portion of the n-type contact region. The illustrative aspects of the invention are designed to solve one or more of the problems herein described and/or one or more other problems not discussed. BRIEF DESCRIPTION OF THE DRAWINGS These and other features of the disclosure will be more readily understood from the following detailed description of the various aspects of the invention taken in conjunction with the accompanying drawings that depict various aspects of the invention. FIG. 1 shows a schematic structure of an illustrative optoelectronic device according to an embodiment. FIGS. 2A and 2B show top isometric views of illustrative optoelectronic devices according to the prior art. FIGS. 3A and 3B show top isometric views of illustrative optoelectronic devices according to embodiments. FIGS. 4A and 4B show illustrative devices including an interdigitated mesa and n-type contact according to embodiments. FIGS. 5A and 5B show illustrative devices including an interdigitated mesa and n-type contact according to embodiments. FIGS. 6A and 6B show illustrative devices including an interdigitated mesa and n-type contact that includes an additional layer according to embodiments. FIGS. 7A and 7B show top and cross section views of an illustrative optoelectronic device according to an embodiment and FIGS. 7C and 7D show top and cross section views of another illustrative optoelectronic device according to an embodiment. FIG. 8 shows a cross section of an illustrative optoelectronic device according to an embodiment. FIG. 9 shows a cross section of an illustrative optoelectronic device according to an embodiment. FIGS. 10A-10D show cross sections of illustrative optoelectronic devices according to embodiments. FIGS. 11A-11D show illustrative configurations for dielectric layers according to embodiments. FIG. 12 shows an illustrative flow diagram for fabricating a circuit according to an embodiment. It is noted that the drawings may not be to scale. The drawings are intended to depict only typical aspects of the invention, and therefore should not be considered as limiting the scope of the invention. In the drawings, like numbering represents like elements between the drawings. DETAILED DESCRIPTION OF THE INVENTION As indicated above, aspects of the invention provide an optoelectronic device with a multi-layer contact. The optoelectronic device can include an n-type semiconductor layer having a surface. A mesa can be located over a first portion of the surface of the n-type semiconductor layer and have a mesa boundary. An n-type contact region can be located over a second portion of the surface of the n-type semiconductor contact layer entirely distinct from the first portion, and be at least partially defined by the mesa boundary. A first n-type metallic contact layer can be located over at least a portion of the n-type contact region in proximity of the mesa boundary, where the first n-type metallic contact layer forms an ohmic contact with the n-type semiconductor layer. A second metallic contact layer can be located over a second portion of the n-type contact region, where the second metallic contact layer is formed of a reflective metallic material. The optoelectronic device can have improved light emission. To this extent, embodiments of the optoelectronic device include: a light emitting diode (LED), an ultraviolet (UV) LED, a photodiode, and a laser diode. As used herein, unless otherwise noted, the term “set” means one or more (i.e., at least one) and the phrase “any solution” means any now known or later developed solution. It is understood that, unless otherwise specified, each value is approximate and each range of values included herein is inclusive of the end values defining the range. As used herein, unless otherwise noted, the term “approximately” is inclusive of values within +/− ten percent of the stated value, while the term “substantially” is inclusive of values within +/− five percent of the stated value. Unless otherwise stated, two values are “similar” when the smaller value is within +/− twenty-five percent of the larger value. A value, y, is on the order of a stated value, x, when the value y satisfies the formula 0.1x≦y≦10x. As also used herein, a layer is a transparent layer when the layer allows at least ten percent of radiation having a target wavelength, which is radiated at a normal incidence to an interface of the layer, to pass there through. Furthermore, as used herein, a layer is a reflective layer when the layer reflects at least ten percent of radiation having a target wavelength, which is radiated at a normal incidence to an interface of the layer. In an embodiment, the target wavelength of the radiation corresponds to a wavelength of radiation emitted or sensed (e.g., peak wavelength +/− five nanometers) by an active region of an optoelectronic device during operation of the device. For a given layer, the wavelength can be measured in a material of consideration and can depend on a refractive index of the material. Additionally, as used herein, a contact is considered “ohmic” when the contact exhibits close to linear current-voltage behavior over a relevant range of currents/voltages to enable use of a linear dependence to approximate the current-voltage relation through the contact region within the relevant range of currents/voltages to a desired accuracy (e.g., +/− one percent). Turning to the drawings, FIG. 1 shows a schematic structure of an illustrative optoelectronic device 10 according to an embodiment. In a more particular embodiment, the optoelectronic device 10 is configured to operate as an emitting device, such as a light emitting diode (LED) or a laser diode (LD). In either case, during operation of the emitting device, application of a bias comparable to the band gap results in the emission of electromagnetic radiation from an active region 18 of the emitting device. Alternatively, the optoelectronic device 10 can operate as a sensing device, such as a photodiode. The electromagnetic radiation emitted or sensed by the optoelectronic device 10 can comprise a peak wavelength within any range of wavelengths, including visible light, ultraviolet radiation, deep ultraviolet radiation, infrared light, and/or the like. In an embodiment, the optoelectronic device 10 is configured to emit (or sense) radiation having a dominant wavelength within the ultraviolet range of wavelengths. In a more specific embodiment, the dominant wavelength is within a range of wavelengths between approximately 210 and approximately 360 nanometers. The optoelectronic device 10 includes a heterostructure 11 comprising a substrate 12, a buffer layer 14 adjacent to the substrate 12, an n-type layer 16 (e.g., a cladding layer, electron supply layer, contact layer, and/or the like) adjacent to the buffer layer 14, and a mesa 17 located adjacent to a portion of the n-type layer 16. The mesa 17 can include an active region 18 having an n-type side adjacent to the n-type layer 16. Furthermore, the heterostructure 11 of the optoelectronic device 10 includes a first p-type layer 20 (e.g., an electron blocking layer, a cladding layer, hole supply layer, and/or the like) adjacent to a p-type side of the active region 18 and a second p-type layer 22 (e.g., a cladding layer, hole supply layer, contact layer, and/or the like) adjacent to the first p-type layer 20. In a more particular illustrative embodiment, the optoelectronic device 10 is a group III-V materials based device, in which some or all of the various layers are formed of elements selected from the group III-V materials system. In a still more particular illustrative embodiment, the various layers of the optoelectronic device 10 are formed of group III nitride based materials. Group III nitride materials comprise one or more group III elements (e.g., boron (B), aluminum (Al), gallium (Ga), and indium (In)) and nitrogen (N), such that BWAlXGaYInZN, where 0≦W, X, Y, Z≦1, and W+X+Y+Z=1. Illustrative group III nitride materials include binary, ternary and quaternary alloys such as, AlN, GaN, InN, BN, AlGaN, AlInN, AlBN, AlGaInN, AlGaBN, AlInBN, and AlGaInBN with any molar fraction of group III elements. An illustrative embodiment of a group III nitride based optoelectronic device 10 includes an active region 18 (e.g., a series of alternating quantum wells and barriers) composed of InyAlxGa1-x-yN, GazInyAlxB1-x-y-zN, an AlxGa1-xN semiconductor alloy, or the like. Similarly, the n-type layer 16, the first p-type layer 20, and the second p-type layer 22 can be composed of an InyAlxGa1-x-yN alloy, a GazInyAlxB1-x-y-zN alloy, or the like. The molar fractions given by x, y, and z can vary between the various layers 16, 18, 20, and 22. When the optoelectronic device 10 is configured to be operated in a flip chip configuration, such as shown in FIG. 1, the substrate 12 and buffer layer 14 can be transparent to the target electromagnetic radiation. To this extent, an embodiment of the substrate 12 can be formed of sapphire, and the buffer layer 14 can be composed of AlN, an AlGaN/AlN superlattice, and/or the like. However, it is understood that the substrate 12 can be formed of any suitable material including, for example, silicon carbide (SiC), silicon (Si), bulk GaN, bulk AlN, bulk or a film of AlGaN, bulk or a film of BN, AlON, LiGaO2, LiAlO2, aluminum oxinitride (AlOxNy), MgAl2O4, GaAs, Ge, or another suitable material. Furthermore, a surface of the substrate 12 can be substantially flat or patterned using any solution. The optoelectronic device 10 can further include a p-type contact 24, which can form an ohmic contact to the second p-type layer 22, and a p-type electrode 26 can be attached to the p-type contact 24. Similarly, the optoelectronic device 10 can include an n-type contact 28, which can form an ohmic contact to the n-type layer 16, and an n-type electrode 30 can be attached to the n-type contact 28. Each contact 24, 28 can be formed of a metal. In an embodiment, the p-type contact 24 and the n-type contact 28 each comprise several conductive and reflective metal layers, while the n-type electrode 30 and the p-type electrode 26 each comprise highly conductive metal. In an embodiment, the second p-type layer 22 and/or the p-type electrode 26 can be transparent to the electromagnetic radiation generated by the active region 18. For example, the second p-type layer 22 and/or the p-type electrode 26 can comprise a short period superlattice lattice structure, such as an at least partially transparent magnesium (Mg)-doped AlGaN/AlGaN short period superlattice structure (SPSL). Furthermore, the p-type electrode 26 and/or the n-type electrode 30 can be reflective of the electromagnetic radiation generated by the active region 18. In another embodiment, the n-type layer 16 and/or the n-type electrode 30 can be formed of a short period superlattice, such as an AlGaN SPSL, which is transparent to the electromagnetic radiation generated by the active region 18. As further shown with respect to the optoelectronic device 10, the device 10 can be mounted to a submount 36 via the electrodes 26, 30 in a flip chip configuration. In this case, the substrate 12 is located on the top of the optoelectronic device 10. To this extent, the p-type electrode 26 and the n-type electrode 30 can both be attached to a submount 36 via contact pads 32, 34, respectively. The submount 36 can be formed of aluminum nitride (AlN), silicon carbide (SiC), and/or the like. Any of the various layers of the heterostructure 11 can comprise a substantially uniform composition or a graded composition. For example, a layer can comprise a graded composition at a heterointerface with another layer. In an embodiment, the first p-type layer 20 comprises a p-type blocking layer (e.g., electron blocking layer) having a graded composition. The graded composition(s) can be included to, for example, reduce stress, improve carrier injection, and/or the like. Similarly, any of the various layers of the heterostructure 11 can comprise a superlattice including a plurality of periods, which can be configured to reduce stress, and/or the like. In this case, the composition and/or width of each period can vary periodically or aperiodically from period to period. It is understood that the layer configuration of the heterostructure 11 described herein is only illustrative. To this extent, a heterostructure for an optoelectronic device described herein can include an alternative layer configuration, one or more additional layers, one or more fewer layers, and/or the like. As a result, while the various layers are shown immediately adjacent to one another (e.g., contacting one another), it is understood that one or more intermediate layers can be present in a heterostructure. For example, an illustrative heterostructure can include an undoped layer located between the active region 18 and one or both of the first p-type layer 20 and the n-type layer 16. FIGS. 2A and 2B show top isometric views of illustrative optoelectronic devices 2A, 2B according to the prior art. Each device 2A, 2B has a heterostructure including an n-type contact layer 4C epitaxially grown over a buffer layer 4B with the buffer layer 4B deposited over a substrate 4A. An n-type metallic contact layer 6A is shown deposited over a portion of a surface of the n-type contact layer 4C. A mesa 8 is epitaxially grown over another portion of the surface of the n-type contact layer 4C and is separated from the metallic contact layer 6A by a small gap of few nanometers. The mesa 8 can include an active region and a set of p-type semiconductor layers, with a p-type metallic contact layer 6B located thereon. In this configuration, the mesa has a set of sides forming a mesa boundary, which defines a lateral extent and shape of the mesa 8. For the semiconductor heterostructure to operate as an optoelectronic device, the heterostructure is connected to positive and negative bias using electrodes 9A and 9B, respectively. The n-type metallic contact layer 6A can comprise any typical metal used for fabrication of ohmic n-type contact to the semiconductor. For example, the n-type metallic contact layer 6A can contain titanium, aluminum, and/or chromium. The n-type metallic contact layer 6A as well as n-type semiconductor contact layer 4C can be light absorbing, especially for light emitting devices operating at the ultraviolet wavelengths, which can be detrimental to the efficiency of the device. FIGS. 3A and 3B show top isometric views of illustrative optoelectronic devices 40A, 40B according to embodiments of the current invention. In each case, the n-type layer 16 (e.g., an n-type cladding layer, an n-type contact layer, and/or the like) and the n-type metallic contact 28 have a shape corresponding to the shape of the mesa 17, which can include the active region (e.g., a light generating or light detecting structure having a set of quantum wells and barriers) and/or one or more p-type semiconductor layers as described herein. In an embodiment, the n-type layer 16 and the n-type metallic contact 28 can be etched to at least a surface of the buffer layer 14. The shape of the n-type layer 16 and the n-type metallic contact 28 can be configured to reduce radiation losses associated with the n-type layer 16 and the n-type metallic contact 28. The n-type layer 16 and the n-type metallic contact 28 can further include a region on which the electrode 28 can be formed. The n-type layer 16 and the buffer layer 14 can comprise group III nitride materials that are transparent to the target radiation. In an embodiment, for a target radiation in the ultraviolet range, the n-type layer 16 can comprise a AlxGa1-xN layer with the molar fraction x being in the range of 0.3 to 0.7. In an embodiment, the buffer layer 14 can comprise AlN. In yet another embodiment, either optoelectronic device 40A, 40B can have a target wavelength in the range of 270-320 nm. The width of the n-type layer 16 can exceed a width of the mesa 17 by an excess width We, which can be defined as the largest distance from the contact boundary (which corresponds to the boundary of the mesa 17) to n-type layer 16 outer edge when measured along a direction normal to the contact boundary. However, as shown in conjunction with the device 40B, the excess width measurement can ignore regions of the n-type layer 16 that exceed a typical excess width We due to the limits of fabrication. For example, the excess width We of the n-type layer 16 can be at least the current spreading length as measured in the n-type layer 16 at the device operating temperature. The current spreading length can be approximated by L=√{square root over ((ρc+ρptp)tn/ρn)} where tp is the thickness of the p-type layer, tn is the thickness of the n-type layer, ρp and ρn are the resistivities of the p-type and n-type layers respectively, and ρc is a specific contact resistivity of the p-type ohmic contact. Using this formula with typical numbers for group III nitride p-type and n-type semiconductor layers: ρc˜5.×10−3 Ωcm2, ρp˜100 Ωcm2, ρn˜0.1 Ωcm2, tp˜100 nm, tn˜1 μm, the current spreading length is about 25 μm. In general, depending on the particular semiconductor structure, the spreading length can be estimated as between approximately 10 μm and approximately 80 μm. FIGS. 3A and 3B show the n-type metallic contact 28 having a comparable excess width and also enclosing the mesa 17. It is understood that the n-type layer 16 can be defined as a domain having a boundary or a set of boundaries where each boundary comprises a connected curve. As used herein, a smallest characteristic length-scale of the n-type metallic contact 28 means: for every point at all the boundaries (and for engineering accuracy, the boundary can be discretized by a set of points) of the n-type contact region, measure a distance along the negative normal direction (positive normal direction points outside of the domain) to the boundary until intersection with any other boundary point. The shortest such distance is defined as a smallest characteristic length-scale of the n-type contact. Please note, that according to such definition, the excess width We corresponds to the smallest characteristic length-scale of the n-type contact. In an embodiment, the n-type layer 16 can comprise a layer with an excess width greater than the current spreading length, and in an embodiment can comprise an excess width of several current spreading lengths. In an embodiment, the n-type layer 16 covers a portion of the buffer layer 14, leaving some of the surface of the buffer layer 14 exposed. In an embodiment, the n-type layer 16 can have a top surface area for an n-type contact region that is at least 5% smaller than a surface area of a top surface of the buffer layer 14. For reliable operation of the device 40, the exposed surface of the buffer layer 14 can be protected with a dielectric layer. The dielectric layer can comprise any suitable insulating material, including for example, SiO2, anodized aluminum oxide (AAO), CaF2, MgF2, and/or the like. It is understood that the further buffer etching in regions not covered by any of the epitaxial layers can be employed resulting in some substrate 12 (FIG. 1) areas being uncovered by semiconductor layers. In an embodiment a buffer layer 14 is etched such that the top surface of the buffer layer is at least 5% smaller than a surface area of the top surface of the substrate. The exposed substrate area(s) also can be protected with any suitable dielectric layer including for example, SiO2, AAO, CaF2, MgF2, and/or the like. In an alternative embodiment, the substrate 12 can be protected with a reflective metallic layer such as aluminum, rhodium or/and the like. In yet another embodiment, the substrate 12 can be protected by a multilayered film comprising an omnidirectional mirror wherein the layers adjacent to substrate can comprise the dielectric layers described herein followed by the reflective metallic layers. The n-type metallic contact 28 comprises a shape forming a pad area 31 that can be contacted by the n-type electrode 30, comprising conductive metals. In an embodiment, the pad area 31 has a size less than one half of a lateral length of an adjacent side of the mesa 17. In an embodiment, an optoelectronic device described herein comprises an n-type semiconductor layer 16 having a surface comprising a mesa region 17 covering either one or several areas of the surface, with at least some of the other areas of the surface covered by an n-type metallic contact 28. The area(s) covered by the n-type metallic contact 28 can be defined as an n-type surface. The mesa(s) 17 and the n-type metallic contact 28 are separated by a gap 29, which can be defined by a set of contact boundaries or a boundary between a mesa region and the n-type metallic contact layer. It is understood that the shapes of the devices 40A, 40B shown in FIGS. 3A and 3B are only illustrative of various possible configurations for a device described herein. To this extent, top views of other illustrative optoelectronic devices 42A, 42B are shown in FIGS. 4A and 4B, respectively. In each case, the device 42A, 42B comprises a complex interdigitated n-type metallic contact 28 being in proximity of a mesa 17 having a complex form including multiple interconnected fingers 43A, 43B. The shape of the mesa 17 and the n-type metallic contact 28 can be selected to, for example, minimize current crowding in the device 42A, 42B. For example, as shown in FIG. 4A, the device 42A has a mesa 17 with fingers 43A, 43B connected in a central region, while the device 42B of FIG. 4B has a mesa 17 with fingers 43A, 43B connected in alternating outer regions thereof to create a serpentine mesa shape. The n-type metallic contact 28 is contacted by an electrode pad 44, on which an electrode 30 is formed. The electrode pad 44 can comprise an ohmic or a reflective metallic electrode and can contact a side surface of the n-type metallic contact 28 and/or extend over a portion of the n-type metallic contact 28. In an embodiment, the metallic electrode can comprise a Ti/Al or Ti/Al/Au metallic contact layer. As illustrated, the electrode 30 can be oriented substantially parallel with a finger as shown in conjunction with the device 42A, or oriented substantially parallel with a connector between fingers as shown in conjunction with the device 42B. Similar to the embodiment shown in FIGS. 3A and 3B, the n-type layer 16 can be partially etched and closely follows the shape of the mesa 17. FIGS. 5A and 5B show top views of other embodiments of illustrative devices 50A, 50B, respectively. In each case, the n-type metallic contact includes two distinct metals. For example, a first metal 28A of the n-type metallic contact forms an interdigitated n-type metallic pattern in close proximity of the mesa 17, while a second metal 28B of the n-type metallic contact comprises a reflective metallic layer. The reflective metallic layer 28B can comprise any type of material reflective to the target radiation. For example, for an optoelectronic device configured to operate as an UV LED, the material can comprise a reflective metallic layer such as aluminum, rhodium, and/or the like. The two metals 28A, 28B are electrically connected. To this extent, the two metals 28A, 28B can be located immediately adjacent to each other on the n-type semiconductor layer 16 such that sidewalls of the respective layers are in contact. In an embodiment, one metal layer 28A, 28B can partially overlap the other metal layer 28A, 28B to ensure the electrical connection. In an embodiment, the metal layers 28A, 28B are deposited using physical vapor deposition, sputtering and/or the like. For example, the metal layer 28A can be deposited first, followed by a high temperature annealing typical and known in the art for formation of an ohmic contact with the semiconductor layer 16. In an embodiment, the annealing can be done at temperatures in the range of 600-1000 C. The annealing time and temperature can be selected depending on the material of semiconductor layer 16, e.g., a group III nitride semiconductor layer. For instance, for an n-type contact layer 16 formed of Al0.5Ga0.5N, the annealing of the n-type ohmic contact 28A can comprise high temperature annealing (temperatures above 700 C). After annealing the metal layer 28A, the reflective metal layer 28B can be deposited with at least portion of the metal layer 28B overlapping the metal layer 28A, thereby forming an electrical contact. In an embodiment, the reflective metal layer 28B can comprise a multilayered structure having at least two sub-layers with the first sub-layer being a highly reflective material and forming domains adjacent to portions of the n-type contact layer 16, with such domains not necessarily overlapping with regions of the n-type contact layer 16 on which the n-type ohmic contact layer 28A is located. The second sub-layer of the reflective metal layer 28B can comprise a contact protective layer overlapping with both layer 28A and the first sub-layer of the layer 28B. As used herein, a highly reflective layer can comprise a layer with at least 50% reflectivity to target radiation at the normal incidence. An n-type electrode pad 52 can be located on a portion of the reflective metallic contact 28B, and an n-type electrode 54 can be formed on the electrode pad 52. The electrode pad 52 can comprise an n-type metallic contact such as Ti/Al, Ti/Al/Au, and/or the like, whereas the n-type electrode 54 can comprise any contact with high electrical conductivity and having low oxidation. For example, the n-type electrode 54 can comprise Au. It is understood that one or more other layers can overlay some or all of the n-type metallic contact layer 28A and/or the reflective metallic layer 28B. To this extent, FIGS. 6A and 6B show top views of other embodiments of illustrative devices 60A, 60B. In this case, each device 60A, 60B includes a layer 62 that covers both of the metallic layers 28A, 28B, but does not cover the mesa 17. For example, both metal layers 28A, 28B can be protected with an overlying dielectric layer 62, which can comprise any suitable dielectric material including for example: SiO2, AAO, CaF2, MgF2, and/or the like. In an embodiment, the n-type layer 16 can be protected by a multilayered film forming an omnidirectional mirror. In this case, the layers adjacent to the n-type layer 16 can comprise dielectric layers described herein followed by the reflective metallic layers. For example, the layer 62 shown in FIGS. 6A and 6B, can comprise omnidirectional mirrors containing a low refractive index dielectric layer (wherein low is when compared to refractive index of the underlying semiconductor layer 16), deposited over the n-type semiconductor layer 16 followed by deposition of a reflective metallic layer. Alternatively, the layer 62 can comprise a Bragg reflector comprising alternating dielectric layers. In an embodiment, the layer 62 can include a Bragg reflector as a sub-layer with a metallic sub-layer deposited over the Bragg reflector sub-layer. The Bragg reflector can comprise HfO2, Al2O3, and SiO2 layers, as well as semiconductor layers. The layers can be either epitaxially grown or sputtered. While it is shown that the layer 62 is deposited over both the n-type metallic ohmic contact layer 28A and the reflective metallic contact layer 28B, it is understood that in an embodiment the n-type metallic contact layer 28A may not be present and the layer 62 can comprise a conducting layer having a multilayered structure. In this case, the layer 62 can be physically spaced from the mesa 17 as is shown in conjunction with the metallic contact layer 28A. In an embodiment of a device described herein, substantially all open areas (e.g., except for a relatively small gap between n and p contacts) are covered with a highly reflective material, which can comprise, for example, a metallic reflective film. In an embodiment, such a metallic reflective film can further incorporate UV transparent plastics such as fluoropolymers, where it is understood that such plastics can be introduced after annealing of the device at high temperature. The introduction of such a reflective layer allows for the emitted light not to be absorbed by the submount metal. An illustrative process of forming contacts and reflective layers for a device described herein can comprise the following: epitaxially growing a set of semiconductor layers forming the semiconductor heterostructure; and fabricating mesa regions by etching semiconductor layers exposing a portion of a surface of the n-type contact layer. The contacts can be formed by: depositing an n-type metallic ohmic contact over a first portion of the surface of the n-type contact layer, followed by contact annealing; and depositing the reflective contact over a second portion of the surface and optionally over an n-type metallic ohmic contact layer. Subsequently, the process can include depositing a protective dielectric layer over the areas covered by n-type metallic ohmic contact layer and reflective metallic contact layer, where the layer can comprise SiO2, AAO, CaF2, MgF2, and/or the like. In an embodiment, the entire device can contain a dielectric layer deposited over the entire lateral area of the semiconductor layers including an area comprising a mesa region. In an embodiment, the deposition of the dielectric protective layer can be followed by deposition of a metallic reflective layer over the sides of the mesa region. Prior to deposition of the dielectric protective layer, the p-type metallic layer can be deposited over a top surface of the mesa region followed by p-type contact annealing. Access to the p-type metallic contact layer as well as the reflective or ohmic metallic contact layer can be achieved by etching a portion of the dielectric protective layer. The etching method can include photolithography, or masking prior to deposition of a dielectric material. FIGS. 7A and 7B show top and side views, respectively, of an illustrative optoelectronic device 70 according to an embodiment, and FIGS. 7C and 7D show top and side views, respectively, of another optoelectronic device 72 according to an embodiment. In each case, the mesa region 17, the n-type layer 16, and the buffer layer 14, each have tapered structures as shown in FIGS. 7B and 7D. The layer 62 and the layer 28B can comprise a reflective metallic domain, and the layer 28A can be an n-type ohmic metallic contact layer. As seen in FIGS. 7B and 7D, the layer 28B can at least partially overlap the layer 28A (or vice versa) in one or more locations. The mesa region 17, the n-type contact layer 16, and the buffer layer 14 can comprise tapered structures with each structure having a tapering angle θ1, θ2, θ3, respectively. As used herein, a tapered structure comprises a semiconductor structure with a set of angled side surfaces (i.e., one or more side surfaces forming a non-zero angle with respect to a normal vector for the surface of the underlying layer as shown). In an embodiment, a tapering angle θ1, θ2, θ3 for at least a portion of each angled side surface in the set of angled side surfaces is between approximately ten and approximately eighty degrees. In an embodiment, the tapering angles θ1, θ2, θ3 are selected to increase (e.g., optimize) light extraction from the device 70, 72. FIG. 8 shows a side view of an illustrative optoelectronic device 80 according to an embodiment. In this case, the device 80 includes an n-type contact layer 16 containing scattering elements 82. For example, the scattering elements 82 can comprise voids within the layer 16. In an embodiment, the scattering elements 82 can be created through etching a pattern within the layer 16. In an illustrative embodiment, the scattering elements 82 comprise an array of voids, where the array can comprise a photonic crystal. Furthermore, the voids can be filled with reflective material and/or with a dielectric material, such as amorphous Al2O3, SiO2, AAO, CaF2, MgF2, and/or the like. It is understood that the n-type layer 16 can be etched prior to deposition of the n-type ohmic metallic contact layer 28 (and reflective metallic contact layer, when included). In an embodiment, a different etching process can be utilized for creating voids of several scales. For example, the n-type layer 16 can include voids of a first scale having a characteristic length-scale (e.g., an average lateral size) on the order of a micron, with voids of a second scale having a characteristic length-scale in the submicron (e.g., an order of magnitude smaller). Furthermore, it is understood that an exposed portion of the buffer layer 14 (e.g., a part of the buffer layer 14 not covered by n-type layer 26) can be further etched to contain voids/scattering elements 84A, 84B. As illustrated, some or all of these elements, such as vacancy 84B, can be subsequently filled with a material, such as a reflective metallic material 52 forming an n-type electrode pad, a dielectric material, and/or the like. In an embodiment, the optoelectronic device 80 comprises an n-type semiconductor layer 16 having a plurality of voids adjacent to a top surface of the semiconductor layer 16, with the voids having a depth of 0.1-50 microns and a lateral size of 0.1-20 microns. As also illustrated, the mesa 17 can include a p-type electrode pad 86 and a p-type electrode 88 formed thereon. FIG. 9 shows a cross section of an illustrative optoelectronic device 90 according to an embodiment. In this case, the device 90 includes a substrate 12 with one or more angled side surfaces. In particular, a side surface of the substrate 12 has a top portion that forms an angle θ4 with respect to a normal vector to a top surface of the substrate 12. The angle θ4 can be configured to increase (e.g., optimize) light extraction from the device 90. FIGS. 10A-10D show cross sections of illustrative optoelectronic devices 100A-100D, respectively, according to embodiments. Each device 100A-100D includes an n-type metallic contact to the n-type layer 16, which is located over a dielectric layer 102 including voids. In embodiments illustrated by devices 100A, 100B, the n-type metallic contact includes a metallic layer 52 which is located over at least a portion of the dielectric layer 102. The metallic layer 52 penetrates the openings in the dielectric layer 102 and directly contacts the n-type layer 16 located below the dielectric layer 102. While not shown for clarity, it is understood that each optoelectronic device 100A, 100B can include one or more additional features as shown and described herein in conjunction with the other embodiments of the optoelectronic device. For example, the metallic contact layer 52A can include two or more metallic contact layers as described herein. As illustrated, the metallic contact layer 52 and the dielectric layer 102 can contact a side surface of the mesa 17. In this case, the portion of the mesa 17 contacted by the metallic contact layer 52 can correspond to an n-type semiconductor layer, e.g., which can be the same layer/material as the n-type layer 16. However, it is understood that this configuration is only illustrative and embodiments in which at least the n-type electrode pad 52 does not contact the mesa 17 are possible. For example, as illustrated by the devices 100C, 100D, the metallic contact layers 52A, 52B can be physically separate from the mesa 17. A typical separation distance can be a few microns (e.g., 2-5 microns). As illustrated by the metallic contact layer 52B, some or all of the metallic contact layer 52B can be deposited directly on the surface of the n-type layer 16. Additionally, a reflective metallic layer 53 is shown deposited over and extending beyond one of the metallic contact layers 52A in order to promote light reflection from the contact region. As further illustrated by the devices 100C, 100D, the metallic layers 52A, 52B can be embedded within the dielectric layer 102. In this case, the dielectric layer 102 can encapsulate the metallic layers 52A, 52B. As shown by the device 100D in FIG. 10D, an embodiment of a device 100D can include a dielectric layer 102 having a thickness configured to substantially align a top surface of the dielectric layer 102 with a top surface of the mesa 17. Subsequently, a metallic p-type contact layer 55 can be deposited over the mesa region 17, which can also extend over portions of the dielectric layer 102. Additionally, as shown in conjunction with the device 100D, the n-type layer 16 and/or the buffer layer 14 can comprise etched layers with the etching selected to form tapered semiconductor layers as described herein. The dielectric layer 102 can be configured to reflect radiation at an angle that is different from the incident angle. To this extent, the dielectric layer 102 can have scattering properties. For example, as illustrated in FIGS. 10A and 10C, an emitted ray 101 can experience total internal reflection (TIR) with the exit surface (e.g., an interface of the substrate 12 with ambient) and have a reflection angle Θ5 (as measured relative to the surface normal) that is greater than the TIR angle. However, after interacting with the dielectric layer 102, the ray 101 can have an angle Θ6 that is smaller than the TIR angle, thereby allowing the ray 101 to exit the device 100A. As illustrated in FIGS. 10B and 10D, a device 100B, 100D also can include a dielectric layer 104 located on an exit surface of the device 100B, 100D, e.g., to act as an anti-reflective coating for the device 100B, 100D. In an embodiment, the dielectric layer 102 and/or the dielectric layer 104 comprises a multi-layered structure, with each layer being transparent to the radiation corresponding to the device 100A-100D (e.g., radiation emitted by an active region of the device). For example, the dielectric layer 102, 104 can comprise a Bragg reflector with the Bragg reflector layers positioned at an angle to the interface between the dielectric layer 102, 104 and an adjacent layer (e.g., the n-type layer 16 for the dielectric layer 102 or the substrate 12 for the dielectric layer 104). The reflection from such a layer can result in an overall reorientation of the reflected ray 101. It is understood that a device 100A-100D can include any combination of one or both dielectric layers 102, 104, each of which can have any of various configurations. To this extent, FIGS. 11A-11D show additional illustrative configurations for dielectric layers according to embodiments. In each case, the dielectric layer can be implemented as a dielectric layer 102 and/or as a dielectric layer 104 as shown in FIGS. 10A-10D. In FIG. 11A, the dielectric layer 106A includes two sub-layers 108A, 108B. For example, the sub-layer 108A can comprise a Bragg reflector with the Bragg reflector layers positioned at an angle to the interface between the sub-layer 108A and the sub-layer 108B. The sub-layer 108B can comprise a graded sub-layer 108B. A dielectric layer 102, 104 described herein can be fabricated using any suitable dielectric material. Illustrative dielectric materials include silicon dioxide, hafnium dioxide, aluminum oxide, calcium fluoride, magnesium fluoride, and/or the like. In an embodiment, the dielectric materials used for the two sub-layers 108A include silicon dioxide alternating with hafnium dioxide. However, it is understood that this is only illustrative. In an embodiment, the dielectric layers are deposited using a sputtering technique, and are deposited at an angle to the surface normal. In an embodiment, the sub-layer 108B can comprise a nanostructured layer with nanostructures having a prolonged shape and inclined at an angle to the surface normal. In an embodiment, the nanostructures are formed from an ultraviolet transparent material such as, for example, silicon dioxide, hafnium dioxide, aluminum oxide, calcium fluoride, magnesium fluoride, and/or the like. For example, FIG. 11B shows an image illustrating nanostructures formed in a structure as well as illustrative attributes of the sub-layers 108A, 108B according to an embodiment. In an embodiment, the sub-layer 108B can have a height of approximately 500 nanometers, with nanostructures (e.g., nanorods) having an average inclination angle φ in a range between 40-65 degrees. The nanostructures can have an average width and spacing that is much smaller than the wavelength of the target radiation. For example, the width and/or spacing can be approximately ten times smaller than the wavelength of the target radiation (e.g., 15-40 nanometers). The nanostructures can provide control over the index of refraction for the sub-layer 108B. For example, the nanostructures result in an averaged index of refraction, which can be altered by changing the size (width and/or length) and/or inclination angle of the nanostructures. Additionally, the sub-layer 108A can comprise variations of the index of refraction that are on the scale of approximately one quarter of the wavelength of the target radiation, which results in the sub-layer 108A forming an angled Bragg reflector or similar one dimensional periodic structures. However, it is understood that the sub-layer can include variations of the index of refraction that are comparable to or larger than the wavelength of the target radiation. A dielectric layer described herein can include any number of one or more sub-layers having inclined nanostructures. Additionally, a sub-layer with inclined nanostructures can be configured to have a laterally variable index of refraction. Similarly, multiple sub-layers having nanostructures can have different attributes (e.g., nanostructure size, density, angles of inclination) to provide different indexes of refraction in a vertical direction. For example, FIG. 11C shows an illustrative dielectric layer 106B with two sub-layers 108C, 108D, each of which includes nanostructures. In sub-layer 108C, the nanostructures have substantially uniform sizes, angles of inclination, and density, thereby providing a substantially uniform angle of refraction for the sub-layer 108C in the lateral and vertical directions. In contrast, the sub-layer 108D has a highly non-uniform index of refraction in the lateral direction due to a lateral variation of the density of the nanostructures. In particular, the sub-layer 108D can include one or more domains 109A with a relatively high density of nanostructures as compared to other domains, one or more domains 109B with no nanostructures, and one or more domains 109C with a relatively low density of nanostructures as compared to other domains that include nanostructures. Such lateral variability in the index of refraction can allow a flat layer to act as a lens. The lateral variation can result from nanostructure variation over the surface. FIG. 11D shows still another illustrative configuration of a dielectric layer 106C according to an embodiment, in which individual Bragg reflective layers 107A-107C are incorporated therein. Each Bragg reflective layer is positioned at an angle Θ with respect to the normal to the surface. The Bragg reflective layers 107A-107C can include one or more Bragg reflective layers, such as the Bragg reflective layer 107C, having an irregular (e.g., curved) domain that can be controlled during the deposition process. Incorporation of a reflective metallic layer, e.g., over an n-type metallic contact layer and/or over a dielectric layer, can serve as an ultraviolet blocking (protecting) layer. For example, such a layer can be partially reflective and partially absorbing to ensure that no UV radiation is emitted from a surface covered by the layer. In such an embodiment, the reflective layer serves as a protective layer to ensure that other components of the device are not exposed to UV radiation. In an embodiment, a protective layer can comprise an absorbing dielectric layer. In an embodiment, the protective layer is deposited over all the surfaces from which ultraviolet radiation is not desired to be emitted, thereby redirecting the ultraviolet radiation towards a radiating set of surfaces, such as substrate surfaces. In such cases, an epoxy, silicon, or similar material that can degrade under UV radiation can be utilized for an under fill layer during packaging and/or mounting of the UV LED die onto a printed board. An under fill layer can provide thermal management and/or mechanical strength for the device. The protective layer also can contribute to protecting top layers of printed boards once all UV radiation is reflected away from the printed board. It is understood that devices described herein can be fabricated using a process that includes: epitaxially growing the semiconductor structure; etching one or more of the semiconductor layers; depositing one or more metallic layers; annealing; depositing dielectric layers; and attaching p-type and n-type electrodes to respective p-type and n-type metallic contact layers. In an embodiment, the fabrication can include: epitaxially growing a plurality of semiconductor layers over a surface of a substrate. The growing can comprise: growing a buffer layer over the substrate; growing an n-type semiconductor contact layer over the buffer layer; and growing an active semiconductor layer over the n-type semiconductor contact layer. Growing the active layer can comprise growing quantum wells and barriers, such as group III nitride semiconductor layers having different semiconductor alloy composition. Subsequently, the process can include: growing a p-type semiconductor contact layer over the active semiconductor layer; etching a first plurality of areas of at least the p-type semiconductor contact layer and the active semiconductor layer, thereby exposing a portion of the surface of the n-type semiconductor contact resulting in formation of a mesa over un-etched areas. The interface between the mesa and the exposed n-type semiconductor area can form a contact boundary. Subsequently, the process can include depositing a first n-type metallic ohmic contact region over a first portion of the exposed n-type semiconductor contact area in a proximity of the contact boundary. The process can include one or more additional acts, which can include annealing a first n-type metallic ohmic contact layer, followed by depositing a second reflective metallic contact region over a second portion of the exposed n-type semiconductor contact area, where the first n-type metallic region and the second metallic contact region at least partially overlap. In an embodiment, prior to deposition of the first and the second metallic contact regions, the exposed n-type semiconductor area is etched to form a plurality of voids. In yet another embodiment, the fabrication of optoelectronic device can include etching the semiconductor heterostructure resulting in at least some semiconductor layers having a tapered structure. While illustrative aspects of the invention have been shown and described herein primarily in conjunction with a heterostructure for an optoelectronic device and a method of fabricating such a heterostructure and/or device, it is understood that aspects of the invention further provide various alternative embodiments. In one embodiment, the invention provides a method of designing and/or fabricating a circuit that includes one or more of the devices designed and fabricated as described herein. To this extent, FIG. 12 shows an illustrative flow diagram for fabricating a circuit 126 according to an embodiment. Initially, a user can utilize a device design system 110 to generate a device design 112 for a semiconductor device as described herein. The device design 112 can comprise program code, which can be used by a device fabrication system 114 to generate a set of physical devices 116 according to the features defined by the device design 112. Similarly, the device design 112 can be provided to a circuit design system 120 (e.g., as an available component for use in circuits), which a user can utilize to generate a circuit design 122 (e.g., by connecting one or more inputs and outputs to various devices included in a circuit). The circuit design 122 can comprise program code that includes a device designed as described herein. In any event, the circuit design 122 and/or one or more physical devices 116 can be provided to a circuit fabrication system 124, which can generate a physical circuit 126 according to the circuit design 122. The physical circuit 126 can include one or more devices 116 designed as described herein. In another embodiment, the invention provides a device design system 110 for designing and/or a device fabrication system 114 for fabricating a semiconductor device 116 as described herein. In this case, the system 110, 114 can comprise a general purpose computing device, which is programmed to implement a method of designing and/or fabricating the semiconductor device 116 as described herein. Similarly, an embodiment of the invention provides a circuit design system 120 for designing and/or a circuit fabrication system 124 for fabricating a circuit 126 that includes at least one device 116 designed and/or fabricated as described herein. In this case, the system 120, 124 can comprise a general purpose computing device, which is programmed to implement a method of designing and/or fabricating the circuit 126 including at least one semiconductor device 116 as described herein. In still another embodiment, the invention provides a computer program fixed in at least one computer-readable medium, which when executed, enables a computer system to implement a method of designing and/or fabricating a semiconductor device as described herein. For example, the computer program can enable the device design system 110 to generate the device design 112 as described herein. To this extent, the computer-readable medium includes program code, which implements some or all of a process described herein when executed by the computer system. It is understood that the term “computer-readable medium” comprises one or more of any type of tangible medium of expression, now known or later developed, from which a stored copy of the program code can be perceived, reproduced, or otherwise communicated by a computing device. In another embodiment, the invention provides a method of providing a copy of program code, which implements some or all of a process described herein when executed by a computer system. In this case, a computer system can process a copy of the program code to generate and transmit, for reception at a second, distinct location, a set of data signals that has one or more of its characteristics set and/or changed in such a manner as to encode a copy of the program code in the set of data signals. Similarly, an embodiment of the invention provides a method of acquiring a copy of program code that implements some or all of a process described herein, which includes a computer system receiving the set of data signals described herein, and translating the set of data signals into a copy of the computer program fixed in at least one computer-readable medium. In either case, the set of data signals can be transmitted/received using any type of communications link. In still another embodiment, the invention provides a method of generating a device design system 110 for designing and/or a device fabrication system 114 for fabricating a semiconductor device as described herein. In this case, a computer system can be obtained (e.g., created, maintained, made available, etc.) and one or more components for performing a process described herein can be obtained (e.g., created, purchased, used, modified, etc.) and deployed to the computer system. To this extent, the deployment can comprise one or more of: (1) installing program code on a computing device; (2) adding one or more computing and/or I/O devices to the computer system; (3) incorporating and/or modifying the computer system to enable it to perform a process described herein; and/or the like. The foregoing description of various aspects of the invention has been presented for purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise form disclosed, and obviously, many modifications and variations are possible. Such modifications and variations that may be apparent to an individual in the art are included within the scope of the invention as defined by the accompanying claims. | <SOH> BACKGROUND ART <EOH>Semiconductor emitting devices, such as light emitting diodes (LEDs) and laser diodes (LDs), include solid state emitting devices composed of group III-V semiconductors. A subset of group III-V semiconductors includes group III nitride alloys, which can include binary, ternary and quaternary alloys of indium (In), aluminum (Al), gallium (Ga), and nitrogen (N). Illustrative group III nitride-based LEDs and LDs can be of the form In y Al x Ga 1-x-y N, where x and y indicate the molar fraction of a given element, 0≦x, y≦1, and 0≦x+y≦1. Other illustrative group III nitride based LEDs and LDs are based on boron (B) nitride (BN) and can be of the form Ga z In y Al x B 1-x-y-z N, where 0≦x, y, z≦1, and 0≦x+y+z≦1. An LED is typically composed of semiconducting layers. During operation of the LED, an applied bias across doped layers leads to injection of electrons and holes into an active layer where electron-hole recombination leads to light generation. Light is generated with uniform angular distribution and escapes the LED die by traversing semiconductor layers in all directions. Each semiconducting layer has a particular combination of molar fractions (e.g., x, y, and z) for the various elements, which influences the optical properties of the layer. In particular, the refractive index and absorption characteristics of a layer are sensitive to the molar fractions of the semiconductor alloy. An interface between two layers is defined as a semiconductor heterojunction. At an interface, the combination of molar fractions is assumed to change by a discrete amount. A layer in which the combination of molar fractions changes continuously is said to be graded. Changes in molar fractions of semiconductor alloys can allow for band gap control, but can lead to abrupt changes in the optical properties of the materials and result in light trapping. A larger change in the index of refraction between the layers, and between the substrate and its surroundings, results in a smaller total internal reflection (TIR) angle (provided that light travels from a high refractive index material to a material with a lower refractive index). A small TIR angle results in a large fraction of light rays reflecting from the interface boundaries, thereby leading to light trapping and subsequent absorption by layers or LED metal contacts. Roughness at an interface allows for partial alleviation of the light trapping by providing additional surfaces through which light can escape without totally internally reflecting from the interface. Nevertheless, light only can be partially transmitted through the interface, even if it does not undergo TIR, due to Fresnel losses. Fresnel losses are associated with light partially reflected at the interface for all the incident light angles. Optical properties of the materials on each side of the interface determines the magnitude of Fresnel losses, which can be a significant fraction of the transmitted light. | <SOH> SUMMARY OF THE INVENTION <EOH>Aspects of the invention provide an optoelectronic device with a multi-layer contact. The optoelectronic device can include an n-type semiconductor layer having a surface. A mesa can be located over a first portion of the surface of the n-type semiconductor layer and have a mesa boundary. An n-type contact region can be located over a second portion of the surface of the n-type semiconductor contact layer entirely distinct from the first portion, and be at least partially defined by the mesa boundary. A first n-type metallic contact layer can be located over at least a portion of the n-type contact region in proximity of the mesa boundary, where the first n-type metallic contact layer forms an ohmic contact with the n-type semiconductor layer. A second metallic contact layer can be located over a second portion of the n-type contact region, where the second metallic contact layer is formed of a reflective metallic material. A first aspect of the invention provides an optoelectronic device comprising: an n-type semiconductor layer having a surface; a mesa located over a first portion of the surface of the n-type semiconductor layer and having a mesa boundary; an n-type contact region located over a second portion of the surface of the n-type semiconductor contact layer entirely distinct from the first portion, wherein the n-type contact region is at least partially defined by the mesa boundary; a first n-type metallic contact layer located over at least a portion of the n-type contact region in proximity of the mesa boundary, wherein the first n-type metallic contact layer forms an ohmic contact with the n-type semiconductor layer; and a second metallic contact layer located over a second portion of the n-type contact region, wherein the second metallic contact layer is formed of a reflective metallic material. A second aspect of the invention provides an optoelectronic device comprising: an n-type group III nitride semiconductor layer having a surface; a mesa located over a first portion of the surface of the n-type group III nitride semiconductor layer and having a mesa boundary, wherein the mesa boundary includes a plurality of interconnected fingers; an n-type contact region located over a second portion of the surface of the n-type group III nitride semiconductor contact layer entirely distinct from the first portion, wherein the n-type contact region is at least partially defined by the mesa boundary; a first n-type metallic contact layer located over at least a portion of the n-type contact region in proximity of the mesa boundary, wherein the first n-type metallic contact layer forms an ohmic contact with the n-type group III nitride semiconductor layer, and wherein the first n-type metallic contact layer extends between the plurality of interconnected fingers; and a second metallic contact layer located over a second portion of the n-type contact region, wherein the second metallic contact layer is formed of a reflective metallic material. A third aspect of the invention provides a method of fabricating an optoelectronic device comprising: forming a mesa having a mesa boundary over a first portion of an n-type semiconductor layer, wherein the mesa includes an active semiconductor layer and a p-type semiconductor contact layer located on an opposite side of the active semiconductor layer as the n-type semiconductor layer, and wherein the n-type semiconductor layer has an n-type contact region located over a second portion of the surface of the n-type semiconductor contact layer entirely distinct from the first portion, wherein the n-type contact region is at least partially defined by the mesa boundary; depositing a first n-type metallic contact layer over a first portion of the n-type contact region in proximity to the mesa boundary; and depositing a second metallic contact layer over a second portion of the n-type contact region. The illustrative aspects of the invention are designed to solve one or more of the problems herein described and/or one or more other problems not discussed. | H01L33405 | 20171031 | 20180308 | 71585.0 | H01L3340 | 2 | HAIDER, WASIUL | Contact Configuration for Optoelectronic Device | UNDISCOUNTED | 1 | CONT-ACCEPTED | H01L | 2,017 |
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15,799,911 | PENDING | DEVICE AND SYSTEM FOR ASSISTING ACTUATION OF A BUCKLE RELEASE | A device and system that can be used to assist actuation of a buckle release is disclosed. A device can comprise a first arm and a second arm joined by a U-shaped connecting portion. The device can also comprise a button contact feature. The device can be inserted over a buckle with the button contact feature over a buckle release button, and the device used to assist engagement of the buckle release button by a person operating the device. A system can comprise a device and various additional features or accessories. | 1. A device for actuating a buckle release button comprising: a first arm, wherein the first arm comprises a first end and a button contact feature with a button contact surface, and wherein the first arm defines a first axis; a second arm, wherein the second arm comprises a second end and defines a second axis; and a connecting portion disposed between the first arm and the second arm. 2. The device of claim 1, wherein the connecting portion comprises a U-shape, and wherein the first arm and the second arm comprise a laterally-opposed configuration. 3. The device of claim 2, further comprising an attachment feature. 4. The device of claim 2, wherein the device has unitary construction. 5. The device of claim 4, wherein the device comprises a polymer material. 6. The device of claim 5, wherein the device is configured to be elastically deformable in one of the first ami, the second arm, and the connecting portion to provide for movement of the button contact surface through a first deflection distance in response to a first deflection force, and wherein the device is configured to produce a first restoring force in response to the movement through the first deflection distance. 7. The device of claim 6, wherein the device comprises a first spring constant. 8. The device of claim 7, wherein the device comprises a relief slot. 9. The device of claim 8, wherein the relief slot is disposed in one of the first arm, the second arm, and the connecting portion. 10. The device of claim 9, wherein one of the first restoring force and the first spring constant is reduced relative to an equivalent device lacking a relief slot. 11. The device of claim 6, wherein the first deflection distance is sufficient to actuate a buckle release button. 12. The device of claim 6, wherein the button contact feature comprises a button contact feature height, and wherein the button contact feature height is configured to provide buckle housing clearance at the first deflection distance. 13. The device of claim 6, wherein the device comprises an inter-arm dimension. 14. The device of claim 13, wherein the inter-arm dimension is configured to provide a clearance fit with respect to a buckle housing. 15. The device of claim 13, wherein the inter-arm dimension is configured to provide a compression fit with respect to a buckle release button. 16. The device of claim 15, wherein insertion of a buckle into the device produces the first deflection force, and wherein the first restoring force produced by the device provides a buckle release actuation assistance. 17. The device of claim 1, further comprising one of a flashlight, a bottle opener, a whistle, a seat belt cutter, and a glass breaker. 18. A system comprising: a buckle release device; and an attachment device; wherein the buckle release device comprises an attachment feature configured to receive the attachment device, and wherein the attachment device is inserted into the attachment feature. 19. The system of claim 18, wherein the attachment device is one of a key ring, a carabiner, a steel cable loop, a chain, a wire, and a lanyard. 20. The system of claim 18, further comprising one of a flashlight and a seat belt cutter. | CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Application Ser. No. 62/415,407, entitled “DEVICE AND SYSTEM FOR ASSISTING ACTUATION OF A BUCKLE RELEASE,” filed on Oct. 31, 2016. The entire disclosure of the aforementioned application is incorporated herein by reference for any purpose. FIELD The present disclosure relates to a device and system for actuation of a buckle release. In particular, the disclosure relates to a device and system that can be used to assist actuation of buckle release buttons in restraint system buckles. BACKGROUND Restraint systems such as child safety seats used in automobiles as well as restraint systems used in other settings frequently include a buckle-type fastening mechanism to secure two or more portions of the restraint system around a restraint system occupant. A buckle-type fastening mechanism generally includes a buckle attached to an end of a first section of restraint system belting and a tongue or latchplate portion attached to a second section of restraint system belting. The tongue is inserted into the buckle where it is releasably latched to secure the first and second sections of restraint system belting. Child safety seats frequently include a third section of belting with a second tongue that is inserted into the buckle adjacent the first tongue, with both tongues being secured by the buckle. A buckle generally comprises a housing containing a spring-loaded latching mechanism for releasably latching the tongue or tongues within the buckle. A typical buckle housing comprises an aperture containing an actuating button for operating and releasing the latching mechanism. A spring in the latching mechanism exerts a bias urging the button and/or latching mechanism toward the latched position. The button can be operated by depressing the button using a thumb or fingertip against the bias of the spring with sufficient pressure to overcome the spring force of the latching mechanism and move the button and mechanism from the latched position to a release position, thereby causing the latching mechanism to release the tongue(s) from the latched condition. In a typical buckle, the area of the actuating button approximates or is configured to be pressed by a person's thumb or fingertip. The surface of the actuating button against which the thumb or fingertip presses is generally flush with or recessed from the surface of the housing surrounding the button. A prior art buckle fastening system 100 is illustrated in FIGS. 1A and 1B. Buckle fastening system 100 includes buckle 101 comprising buckle housing 102 and buckle release button 103. Buckle fastening system 100 also includes first and second tongues 104 and 105. Buckle housing 102 has a depth d. Buckle housing 102 further includes a button surround 106 defining an opening in the front face of the buckle that defines the opening for buckle release button 103. Buckle release buttons can be configured in a variety of shapes, including the square and circular buttons 203A and 203B of prior art buckle fastening systems 200A and 200B illustrated in FIGS. 2A and 2B, respectively, as well as various other geometric and irregular shapes. Buckle fastening systems such as those described above can be inconvenient or challenging for certain people to operate for various reasons, including individual variability in hand and finger size and strength, certain physical or medical conditions such as tendonitis and arthritis, and the like. Likewise, the force required for actuation of buckle releases used for certain car seat models can be relatively high, creating discomfort, pain, or fatigue for users, for example, that may be required to operate such a buckle on a frequent basis in various circumstances. Devices and systems that can be used to assist actuation of buckle releases are desirable. The present disclosure provides devices and systems that can be used to assist actuation of a restraint system buckle release button. SUMMARY In various embodiments, a device for actuating a buckle release button can comprise a first arm, a second arm, and a connecting portion disposed between the first arm and the second arm. A first arm can comprise a first end and a button contact feature with a button contact surface. The first arm can define a first axis, and the second arm can define a second axis. The connecting portion can comprise a U-shape, and the first arm and the second arm can comprise a laterally-opposed configuration. A device for actuating a buckle release button can comprise an attachment feature. A device can have a unitary constriction and can comprise a polymer material. A device can be configured to be elastically deformable in one of the first arm, the second arm, and the connecting portion to provide for movement of the button contact surface through a first deflection distance in response to a first deflection force. A device can be configured to provide a first restoring force in response to the movement through the first deflection distance. A device can comprise a first spring constant. A device can comprise a relief slot. A relief slot can be disposed in one of the first arm, the second arm, and the connecting portion of a device. A relief slot can provide for one of a reduced first restoring force and a reduced first spring constant relative to an equivalent device lacking a relief slot. A first deflection distance can be sufficient to actuate a buckle release device. A button contact feature can comprise a button contact feature height. The button contact feature height can be configured to provide buckle housing clearance at the first deflection distance. A device can comprise an inter-arm dimension. In various embodiments, an inter-arm dimension can be configured to provide a clearance fit with respect to a buckle housing. In various embodiments, an inter-arras dimension can be configured to provide a compression fit with respect to a buckle release button. Insertion of a buckle into a device configured to provide a compression fit with respect to a buckle release button can produce a first deflection force, and the first restoring force produced by the device in response to the first deflection force can provide buckle release actuation assistance. In various embodiments, a system for actuating a buckle release is provided. A system can comprise a buckle release device and an attachment device. A buckle release device can comprise an attachment feature configured to receive an attachment device. The attachment device can be inserted into the attachment feature and can be removably attached to the attachment feature. An attachment device can comprise one of a key ring, a carabiner, a steel cable loop, a chain, a wire, and a lanyard. A system in accordance with various embodiments can comprise one of a flashlight and a seat belt cutter. BRIEF DESCRIPTION OF THE DRAWINGS The subject matter of the present disclosure is particularly pointed out and distinctly claimed in the concluding portion of the specification. A more complete understanding of the present disclosure, however, may best be obtained by referring to the detailed description and claims when considered in connection with the drawing figures. FIGS. 1A and 1B illustrate front and side views of a prior art buckle fastening system, respectively; FIGS. 2A and 2B illustrate prior art buckle fastening systems having different buckle release button shapes; FIGS. 3A and 3B illustrate perspective views of a device for actuating a buckle release button in accordance with various embodiments; FIG. 4 illustrates a side view of a device for actuating a buckle release button in accordance with various embodiments; FIG. 5 illustrates a side view of a device for actuating a buckle release button in accordance with various embodiments; FIG. 6 illustrates a front perspective view of a device for actuating a buckle release button in accordance with various embodiments; FIG. 7 illustrates a side view of a device for actuating a buckle release button in accordance with various embodiments; FIGS. 8A and 8B illustrate side and perspective views of a device for actuating a buckle release button in accordance with various embodiments; and FIGS. 9A and 9B illustrate side views of devices for actuating a buckle release button that include a belt cutter in accordance with various embodiments. DETAILED :DESCRIPTION The detailed description of exemplary embodiments herein makes reference to the accompanying drawings, which show exemplary embodiments by way of illustration and their best mode. While these exemplary embodiments are described in sufficient detail to enable those skilled in the art to practice the inventions, it should be understood that other embodiments may be realized and that logical and mechanical changes may be made without departing from the spirit and scope of the inventions. Thus, the detailed description herein is presented for purposes of illustration only and not of limitation. For example, the steps recited in any of the method or process descriptions may be executed in any order and are not necessarily limited to the order presented. Furthermore, any reference to singular includes plural embodiments, and any reference to more than one component or step may include a singular embodiment or step. Also, any reference to attached, fixed, connected or the like may include permanent, removable, temporary, partial, full and/or any other possible attachment option. Additionally, any reference to without contact (or similar phrases) may also include reduced contact or minimal contact. As used herein, the term “actuate” means to cause a device to operate, such as a fastening mechanism release. As used herein, the term “spring constant” means an approximation of a factor characteristic of an elastically deformable material in a particular configuration within the elastic limits of the material in the configuration. As used herein, the term “unitary construction” means constructed of a single piece of material. With reference to FIGS. 3A and 3B, a device 300 is illustrated. As described herein, device 300 can be used to assist actuation of a buckle fastening system. In accordance with various embodiments, device 300 can comprise a first arm 301, a second arm 302, and a connecting portion 305 disposed between the first arm and the second arm. First arm 301 can have an elongated configuration and define a first axis A-A′, and second arm 302 can have an elongated configuration and defines a second axis B-B′. In various embodiments, a first arm, second arm, and/or connecting portion can have a square or rectangular cross section, or they can have a circular, ellipsoid, or other geometric or non-geometric cross section. Device 300 can be configured such that first arm 301 and second arm 302 comprise a laterally-opposed configuration, as illustrated, with distal end 303 of first arm 301 and distal end 304 of second arm 302 configured opposite one another. Connecting portion 305 can comprise a U-shaped segment joining the proximal ends of first arm 301 and second arm 302. In various embodiments, axes A-A′ and B-B′ of a device such as device 300 can be substantially aligned with one another, or the axes may converge or diverge from the distal ends of the first and second arms to the proximal portion of the arms. In various embodiments, a connecting portion can have other configurations or profiles, such as a rectangular profile or any other profile suitable to provide a first device arm and a second device arm in a laterally-opposed configuration. First arm 301 and second arm 302 can define a buckle space 306 between the interior surfaces of the arms. Device 300 can comprise a button contact feature 307 extending into the buckle space 306 from the interior surface of first arm 301. Button contact feature 307 can comprise a button contact surface 308 facing toward second arm 302. Button contact feature 307 may be located near the distal end of first arm 301. In various embodiments, first arm 301 may extend distally past the location of button contact feature 307. Button contact feature 307 and button contact surface 308 can be configured to operatively engage a buckle fastening system button, as described in greater detail below. In various embodiments, device 300 can comprise an attachment feature 309. An attachment feature such as attachment feature 309 can comprise a flange or protrusion configured to facilitate attachment of device 300 to a set of keys, for example, by using an attachment device such as a key ring, carabiner, a steel cable loop, a chain, a wire, or a lanyard. Attachment feature 309 can comprise an aperture 310 through which an attachment device can be inserted. With reference briefly to FIG. 6, a key ring 612 is illustrated inserted into aperture 610 of attachment feature 609 for device 600. With reference once more to FIGS. 3A and 3B, attachment feature 309 can be located on an outer surface of connecting portion 305, first arm 301, or second arm 302, or any other suitable location. In various embodiments, a connecting feature need not comprise a protrusion, and instead can comprise an aperture or other feature of device 300 that does not extend from a surface of device 300. In various embodiments, device 300 can comprise a relief slot 311. Relief slot 311 can be disposed in one of the first arm 301, the second arm 302, and the connecting portion 305. In various embodiments, relief slot 311 may be disposed in more than one portion of device 300. For example and as illustrated, relief slot 311 extends through connecting portion 305 and into proximal portions of first arm 301 and second arm 302. In various embodiments, a relief slot may also serve as an attachment feature. In various embodiments and as further described below, a relief slot such as relief slot 311 may be configured to reduce one of the first restoring force and the first spring constant of device 300 as compared to an equivalent device that is not configured with a relief slot. In various embodiments, a device such as device 300 may be manufactured from a polymer material. Polymer materials that may be used can include, for example, high density polyethylene (HDPE), acrylonitrile butadiene styrene (ABS), polypropylene (PP), polyester (PES), polyethylene terephthalate (PET), polyvinyl chloride (PVC), polyamides (PA) including various nylons, polyethylene/acrylonitrile butadiene styrene (PE/ABS), and polycarbonate (PC), polycarbonate/acrylonitrile butadiene styrene (PC/ABS), as well as various resins or materials compatible with various additive manufacturing processes and/or 3D printers, such as Stratasys PolyJet materials. In various embodiments, a device can comprise natural materials such as wood, bamboo, hemp- or algal-based biopolymers, and the like. Natural materials can be used in a composite material, for example, a wood and adhesive laminate (i.e., plywood). In various embodiments comprising a laminated material, layers may be oriented such that the layer arrangement is visible in a side view. In various embodiments comprising laminate wood or plywood, the grains of the veneers may be configured to permit a suitable level of flexibility and/or a suitable spring constant. Composite materials such as carbon fiber-, graphite fiber-, and graphene fiber-reinforced polymers may be used in a device in accordance with various embodiments. Likewise, a device can comprise metals or metal alloys including steel, titanium, chromium, cobalt-chrome, stainless steel, aluminum, and the like. In various embodiments, a device such as device 300 can comprise a phosphorescent (and/or photoluminescent) material to provide the device with a capacity to glow in dark conditions. For example, a phosphorescent material such as zinc sulfide or strontium aluminate can be incorporated into the device, such as by incorporation into a polymer composite used to manufacture the device or by applying to the device in a coating. Use of phosphorescent material in a device to confer a glow-in-the-dark characteristic can facilitate a user's ability to locate the device under dark conditions. In various embodiments, a device such as device 300 may be unitarily constructed, such as by injection molding or additive manufacturing as a single component. In various other embodiments, a device can comprise two or more components attached to one another by various mechanical attachment methods including adhesives, welding, fastening, joinery, hinge, or other mechanical attachment. For example and with reference briefly to FIG. 5, device 500 comprises a hinge 520 configured in the connecting portion 505 between first arm 501 and second arm 502. Any of a variety of hinge configurations may be suitable for use in a device in accordance with various embodiments of the present disclosure. In various embodiments, a hinge or other mechanical attachment can include a spring configured to bias the first arm and the second arm of the device toward an open position suitable to receive a buckle in buckle space 506. With reference again to FIGS. 3A and 3B, the illustrated device 300 comprises a unitary construction. Device 300 can he configured to be elastically deformable in one of the first arm 301, the second arm 302, and the connecting portion 305. The elastically deformable configuration of device 300 can provide for movement of button contact surface 308 through a first deflection distance relative to the position of the second arm 302 in response to a first deflection force. The device can be configured to produce a first restoring force in response to movement through the first deflection distance biased in a direction opposite the first deflection distance. In various embodiments, the first restoring force can be produced as a function of the spring constant of an elastically deformable material used to fabricate the device, for example, for unitarily constructed devices such as device 300, in response to movement of the device through the first deflection distance. In various other embodiments, the first restoring force can be produced by a spring or other component of a mechanical connection, such as the hinge mechanism illustrated for device 500 (FIG. 5). In various embodiments, the first deflection distance can be in a direction toward the second arm. For example and with reference now to FIG. 4, typical buckle housings used for buckle fastening mechanisms may have buckle housing depths of from about 0.75 in to about 1.25 in. A device such as device 400 can be configured such that distance D1 (i.e., the inter-arm dimension) provides for clearance of a typical buckle housing relative to a buckle housing depth dimension, enabling an operator to insert device 400 around a buckle housing without deflection or deformation of the device. The operator may position device 400 relative to the buckle so that button contact feature 407 is positioned over the buckle release button. When device 400 is suitably positioned, the operator may squeeze device 400 to compress the device, engaging button contact surface 408 with the underlying buckle release button as the button contact surface travels through the first deflection distance in response to the first deflection force provided by the operator. In operation, the first deflection distance may be suitable to actuate the buckle release button, releasing the buckle from the latched condition to the unlatched condition. A device may be configured to provide a first deflection distance suitable to produce a sufficient button travel distance for various buckle release buttons. For example, the button travel distance required for actuation of various buckle release buttons can be from about 0.10 in to about 0.40 in. A device may also be configured to provide any additional deflection distance necessary to provide a device with a clearance fit (i.e., the distance between the button contact surface and the button surface). In various embodiments, a device may be configured to provide a first deflection distance within the range of from about 0.10 in to about 1.30 in. In various embodiments, a device can be configured to be compatible with a particular buckle fastening system or with selected buckle fastening systems, and different devices can be configured to operate with different buckle fastening systems. A device in accordance with various embodiments can be configured to provide a first deflection distance sufficient to produce actuation of various buckle release buttons for any buckle fastening system now in existence or that may be produced in the future. In operation of a device in accordance with the embodiment described above providing a clearance fit relative to a buckle fastening system, an operator must overcome the restoring force produced by the device in response to elastic deformation of the device and movement of the button contact surface through the first deflection distance. In various embodiments, the restoring force and/or spring constant of the device may depend on the configuration of the device, including, for example, the materials, dimensions, and other features of the device. Additionally, in operation of a device in accordance with the embodiment described above, the operator must overcome the force biasing the buckle release button toward the latched position. The restoring force and/or spring constant of a device may depend on the configuration of the device, including the material used, the shape and dimensions of the device, the presence, location, and configuration of features such as a relief slot or a hinge, and the like. In various embodiments, a device can be configured such that the force required to produce a first deflection distance suitable to actuate a buckle release button can be from about 1.0 newtons to about 8.0 newtons. For example, the force required to produce the first deflection distance may be about 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, or about 8.0 newtons. In various embodiments, the force required to produce a first deflection distance suitable to actuate a buckle release button can be produced by a device operator with a grip force that is lower than that of an average population to allow a device to be operated by individuals with various physical conditions that may negatively affect grip force. For example, a grip force required to produce a first deflection distance suitable to actuate a buckle release button can be less than about 50 N, or less than about 40 N, or less than about 30 N, or less than about 25 N, or less than about 20 N, or less than about 15 N, or less than about 10 N. In various embodiments, a device can comprise a relief slot such as relief slot 311 (FIG. 3) that may be configured to provide a reduced first restoring force and/or spring constant as compared to an equivalent device comprising the same material and the same dimensions but lacking the relief slot. In accordance with various embodiments of the present disclosure, a device can be configured to provide suitable strength and structural rigidity for durability and reliable operation of the device over many buckle release cycles. A device can also be configured to provide a restoring force and/or spring constant during operation of the device to produce a first deflection distance that is sufficiently low that it is not prohibitive to users. For examples, users of a device may have certain physical or medical limitations that present challenges to compression of a buckle release button without the aid of a device as disclosed herein, or to compression of a device such as those disclosed herein that do not include a feature configured to reduce the restoring force and/or spring force constant such as a relief slot or a hinge. A relief slot can be disposed in one of the first arm, the second arm, and the connecting portion. The configuration of a relief slot, including the position and size can be adjusted to “tune” the restoring force and/or spring force constant of a device. For example, a longer or a wider relief slot can produce a decreased spring force constant compared to a shorter or a narrower relief slot. In various embodiments, a device can be configured with relief areas. A relief area may be provided for various reasons, such as to reduce the amount of material required to manufacture a device and/or to reduce the occurrence of manufacturing irregularities such as sink marks or depressions that may occur in thicker portions of injection molded devices. With reference briefly to FIGS. 8A and 8B, a device 800 with a relief area 850 is illustrated. Relief area 850 is defined by a perimeter wall 851 and an inner wall 852. Device 800 can comprise a pair of relief areas such as relief area 850 configured on opposite sides of first arm 801. In various embodiments, a configuration of a device such as device 400 (FIG. 4) can provide an operator with certain benefits facilitating exertion of sufficient force to produce the first deflection distance. For example, the configuration of the device can provide enhanced ergonomics, such as by providing added surface area by which an operator can exert force on the buckle release button, permitting engagement of additional fingers or portions of the operator's hand(s), or by providing a mechanical advantage, such as by extension of the distal ends of the first arm and/or the second arm distally from the connecting portion (i.e., the fulcrum) to produce enhanced leverage (i.e., via a class two lever) with the operator able to exert force distally to the button the load). In various other embodiments, a device such as device 400 can be configured such that distance D1 provides for a compression fit around a buckle housing and/or buckle release button. For example, a device can be configured such that distance D1 is less than a buckle housing depth and/or a distance from the front face of a buckle button in a latched position and the back of the buckle housing. In such an embodiment, insertion of a device around a buckle will produce a first deflection distance resulting in the buckle contact surface moving away from the second arm of the device. A tapered front surface of the button contact feature may facilitate opening of the arms of the device and movement of the buckle contact surface through a first deflection distance in response to contact with a button housing and lateral pressure and movement of the device relative to the buckle housing to produce insertion of the buckle. The first restoring force produced by the device can provide buckle release actuation assistance, with the bias of the device in a direction opposite of that producing the first deflection distance tending to produce depression of a buckle release button when the button contact surface engages the button. In various embodiments, a device can be configured such that the restoring force is sufficient to actuate a buckle release button, or a device can be configured such that the restoring force is sufficient to partially actuate a release button, and further compressive force must be provided by an operator to fully actuate a buckle release button. In such embodiments, the compressive force provided by an operator may be less than that required for an equivalent device configured to provide a clearance fit rather than a compression fit. In various embodiments, the button contact feature may be configured to engage and/or actuate a buckle release button of one or more buckle fastening systems. For example, the button contact surface may be configured with a length and a width suitable to engage a button surface of one or more buckle fastening systems without interference from a surrounding buckle housing. For example, a button contact surface may be configured with a length and width of about 0.5 in in each dimension, and such a button configuration may be compatible with square or rectangular buttons as well as round, oval, or irregularly shaped buttons with dimensions larger than that of the button contact surface. Likewise, a button contact feature may be configured with a button contact feature height H (FIG. 4) suitable to provide actuation of one or more buckle fastening system buttons while preventing contact or interference between the buckle housing and the inner surface of the first arm (i.e., buckle housing clearance) during operation, such as when the button contact feature has moved through a first deflection distance. Moreover, a device may be configured with a buckle space depth D2 suitable to prevent interference between an inner wall of the connecting portion and the lateral wall of a buckle housing, and/or to provide sufficient space for an operator to insert one or more fingers between the inner wall of the connecting portion and the buckle housing to facilitate removal of the device from the buckle following actuation of the buckle release button. In various embodiments, D2 can be from about 1.25 in to about 2.5 in. A device disclosed herein may provide certain advantages, such as reducing pressure transmitted from the buckle housing to a restrained child or passenger during actuation of the buckle release button due to the laterally-opposed configuration of the first arm and the second arm. In contrast, simple operation of a button by depression with an operator's finger or other prior art tools for pressing a button that lack an opposing arm either transmit pressure through the buckle housing to the person under the buckle housing or require the operator to use his hand or fingers to provide an opposing force. In addition, the devices disclosed herein do not require attachment to the buckle or an associated strap, as required by other prior art devices. Instead, the devices disclosed herein are designed to be removably inserted around a buckle with each use, with the device remaining under the control and supervision of a mature operator, for example, a driver or parent, thereby preventing inadvertent or unsupervised operation by a restrained child or other passenger at inappropriate moments. In various embodiments, a system that can be used to assist actuation of a buckle release button is provided. A system can comprise a device in accordance with the present disclosure. A system can further comprise an attachment device. The attachment device can be connected to the attachment feature. An attachment device can comprise a ring, a chain, a carabiner, a wire, a cable, a lanyard, a strap, or similar device. An attachment device can be any device suitable to attach the device, for example, to an operator's key set or other similarly accessible and portable accessory. In various embodiments, a system can comprise a light. A light can be incorporated in a buckle release device. For example and with reference to FIG. 6, a light 630 can be inserted into distal end of first arm 601 of device 600. A light can also be inserted in other locations in a device, such as the second arm or the connecting portion. A system can comprise, for example, an LED flashlight removably inserted into a buckle release device. A system can further comprise a battery for a light inserted into the buckle release device. The device can be configured so that the light and/or battery are removably inserted so that the battery can be replaced as needed. A system can further comprise a switch for operation of a light, such as switch 631. A switch may be co-located with the light and the buckle release device configured to permit access to the switch on the inserted light, or the switch may be located remotely from the light, with wiring or other circuitry running between the light and the switch. A switch may be located in a position that provides for convenient operation of the light during operation of the buckle release device, such as insertion of the buckle release device over a buckle. In various embodiments, a system can comprise a whistle. A whistle may be attached to a buckle release device or integrated into a buckle release device. A whistle may provide an operator with convenient access to a safety whistle for use in emergency situations. In various embodiments, a system can comprise a glass breaker. A glass breaker can comprise a pointed steel tip, such as a tungsten carbide tip, attached to the buckle release device. A glass breaker can also comprise an automatic center punch tool, such as a spring loaded automatic center punch. A glass breaker may be attached, for example, at the distal end of the first arm or the second arm or to an outer wall of the connecting portion. In various embodiments, a system can also comprise a bottle opener. With reference to FIG. 7, a system can comprise a device 700 with a bottle opener 740 located in an outer wall of first arm 701. A system can comprise a device with a bottle opener located in other locations of the device, such as the second arm or the connecting portion. In various embodiments, a system can comprise a seat belt cutter. A seat belt cutter can be integrated into a buckle release device for use in emergency situations. Referring now to FIGS. 9A and 9B, devices with integrated seat belt cutters are shown. Device 900A illustrated in FIG. 9A includes a seat belt cutter comprising blade 960A embedded in first arm 901A of device 900A with a belt slot 961A opening into the interior of the device. Device 900B illustrated in FIG. 9B includes a seat belt cutter comprising blade 960B with a belt slot 961B opening toward the top of first arm 901B. In operation, a device such as device 900A or 900B comprising a seat belt cutter is positioned such that a seat belt is inserted into the opening of a belt slot such as 961A or 961B, and the device is moved relative to the inserted seat belt such that the blade (e.g., blade 960A or 960B) contacts and cuts the inserted seat belt. In various embodiments, a seat belt cutter may be configured so as to minimize risk of inadvertent contact with clothing or a child or person restrained by a buckle fastening mechanism during use of the buckle release device. For example a seat belt cutter may comprise a removable safety gate that can be opened to expose the seat belt cutter blade and permit insertion of a seat belt into the cutter. EXAMPLE 1 Non-Destructive Defection Test Data for Device Prototypes Constructed from ABS and Polypropylene Prototypes of a device for actuating a buckle release in accordance with various embodiments of the present disclosure were manufactured from acrylonitrile butadiene styrene (ABS) and from polypropylene and subjected to non-destructive testing to determine the pressure required to achieve various deflections of the button contact surface. The results are shown in Table 1. TABLE 1 Results of non-destructive deflection distance testing. Polypropylene ABS Pressure Deflection Deflection 0.42 lbs 0.05 in 0.10 in 0.98 lbs 0.16 in 0.24 in 1.40 lbs 0.31 in 0.46 in For the polypropylene prototype, 1.63 lbs of pressure was required to produce sufficient deflection of the button contact surface to contact the opposite arm (0.56 inches of deflection). For the ABS prototype, 1.74 lbs of pressure was required to produce sufficient deflection of the button contact surface to contact the opposite arm (0.67 inches of deflection). Benefits, other advantages, and solutions to problems have been described herein with regard to specific embodiments. Furthermore, the connecting lines shown in the various figures contained herein are intended to represent exemplary functional relationships and/or physical couplings between the various elements. It should be noted that many alternative or additional functional relationships or physical connections may be present in a practical system. However, the benefits, advantages, solutions to problems, and any elements that may cause any benefit, advantage, or solution to occur or become more pronounced are not to be construed as critical, required, or essential features or elements of the inventions. The scope of the invention is accordingly to be limited by nothing other than the appended claims, in which reference to an element in the singular is not intended to mean “one and only one” unless explicitly so stated, but rather “one or more.” Moreover, where a phrase similar to “at least one of A, B, or C” is used in the claims, it is intended that the phrase be interpreted to mean that A alone may be present in an embodiment, B alone may be present in an embodiment, C alone may be present in an embodiment, or that any combination of the elements A, B and C may be present in a single embodiment; for example, A and B, A and C, B and C, or A and B and C. Different cross-hatching is used throughout the figures to denote different parts but not necessarily to denote the same or different materials. Devices, systems, and methods are provided herein. It the detailed description herein, references to “one embodiment”, “an embodiment”, “an example embodiment”, etc., indicate that the embodiment described may include a particular feature, structure, or characteristic, but every embodiment may not necessarily include the particular feature, structure, or characteristic. Moreover, such phrases are not necessarily referring to the same embodiment, Further, when a particular feature, structure, or characteristic is described in connection with an embodiment, it is submitted that it is within the knowledge of one skilled in the art to affect such feature, structure, or characteristic in connection with other embodiments whether or not explicitly described. After reading the description, it will be apparent to one skilled in the relevant art(s) how to implement the disclosure in alternative embodiments. Furthermore, no element, component, or method step in the present disclosure is intended to be dedicated to the public regardless of whether the element, component, or method step is explicitly recited in the claims. No claim element herein is to be construed under the provisions of 35 U.S.C. 112(f), unless the element is expressly recited using the phrase “means for.” As used herein, the terms “comprises”, “comprising”, or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. | <SOH> BACKGROUND <EOH>Restraint systems such as child safety seats used in automobiles as well as restraint systems used in other settings frequently include a buckle-type fastening mechanism to secure two or more portions of the restraint system around a restraint system occupant. A buckle-type fastening mechanism generally includes a buckle attached to an end of a first section of restraint system belting and a tongue or latchplate portion attached to a second section of restraint system belting. The tongue is inserted into the buckle where it is releasably latched to secure the first and second sections of restraint system belting. Child safety seats frequently include a third section of belting with a second tongue that is inserted into the buckle adjacent the first tongue, with both tongues being secured by the buckle. A buckle generally comprises a housing containing a spring-loaded latching mechanism for releasably latching the tongue or tongues within the buckle. A typical buckle housing comprises an aperture containing an actuating button for operating and releasing the latching mechanism. A spring in the latching mechanism exerts a bias urging the button and/or latching mechanism toward the latched position. The button can be operated by depressing the button using a thumb or fingertip against the bias of the spring with sufficient pressure to overcome the spring force of the latching mechanism and move the button and mechanism from the latched position to a release position, thereby causing the latching mechanism to release the tongue(s) from the latched condition. In a typical buckle, the area of the actuating button approximates or is configured to be pressed by a person's thumb or fingertip. The surface of the actuating button against which the thumb or fingertip presses is generally flush with or recessed from the surface of the housing surrounding the button. A prior art buckle fastening system 100 is illustrated in FIGS. 1A and 1B . Buckle fastening system 100 includes buckle 101 comprising buckle housing 102 and buckle release button 103 . Buckle fastening system 100 also includes first and second tongues 104 and 105 . Buckle housing 102 has a depth d. Buckle housing 102 further includes a button surround 106 defining an opening in the front face of the buckle that defines the opening for buckle release button 103 . Buckle release buttons can be configured in a variety of shapes, including the square and circular buttons 203 A and 203 B of prior art buckle fastening systems 200 A and 200 B illustrated in FIGS. 2A and 2B , respectively, as well as various other geometric and irregular shapes. Buckle fastening systems such as those described above can be inconvenient or challenging for certain people to operate for various reasons, including individual variability in hand and finger size and strength, certain physical or medical conditions such as tendonitis and arthritis, and the like. Likewise, the force required for actuation of buckle releases used for certain car seat models can be relatively high, creating discomfort, pain, or fatigue for users, for example, that may be required to operate such a buckle on a frequent basis in various circumstances. Devices and systems that can be used to assist actuation of buckle releases are desirable. The present disclosure provides devices and systems that can be used to assist actuation of a restraint system buckle release button. | <SOH> SUMMARY <EOH>In various embodiments, a device for actuating a buckle release button can comprise a first arm, a second arm, and a connecting portion disposed between the first arm and the second arm. A first arm can comprise a first end and a button contact feature with a button contact surface. The first arm can define a first axis, and the second arm can define a second axis. The connecting portion can comprise a U-shape, and the first arm and the second arm can comprise a laterally-opposed configuration. A device for actuating a buckle release button can comprise an attachment feature. A device can have a unitary constriction and can comprise a polymer material. A device can be configured to be elastically deformable in one of the first arm, the second arm, and the connecting portion to provide for movement of the button contact surface through a first deflection distance in response to a first deflection force. A device can be configured to provide a first restoring force in response to the movement through the first deflection distance. A device can comprise a first spring constant. A device can comprise a relief slot. A relief slot can be disposed in one of the first arm, the second arm, and the connecting portion of a device. A relief slot can provide for one of a reduced first restoring force and a reduced first spring constant relative to an equivalent device lacking a relief slot. A first deflection distance can be sufficient to actuate a buckle release device. A button contact feature can comprise a button contact feature height. The button contact feature height can be configured to provide buckle housing clearance at the first deflection distance. A device can comprise an inter-arm dimension. In various embodiments, an inter-arm dimension can be configured to provide a clearance fit with respect to a buckle housing. In various embodiments, an inter-arras dimension can be configured to provide a compression fit with respect to a buckle release button. Insertion of a buckle into a device configured to provide a compression fit with respect to a buckle release button can produce a first deflection force, and the first restoring force produced by the device in response to the first deflection force can provide buckle release actuation assistance. In various embodiments, a system for actuating a buckle release is provided. A system can comprise a buckle release device and an attachment device. A buckle release device can comprise an attachment feature configured to receive an attachment device. The attachment device can be inserted into the attachment feature and can be removably attached to the attachment feature. An attachment device can comprise one of a key ring, a carabiner, a steel cable loop, a chain, a wire, and a lanyard. A system in accordance with various embodiments can comprise one of a flashlight and a seat belt cutter. | A44B112573 | 20171031 | 20180503 | 96248.0 | A44B1125 | 1 | LEE, MICHAEL S | DEVICE AND SYSTEM FOR ASSISTING ACTUATION OF A BUCKLE RELEASE | MICRO | 0 | ACCEPTED | A44B | 2,017 |
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15,799,927 | PENDING | Novel Reagents for Directed Biomarker Signal Amplification | Described herein are methods, compositions and articles of manufacture involving neutral conjugated polymers including methods for synthesis of neutral conjugated water-soluble polymers with linkers along the polymer main chain structure and terminal end capping units. Such polymers may serve in the fabrication of novel optoelectronic devices and in the development of highly efficient biosensors. The invention further relates to the application of these polymers in assay methods. | 1-40. (canceled) 41. A polymer-biomolecule conjugate comprising: a water soluble conjugated polymer; and a biomolecule covalently linked to the water soluble conjugated polymer; wherein the water soluble conjugated polymer is of the formula: wherein: each R is independently a non-ionic side group capable of imparting solubility in water; MU is a polymer modifying unit or band gap modifying unit that is evenly or randomly distributed along the polymer main chain and is optionally substituted with one or more optionally substituted substituents selected from halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl, C1-C12 haloalkyl, C1-C12 alkoxy, C2-C18 (hetero)aryloxy, C2-C18 (hetero)arylamino, a C2-C18 (hetero)aryl group and (CH2)x′(OCH2CH2)y′OCH3 where x′ is independently an integer from 0-20 and y′ is independently an integer from 0 to 50; L1 and L2 are linkers each independently an aryl or a heteroaryl group evenly or randomly distributed along the polymer main chain and are substituted with one or more pendant chains terminated with: i) a functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated ester, N-hydroxysuccinimidyl, hydrazine, hydrazide, hydrazone, azide, alkyne, aldehyde, thiol, and protected groups thereof for conjugation to a molecule or biomolecule; or ii) a conjugated organic dye or the covalently linked biomolecule; G1 and G2 are each independently selected from hydrogen, halogen, alkyne, optionally substituted aryl, optionally substituted heteroaryl, halogen substituted aryl, boronic acid substituted aryl, boronic ester substituted aryl, boronic ester, boronic acid, optionally substituted fluorene and aryl or heteroaryl substituted with one or more pendant chains terminated with: i) a functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazine, hydrazide, hydrazone, azide, alkyne, aldehyde, thiol, and protected groups thereof for conjugation to a molecule or biomolecule; or ii) a conjugated organic dye or the covalently linked biomolecule; n is an integer from 1 to about 10,000; and a, b, c and d define the mol % of each unit within the structure which each can be evenly or randomly repeated and where a is a mol % from 10 to 100%, b is a mol % from 0 to 90%, and each c and d are mol % from 0 to 25%. 42. The polymer-biomolecule conjugate according to claim 41, wherein the biomolecule is a sensor biomolecule capable of interacting with a target molecule. 43. The polymer-biomolecule conjugate according to claim 41, wherein the biomolecule is a protein, a peptide, an affinity ligand, an antibody, an antibody fragment, a sugar, a lipid, a nucleic acid, an aptamer, avidin, streptavidin, neutravidin, avidinDN or avidinD. 44. The polymer-biomolecule conjugate according to claim 43, wherein the biomolecule is an antibody or antibody fragment. 45. The polymer-biomolecule conjugate according to claim 41, wherein MU is selected from optionally substituted benzothiadiazole, optionally substituted benzoxidazole, optionally substituted benzoselenadiazole, optionally substituted benzotellurodiazole, optionally substituted naphthoselenadiazole, optionally substituted 4,7-di(thien-2-yl)-2,1,3-benzothiadiazole, squaraine dyes, optionally substituted quinoxaline, optionally substituted perylene, optionally substituted perylene diimide, optionally substituted diketopyrrolopyrrole, thienopyrazine low bandgap commercial dyes, olefin and cyano-substituted olefins and isomers thereof. 46. The polymer-biomolecule conjugate according to claim 45, wherein MU is selected from the group consisting of a′-k′ having the structures: wherein * is a site for covalent attachment to the backbone of the conjugated polymer and each R is a side group capable of imparting solubility in water. 47. The polymer-biomolecule conjugate according to claim 46, wherein MU is selected from one of the following: wherein * is a site for covalent attachment to the backbone of the conjugated polymer. 48. The polymer-biomolecule conjugate according to claim 41, wherein MU is a phenyl. 49. The polymer-biomolecule conjugate according to claim 48, wherein MU is wherein * is a site for covalent attachment to the backbone of the conjugated polymer. 50. The method according to claim 41, wherein each R is a non-ionic side group capable of imparting solubility in water in excess of 10 mg/mL. 51. The polymer-biomolecule conjugate according to claim 41, wherein each R comprises an ethylene glycol oligomer. 52. The polymer-biomolecule conjugate according to claim 51, wherein each R is a non-ionic side group comprising mPEG5, mPEG8, mPEG11 or mPEG24. 53. The polymer-biomolecule conjugate according to claim 51, wherein each R is independently selected from (CH2)x′(OCH2CH2)y′OCH3 wherein x′ is independently an integer from 0-20 and y′ is independently an integer from 0 to 50, and a benzyl substituted with one or more groups selected from halogen, hydroxyl, C1-C12 alkoxy and (OCH2CH2)zOCH3 wherein z is independently an integer from 0 to 50. 54. The polymer-biomolecule conjugate according to claim 51, wherein each R is (CH2)x′(OCH2CH2)y′OCH3 wherein x′ is independently an integer from 0-20 and y′ is independently an integer from 0 to 50. 55. The polymer-biomolecule conjugate according to claim 41, wherein each R is a dendrimer of PAMAM, PEA, PEHAM, PPI, tri-branched benzoate, or glycerol with a generation of 1 to 4 and optional terminal substitutions selected from ( - - - - - )CH2CH2O)jCH3 and ( - - - - - )(OCH2CH2)jCH3 where j is an integer from 0 to 25 and the dotted lines ( - - - - - ) are each independently selected from any one or a combination of, C1-C12 alkyl, C1-C12 alkoxy, C2-C12 alkene, amido, amino, aryl, (CH2)r(OCH2CH2)s(CH2)r where each r is independently an integer from 0-20, s is independently an integer from 0 to 50, carbamate, carboxylate, C3-C12 cycloalkyl, imido, phenoxy and C4-C18(hetero)aryl group. 56. The method according to claim 41, wherein wherein L1 and/or L2 are present and have the structure: wherein: * is a site for covalent attachment to the backbone of the conjugated polymer; each R′ is different from R and is independently selected from H, halogen, C1-C12 alkyl, (C1-C12 alkyl)NH2, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl, C1-C12 haloalkyl, C2-C18(hetero)aryl, C2-C18(hetero)arylamino, —[CH2—CH2]r′—Z1 wherein Z1 is —OH or —COOH and r′ is an integer from 1 to 20, (C1-C12)alkoxy-X1 wherein X1 is —NH2, —NHCOOH, —NHCOOC(CH3)3, —NHCO(C3-C12)cycloalkyl(C1-C4)alkyl-N-maleimide or —NHCO[CH2—CH2—O]s′(CH2)s′NH2 and each s′ is independently an integer from 1 to 20, (CH2)3(OCH2CH2)x″OCH3 wherein x″ is an integer from 0 to 50, and a benzyl optionally substituted with one or more halogen, hydroxyl, C1-C12 alkoxy or (OCH2CH2)y″OCH3 wherein y″ is an integer from 0 to 50. 57. The polymer-biomolecule conjugate according to claim 41, wherein L1 and/or L2 are present and have the structure: wherein: * is a site for covalent attachment to the backbone of the conjugated polymer; each R25 is independently a bond, C1-C20 alkyl, C1-C20 alkoxy, C2-C20 alkene, C2-C20 alkyne, C3-C20 cycloalkyl, C1-C20 haloalkyl; (CH2)x(OCH2CH2)p(CH2)x where each x is independently an integer from 0-20, p is independently an integer from 0 to 50; aryl, C2-C18(hetero)aryl, phenoxy, amido, amino, carbamate, carboxylate, carbonates, sulfide, disulfide, or imido groups; and at least one R25 is terminated with a functional group selected from amine, carbamate, carboxylate, carboxylic acid, maleimide, activated ester, N-hydroxysuccinimidyl, hydrazine, hydrazide, hydrazone, azide, alkyne, aldehyde and thiols, or a conjugated organic dye or the covalently linked biomolecule. 58. The polymer-biomolecule conjugate according to claim 41, wherein L1 and/or L2 is conjugated to a signaling chromophore. 59. The polymer-biomolecule conjugate according to claim 41, wherein G1 or G2 comprise the covalently linked biomolecule. 60. The polymer-biomolecule conjugate according to claim 55, wherein at least one of G1 and G2 has the structure: wherein: * is a site for covalent attachment to the backbone of the conjugated polymer; and R11 is a bond, C1-C20 alkyl, C1-C20 alkoxy, C2-C20 alkene, C2-C20 alkyne, C3-C20 cycloalkyl, C1-C20 haloalkyl, (CH2)x(OCH2CH2)p(CH2)x wherein each x is independently an integer from 0-20 and p is an integer from 0 to 50, aryl, C2-C18(hetero)aryl, phenoxy, amido, amino, carbamate, carboxylate, carbonate, sulfide, disulfide, or imido groups; and is terminated with a functional group covalently linked to the biomolecule. | CROSS-REFERENCE This application is a continuation of application Ser. No. 15/239,713, filed Aug. 17, 2016; which application is a continuation of application Ser. No. 14/821,386, filed Aug. 7, 2015 and issued as U.S. Pat. No. 9,547,008; which application is a continuation of application Ser. No. 14/018,985, filed Sep. 5, 2013 and issued as U.S. Pat. No. 9,139,869; which application is a continuation of application Ser. No. 13/009,764, filed Jan. 19, 2011 and issued as U.S. Pat. No. 8,575,303, which claims the benefit of U.S. Provisional Application Ser. No. 61/296,379, filed Jan. 19, 2010 and U.S. Provisional Application Ser. No. 61/358,406, filed Jun. 24, 2010, which applications are incorporated herein by reference in their entireties. BACKGROUND OF THE INVENTION Fluorescent hybridization probes have developed into an important tool in the sequence-specific detection of DNA and RNA. The signals generated by the appended fluorescent labels (or dyes) can be monitored in real time and provide simple, rapid, and robust methods for the detection of biological targets and events. Utility has been seen in applications ranging from microarrays and real time PCR to fluorescence in situ hybridization (FISH). Recent work in the area of multichromophores, particularly regarding conjugated polymers (CPs) has highlighted the potential these materials have in significantly improving the detection sensitivity of such methods (Liu and Bazan, Chem. Mater., 2004). The light harvesting structures of these materials can be made water soluble and adapted to amplify the fluorescent output of various probe labels (See U.S. patent application Ser. No. 10/600,286, filed Jun. 20, 2003 and Gaylord, Heeger, and Bazan, Proc. Natl. Acad. Sci., 2002, both of which are incorporated herein by reference in their entirety). Results such as these indicate CPs to be highly promising in the field of nucleic acid diagnostics, particularly where sample quantities are scarce. However, there exist methods for the amplification (or replication) of nucleic acid targets, i.e., PCR. Comparatively, in the field of protein recognition, there are no such simple methods for amplifying the targeted materials. As such, signal enhancement arising from CP application is of high consequence in this area. Dye-labeled antibodies are regularly used for the detection of protein targets in applications such as immunohistochemistry, protein arrays, ELISA tests, and flow cytometry. Integrating CP materials into such methodologies promises to provide a dramatic boost in the performance of such assays, enabling detection levels previously unattainable with conventional fluorescent reporters (e.g., dyes). Beyond addition signal, one of the other key drivers in biological detection formats is the ability to detect multiple analytes in the same test or multiplexing. This is commonly achieved by using fluorescent reporters with operate at different, decernable wavelengths. CP materials are ideally suited to provide a platform for expanded multiplexing. This can be achieved by tuning the structure of different CPs to operate at different wavelengths or by incorporating a dye within the polymer-biomolecule conjugate. The material and methods to produce higher sentivity biological assays and increase multiplexing are highly desired in both molecular (nucleic acid) and immunoassay formats. SUMMARY OF THE INVENTION Provided herein are water soluble conjugated polymers of Formula (I): wherein: each R is independently a non-ionic side group capable of imparting solubility in water in excess of 10 mg/mL; MU is a polymer modifying unit or band gap modifying unit that is evenly or randomly distributed along the polymer main chain and is optionally substituted with one or more optionally substituted substituents selected from halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl, C1-C12 haloalkyl, C1-C12 alkoxy, C2-C18(hetero)aryloxy, C2-C18(hetero)arylamino, (CH2)x′(OCH2CH2)y′OCH3 where each x′ is independently an integer from 0-20, y′ is independently an integer from 0 to 50, or a C2-C18(hetero)aryl group; each optional linker L1 and L2 are aryl or hetroaryl groups evenly or randomly distributed along the polymer main chain and are substituted with one or more pendant chains terminated with a functional group for conjugation to another substrate, molecule or biomolecule selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof; G1 and G2 are each independently selected from hydrogen, halogen, amine, carbamate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiol, optionally substituted aryl, optionally substituted heteroaryl, halogen substituted aryl, boronic acid substituted aryl, boronic ester substituted aryl, boronic esters, boronic acids, optionally substituted fluorene and aryl or hetroaryl substituted with one or more pendant chains terminated with a functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule; wherein the polymer comprises at least 1 functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, and thiols within G1, G2, L1 or L2 that allows, for functional conjugation to another molecule, substrate or biomolecule; each dashed bond, - - - - - - , is independently a single bond, triple bond or optionally substituted vinylene (—CR5═CR5—) wherein each R5 is independently hydrogen, cyano, C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl or a C2-C18(hetero)aryl group, wherein each C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl or a C2-C18(hetero)aryl group is optionally substituted with one or more halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl group, C1-C12 alkoxy, or C1-C12 haloalkyl; and n is an integer from 1 to about 10,000; and a, b, c and d define the mol % of each unit within the structure which each can be evenly or randomly repeated and where a is a mol % from 10 to 100%, b is a mol % from 0 to 90%, and each c and d are mol % from 0 to 25%. In one aspect, water soluble conjugated polymers of Formula (I) have the structure of Formula (Ia): wherein R, L1, L2, G1, G2, MU, a, b, c, d and n are described previously for formula (I). In some embodiments, each R is independently (CH2)x(OCH2CH2)yOCH3 where each x is independently an integer from 0-20, each y is independently an integer from 0 to 50, or a benzyl optionally substituted with one or more halogen, hydroxyl, C1-C12 alkoxy, or (OCH2CH2)zOCH3 where each z is independently an integer from 0 to 50. In some instances, each R is (CH2)3(OCH2CH2)11OCH3. In other embodiments, each R is a benzyl substituted with at least one (OCH2CH2)10OCH3 group. In some instances, the benzyl is substituted with two (OCH2CH2)10OCH3 groups. In other instances, the benzyl is substituted with three (OCH2CH2)10OCH3 groups. In some embodiments, optional linkers L1 or L2 have the structure: *=Site for covalent attachment to unsaturated backbone; wherein R3 is independently hydrogen, halogen, alkoxy(C1-C12), C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl or a C2-C18(hetero)aryl group, wherein each C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl or a C2-C18(hetero)aryl group is optionally substituted with one or more halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl group, C1-C12 alkoxy, or C1-C12 haloalkyl; and q is an integer from 0 to 4. In other embodiments, optional linkers L1 or L2 have the structure: *=site for covalent attachment to unsaturated backbone wherein A is a site for conjugation, chain extension or crosslinking and is —[O—CH2—CH2]q—W, or (C1-C12)alkoxy-X or C2-C18(hetero)aryl, phenoxy, amido, amino, carbamate, carboxylate, carbonates, sulfide, disulfide, or imido groups terminated with a functional group selected from amine, carbamate, carboxylate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule; W is —OH or —COOH; X is —NH2, —NHCOOH, —NHCOOC(CH3)3, —NHCO(C3-C12)cycloalkyl(C1-C4)alkyl-N-maleimide; or —NHCO[CH2—CH2—O]tNH2; q is an integer from 1 to 20; and t is an integer from 1 to 8. In yet other embodiments, optional linkers L1 or L2 have the structure: *=site for covalent attachment to backbone wherein R25 are each independently any one of or a combination of a bond, C1-C20 alkyl, C1-C20 alkoxy, C2-C20 alkene, C2-C20 alkyne, C3-C20 cycloalkyl, C1-C20 haloalkyl, (CH2)x(OCH2CH2)p(CH2)x where each x is independently an integer from 0-20, p is independently an integer from 0 to 50, aryl, C2-C18(hetero)aryl, phenoxy, amido, amino, carbamate, carboxylate, carbonates, sulfide, disulfide, or imido groups; wherein at least one R25 is terminated with a functional group selected from amine, carbamate, carboxylate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule. In further embodiments, optional linkers L1 or L2 have the structure: *=site for covalent attachment to unsaturated backbone; wherein R35 is any one of or a combination of a bond, C1-C20 alkyl, C1-C20 alkoxy, C2-C20 alkene, C2-C20 alkyne, C3-C20 cycloalkyl, C1-C20 haloalkyl, (CH2)x(OCH2CH2)p(CH2)x where each x is independently an integer from 0-20, p is independently an integer from 0 to 50, aryl, C2-C18(hetero)aryl, phenoxy, amido, amino, carbamate, carboxylate, carbonates, sulfide, disulfide, or imido groups terminated with a functional group selected from amine, carbamate, carboxylate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule. In further embodiments, optional linkers L1 or L2 are selected from the group consisting of a-h having the structures: *=site for covalent attachment to unsaturated backbone; wherein R′ is independently H, halogen, C1-C12 alkyl, (C1-C12 alkyl)NH2, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl, C1-C12 haloalkyl, C2-C18(hetero)aryl, C2-C18(hetero)arylamino, —[CH2—CH2]r′—Z1, or (C1-C12)alkoxy-X1; and wherein Z1 is —OH or —COOH; X1 is —NH2, —NHCOOH, —NHCOOC(CH3)3, —NHCO(C3-C12)cycloalkyl(C1-C4)alkyl-N-maleimide; or —NHCO[CH2—CH2—O]s′(CH2)s′NH2; r′ is an integer from 1 to 20; and each s′ is independently an integer from 1 to 20, (CH2)3(OCH2CH2)x″OCH3 where x″ is independently an integer from 0 to 50, or a benzyl optionally substituted with one or more halogen, hydroxyl, C1-C12 alkoxy, or (OCH2CH2)y″OCH3 where each y″ is independently an integer from 0 to 50 and R′ is different from R; wherein k is 2, 4, 8, 12 or 24; wherein R15 is selected from the group consisting of l-t having the structure: *=site for covalent attachment to backbone. In yet further embodiments, optional linkers L1 or L2 are In some embodiments, G1 and G2 are each independently selected from hydrogen, halogen, alkyne, optionally substituted aryl, optionally substituted heteroaryl, halogen substituted aryl, boronic acid substituted aryl, boronic ester substituted aryl, boronic esters, boronic acids, optionally substituted fluorine and aryl or hetroaryl substituted with one or more pendant chains terminated with a functional group, molecule or biomolecule selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule. In some embodiments, G1 and G2 each independently have the structure wherein R11 is any one of or a combination of a bond, C1-C20 alkyl, C1-C20 alkoxy, C2-C20 alkene, C2-C20 alkyne, C3-C20 cycloalkyl, C1-C20 haloalkyl, (CH2)x(OCH2CH2)p(CH2)x where each x is independently an integer from 0-20, p is independently an integer from 0 to 50, aryl, C2-C18(hetero)aryl, phenoxy, amido, amino, carbamate, carboxylate, carbonates, sulfide, disulfide, or imido groups terminated with a functional group selected from amine, carbamate, carboxylate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule. In other embodiments, G1 and G2 are each independently selected from the group consisting of 1-31 having the structures: *=site for covalent attachment to backbone wherein R15 is selected from the group consisting of l-t having the structure: and k is 2, 4, 8, 12 or 24. In further embodiments, G1 and G2 are optionally substituted aryl or heteroaryl wherein the optional substituent is selected from halogen, amine, carbamate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiol, boronic acid, boronate radical, boronic esters and optionally substituted fluorene. In some embodiments, G1 and G2 are the same. In other embodiments, G1 and G2 are different. In further embodiments, the polymer contains a single conjugation site at only one terminus of the polymer chain G1 or G2. In yet further embodiments, G1 and G2 is In some embodiments, MU is selected from the group consisting of a′-k′ having the structure: *=site for covalent attachment to unsaturated backbone wherein R is a non-ionic side group capable of imparting solubility in water in excess of 10 mg/mL. In some embodiments, the water soluble conjugated polymer has the structure of formula: wherein at least one of G1 or G2 comprises a functional conjugation site. In some embodiments, the water soluble conjugated polymer has the structure of formula: wherein L1 comprises a functional conjugation site. In some embodiments, the water soluble conjugated polymer has the structure of formula: wherein at least one of G1 or G2 comprises a functional conjugation site. In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In some instances, a signaling chromophore is attached to the polymer via the NH2 group. In certain instances, the signaling chromophore is Cy3 or Dylight 594 dye. In certain instances, the linker, is about 10% of the entire polymer. In other instances, the polymer is conjugated to a secondary dye reporter and an antibody. In some embodiments of conjugated polymers described herein, the polymer is further conjugated to additional molecules. In some embodiments, the polymer is conjugated to a streptavidin, antibody or nucleic acid and used as a direct fluorescent reporter. In certain embodiments, the polymer is conjugated to a streptavidin. In other embodiments, the polymer is conjugated to thiol groups at the hinge region of an antibody. In yet other embodiments, the polymer is conjugated to an amine group on a protein which is modified with a heterobifuntional linker. In further embodiments, the polymer is conjugated to a nucleic acid. In yet further embodiments, the polymer is conjugated to an antibody. In certain instances, the polymer is conjugated to a monoclonal antibody, a secondary antibody or a primary antibody. In other instances, a polymer antibody conjugate is excited at about 405 nm in a flow cytometry assay where the specific signal is at least 3 fold greater than the same antibody conjugated to Pacific Blue. In some embodiments of conjugated polymers described herein, the polymer is purified by ion exchange chromatography. In other embodiments, the polymer is >95% pure. In some embodiments of conjugated polymers described herein, the polymer is used in flow cytometry assays to identify different cell markers or cell types. In other embodiments, the polymer is used to sort cells. In yet other embodiments, the polymer is used to sort cells for use in therapeutics. In some embodiments of conjugated polymers described herein, the polymer is used for intracellular staining. In certain instances, the polymer is used in flow cytometry assays to identify different cell markers or cell types. In some embodiments of conjugated polymers described herein, the polymer comprises a minimum number average molecular weight of greater than 40,000 g/mol and a water solubility of greater than 50 mg/mL in pure water or a phosphate buffered saline solution. In some embodiments of conjugated polymers described herein, the polymer comprises at least two unique conjugation linkers which can conjugated to two unique materials. Also provided herein are assay methods comprising providing a sample that is suspected of containing a target biomolecule; providing a sensor protein conjugated to at least one signaling chromophore and is capable of interacting with the target biomolecule or a target-associated biomolecule; providing a water soluble conjugated polymer described herein; contacting the sample with the sensor protein and the conjugated polymer in a solution under conditions in which the sensor protein can bind to the target biomolecule or a target-associated biomolecule if present; applying a light source to the sample that can excite the conjugated polymer; and detecting whether light is emitted from the signaling chromophore. In some embodiments, the sensor protein is an antibody. In other embodiments, the sensor protein comprises a plurality of sensor proteins conjugated to a plurality of signaling chromophores, wherein at least two of the plurality of chromophores emit different wavelengths of light upon energy transfer from the multichromophore. Also provided herein are conjugated polymer complexes comprising a polymer coupled to at least one biomolecule selected from the group consisting of a sensor biomolecule, a bioconjugate and a target biomolecule wherein the polymer is covalently bound by at least one bioconjugation site pendant thereto, and the polymer comprises a signaling chromophore or a signaling chromophore optionally is covalently bound to the polymer or the sensor biomolecule; wherein the polymer comprises the structure of formula: wherein: each R is a non-ionic side group capable of imparting solubility in water in excess of 10 mg/mL; MU is a polymer modifying unit or band gap modifying unit that is evenly or randomly distributed along the polymer main chain and is optionally substituted with one or more optionally substituted substituents selected from halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl, C1-C12 haloalkyl, C1-C12 alkoxy, C2-C18(hetero)aryloxy, C2-C18(hetero)arylamino, (CH2)x′(OCH2CH2)y′OCH3 where each x′ is independently an integer from 0-20, y′ is independently an integer from 0 to 50, or a C2-C18(hetero)aryl group; each optional linker L1 and L2 are aryl or hetroaryl groups evenly or randomly distributed along the polymer main chain and are substituted with one or more pendant chains terminated with a functional group for conjugation to another molecule, substrate or biomolecule selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof; G1 and G2 are each independently selected from hydrogen, halogen, amine, carbamate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiol, optionally substituted aryl, optionally substituted heteroaryl, halogen substituted aryl, boronic acid substituted aryl, boronic ester substituted aryl, boronic esters, boronic acids, optionally substituted fluorene and aryl or hetroaryl substituted with one or more pendant chains terminated with a functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule; wherein the polymer comprises at least 1 functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, and thiols within G1, G2, L1 or L2 that allows, for functional conjugation to another molecule, substrate or biomolecule; n is an integer from 1 to about 10,000; and a, b, c and d define the mol % of each unit within the structure which each can be evenly or randomly repeated and where a is a mol % from 10 to 100%, b is a mol % from 0 to 90%, and each c and d are mol % from 0 to 25%. In some embodiments, the sensor biomolecule is selected from the group consisting of an avidin, streptavidin, neutravidin, avidinDN, and avidinD. In other embodiments, the conjugated polymer complex is further configured to bind to a complex selected from the group consisting of a biotin-labeled antibody, biotin-labeled protein, and biotin-labeled target biomolecule. In further embodiments, the sensor biomolecule is an antibody. In yet further embodiments, both the signaling chromophore and the sensor biomolecule are covalently linked to the multichromophore through a plurality of linkers. In some other embodiments, both the signaling chromophore and the sensor biomolecule are covalently linked to the polymer through a central linking site that covalently binds the polymer, the signaling chromophore and the sensor biomolecule. In yet other embodiments, the signaling chromophore, when covalently bound to the polymer or the sensor biomolecule, is an organic dye. Also provided herein are water soluble conjugated polymer having the structure of Formula (Ia): wherein: each R is independently (CH2)x(OCH2CH2)yOCH3 where each x is independently an integer from 0-20, y is independently an integer from 0 to 50, or a benzyl optionally substituted with one or more halogen, hydroxyl, C1-C12 alkoxy, or (OCH2CH2)zOCH3 where each z is independently an integer from 0 to 50; each optional linker L1 or L2 is selected from the group consisting of a-i having the structure *=site for covalent attachment to unsaturated backbone wherein R′ is independently H, halogen, C1-C12 alkyl, (C1-C12 alkyl)NH2, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl, C1-C12 haloalkyl, C2-C18(hetero)aryl, C2-C18(hetero)arylamino, —[CH2—CH2]r′—Z1, or (C1-C12)alkoxy-X1; and wherein Z1 is —OH or —COOH; X1 is —NH2, —NHCOOH, —NHCOOC(CH3)3, —NHCO(C3-C12)cycloalkyl(C1-C4)alkyl-N-maleimide; or —NHCO[CH2—CH2—O]s′(CH2)s′NH2; r′ is an integer from 1 to 20; and each s′ is independently an integer from 1 to 20, (CH2)3(OCH2CH2)x″OCH3 where x″ is independently an integer from 0 to 50, or a benzyl optionally substituted with one or more halogen, hydroxyl, C1-C12 alkoxy, or (OCH2CH2)y″OCH3 where each y″ is independently an integer from 0 to 50 and R′ is different from R; wherein R15 is selected from the group consisting of l-t having the structure: and k is 2, 4, 8, 12 or 24; *=site for covalent attachment to backbone MU is a polymer modifying unit or band gap modifying unit that is selected from the group consisting of a′-k′ having the structure: *=site for covalent attachment to unsaturated backbone; wherein R is a non-ionic side group capable of imparting solubility in water in excess of 10 mg/mL; G1 and G2 are each independently selected from the group consisting of 1-31 having the structures: wherein the polymer comprises at least 1 functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, and thiols within G1, G2, L1 or L2 that allows, for functional conjugation to another molecule, substrate or biomolecule; n is an integer from 1 to about 10,000; and a, b, c and d define the mol % of each unit within the structure which each can be evenly or randomly repeated and where a is a mol % from 10 to 100%, b is a mol % from 0 to 90%, and each c and d are mol % from 0 to 25%. Also provided herein are water soluble conjugated polymer having the structure of Formula: wherein Ar is an aryl or heteroaryl and is optionally substituted with one or more optionally substituted substituents selected from halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl, C1-C12 haloalkyl, C1-C12 alkoxy, C2-C18(hetero)aryloxy, C2-C18(hetero)arylamino, (CH2)x′(OCH2CH2)y′OCH3 where each x′ is independently an integer from 0-20, y′ is independently an integer from 0 to 50; and dashed bonds, L1, L2, G1, G2, MU, a, b, c, d and n are described previously for formula (I). INCORPORATION BY REFERENCE All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which: FIG. 1. Schematic of binding of a conjugated polymer in one embodiment of the invention. FIG. 2. Schematic of a bioconjugated polymer of one embodiment of the invention. FIG. 3. Schematic of exemplary conjugated polymers conjugated (A) antibody; (B) an avidin; (C) nucleic acid; (D) dye, e.g., chromophore. FIG. 4. Schematic of (A) a polymer conjugated to dye-labeled antibody resulting in FRET; (B) a polymer conjugated dye-labeled strepavidin resulting in FRET; (C) nucleic acid probe sequences labeled with a quencher molecule conjugated to a conjugated polymer; (D) nucleic acid probe sequences labeled with a quencher molecule conjugated polymer-dye tandem complex. FIG. 5. Schematic of various methods of assaying for a target biomolecule or target associated biomolecule. (A) Conjugated polymer linked to a bioconjugate; (B) polymer and dye labeled antibodies recognize a common target; (C) sensor biomolecule conjugated to both a dye and a second bioconjugate; (D) second bioconjugate and the signaling chromopohre both conjugated to a nucleic acid. FIG. 6. Schematic of an addition of a second linking site within the polymer. FIG. 7. Schematic of a polymer conjugated to a dye and a biomolecule and resulting energy transfer (A) polymer is conjugated to both a bioconjugate; (B) polymer is conjugated to a strepavidin and a dye; (C) polymer is conjugated to a nucleic acid and a dye. FIG. 8. Schematic of indirect associations with a sensor biomolecule or target associated biomolecule. (A) biotinylated antibody interacting with a covalent conjugate of the conjugated polymer; (B) biotinylated antibody conjugated polymer-dye tandem complex; (C) biotinylated nucleic acid interacting with a covalent conjugate of the conjugated polymer; (D) biotinylated nucleic conjugated polymer-dye tandem complex; (E) nucleic acid with digoxygenin moiety interacting with a covalent conjugate of the conjugated polymer; (F) nucleic acid with digoxygenin moiety conjugated polymer-dye tandem complex. FIG. 9. Schematic of exemplary conjugated polymers conjugated to secondary antibodies ( ) and primary antibodies (B). FIG. 10. Schematic of a sandwich-type complex. (A) conjugated polymer complex bioconjugated to a strepavidin; (B) biotin-labeled 1° antibody e used to probe the target protein directly. FIG. 11. Schematic of appending one or two phenyl capping units to a fluorene polymer. FIG. 12. Block diagram showing a representative example logic device. FIG. 13. Block diagram showing a representative example of a kit. FIG. 14. Schematic of a streptavidin conjugation with a conjugated polymer and the resulting conjugate structure (top) and Coomassie stained agarose gel representative of the streptavidin-attached CP (below). FIG. 15. Representative acrylamide gel depiction of biotinylated polymer alone or bound to Cy5-labeled streptavidin. FIG. 16. Schematic of streptavidin-attached conjugated polymer of FIG. 14 binding to biotinylated microspheres (top) and plot of fluorescence excitation of control biotinylated microspheres and microspheres bound to streptavidin conjugated polymer. FIG. 17. Schematic of streptavidin-attached conjugated polymer of FIG. 14 selectively bound to biotinylated microspheres and energy transfer to dye acceptors on co-localized streptavidin-dye conjugates (top) and plot of energy transfer from streptavidin-attached conjugated polymer to dye acceptor (bottom). FIG. 18. Schematic of biotinylated polymer of FIG. 14 binding to streptavidin coated microspheres (top) and plot of fluorescence excitation of control streptavidin coated microspheres and microspheres bound to biotinylated polymer. FIG. 19. Schematic of biotinylated polymer of FIG. 14 binding to dye-labeled streptavidin conjugates and FRET (top); plot of energy transfer from biotinylated polymer to two different dye acceptors (bottom left) and titration plot of polymer saturation (bottom right). FIG. 20. Flow cytometry analysis of CD4 marking of Cyto-trol cells with 440 nm polymer-streptavidin-conjugates. FIG. 21. (A) Polymer structure of Example 38b conjugated to (from left to right) FITC, Cy3, DyLight 594 and DyLight633; (B) Comparison of the fluorescence of the dye (DyLight594) excited near its absorbance maximum (lower curve) and polymer-dye conjugate excited at 405 nm (upper curve); (C) Comparison of the fluorescent signal of the base polymer (no dye, peak emission near 420 nm) to that of the polymer-dye conjugate (peak emission near 620 nm). FIG. 22. Plot of flow testing of monoclonal antibody (antiCD4) conjugates on whole lysed blood samples. FIG. 23. Plot of florescence of a dye (DyLight594) and a polymer-dye conjugate by excitation of dye at 594 nm and the polymer-dye conjugate at 380 nm. FIG. 24. Plot of fluorescent immunoassay (ELISA) with streptavidin-attached conjugated polymer. FIG. 25. Plot of fluorescent intensity vs. temperature of a DNA oligomer-polymer conjugate hybridized to a target. FIG. 26. Ion exchange chromatogram for a polymer antibody conjugate to remove free polymer (left) and an SEC chromatogram showing the separation of final conjugate from free antibody. In both chromatograms absorbance was monitored at 280 nm (lower curves) and 407 nm (upper curves). FIG. 27. Sandwich immunoassay on Luminex assay (left) and corresponding results on the Luminex system using 532 nm excitation of both the conjugated polymer and PE streptavidin detection conjugates. FIG. 28. Data on left show results obtained with compensation beads while the data set on the right results from a 4 color assay on human blood samples. FIGS. 29. (A) and (B) Schematic of covalent linkage of conjugated polymer to 2° antibody. FIG. 30. Schematic of conjugated polymers in Fluorescent Immuno Assay (FIA). (A) conjugated polymer covalently linked to a detection antibody; (B) biotin binding protein covalently bound to the conjugated polymer and interacting with a biotinylated detection antibody; (C) secondary antibody covalently linked to the conjugated polymer and interacting with a detection antibody. FIG. 31. (A) Schematic of nucleic acid probe sequences labeled with a quencher molecule conjugated to a conjugated polymer; (B) nucleic acid probe sequences labeled with a quencher molecule conjugated to a conjugated polymer-dye tandem complex. FIG. 32. Schematic of modifications of the HybProbe detection technique. (A) conjugated polymer covalently linked to the donor probe and resulting energy transfer to acceptor probe; (B) “Signal off” modification of the HybProbe approach where the conjugated polymer is quenched by an acceptor probe. FIG. 33. Comparison of non-specific binding in various polymers (top) in a Jurkat cell (lymphocyte cell line) model; (bottom) plot ranking the polymers in terms of signal generated purely by non-specific binding (NSB). FIG. 34. Histograms collected from flow cytometry analysis (405 nm excitation in a BD LSR-II cytometer) using a Jurkat cell line; (left) unstained cells and a negative control, anionic P4 polymer; (middle) range of different polymer and polymer side chain combinations tested on the same cells; (right) neutral polymer P20 showed almost no off set from the untreated cells. FIG. 35. Gel electrophoresis depicting relative mobility of avidin as a function of the degree of conjugation with polymer AA1. FIG. 36. Fractionation of crude polymer-avidin conjugate mixtures on a Superdex 200 size exclusion column; (top) monitoring fractions by UV absorbance; (bottom) gel electrophoresis of selected fractions to visualize the degree to which avidin was attached to polymer. FIG. 37. Gel electrophoresis of conjugation reactions performed with polymer in varying molar excess to streptavidin; (left) UV illumination; (right) 532 nm excitation. FIG. 38. Plot depicting purification of polymer streptavidin conjugates with polymers exemplified in Example 9, denoted P30, (top) crude samples; (bottom) purified conjugates). DETAILED DESCRIPTION OF THE INVENTION Before the present invention is described in further detail, it is to be understood that this invention is not limited to the particular methodology, devices, solutions or apparatuses described, as such methods, devices, solutions or apparatuses can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention. Use of the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. Thus, for example, reference to “an aggregation sensor” includes a plurality of aggregation sensors, reference to “a probe” includes a plurality of probes, and the like. Additionally, use of specific plural references, such as “two,” “three,” etc., read on larger numbers of the same subject less the context clearly dictates otherwise. Terms such as “connected,” “attached,” “conjugated” and “linked” are used interchangeably herein and encompass direct as well as indirect connection, attachment, linkage or conjugation unless the context clearly dictates otherwise; in one example, the phrase “conjugated polymer” is used in accordance with its ordinary meaning in the art and refers to a polymer containing an extended series of unsaturated bonds, and that context dictates that the term “conjugated” should be interpreted as something more than simply a direct or indirect connection, attachment or linkage. Where a range of values is recited, it is to be understood that each intervening integer value, and each fraction thereof, between the recited upper and lower limits of that range is also specifically disclosed, along with each subrange between such values. The upper and lower limits of any range can independently be included in or excluded from the range, and each range where either, neither or both limits are included is also encompassed within the invention. Where a value being discussed has inherent limits, for example where a component can be present at a concentration of from 0 to 100%, or where the pH of an aqueous solution can range from 1 to 14, those inherent limits are specifically disclosed. Where a value is explicitly recited, it is to be understood that values which are about the same quantity or amount as the recited value are also within the scope of the invention, as are ranges based thereon. Where a combination is disclosed, each subcombination of the elements of that combination is also specifically disclosed and is within the scope of the invention. Conversely, where different elements or groups of elements are disclosed, combinations thereof are also disclosed. Where any element of an invention is disclosed as having a plurality of alternatives, examples of that invention in which each alternative is excluded singly or in any combination with the other alternatives are also hereby disclosed; more than one element of an invention can have such exclusions, and all combinations of elements having such exclusions are hereby disclosed. Unless defined otherwise or the context clearly dictates otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred methods and materials are now described. All publications mentioned herein are hereby incorporated by reference for the purpose of disclosing and describing the particular materials and methodologies for which the reference was cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention. Definitions In describing the present invention, the following terms will be employed, and are intended to be defined as indicated below. “Alkyl” refers to a branched, unbranched or cyclic saturated hydrocarbon group of 1 to 24 carbon atoms optionally substituted at one or more positions, and includes polycyclic compounds. Examples of alkyl groups include optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, n-decyl, hexyloctyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like, as well as cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, and norbornyl. The term “lower alkyl” refers to an alkyl group of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Exemplary substituents on substituted alkyl groups include hydroxyl, cyano, alkoxy, ═O, ═S, —NO2, halogen, haloalkyl, heteroalkyl, carboxyalkyl, amine, amide, thioether and —SH. “Alkoxy” refers to an “—Oalkyl” group, where alkyl is as defined above. A “lower alkoxy” group intends an alkoxy group containing one to six, more preferably one to four, carbon atoms. “Alkenyl” refers to a branched, unbranched or cyclic hydrocarbon group of 2 to 24 carbon atoms containing at least one carbon-carbon double bond optionally substituted at one or more positions. Examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), 1-methylvinyl, cyclopropenyl, 1-butenyl, 2-butenyl, isobutenyl, 1,4-butadienyl, cyclobutenyl, 1-methylbut-2-enyl, 2-methylbut-2-en-4-yl, prenyl, pent-1-enyl, pent-3-enyl, 1,1-dimethylallyl, cyclopentenyl, hex-2-enyl, 1-methyl-1-ethylallyl, cyclohexenyl, heptenyl, cycloheptenyl, octenyl, cyclooctenyl, decenyl, tetradecenyl, hexadecenyl, eicosenyl, tetracosenyl and the like. Preferred alkenyl groups herein contain 2 to 12 carbon atoms. The term “lower alkenyl” intends an alkenyl group of 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms. The term “cycloalkenyl” intends a cyclic alkenyl group of 3 to 8, preferably 5 or 6, carbon atoms. Exemplary substituents on substituted alkenyl groups include hydroxyl, cyano, alkoxy, ═O, ═S, —NO2, halogen, haloalkyl, heteroalkyl, amine, thioether and —SH. “Alkenyloxy” refers to an “—Oalkenyl” group, wherein alkenyl is as defined above. “Alkylaryl” refers to an alkyl group that is covalently joined to an aryl group. Preferably, the alkyl is a lower alkyl. Exemplary alkylaryl groups include benzyl, phenethyl, phenopropyl, 1-benzylethyl, phenobutyl, 2-benzylpropyl and the like. “Alkylaryloxy” refers to an “—Oalkylaryl” group, where alkylaryl is as defined above. “Alkynyl” refers to a branched or unbranched hydrocarbon group of 2 to 24 carbon atoms containing at least one —C “Amide” refers to —C(O)NR′R″, where R′ and R″ are independently selected from hydrogen, alkyl, aryl, and alkylaryl. “Amine” refers to an —N(R′)R″ group, where R′ and R″ are independently selected from hydrogen, alkyl, aryl, and alkylaryl. “Aryl” refers to an aromatic group that has at least one ring having a conjugated pi electron system and includes carbocyclic, heterocyclic, bridged and/or polycyclic aryl groups, and can be optionally substituted at one or more positions. Typical aryl groups contain 1 to 5 aromatic rings, which may be fused and/or linked. Exemplary aryl groups include phenyl, furanyl, azolyl, thiofuranyl, pyridyl, pyrimidyl, pyrazinyl, triazinyl, biphenyl, indenyl, benzofuranyl, indolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridopyridinyl, pyrrolopyridinyl, purinyl, tetralinyl and the like. Exemplary substituents on optionally substituted aryl groups include alkyl, alkoxy, alkylcarboxy, alkenyl, alkenyloxy, alkenylcarboxy, aryl, aryloxy, alkylaryl, alkylaryloxy, fused saturated or unsaturated optionally substituted rings, halogen, haloalkyl, heteroalkyl, —S(O)R, sulfonyl, —SO3R, —SR, —NO2, —NRR′, —OH, —CN, —C(O)R, —OC(O)R, —NHC(O)R, —(CH2)nCO2R or —(CH2)nCONRR′ where n is 0-4, and wherein R and R′ are independently H, alkyl, aryl or alkylaryl. “Aryloxy” refers to an “—Oaryl” group, where aryl is as defined above. “Carbocyclic” refers to an optionally substituted compound containing at least one ring and wherein all ring atoms are carbon, and can be saturated or unsaturated. “Carbocyclic aryl” refers to an optionally substituted aryl group wherein the ring atoms are carbon. “Halo” or “halogen” refers to fluoro, chloro, bromo or iodo. “Halide” refers to the anionic form of the halogens. “Haloalkyl” refers to an alkyl group substituted at one or more positions with a halogen, and includes alkyl groups substituted with only one type of halogen atom as well as alkyl groups substituted with a mixture of different types of halogen atoms. Exemplary haloalkyl groups include trihalomethyl groups, for example trifluoromemyl. “Heteroalkyl” refers to an alkyl group wherein one or more carbon atoms and associated hydrogen atom(s) are replaced by an optionally substituted heteroatom, and includes alkyl groups substituted with only one type of heteroatom as well as alkyl groups substituted with a mixture of different types of heteroatoms. Heteroatoms include oxygen, sulfur, and nitrogen. As used herein, nitrogen heteroatoms and sulfur heteroatoms include any oxidized form of nitrogen and sulfur, and any form of nitrogen having four covalent bonds including protonated forms. An optionally substituted heteroatom refers to replacement of one or more hydrogens attached to a nitrogen atom with alkyl, aryl, alkylaryl or hydroxyl. “Heterocyclic” refers to a compound containing at least one saturated or unsaturated ring having at least one heteroatom and optionally substituted at one or more positions. Typical heterocyclic groups contain 1 to 5 rings, which may be fused and/or linked, where the rings each contain five or six atoms. Examples of heterocyclic groups include piperidinyl, morpholinyl and pyrrolidinyl. Exemplary substituents for optionally substituted heterocyclic groups are as for alkyl and aryl at ring carbons and as for heteroalkyl at heteroatoms. “Heterocyclic aryl” refers to an aryl group having at least 1 heteroatom in at least one aromatic ring. Exemplary heterocyclic aryl groups include furanyl, thienyl, pyridyl, pyridazinyl, pyrrolyl, N-lower alkyl-pyrrolo, pyrimidyl, pyrazinyl, triazinyl, tetrazinyl, triazolyl, tetrazolyl, imidazolyl, bipyridyl, tripyridyl, tetrapyridyl, phenazinyl, phenanthrolinyl, purinyl, perylene, perylene diimide, diketopyrrolopyrrole, benzothiodiazol, benzoxadiazol, thienopyrazine and the like. “Hydrocarbyl” refers to hydrocarbyl substituents containing 1 to about 20 carbon atoms, including branched, unbranched and cyclic species as well as saturated and unsaturated species, for example alkyl groups, alkylidenyl groups, alkenyl groups, alkylaryl groups, aryl groups, and the like. The term “lower hydrocarbyl” intends a hydrocarbyl group of one to six carbon atoms, preferably one to four carbon atoms. A “substituent” refers to a group that replaces one or more hydrogens attached to a carbon or nitrogen. Exemplary substituents include alkyl, alkylidenyl, alkylcarboxy, alkoxy, alkenyl, alkenylcarboxy, alkenyloxy, aryl, aryloxy, alkylaryl, alkylaryloxy, —OH, amide, carboxamide, carboxy, sulfonyl, ═O, ═S, —NO2, halogen, haloalkyl, fused saturated or unsaturated optionally substituted rings, —S(O)R, —SO3R, —SR, —NRR′, —OH, —CN, —C(O)R, —OC(O)R, —NHC(O)R, —(CH2)nCO2R or —(CH2)nCONRR′ where n is 0-4, and wherein R and R′ are independently H, alkyl, aryl or alkylaryl. Substituents also include replacement of a carbon atom and one or more associated hydrogen atoms with an optionally substituted heteroatom. “Sulfonyl” refers to —S(O)2R, where R is alkyl, aryl, —C(CN)═C-aryl, —CH2CN, alkylaryl, or amine. “Thioamide” refers to —C(S)NR′R″, where R′ and R″ are independently selected from hydrogen, alkyl, aryl, and alkylaryl. “Thioether” refers to —SR, where R is alkyl, aryl, or alkylaryl. As used herein, the term “binding pair” refers to first and second molecules that bind specifically to each other with greater affinity than to other components in the sample. The binding between the members of the binding pair is typically noncovalent. Exemplary binding pairs include immunological binding pairs (e.g. any haptenic or antigenic compound in combination with a corresponding antibody or binding portion or fragment thereof, for example digoxigenin and anti-digoxigenin, fluorescein and anti-fluorescein, dinitrophenol and anti-dinitrophenol, bromodeoxyuridine and anti-bromodeoxyuridine, mouse immunoglobulin and goat anti-mouse immunoglobulin) and nonimmunological binding pairs (e.g., biotin-avidin, biotin-streptavidin, hormone [e.g., thyroxine and cortisol]-hormone binding protein, receptor-receptor agonist or antagonist (e.g., acetylcholine receptor-acetylcholine or an analog thereof) IgG-protein A, lectin-carbohydrate, enzyme-enzyme cofactor, enzyme-enzyme-inhibitor, and complementary polynucleotide pairs capable of forming nucleic acid duplexes) and the like. One or both member of the binding pair can be conjugated to additional molecules. The terms “polynucleotide,” “oligonucleotide,” “nucleic acid” and “nucleic acid molecule” are used interchangeably herein to refer to a polymeric form of nucleotides of any length, and may comprise ribonucleotides, deoxyribonucleotides, analogs thereof, or mixtures thereof. These terms refer only to the primary structure of the molecule. Thus, the terms includes triple-, double- and single-stranded deoxyribonucleic acid (“DNA”), as well as triple-, double- and single-stranded ribonucleic acid (“RNA”). It also includes modified, for example by alkylation, and/or by capping, and unmodified forms of the polynucleotide. Additional details for these terms as well as for details of base pair formation can be found in U.S. application Ser. No. 11/344,942, filed Jan. 31, 2006, which is incorporate herein by reference in its entirety. “Complementary” or “substantially complementary” refers to the ability to hybridize or base pair between nucleotides or nucleic acids, such as, for instance, between a sensor peptide nucleic acid and a target polynucleotide. Complementary nucleotides are, generally, A and T (or A and U), or C and G. Two single-stranded polynucleotides or PNAs are said to be substantially complementary when the bases of one strand, optimally aligned and compared and with appropriate insertions or deletions, pair with at least about 80% of the bases of the other strand, usually at least about 90% to 95%, and more preferably from about 98 to 100%. Alternatively, substantial complementarity exists when a polynucleotide or PNA will hybridize under selective hybridization conditions to its complement. Typically, selective hybridization will occur when there is at least about 65% complementary over a stretch of at least 14 to 25 bases, preferably at least about 75%, more preferably at least about 90% complementary. See, M. Kanehisa Nucleic Acids Res. 12:203(1984). “Preferential binding” or “preferential hybridization” refers to the increased propensity of one polynucleotide or PNA to bind to its complement in a sample as compared to a noncomplementary polymer in the sample. Hybridization conditions for polynucleotides will typically include salt concentrations of less than about 1M, more usually less than about 500 mM and preferably less than about 200 mM. In the case of hybridization between a peptide nucleic acid and a polynucleotide, the hybridization can be done in solutions containing little or no salt. Hybridization temperatures can be as low as 5° C., but are typically greater than 22° C., more typically greater than about 30° C., and preferably in excess of about 37° C. Longer fragments may require higher hybridization temperatures for specific hybridization. Other factors may affect the stringency of hybridization, including base composition and length of the complementary strands, presence of organic solvents and extent of base mismatching, and the combination of parameters used is more important than the absolute measure of any one alone. Other hybridization conditions which may be controlled include buffer type and concentration, solution pH, presence and concentration of blocking reagents to decrease background binding such as repeat sequences or blocking protein solutions, detergent type(s) and concentrations, molecules such as polymers which increase the relative concentration of the polynucleotides, metal ion(s) and their concentration(s), chelator(s) and their concentrations, and other conditions known in the art. “Multiplexing” herein refers to an assay or other analytical method in which multiple analytes can be assayed simultaneously. “Having” is an open ended phrase like “comprising” and “including,” and includes circumstances where additional elements are included and circumstances where they are not. “Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. The embodiments disclosed herein relate generally to compositions of conjugated polymer materials that contain active functional groups for conjugation (or attachment) to other molecules, substrates or the like. Certain embodiments describe methods and compositions that provide for specific control of the incorporation and subsequent conjugation of such functional sites. Linkers can be incorporated at one or both ends of a conjugated polymer chain or internally controlled by ratio of monomers used in the polymerizations. Such linkers can be the same or different to allow for more than one distinct entity to be attached to the conjugated polymer structure. Further embodiments describe conjugated polymer compositions that not only provide for active conjugation sites but also are solublized through the use of non-ionic side chains (no formal charges). Such embodiments exhibit exceptional water solubility and provide minimal interactions with biological molecules and other common biological assay components. The embodiments disclosed herein further relate generally to assays and complexes including conjugated polymers useful for the identification of target biomolecules or biomolecules associated with target molecules through enhanced signal afforded by their unique properties. In certain general embodiments the conjugated polymer serves directly as the optical reporter bound to a biomolecule, substrate or other assay component. The conjugated polymers act as extended light harvesting structures that when excited can absorb more energy than conventional organic dyes. The polymer then re-emits the light which can be detected or measured. The signals generated from such conjugated polymer complexes can be significantly greater than those obtained from other fluorescent reporters. In other embodiments one aspect includes energy transfer from conjugated polymers to dyes bound to the polymer or to a sensor which can be a biomolecule including a bioconjugate (e.g., an antibody, a streptavidin or nucleic acid sequence). In such embodiments it is common to observe amplified dye signal (relative to direct dye excitation) as a result of the conjugated polymer excitation and subsequent energy transfer. Further it is possible to use a range of dyes with varing energy to create a basis for a multicolor or multiplex detection format. In certain embodiments the neutral conjugated polymers are bound to antibodies for the identification of specific cell markers and cell types in flow cytometry and cell sorting assays. In other embodiments the conjugated polymers are further bound to a secondary dye reporter. In further embodiments the polymer and polymer-dye structures are bound to monoclonal antibodies. In other embodiments the neutral conjugated polymers are bound to antibodies for use in various sandwich immunoassays. In one embodiment, an approach modifying a format as followed in relation to nucleic acid sensor assays as described in Gaylord, Heeger, and Bazan, J. Am. Chem. Soc., 2003 can be followed. Specifically, signal amplification of conjugated polymers can be based on binding events to indicate a hybridization event. Any established conjugated polymers can be chosen as the donor, and one or more dye, preferably a dye with a history of efficient energy transfer, for example, fluorescein and Cy3, can be chosen as the acceptors. It is envisioned that the dye can be directly conjugated to a sensor molecule. As shown schematically in FIG. 1, the sensor can be a biomolecule (e.g., an antibody) in a solution or on a substrate, to which conjugated polymers can be added. In the embodiment shown in FIG. 1, a dye can be covalently linked (bioconjugated) to an antibody (Y-shaped structure), which possesses a net negative charge. Addition of conjugated polymers (shown as wavy lines) can result in interaction or binding between the conjugated polymer and the antibody, bringing the conjugated polymers and dye into close proximity. Interaction or binding can be achieved by any known method including, but not limited to, avidin/biotin labeling. Distance requirements for fluorescence resonance energy transfer (FRET) can thus be met, and excitation of the polymer with light (shown as hv) results in amplified dye emission. It is envisioned that the conjugated polymers can be excited at a wavelength where the dye does not have significant absorbance. In one embodiment the dye emission can be at a longer wavelength than the conjugated polymer emission. In use it is envisioned that an assay method can include the steps of providing a sample that is suspected of containing a target biomolecule, providing a sensor conjugated to a signaling chromophore and capable of interacting with the target biomolecule, providing a conjugated polymer that interacts with the sensor and upon excitation is capable of transferring energy to the sensor signaling chromophore and contacting the sample with the sensor and the conjugated polymer in a solution under conditions in which the sensor can bind to the target biomolecule if present. Next, the method can include applying a light source to the sample that can excite the conjugated polymer, and detecting whether light is emitted from the signaling chromophore. As disclosed herein, interaction or binding between conjugated polymers and dye-labeled antibodies can be a viable approach for increasing detection sensitivities, for example of a biomolecule target. In a further embodiment, covalently attaching the conjugated polymers to a dye, biomolecule (e.g., an antibody complex) or both offers several advantages including reduced background and/or improved energy transfer. In the case of direct linkage to a biomolecule, biorecognition events, rather than non-specific polymer interaction or binding events (such as those described above in FIG. 1), should govern conjugated polymer presence. In this manner, nonspecific binding of conjugated polymers to biomolecules can be eliminated, reducing any background emission resulting from the conjugated polymer itself. The abovementioned biomolecules include but are not limited to proteins, peptides, affinity ligands, antibodies, antibody fragments, sugars, lipids, enzymes and nucleic acids (as hybridization probes and/or aptamers). In general, in another aspect the invention includes the bioconjugation of polymers to affinity ligands (affinity ligands describing a biomolecule that has an affinity for another biomolecule). FIG. 2 illustrates a class of materials in which a conjugated polymer (shown as a wavy line) is linked to a dye, biomolecule, or biomolecule/dye complex (labeled X). Linking to the conjugated polymer can be via a first functionality linker A on the conjugated polymer that serves as a bioconjugation site capable of covalently linking with a second functionality linker A′ linked to a biomolecule and/or dye (see X). This arrangement can fix the distance between the conjugated polymer and X, thereby ensuring only specific interactions between polymer and X. It is envisioned that a biomolecule component X in this embodiment can be any of the various biomolecules disclosed herein, including but not limited to an antibody, protein, affinity ligand, enzyme or nucleic acid. Linker A can be anywhere on the conjugated polymer including terminal positions of the polymer, internally on a repeating subunit, in between repeating subunits or any combination thereof. Likewise, Linker A′ can be linked anywhere on a biomolecule and/or dye. The linking chemistry for A-A′ can include, but is not limited to, maleimide/thiol; thiol/thiol; pyridyldithiol/thiol; succinimidyl iodoacetate/thiol; N-succinimidylester (NHS ester), sulfodicholorphenol ester (SDP ester), or pentafluorophenyl-ester (PFP ester)/amine; bissuccinimidylester/amine; imidoesters/amines; hydrazine or amine/aldehyde, dialdehyde or benzaldehyde; isocyanate/hydroxyl or amine; carbohydrate-periodate/hydrazine or amine; diazirine/aryl azide chemistry; pyridyldithiol/aryl azide chemistry; alkyne/azide; carboxy-carbodiimide/amine; amine/Sulfo-SMCC (Sulfosuccinimidyl 4-[N-maleimidomethyl]cyclohexane-1-carboxylate)/thiol; and amine/BMPH (N-[β-Maleimidopropionic acid]hydrazide*TFA)/thiol. It is envisioned that the X in this context can be, but is not limited to, a dye, fluorescence protein, nanomaterial (e.g., Quantum Dot), chemluminescence-generating molecule, a conjugate between dye and chemluminescence-generating molecule, a conjugate between fluorescence protein and chemluminescence-generating molecule, a conjugate between nanomaterial (e.g., Quantum Dot) and chemluminescence-generating molecule, streptavidin, avidin, enzyme, substrate for an enzyme, substrate analog for an enzyme, receptor, ligand for a receptor, ligand analog for a receptor, DNA, RNA, modified nucleic acid, DNA aptamer, RNA aptamer, modified nucleic aptamer, peptide aptamer, antibody, antigen, phage, bacterium or conjugate of any two of the items described above. In another aspect, the invention includes the use of conjugated polymers as direct labels. FIG. 3 shows examples of labeled conjugated polymers. In one embodiment, FIG. 3A, a polymer (shown as encircled hexagons) is shown conjugated to an antibody which can be, for example, a 1° or 2° antibody. The conjugate of the polymer and the antibody can be used as a direct reporter, for example, in an assay. In additional embodiments, the signal from the polymer is not modulated by other assay components rather it is dependent on its presence in the assay at the time of detection as a function of specific biomolecule recognition. Excitation of the polymer with light (not shown) can result in polymer emission, indicating the presence of the antibody (1° or 2°) in the assay or assay solution. FIGS. 3B and 3C further exemplify the use of conjugated polymers as biomolecule labels capable of detecting specific targets and target associated biomolecules. FIG. 3B depicts a polymer avidin (streptavidin, neutraAvidin, etc.) conjugate capable of binding to biotin modified molecules, biomolecules or substrates. FIG. 3C depicts a nucleic acid (DNA, RNA, PNA, etc.) conjugate capable of hybridizing to complementary nucleic acid sequences. Linkage or conjugation of fluorescent conjugated polymer to a molecule capable of recognizing a target biomolecule or target associated molecule (such as those exemplified in FIG. 3) provides a direct means of detection. In additional embodiments, the signals generated from excitation of the conjugated polymer are not modulated by other assay components except those which are directly conjugated to the polymer. In such embodiments the polymer complex is acting directly as a fluorescent label. In another embodiment shown in FIG. 3D, the conjugated polymer is labeled with a dye, for example, a chromophore. In this case, the conjugated polymer can act as a donor and the dye can act as an acceptor in an energy transfer process. Here, the conjugated polymer can act as a light harvester, and excitation of the conjugated polymer is followed by the channeling of the excitations to the dye via an energy transfer process including, but not limited to, FRET. This results in amplified dye emission (as compared to direct excitation of the dye). The fluorescence of the donor conjugated polymer, in one embodiment, can be quenched (e.g., >90% quenching). This is exemplified in Example 38 and shown in FIG. 21, by way of example only. In some instances, the conjugated polymer in FIG. 3D (and similar drawings disclosed herein) can have multiple dye attachments which can be positioned internally or at the terminus of the polymer structure (single dye shown for illustrative purposes only). In the case of direct linkage to a dye (FIG. 3D) or biomolecule/dye complex (as exemplified in FIG. 4), donor-acceptor distances can be fixed, rather than dependent on the strength of interaction or binding, and energy transfer efficiency can be significantly increased. This has significant consequences in the context of improving dye signaling (or quenching) and reducing background fluorescence associated with donor-acceptor cross-talk. Cross-talk in this case refers to the overlap between conjugated polymer (donor) and dye (acceptor) emission peaks. Conjugated polymers which bind non-specifically at distances too great for energy transfer can contribute to the background fluorescence (or crosstalk). Shorter (fixed) distances between the donor and acceptor can not only facilitate direct dye amplification, but also can greatly quench the donor emission, as depicted in FIG. 21 by way of example only. This results in less donor emission at the acceptor emission wavelengths, which subsequently reduces or even eliminates the need for cross-talk correction. In further embodiments the localization of the conjugated polymer and a signaling chromophore are brought together by recognition event, for example by the binding of two affinity pairs or by co-recognition of the same target molecule or target associated molecule (FIG. 5). Such embodiments could be performed in solution based formats or in such configurations where one or more of elements is bound to another biomolecule (cell, tissue, protein, nucleic acid, etc.) or a substrate (bead, well plate, surface, tube, etc.). In general, another aspect the invention includes a method of assaying for a target biomolecule or target associated biomolecule. As shown in FIG. 5A, in one embodiment a conjugated polymer (shown as a wavy line) can be linked to a first bioconjugate (shown as a Y-shaped object), for example, a 2° antibody that is specific for second a dye-labeled bioconjugate, for example, a 1° antibody. Here, the recognition event between the 1° and 2° antibody will result in the reduction of distance between the donor conjugated polymer and acceptor dye. In a similar embodiment depicted in FIG. 5B, polymer and dye labeled antibodies recognize a common target. After either of these recognition events, excitation of the donor conjugated polymer with light (shown as hv) will result in energy transfer, e.g., FRET, to the acceptor dye (shown as curved arrow), and amplified dye emission (in comparison with direct excitation of the dye) will be observed. In use it is envisioned that an assay method could include providing a sample that is suspected of containing a target biomolecule by the steps of providing a first bioconjugate, for example, a 1° antibody conjugated to a signaling chromophore and capable of interacting with the target biomolecule. This is followed by providing a second bioconjugate, for example, a 2° antibody or 1° antibody, conjugated to a polymer, wherein the second bioconjugate can bind to the first bioconjugate or target and wherein upon such binding excitation of the conjugated polymer is capable of transferring energy to the signaling chromophore. Next, the method includes contacting the sample with the first bioconjugate in a solution under conditions in which the first bioconjugate can bind to the target biomolecule if present and contacting the solution with the second bioconjugate. The method then includes applying a light source to the target biomolecule or tagged target biomolecule, wherein the light source can excite the conjugated polymer and subsequently detecting whether light is emitted from the signaling chromophore. In another aspect, the invention includes a method of assaying a sample using a conjugated polymer and a sensor biomolecule complex. As shown in FIGS. 5C and D, a polymer (shown as a wavy line) can be conjugated to a first bioconjugate, for example, streptavidin (SA) which has a strong affinity for biotin. In FIG. 5C, a sensor biomolecule (e.g., an antibody which can be a 1° or 2° antibody), is conjugated to both a dye and a second bioconjugate (e.g., a biotin moiety). Similar embodiments are depicted in FIG. 5D where the second bioconjugate (e.g., a biotin moiety) and the signaling chromopohre are both conjugated to a nucleic acid. After a biorecognition event between the first and second bioconjugates (e.g. between SA and biotin), the conjugated polymer and dye will be brought into close proximity, and excitation of the donor conjugated polymer will result in energy transfer to the acceptor dye. Dye emission will indicate the presence of the first bioconjugate (e.g., the antibody or nucleic acid). In comparison with direct excitation of the dye, amplification of the dye signal intensity will be observed when excited indirectly through an energy transfer process, e.g., FRET. A method of using the embodiment shown in FIGS. 5C and D can include the steps of providing a sample that is suspected of containing a target biomolecule, providing a conjugated polymer comprising a covalently linked first bioconjugate (e.g., SA), providing a sensor biomolecule complex comprising a sensor biomolecule capable of interacting with the target molecule, a signaling chromophore, and covalently linked second bioconjugate capable of binding with the first bioconjugate, wherein upon such binding excitation of the conjugated polymer is capable of transferring energy to the signaling chromophore. The method can further include the steps of contacting the sample with the sensor biomolecule complex in a solution under conditions in which the sensor biomolecule can bind to the target biomolecule if present, contacting the solution with the conjugated polymer, applying a light source to the sample that can excite the conjugated polymer, and detecting whether light is emitted from the signaling chromophore. Further the conjugated polymer can contain additional linking site suitable for conjugation or attachment to more than one species. FIG. 6 exemplifies the addition of a second linking site within the polymer. Such linkers A and B can be the same or different to allow for orthogonal conjugation of different species. The linkers can be anywhere on the polymer including terminal and internal positions. The linking chemistry for A-A′ and B-B′ (and optionally C-C′, D-D′, etc.) can include, but is not limited to, maleimide/thiol; thiol/thiol; pyridyldithiol/thiol; succinimidyl iodoacetate/thiol; N-succinimidylester (NHS ester), sulfodicholorphenol ester (SDP ester), or pentafluorophenyl-ester (PFP ester)/amine; bissuccinimidylester/amine; imidoesters/amines; hydrazine or amine/aldehyde, dialdehyde or benzaldehyde; isocyanate/hydroxyl or amine; carbohydrate-periodate/hydrazine or amine; diazirine/aryl azide chemistry; pyridyldithiol/aryl azide chemistry; alkyne/azide; carboxy-carbodiimide/amine; amine/Sulfo-SMCC (Sulfosuccinimidyl 4-[N-maleimidomethyl]cyclohexane-1-carboxylate)/thiol; and amine/BMPH (N-[β-Maleimidopropionic acid]hydrazide*TFA)/thiol. A tri-functional linker such as the commercially available Sulfo-SBED Sulfosuccinimidyl[2-6-(biotinamido)-2-(p-azidobenzamido)-hexanoamido]-ethyl-1,3′-dithiopropionate can serve well in the three way linkage among X, Y, and conjugated polymer. In the embodiment illustrated in FIG. 6, X or Y can be, but are not limited to, a dye, fluorescence protein, nanomaterial (e.g., Quantum Dot), chemluminescence-generating molecule, a conjugate between dye and chemluminescence-generating molecule, a conjugate between fluorescence protein and chemluminescence-generating molecule, a conjugate between nanomaterial (e.g., Quantum Dot) and chemluminescence-generating molecule, streptavidin, avidin, enzyme, substrate for an enzyme, substrate analog for an enzyme, receptor, ligand for a receptor, ligand analog for a receptor, DNA, RNA, modified nucleic acid, DNA aptamer, RNA aptamer, modified nucleic aptamer, peptide aptamer, antibody, antigen, phage, bacterium or conjugate of any two of the items described above. In general, in another aspect the invention provides a conjugated polymer complex including a polymer, a sensor biomolecule and a signaling chromophore for identifying a target biomolecule. As shown in FIG. 6, in one embodiment a polymer (wavy line) can be bioconjugated to a dye X via linker functionalities A-A′ and a biomolecule Y via linker functionalities B-B′. As depicted in FIG. 7, in one embodiment a polymer can be bioconjugated to both a dye and a biomolecule, for example a biorecognition molecule. Useful biomolecules can include but are not limited to antibodies (FIG. 7A), avidin derivatives (FIG. 7B) affinity ligands, nucleic acids (FIG. 7C), proteins, nanoparticles or substrates for enzymes. The benefits of covalently linking a dye in proximity to a polymer have been described above. By affixing both an acceptor dye and a biorecognition molecule to a polymer, the benefits are two fold, by both fixing donor-acceptor distances, such that an acceptor is guaranteed to be within the vicinity of a donor conjugated polymer (and vice versa), and also increasing the specificity of polymer binding to indicate a biorecognition event. These covalent complexes can be made via the monomer, polymer and linking chemistries described herein. In use, the embodiments shown in FIG. 6 can be a conjugated polymer complex for identifying a target biomolecule wherein the complex includes a conjugated polymer, a signaling chromophore covalently linked to the conjugated polymer and a sensor biomolecule covalently linked to the conjugated polymer. The signaling chromophore of the complex is capable of receiving energy from the conjugated polymer upon excitation of the conjugated polymer and the sensor biomolecule is capable of interacting with the target biomolecule. It is envisioned that the biomolecules can include but are not limited to an antibody, protein, affinity ligand, peptide, or nucleic acid. In one embodiment shown in FIG. 7A, a polymer is conjugated to both a bioconjugate, for example, an antibody (1° or 2°) and a dye. Covalent linkage between the donor conjugated polymer and acceptor dye ensures close proximity. Excitation of the donor conjugated polymer results in energy transfer, e.g., FRET, to the acceptor dye. Where the bioconjugate is an antibody, if the antibody binds to its target (e.g., antigen), this will be indicated by dye emission upon donor polymer excitation. In an alternative embodiment, as shown in FIG. 7B, a polymer can be conjugated to both a SA and a dye. Again, covalent linkage between the donor conjugated polymer and acceptor dye ensure close proximity, and excitation of the donor conjugated polymer results in energy transfer to the acceptor dye. The SA complex can be used to label or detect a biotin-labeled biomolecule such as a biotinylated antibody or nucleic acid. Polymer excitation followed by energy transfer to the dye label will result in greatly enhanced detection signals (i.e., greater sensitivity). The example exemplified in FIG. 7A is a conjugated polymer labeled with a dye acceptor and further conjugated to an antibody. This Tandem configuration can be used in similar fashion as those described for the structure in FIG. 3A but are useful in generating a secondary signal for detection, often in multiplex formats. The conjugated polymer complexes in FIG. 7 can have multiple dye attachments which can be positioned internally or at the terminus of the polymer structure (single dye shown for illustrative purposes only). In other embodiments as shown in FIGS. 3A and 7A, a sensor biomolecule for example a 1° antibody (Y shape) is conjugated covalently linked to the conjugated polymer (encircled hexagons) or conjugated polymer-dye tandem complex (hexagons with pendant encircled star). Upon conjugated polymer excitation, emission from the conjugated polymer (FIG. 3A) or dye (FIG. 7A) will indicate presence of the biocomplex and by extension with appropriate assay design that of the target recognized by the sensor molecule allowing use as a reporter, for example in an assay. FIGS. 29A and 29B represent comparable examples with covalent linkage of the conjugated polymer to a 2° antibody. As an alternative embodiment, the conjugated polymer may be associated indirectly with the sensor biomolecule or target associated biomolecule. FIGS. 8C and 8D illustrate a sequence specific oligonucleotide probe (wavy line) covalently conjugated to a biotin moiety (drop shape). Here the conjugated polymer (encircled hexagons) or conjugated polymer-dye tandem complex (hexagons with pendant encircled star) is covalently bound or conjugated to a biotin recognizing protein (for example, avidin, streptavidin or similar with high specific affinity for the ligand biotin). FIGS. 8A and 8B illustrate comparable examples with a biotinylated antibody interacting with a covalent conjugate of the conjugated polymer (FIG. 8A) and conjugated polymer-dye tandem complex (FIG. 8B) to the biotin recognizing protein. Indirect association of the target associated biomolecule with the conjugated polymer is not limited to biotin mediated interactions. FIGS. 8E and F represent sequence specific oligonucleotides (wavy line) which have been covalently labeled with a digoxygenin moiety (7 pointed star). In turn the digoxygenin moiety has been recognized by a primary antibody covalently linked to the conjugated polymer (FIG. 8E) and the conjugated polymer-dye tandem complex (FIG. 8F). Although not shown pictorially, further embodiments employing indirect detection of digoxygenin using biotinylated antibodies and biotin recognizing proteins covalently linked to conjugated polymers (or conjugated polymer-dye tandem complexes) or unlabelled primary antibodies recognizing digoxygenin and appropriate secondary antibodies covalently linked to the conjugated polymer (or conjugated polymer-dye tandem complexes) are intended. A number of further embodiments are also predicated on energy transfer (for example but not limited to FRET) between the conjugated polymer and an acceptor dye. Given the potential for multiplexing analysis, it is envisioned that the conjugated polymer can be linked to a number of dyes or signaling chromophores, including, but not limited to, fluorescein, 6-FAM, rhodamine, Texas Red, California Red, iFluor594, tetramethylrhodamine, a carboxyrhodamine, carboxyrhodamine 6G, carboxyrhodol, carboxyrhodamine 110, Cascade Blue, Cascade Yellow, coumarin, Cy2®, Cy3®, Cy3.5®, Cy5®, Cy5.5®, Cy7®, Cy-Chrome, DyLight 350, DyLight 405, DyLight 488, DyLight 549, DyLight 594, DyLight 633, DyLight 649, DyLight 680, DyLight 750, DyLight 800, phycoerythrin, PerCP (peridinin chlorophyll-a Protein), PerCP-Cy5.5, JOE (6-carboxy-4′,5′-dichloro-2′,7′-dimelhoxyfluorescein), NED, ROX (5-(and-6)-carboxy-X-rhodamine), HEX, Lucifer Yellow, Marina Blue, Oregon Green 488, Oregon Green 500, Oregon Green 514, Alexa Fluor® 350, Alexa Fluor® 430, Alexa Fluor® 488, Alexa Fluor® 532, Alexa Fluor®546, Alexa Fluor® 568, Alexa Fluor® 594, Alexa Fluor® 633, Alexa Fluor® 647, Alexa Fluor® 660, Alexa Fluor® 680, 7-amino-4-methylcoumarin-3-acetic acid, BODIPY® FL, BODIPY® FL-Br2, BODIPY® 530/550, BODIPY® 558/568, BODIPY® 564/570, BODIPY® 576/589, BODIPY®581/591, BODIPY® 630/650, BODIPY® 650/665, BODPY® R6G, BODIPY® TMR, BODIPY® TR, conjugates thereof, and combinations thereof. These embodiments include modifications of the above examples where the acceptor dye serves as the assay reporter (as exemplified in FIGS. 3D, 4D, 7, 8B, 8D, 8E, 29B, wherein the encircled ten pointed star represents the dye). In certain embodiments the conjugated polymer conjugates provided in FIGS. 2-10, 29 and 30 are intended for but not limited to use in flow cytometry, cell sorting, molecular diagnositics, fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), polymerase chain reaction, microscopy (fluorescent, confocal, 2 photon, etc.), blotting (e.g. northern, southern, western), cytomic bead arrays (Luminex formats, etc.), fluorescent immune assay (FIA or ELISA), nucleic acid sequencing and microarrays. Embodiments are also envisaged where conjugated polymers are used to enhance the detection and quantification of nucleic acids using sequence specific fluorescent probes combined with nucleic acid amplification techniques such as but not limited to polymerase chain reaction, transcription mediated amplification, rolling circle amplification, recombinase polymerase amplification, helicase dependent amplification and Linear-After-The-Exponential polymerase chain reaction. FIG. 32 represents modifications of the HybProbe detection technique. In FIG. 32A, the dye conventionally used as an energy transfer donor is replaced by the conjugated polymer (hexagon chain) which is covalently linked to the donor probe (wavey helical structure represented as right hand helical duplex due to association with nucleic acid target depicted a longer helical wavy line). Upon sequence specific hybridization the donor and acceptor (represented similarly to donor probe but on left hand side of nucleic acid target) probes are spatially juxtaposed on the target nucleic acid strand of interest in sufficiently close proximity to allow energy transfer to take place between the fluors. Excitation energy is transduced through the conjugated polymer and emitted as a readable signal by the dye (encircled ten pointed star) to allow nucleic acid quantification, detection and/or characterization. Presence of increased template allows increased numbers of probe co-hybridisation events and thus correlates to increased specific signal from the acceptor dye. In combination with the melt curve technique commonly employed in HybProbe experiments it is envisaged that sequence specific information corresponding to sequence variations will be collectable in appropriately designed experiments. FIG. 32B represents a “signal off” modification of the HybProbe approach where the conjugated polymer is quenched by an acceptor probe consisting of a small molecule fluorescence quencher (for example but not limited to Black Hole Quenchers™, Iowa Black® or Dabsyl). In another embodiment, conjugated polymer and conjugated polymer-dye tandem complexes similar to those described in FIGS. 4C and 4D are used in the detection, quantification and/or characterization of nucleic acid targets. Nucleic acid probe sequences labeled with a quencher molecule (black circle, for example but not limited to Black Hole Quenchers™, Iowa Black® or Dabsyl) are also conjugated to a conjugated polymer (FIGS. 4C and 31A) and a conjugated polymer-dye tandem complex (FIGS. 4D and 31B). In FIGS. 4C and D the recognition of the target sequence leads to a hybridization and separation of the quencher from the conjugated polymer or conjugated polymer-dye tandem complex and upon polymer excitation produces an increase in fluorescent signal. In FIGS. 31A and 31B the nucleic acid probe conjugate will hybridize to a complementary target sequence and by treatment with specific enzymes the probe sequence is cleaved or hydrolyzed freeing the conjugated polymer or conjugated conjugated polymer-dye tandem complex from the quencher and upon polymer excitation produces an increase in fluorescent signal. The most common example of the methods described in FIG. 31 is the use of DNA polymerase enzymes which contain nuclease activity (e.g. TaqMan PCR assays). FIG. 9 shows examples of conjugated polymer (hexagons) conjugated to secondary antibodies (FIG. 9A) and primary antibodies (FIG. 9B) (antibodies shown as Y-shaped structures). In an assay, an unlabeled 1° antibody can bind to an antigen, for example, a target protein (shown as a black triangle). Addition of the 2° antibody, which is conjugated to a polymer, can bind specifically to the 1° antibody. After washing to remove unbound 2° antibody and upon application of light of suitable excitation wavelength, observance of polymer emission is indicative of specific binding (FIG. 9A). In other assay embodiments, a polymer-labeled 1° antibody can directly bind a target protein, shown as a black triangle, and after washing to remove unbound 1° antibody and upon application of light of suitable excitation wavelength, observance of polymer emission is indicative of specific binding (FIG. 9B). Optionally, whether conjugated to the 1° or 2° antibody, the polymer may be further conjugated to a dye. In such a case, optical excitation of the conjugated polymer can result in energy transfer to the dye, and amplified dye emission, in comparison to direct dye excitation results. Observance of dye emission is indicative of specific binding. FIG. 10 shows an example of a sandwich-type complex of one embodiment of the invention. In the assay shown in FIG. 10A the conjugated polymer complex is composed of a polymer (shown as hexagons) that is bioconjugated a biomolecule, for example, streptavidin (X shape). After an unlabeled 1° antibody binds the target (e.g. protein), shown as a black triangle, a biotin-labeled 2° antibody binds specifically to the 1° antibody. In a separate step, addition of the conjugated polymer complex will result in specific binding between the biotin and streptavidin. Excitation of the conjugated polymer will result in polymer emission, indicating the presence of the target protein. Additionally in another embodiment, a biotin-labeled 1° antibody may be used to probe the target protein directly (FIG. 10B). After this binding event takes place, addition of a streptavidin-polymer complex will result in specific binding between the biotin and streptavidin, and excitation of the conjugated polymer will result in polymer emission, indicating the presence of the target protein. Optionally, the polymer may be further conjugated to a dye. In such a case, optical excitation of the polymer will result in amplified dye emission, as compared to direct excitation of the dye. Signals arising from dye emission will indicate the presence of the target protein. FIG. 30 depicts example embodiments around the use of conjugated polymers in Fluorescent Immuno Assay (FIA). In FIG. 30 panels A-C analyte antigen is immobilised on a surface which can include but is not limited to a microtitre plate well, bead particle, glass slide, plastic slide, lateral flow strip, laminar flow device, microfluidic device, virus, phage, tissue or cell surface. Analyte molecules are then detected by use of labelled detection conjugates or sensor biomolecules. In FIG. 30A, a conjugated polymer covalently linked to a detection antibody is utilized for detection. In FIG. 30B, a biotin binding protein (for example but not limited to avidin, streptavidin or other high affinity biotin specific derivatives) covalently bound to the conjugated polymer and interacting with a biotinylated detection antibody is utilized for detection. In FIG. 30C, a secondary antibody covalently linked to the conjugated polymer and interacting with a detection antibody is utilized for detection. In FIG. 5B, a homogenous, solution based example is also embodied where two separate antibodies each bind to the antigen of interest. One antibody is covalently linked to the conjugated polymer, the other to a dye. When bound to the antigen, the respective fluorophores are brought into sufficient spatial proximity for energy transfer to occur. In assays predicated on the designs in FIG. 30 and FIG. 5B, the sample is interrogated with light matched to the excitation of the conjugated polymer and signal reported at the emission wavelength of the dye. In the examples embodied in FIG. 30 A-C the use of a polymer-dye tandem complex is further disclosed. In such cases, optical excitation of the polymer will result in amplified dye emission, as compared to direct excitation of the dye. Signals arising from dye emission will indicate the presence of the target. In a further aspect, the invention provides for the multiplexing of donor energy transfer to multiple acceptors. By using a conjugated polymer as a donor in an energy transfer system, benefits also include the ability to multiplex. A single donor can transfer energy to several dyes; thus with a single excitation source, the intensity of multiple dyes can be monitored. This is useful for applications including but not limited to cell imaging (i.e. immunohistochemistry), flow cytometry and cell sorting, where the different types of cells can be monitored by protein-antibody recognition events. In one embodiment, two dye-labeled antibodies can be incubated with a biological material, for example, a cultured cell line, tissue section or blood sample. Antibodies are able to recognize cells with a target protein expressed on its surface and specifically bind only to those proteins. By labeling the two antibodies with different dyes, it is possible to monitor for the expression of two different proteins or different cell types simultaneously. Typically, this would require two scans, excitations or images, once each with the correct excitation wavelength. As a final step prior to analysis, these two images or data sets would have to be overlaid or combined. By using antibodies conjugated with both a dye and a conjugated polymer, one excitation wavelength can be used for the conjugated polymer to excite both dyes, and a single image or scan will include data sets from each of the two antibodies. This can be done with any number of antibody combinations provided there is sufficient ability to resolve the resulting signals. It is envisioned that the invention described herein can be used to increase the sensitivity of any of a number of commercially available tests including but not limited to the OraQuick Rapid HIV-1/2 Antibody Test, manufactured by OraSure Technologies, Inc. (Bethlehem, Pa.), which is a FDA-approved HIV diagnostic test for oral fluid samples. This test can provide screening results with over 99 percent accuracy in as little as 20 minutes. Conjugated Polymers Light harvesting conjugated polymer systems can efficiently transfer energy to nearby luminescent species. Mechanisms for energy transfer include, for example, resonant energy transfer (Forster (or fluorescence) resonance energy transfer, FRET), quantum charge exchange (Dexter energy transfer) and the like. Typically, however, these energy transfer mechanisms are relatively short range, and close proximity of the light harvesting conjugated polymer system to the signaling chromophore is required for efficient energy transfer. Amplification of the emission can occur when the number of individual chromophores in the light harvesting conjugated polymer system is large; emission from a fluorophore can be more intense when the incident light (the “pump light”) is at a wavelength which is absorbed by the light harvesting conjugated polymer system and transferred to the fluorophore than when the fluorophore is directly excited by the pump light. The conjugated polymers used in the present invention can be charge neutral, cationic or anionic. In some embodiments, the conjugated polymers are polycationic conjugated polymers. In other embodiments, the conjugated polymers are polyanionic conjugated polymers. In further embodiments, the conjugated polymers can include cationic, anionic, and/or neutral groups in various repeating subunits. In yet other embodiments, the conjugated polymers are neutral conjugated polymers. In some instances, conjugated polymers contain groups such as ethylene glycol oligomers, ethylene glycol polymers, ω-ammonium alkoxy salts, and/or ω-sulfonate alkoxy salts that impart solubility in aqueous solutions. In some instances the neutral conjugated polymers with non-ionic side chains are soluble in greater than 10 mg/mL in water or phosphate buffered saline solutions and in certains cases the solubility is greater than 50 mg/mL. In some embodiments the conjugated polymers contain either a terminal linking site (e.g., capping unit), internal linking site or both. In some embodiments, a conjugated polymer is one that comprises “low bandgap repeat units” of a type and in an amount that contribute an absorption to the polymer in the range of about 450 nm to about 1000 nm. The low bandgap repeat units may or may not exhibit such an absorption prior to polymerization, but does introduce that absorption when incorporated into the conjugated polymer. Such absorption characteristics allow the polymer to be excited at wavelengths that produce less background fluorescence in a variety of settings, including in analyzing biological samples and imaging and/or detecting molecules. Shifting the absorbance of the conjugated polymer to a lower energy and longer wavelength thus allows for more sensitive and robust methods. Additionally, many commercially available instruments incorporate imaging components that operate at such wavelengths at least in part to avoid such issues. For example, thermal cyclers that perform real-time detection during amplification reactions and microarray readers are available which operate in this region. Providing polymers that absorb in this region allows for the adaptation of detection methods to such formats, and also allows entirely new methods to be performed. Incorporation of repeat units that decrease the band gap can produce conjugated polymers with such characteristics. Exemplary optionally substituted species which result in polymers that absorb light at such wavelengths include 2,1,3-benzothiadiazole, benzoxidazole, benzoselenadiazole, benzotellurodiazole, naphthoselenadiazole, 4,7-di(thien-2-yl)-2,1,3-benzothiadiazole, squaraine dyes, quinoxalines, perylene, perylene diimides, diketopyrrolopyrrole, thienopyrazine low bandgap commercial dyes, olefins, and cyano-substituted olefins and isomers thereof. Further details relating to the composition, structure, properties and synthesis of suitable conjugated polymers can be found in U.S. patent application Ser. No. 11/329,495, filed Jan. 10, 2006, now published as US 2006-0183140 A1, which is incorporated herein by reference in the entirety. In one aspect, provided herein are conjugated polymers of Formula (I): wherein: each R is independently a non-ionic side group capable of imparting solubility in water in excess of 10 mg/mL; MU is a polymer modifying unit or band gap modifying unit that is evenly or randomly distributed along the polymer main chain and is optionally substituted with one or more optionally substituted substituents selected from halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl, C1-C12 haloalkyl, C1-C12 alkoxy, C2-C18(hetero)aryloxy, C2-C18(hetero)arylamino, (CH2)x′(OCH2CH2)y′OCH3 where each x′ is independently an integer from 0-20, y′ is independently an integer from 0 to 50, or a C2-C18(hetero)aryl group; each optional linker L1 and L2 are aryl or hetroaryl groups evenly or randomly distributed along the polymer main chain and are substituted with one or more pendant chains terminated with a functional group for conjugation to another substrate, molecule or biomolecule selected from amine, carbamate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof; G1 and G2 are each independently selected from hydrogen, halogen, amine, carbamate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiol, optionally substituted aryl, optionally substituted heteroaryl, halogen substituted aryl, boronic acid substituted aryl, boronic ester substituted aryl, boronic esters, optionally substituted fluorine and aryl or hetroaryl substituted with one or more pendant chains terminated with a functional group, molecule or biomolecule selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule; wherein the polymer comprises at least 1 functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, and thiols within G1, G2, L1 or L2 that allows, for functional conjugation to another molecule, substrate or biomolecule; each dashed bond, - - - - - - , is independently a single bond, triple bond or optionally substituted vinylene (—CR5═CR5—) wherein each R5 is independently hydrogen, cyano, C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl or a C2-C18(hetero)aryl group, wherein each C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl or a C2-C18(hetero)aryl group is optionally substituted with one or more halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl group, C1-C12 alkoxy, or C1-C12 haloalkyl; and n is an integer from 1 to about 10,000; and a, b, c and d define the mol % of each unit within the structure which each can be evenly or randomly repeated and where a is a mol % from 10 to 100%, b is a mol % from 0 to 90%, and each c and d are mol % from 0 to 25%. Non-ionic side groups capable of imparting solubility in water as used herein refer to side groups which are not charged and allow the resulting polymer to be soluble in water or aqueous solutions with no visible particulates. In some embodiments, each R is independently a non-ionic side group capable of imparting solubility in water in excess of 10 mg/mL, in excess of 15 mg/mL, in excess of 20 mg/mL, in excess of 25 mg/mL, in excess of 30 mg/mL, in excess of 35 mg/mL, in excess of 40 mg/mL, in excess of 45 mg/mL, in excess of 50 mg/mL, in excess of 60 mg/mL, in excess of 70 mg/mL, in excess of 80 mg/mL, in excess of 90 mg/mL or in excess of 100 mg/mL. In some embodiments, conjugated polymers described herein comprises a minimum number average molecular weight of greater than 5,000 g/mol, greater than 10,000 g/mol, greater than 15,000 g/mol, greater than 20,000 g/mol, greater than 25,000 g/mol, greater than 30,000 g/mol, greater than 40,000 g/mol, greater than 50,000 g/mol, greater than 60,000 g/mol, greater than 70,000 g/mol, greater than 80,000 g/mol, greater than 90,000 g/mol, or greater than 100,000 g/mol. In some embodiments, each R is independently (CH2)x(OCH2CH2)yOCH3 where each x is independently an integer from 0-20, each y is independently an integer from 0 to 50, or a benzyl optionally substituted with one or more halogen, hydroxyl, C1-C12 alkoxy, or (OCH2CH2)zOCH3 where each z is independently an integer from 0 to 50. In some instances, each R is (CH2)3(OCH2CH2)11OCH3. In other embodiments, each R is independently a benzyl substituted with at least one (OCH2CH2)zOCH3 group where each z is independently an integer from 0 to 50. In some instances, each R is a benzyl substituted with at least one (OCH2CH2)10OCH3 group. In other instances, each R is a benzyl substituted with at least two (OCH2CH2)10OCH3 groups. In further instances, each R is a benzyl substituted with at least three (OCH2CH2)10OCH3 groups. In further embodiments, each R is independently where k and l are independant integers from 0 to 25; *=site for covalent attachment. In yet further embodiments, each R is independently is a dendrimer of PAMAM, PEA, PEHAM, PPI, tri-branched benzoate, or glycerol with a generation of 1 to 4 and optionally terminal substitutions, said optionally terminal substitutions are ( - - - - - )(CH2CH2O)jCH3 or ( - - - - - )(OCH2CH2)jCH3 and j is an integer from 0 to 25 and the dotted lines ( - - - - - ) are each independently selected from any one or a combination of, C1-C12 alkyl, C1-C12 alkoxy, C2-C12 alkene, amido, amino, aryl, (CH2)r(OCH2CH2)s(CH2)r where each r is independently an integer from 0-20, s is independently an integer from 0 to 50, carbamate, carboxylate, C3-C12 cycloalkyl, imido, phenoxy, or C4-C18(hetero)aryl groups. In alternative embodiments, each R is independently, Where k and l are independant integers from 0 to 25 and the dotted lines ( - - - - - ) are each independently selected from any one or a combination of, C1-C12 alkyl, C1-C12 alkoxy, C2-C12 alkene, amido, amino, aryl, (CH2)r(OCH2CH2)s(CH2)r where each r is independently an integer from 0-20, s is independently an integer from 0 to 50, carbamate, carboxylate, C3-C12 cycloalkyl, imido, phenoxy, or C4-C18(hetero)aryl groups; *=site for covalent attachment. In alternative embodiments, each R is independently, Where k and l are independant integers from 0 to 25 and the dotted lines ( - - - - - ) are each independently selected from any one or a combination of, C1-C12 alkyl, C1-C12 alkoxy, C2-C12 alkene, amido, amino, aryl, (CH2)r(OCH2CH2)s(CH2)r where each r is independently an integer from 0-20, s is independently an integer from 0 to 50, carbamate, carboxylate, C3-C12 cycloalkyl, imido, phenoxy, or C4-C18(hetero)aryl groups; *=site for covalent attachment. In some embodiments, conjugated polymers described herein contain no optional linkers, L1 and/or L2. In other embodiments, conjugated polymers contain at least about 0.01 mol %, at least about 0.02 mol %, at least about 0.05 mol %, at least about 0.1 mol %, at least about 0.2 mol %, at least about 0.5 mol %, at least about 1 mol %, at least about 2 mol %, at least about 5 mol %, at least about 10 mol %, at least about 20 mol %, or about 25 mol % of optional linkers, L1 and/or L2. In some embodiments, conjugated polymers contain up to 50 mol % total of optional linkers, L1 and L2, and may contain about 40 mol % or less, about 30 mol % or less, about 25 mol % or less, about 20 mol % or less, about 15 mol % or less, about 10 mol % or less, or about 5 mol % or less. Linkers can be evenly or randomly distributed along the polymer main chain. In some embodiments, optional linkers L1 or L2 have the structure: *=site for covalent attachment to unsaturated backbone wherein R3 is independently hydrogen, halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl or a C2-C18(hetero)aryl group, wherein each C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl or a C2-C18(hetero)aryl group is optionally substituted with one or more halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl group, C1-C12 alkoxy, or C1-C12 haloalkyl; and q is an integer from 0 to 4. In some embodiments, optional linkers L1 or L2 have the structure represented by: *=site for covalent attachment to unsaturated backbone wherein A is a site for conjugation, chain extension or crosslinking and is —[O—CH2—CH2]t-W, or (C1-C12)alkoxy-X; W is —OH or —COOH; X is —NH2, —NHCOOH, —NHCOOC(CH3)3, —NHCO(C3-C12)cycloalkyl(C1-C4)alkyl-N-maleimide; or —NHCO[CH2—CH2—O]uNH2; t is an integer from 1 to 20; and u is an integer from 1 to 8. In other embodiments, optional linkers L1 or L2 are selected from the group consisting of a-h having the structure: *=site for covalent attachment to unsaturated backbone wherein R′ is independently H, halogen, C1-C12 alkyl, (C1-C12 alkyl)NH2, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl, C1-C12 haloalkyl, C2-C18(hetero)aryl, C2-C18(hetero)arylamino, —[CH2—CH2]r′—Z1, or (C1-C12)alkoxy-X1; and wherein Z1 is —OH or —COOH; X1 is —NH2, —NHCOOH, —NHCOOC(CH3)3, —NHCO(C3-C12)cycloalkyl(C1-C4)alkyl-N-maleimide; or —NHCO[CH2—CH2—O]s′(CH2)s′NH2; r′ is an integer from 1 to 20; and each s′ is independently an integer from 1 to 20, (CH2)3(OCH2CH2)x″OCH3 where x″ is independently an integer from 0 to 50, or a benzyl optionally substituted with one or more halogen, hydroxyl, C1-C12 alkoxy, or (OCH2CH2)y″OCH3 where each y″ is independently an integer from 0 to 50 and R′ is different from R; wherein R15 is selected from the group consisting of l-t having the structure: and k is 2, 4, 8, 12 or 24; *=site for covalent attachment to backbone. In certain embodiments, optional linkers L1 or L2 are In some embodiments, G1 and G2 are optionally substituted aryl wherein the optional substituent is selected from halogen, amine, carbamate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, boronic acid, boronate radical, boronic esters and optionally substituted fluorene. In other embodiments, G1 and G2 are the same. In further embodiments, G1 and G2 are different. G1 and G2 can be activated units that allow further conjugation, crosslinking, or polymer chain extension, or they may be nonactivated termination units. In some embodiments, G1 and G2 are independently selected from structures represented by: *=site for covalent attachment to backbone wherein R11 is any one of or a combination of a bond, C1-C20 alkyl, C1-C20 alkoxy, C2-C20 alkene, C2-C20 alkyne, C3-C20 cycloalkyl, C1-C20 haloalkyl, (CH2)x(OCH2CH2)p(CH2)x where each x is independently an integer from 0-20, p is independently an integer from 0 to 50, aryl, C2-C18(hetero)aryl, phenoxy, amido, amino, carbamate, carboxylate, carbonates, sulfide, disulfide, or imido groups terminated with a functional group selected from amine, carbamate, carboxylate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule. In other embodiments, G1 and G2 are independently selected from the group consisting of 1-18 having the structure: *=site for covalent attachment to backbone wherein R15 is selected from the group consisting of l-t having the structure: and k is 2, 4, 8, 12 or 24. In further embodiments, G1 and G2 is * or In some embodiments, optional linkers, L1 and/or L2, G1, and/or G2 can be further conjugated to an organic dye, a biomolecule or a substrate. Covalent linkage can be introduced by any known method and can include, but is not limited to, chemistry involving maleimide/thiol; thiol/thiol; pyridyldithiol/thiol; succinimidyl iodoacetate/thiol; N-succinimidylester (NHS ester), sulfodicholorphenol ester (SDP ester), or pentafluorophenyl-ester (PFP ester)/amine; bissuccinimidylester/amine; imidoesters/amines; hydrazine or amine/aldehyde, dialdehyde or benzaldehyde; isocyanate/hydroxyl or amine; carbohydrate-periodate/hydrazine or amine; diazirine/aryl azide chemistry; pyridyldithiol/aryl azide chemistry; alkyne/azide; carboxy-carbodiimide/amine; amine/Sulfo-SMCC (Sulfosuccinimidyl 4-[N-maleimidomethyl]cyclohexane-1-carboxylate)/thiol; and amine/BMPH (N-[β-Maleimidopropionic acid]hydrazide*TFA)/thiol. In some embodiments, MU is selected from the group consisting of a′-k′ having the structure: =site for covalent attachment to unsaturated backbone wherein R is a non-ionic side group capable of imparting solubility in water in excess of 10 mg/mL. Non-ionic side groups include those previously described for polymers of Formula (I). As used herein, in some embodiments, a pendant chain is any one of or a combination of a bond, C1-C20 alkyl, C1-C20 alkoxy, C2-C20 alkene, C2-C20 alkyne, C3-C20 cycloalkyl, C1-C20 haloalkyl, (CH2)x(OCH2CH2)p(CH2)x where each x is independently an integer from 0-20, p is independently an integer from 0 to 50, aryl, C2-C18(hetero)aryl, phenoxy, amido, amino, carbamate, carboxylate, carbonates, sulfide, disulfide, or imido groups which connects a polymer with a functional group for conjugation to another substrate, molecule, or biomolecule. In some embodiments, conjugated polymers of Formula (I) have the structure of Formula (Ia): wherein R, L1, L2, G1, G2, MU, a, b, c, d and n are described previously for formula (I). In a further aspect, conjugated polymers of Formula I have the structure of Formula (Ib): wherein at least one of G1 or G2 comprises a functional conjugation cite. In a further aspect, conjugated polymers of Formula I have the structure of Formula (Ic): wherein L1 comprises a functional conjugation cite. In a further aspect, conjugated polymers of Formula I have the structure of Formula (Id): wherein at least one of G1 or G2 comprises a functional conjugation cite. In a further aspect, conjugated polymers of Formula I have the structure of Formula (II): wherein L1, G1, G2, a, c, n and dashed bonds are described previously for formula (I). In some embodiments, conjugated polymers of Formula (II) have the structure of Formula (IIa): wherein L1, G1, G2, a, c, and n are described previously for formula (I). In a further aspect, conjugated polymers of Formula I have the structure of Formula (III): wherein L1, G1, G2, a, c, n and dashed bonds are described previously for formula (I). In some embodiments, conjugated polymers of Formula (III) have the structure of Formula (IIIa): wherein L1, G1, G2, a, c, and n are described previously for formula (I). In a further aspect, conjugated polymers of Formula I have the structure of Formula (IV): wherein each R5 is independently hydrogen, cyano, C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl or a C2-C18(hetero)aryl group, wherein each C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl or a C2-C18(hetero)aryl group is optionally substituted with one or more halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl group, C1-C12 alkoxy, or C1-C12 haloalkyl; and L1, G1, G2, a, c, n and dashed bonds are described previously for formula (I). In a further aspect, conjugated polymers of Formula I have the structure of Formula (V): wherein each R5 is independently hydrogen, cyano, C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl or a C2-C18(hetero)aryl group, wherein each C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl or a C2-C18(hetero)aryl group is optionally substituted with one or more halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl group, C1-C12 alkoxy, or C1-C12 haloalkyl; and L1, G1, G2, a, c, n and dashed bonds are described previously for formula (I). Also provided herein are polymers having the structure of the following formula: wherein: G1 and G2 are each independently selected from hydrogen, halogen, amine, carbamate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, optionally substituted aryl, halogen substituted aryl, boronic acid substituted aryl, boronic ester substituted aryl, boronic esters and optionally substituted fluorene; L is a bond or an aryl or heteroaryl group that is evenly or randomly distributed along the polymer main chain and is optionally substituted with one or more optionally substituted substituents selected from halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl, C1-C12 haloalkyl, C1-C12 alkoxy, C2-C18(hetero)aryloxy, C2-C18(hetero)arylamino, (CH2)x(OCH2CH2)pOCH3 where each x is independently an integer from 0-20, p is independently an integer from 0 to 50, or a C2-C18(hetero)aryl group; L1, L1′, L2 and L2′are each independently a covalent bond, a C1-C12 alkylene, a C3-C12 cycloalkylene, a C2-C12 alkenylene, a C2-C12 alkynylene, a (C6-C18)aryl(C1-C12)alkylene, a (C6-C18)aryl(C2-C12)alkenylene, a (C6-C18)aryl(C1-C12)alkynylene, a C6-C18 arylene group, —Y1—[O—Y2]p—, —O—Y1—[O—Y2]p— wherein each C1-C12 alkylene, C3-C12 cycloalkylene, (C6-C18)aryl(C1-C12)alkylene, or C6-C18 arylene group is optionally substituted with one or more halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl group, C1-C12 alkoxy, C1-C12 haloalkyl, —Y1—[O—Y2]p— or —O—Y1—[O—Y2]p—; q is 0 or an integer from 1 to 8; p is 0 or an integer from 1 to 24; Y1 and Y2 are each independently a covalent bond, or a C1-12 alkylene group, a C3-C12 cycloalkylene, a C2-C18(hetero)arylene, a (C6-C18)aryl(C1-C12)alkylene, wherein each C1-12 alkylene group, a C3-C12 cycloalkylene, a C2-C18(hetero)arylene, a (C6-C18)aryl(C1-C12)alkylene is optionally substituted with one or more halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl group, C1-C12 alkoxy, or C1-C12 haloalkyl; E1 and E1′ are each independently, hydrogen, C1-C6 alkyl, —OH, —COOH, —SH, —SR, —SHR+, SR2+, —SO3−, —PO4−, Br, —NH2, —NHR, —NR2, —NH3+, —NH2R+, —NHR2+ or —NR3+, wherein and each R is independently a C1-C6 alkyl and —SHR+, SR2+, —SO3−, —PO4−, —NH3+, —NH2R+, —NHR2+ or —NR3+ each optionally has an associated counterion; and n is an integer from 1 to about 1,000. Also provided herein are polymers having the structure of the following formula: wherein each R is independently O(CHx), or (CH2)3(OCH2CH2)pOCH3 where each x is independently an integer from 0-20, each p is independently an integer from 0 to 50, or a benzyl optionally substituted with one or more halogen, hydroxyl, C1-C12 alkoxy, or (OCH2CH2)mOCH3 where each m is independently an integer from 0 to 50; G1 is selected from hydrogen, halogen, amine, carbamate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, optionally substituted aryl, halogen substituted aryl, boronic acid substituted aryl, boronic ester substituted aryl, boronic esters and optionally substituted fluorene; and n is an integer from 1 to about 10,000. Additional embodiments of conjugated polymers are described in the following Examples. Preparation of Conjugated Polymers The synthesis of conjugated polymers described herein may be accomplished using means described in the chemical literature, using the methods described herein, or a combination thereof. Conjugated polymers described herein may be synthesized using standard synthetic techniques known to those of skill in the art or using methods known in the art in combination with methods described herein. In additions, solvents, temperatures and other reaction conditions presented herein may vary according to the practice and knowledge of those of skill in the art. The starting material used for the synthesis of the conjugated polymers of Formula (1) and polymers having the structures described in the prior section as described herein can be obtained from commercial sources, such as Aldrich Chemical Co. (Milwaukee, Wis.), Sigma Chemical Co. (St. Louis, Mo.), or the starting materials can be synthesized. The polymers described herein, and other related polymers having different substituents can be synthesized using techniques and materials known to those of skill in the art, such as described, for example, in March, DVANCED ORGANIC CHEMISTRY 4th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3′ Ed., (Wiley 1999) (all of which are incorporated by reference in their entirety). General methods for the preparation of polymers as disclosed herein may be derived from known reactions in the field, and the reactions may be modified by the use of appropriate reagents and conditions, as would be recognized by the skilled person, for the introduction of the various moieties found in the formulae as provided herein. As a guide the following synthetic methods may be utilized. Generally, polymerization of fluorene polymeric structures may be accomplished using polymerization techniques known to those of skill in the art or using methods known in the art in combination with methods described herein. For example, polymerization can be achieved via Suzuki coupling with a commercially available fluorene-dihalide monomer, e.g., 2,7-dibromofluorene, and its diboronic acid or ester derivative: Structures A-1 and A-2 are catalyzed by a metal catalyst to form exemplary polymer A-3 with termination points, labeled Y. Each Y is independently —H, —Br, —B(OH)2, or boronic ester, e.g., 4,4,5,5,-tetramethyl-1,3,2-dioxaborolanyl. Synthesis of diboronic ester derivatives from a fluorene-dihalide monomer can also be accomplished via Suzuki coupling with bis(pinacolato)diboron: Substituents such as ethylene glycol oligomers or ethylene glycol polymers may be attached to monomers prior to polymerization or to the polymer itself after polymerization. An exemplary scheme of synthesizing substituted fluorene monomers with mPEGylated groups is as follows: 2,7-dibromofluorene (B-1) and 3-bromopropanol in the presence of a strong base such as sodium hydroxide, potassium hydroxide, or the like and a phase transfer catalyst, e.g. tetrabutylammonium bromide, is heated and reacted to completion to form 2,7-dibromo-9,9-di(3′-hydroxypropanyl)fluorene (B-2). —OH groups of B-2 are tosylated with tosyl chloride in the presence of pyridine and allowed to react to completion to form 2,7-dibromo-9,9-di(3′-methylbenzenesulfonatopropanyl)fluorene (B-3). B-3 is then reacted with a mPEG(x) alcohol in the presence of potassium tert-butoxide to form B-4 with attached mPEG chains. mPEG alcohols can have 1-50 mPEG chains. Typical sizes include but are not limited to mPEG5, mPEG8, mPEG11, mPEG24. In an alternative scheme, mPEG alcohols can be tosylated first via tosyl chloride and then reacted to B-2 to form B-4. Substituted monomers, such as exemplary structure B-4, can be further derivatized to diboronic esters in the schemes disclosed herein and subsequently be used for polymerization such as via Suzuki coupling. Polymeric fluorenes may also be obtained through the use of other reaction schemes involving organometallic catalysis. For example, the Yamamoto reaction uses a nickel(0)-based catalyst for the homo-coupling of aryl halide monomers like exemplary structure B-4. Additionally, conjugated polymers can be synthesized using Stille, Heck, and Sonogashira coupling reactions. See, e.g., Yamamoto et al., Macromolecules 25: 1214-1223, 1992; Kreyenschmidt et al., Macromolecules 28: 4577-4582, 1995; and Pei et al., J. Am. Chem. Soc. 118: 7416-7417, 1996 regarding Yamamoto reaction schemes. See, also, Leclerc, Polym. Sci. Part A: Polym. Chem. 39: 2867-2873, 2001 for Stille reaction schemes; Mikroyannidis et al., J. Polym. Sci. Part A: Polym. Chem. 45: 4661-4670, 2007 for Heck reaction schemes; and Sonogashira et al., Tetrahedron Lett. 16: 4467-4470, 1975 and Lee et al., Org. Lett. 3: 2005-2007, 2001 for Sonogashira reaction schemes. Linkers and capping units can be conjugated to a fluorene polymer backbone via similar mechanisms as described previously. For example, bromo- and boronic esters of capping units can be used to append one or both ends of a polymer. Utilizing both bromo- and boronic esters of capping units will append both ends of polymer. Utilizing only one form, either a bromo- or boronic ester of a capping unit, will append only those ends terminated with its respective complement and for symmetric A-A+B-B polymerizations can be used to statistically modify only one end of a polymer. For asymmetric polymers this approach is used to chemically ensure the polymers are only modified at a single chain terminus. FIG. 11 depicts appending an exemplary fluorene polymer with Y ends with one or more phenyl groups with bromobenzene, phenyl boronic acid or both using Suzuki coupling. Capping units can also be appended asymmetrically by first reacting a bromo-capping unit with a polymer with Y ends and subsequently reacting the polymer with a boronic ester capping unit. Exemplary bromo- and boronic ester capping units include but are not limited to the following structures: Further capping units can be found in structures 1-31 described herein or in the following Examples and methods for their attachment. The incorporation of optional linkers into conjugated polymer backbones further described in U.S. application Ser. No. 11/868,870, filed Oct. 8, 2007 and published as U.S. Application No. 2008/0293164, which application is herein incorporated by reference in its entirety. A desired optional linker incorporation can be achieved by varying the molar ratio of optional linker to bi-functional monomer. For example, an optional linker can be incorporated by substituting a percentage of one of the bi-functional monomers with a similar bi-functional optional linker which comprises the conjugation site of interest. The number and type of linking site included in the polymer is controlled by the feed ratio of the monomers to optional linker in the polymerization reaction. By varying the feed ratio, conjugated polymers can contain at least about 0.01 mol % of linker, L, and may contain at least about 0.02 mol %, at least about 0.05 mol %, at least about 0.1 mol %, at least about 0.2 mol %, at least about 0.5 mol %, at least about 1 mol %, at least about 2 mol %, at least about 5 mol %, at least about 10 mol %, at least about 20 mol %, or at least about 30 mol %. The conjugated polymers may contain up to 100 mol % of linker, L, and may contain about 99 mol % or less, about 90 mol % or less, about 80 mol % or less, about 70 mol % or less, about 60 mol % or less, about 50 mol % or less, or about 40 mol % or less. Linkers can be evenly or randomly distributed along the polymer main chain. In further embodiments, an optional linker can further allow covalent attachment of the resulting polymer to biomolecules, secondary reporters or other assay components. In alternative embodiments, the methods described herein to incorporate optional linkers may be used in combination with methods of introducing capping units with linking sites to produce polymers with both internal and terminal linking sites for conjugation. A non-limiting application of a polymer with both optional linkers and terminal capping units with linking sites for conjugation are polymer-dye-biomolecule tandem conjugates where the polymer is used as an energy transfer donor, such as in FRET, to a secondary dye acceptor thus shifting the emission wavelength to that of the corresponding dye. The person skilled in the art may further appreciate various syntheses and polymerization methods and embodiments of the present disclosure upon review of the following illustrative and non-limiting Examples. Antigen-Antibody Interactions The interactions between antigens and antibodies are the same as for other noncovalent protein-protein interactions. In general, four types of binding interactions exist between antigens and antibodies: (i) hydrogen bonds, (ii) dispersion forces, (iii) electrostatic forces between Lewis acids and Lewis bases, and (iv) hydrophobic interactions. Certain physical forces contribute to antigen-antibody binding, for example, the fit or complimentary of epitope shapes with different antibody binding sites. Moreover, other materials and antigens may cross-react with an antibody, thereby competing for available free antibody. Measurement of the affinity constant and specificity of binding between antigen and antibody is a pivotal element in determining the efficacy of an immunoassay, not only for assessing the best antigen and antibody preparations to use but also for maintaining quality control once the basic immunoassay design is in place. Antibodies Antibody molecules belong to a family of plasma proteins called immunoglobulins, whose basic building block, the immunoglobulin fold or domain, is used in various forms in many molecules of the immune system and other biological recognition systems. A typical immunoglobulin has four polypeptide chains, containing an antigen binding region known as a variable region and a non-varying region known as the constant region. Native antibodies and immunoglobulins are usually heterotetrameric glycoproteins of about 150,000 Daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies between the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has at one end a variable domain (VH) followed by a number of constant domains. Each light chain has a variable domain at one end (VL) and a constant domain at its other end. The constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain. Depending on the amino acid sequences of the constant domain of their heavy chains, immunoglobulins can be assigned to different classes. There are at least five (5) major classes of immunoglobulins: IgA, IgD, IgE, IgG and IgM, and several of these may be further divided into subclasses (isotypes), e.g. IgG-1, IgG-2, IgG-3 and IgG-4; IgA-1 and IgA-2. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known. Further details regarding antibody structure, function, use and preparation are discussed in U.S. Pat. No. 6,998,241, issued Feb. 14, 2006, the entire contents of which are incorporated herein by reference. Sandwich Assays Antibody or multiple antibody sandwich assays are well known to those skilled in the art including a disclosed in U.S. Pat. No. 4,486,530, issued Dec. 4, 1984, and references noted therein. The structures described in FIGS. 6, 7, 8, 9, 10 and 14 can be used directly as described or in various sandwich configurations including those described in Example 37. A sandwich configuration or a sandwich assay refers to the use of successive recognition events to build up layers of various biomolecules and reporting elements to signal the presence of a particular biomolecule, for example a target biomolecule or a target-associated biomolecule. A standard example of this would be the successive use of antibodies. In these assays, a primary antibody binds the target, the secondary antibody binds the primary, a third antibody can bind the secondary and so on. With each successive layer additional reporting groups can be added. Another strategy is using a repetitive addition of alternating layers of two (or more) mutually-recognizable components, or more than two components in a chain-recognition relationship, which comprise one or both of the components in a form of multimeric structure. In such a setup, one or more of the functional group(s) in each of the multimeric structure can be labeled with reporting group(s) and the unoccupied functional group(s) can serve as the recognition site for the other component(s), and this system will subsequently provide a platform for signal amplification. A typical example of this approach is the use of streptavidin-reporter conjugate and biotinylated anti-streptavidin antibody. In such assays, a biotinylated sensor molecule (nucleic acid or antibody) can be used to bind a target biomolecule, which is subsequently recognized by a detection system containing a streptavidin-reporter conjugate and biotinylated anti-streptavidin antibody. The sandwich structure in this case can be built up by successive rounds of biotinylated antibodies and labeled streptavidin complexes interaction to achieve the signal amplification. With an additional conjugation of a conjugated polymer to either the biotinylated antibody or the streptavidin-reporter complex, it is possible to further increase the signal output. In essence, the integration of a conjugated polymer in this type of signal amplification system can further amplify signals to a higher level. The bioconjugated polymer complexes described in FIGS. 6, 7, 8, 9, 10, 14, 15, 16 and 17 can be used to create optically enhanced sandwich assays by directly integrating a light harvesting conjugated polymer into commonly utilized recognition elements. The benefits of the conjugated polymer conjugated structures can also be applied directly to the primary target recognition elements without the need for successive recognition elements. For example, a primary antibody can be directly conjugated to polymer-dye complex such as shown in FIG. 14. Such a complex can be used to directly probe the presence of a target biomolecule. Polynucleotides Amplified target polynucleotides may be subjected to post amplification treatments. For example, in some cases, it may be desirable to fragment the target polynucleotide prior to hybridization in order to provide segments which are more readily accessible. Fragmentation of the nucleic acids can be carried out by any method producing fragments of a size useful in the assay being performed; suitable physical, chemical and enzymatic methods are known in the art. An amplification reaction can be performed under conditions which allow the sensor polynucleotide to hybridize to the amplification product during at least part of an amplification cycle. When the assay is performed in this manner, real-time detection of this hybridization event can take place by monitoring for light emission during amplification. Real time PCR product analysis (and related real time reverse-transcription PCR) provides a well-known technique for real time PCR monitoring that has been used in a variety of contexts, which can be adapted for use with the methods described herein (see, Laurendeau et al. (1999) “TaqMan PCR-based gene dosage assay for predictive testing in individuals from a cancer family with INK4 locus haploinsufficiency” Clin Chem 45(7):982-6; Laurendeau et al. (1999) “Quantitation of MYC gene expression in sporadic breast tumors with a real-time reverse transcription-PCR assay” Clin Chem 59(12):2759-65; and Kreuzer et al. (1999) “LightCycler technology for the quantitation of bcr/abl fusion transcripts” Cancer Research 59(13):3171-4, all of which are incorporated by reference). Samples In principle, a sample can be any material suspected of containing a target biomolecule (e.g., antibody, protein, affinity ligand, peptide, nucleic acid and the like) capable of causing excitation of a conjugated polymer complex. In some embodiments, the sample can be any source of biological material which comprises biomolecules that can be obtained from a living organism directly or indirectly, including cells, tissue or fluid, and the deposits left by that organism, including viruses, mycoplasma, and fossils. The sample may comprise a target biomolecule prepared through synthetic means, in whole or in part. Typically, the sample is obtained as or dispersed in a predominantly aqueous medium. Nonlimiting examples of the sample include blood, urine, semen, milk, sputum, mucus, a buccal swab, a vaginal swab, a rectal swab, an aspirate, a needle biopsy, a section of tissue obtained for example by surgery or autopsy, plasma, serum, spinal fluid, lymph fluid, the external secretions of the skin, respiratory, intestinal, and genitourinary tracts, tears, saliva, tumors, organs, samples of in vitro cell culture constituents (including but not limited to conditioned medium resulting from the growth of cells in cell culture medium, putatively virally infected cells, recombinant cells, and cell components), and a recombinant library comprising polynucleotide sequences. The sample can be a positive control sample which is known to contain the target biomolecule or a surrogate therefore. A negative control sample can also be used which, although not expected to contain the target biomolecule, is suspected of containing it (via contamination of one or more of the reagents) or another component capable of producing a false positive, and is tested in order to confirm the lack of contamination by the target biomolecule of the reagents used in a given assay, as well as to determine whether a given set of assay conditions produces false positives (a positive signal even in the absence of target biomolecule in the sample). The sample can be diluted, dissolved, suspended, extracted or otherwise treated to solubilize and/or purify any target polynucleotide present or to render it accessible to reagents which are used in an amplification scheme or to detection reagents. Where the sample contains cells, the cells can be lysed or permeabilized to release the polynucleotides within the cells. One step permeabilization buffers can be used to lyse cells which allow further steps to be performed directly after lysis, for example a polymerase chain reaction. Organic Dyes Organic dyes include signaling chromophores and fluorophores. In some embodiments, a signaling chromophore or fluorophore may be employed, for example to receive energy transferred from an excited state of an optically active unit, or to exchange energy with a labeled probe, or in multiple energy transfer schemes. Fluorophores useful in the inventions described herein include any substance which can absorb energy of an appropriate wavelength and emit or transfer energy. For multiplexed assays, a plurality of different fluorophores can be used with detectably different emission spectra. Typical fluorophores include fluorescent dyes, semiconductor nanocrystals, lanthanide chelates, and fluorescent proteins. Exemplary fluorescent dyes include fluorescein, 6-FAM, rhodamine, Texas Red, tetramethylrhodamine, a carboxyrhodamine, carboxyrhodamine 6G, carboxyrhodol, carboxyrhodamine 110, Cascade Blue, Cascade Yellow, coumarin, Cy2®, Cy3®, Cy3.5®, Cy5®, Cy5.5®, Cy-Chrome, DyLight 350, DyLight 405, DyLight 488, DyLight 549, DyLight 594, DyLight 633, DyLight 649, DyLight 680, DyLight 750, DyLight 800, phycoerythrin, PerCP (peridinin chlorophyll-a Protein), PerCP-Cy5.5, JOE (6-carboxy-4′,5′-dichloro-2′,7′-dimelhoxyfluorescein), NED, ROX (5-(and-6)-carboxy-X-rhodamine), HEX, Lucifer Yellow, Marina Blue, Oregon Green 488, Oregon Green 500, Oregon Green 514, Alexa Fluor® 350, Alexa Fluor® 430, Alexa Fluor® 488, Alexa Fluor® 532, Alexa Fluor® 546, Alexa Fluor® 568, Alexa Fluor® 594, Alexa Fluor® 633, Alexa Fluor® 647, Alexa Fluor® 660, Alexa Fluor® 680, 7-amino-4-methylcoumarin-3-acetic acid, BODIPY® FL, BODIPY® FL-Br2, BODIPY® 530/550, BODIPY® 558/568, BODIPY® 564/570, BODIPY® 576/589, BODIPY® 581/591, BODIPY® 630/650, BODIPY® 650/665, BODPY® R6G, BODIPY® TMR, BODIPY® TR, conjugates thereof, and combinations thereof. Exemplary lanthanide chelates include europium chelates, terbium chelates and samarium chelates. A wide variety of fluorescent semiconductor nanocrystals (“SCNCs”) are known in the art; methods of producing and utilizing semiconductor nanocrystals are described in: PCT Publ. No. WO 99/26299 published May 27, 1999, inventors Bawendi et al.; U.S. Pat. No. 5,990,479 issued Nov. 23, 1999 to Weiss et al.; and Bruchez et al., Science 281:2013, 1998. Semiconductor nanocrystals can be obtained with very narrow emission bands with well-defined peak emission wavelengths, allowing for a large number of different SCNCs to be used as signaling chromophores in the same assay, optionally in combination with other non-SCNC types of signaling chromophores. Exemplary polynucleotide-specific dyes include acridine orange, acridine homodimer, actinomycin D, 7-aminoactmomycin D (7-AAD), 9-amino-6-chlor-2-methoxyacridine (ACMA), BOBO™-1 iodide (462/481), BOBO™-3 iodide (570/602), BO-PRO™-1 iodide (462/481), BO-PRO™-3 iodide (575/599), 4′,6-diamidino-2-phenylindole, dihydrochloride (DAPI), 4′,6-diamidino-2-phenylindole, dihydrochloride (DAPI), 4′,6-diamidino-2-phenylindole, dilactate (DAPI, dilactate), dihydroethidium (hydroethidine), dihydroethidium (hydroethidine), dihydroethidium (hydroethidine), ethidium bromide, ethidium diazide chloride, ethidium homodimer-1 (EthD-1), ethidium homodimer-2 (EthD-2), ethidium monoazide bromide (EMA), hexidium iodide, Hoechst 33258, Hoechst 33342, Hoechst 34580, Hoechst S769121, hydroxystilbamidine, methanesulfonate, JOJO™-1 iodide (529/545), JO-PRO™-1 iodide (530/546), LOLO™-1 iodide (565/579), LO-PRO™-1 iodide (567/580), NeuroTrace™ 435/455, NeuroTrace™ 500/525, NeuroTrace™ 515/535, NeuroTrace™ 530/615, NeuroTrace™ 640/660, OliGreen, PicoGreen® ssDNA, PicoGreen® dsDNA, POPO™-1 iodide (434/456), POPO™-3 iodide (534/570), PO-PRO™-1 iodide (435/455), PO-PRO™-3 iodide (539/567), propidium iodide, RiboGreen®, SlowFade®, SlowFade® Light, SYBR® Green I, SYBR® Green II, SYBR® Gold, SYBR® 101, SYBR® 102, SYBR® 103, SYBR® DX, TO-PRO®-1, TO-PRO®-3, TO-PRO®-5, TOTO®-1, TOTO®-3, YO-PRO®-1 (oxazole yellow), YO-PRO®-3, YOYO®-1, YOYO®-3, TO, SYTOX® Blue, SYTOX® Green, SYTOX® Orange, SYTO® 9, SYTO® BC, SYTO® 40, SYTO® 41, SYTO® 42, SYTO® 43, SYTO® 44, SYTO® 45, SYTO® Blue, SYTO® 11, SYTO® 12, SYTO® 13, SYTO® 14, SYTO® 15, SYTO® 16, SYTO® 20, SYTO® 21, SYTO® 22, SYTO® 23, SYTO® 24, SYTO® 25, SYTO® Green, SYTO® 80, SYTO® 81, SYTO® 82, SYTO® 83, SYTO® 84, SYTO® 85, SYTO® Orange, SYTO® 17, SYTO® 59, SYTO® 60, SYTO® 61, SYTO® 62, SYTO® 63, SYTO® 64, SYTO® Red, netropsin, distamycin, acridine orange, 3,4-benzopyrene, thiazole orange, TOMEHE, daunomycin, acridine, pentyl-TOTAB, and butyl-TOTIN. Asymmetric cyanine dyes may be used as the polynucleotide-specific dye. Other dyes of interest include those described by Geierstanger, B. H. and Wemmer, D. E., Annu. Rev. Vioshys. Biomol. Struct. 1995, 24, 463-493, by Larson, C. J. and Verdine, G. L., Bioorganic Chemistry: Nucleic Acids, Hecht, S. M., Ed., Oxford University Press: New York, 1996; pp 324-346, and by Glumoff, T. and Goldman, A. Nucleic Acids in Chemistry and Biology, 2nd ed., Blackburn, G. M. and Gait, M. J., Eds., Oxford University Press: Oxford, 1996, pp 375-441. The polynucleotide-specific dye may be an intercalating dye, and may be specific for double-stranded polynucleotides. The term “fluorescent protein” includes types of protein known to absorb and emit light. One of the more commonly used classes of such materials are phycobiliproteins. Examples include but are not limited to phycoerythrin (PE and R-PE), allophycocyanin (APC) and PerCP. Other classes include green fluorescent protein and related versions. The term “green fluorescent protein” refers to both native Aequorea green fluorescent protein and mutated versions that have been identified as exhibiting altered fluorescence characteristics, including altered excitation and emission maxima, as well as excitation and emission spectra of different shapes (Delagrave, S. et al. (1995) Bio/Technology 13:151-154; Heim, R. et al. (1994) Proc. Natl. Acad. Sci. USA 91:12501-12504; Heim, R. et al. (1995) Nature 373:663-664). Delgrave et al. isolated mutants of cloned Aequorea victoria GFP that had red-shifted excitation spectra. Bio/Technology 13:151-154 (1995). Heim, R. et al. reported a mutant (Tyr66 to His) having a blue fluorescence (Proc. Natl. Acad. Sci. (1994) USA 91:12501-12504). Substrates In some embodiments, an assay component can be located upon a substrate. The substrate can comprise a wide range of material, either biological, nonbiological, organic, inorganic, or a combination of any of these. For example, the substrate may be a polymerized Langmuir Blodgett film, functionalized glass, Si, Ge, GaAs, GaP, SiO2, SiN4, modified silicon, or any one of a wide variety of gels or polymers such as (poly)tetrafluoroethylene, (poly)vinylidenedifluoride, polystyrene, cross-linked polystyrene, polyacrylic, polylactic acid, polyglycolic acid, poly(lactide coglycolide), polyanhydrides, poly(methyl methacrylate), poly(ethylene-co-vinyl acetate), polysiloxanes, polymeric silica, latexes, dextran polymers, epoxies, polycarbonates, or combinations thereof. Conducting polymers and photoconductive materials can be used. Substrates can be planar crystalline substrates such as silica based substrates (e.g. glass, quartz, or the like), or crystalline substrates used in, e.g., the semiconductor and microprocessor industries, such as silicon, gallium arsenide, indium doped GaN and the like, and includes semiconductor nanocrystals. The substrate can take the form of a photodiode, an optoelectronic sensor such as an optoelectronic semiconductor chip or optoelectronic thin-film semiconductor, or a biochip. The location(s) of probe(s) on the substrate can be addressable; this can be done in highly dense formats, and the location(s) can be microaddressable or nanoaddressable. Silica aerogels can also be used as substrates, and can be prepared by methods known in the art. Aerogel substrates may be used as free standing substrates or as a surface coating for another substrate material. The substrate can take any form and typically is a plate, slide, bead, pellet, disk, particle, microparticle, nanoparticle, strand, precipitate, optionally porous gel, sheets, tube, sphere, container, capillary, pad, slice, film, chip, multiwell plate or dish, optical fiber, etc. The substrate can be any form that is rigid or semi-rigid. The substrate may contain raised or depressed regions on which an assay component is located. The surface of the substrate can be etched using well known techniques to provide for desired surface features, for example trenches, v-grooves, mesa structures, or the like. Surfaces on the substrate can be composed of the same material as the substrate or can be made from a different material, and can be coupled to the substrate by chemical or physical means. Such coupled surfaces may be composed of any of a wide variety of materials, for example, polymers, plastics, resins, polysaccharides, silica or silica-based materials, carbon, metals, inorganic glasses, membranes, or any of the above-listed substrate materials. The surface can be optically transparent and can have surface Si—OH functionalities, such as those found on silica surfaces. The substrate and/or its optional surface can be chosen to provide appropriate characteristics for the synthetic and/or detection methods used. The substrate and/or surface can be transparent to allow the exposure of the substrate by light applied from multiple directions. The substrate and/or surface may be provided with reflective “mirror” structures to increase the recovery of light. The substrate and/or its surface is generally resistant to, or is treated to resist, the conditions to which it is to be exposed in use, and can be optionally treated to remove any resistant material after exposure to such conditions. Polynucleotide or polypeptide probes can be fabricated on or attached to the substrate by any suitable method, for example the methods described in U.S. Pat. No. 5,143,854, PCT Publ. No. WO 92/10092, U.S. patent application Ser. No. 07/624,120, filed Dec. 6, 1990 (now abandoned), Fodor et al., Science, 251: 767-777 (1991), and PCT Publ. No. WO 90/15070). Techniques for the synthesis of these arrays using mechanical synthesis strategies are described in, e.g., PCT Publication No. WO 93/09668 and U.S. Pat. No. 5,384,261. Still further techniques include bead based techniques such as those described in PCT Appl. No. PCT/US93/04145 and pin based methods such as those described in U.S. Pat. No. 5,288,514. Additional flow channel or spotting methods applicable to attachment of sensor polynucleotides or polypeptides to the substrate are described in U.S. patent application Ser. No. 07/980,523, filed Nov. 20, 1992, and U.S. Pat. No. 5,384,261. Reagents are delivered to the substrate by either (1) flowing within a channel defined on predefined regions or (2) “spotting” on predefined regions. A protective coating such as a hydrophilic or hydrophobic coating (depending upon the nature of the solvent) can be used over portions of the substrate to be protected, sometimes in combination with materials that facilitate wetting by the reactant solution in other regions. In this manner, the flowing solutions are further prevented from passing outside of their designated flow paths. Typical dispensers include a micropipette optionally robotically controlled, an ink-jet printer, a series of tubes, a manifold, an array of pipettes, or the like so that various reagents can be delivered to the reaction regions sequentially or simultaneously. The substrate or a region thereof may be encoded so that the identity of the sensor located in the substrate or region being queried may be determined. Any suitable coding scheme can be used, for example optical codes, RFID tags, magnetic codes, physical codes, fluorescent codes, and combinations of codes. Excitation and Detection Any instrument that provides a wavelength that can excite the conjugated polymer complex and is shorter than the emission wavelength(s) to be detected can be used for excitation. Commercially available devices can provide suitable excitation wavelengths as well as suitable detection components. Exemplary excitation sources include a broadband UV light source such as a deuterium lamp with an appropriate filter, the output of a white light source such as a xenon lamp or a deuterium lamp after passing through a monochromator to extract out the desired wavelengths, a continuous wave (cw) gas laser, a solid state diode laser, or any of the pulsed lasers. Emitted light can be detected through any suitable device or technique; many suitable approaches are known in the art. For example, a fluorimeter or spectrophotometer may be used to detect whether the test sample emits light of a wavelength characteristic of the signaling chromophore upon excitation of the conjugated polymer. Compositions of Matter Also provided are compositions of matter of any of the molecules described herein in any of various forms. The conjugated polymers and complexes including conjugated polymers as described herein may be provided in purified and/or isolated form. The conjugated polymers and complexes including conjugated polymers may be provided in either crystalline or amorphous form. The conjugated polymers and complexes including conjugated polymers may be provided in solution, which may be a predominantly aqueous solution, which may comprise one or more of the additional solution components described herein, including without limitation additional solvents, buffers, biomolecules, polynucleotides, fluorophores, etc. In addition, a mixture of CPs in solution is also able to provide improved detection sensitivity as compared to that for a single CP/dye system. The conjugated polymers and complexes including conjugated polymers can be present in solution at a concentration at which a first emission from the first optically active units can be detected in the absence of biomolecule target or a biomolecule associated therewith. The solution may comprise additional components as described herein, including labeled probes such as fluorescently labeled antibodies or polynucleotides, specific for a species or a class of biomolecule target or a biomolecule associated therewith for the conjugated polymers and complexes including conjugated polymers. The conjugated polymers and complexes including conjugated polymers may be provided in the form of a film. The compositions of matter may be claimed by any property described herein, including by proposed structure, by method of synthesis, by absorption and/or emission spectrum, by elemental analysis, by NMR spectra, or by any other property or characteristic. In some embodiments expression of a gene is detected in a sample. In a further embodiment identification of a cell marker or cell type is detected in a sample either in a flow cytometer, cell sorter, microscope, plate reader or fluorescence imager. In a further embodiment the identification of cell type or marker is used in the diagnosis of lymphoma or other circulating cancers. In a further embodiment the identification of cell type or marker is used in the diagnosis and monitoring of HIV infection. In a further embodiment the identification of cell type or marker is used to sort cells for therapeutic application. In a further embodiment, a measured result of detecting a biomolecule target or a biomolecule associated therewith can be used to diagnose a disease state of a patient. In yet another embodiment the detection method of the invention can further include a method of diagnosing a disease state. In a related embodiment, the method of diagnosing a disease can include reviewing or analyzing data relating to the presence of a biomolecule target or a biomolecule associated therewith and providing a conclusion to a patient, a health care provider or a health care manager, the conclusion being based on the review or analysis of data regarding a disease diagnosis. Reviewing or analyzing such data can be facilitated using a computer or other digital device and a network as described herein. It is envisioned that information relating to such data can be transmitted over the network. In practicing the methods of the present invention, many conventional techniques in molecular biology are optionally utilized. These techniques are well known and are explained in, for example, Ausubel et al. (Eds.) Current Protocols in Molecular Biology, Volumes I, II, and III, (1997), Ausubel et al. (Eds.), Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology, 5th Ed., John Wiley & Sons, Inc. (2002), Sambrook et al., Molecular Cloning: A Laboratory Manual, 3rd Ed., Cold Spring Harbor Laboratory Press (2000), Innis et al. (Eds.) PCR Protocols: A Guide to Methods and Applications, Elsevier Science & Technology Books (1990), and Greg T. Hermanson, Bioconjugate Techniques, 2nd Ed., Academic Press, Inc. (2008) all of which are incorporated herein by reference. FIG. 12 is a block diagram showing a representative example logic device through which reviewing or analyzing data relating to the present invention can be achieved. Such data can be in relation to a disease, disorder or condition in a subject. FIG. 12 shows a computer system (or digital device) 800 connected to an apparatus 820 for use with the conjugated polymers or conjugated polymers complexes 824 to, for example, produce a result. The computer system 800 may be understood as a logical apparatus that can read instructions from media 811 and/or network port 805, which can optionally be connected to server 809 having fixed media 812. The system shown in FIG. 12 includes CPU 801, disk drives 803, optional input devices such as keyboard 815 and/or mouse 816 and optional monitor 807. Data communication can be achieved through the indicated communication medium to a server 809 at a local or a remote location. The communication medium can include any means of transmitting and/or receiving data. For example, the communication medium can be a network connection, a wireless connection or an internet connection. It is envisioned that data relating to the present invention can be transmitted over such networks or connections. In one embodiment, a computer-readable medium includes a medium suitable for transmission of a result of an analysis of a biological sample. The medium can include a result regarding a disease condition or state of a subject, wherein such a result is derived using the methods described herein. Kits Kits comprising reagents useful for performing described methods are also provided. In some embodiments, a kit comprises reagents including conjugated polymers or conjugated polymers complexes, bioconjugates, for example, antibodies, nucleic acids, and other components as described herein. The kit may optionally contain one or more of the following: one or more labels that can be incorporated into conjugated polymers or conjugated polymers complexes; and one or more substrates which may or may not contain an array, etc. The components of a kit can be retained by a housing. Instructions for using the kit to perform a described method can be provided with the housing, and can be provided in any fixed medium. The instructions may be located inside the housing or outside the housing, and may be printed on the interior or exterior of any surface forming the housing that renders the instructions legible. A kit may be in multiplex form for detection of one or more different target biomolecules or biomolecules associated therewith. As described herein and shown in FIG. 13, in certain embodiments a kit 903 can include a container or housing 902 for housing various components. As shown in FIG. 13, and described herein, in one embodiment a kit 903 comprising one or more conjugated polymers or conjugated polymers complexes reagents 905, and optionally a substrate 900 is provided. As shown in FIG. 13, and described herein, the kit 903 can optionally include instructions 901. Other embodiments of the kit 903 are envisioned wherein the components include various additional features described herein. EXAMPLES The following examples provide illustrative methods for making and testing the effectiveness of the conjugated polymers described herein. These examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein. All of the methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. It will be apparent to those of skill in the art that variations may be applied to the methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the claims. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the appended claims. Example 1: Synthesis of a Polymer of Formula (I) Example 1a: Synthesis of Monomers, 2,7-dibromo-9,9-di(2′,5′,8′,11′,14′,17′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)fluorene (A) and 9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-2,7-di(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolanyl)fluorene (B) for Subsequent Polymerization Step 1: 2,7-dibromo-9,9-di(3′-hydroxypropanyl)fluorene. 2,7-dibromofluorene (9.72 g, 30 mmol), tetrabutylammonium bromide (300 mg, 0.93 mmol), and DMSO (100 mL) were added to a 3-neck flask under nitrogen(g), followed by the addition of 50% NaOH (15 mL, 188 mmol) via syringe. The mixture was heated to 80° C., and 3-bromopropanol (6.70 mL, 77 mmol) was added dropwise via addition funnel, and the reaction mixture was stirred at 80° C. for another 2 hours. Upon completion, the mixture was cooled to room temperature and quenched with water (250 mL). The aqueous layer was extracted with ethyl acetate (3 150 mL portions). The organic layers were combined, washed with water, then dried over MgSO4, and filtered. The solvent was removed and the residual was recrystallized in chloroform to yield pale yellow needle crystals (9.20 g, 70%). Step 2: 2,7-dibromo-9,9-di(3′-methylbenzenesulfonatopropanyl)fluorene. 2,7-dibromo-9,9-di(3′-hydroxypropanyl)fluorene (500 mg, 1.14 mmol) was dissolved in dichloromethane (5 mL) at 0° C. under nitrogen(g). To the mixture, added p-toluenesulfonyl chloride (650 mg, 3.40 mmol), followed by pyridine (0.39 mL, 4.77 mmol). Allowed reaction to stir at 0° C. and naturally rise to room temperature over night. The reaction was quenched with water (15 mL). Removal of solvent by vacuo resulted solids formation. Filtered off solids to yield white solids (758 mg, 89%). Step 3: 2,7-dibromo-9,9-di(2′,5′,8′,11′,14′,17′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)fluorene (A). mPEG11 alcohol (770 mg, 1.49 mmol) was dissolved in anhydrous THF (2 mL) at 0° C. under nitrogen. To the mixture, was added potassium tert-butoxide (1.63 mmol, 1.63 mL, 1M in THF). After 10 min stirring, 2,7-dibromo-9,9-di(3′-methylbenzenesulfonatopropanyl)fluorene (504 mg, 0.673 mmol) in 10 mL of THF was added via a syringe. The mixture was allowed to room temperature and stirred overnight. The reaction mixture was diluted with THF. The insoluble inorganic salt was removed by filtration. Concentration of the filtrate yielded crude product, which was purified by column chromatography (DCM-MeOH) to yield a colorless oil (605 mg, 62.5%). Step 4: 9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-2,7-di(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolanyl)fluorene (B). 2,7-dibromo-9,9-di(2′,5′,8′,11′,14′,17′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)fluorene (1.510 g, 1.501 mmol), bis(pinacolato)diboron (800 mg, 3.15 mmol), potassium acetate (619 mg, 6.31 mmol), Pd(dppf)Cl2 [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)](51.5 mg, 0.063 mmol) and DMSO (30 mL) were mixed under N2. The mixture was heated at 80° C. for 5.5 hour. Upon completion, the DMF was distilled and water (50 mL) was added. The product was extracted with DCM (3×40 mL). The organic layers were combined and concentrated. The crude product was purified by column chromatography (DCM-MeOH) to give colorless oil (1.015 g, 63%). Example 1b: Polymerization of Monomers (A) and (B) 2,7-dibromo-9,9-di(2′,5′,8′,11′,14′,17′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)fluorene (A) (0.084 mmol, 120 mg), 9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-3 8′-yl)-2,7-di(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolanyl)fluorene (B) (0.088 mmol, 135 mg), and palladium tetra(triphenylphosphine) (0.0035 mmol, 4 mg) were combined in a round bottom flask equipped with a stirbar. Next, 0.35 mL of 2M potassium carbonate (aq) and 1.9 mL of tetrahydrofuran were added and the flask is fitted with a vacuum adaptor and put on a Schlenk line. The mixture was degassed using 3 freeze-pump-thaw cycles. The degassed mixture was heated to 80° C. under nitrogen with vigorous stirring for 18 hours. The reaction mixture was then cooled and the solvent removed with rotary evaporation. The resulting semisolid was diluted with ca. 50 mL water and filtered through glass fiber filter paper. Ethanol was added to adjust the solvent to 20% ethanol in water. Preparative gel permeation chromatography was performed with G-25 desalting medium to remove excess salts from the polymer. Solvent in the fractions was removed with rotary evaporation and 100 mg of poly [2,7{9,9-bis (2, 5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene] was collected as an amber oil. Example 2: Synthesis of Asymmetric Polymers of Formula (I) Via Suzuki Coupling Example 2a: Synthesis of Asymmetric Monomer, 2-bromo-9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-7-(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolan-2-yl)fluorene (C) for Subsequent Polymerization Step 2: 2-dibromo-7-iodofluorene. 2-bromofluorene (10.01 g, 40.84 mmol), acetic acid (170 mL), water (8 mL), iodine (4.34 g, 17.20 mmol), potassium iodate (2.18 g, 10.19 mmol) and sulfuric acid (4 mL) were mixed under nitrogen. The resulting mixture was heated at 80° C. for 2 h and cooled to room temperature. The formed precipitate which is the desired product was collected after filtration and acetic acid wash (13.68 g, 90%). Step 2: 2-dibromo-9,9-di(3′hydroxypropanyl)-7-iodofluorene. 2-dibromo-7-iodofluorene (2.186 g, 5.892 mmol), tetrabutylammonium bromide (60 mg, 0.186 mmol), and DMSO (25 mL) were added to a 3-neck flask under nitrogen(g), followed by the addition of 50% NaOH (4 mL, 50 mmol) via syringe. The mixture was heated to 80° C., and 3-bromopropanol (1.33 mL, 14.7 mmol) was added slowly, and the reaction was stirred at 80° C. for another 1 hour. Upon completion, the mixture was cooled to room temperature and quenched with water. The precipitate as crude product was collected after filtration. The crude product was purified by column chromatography (eluant: hexane-ethylacetate) to give pale yellow solid (2.15 g, 75%). Step 3: 2-bromo-9,9-di(3′-hydroxypropanyl)-7-(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolan-2-yl)fluorene. 2-dibromo-9,9-di(3′hydroxypropanyl)-7-iodofluorene (2.454 g, 5.037 mmol), bis(pinacolato)diboron (1.407 g, 5.541 mmol), potassium acetate (1.483 g, 15.11 mmol), Pd(dppf)Cl2 (123 mg, 0.15 mmol) and DMSO (25 mL) were mixed under N2. The mixture was heated at 80° C. for 1.5 hour. Upon completion, the mixture was cooled to room temperature and quenched with water (50 mL). The product was extracted with DCM (3×40 mL). The organic layers were combined and concentrated. The crude product was purified by column chromatography (eluant: hexane-ethylacetate) to give pale solid (2.09 g, 85%). Step 4: 2-bromo-9,9-di(3′-methanesulfanotopropanyl)-7-(4″,4″,5″5″-tetrarop-tetramethyl-″,3″,2″-dioxaborolan-2-yl)fluorene. 2-bromo-9,9-di(3′-hydroxypropanyl)-7-(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolan-2-yl)fluorene (2.280 g, 4.694 mmol) and p-toluenesulfonyl chloride (2.684 g, 14.08 mmol) were dissolved in dichloromethane at room temperature under N2. Triethylamine (3.95 mL, 28.2 mmol) was added slowly via syringe. The mixture was stirred at room temperature over night. The mixture was then concentrated and purified by column chromatography (Hexane-EtOAc) to yield pale solid (2.66 g, 72%). Step 5: 2-bromo-9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-7-(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolan-2-yl)fluorine (C). mPEG11 alcohol (3.331 g, 6.448 mmol) was dissolved in anhydrous THF (20 mL) at 0° C. under nitrogen. To the mixture, was added potassium tert-butoxide (7.74 mmol, 7.74 mL, 1M in THF). After 10 min stirring, 2-bromo-9,9-di(3′-methanesulfanotopropanyl)-7-(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolan-2-yl)fluorine (2.052 g, 2.579 mmol) in 20 mL of anhydrous THF was added via a syringe. The mixture was allowed to room temperature and stirred overnight. After evaporation of THF, brine (50 mL) was added and crude product was extracted with dichloromethane (3×40 mL). The combined organic layers were concentrated and purified by column chromatography (DCM-isopropanol) to give colorless gel-like product (2.164 g, 57%). Example 2b: Synthesis of an Asymmetric Polymer Via Suzuki Coupling Polymerization Asymmetric polymers are synthesized using conditions similar to polymerization conditions as described in Example 1b. Example 3: Synthesis of a Linker or Capping Unit Example 3a: Synthesis of Linker or Capping Unit, Tert-butyl 4-(3,5-dibromophenoxy)butylcarbamate Step 1: 4-(3,5-dibromophenoxy)butan-1-amine. 1-(4′-phthalimidobutoxy)3,5-dibromobenzene (1.0 g, 2.20 mmol) was dissolved in ethanol (45 mL) for 5 minutes under nitrogen. Hydrazine monohydrate (610 mg, 12.1 mmol) was added and the reaction was refluxed at 80° C. for 2 hours. To the reaction aqueous 1M HCl (17.7 mL, 17.7 mmol) was added and refluxed at 105° C. for another 2 hours. The aqueous layer was extracted with dichloromethane (2×150 mL). The organic layers were combined, washed with saturated NaHCO3 (3×), water, and brine, then dried over MgSO4, and filtered. Removal of solvent yielded a yellow oil (560 mg, 78%). Step 2: Tert-butyl 4-(3,5-dibromophenoxy)butylcarbamate. 4-(3,5-dibromophenoxy)butan-1-amine (397 mg, 1.23 mmol) was dissolved in anhydrous THF (24.6 mL) under nitrogen. Di-tert-butyl dicarbonate (423 mL, 1.84 mmol) was added to the mixture and refluxed reaction at 40° C. for 2 hours. After extraction of the reaction with dichloromethane (2×50 mL), the organic layers were combined, washed with saturated NaHCO3, water, and brine, then dried over MgSO4, and filtered. The solvent is removed and the residue is purified by column chromatography (9:1, hexanes: EtOAc) to give a white solid (306 mg, 59%). Example 3b: Synthesis of Linker or Capping Unit, Tert-butyl-4-(2,7-dibromo-9-methyl-9H-fluoren-9-yl)butylcarbamate Step 1: 2,7-dibromo-9-methyl-9H-fluorene. 2,7-dibromofluorene (30 g, 92.59 mmol) was dissolved in anhydrous THF (300 mL) under nitrogen and cooled to −78° C. To solution at −78° C., added n-butyllithium (40.36 mL, 100.9 mmol) over 5 minutes and allowed reaction stir for another 10 minutes. To reaction, then add methyl iodide (6.29 mL, 100.9 mmol) and allowed reaction to stir at −78° C. for 2.0 hours. The reaction was poured into a mixture of dichloromethane and water. The organic layer was collected, and the water layer was further extracted with dichloromethane. Combined all organic layers and removed solvent via vacuo. The crude material was triturated with hexanes and filtered using Buchner funnel to give white solids (22 g, 70%). 1H NMR (500 MHz, CDCl3): δ=7.62 (s, 2H), 7.56-7.58 (d, 2H), 7.48-7.50 (dd, 2H), 3.90-3.94 (q, 1H), 1.49-1.51 (d, 3H). Step 2: 2-(4-(2,7-dibromo-9-methyl-9H-fluoren-9-yl)butyl)isoindoline-1,3-dione. 2,7-dibromo-9-methyl-9H-fluorene (10.0 g, 29.58 mmol) was dissolved in 50 mL DMSO under nitrogen. To mixture was added KOH (2.01 g, 35.79 mmol), water (1.5 mL), N-(4-bromobutyl)phthalimide (9.93 g, 35.2 mmol), and stirred reaction at room temperature for 2.0 hours, then at 50° C. for 3.0 hours. The reaction was cooled to room temperature and diluted with dichloromethane. The organic layer was washed with brine (2×), and water. Removal of solvent yield a solid, which was purified by column chromatography (7:3, hexanes:EtOAc) to yield white solids (3.08 g, 20%). 1H NMR (500 MHz, CDCl3): δ=7.81-7.83 (m, 2H), 7.68-7.71 (m, 2H), 7.48-7.51 (m, 4H), 7.41-7.44 (dd, 2H), 3.46-3.49 (t, 2H), 2.00-2.04 (p, 2H), 1.47-1.49 (m, 2H), 1.45 (s, 3H), 0.65-0.68 (m, 2H). Step 3: 4-(2,7-dibromo-9-methyl-9H-fluoren-9-yl)butan-1-amine. 2-(4-(2,7-dibromo-9-methyl-9H-fluoren-9-yl)butyl)isoindoline-1,3-dione (3.08, 5.71 mmol) was dissolved in ethanol (250 mL) under nitrogen. To the mixture was added hydrazine monohydrate (2.77 mL, 57.1 mmol), and the reaction was refluxed at 80° C. for 3.0 hours. The reaction was cooled to room temperature, and added 1M HCl (˜100 mL). The mixture was stirred for 30 minutes or until all solids were dissolved. Dichloromethane was added to the solution and the organic layer was extracted with saturated NaHCO3 three times, and washed with water. The organic layers were collected and removed solvent by vacuo to give an yellow oil (2.33 g, 100%). 1H NMR (500 MHz, CD2Cl2): δ=7.57 (d, 2H), 7.52 (d, 2H), 7.46-7.48 (dd, 2H), 2.39-2.42 (t, 2H), 1.95-1.98 (t, 2H), 1.44 (s, 3H), 1.17-1.23 (m, 2H), 0.59-0.65 (m, 2H). Step 4: tert-butyl-4-(2,7-dibromo-9-methyl-9H-fluoren-9-yl)butylcarbamate. 4-(2,7-dibromo-9-methyl-9H-fluoren-9-yl)butan-1-amine (2.39 g, 5.84 mmol) was dissolved in anhydrous THF (20 mL) under nitrogen. To solution, was added di-tert-butyl-dicarbonate (2.01 mL, 8.76 mmol), and the reaction was stirred at 40° C. for 3 hours. The reaction was cooled to room temperature and concentrated via vacuo. Crude solids were triturated with hexanes and filtered using buchner funnel to yield the desired white solids (2.34 g, 79%). 1H NMR (500 MHz, CDCl3): δ=7.53 (d, 2H), 7.45-7.47 (d, 4H), 4.30 (s, 1H), 2.88-2.90 (q, 2H), 1.93-1.96 (t, 2H), 1.43 (s, 3H), 1.41 (s, 9H), 1.25-1.28 (m, 2H), 0.59-0.66 (m, 2H). Example 4: Synthesis of a Linker or Capping Unit Example 4a: Synthesis of Tert-butyl 4-(4-bromophenoxy)butylcarbamate Step 1: N(4-(4-bromophenoxy)butyl)phthalimide. Combined 4-bromophenol (4.64 g, 26.8 mmol), N-(4-bromobutylphthalimide) (6.30 g, 22.33 mmol), K2CO3 (11.09 g, 80.38 mmol), 18-crown-6 (265 mg, 1.00 mmol), and acetone (100 mL), and refluxed reaction under nitrogen at 70° C. over night. The reaction was cooled to room temperature and removed solvent by vacuum. The crude mixture was diluted with dichloromethane (200 mL) and washed with water (3×), then dried over MgSO4, and filtered. Removal of solvent, followed by trituration with hexanes, and filtered using Buchner funnel to yield a white solid (6.03 g, 71%). Step 2: 4-(4-bromophenoxy)butan-1-amine. N(4-(4-bromophenoxy)butyl)phthalimide (6.01 g, 16.1 mmol) is dissolved in ethanol (200 mL) under nitrogen, followed by the addition of hydrazine monohydrate (7.8 mL, 161 mmol). The reaction was refluxed at 80° C. for 2 hours. Once reaction completed (solids formed at the top layer), cooled reaction to room temperature and neutralized with 1M HCl (50 mL). The mixture is allowed to stir until all solids are completely dissolved and diluted with dichloromethane (150 mL). The solution was extracted with two portions of saturated NaHCO3 (2×). The organic layers were combined, washed with brine and water, then dried over MgSO4, and filtered. Removal of solvent yields a yellow oil (2.93 g, 75%). Step 3: Tert-butyl 4-(4-bromophenoxy)butylcarbamate. 4-(4-bromophenoxy)butan-1-amine (1.0 g, 4.09 mmol) was dissolved in anhydrous THF (20 mL) under nitrogen and stirred until solution is homogenous. Di-tert-butyl-dicarbonate (1.34 g, 6.14 mmol) was added and the reaction was stirred at 40° C. for 2 hours. The reaction was quenched with water (30 mL) and stirred at room temperature for 1.0 hour. The aqueous layer was extracted with ethyl acetate (50 mL×2). The organic layers were combined, washed with saturated NaHCO3, water, and brine, then dried over MgSO4, and filtered. Removal of solvent yield a solid, which was purified by column chromatography (9:1, hexanes:EtOAc) to yield white solids (1.0 g, 71%). Example 4b: Synthesis of tert-butyl 4-(4-bromophenyl)butanoate Allowed tert-butanol to melt and added 20 mL to round bottom flask. To the solution, added di-tert-butyl-dicarbonate (1.79 g, 8.22 mmol) and 4-(4-bromophenyl)butyric acid (1.0 g, 4.11 mmol). To reaction, then added DMAP (150.7 mg, 1.23 mmol) and stirred reaction at room temperature over night. The reaction was concentrated via vacuo, and re-diluted in ethyl acetate. The organic layer was washed with 1M HCl, brine, and water. After removal of solvent, the crude solids were purified via column chromatography (20:1, hexanes:EtOAc) to give the desired product (570 mg, 46%), which is a clear oil. 1H NMR (500 MHz, CD2Cl2): δ=7.39-7.41 (d, 2H), 7.03-7.09 (d, 2H), 2.57-2.60 (t, 2H), 2.18-2.21 (t, 2H), 1.83-1.186 (p, 2H), 1.42 (s, 9H). Example 4c: Synthesis of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butanoic acid Combined 4-(4-bromophenyl)butyric acid (10 g, 41.13 mmol), bis(pinacolato)diboron (15.67 g, 61.70 mmol), potassium acetate (12.1 g, 123.4 mmol), and DMSO (100 mL), and purged mixture with nitrogen for 10 minutes at room temperature. To reaction under nitrogen, added Pd(dppf)Cl2 and purged reaction again with nitrogen for another 20 minutes at room temperature. The reaction was then refluxed at 80° C. over night. After cooling to room temperature, the reaction was quenched with water and stirred for 1.0 hour. The solids formed were filtered using Buchner funnel. The crude solids were purified via column chromatography (8.5:1.5, hexanes:EtOAc). The desired fractions were collected and concentrated via vacuo, and triturated with hexanes and filtered to give the desired white solids (6.7 g, 56%). Example 5: Synthesis of Linker or Capping Unit, Tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)butylcarbamate Combined tert-butyl 4-(4-bromophenoxy)butylcarbamate from Example 4a (500 mg, 1.45 mmol), potassium acetate (428 mg, 4.36 mmol), bis(pinacolato)diboron (737 mg, 2.90 mmol) and DMSO (12 mL), and purged mixture with nitrogen for 10 minutes at room temperature. To mixture was added Pd(dppf)Cl2 (59.3 mg, 0.07 mmol) and continued to stir solution at room temperature under nitrogen for another 20 minutes. After refluxing at 80° C. for 3 hours, the reaction was cooled to room temperature and quenched with water (30 mL). The aqueous layer was extracted with dichloromethane (50 mL×2). The organic layers were combined, washed with brine, then dried over MgSO4, and filtered. Removal of solvent yield a dark brown oil, which was purified by column chromatography (9:1, hexanes:EtOAc) to yield a light yellow oil (539 mg, 95%). Example 6: Synthesis of Linker or Capping Unit with Long Oligoether Spacer Between Arylhalide Phenyl and FMOC Protected Primary Amine 4-(4-bromophenoxy)butan-1-amine+oligoether-FMOC+N,N′-dicyclohexylcarbodiimide (DCC) (9H-fluoren-9-yl)methyl 80-(4-bromophenoxy)-75-oxo-3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,48,51,54,57,60,63,66,69,72-tetracosaoxa-76-azaoctacontylcarbamate. 4-(4-bromophenoxy)butan-1-amine (21.5 mg, 0.09 mmol), 1-(9H-fluoren-9-yl)-3-oxo-2,7,10,13,16,19,22,25,28,31,34,37,40,43,46,49,52,55,58,61,64,67,70,73,76-pentacosaoxa-4-azanonaheptacontan-79-oic acid (100 mg, 0.073 mmol), and N,N′-dimethylaminopyridine (5.4 mg, 0.044 mmol) were combined in a round bottom flask flushed with nitrogen and charged with a Teflon stirbar. Next 5 mL of anhydrous dichloromethane was added via syringe. N,N-Dicyclohexylcarbodiimide (23 mg, 0.11 mmol) is transferred to a second flask flushed with nitrogen and charged with a stirbar and 5 mL of anhydrous dichloromethane is added via syringe. While stirring the first solution, add the dicyclohexylcarbodiimide solution slowly, dropwise. The reaction is then allowed to proceed overnight. The following day solids from the reaction were filtered off and the filtrate was concentrated onto silica. Column chromatography in methanol and dichloromethane gave a clear thick oil (83.3 mg, 71% yield). Example 7: Synthesis of Polymer, Poly[2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene}-co-3,5-phenylbut-1′-oxy-4″-amine], with an Internal Linking Site The incorporation of internal conjugation sites into conjugated polymer backbones is described in U.S. application Ser. No. 11/868,870, filed Oct. 8, 2007 and published as U.S. Application No. 2008/0293164, which application is herein incorporated by reference in its entirety. Provided is a modified synthesis based on the protocol. 2,7-dibromo-9,9-di(2′,5′,8′,11′,14′,17′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)fluorene (0.084 mmol, 120 mg), 9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-2,7-di(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolanyl)fluorene (0.088 mmol, 135 mg), tert-butyl-4-(3,5-dibromophenoxy)butylcarbamate (0.0044 mmol, 2.0 mg), and palladium tetra(triphenylphosphine) (0.0035 mmol, 4 mg) are combined in a round bottom flask equipped with a stirbar. Next, 0.35 mL of 2M potassium carbonate (aq) and 1.9 mL of tetrahydrofuran are added and the flask is fitted with a vacuum adaptor and put on a Schlenk line. The mixture is degassed using 3 freeze-pump-thaw cycles. The degassed mixture is heated to 80 C under nitrogen with vigorous stirring for 18 hours. The reaction mixture is then cooled and the solvent is removed with rotary evaporation. Next, 4 mL of 4 M HCl in dioxane is added and the mixture is stirred for no less than 4 hours. The solution is neutralized with 2M potassium carbonate solution. The bulk of the solvent is again removed with rotary evaporation. The resulting semisolid is diluted with ca. 50 mL water and filtered through glass fiber filter paper. Ethanol is added to adjust the solvent to 20% ethanol in water. Preparative gel permeation chromatography is performed with G-25 desalting medium to remove excess salts from the polymer. Solvent in the fractions is removed with rotary evaporation and 100 mg of poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene}-co-3,5-tert-butyl-4-(4-bromophenoxy)amine] is collected as an amber oil. Example 8: Synthesis of Phenylene Vinylene Co-Polymer with an Internal Linking Site A modified synthesis similar to that described in Examples 7 and 15. Example 9: Synthesis of Polymer with Exclusively Terminal Amine Capping Units 2,7-(Poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene])-diphen-4-oxybutyl-4′-amine. 2,7-dibromo-9,9-di(2′,5′,8′,11′,14′,17′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)fluorene (0.163 mmol, 235 mg), 9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-2,7-di(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolanyl)fluorene (0.163 mmol, 250 mg), and palladium tetra(triphenylphoshine) (0.0065, 7.5 mg) are combined in a round bottom flask equipped with a stirbar. Next, 0.75 mL of 2M potassium carbonate (aq) and 3 mL of tetrahydrofuran are added and the flask is fitted with a vacuum adaptor. The reaction mixture is put on a Schenk line and is degassed with three freeze-pump-thaw cycles and then heated to 80 C under nitrogen with vigorous stirring for 18 hours. A solution of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)butylcarbamate (0.064 mmol, 25 mg) in 0.5 mL tetrahydrofuran is degassed with three freeze-pump-thaw cycles and then added to the polymerization reaction via cannula under excess nitrogen pressure. The reaction is allowed to continue for an additional 4 hours at 80 C with stirring. Next, a solution of tert-butyl 4-(4-bromophenoxy)butylcarbamate (0.192 mmol, 66 mg) in 0.5 mL of THF is degassed with three freeze-pump-thaw cycles and then added to the polymerization reaction via cannula under excess nitrogen pressure. The reaction was allowed to proceed overnight. The reaction mixture was allowed to cool and solvent was removed with rotary evaporation. A 4 mL portion of 4M HCl in dioxane was added to the residue and stirred for a minimum of 4 hours. The solution was neutralized with 2 M potassium carbonate (aq) and then the solvent was removed under vacuum. The resulting residue was diluted to ˜30 mL with 20% ethanol in water and filtered. Preparative gel permeation chromatography is performed with G-25 desalting medium to remove excess salts from the polymer. Solvent in the fractions is removed with rotary evaporation and 337 mg of polymer is collected as an amber oil. The order of end linker addition (aryl hylide or boronic ester/acid) can be reversed. Similar processes can be used to add alternative linkers or end capping units. Example 10: Synthesis of Polymer, 2-(Poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene])-phen-4-oxybutyl-4′-amine, Statistically Enriched in Chains with a Single Terminal Amine Capping Unit 2,7-dibromo-9,9-di(2′,5′,8′,11′,14′,17′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)fluorene (0.163 mmol, 235 mg), 9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-2,7-di(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolanyl)fluorene (0.163 mmol, 250 mg), and palladium tetra(triphenylphoshine) (0.0065, 7.5 mg) are combined in a round bottom flask equipped with a stirbar. Next, 0.75 mL of 2M potassium carbonate (aq) and 3 mL of tetrahydrofuran are added and the flask is fitted with a vacuum adaptor. The reaction mixture is put on a Schenk line and is degassed with three freeze-pump-thaw cycles and then heated to 80 C under nitrogen with vigorous stirring for 18 hours. A solution of tert-butyl 4-(4-bromophenoxy)butylcarbamate (0.049 mmol, 17 mg) in 0.5 mL tetrahydrofuran is degassed with three freeze-pump-thaw cycles and then added to the polymerization reaction via cannula under excess nitrogen pressure. The reaction is allowed to continue for an additional 4 hours at 80 C with stirring. Next, a solution of phenylboronic acid (0.150 mmol, 18 mg) in 0.5 mL of THF is degassed with three freeze-pump-thaw cycles and then added to the polymerization reaction via cannula under excess nitrogen pressure. The reaction was allowed to proceed overnight. The reaction mixture was allowed to cool and solvent was removed with rotary evaporation. A 4 mL portion of 4M HCl in dioxanewas added to the residue and stirred for a at least 4 hours. The solution was neutralized with 2 M potassium carbonate (aq) and then the solvent was removed under vacuum. The resulting residue was diluted to ˜30 mL with 20% ethanol in water and filtered. Preparative gel permeation chromatography is performed with G-25 desalting medium to remove excess salts from the polymer. Solvent in the fractions is removed with rotary evaporation and 315 mg of polymer is collected as an amber oil. Resulting polymers contain chains with an enriched fraction of chains with one amine linker plus chains with 2 linkers and no linkers. Example 11: Synthesis of Polymer Statistically Enriched in Chains with a Single Terminal Capping Unit with a Long Oligoether Spacer (24 Repeats) Between the Polymer Chain and the Primary Amine Linking Group 2-(Poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene])-phen-4-oxybutyl-4′-amine. 2,7-dibromo-9,9-di(2′,5′,8′,11′,14′,17′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)fluorene (0.163 mmol, 235 mg), 9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-2,7-di(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolanyl)fluorene (0.163 mmol, 250 mg), and palladium tetra(triphenylphoshine) (0.0065, 7.5 mg) are combined in a round bottom flask equipped with a stirbar. Next, 0.75 mL of 2M potassium carbonate (aq) and 3 mL of tetrahydrofuran are added and the flask is fitted with a vacuum adaptor. The reaction mixture is put on a Schenk line and is degassed with three freeze-pump-thaw cycles and then heated to 80 C under nitrogen with vigorous stirring for 18 hours. A solution of tert-butyl 4-(4-bromophenoxy)butylcarbamate (0.049 mmol, 17 mg) in 0.5 mL tetrahydrofuran is degassed with three freeze-pump-thaw cycles and then added to the polymerization reaction via cannula under excess nitrogen pressure. The reaction is allowed to continue for an additional 4 hours at 80 C with stirring. Next, a solution of phenylboronic acid (0.150 mmol, 18 mg) in 0.5 mL of THF is degassed with three freeze-pump-thaw cycles and then added to the polymerization reaction via cannula under excess nitrogen pressure. The reaction was allowed to proceed overnight. The reaction mixture was allowed to cool and solvent was removed with rotary evaporation. A 4 mL portion of 4M HCl in dioxanewas added to the residue and stirred for a minimum of 4 hours. The solution was neutralized with 2 M potassium carbonate (aq) and then the solvent was removed under vacuum. The resulting residue was diluted to ˜30 mL with 20% ethanol in water and filtered. Preparative gel permeation chromatography is performed with G-25 desalting medium to remove excess salts from the polymer. Solvent in the fractions is removed with rotary evaporation and 315 mg of polymer is collected as an amber oil. Example 12: Synthesis of an Asymmetric Polymer with a Terminal Carboxylic Capping Unit Added During Polymerization Reaction The linking monomer is added during the polymerization reaction as described in Examples 9, 10 and 11. The carboxylic acid group can later be converted to an activated ester such as N-hydroxysuccinimidyl as is described in Example 29. Example 13: Synthesis of an Asymmetric Polymer with a Terminal Carboxylic Acid Capping Unit Added Post Polymerization The linking monomer is added after the polymerization reaction is completed and polymer purified. Linker addition is done under similar reaction conditions as those described in Examples 9, 10 and 11. The carboxylic acid group can later be converted to an activated ester such as N-hydroxysuccinimidyl as is described in Example 29. Example 14: Synthesis of an Polymer with Branched PEG Groups Example 14a: Synthesis of Monomers, (D) and (E) for Subsequent Polymerization Step 1: 2,7-dibromo-9,9-bis(3,5-dimethoxybenzyl)fluorene. 2,7-dibromofluorene (4.16 g, 12.8 mmol) and tetrabutylammonium bromide (362 mg, 1.12 mmol) were added to a round bottom flask charged with a Teflon stirbar. Next, 60 mL of dimethylsulfoxide was added to the flask and the mixture was stirred for 5 minutes. A portion of 50% NaOH aqueous solution (5.2 mL) was added followed immediately by 3,5-dimethoxybenzyl bromide (7.14 g, 31 mmol). Over the course of 2 hours the solution changes color from orange to blue. The reaction is stirred overnight. The resulting mixture is slowly poured into 200 mL of water and then extracted with three 100 mL portions of dichloromethane. The organic layers are combined and dried over magnesium sulfate and then filtered. The crude product is purified by column chromatography using hexanes and dichloromethane as eluent to give a pale yellow solid (6.63 g, 79% yield). Step 2: 2,7-dibromo-9,9-bis(3,5-dihydroxybenzyl)-9H-fluorene. 2,7-dibromo-9,9-bis(3,5-dimethoxybenzyl)-9H-fluorene (1.3 g, 2.08 mmol) was added to a round bottom flask charged with a stirbar and equipped with a rubber septum. The flask is purged with nitrogen for 10 min. Anhydrous dichloromethane (20 mL) is transferred to the flask via cannula and the mixture is stirred until the solids are completely dissolved. The solution is then cooled with a dry ice/acetone bath for 10 minutes. BBr3 (6.1 mL, 63.3 mmol) is added dropwise via cannula with constant stirring. The bath is allowed to warm to room temperature and the mixture is stirred overnight. The reaction is quenched with the slow addition of 125 mL of water. The solution is then extracted with 3 portions of ethyl acetate (50 mL). The organic layer is dried over MgSO3, filtered, and dried onto silica. Flash chromatography of the crude using ethyl acetate in dichloromethane gives an off-white crystalline solid (800 mg, 68% yield). Step 3: 2,7-dibromo-9,9-bis(3,5-(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yl) benzyl)-9H-fluorene (D). 2,7-dibromo-9,9-bis(3,5-dihydroxybenzyl)-9H-fluorene (537 mg, 0.945 mmol), 2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yl 4-methylbenzenesulfonate (2.788 g, 4.156 mmol), potassium carbonate (1.57 g, 11.34 mmol) and acetone (80 mL) are transferred to a round bottom flask charged with a Teflon stirbar and equipped with a reflux condenser. The mixture is refluxed with constant stirring overnight. The mixture is then allowed to cool to room temperature and the acetone is removed under vacuum. After extracting with 3 portions of dichloromethane, the organic layer is dried over MgSO4, filtered, and the filtrate is concentrated onto silica. Column chromatography using methanol and dichloromethane affords the product as a slightly colored thick oil (1.69 g, 70% yield). Step 4: 2,7-di(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolanyl)-9,9-bis(3,5-(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yl) benzyl)-9H-fluorene (E). Monomer (E) is synthesized using conditions similar to conditions as described in Example 1. Example 14b: Polymerization of (D) and (E) Polymerization of (D) and (E) are polymerized using conditions similar to polymerization conditions as described in Example 1b. Example 15: Synthesis of a Neutral Base Phenylene Vinylene Co-Polymer 2,7-dibromo-9,9-di(2′,5′,8′,11′,14′,17′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)fluorene (0.25 mmol), 1,4-divinylbenzene (32.3 mg, 0.25 mmol), palladium acetate (3 mg, 0.013 mmol), tri-ortho-tolylphosphine, (10 mg, 0.033 mmol), and potassium carbonate (162 mg, 1.2 mmol) are combined with 5 mL of DMF in a small round bottom flask charged with a Teflon coated stirbar. The flask is fitted with a needle valve and put in a Schlenk line. The solution is degassed by three cycles of freezing, pumping, and thawing. The mixture is then heated to 100° C. overnight. The polymer can be subsequently reacted with terminal linkers or capping units using similar (in situ) protocols to those provided in the previous examples (9, 10 and 11) or by modifying them post polymerization work up as a separate set of reactions. Example 16: Synthesis of a Branched Phenylene Vinylene Co-Polymer 2,7-dibromo-9,9-bis(3,5-(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yl) benzyl)-9H-fluorene (636 mg, 0.25 mmol), 1,4-divinylbenzene (32.3 mg, 0.25 mmol), palladium acetate (3 mg, 0.013 mmol), tri-ortho-tolylphosphine, (10 mg, 0.033 mmol), and potassium carbonate (162 mg, 1.2 mmol) were combined with 5 mL of DMF in a small round bottom flask charged with a Teflon coated stirbar. The flask was fitted with a needle valve and put in a Schlenk line. The solution was degassed by three cycles of freezing, pumping, and thawing. The mixture was then heated to 100° C. overnight. The polymer can be subsequently reacted with terminal linkers or capping units using similar (in situ) protocols to those provided in Example 5 or by modifying them post polymerization work up as a separate set of reactions. Example 17: Synthesis of a Branched Phenylene Vinylene Co-Polymer with Functional Amines for Covalent Conjugation. Poly [2,7-divinyl{9,9-bis(3,5-(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yl)benzyl)-9H-fluorene}-alt-1,4-benzene-co-4-phenoxybutyl-N-t-butylcarbamate] Step 1: Polymerization 2,7-dibromo-9,9-bis(3,5-(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yl) benzyl)-9H-fluorene (636 mg, 0.25 mmol), 1,4-divinylbenzene (32.3 mg, 0.25 mmol), palladium acetate (3 mg, 0.013 mmol), tri-ortho-tolylphosphine, (10 mg, 0.033 mmol), and potassium carbonate (162 mg, 1.2 mmol) were combined with 5 mL of DMF in a small round bottom flask charged with a Teflon coated stirbar. The flask was fitted with a needle valve and put in a Schlenk line. The solution was degassed by three cycles of freezing, pumping, and thawing. The mixture was then heated to 100° C. overnight. Step 2: Linker Addition The next morning divinylbenzene (10 mg, 0.077 mmol) was transferred to a small round bottom flask with 1 mL of DMF. The flask was fitted with a needle valve and put in a Schlenk line. The solution was degassed by three cycles of freezing, pumping, and thawing. The solution was transferred via cannula through the needle valves and into the polymerization reaction. After this addition the reaction was allowed to continue at 100° C. overnight. The next day tert-butyl 4-(4-bromophenoxy)butylcarbamate (53 mg, 0.15 mmol) and 1 mL of DMF were transferred to a small round bottom flask. The flask was fitted with a needle valve and put in a Schlenk line. The solution was degassed by three cycles of freezing, pumping, and thawing. The solution was transferred via cannula through the needle valves and into the polymerization reaction. After this addition the reaction was allowed to continue at 100° C. overnight. Step 3: Work Up The reaction is then cooled and diluted with 100 mL of water. The aqueous solution was filtered twice through G-6 glass fiber filter paper. The filtrate was evaporated to dryness and re-diluted with dichloromethane. The organic layer was dried over MgSO4 and filtered. The filtrate was evaporated to yield an amber colored oil (342 mg, 56% yield). A 4 mL portion of 4M HCl in dioxane was added to the polymer residue and stirred for a minimum of 4 hours. The solution was neutralized with 2 M potassium carbonate (aq) and then the solvent was removed under vacuum. The resulting residue was diluted to ˜30 mL with 20% ethanol in water and filtered. Preparative gel permeation chromatography is performed with G-25 desalting medium to remove excess salts from the polymer. Solvent in the fractions is removed with rotary evaporation and the polymer is collected as an amber oil. The linker or capping unit addition steps can be performed in the polymerization reaction as presented above or alternatively, in some embodiments, can be performed in a separate set of reactions after the polymerization work up. In the latter case, the polymer is reacted under the analogous conditions as those provided in the example. In other embodiments, it is also possible to react with a combination of terminal monomers to introduce polymers with bi-functionality, allowing the polymer to be conjugated to more than one entity. Example 18: Synthesis of a Fluorene Monomer with Glycerol-Based Dendrimers Step 1: Dimethyl 3,3′-(2,7-dibromo-9H-fluorene-9,9-diyl)dipropanoate. 2,7-Dibromofluorene (1 g, 3.1 mmol), methyl acrylate (861 mg, 10 mmol) tetrabutylammonium bromide (100 mg, 0.3 mmol) and toluene (5 mL) were added to a small round bottom flask with a Teflon-coated stirbar. Next 2 mL of 50% NaOH (aq) is added while stirring. The reaction is allowed to proceed overnight. The next day the toluene layer is transferred to a flask and the aqueous layer extracted with two portions of toluene. The organic layers are combined, dried with Mg2SO4, and filtered. Silica (2 g) is added to the filtrate and the solution is evaporated. The product is obtained as a white solid (1.23 g, 80% yield) after purification by column chromatography. Step 2: 3,3′-(2,7-dibromo-9H-fluorene-9,9-diyl)dipropanoic acid. Dimethyl 3,3′-(2,7-dibromo-9H-fluorene-9,9-diyl)dipropanoate (1.23 g, 2.5 mmol) is transferred to a small round bottom flask equipped with a Teflon-coated stirbar. A mixture of THF:MeOH: H2O, 3:2:1, (10 mL) is added and the mixture is stirred for 1 hr. Then a 1 mL portion of 1M NaOH (aq) is added and the mixture is stirred overnight. The next day the water layer is isolated and extracted with 20 mL portions diethyl ether three times. Next the water layer is acidified to ˜pH 2. The water layer is extracted three times with 20 mL portions of dichloromethane. The organic layers are combined and dried with Mg2SO4. The organic solution is filtered and the solvent evaporated to obtain the product as an off-white solid (948 mg, 90% yield). Step 3: 3,3′-(2,7-Dibromo-9H-fluorene-9,9-diyl)bis(N-(7,15-bis((2,3-dihydroxypropoxy)methyl)-1,3,19,21-tetrahydroxy-5,9,13,17-tetraoxahenicosan-11-yl)propanamide). 3,3′-(2,7-Dibromo-9H-fluorene-9,9-diyl)dipropanoic acid (500 mg, 1.1 mmol), 11-amino-7,15-bis((2,3-dihydroxypropoxy)methyl)-5,9,13,17-tetraoxahenicosane-1,3,19,21-tetraol (1.954, 3.3 mmol) (prepared as per ref. Heek, T.; Fasting, C.; Rest, C.; Zhang, X.; Wurthner, F.; Haag, R. Chem. Commun., 2010, 46, 1884-1886), and N,N′-dimethylaminopyridine (61 mg, 0.5 mmol) are combined in a round bottom flask equipped with a Teflon-coated stirbar and sealed with a rubber septum. The flask was flushed with N2 and 10 mL of anhydrous dichloromethane was added via syringe. The mixture is stirred to dissolve the solids. In another round bottom flask equipped with a Teflon-coated stirbar, dicyclohexylcarbodiimide (DCC, 910 mg 4.4 mmol) transferred and the flask is sealed with a rubber septum. Next, 5 mL of anhydrous dichloromethane is transferred to the flask via syringe. The DCC solution is transferred to the fluorene reaction mixture via a syringe dropwise. The reaction is allowed to react overnight. The next day the reaction mixture is filtered. The filtrate is purified by column chromatography to afford a clear oil (1.24 g, 70% yield). Example 19: Synthesis of a Fluorene Monomer PAMAM-Based Dendritic Side Chain Capped with methylPEG Chains Step 1: 9,9′-(3,3′-Diamido(tetramethyl PAMAM G[2])-2,7-dibromofluorene (i). Dimethyl 3,3′-(2,7-dibromo-9H-fluorene-9,9-diyl)dipropanoate (g, 2.0 mmol) is transferred to a round bottom flask equipped with a stirbar and sealed with a rubber septum. The flask is flushed with nitrogen and 10 mL of dry methanol is transferred to the flask via syringe and the solid is dissolved by stirring. Ethylenediamine (5.5 mL, 82 mmol) is added via syringe slowly and the mixture is allowed to stir for 2 hours. The septum is removed and the methanol and unreacted ethylenediamine is removed under vacuum. Another 10 mL portion of methanol is added and stirred and then was evaporated to remove any remaining ethylenediamine. The residue remaining in the flask was then sealed again with a septum, flushed with nitrogen, and dry methanol (10 mL) was added and stirred. Methyl acrylate (7.2 mL, 80 mmol) is added slowly via syringe and the mixture is allowed to stir for 2 hours. The septum is again removed and the methanol and methyl acrylate are removed under vacuum. A 10 mL portion of toluene is added, the mixture stirred, and the solvent removed under vacuum affording an off-white solid (1.79 g, quantitative yield). Step 2: 9,9′-(3,3′-Diamido(PAMAM G[2] tetraacid)-2,7-dibromofluorene (ii). 9,9′-(3,3′-Diamido(tetramethyl PAMAM G[2])-2,7-dibromofluorene (i) (1.79 g, 2 mmol) is transferred to a small round bottom flask equipped with a Teflon-coated stirbar. A mixture of THF:MeOH: H2O, 3:2:1, (10 mL) is added and the mixture is stirred for 1 hr. Then a 1 mL portion of 1M NaOH (aq) is added and the mixture is stirred overnight. The next day the water layer is isolated and extracted with 20 mL portions diethyl ether three times. Next the water layer is acidified to ˜pH 2. The water layer is extracted three times with 20 mL portions of dichloromethane. The organic layers are combined and dried with Mg2SO4. The organic solution is filtered and the solvent evaporated to obtain the product as an off-white solid (1.51 g, 90% yield). Step 3: 9,9′-(3,3′-Diamido(PAMAM G[2] N-(2,5,8,11,14,17,20,23-octaoxapentacosan-25-yl)propionamidyl)-2,7-dibromofluorene (iii). 9,9′-(3,3′-Diamido(PAMAM G[2] tetraacid)-2,7-dibromofluorene (ii) (500 mg, 0.6 mmol), 2,5,8,11,14,17,20,23-octaoxapentacosan-25-amine (1.15 g, 3 mmol)), and N,N′-dimethylaminopyridine (12 mg, 0.1 mmol) are combined in a round bottom flask equipped with a Teflon-coated stirbar and sealed with a rubber septum. The flask was flushed with N2 and 10 mL of anhydrous dichloromethane was added via syringe. The mixture is stirred to dissolve the solids. In another round bottom flask equipped with a Teflon-coated stirbar, dicyclohexylcarbodiimide (DCC, 825 mg 4.0 mmol) transferred and the flask is sealed with a rubber septum. Next, 5 mL of anhydrous dichloromethane is transferred to the flask via syringe. The DCC solution is transferred to the fluorene reaction mixture via a syringe dropwise. The reaction is allowed to react overnight. The next day the reaction mixture is filtered. The filtrate is purified by column chromatography to afford a clear oil (967 g, 70% yield). Example 20: Synthesis of a Fluorene Monomer with Highly Branched PEGylated Side Chains Based on a Trihydroxybenzene Linkage Step 1: Methyl 3,4,5-tris(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yloxy)benzoate (iv). Methyl 3,4,5-trihydroxybenzoate (200 mg, 1.1 mmol), 2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yl 4-methylbenzenesulfonate (2.58 g, 3.85 mmol), and 18-crown-6 (100 mg, 0.38 mmol) are transferred to a round bottom flask equipped with a Teflon-coated stirbar. Acetone (10 mL) is added and the flask is equipped with a reflux condenser. The mixture is refluxed with constant stirring overnight. The next day silica (4 g) is added and the solvent evaporated. After purification by column chromatography, a clear oil is obtained (887 mg, 48% yield). Step 2: 3,4,5-Tris(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yloxy)-N-(2-aminoethyl)benzamide (v). Methyl 3,4,5-tris(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yloxy)benzoate (iv) (887 mg, 0.52 mmol) flask is transferred to a round bottom flask equipped with a stirbar and sealed with a rubber septum. The flask is flushed with nitrogen and 10 mL of dry methanol is transferred to the flask via syringe and the solid is dissolved by stirring. Ethylenediamine (0.7 mL, 10.4 mmol) is added via syringe slowly and the mixture is allowed to stir for 2 hours. The septum is removed and the methanol and unreacted ethylenediamine is removed under vacuum. The product is obtained as an oil (886 mg, quanitative yield). Step 3:] 3,3′-(2,7-Dibromo-9H-fluorene-9,9-diyl)bis(N-(2-3,4,5-tris(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yloxy)-benzamidyl-N amidoethyl)propanamide) (vi). 3,4,5-Tris(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yloxy)-N-(2-aminoethyl)benzamide (v) (886 mg, 0.52 mmol), 3,3′-(2,7-Dibromo-9H-fluorene-9,9-diyl)dipropanoic acid (112 mg, 0.24 mmol), and N,N′-dimethylaminopyridine (12 mg, 0.1 mmol) are combined in a round bottom flask equipped with a Teflon-coated stirbar and sealed with a rubber septum. The flask was flushed with N2 and 10 mL of anhydrous dichloromethane was added via syringe. The mixture is stirred to dissolve the solids. In another round bottom flask equipped with a Teflon-coated stirbar, dicyclohexylcarbodiimide (DCC, 148 mg 0.72 mmol) transferred and the flask is sealed with a rubber septum. Next, 5 mL of anhydrous dichloromethane is transferred to the flask via syringe. The DCC solution is transferred to the fluorene reaction mixture via a syringe dropwise. The reaction is allowed to react overnight. The next day the reaction mixture is filtered. The filtrate is purified by column chromatography to afford a clear oil (924 mg, 70% yield). Example 21. Dual End Capped Polymer Used to Create a Polymer-Dye Label for Biomolecule or Substrate Conjugation Step 1: Synthesis of an Asymmetric Neutral Water-Soluble Polymer with a t-BOC Protected Amine Pendant Group at One Terminus of the Polymer. 2-bromo-7-(4″-phenoxybutyl-1-tert-butyl carbamate)-poly-2,7 {9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene. 2-bromo-9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-7-(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolan-2-yl)fluorene (1.0 g, 0.674 mmol), 3 mL of tetrahydrofuran, and 2 mL of 2M potassium carbonate (aqueous) were transferred to a small round bottom flask charged with a Teflon stirbar. The flask was fitted with a septum and the solution is degassed by sparging with Ar for 15 minutes. Palladium tetra(triphenylphoshine) (15.6 mg, 0.013 mmol) was added through the neck of the flask and the flask was transferred to a reflux condenser equipped with a needle valve and fixed to a Schlenk line. The solution was quickly frozen solid with liquid nitrogen and was further degassed using freeze-pump-thaw technique. Once degassed the reaction was heated to 80° C. with constant stirring. The reaction was allowed to proceed overnight. The next day tert-butyl 4-(4-bromophenoxy)butylcarbamate (35 mg, 0.10 mmol) in 1 mL of THF was degassed with three freeze-pump-thaw cycles and then added to the polymerization reaction via cannula under excess nitrogen pressure. The reaction continued overnight at 80° C. The next day the reaction mixture was cooled and the bulk of the solvent was removed under vacuum. The remaining material was transferred to a small Erlenmeyer flask with a total of ˜50 mL of dichloromethane. The solution was stirred for 30 minutes. Approximately 1 g of MgSO4(anhydrous) was added to the solution and the mixture was filtered through a fluted paper filter. The filtrate was evaporated and 410 mg (47% yield) of an amber oil was collected. Step 2: Synthesis to Append a Terminal Linking Monomer with a t-Butyl Ester at the Terminus Opposite the Protected Amine Pendant. 2-(4-(tert-butyl 1-phenoxy-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-oate))-7-(4″-phenoxybutyl-1-tert-butyl carbamate)-poly-2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene. 2-Bromo-7-(4″-phenoxybutyl-1-tert-butyl carbamate)-poly-2,7 {9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene (410 mg, 0.32 mmol of repeat unit), tert-butyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-3,6,9,12,15,18,21-heptaoxatetracosan-24-oate (33 mg, 0.048 mmol), 2 mL of tetrahydrofuran, and 1.5 mL of 2M potassium carbonate (aqueous) were transferred to a small round bottom flask charged with a Teflon stirbar. The flask was fitted with a septum and the solution is degassed by sparging with Ar for 15 minutes. Palladium tetra(triphenylphoshine) (15 mg, 0.013 mmol) was added through the neck of the flask and the flask was transferred to a reflux condenser equipped with a needle valve and fixed to a Schlenk line. The solution was quickly frozen solid with liquid nitrogen and was further degassed using freeze-pump-thaw technique. Once degassed the reaction was heated to 80° C. with constant stirring. The reaction was allowed to proceed overnight. The remaining material was transferred to a small Erlenmeyer flask with a total of ˜50 mL of dichloromethane. The solution was stirred for 30 minutes. Approximately 1 g of MgSO4(anhydrous) was added to the solution and the mixture was filtered through a fluted paper filter. The filtrate was evaporated and 351 mg (78% yield) of an amber oil was collected. Step 3: Synthesis of a Neutral Water-Soluble Polymer with Primary Amine at One Terminus and a t-Butyl Ester Pendant on the Other. 2-(4-(tert-butyl 1-phenoxy-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-oate))-7-(4″-phenoxybutyl-1-amino)-poly-2,7 {9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene. 2-(4-(tert-butyl 1-phenoxy-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-oate))-7-(4″-phenoxybutyl-1-tert-butyl carbamate)-poly-2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene (23 mg, 0.018 mmol) and 0.5 mL of 4M HCl in dioxane were combined in a 1 dram vial with a Teflon-coated stirbar. The mixture was stirred for 4 hours. The mixture was neutralized with 2M potassium carbonate (aqueous). The solution was then diluted to 50 mL of roughly 20% ethanol in water and filtered through G-6glass fiber filter paper. The filtrate was desalted by centrifugation in a 4 mL 10 KDa cutoff centrifuge filter. The retentate was evaporated under vacuum and two 1 mL portions of toluene were added and removed under vacuum to remove any remaining water. A thick amber liquid was recovered from the desalting (21 mg, 85% yield). Step 4: Attachment of an NHS-Functionalized Dye to a Primary Amine Pendant on a Neutral Water-Soluble Polymer. 2-(4-(tert-butyl 1-phenoxy-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-oate))-7-(4″-phenoxybutyl-1-amido-DYE)-poly-2,7 {9,9-bis(2, 5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene. 2-(4-(tert-butyl 1-phenoxy-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-oate))-7-(4″-phenoxybutyl-1-amino)-poly-2,7 {9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene (518 ug, 0.4 μM) was dissolved in 100 μL of dry dichloromethane in a glass vial. A small crystal of 4-N,N′-dimethylaminopyridine was added. In another vial 65 μg (0.06 □uM) of NHS-functionalized DyLight 594 (Pierce) was dissolved in 50 μL of dry dichloromethane. The two solutions were combined and allowed to stir in a sealed vial for 4 hours covered in foil. The solvent was then evaporated and the remaining material was dissolved in 95% ethanol and injected onto a Sepharose 6 column. The remaining dye was separated from the polymer. A solution of dye-labeled polymer was obtained from combining fractions (˜100 μg, 20% yield). Step 5: Hydrolysis of the t-Butyl Ester Pendant on the Dye-Labeled Neutral Water-Soluble Polymer to Form the Carboxylic Acid Pendant on One of the Termini. 2-(4-(1-phenoxy-3,6,9,12,15,18,21,24-octaoxaheptacosane-27-acid))-7-(4″-phenoxybutyl-1-amido-DYE)-poly-2,7 {9, 9-bis(2, 5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene. The polymer was combined with ZnBr2 in dichloromethane and stirred overnight. The next day a portion of water was added and the mixture was stirred for 1 hour. The solvent was evaporated and the residue was dissolved in 20% ethanol in water. The filtrate was then desalted by centrifugation in a 4 mL 10 KDa cutoff centrifuge filter. The retentate was evaporated under vacuum and two 1 mL portions of toluene were added and removed under vacuum to remove any remaining water. Activation (for subsequent conjugation) of the second functional group in this example (carboxylic acid) can be achieved using a number of different methods including those described in Examples 29 and other examples with carboxylic acid to amine to maleimide. One such method is given below in Step 6, by way of example only. Step 6: NHS Activation of the Carboxylic Acid Penant of a Dye-Labeled Neutral Water-Soluble Polymer. 2-(4-(1-phenoxy-3,6,9,12,15,18,21,24-octaoxaheptacosane-27-N-hydroxysuccinimidyl ester))-7-(4″-phenoxybutyl-1-amido-DYE)-poly-2,7 {9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene. 2-(4-(1-phenoxy-3,6,9,12,15,18,21,24-octaoxaheptacosane-27-acid))-7-(4″-phenoxybutyl-1-amido-DYE)-poly-2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene and O—(N-Succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate and DIPEA are combined in dry acetonitrile and allowed to react under nitrogen for 30 min. The solution is evaporated and the solid is resuspended in dry dichloromethane. Solids are filtered off and the filtrate is evaporated to afford the NHS ester. In further embodiments, various commonly used protecting groups can be used with those functional groups provided (amine and carboxylic acid). Additionally different capping monomers and protecting group combinations can be used to produce polymers with different functional groups for conjugation. Eliminating or substituting the dye labeling step for another entity will result in a polymer with two different functional groups for conjugation. The dye attachment via NHS/amine chemistry can be performed under a variety of commonly used conditions. Dye attachment can also be performed with other functional chemistries. Example 22. Asymmetric Polyfluorene Synthesis Using Non-Regulated Suzuki Conditions Step 1: Polymerization Method A: A solution of K2CO3 in water (2M, 4 mL) was added to a stirred mixture of 2-bromo-9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-7-(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolan-2-yl)fluorene (A) (2.3 g, 1.5 mmol) and THF (6 mL) in a round bottom flask. This mixture was degassed with argon for 15 min. Palladium tetrakis(triphenylphosphine) (38.5 mg, 0.03 mmol) was added to the mixture and the flask was attached to a reflux condenser. The reaction vessel was degassed via 3 freeze-pump-thaw cycles and then heated to 80° C. for 12 h. The reaction mixture was cooled to 23° C. and solvent removed by rotary evaporation. The resulting residue was transferred to an Erlenmeyer flask and diluted with 20% EtOH/H2O (75 mL). EDTA (300 mg, 1.0 mmol) was added to the mixture and stirred at 23° C. for 1 h. The mixture was filtered through a glass fiber filter paper and the filter paper rinsed with 20% EtOH/H2O. The resulting filtrate was then filtered through a 0.45 um cup filter. The filtered reaction mixture was purified using tangential flow filtration (TFF) and was diafiltered into 20% ethanol using a 10,000 molecular weight cutoff membrane (regenerated cellulose Prep/Scale TFF cartridge system, Millipore, Billerica, Mass.) until conductivity of the filtrate measured less than 0.01 mS/cm. The solvent was then removed under vacuum to give poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene] (B) as a gel-like product (1.41 g, 71%) Molecular weight determined by GPC analysis relative to polystyrene standards (Mn=51,000, Mw=108,000, Mp=90,000, D=2.1). The extent of end linker incorporation was determined by first converting the acid to an NHS ester (similar protocol to that provided in Example 29) then reacting with an amine functional dye. After purification of free dye the ratio of dye to polymer was determined from absorbance measurements, factoring in the difference in extinction coefficients and polymer molecular weight. Method B: A solution of K2CO3 in water (2M, 4 mL) was added to a stirred mixture of 2-bromo-9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-7-(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolan-2-yl)fluorene (A) (2.3 g, 1.5 mmol) and DMF (6 mL) in a round bottom flask. This mixture was degassed with argon for 15 min. Palladium tetrakis(triphenylphosphine) (38.5 mg, 0.03 mmol) was added to the mixture and the flask was attached to a reflux condenser. The reaction vessel was degassed via 3 freeze-pump-thaw cycles and then heated to 80° C. for 12 h. Work-up and purification was performed in a manner similar to previously described Method A. Molecular weight determined by GPC analysis relative to polystyrene standards (Mn=96,000, Mw=231,000, Mp=185,000, D=2.4). Method C: Cs2CO3 (2.08 g, 6.4 mmol) was added to a stirred mixture of 2-bromo-9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-7-(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolan-2-yl)fluorene (A) (200 mg, 0.135 mmol) and DMF (7 mL) in a round bottom flask. This mixture was degassed with argon for 15 min. Palladium tetrakis(triphenylphosphine) (15.6 mg, 10 mol %) was added to the mixture and the flask was attached to a reflux condenser. The reaction vessel was degassed via 3 freeze-pump-thaw cycles and then heated to 80° C. for 12 h. Work-up and purification was performed in a manner similar to previously described Method A. Molecular weight determined by GPC analysis relative to polystyrene standards (Mn=95,000, Mw=218,000, Mp=206,000, D=2.3). Step 2: End Capping -(4-iodophenyl)butanoic acid (227 mg, 0.783 mmol) was washed into a flask containing poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene](B) (1.00 g, 0.783 mmol) using THF (3.5 mL). A solution of K2CO3 in water (2M, 2.3 mL) was added to the flask and this mixture was degassed with argon for 15 min. Palladium tetrakis(triphenylphosphine) (36 mg, 4 mol %) was added to the mixture and the flask was attached to a reflux condenser. The reaction vessel was degassed via 3 freeze-pump-thaw cycles and then heated to 80° C. for 12 h. The reaction mixture was cooled to 23° C. and the solvent removed with rotary evaoporation. The resulting residue was transferred to an Erlenmeyer flask and diluted with 20% EtOH/H2O (150 mL). EDTA (500 mg) was added to the mixture and stirred at 23° C. for 1 h. The mixture was filtered through a glass fiber filter paper and the filter paper rinsed with 20% EtOH/H2O. The resulting filtrate was then filtered through a 0.45 um cup filter. The filtered reaction mixture was purified using tangential flow filtration (TFF) and was diafiltered into 20% ethanol using a 10,000 molecular weight cutoff membrane (regenerated cellulose Prep/Scale TFF cartridge system, Millipore, Billerica, Mass.) until conductivity of the filtrate measured less than 0.01 mS/cm. The solvent was then removed under vacuum to give 4-(Poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene]yl)phenyl)butanoic acid (C) as a gel-like product (388 mg, 39%) Molecular weight determined by GPC analysis relative to polystyrene standards (Mn=89,000, Mw=196,000, Mp=124,000, D=2.2). The extent of end linker incorporation was determined by first converting the acid to an NHS ester (similar protocol to that provided in Example 29) then reacting with an amine functional dye. After purification of free dye the ratio of dye to polymer was determined from absorbance measurements, factoring in the difference in extinction coefficients and polymer molecular weight. Step 3: Amine Activation 4-(Poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene]yl)phenyl)butanoic acid (C) (200 mg, 0.156 mmol) was dissolved in 2 mL ethanol, then added drop-wise to 23 mL of MES buffer (50 mM, pH 5) at 4° C. while stirring. N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (576 mg, 3.00 mmol) was added in portions, followed by N-hydroxy succinimide (115 mg, 1.00 mmol) in one portion. The solution was stirred for 30 minutes, ethylene diamine (0.501 mL, 7.50 mmol) was added drop-wise and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then desalted over a G25 desalting column and the solvent removed via rotary evaporation to give N-(2-aminoethyl)-4-(Poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene]yl)butanamide as a clear yellow oil (190 mg, 95%). Molecular weight determined by GPC analysis relative to polystyrene standards (Mn=89,000, Mw=196,000, Mp=124,000, D=2.2). Extent of amine conversion was determined by reacting the amine polymer with an NHS active dye in similar fashion as that described in Example 38. Example 23. Asymmetric Polyfluorene Synthesis Using Linker Modified End Caps to Regulate the Suzuki Polymerization Step 1: Polymerization/End Capping/Work-Up A solution of K2CO3 in water (2M, 4 mL) was added to a stirred mixture of 2-bromo-9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-7-(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolan-2-yl)fluorene (A) (2.3 g, 1.55 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butanoic acid (B) (6.7 mg, 2 mol %), and DMF (6 mL) in a round bottom flask equipped with a side-arm stopcock. This mixture was degassed with argon for 25 min. Palladium tetrakis(triphenylphosphine) (38.5 mg, 2 mol %) was then added to the mixture and the flask was attached to a reflux condenser. The reaction vessel was further degassed via 3 freeze-pump-thaw cycles and then heated to 80° C. Separately, 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butanoic acid (B) (230 mg, 0.793 mmol) was dissolved in DMF (3 mL) in a found bottom flask equipped with a side arm stopcock. This solution was sparged with argon for 15 minutes, attached to a reflux condenser, and degassed via three freeze-pump thaw cycles. Upon thawing the solution was added to the reaction mixture after two hours of reaction time using an argon flushed syringe. The reaction mixture was stirred for an additional 12 h at 80° C. The reaction mixture was cooled to 23° C. and solvent removed with rotary evaporation. The resulting residue was transferred to an Erlenmeyer flask and diluted with 20% EtOH/H2O (75 mL). EDTA (300 mg, 1.00 mmol) was added to the mixture and stirred at 23° C. for 1 h. The mixture was filtered through a glass fiber filter paper and the filter paper rinsed with 20% EtOH/H2O. The resulting filtrate was then filtered through a 0.45 um cup filter. The filtered reaction mixture was purified and size fractionated using tangential flow filtration (TFF) and was diafiltered into 20% ethanol using a 30,000 molecular weight cutoff membrane (polyethersulfone Prep/Scale TFF cartridge system, Millipore, Billerica, Mass.) until conductivity of the filtrate measured less than 0.01 mS/cm and Mn of the retentate measured more than 70,000 by GPC. The solvent was then removed under vacuum to give 4-(Poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene]yl)phenyl)butanoic acid as a gel-like product (1.41 g, 71%). Molecular weight determined by GPC analysis relative to polystyrene standards (Mn=68,000, Mw=134,000, Mp=122,000, D=1.9). The extent of end linker incorporation was determined by first converting the acid to an NHS ester (similar protocol to that provided in Example 29) then reacting with an amine functional dye. After purification of free dye the ratio of dye to polymer was determined from absorbance measurements, factoring in the difference in extinction coefficients and polymer molecular weight. Despite having a molecular weight in excess of 50,000 g/mole the polymer is soluble in both water and phosphate buffered saline solutions at concentrations easily greater than 10 mg/mL. In many conjugation experiments the polymer provided (and other described herein with similar structure) was concentrated to 50 mg/mL or higher which is remarkable for a neutral conjugated polymer. The moderate molecular weight also provides extinction coefficients greater than 2,500,000 M−1cm−1. The large extinction coefficient and quantum yield of 60% (PBS) provide for exceptionally bright fluorescent reporters for use in biological assays including their use in flow cytometry. Step 2: Amine Activation 4-(Poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene]yl)phenyl)butanoic acid (C) (500 mg, 0.13 mmol) was dissolved in 2 mL ethanol, then added drop-wise to 23 mL of MES buffer (50 mM, pH 5) at 4° C. while stirring. N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride was added in portions, followed by N-hydroxy succinimide (0.52 g) in one portion. The solution was stirred for 30 minutes, ethylene diamine (2.8 mL) was added drop-wise and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then desalted over a G25 desalting column and the solvent removed via rotary evaporation to give N-(2-aminoethyl)-4-(Poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene]yl)butanamide as a yellow oil (450 mg, 90%). Extent of amine conversion was determined by reacting the amine polymer with an NHS active dye in similar fashion as that described in Example 38. Example 24. Yamamoto Polymerization of PEG Modified Polyfluorene Step 1: Yamamoto Polymerization/Work-up In a dry box, Ni(COD)2 (0.387 g, 1.41 mmol), 2,2′-bipyridyl (0.220 g, 1.41 mmol), COD (0.152 g, 1.41 mmol) and anhydrous DMF (16 ml) were added to a long-neck round bottom flask. [00251] 2,7-dibromo-9,9-di(2′,5′,8′,11′,14′,17′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)fluorene (A) (1.00, 0.696) was weighed into a 40 ml vial and dissolved in anhydrous DMF (8 ml). The flask was sealed with a septum and the vial was closed with a septum screw cap. The catalyst mixture and the monomer solution were transferred out of the dry box and were placed under static argon. The reaction flask was heated to 70° C. for 45 min. The monomer solution was then was quickly transferred from the vial to the catalyst mixture flask with an argon flushed syringe. The reaction mixture was then heated to 70° C. for 6 h. The reaction mixture was cooled and solvent removed by rotary evaporation. The resultant black residue was re-dissolved in 20% EtOH (80 mL) and centrifuged at 2400 rpm for 12 hours. The supernatant was then decanted and filtered through a 0.45 um cup filter. The filtered reaction mixture was purified using tangential flow filtration (TFF) and was diafiltered into 20% ethanol using a 10,000 molecular weight cutoff membrane (polyethersulfone Prep/Scale TFF cartridge system, Millipore, Billerica, Mass.) until GPC analysis of retentate indicated the absence of low molecular weight material. The solvent was then removed under vacuum to give poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene] (B) as a viscous oil (0.700 g, 79%) Molecular weight determined by GPC analysis relative to polystyrene standards (Mn=62,000, Mw=127,000, Mp=93,000, D=2.0). Step 2: End Capping: End Capping is Performed in a Manner Similar to Example 22, Step 2. Step 3: Amine Activation: Amine Activation is Performed in a Manner Similar to Example 22, Step 3. Example 25. Synthesis of a Tandem Polymer with Two Different Linkers Step 1: Polymerization In a dry box, Ni(COD)2 (0.765 g, 2.78 mmol), 2,2′-bipyridyl (0.435 g, 2.78 mmol), COD (0.301 g, 2.78 mmol) and anhydrous DMF (20 ml) were added to a long-neck round bottom flask. 2,7-dibromo-9,9-di(2′,5′,8′,11′,14′,17′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)fluorene (A) (1.80, 1.26 mmol) and tert-butyl 4-(2,7-dibromo-9-methyl-9H-fluoren-9-yl)butylcarbamate (B) (0.071 g, 0.126 mmol) were added to a 40 ml vial and dissolved in anhydrous DMF (30 ml). The flask was sealed with a septum and the vial was closed with a septum screw cap. The catalyst mixture and the monomer solution were transferred out of the dry box and were placed under static argon. The reaction flask was heated to 70° C. for 45 min. The monomer solution was then was quickly transferred from the vial to the catalyst mixture flask with an argon flushed syringe. The reaction mixture was then heated to 70° C. for 6 h. The reaction mixture was cooled and solvent removed by rotary evaporation. The resultant black residue was re-dissolved in 20% EtOH (80 mL) and centrifuged at 2400 rpm for 12 hours. The supernatant was then decanted and filtered through a 0.45 um cup filter. The filtered reaction mixture was purified using tangential flow filtration (TFF) and was diafiltered into 20% ethanol using a 10,000 molecular weight cutoff membrane (polyethersulfone Prep/Scale TFF cartridge system, Millipore, Billerica, Mass.) until GPC analysis of retentate indicated the absence of low molecular weight material. The solvent was then removed under vacuum to give 2,7-dibromo-poly-[2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene-co-2,7-(9-methyl-9′-(butyl-4-t-butylcarbamate)fluorene)] (C) as a viscous oil (1.3 g, 45%) Molecular weight determined by GPC analysis relative to polystyrene standards (Mn=72,000, Mw=156,000, Mp=138,000, D=2.1). Step 2: End Capping A solution of K2CO3 in water (2M, 4 mL) was added to a stirred mixture of 2,7-dibromo-poly-[2,7 {9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene-co-2,7-(9-methyl-9′-(butyl-4-t-butylcarbamate)fluorene)] (C) (800 mg, 0.67 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butanoic acid (D) (120 mg, 0.41 mmol), and DMF (6 mL) in a round bottom flask. This mixture was degassed with argon for 15 min. Palladium tetrakis(triphenylphosphine) (50 mg, 6 mol %) was added to the mixture and the flask was attached to a reflux condenser. The reaction vessel was degassed via 3 freeze-pump-thaw cycles and then heated to 80° C. for 12 h. The reaction mixture was cooled to 23° C. and concentrated in vacuo to a volume of 2 mL. The crude reaction mixture was transferred to an Erlenmeyer flask and diluted with 20% EtOH/H2O (75 mL). EDTA (300 mg, 2.00 mmol) was added to the mixture and stirred at 23° C. for 1 h. The mixture was filtered through a glass fiber filter paper and the filter paper rinsed with 20% EtOH/H2O. The resulting filtrate was then filtered through a 0.45 um cup filter. The filtered reaction mixture was purified and size fractionated using tangential flow filtration (TFF) and was diafiltered into 20% ethanol using a 10,000 molecular weight cutoff membrane (polyethersulfone Prep/Scale TFF cartridge system, Millipore, Billerica, Mass.) until conductivity of the filtrate measured less than 0.01 mS/cm. The solvent was then removed under vacuum to give 4-(4-(2-bromo-poly-[2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene-co-2,7-(9-methyl-9′-(butyl-4-t-butylcarbamate)fluorene)])phenyl)butanoic acid (E) as a yellow oil (660 mg, 82%). Step 3: Linker Deprotection Trifluoroacetic acid (4 mL) was added dropwise to a stirred solution of 4-(4-(2-bromo-poly-[2,7 {9,9-bis(2,5, 8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene-co-2,7-(9-methyl-9′-(butyl-4-t-butylcarbamate)fluorene)])phenyl)butanoic acid (E) (200 mg, 0.169 mmol) and dichloromethane (16 mL) in a round bottom flask. The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was redissolved in minimal 20% EtOH and 1M HCl was added to the solution until pH=7. The neutralized solution was then desalted over G25 gel and the resultant material was concentrated to dryness to yield a clear pale yellow oil (F). Examples of dye incorporation, linker activation and bioconjugation are contained in further Example 38 and related examples. Example 26: Synthesis of a Tandem Polymer with Two Different Linkers Using End Capping Units to Regulate the Polymerization Reaction Step 1: Yamamoto Polymerization In a dry box, Ni(COD)2 (0.433 g, 8.40 mmol), 2,2′-bipyridyl (0.246 g, 8.40 mmol), COD (0.170 g, 8.40 mmol) and anhydrous DMF (15 ml) were added to a long-neck round bottom flask. 2,7-dibromo-9,9-di(2′,5′,8′,11′,14′,17′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)fluorene (A) (1.00, 0.696 mmol), tert-butyl 4-(2,7-dibromo-9-methyl-9H-fluoren-9-yl)butylcarbamate (B) (0.037 g, 0.069 mmol), and tert-butyl 4-(4-bromophenyl)butanoate (C) (0.004 g, 0.007 mmol) were added to a 40 ml vial and dissolved in anhydrous DMF (10 ml). The flask was sealed with a septum and the vial was closed with a septum screw cap. The catalyst mixture and the monomer solution were transferred out of the dry box and were placed under static argon. The reaction flask was heated to 70° C. for 45 min. The monomer solution was then was quickly transferred from the vial to the catalyst mixture flask with an argon flushed syringe. The reaction mixture was then heated to 70° C. for 6 h. The reaction mixture was cooled and solvent removed by rotary evaporation. The resultant black residue was re-dissolved in 20% EtOH (80 mL) and centrifuged at 2400 rpm for 12 hours. The supernatant was then decanted and filtered through a 0.45 um cup filter. The filtered reaction mixture was purified using tangential flow filtration (TFF) and was diafiltered into 20% ethanol using a 10,000 molecular weight cutoff membrane (polyethersulfone Prep/Scale TFF cartridge system, Millipore, Billerica, Mass.) until GPC analysis of retentate indicated the absence of low molecular weight material. The solvent was then removed under vacuum to give tert-butyl 4-(4-(2-bromo-poly-[2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene-co-2,7-(9-methyl-9′-(butyl-4-t-butylcarbamate)fluorene)])phenyl)butanoate (D) as a viscous oil (664 g, 80%). Molecular weight determined by GPC analysis relative to polystyrene standards (Mn=50,000, Mw=88,000, Mp=174,000, D=1.8). Step 2: Linker Deprotection Trifluoroacetic acid (6 mL) was added dropwise to a stirred solution of Polymer (300 mg, X mmol) and dichloromethane (24 mL) in a round bottom flask. The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was redissolved in minimal 20% EtOH and 1M HCl was added to the solution until pH=7. The neutralized solution was then desalted over G25 gel and the resultant material was concentrated to dryness to yield a clear pale orange oil (261 mg, 87%). Examples of dye incorporation, linker activation and bioconjugation are contained in further Example 38 and related examples. Example 27. Dual Functional Asymmetric Polymer with Both Internal and Terminal Conjugation Sites Used to Create a Polymer-Dye Label for Biomolecule or Substrate Conjugation Suzuki polymerization of 2-bromo-9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-7-(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolan-2-yl)fluorene is performed under those conditions described in Example 23 where y % is the mol % of the end linker used to regulate the polymerization and ensure high incorporation of linker. The linker in this example is 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butanoic acid. In this example, x mol % of the internal linker is also added to the polymerization to incorporate the second linking site into the polymer. This method for incorporating the internal linker is generally described in Examples 21, 25 and 26. The internal linker must be incorporated during the polymerization as indicated, however, it is expected that it would be possible to add the terminal linker as a separate step as described in Examples 9, 10, 11 and 21. Example 28: Enrichment of Linker-Functionalized Polymers The synthesis of linker-functionalized polymers can yield a mixture of chains with and without linker functionalities. Because conjugation efficiency is expected to improve with higher purity polymers for conjugation, the methods described in this example address this by enriching for chains containing linker. For a polymer batch containing a mixture of a COOH-modified and unmodified polymer: Dissolve polymer in 95% EtOH, then dilute with water to a final EtOH concentration of 20%. Desalt the polymer using 10 kDa MWCO filter until conductance is <0.1 mS/cm. Inject onto Q-Sepharose column, ensuring that the polymer load is suitable for the column capacity. Pass 20% EtOH in water over column to wash out unbound polymer. Release bound material by changing the eluting buffer to 1M NaCl in 20% EtOH in water for two column volumes to trigger the release of the bound polymeric material. Collect enriched material. The polymer is passed over a strong anion exchanger such as a Q-Sepharose column. Polymer chains bearing a functional carboxylic acid group will bind the strong anion exchanger, and polymer that is not functionalized will not bind and instead will wash through. After the non-functionalized polymer has passed through the column, the column is washed with 1M NaCl, which triggers the release of the acid-functionalized polymer by screening the acid group from the media. By using this method, the percent functional polymer has been shown to increase from 25% of polymer chains bearing a carboxylic acid group to >80% of polymer chains bearing a carboxylic acid group. This increase in functional chains has been shown by analyzing the absorbance ratios of polymer-dye conjugates pre- and post-enrichment. This procedure is also described in Example 38. A similar process has been validated for the enrichement of amine containing polymers. In that case an anionic exchange resin, SP Sephrose (or similar), is loaded at reduced conductivity (below 0.01 mS/cm). Example 29: Preparation of Polymer-Streptavidin Conjugates Via NHS/Amine Coupling Example 29a: Polymer Modifications Polymer Modification—Carboxylic Acid to Amine Conversion 1.35 g of a carboxylic acid terminated polymer was dissolved at in 9 mL ethanol, then added dropwise to 80 mL of 4° C. 50 mM MES, pH 5 while stirring. 0.52 g N-hydroxy succinimide was added in one portion. Once the N-hydroxy succinimide had dissolved, 2.3 g N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride was added in portions. After stirring the solution for 30 minutes, 2.8 mL of ethylene diamine was added dropwise. The solution was stirred overnight at room temperature and purified by tangential flow filtration (MWCO=10 kDa). 1.22 g yield (90%). Polymer Modification—Amine to Carboxylic Acid Conversion 70 mg of an amine-terminated polymer was dissolved in 7 mL DMSO. 2.3 mg DIPEA was added to the polymer solution. 2.2 mg DMAP was dissolved in 220 μL DMSO and added to the resulting polymer solution. 5.5 mg succinic anhydride was dissolved in 550 μL DMSO and added to the resulting polymer solution. The solution was agitated at room temperature overnight. The reaction was then purified over Amicon Ultra centrifugal filtration units (MWCO=10 kDa) with 25 mM MES pH 5 buffer. 62 mg yield (89%). Polymer Modification—Carboxylic Acid to NHS-Ester Conversion 60 mg of a carboxylic acid-terminated polymer was dissolved in 600 μL acetonitrile. 1.2 μg DIPEA was added to the polymer solution. 2.8 mg N,N,N′,N′-Tetramethyl-O—(N-succinimidyl)uronium was dissolved in 370 μL acetonitrile and added to the polymer solution. The solution was agitated at room temperature for 15 minutes. After the reaction is complete, the solvent was evaporated under reduced pressure. 50 mg yield (83%). Example 29b: Protein-Polymer Conjugation Streptavidin protein is dissolved in 50 mM NaHCO3 pH 8.2 buffer to make a 1 mg/mL solution. Crude activated polymer (10-15 eq or as required) solution from Step 2 is added to the aqueous streptavidin protein solution; the protein concentration is adjust with buffer to ensure that the volume of organic solvent added is <10% of the total volume, if necessary. The solution is agitated at room temperature for 3 hr and the reaction transferred to a Amicon Ultra filter (MWCO=10 kDa) to remove DMF. The protein is recovered into the initial volume with 25 mM PO4 pH 6.5 buffer. Purification of the Protein-Polymer Conjugate A 1 mL HiTrap SP Sepharose FF column is equilibrated with 20 mM Na Citrate pH 3 buffer. 1 mL (0.3-1 mg/mL) of Streptavidin-polymer conjugate is loaded in 25 mM NaHPO4 pH 6.5. The sample is wash through column with 20 mM Na Citrate pH 3 buffer until a stable baseline is obtained. Multiple 1 mL aliquots of sample may subsequently be loaded and washed. The column is washed with a minimum of 10 column volumes of 20 mM Na Citrate pH 3 buffer. The conjugate is eluted with 10 column volumes of 20 mM Na Citrate in 0.6 M NaCl pH 7.6 buffer and the column is stripped with 10 column volumes of 20% ethanol in the elution buffer. The elution peak is concentrated with an Amicon Ultra filter (MWCO=10 kDa) to reduce the volume to ˜200 μl. A 10×300 mm Superose 12 column is equilibrated with 20 mM Na Citrate in 0.6 M NaCl pH 7.6 buffer. 200 μL of concentrated Streptavidin-polymer conjugate is loaded and eluted with 20 mM Na Citrate in 0.6 M NaCl pH 7.6 buffer exchanged into PBS+0.05% NaN3 using Amicon Ultra Centrifugation filters (10 kD MWCO). Elutions are concentrated to desired concentration for testing; at around 2 μM Streptavidin. Characterization of a Purified Protein-Polymer Conjugate A 4-20% acrylamide Tris-HCl Ready Gel (BioRad) is prepared and the gel is loaded with the conjugate along with free streptavidin and free polymer in separate lanes. Gel electrophoresis is performed in 25 mM Tris 192 mM, Glycine pH 8.3 and stained with Coomassie to visualize the protein. The gel is stained for 30 minutes then destained with commercial destain overnight. Agarose gel conditions were also used to characterize polymer-streptavidin conjugates, an example which is shown in FIG. 29. In alternative embodiments, the above example can be adapted to allow for conjugation of the polymer to biomolecules or dyes, including but not limited to, antibodies and nucleic acids. The amine on the polymer is converted to a maleimide and a carboxylic acid (further activated to form the NHS ester) using alternative crosslinkers or modifiers. In certain embodiments, conjugation of the same polymer to other biomolecules (streptavidin, antibody fragments, nucleic acids) is facilitated using malimide-thiol chemistry (using SATA linkers to convert free amines on the biomolecule or TCEP (or DPP) reduction of an antibody to create free thiols). Example 30: Preparation of Polymer-Streptavidin Conjugates Via Hydrazide/Benzaldehyde Coupling Step 1: Streptavidin-4FB Modification Streptavidin protein is reconstituted at 1.7 mg/mL and exchange into reaction buffer, 50 mM NaHCO3, pH 8. 15 molar equivalents of bifunctional benzaldehyde/succinimidyl linker, S-4FB (Solulink, San Diego, Calif.) 20 mg/mL in anhydrous DMSO is added to streptavidin, ensuring that the organic phase is less than 10% of the total volume. Reaction is mixed on shaker for 4 hours at room temperature and unreacted linker is subsequently filtered away via Amicon Ultra filter, 10 kD MWCO with 50 mM MES buffer, pH 5; centrifuged at 2400 rpm and a repeated wash×3. Streptavidin protein is recovered in its initial volume, targeting 1.7 mg/mL in conjugation buffer, 50 mM NaPO4, pH 6.5. Step 2: Polymer Modification Polymer with terminal amine group (1 molar eq) is dissolved with DMF to make a 10 mg/mL solution. 20 molar equivalents of a bifunctional hydrazine/succinimidyl linker, SHTH (Solulink, San Diego, Calif.) at 80 mg/mL in anhydrous DMSO is added to the polymer solution. 1 drop of DIPEA is added to the reaction by a syringe and 22 g needle. The solution is agitated at room temperature for 4 hr and the reaction transferred to a Amicon Ultra filter (MWCO=10 kDa) filled with 25 mM MES pH 5 buffer. The solution is then centrifuged. The filter is refilled and washed with the following wash buffers: 1×DI H2O+1 drop 1M HCl 1×DI H2O+1 drop 1M NaOH 3×50 mM MES,pH 5 Step 3: Protein-Polymer Conjugation 15 equivalents of modified polymer from Step 2 are added with desired amount of modified protein from Step 1. Aniline is added to the reaction for a final concentration of 10 mM and allowed to mix for 12 hours. The reaction is purified with Amicon Ultra filter (MWCO=10 kDa) to remove DMF and recovered with 25 mM PO4 pH 6.5 buffer. Step 4: Purification of the Protein-Polymer Conjugate A 1 mL HiTrap SP Sepharose FF column is equilibrated with 20 mM Na Citrate pH 3 buffer. 1 mL (0.3-1 mg/mL) of Streptavidin-polymer conjugate is loaded in 25 mM NaHPO4 pH 6.5. The sample is wash through column with 20 mM Na Citrate pH 3 buffer until a stable baseline is obtained. Multiple 1 mL aliquots of sample may subsequently be loaded and washed. The column is washed with a minimum of 10 column volumes of 20 mM Na Citrate pH 3 buffer. The conjugate is eluted with 10 column volumes of 20 mM Na Citrate in 0.6 M NaCl pH 7.6 buffer and the column is stripped with 10 column volumes of 20% ethanol in the elution buffer. The elution peak is concentrated with an Amicon Ultra filter (MWCO=10 kDa) to reduce the volume to ˜200 μl. A 10×300 mm Superose 12 column is equilibrated with 20 mM Na Citrate in 0.6 M NaCl pH 7.6 buffer. 200 μL of concentrated Streptavidin-polymer conjugate is loaded and eluted with 20 mM Na Citrate in 0.6 M NaCl pH 7.6 buffer. Fractions are pooled and buffer exchanged into PBS+0.05% NaN3 using Amicon Ultra Centrifugation filters (10 kD MWCO). Elutions are concentrated to desired concentration for testing; at around 2 M Streptavidin. Step 5: Characterization of a Purified Protein-Polymer Conjugate A 4-20% acrylamide Tris-HCl Ready Gel (BioRad) is prepared and the gel is loaded with the conjugate along with free streptavidin and free polymer in separate lanes. Gel electrophoresis is performed in 25 mM Tris 192 mM, Glycine pH 8.3 and stained with Coomassie to visualize the protein. The gel is stained for 30 minutes then destained with commercial destain overnight. FIG. 14 top, depicts conjugation of streptavidin to a polymer of formula (Vb) in cartoon format. FIG. 14, bottom, is a Coomassie stain of acrylamide gel which depicts the mobility of the conjugate is retarded relative to the free protein indicating an increase in mass. A neutral polymer alone shows no evidence of staining and without a formal charge, the polymer is not mobile in the electrophoritic field. In alternative embodiments, the above example can be adapted to allow for conjugation of the polymer to biomolecules or dyes, including but not limited to, antibodies and nucleic acids. The amine on the polymer is converted to a maleimide and a carboxylic acid (further activated to form the NHS ester) using alternative crosslinkers or modifiers. In certain embodiments, conjugation of the same polymer to other biomolecules (streptavidin, antibody fragments, nucleic acids) is facilitated using malimide-thiol chemistry (using SATA linkers to convert free amines on the biomolecule or TCEP reduction of an antibody to create free thiols) and NHS-amine chemistry (reacting the NHS polymer directly with lysines on the protein or nucleic acid). Example 31: Preparation of Biotin-Labeled Polymers Amine functionalized polymer of formula (Vc) is dissolved at 10 mg/mL in anhydrous DMF and divided into two portions. NHS-biotin (0.9 mg in 90 μL, 88 equivalents) (Pierce, 20217) and NHS-LC-LC-biotin (Pierce, 21343) at 10 mg/mL (1.5 mg in 150 μL, 88 equivalents) are dissolved in anhydrous DMF. The NHS-biotin and NHS-LC-LC-biotin solutions are immediately added to the two portions of polymer solution and allowed to mix on a shaker overnight in the dark. Excess reactant is removed by washing the solution using Amicon Ultra-4 mL 10 kD MWCO filter cartridges in a series of wash steps: First, the cartridge is first filled approximately halfway with water, and the reaction solution (by pipet) subsequently added directly into the water. Next, the cartridge is filled with water until it is full. The solution is mixed by pipetting up and down. Then, the cartridge is centrifuged at 2400 rpm for 30 minutes, or until the volume is reduced to 250 LL. The cartridge is then refilled with water 1 drop of 1M HCl is added; the solution is mixed, and centrifuged at 2400 rpm for 30 minutes, or until the volume was reduced to 250 μL. Next, the cartridge is refilled with water, 1 drop of 1M NaOH is added; the solution is mixed, and centrifuged at 2400 rpm for 30 minutes, or until the volume is reduced to 250 μL. The cartridge is then refilled with water, mixed and centrifuged at 2400 rpm for 30 minutes, or until the volume is reduced to 250 μL. This final step is repeated for a total of 5 washes. Characterization of a Purified Biotin-Labeled Polymer Excess biotin-labeled polymer is incubated with a Cy5-labeled streptavidin in DPBS buffer plus 0.2% BSA and 0.05% NaN3. A 0.8% agarose gel is is prepared and the gel is loaded with the conjugate along with free Cy5-streptavidin and free biotinylated polymer in separate lanes. Gel electrophoresis is performed in 10 mM NaHCO3 pH10 and and visualized using a Typhoon gel imager with 457 nm and 635 nm laser excitation. FIG. 15 (bottom) depicts retardation of mobility of the polymer-streptavidin complex relative to the free protein indicating an increase in mass. The polymer alone shows little mobility on its own due to a lack of formal charge. This protocol is adapted to successfully biotin-modify a range of conjugated polymers containing both internal and terminal amine linkers. Example 32: Functional Testing of Covalent Polymer Streptavidin Conjugates by Selective Binding to Biotinylated Microspheres Materials Required: 1×TBST: 50 mM Tris-HCl, 150 mM NaCl, 0.1% Tween20, pH 7.5; Biotin microspheres (10 mg/mL in TBST); BSA (1 mg/mL); AvDN (220 μM); and Polymer-Strepavidin (SA) conjugate: (1 μM with regard to SA, provided at 5 μM). Preparation of Master Mixes: Prepare in labelled 1.5 mL microfuge tubes: Experimental master mix Negative control master mix 14 μl TBST 9 μl TBST 6 μl BSA stock 6 μl BSA stock 5 μl bead stock 5 μl avidin stock 5 μl bead stock Briefly vortex both tubes and allow 20-30 minutes to pre-incubate the negative control beads with excess avidin before proceeding. A variable speed orbital mixer at 800 RPM for incubation is suggested to keep beads from settling. Bead Hybridization: Pipette 10 μL of each master mix into separate labelled 1.5 ml microfuge tubes. Add 2 μL of polymer-SA conjugate to each. Prepare additional tube containing 10 μL master mix and no polymer to be used as a blank. Briefly vortex and pulse spin all tubes. Transfer to variable speed orbital mixer and incubate for 30 mins at 800 RPM. Bead Processing/Washing: Add 0.5 ml TBST to all samples and controls and vortex briefly. Centrifuge at 1200 g for 2 min and remove 480 μl supernatant being diligent not to disturb bead pellet. Add 0.5 ml TBST to all samples and controls and vortex briefly. Centrifuge at 1200 g for 2 min and remove 500 μl supernatant being diligent not to disturb bead pellet. Repeat steps 3 and 4. Remove as much of remaining supernatant as possible using P200 pipette without disturbing bead pellet. Add 100 μL TBST and vortex briefly to re-suspend beads. Bead Measurement: Transfer 100 μL of positive, negative and blank beads to a BLACK 96 well plate. Excite wells at 430 nm and collect emission in the range 450-650 nm using required slit widths and/or sensitivity setting to achieve measurable signals above background. Compare emission of positive and negative control beads. FIG. 16 shows the polymer streptavidin conjugate was bound to a biotinylated microsphere. Excitation at 440 nm in a florometer resulted in emission from the polymer as indicated by the solid curve. The dashed curve represents the negative control where the biotin bead was first treated with excess avidin to block the biotin binding sites prior to treatment with the polymer streptavidin conjugate. Example 33: Functional Testing of Covalent Polymer Streptavidin Conjugates by Selective Binding to Biotinylated Microspheres and FRET to Dye Acceptors on Co-Localized Streptavidin-Dye Conjugates Materials Required: 1×TBST: 50 mM Tris-HCl, 150 mM NaCl, 0.1% Tween20, pH 7.5. Biotin microspheres (10 mg/mL in TBST). Cy3-SA (1 μM or 50 μg/mL). Polymer-Strepavidin (SA) conjugate: (1 μM with regard to SA, provided at 5 μM). Bead Preparation and Hybridization: Prepare in labelled 1.5 mL microfuge tubes: Blank control Cy3-SA control FRET-SA Control 16 μl TBST 14 μl TBST 14 μl TBST 4 μl bead stock 2 μl Cy3-SA stock 2 μl Cy3-SA stock 4 μl bead stock 2 μl polymer-SA stock 4 μl bead stock Briefly vortex all tubes and transfer to variable speed orbital mixer for incubation of at least 30 mins at 800 RPM. Bead Processing/Washing: Add 0.5 ml TBST to all samples and controls and vortex briefly. Centrifuge at 1200 g for 2 min and remove 480 μl supernatant being diligent not to disturb bead pellet. Add 0.5 ml TBST to all samples and controls and vortex briefly. Centrifuge at 1200 g for 2 min and remove 500 μl supernatant being diligent not to disturb bead pellet. Repeat steps 3 and 4. Remove as much of remaining supernatant as possible using P200 pipette without disturbing bead pellet. Add 100 μL TBST and vortex briefly to re-suspend beads. Bead Measurement: Transfer 100 μL of all samples to a BLACK 96 well plate. Excite wells at 430 nm and collect emission in the range 450-650 nm using required slit widths and/or sensitivity setting to achieve measurable signals above background. Detect and record polymer emission in the range of 480-500 nm and Cy3 emission at the expected 570 nm. FIG. 17 shows the polymer streptavidin conjugate was bound to a biotinylated microsphere. Excitation at 440 nm in a florometer resulted in energy transfer between the polymer and a Cy3 dye conjugated to a different streptavidin protein as indicated by the solid upper curve. The dashed curve shows beads alone and the lower solid curve direct excitation of the Cy3-streptavidin conjugate at 440 nm. Example 34: Functional Testing of Biotin-Labeled Polymers by Selective Binding to Avidin Coated Microspheres Materials Required: 1×TBST: 50 mM Tris-HCl, 150 mM NaCl, 0.1% Tween20, pH 7. SA microspheres (10 mg/mL in TBST). Biotin (1 mM). 440 nm biotin-polymer conjugate: (46 μM). Bead Preparation and Hybridization: Prepare in labelled 1.5 mL microfuge tubes: Blank control Negative control Positive Control 16 μl TBST 11 μl TBST 15 μl TBST 4 μl bead stock 4 μl biotin stock 4 μl bead stock 4 μl bead stock Briefly vortex all tubes and transfer to variable speed orbital mixer for incubation of 20-30 mins at 800 RPM to ensure biotin has blocked all SA sites on negative control beads. Add 1 uL of polymer-biotin stock to both positive and negative control tubes. Vortex briefly and transfer to variable speed orbital mixer and incubate for 30 mins at 800 RPM. Bead Processing/Washing: Add 0.5 ml TBST to all samples and controls and vortex briefly. Centrifuge at 1200 g for 2 min and remove 480 μl supernatant being diligent not to disturb bead pellet. Add 0.5 ml TBST to all samples and controls and vortex briefly. Centrifuge at 1200 g for 2 min and remove 500 μl supernatant being diligent not to disturb bead pellet. Repeat steps 3 and 4. Remove as much of remaining supernatant as possible using P200 pipette without disturbing bead pellet. Add 100 μL TBST and vortex briefly to re-suspend beads. Bead Measurement: Transfer 100 μL of all samples to a BLACK 96 well plate. Excite wells at 430 nm and collect emission in the range 450-650 nm using required slit widths and/or sensitivity setting to achieve measurable signals above background. Compare emission of positive and negative control beads. FIG. 18 shows the biotin modified polymer was bound to a streptavidin microsphere (top). In FIG. 18 (bottom), excitation at 440 nm in a florometer resulted in emission from the polymer as indicated by the solid upper curve. The lower solid curve represents the negative control where the streptavidin bead was first treated with excess biotin to block the binding sites prior to treatment with the biontinylated polymer. The lower solid curve represents beads alone. Example 35: Selective Binding of Biotin-Labeled Polymer to Dye-Labeled SA Conjugates to Validate FRET Properties and Functional Activity of the Polymer Modification Materials Required: Biotin-Polymer Conjugate: (46 μM). Cy3-SA conjugate (1 mg/mL or 18.9 μM). BLACK 96-well plate. Forming the Biotin-Streptavidin Complex: In a 1.5 mL microfuge tube, combine 9.4 μL of the biotin-polymer conjugate and 2.9 μL of the Cy3-SA. Vortex to mix, then incubate on a shaker (under foil) for 0.5 h. Longer incubation times are also suitable. Instrument Settings: Model experiments were conducted on a BioTek Synergy 4 in the Fluorescence mode with the following settings: Emission: 400-750 nm in 5 nm steps and Sensitivity level: 50. Plate Layout: Prepare solutions in a BLACK 96-well plate as in the below table. Take care to add the A+B solution last, after all other materials have been added: Material Well 1 Well 2 Well 3 Polymer-biotin 9.4 μL* 9.4 μL — Cy3-SA 2.9 μL* — 2.9 μL Buffer 100 μL 100 μL 100 μL *Pre-incubated in the first step, Forming the Biotin-Streptavidin Complex. FIG. 19 shows the biotin modified polymer was bound to a dye labeled streptavidin (Cy3 or Texas Red—top). Excitation at 440 nm in a florometer resulted in emission from the dye acceptors at their respective emission wavelength (approximately 570 nm and 620 nm respectively—bottom left) as well as some residual emission from the polymer (approximately 520 nm). A titration was also performed to saturate the binding of polymer to the streptavidin (bottom right). The solid curve indicates the emission from the Cy3 label on the streptavidin via energy transfer from the polymer at 440 nm excitation. The dotted curve represents the negative control where the streptavidin was first treated with excess biotin to block the binding sites prior to treatment with the biontinylated polymer. Example 36: Polymer-Streptavidin Conjugates for Use in Flow Cytometry Polymer bioconjugates are evaluated by Stain Index, as defined by Becton Dickinson (BD) Biosciences on a flow cytometer. See, e.g., H. Maeker and J. Trotter, BD Biosciences Application Note: “Selecting Reagents for Multicolour Flow Cytometry”, September 2009. The stain index reports a measure of the polymer's brightness, nonspecific binding and can also be related by the Resolution Index on a flow cytometer. Flow cytometry provides a method through which to measure cells of a specific phenotype or analytes of interest on specific microspheres. This can be done with direct labeling of a primary antibody or, if signal amplification is desired, through a secondary antibody or the avidin-biotin complexation with avidin-polymer conjugates. Procedure for Cell Staining Cells of interest are taken up in sufficient quantity, at least 105 per test condition. Cells are then spun down at 250 rcf for 3 minutes, washed in DPBS+0.2% BSA and 0.05% NaN3 (staining buffer), then resuspended in staining buffer at 1×107 cells/mL. For primary incubation, cells are incubated with a primary conjugate (reporter labeled antibody) specific to an antigen of interest, negative cells serve as a negative non-specific binding reference. A control population or an established commercial conjugate is used as a positive control. Primary polymer conjugates are incubated at 4° C. with 4×105 cell aliquots at concentrations with volume dilutions from 10-330 nM for 30 minutes. Following primary incubation, cells are rinsed with 5 volumes staining buffer and spun down at 250 rcf for 3 minutes; this rinse is repeated three times. Cells are resuspended for testing at 8×105 cells/mL in DPBS+0.2% BSA, 0.05% NaN3. For secondary antibody labeling, an unlabeled primary antibody to the antigen of interest is incubated at 0.4 ug/uL, or other titrated amount, at 4° C. with 4×105 cells per test condition for 30 min. Following primary incubation, cells are rinsed with 5 volumes staining buffer and spun down at 250 rcf for 3 minutes; this rinse is repeated three times. Species reactive secondary polymer conjugates are incubated at 4° C. with 4×105 cell aliquots at concentrations with volume dilutions from 10-330 nM for 30 minutes. Following secondary incubation, cells are rinsed with 5 volumes staining buffer and spun down at 250 rcf for 3 minutes; this rinse is repeated three times. Cells are resuspended for testing at 8×105 cells/mL in DPBS+0.2% BSA, 0.05% NaN3. For streptavidin-polymer conjugate labeling, cells are incubated with a biotinylated primary antibody to the marker of interest, as detailed above for the secondary antibody labeling, instead of an unlabeled primary. Following the primary washing, cells are resuspended and divided in 4×105 cell aliquots and incubated with streptavidin-polymer conjugates at 1-100 nM volume dilutions for 30 minutes at 4° C. Following secondary incubation, cells are rinsed with 5 volumes staining buffer and spun down at 250 rcf for 3 minutes; this rinse is repeated three times. Cells are resuspended for testing at 8×105 cells/mL in DPBS+0.2% BSA, 0.05% NaN3. If further signal amplification is desired, cells and be incubated with an unlabeled primary antibody and then subsequently follow with a species reactive biotinylated secondary antibody prior to incubation with streptavidin conjugates. The incubation steps, washing protocol and testing protocol should follow as previously detailed. These flow testing procedures have been developed specific to CD4 markers on Cyto-trol cells. Cell preparation and incubation protocols may vary with cell type and an optimal staining, washing and handling protocol should be developed specific to cell type. Working concentration ranges of antibodies have been identified as optimal for both CD4 (35-50% population) and CD45 (85% population) markers on Cyto-trol control lymphocytes as well as on Whole Lysed Blood (for primary antibody only). Markers which have populations significantly different than these ranges may fall outside of the suggested titration ranges. Testing was also done on a Jurkat cell line grown in culture following similar protocols. In these tests a CD45 marker was used. As there are no negative cell populations a different negative control procedure was used. In the negative control samples the primary antibody was omitted from the primary incubation step. This step and all subsequent steps were performed according to the standard protocol. Again a commercially dye-antibody or dye-strepatvidin conjugate were used as a positive control. Procedure for Flow Cytometry Analysis Flow testing was done in test tubes, at 0.5 mL volumes on a BD LSR II Flow Cytometer. Flow testing is performed using the voltage settings determined from daily calibration of the cytometer with calibration particles by flow facility staff. Lymphocyte specific gating by forward scatter vs. side scatter is performed on unstained cell samples as a background control. Standard doublet gating is performed for both forward scatter and side scatter area vs. width profiles. With only a single color, no compensation is required. Data are collected for all forward and side scatter parameters and fluorescence measurements are made using BD's standard Pacific Blue channel. Pacific Blue data utilizes excitation with the 408 nm Violet lasers and a 450/50 BP filter. Samples are collected for 30,000 events within the stated gating parameters. Representative Experiments: CD4 marking was measured on Cyto-trol cells, lyophilized human lymphocytes for analysis of polymer performance in flow. Cyto-trol cells (Beckman Coulter) were reconstituted in the provided reconstitution buffer and allowed to swell for 15 minutes at room temperature. Cells were then spun down at 250 rcf for 3 minutes, washed in DPBS+0.2% BSA and 0.05% NaN3 (staining/testing buffer), then resuspended in staining buffer at 1×107 cells/mL. Cell suspension was divided in two; half the cells were incubated with biotinylated anti-CD4 at 0.4 ug/uL, the other half of the cells were incubated with staining buffer as a negative control for 30 min. Following primary incubation, cells were rinsed with 5 volumes staining buffer and spun down at 250 rcf for 3 minutes; this rinse was repeated three times. Cells were resuspended at prior volume in staining buffer. 4×105 cells were measured per test and divided out accordingly, streptavidin-fluorophore conjugates prepared in Example 19 were incubated at 100 nM with each aliquot of cells for 30 min, allowing the avidin-biotin complex to form. Following the secondary incubation, cells were rinsed and detailed previously. Final cell suspensions were made for testing at 8×105 cells/mL. Flow analysis was performed on a BD LSR II flow cytometer at The Scripps Research Institute (TSRI), San Diego, Calif. Routine calibration with Rainbow fluorescent particles for aligning fluorescent channels on the cytometer was performed by staff at TSRI, all calibrated voltages were used, per staff recommendation. All samples were excited with a 408 nm Violet laser, the polymer conjugate was measured in the AmCyan channel with a 525/50 filter. All samples were initially referenced to unstained cells. The polymer streptavidin conjugate from FIG. 14 showed specific secondary labeling of the primary identified CD4 positive cells, with the positive cells as 44% of the population. The polymer streptavidin conjugate demonstrated a positive stain index showed low non-specific binding with reference to unstained cells and its respective negative control (FIG. 20. (A)). This provides evidence that the polymer, although its peak absorbance is a 440 nm, is a viable fluorescent material for use in flow cytometry with Violet laser excitation. Secondary Antibody polymer conjugate on Cyto-trol cells Amine-functionalized 405 polymer was conjugated to goat anti-mouse IgG κ1 purified antibody by route of maleimide-thiol conjugation and TCEP partial reduction of the antibody. The polymer and conjugation procedure are provided specifically in Example 46. Conjugates were tested on Cyto-trol cells (Beckman Coulter), a fixed and lypholized lymphocyte cell population for control testing of specific human antigens. Cell staining followed secondary cell staining protocol. Cells were incubated with and without (negative control) unlabeled anti-CD4 (RPA-T4 clone, BD Biosciences) raised in mouse against the human antigen. After complete washing of primary antibody incubation, cells were incubated with polymer labeled goat anti-mouse conjugates for specific labeling of primary identified CD4 positive cells. Secondary labeling occurs by Fc recognition and binding of the mouse primary antibody by the secondary goat IgG, raised against murine species. A positive control was used by incubation with commercially available Pacific Blue goat anti-mouse IgG (Invitrogen) as the secondary labeling species. FIG. 20 (B) depicts the specific recognition of CD4 specific cells by the secondary fluorescent conjugates. Unstained cells show a negative control and natural autoflourescence of the cells, and incubation of polymer conjugate on cells with no primary labeling show minimal non-specific binding of the conjugate to unlabeled cells. Positive control, Pacific Blue goat anti-mouse shows the commercially available standard for CD4 labeling by secondary antibody with Violet excitation. 405 polymer-goat anti-mouse conjugate (red) shows positive identification of CD4 positive cells, a minimal shift in the negative cell population and great fluorescent signal and resolution that Pacific Blue standard. FIG. 20 (C) depicts Streptavidin polymer conjugates on Jurkat cells. Conjugates were produced with the polymer provided in Example 11 using the protocol defined in Example 29. The stain index for the polymer streptavidin conjugate was over 10 fold higher than that obtained for the commercially available Pacific Blue streptavidin control conjugate. FIG. 20 (D) depicts a primary monoclonal antibody polymer (antiCD4, RPA-T4) conjugate evaluated on Cyto-trol cells using the protocols defined above. The conjugate was prepared using the polymers and protocols defined in Example 46. Additional details on the conjugation can also be found in Example 39. Example 37: Preparation of Polymer Conjugated to —COOH Beads Via EDC Coupling Materials (Per 100 μL of Beads) LodeStars —COOH functionalized magnetic beads (Varian, Inc. PL6727-0001) (100 μL of suspension at spec'd 30 mg/mL). Polymer with amine terminal ends from Example 17 (125 μL at 1.6 μM in 25 mM MES pH 5, for a 10-fold excess over theoretical bead capacity). 10 mM NaOH (2 mL). DI H2O (3 mL). 25 mM cold MES, pH 5. EDC at 50 mg/mL in 25 mM cold MES, pH 5 (100 μL). NHS at 50 mg/mL in 25 mM cold MES, pH 5 (100 μL). 100 mM Tris/HCl pH 7.4 (1 mL). Centrifuge and black flat-bottom 96-well plate. Antibody capacity was given at 10 ug/mg bead, giving an amine coupling capacity of 2 nmol polymer/mL bead (at 30 mg/mL). A 10 fold-excess of polymer over the suggested capacity was used to target the antibody concentration given in Varian's protocol. Bead Washing Beads were washed collectively as 600 μL and then split into 6×100 μL samples for coupling. Beads were washed 2× with 1 mL 10 mM NaOH, then 3× with 1 mL DI H2O; in between washes, the tube was centrifuged 1 min at 3000 rpm to recollect the beads as a pellet, supernatant was discarded and beads were resuspended in the next wash. After the final wash, beads were resuspended in 600 μL cold 25 mM MES, pH 5 and aliquoted into 6×100 μL volumes in microcentrifuge tubes. Beads were centrifuged again 1 min at 3000 rpm and supernatant was discarded. EDC Activation 100 μL of the EDC solution was added to each reaction set. 100 μL of the NHS solution was added to each reaction set. Beads were resuspended by vortexing and then allowed to mix on a rotator for 30 minutes. Beads were washed 2× in cold 25 mM MES pH 5, pelleted by centrifuging for 1 min at 3000 rpm and the supernatant was discarded. Beads were resuspended in 125 μL cold 25 mM MES, pH 5. Polymer Coupling 125 μL of polymer at 1.6 μM was added. Samples were vortexed to mix thoroughly and then reacted at RT on a mixer for 3 hours. Beads were pelleted by centrifuging for 1 min at 3000 rpm; supernatant was discarded. Beads were resuspended in 1 mL 100 mM Tris/HCl to block unreacted —COOH sites, vortexed and mixed for 1 hour. Beads were recollected by centrifugation and resuspended in 100 μL 25 mM MES. At this point, the supernatant of several tubes were yellow in color and had significant absorbance at 440 nm; the beads were washed 6 times until absorbance was at baseline. Beads sat for an additional 2 days prior to fluorescence measurement, after sitting in solution for 2 days, the supernatant was again yellow in color and had measureable absorbance. Beads were washed 3 more times with 30 minute mixes in between until no absorbance was measureable. At 2 days following fluorescence measurements, the supernatant remained clear and free of measureable absorbance. Example 38: Preparation of Polymer-Dye Conjugates Example 38a: Preparation of Polymer-Dye Conjugate at Polymer Terminal 0.5 mg amine-terminated polymer was dissolved in 15 μL DMSO. The polymer solution was then exchanged into 50 mM NaHCO3/Na2CO3, pH 8 buffer and recovered in buffer at ˜5 mg/mL as determined by UV-VIS absorbance. 50 μg NHS-ester dye (DyLight 594) was dissolved at 10 mg/mL in anhydrous DMSO, which was then immediately added to 120 μg of polymer. The tube was mixed on shaker (600-800 rpm) for 1 h and subsequently diluted to 100 μL with 20% EtOH in water. The mixture was added to a 30 cm Superdex 200 SEC column in 0.6M NaCl and 20% EtOH to separate polymer-dye conjugate from unreacted dye. The addition of dye can be used to estimate the incorporation of linker on the polymer structure by measuring an absorbance ratio based on the relative extinction coefficients of the polymer and dye. Using the molecular weight of the polymer it is possible to estimate the number of polymer chains which contain a linker. In additional embodiments, polymers with a carboxylic acid side chain are modified with amine functional dyes using standard EDC conjugation procedures or by first converting to the NHS ester using the protocol similar to that described in Example 29. Thiol dyes conjugated to maleimide terminated polymers have also been demonstrated. Any range of chemistry pairs would be expected to work in similar fashion to conjugate a polymer and dye. Example 38b: Preparation of Polymer-Dye Conjugate at Internal Position In a glovebox, 100 mg polymer with internal amine functionalities was dissolved in 10 mL anhydrous DMSO in a 20 mL amber scintillation vial. 0.32 mL DIPEA was added to the polymer solution. 24 mg of NHS-ester dye (Cy3) was dissolved in 2.4 mL in anhydrous DMSO and added to the polymer solution. The vial was tightly sealed, then removed from the glovebox and stirred at room temperature for 48 hours. The reaction was then purified over Amicon Ultra centrifugal filtration units (MWCO=30 kDa) with 20% ethanol in water until all free dye was removed. Purity was verified by running a 0.15 mg sample over a 30 cm Superdex 200 SEC column in 0.6M NaCl and 20% ethanol. 90 mg yield (90%). The addition of dye can be used to estimate the incorporation of linker monomers in the polymer structure by measuring an absorbance ratio based on the relative extinction coefficients of the polymer and dye. For polymers described above, the ratio of linker monomers (or dye attachments) per fluorene monomer in the final polymer are in general agreement with the molar feed ratio of monomers used in the polymerization reaction. Polymers with a carboxylic acid side chain can also be modified with amine functional dyes using standard EDC conjugation procedures or by first converting to the NHS ester using the protocol similar to that described in Example 29. Analogous procedures can be used to conjugate a range of dyes including Cy3, DyLight 549, DyLight 633, FAM, FITC, Alexa633, Alexa647 and several others. Polymers with a carboxylic acid side chain can also be modified with amine functional dyes using standard EDC conjugation procedures. FIG. 21 (A) shows the polymer structure above conjugated to (from left to right) FITC, Cy3, DyLight 594 and DyLight633. The polymer alone is show for reference (far left). Note in each case the amount of residual donor (polymer) emission is minimal. The data highlight the capability of generating several diagnostic signals at different wavelengths for multiplex applications. In this embodiment a single light source is capable of generating five distinct emission wavelengths. Example 38c: Energy Transfer Evaluation for Polymer-Dye Conjugates Based on Polymer Excitation for Use in Polymer Tandem Conjugates FIG. 21 (B) depicts a comparison of the fluorescence of the dye (DyLight594) excited near its absorbance maximum (lower curve) and polymer-dye conjugate excited at 405 nm (upper curve). Dye emission around 620 nm was over 5 fold brighter from the polymer-dye conjugate at the same molar concentration of dye versus direct dye excitation. Such embodiments highlight the signal amplification afforded by the disclosed polymer donors in energy transfer processes. The picture in the upper left corner highlights the visual color change in the emission of the complex based on dye conjugation. The polymer solution emits blue in the absence of dye and red upon dye conjugation (post purification). FIG. 21 (C) compares the fluorescent signal of the base polymer (no dye, peak emission near 420 nm) to that of the polymer-dye conjugate (peak emission near 620 nm). The DyLight594 dye quenches>98% of the polymer emission when conjugated to the polymer above (Example 38b). This is a feature of the polymer materials as any remaining donor emission could manifest as background signal in multiplex assay formats. The ability to conjugate the dye directly to the polymer structure and vary the number of attachment sites provides for efficient transfer that can be regulated by chemical design. Example 39: Flow Testing of Monoclonal Antibody (antiCD4) Conjugates on Whole Lysed Blood Samples Polymer conjugates of primary antiCD4 antibody (RPA-T4 clone) were produced using 3 different conjugation routes as provided in Examples 45, 46 and 49. 1) Amine modified polymer converted to a maleimide reactive group using SMCC (maleimide/NHS crosslinker) reacted with thiol groups on the antibody introduced by reacting SATA (thiol/NHS cross linker) with lysine (amine) groups (CJ11-2, FIG. 22). 2) Same polymer modified with SMCC (malemide) but with thiol groups introduced on antibody using TCEP to partially reduce the disulfide linkages in the antibody (CJ13-2, FIG. 22 and FIG. 20D). 3) A carboxylic acid terminated polymer activated with TSTU to form the NHS ester was reacted directly with the lysine (amine) groups on the antibody (CJ04-2 FIG. 22). All conjugates were made from the same polymer structure and batch. The polymer was synthesized using the protocol depicted in Example 12 with an amine end capping unit in place of the carboxylic acid capping unit shown. The NHS/amine conjugation was done with the protocol described in Example 45. The maleimide/thiol conjugation reactions were done in lines with those protocols described in Examples 46 and 49. FIG. 22 depicts the performance of these conjugates in flow cytometry conduced as follows. 100 μl whole human blood from a healthy volunteer was aliqoted into FACS tubes (duplicates for each sample). Antibody conjugates were diluted in wash buffer (PBS with 0.5% BSA and 0.1% Sodium Azide) and added to the blood at specified concentrations. Samples were vortexed vigorously then incubated for 15-30 mins in the dark at room temperature. 2 ml of 1×BD FACS Lyse solution was added to each sample and mixed in by vigorous vortexing prior to a further 10 mins incubation in the dark at room temperature. Samples were centrifuged for 5 min at 500 g and the supernatant tipped off and discarded. Samples were vortexed and 3 ml of wash buffer (PBS with 0.5% BSA and 0.1% Sodium Azide) added. Centrifugation was repeated at 500 g for a further 5 min. The resulting supernatant was tipped off and discarded and the remaining cell pellet vortexed. Samples were run on a BD LSRII flow cytometer acquiring all violet channels equipped with a violet laser and 450/50 nm filter that had been set up and precalibrated against BD CST beads. All polymer conjugate samples (CJ04-2, CJ11-2 and CJ13-1 lines) showed minimal non specific binding compared to unstained cells. Further, all polymer conjugates produced significantly higher positive signals than a commercially available Pacific Blue control conjugate of the same antibody clone which is commonly used for flow cytometry at compatible wavelengths. The best performing conjugates from this set provided over 6 fold high stain index than the commercially available Pacific Blue control antibody. Example 40: Preparation of Polymer-Dye Conjugate The polymer is conjugated to a dye, Dylight 594, and purified in a manner similar to the methods as described in Example 36. FIG. 23 depicts a comparison of the florescence of the dye (DyLight594) and polymer-dye conjugate. The dye was excited at 594 nm and the polymer-dye conjugate at 380 nm. Example 41: Fluorescent Immunoassay (ELISA) with Streptavidin-Conjugated Polymer An immunoassay for human IgG was developed as a demonstrative system in 96 well plate format. In further embodiments, similar functionality would be equally applicable in other formats including suspended microspheres and protein chip microarrays. Step 1: Preparation of Reagents. Wash concentrate was prepared by dissolving 79.2 g Tris base pre-set crystals (pH 7.7), 225 g sodium chloride and 0.5 g Thimerosol in 1000 mL deionised water. Wash solution was prepared by adding 100 mL wash concentrate to 2400 mL deionised water. Subsequently, 10 mL 10% Triton X-100 was added. The basic assay buffer was prepared by dissolving 14.8 g Tris base pre-set crystals (pH 7.7), 18 g sodium chloride and 0.5 g Thimerosol in 2000 mL Milli-Q water (conductivity 18.2 mΩcm). Subsequently, 2 mL 10% Tween 20 and 10 g Bovine Serum Albumin Fraction V, essentially gamma globulin free were added. The solution was filtered and stored at 4° C. Step 2: Preparation of Capture Antibody Coated Plates. Capture antibody was coated onto the surface of Nunc white Maxisorp 96 well plates at a concentration of approximately imicrogramme per well. The plates were sealed and stored overnight at 4° C. Subsequently, the plates were washed once with wash solution and tapped dry on absorbent paper. Unless otherwise stated all plate washing in this example was performed on an automated microtitre plate washer. Two hundred and fifty (250) microlitres of blocking buffer (0.1M PBS containing 2% BSA) were added to each well, the plates re-sealed and stored at 4° C. until use. Step 3: Immunoassay. Capture antibody-coated microtitre plates were washed twice with wash solution and tapped dry on absorbent paper. Two hundred (200) μL of either assay standard or experimental unknown sample were added in quadruplicate to appropriate wells of the coated plate. The plates were incubated on a shaker for 2 hours at 18° C. Subsequently, the plates were washed three times with wash solution, tapped dry on absorbent paper, and 200 μL of biotinylated detection antibody at a previously determined optimal concentration (diluted in assay buffer and filtered before use) were added to each well. The plates were incubated on an orbital shaker at ambient temperature for a further 60 minutes. The plates were then washed three times and tapped dry on absorbent paper. Two hundred (200) μL of 0.2 micron syringe filtered Streptavidin-polymer conjugate as prepared in Example 30 diluted to a concentration previously determined as suitable in assay buffer. The polymer was a fluorene polymer with neutral PEG11 side chains and an amine conjugation site. The plates were incubated on an orbital shaker at ambient temperature for a further 2 hours. The plates were then washed six times, tapped dry, turned around 180o, and re-washed a further six times. The plates were again tapped dry on absorbent paper. Two hundred (200) μL of filtered release reagent (0.1M sodium hydroxide, 2% Triton X-100) were added using a multi-channel pipette, the plates shaken for 60 minutes at ambient temperature and the fluorescence measured with a Victor Fluorometer. The plate was then sealed, stored overnight at 4° C. and re-read in the Victor Fluorimeter the following morning. Fluorescence counts were analysed using the Multicalc Software from Perkin Elmer to determine lower limit of assay detection and assorted similar parameters. Alternative conditions were also evaluated to release the conjugate from the well plate surface to improve the fluorescent readout. A representative data set is shown in FIG. 24. Comparisons were also made to commercially available SA-dye conjugates. The polymer conjugates demonstrated superior detection limits relative to the dye conjugates as was expected due to the collective optical properties. Example 42: Synthesis, Conjugation and Application of Para-Phenylene Vinylene Co-Polymer with Active Functional Linker for Bioconjugation Poly(1,4-(di2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yl 2,5-dibromoterephthalate)-vinyl-alt-para(2-methoxy-5-2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yl benzene)-vinylene) with phenylbutoxyamino termini. Di-2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yl 2,5-dibromoterephthalate (2.0 g, 1.52 mmol),34-(4-methoxy-2,5-divinylphenoxy)-2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontane (1.11 g, 1.52 mmol), palladium acetate (13.6 mg, 0.061 mmol), tri-o-tolylphosphine (37 mg, 0.121 mmol), triethylamine (1 mL, 7.6 mmol) and 4 mL of DMF were combined in a small round bottom flask, equipped with a Teflon stribar, fitted with a needle valve and transferred to a Schlenk line. The solution was degassed via three freeze-pump-thaw cycles, put under nitrogen and heated to 100 C with constant stirring overnight. Next di-2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yl 2,5-dibromoterephthalate (2.0 g, 1.52 mmol) (100 mg, 5 mol %), palladium acetate (5 mg), and tri-o-tolylphosphine and 0.5 mL DMF were combined in a small round bottom flask which is fitted with a needle valve and transferred to the Schlenk line. The solution was degassed via three cycles of freeze-pump-thaw and once warmed to room temperature was transferred to the polymerization reaction via cannula to exclude air and moisture. Allowed the mixture to react overnight. Next 4-(4-bromophenoxy)butan-1-amine (43 mg, 15 mol %) and 0.5 mL of DMF were combined in a small round bottom flask, equipped with a Teflon stribar, fitted with a needle valve and transferred to a Schlenk line. Once warmed to room temperature the solution was transferred to the polymerization reaction via cannula to exclude air and moisture. Allowed the mixture to react overnight. The next day the reaction was cooled to room temperature and the bulk of triethylamine was removed under vacuum. The reaction mixture was diluted with ˜30 mL of water and filtered through G 6 glass fiber filter paper. The filtrate was transferred to several Amicon filters (10 kDa cutoff) to concentrate the polymer and remove DMF. The remaining water is removed under vacuum and the residue is extracted into methylene chloride. The methylene chloride solution is dried over magnesium sulfate and filtered. The solvent is removed leaving behind a dark red thick oil, approximately 900 mg. The polymer was found to have a Mn of 20,400 g/mol as determined by GPC analysis relative to polystyrene standards. Incorporation of the amine linker was verified by conjugating a dye to the final polymer as described in Example 38. The polymer was then conjugated to streptavidin protein as follows: Amine polymer was dissolved at 50 mg/ml and desalted and buffer exchanged into 100 mM phosphate buffer pH 7.5. Polymer concentration was assessed by absorbance and 25 molar equivalents of SMCC (10 mg/ml in anhydrous DMSO) added. The reaction was mixed for 60 mins at room temperature and then desalted and buffer exchanged into PBS pH7.0+5 mM EDTA prior to repeat polymer concentration determination and confirmation of malemide functionality by SAMSA-fluorescein dye test. Streptavidin (5 mg/ml in 100 mM phosphate buffer pH7.5) was activated by addition of 20 molar equivalents of SATA (5 mg/ml in anhydrous DMSO). The reaction was mixed at room temperature for 60 mins prior to quenching (>15 mins room temp) with 10% (v/v) 50 mM EDTA, 2.5M hydroxylamine pH7.0. The activated protein was desalted and buffer exchanged into the same buffer as the activated polymer prior to an performance of an Ellman's assay to confirm and quantify thiol incorporation. Both the activated polymer and streptavidin were used as follows without delay. A greater than order of magnitude molar excess of SMCC activated polymer was added to the SATA activated streptavidin and the two mixed for 2 hours at room temperature prior to quenching with 20 molar equivalents of N-ethylmaleimide which was mixed in for 15 minutes at room temperature. Ion exchange and size exclusion chromatography were used to purify the bioconjugate of unreacted polymer and streptavidin. Appropriate fractions were pooled to maximize yield and performance and then concentrated by ultrafiltration. The conjugate was tested and its performance compared to a commercially available streptavidin-phycoerythrin (SA-PE) conjugate designed for purpose in a model Luminex xMap assay (FIG. 27, left). Donkey anti-mouse IgG antibody was covalently conjugated to xMap beads. A standard curve titration of Mouse IgG was then performed under standard Luminex xMap assay conditions (FIG. 27, right). Replicate samples were detected using either 4 μg/mL streptavidin-phycoerythrin or streptavidin conjugated polymer conjugate prepared as above (concentration not rigorously controlled). Samples were then read on a Luminex instrument. Absolute signals were found to be lower using the conjugated polymer. This is partially attributed to a non-ideal match between the polymer spectra and the excitation and emission optics in the instrument as well as the putative lower concentration of detection reagent used compared with the commercially available phycoerythrin product. However, the proportional background (non specific signal) from the polymer was also markedly lower resulting in a very comparable lower limit of detection for both detection formats (Fluorescence highest point in standard curve/fluorescence zero concentration of analyte (MFI/zero): 21.8 PE, 26.6 Polymer). Example 43: Synthesis of a Fluorene Co-Polymer with a DPP Band Gap Modifying Unit To a 25 mL round-bottomed flask were added: PEGylated dibromo-DPP monomer (110 mmol), PEGylated fluorene diboronicester (110 mmol), THF (2.4 mL) solvent, 2M K2CO3 (1.6 three freeze-pump-thaw cycles and then stirred under argon at 80 C over night. The resulting mixture was allowed to r.t. and diluted with water. Polymer was collected after dichloromethane extraction. The resulting polymer was found to have an absorption maxima at 520 nm and emission maxima at 590 nm with quantum yield of 6% in water. The polymer had a MW estimated at 16,000 by GPC analysis relative to polystyrene standards and was soluble in water, methanol and dichloromethane. End linker incorporation can be performed using methods similar to those described above and including methods described in Examples 9, 10 and 11. Example 44: Synthesis of a Substituted Divinylbenzene Polymer Methods used to prepare the polymer above were similar to those provided in Example 38. General methods for the preparation of divinylbenzene polymers as disclosed herein may be derived from known reactions in the field as well as methods found herein, and the reactions may be modified by the use of appropriate reagents and conditions, as would be recognized by the skilled person, for the introduction of the various moieties found in the formulae as provided herein. Example 45: Conjugation of Polymer to an Amine on a Primary Antibody Procedure for Production of NHS Ester Polymer-Antibody Conjugate Primary monoclonal antibody, anti-CD4 (RPA-T4 clone) was desalted, and exchanged into 50 mM NaHCO3 buffer, pH 8.2 at 1 mg/mL. Enriched NHS functionalized polymer was dissolved into anhydrous dimethyl sulfoxide (DMSO) at 100 mg/mL. Polymer solution was added at 30 fold molar excess of antibody into the antibody solution and allowed to mix by agitation for 3 hours at RT. Protein concentration was adjusted with buffer prior to incubation to ensure the volume of organic solvent was <10% the total volume. Following ultrafiltration over a 10 KDa MWCO filter device, ion exchange and size exclusion chromatographic techniques were then used to purify the bioconjugate of unreacted polymer and antibody, respectively. Appropriate fractions were pooled to maximize yield and buffer exchanged into PBS+0.05% NaN3 and simultaneously concentrated by ultrafiltration as above. Degree of labeling (indicated as p above) was determined via absorbance at 405 nm and a corrected 280 nm value. The polymer conjugate (CJ04-02) provided in Example 39 (FIG. 22) had an F/P (# of polymers per antibody) of approximately 2.04. This conjugate demonstrated flow performance as determined by stain index measurements which were greater than 3 fold higher than a Pacific Blue control conjugate of the same antibody. Example 46: Conjugation of Polymer to an Antibody Using Malemide/Thiol Chemistry Malemide/Thiol Conjugation of Polymers to Partially Reduced Antibodies Secondary antibody, goat anti-mouse IgG (H+L) was reconstituted in PBS+10 mM acetic acid and desalted/exchanged into 50 mM Tris-HCl buffer, pH7.4 at 1.0 mg/mL. TCEP (tris(2-carboxyethyl)phosphine) was dissolved in 50 mM Tris-HCl buffer, pH7.4, added at 6 molar excess with a final TCEP concentration of 10 mM and mixed for 30 minutes at room temperature. The modified protein was purified over a PD-10 desalting column to remove excess TCEP and exchanged into reaction buffer, 100 mM NaPO4, pH 6.5 reaction buffer with 10 mM EDTA. Amine-activated polymer was dissolved in anyhydrous DMSO at 10 mg/mL and mixed with succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) linker. The linker was added at 50 mg/mL, 20 molar excess in DMSO to the polymer solution and activated by diisopropylethylamine (DIPEA). The reaction was purified over Amicon Ultra centrifugation filters and exchanged into reaction buffer, 100 mM NaPO4, pH 6.5 reaction buffer with 10 mM EDTA. Immediately following disulfide reduction, maleimide functionalized polymer in reaction buffer at 10 mg/mL was added in 20 molar excess of antibody and allowed to mix for 4 hours. Ion exchange and size exclusion chromatographic techniques were then used to purify the bioconjugate of unreacted polymer and antibody, respectively. Degree of labeling (indicated as p above) is determined via absorbance at 405 nm and a corrected 280 nm value. The polymer conjugate provided in Example 36 (FIG. 20B) had an F/P (# of polymers per antibody) of approximately 2. This conjugate demonstrated flow performance as determined by stain index measurements which were greater than 4 fold higher than a Pacific Blue control conjugate of the same antibody. Malemide/Thiol Conjugation of Polymers to Thiol Modified Antibodies Secondary antibody, goat anti-mouse IgG (H+L) was reconstituted in PBS+10 mM acetic acid and desalted/exchanged into 100 mM phosphate pH7.5 buffer. SATA (N-succinimidyl-S-acetylthioacetate) was dissolved anhydrous DMSO, added at 15 molar excess and mixed for 60 minutes at room temperature. After quenching with a hydroxylamine solution, the modified protein was desalted over a PD-10 column to remove excess SATA and exchanged into reaction buffer, 5 mM EDTA, PBS pH 7.0 buffer. Amine-activated polymer was dissolved in anyhydrous DMSO at 10 mg/mL and mixed with succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) linker. The linker was added at 50 mg/mL, 20 molar excess in DMSO to the polymer solution and activated by diisopropylethylamine (DIPEA). The reaction was purified over Amicon Ultra centrifugation filters and exchanged into reaction buffer, 5 mM EDTA, PBS pH 7.0 buffer. Immediately following activation of the antibody, maleimide functionalized polymer in reaction buffer at 10 mg/mL was added in 20 molar excess of antibody and allowed to mix for 4 hours. Ion exchange and size exclusion chromatographic techniques were then used to purify the bioconjugate of unreacted polymer and antibody, respectively. Degree of labeling (indicated as p above) is determined by absorbance at 405 nm and a corrected 280 nm value. The resulting purified conjugates were flow tested in similar fashion as those described in Example 36 for the conjugates prepared using TCEP reduction (data not provided). The polymer structures defined in Example 39 were used to prepare primary antiCD4 (RPA-T4) antibody conjugates in similar fashion to those described in the example above. 30 eq of polymer were reacted with the SATA modified antibody (CJ11-2, FIG. 22) and TCEP reduced antibody (CJ13-1, FIG. 20D and FIG. 22) to produce polymer conjugates for testing in flow cytometry assays after purification. SMCC modified polymers from Examples 23 and 26 were also successfully conjugated to antiCD4 (RPA-T4) and antiCD8 (RPA-T8) antibodies using the TCEP reduction method. DTT reduction was also successfully performed in place of TCEP. Performance in flow cytometry of the antiCD4 and antiCD8 conjugates were evaluated in similar fashion to those described in Example 39 (FIG. 22). Example 47: Polymer Conjugation to a DNA Oligomer Azide Polymer Synthesis for Click Conjugation to Alkyne Terminated DNA Oligo A solution of azidohexanoic acid NHS ester (2.5 mg) in anhydrous DMF (100 μL) was added to a solution of the amine-functional polymer (9.9 mg) in anhydrous DMF (100 μL) under argon. Diisopropylethylamine (2 μL) was then added. The reaction was agitated at room temperature for 15 hours. Water was then added (0.8 mL) and the azide-modified polymer was purified over a NAP-10 column. The eluent was freeze dried overnight. Yield 9.4 mg, 95%. Oligo Synthesis with Pendant Alkyne (Hexyne) for Click Conjugation to Azide Polymer The 3′ propanol oligo A8885 (sequence YATTTTACCCTCTGAAGGCTCCP, where Y=hexynyl group and P=propanol group (SEQ ID NO: 1)) was synthesized using 3′ spacer SynBase™ CPG 1000 column on an Applied Biosystems 394 automated DNA/RNA synthesizer. A standard 1.0 mole phosphoramidite cycle of acid-catalyzed detritylation, coupling, capping and iodine oxidation was used. The coupling time for the standards monomers was 40 s, and the coupling time for the 5′ alkyne monomer was 10 min. The oligo was cleaved from the solid support and deprotected by exposure to concentrated aqueous ammonia for 60 min at room temperature, followed by heating in a sealed tube for 5 h at 55° C. The oligo was then purified by RP-HPLC under standard conditions. Yield 34 OD. Solution Phase Click Conjugation: Probe Synthesis A solution of degassed copper sulphate pentahydrate (0.063 mg) in aqueous sodium chloride (0.2 M, 2.5 μL) was added to a degassed solution of tris-benzo triazole ligand (0.5 mg) and sodium ascorbate (0.5 mg) in aqueous sodium chloride (0.2 M, 12.5 μL). Subsequently, a degassed solution of oligo A8885 (50 nmole) in aqueous sodium chloride (0.2 M, 30 μL) and a degassed solution of azide polymer (4.5 mg) in anhydrous DMF (50 μL) were added, respectively. The reaction was degassed once more with argon for 30 s prior to sealing the tube and incubating at 55° C. for 2 h. Water (0.9 mL) was then added and the modified oligo was purified over a NAP-10 column. The eluent was freeze-dried overnight. The conjugate was isolated as a distinct band using PAGE purification and characterized by mass spectrometry. Yield estimated at 10-20%. Fluorescence Studies The oligo-polymer conjugate was used as a probe in fluorescence studies. The probe was hybridized with the target A8090 (sequence GGAGCCTTCAGAGGGTAAAAT-Dabcyl (SEQ ID NO: 2)), which was labeled with dabcyl at the 3′ end to act as a fluorescence quencher. The target and probe were hybridized, and fluorescence monitored in a Peltier-controlled variable temperature fluorimeter. The fluorescence was scanned every 5° C. over a temperature range of 30 C to 80° C. at a rate of 2° C./min. FIG. 25 shows increasing fluorescence intensity or emission with increasing temperature, indicating that as the probe-target pair melt, the polymer and quencher separate and fluorescence is recovered. Polymer conjugation to nucleic acids can also be performed using methods adapted from the protocols described in Examples 14, 45 and 46. Example 48: Purification of Polymer Antibody Conjugates Polymer antibody conjugates produced via the protocols described in Examples 45, 46 and 49 were purified using a two step method. First ion exchange is used to remove free, unreacted polymer. As the polymers described in this invention do not possess any formal charge they do not bind to the ion exchange media. Proteins (antibodies), however, do contain charged groups and are commonly bound to various ion exchange media for purification. In the examples provided the pH and conductivity of the conjugate solution (post reaction) was lowered to improve the binding of the free antibody and conjugate to the cationic exchange resin. After loading the conjugate, the resin is washed to baseline (measuring both 280 and 407 nm absorbance) to ensure all free polymer is removed. Bound antibody and polymer antibody conjugate are eluted by increasing the pH and ionic strength. A representative example of this separation is provided below in FIG. 26 (left) where the left peak represents the free polymer and the right peak the eluted conjugate and free protein. Removal of free polymer can also be achieved using affinity chromatograph methods in a similar fashion. Specific affinity resin can be used to bind the free protein and conjugate while removing polymer. After the polymer is removed, the conjugate solution is concentrated and loaded on a size exclusion column to separate any un-reacted or free antibody from the polymer. The polymer compositions described in Examples 43 and 44 elute much earlier than then antibodies despite having a lower molecular weight. This is expected to be a result of the rigid polymer structure. The conjugates thus elute well before any free antibody providing near base line separation of the desired conjugate. Isolating fractions near the center of the distribution also ensures no free antibody is included. A representative example of this separation is provided below in FIG. 26 (right) where the left peak represents the conjugate and the small peak on the far right the free antibody. Retention times of the individual components was verified in an independant experiment. Taken together the purification ensures that both free antibody and free polymer are removed. Purity of the resulting conjugates is reasonably estimated at >95%. Pooled samples can be concentrated and concentration measured by absorbance at 280 and 407 nm, being sure to correct for the polymer absorbance at 280 nm. Such measurements also allow for the determination of polymer to antibody labelling ratios (F/P). Example 49: Dye Labeling and Linker Activation of Tandem Polymer Tandem Dye Conjugation In a glovebox, 93 mg tandem polymer (from Example 26) was dissolved at 15 mg/mL in anhydrous DMSO in a glass vial with stir bar. 22.5 mg Cy3-NHS ester was also dissolved at 15 mg/mL in anhydrous DMSO and added to the polymer solution, followed by 0.3 mL diisopropylethylamine. After stirring for 48 h at room temperature, the solution was diluted to 90 mL with 20% EtOH in water and concentrated over Amicon Ultra-15 filters. The retentate was repeatedly diluted and concentrated over the filters until excess Cy3 was removed. 90% yield. Labeling and linker content were validated by measuring and taking the ratio of polymer and dye absorbance as described in Example 38. Amine Modification of Tandem (Aqueous Conditions) 100 mg of polymer-dye conjugate was dissolved at 150 mg/mL in ethanol. This was added dropwise to 6 mL 50 mM MES buffer (pH 5) at 4° C. 38 mg N-hydroxy succinimide was added in one portion, and the solution was stirred to dissolve the solids. After dissolution, 192 mg of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride was added in portions while stirring. After stirring the solution for 30 minutes, 33 μL of ethylene diamine was added. After stirring overnight at room temperature, the solution was diluted to 90 mL with 20% EtOH in water and concentrated over Amicon Ultra-15 filters. The retentate was repeatedly diluted and concentrated over the filters a total of four times to remove impurities. 90% yield, 60% conversion. Linker conversion was verified by conjugating a second dye to the terminal amine as described in Example 38. Tandem Conjugation to a Primary Antibody Primary monoclonal antibody, anti-CD8 (RPA-T8 clone) was desalted/exchanged into 5 mM EDTA, 50 mM phosphate 150 mM NaCl pH 7.0 buffer. TCEP (tris(2-carboxyethyl)phosphine) was dissolved water and added at 12 molar excess and mixed for 90 minutes at 30° C. The modified protein was purified over a PD-10 desalting column to remove excess TCEP and exchanged into 5 mM EDTA, 50 mM phosphate 150 mM NaCl pH 7.0 buffer. Amine-activated tandem polymer was dissolved in ethanol at 50 mg/mL and this solution was mixed with two volumes of 100 mM phosphate pH 7.5 buffer. This solution was then desalted/exchanged into 100 mM phosphate pH 7.5 buffer using a PD-10 desalting column. To this solution was added 25 molar excess of succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) linker (prepared as a 10 mg/ml solution in anhydrous DMSO). The resulting solution was rollermixed at 20° C. for 60 minutes before being desalted/exchanged into 5 mM EDTA, 50 mM phosphate 150 mM NaCl pH 7.0 buffer using a PD-10 desalting column. Immediately following disulfide reduction, the maleimide functionalized polymer was added in 25 molar excess of antibody and allowed to mix for 2 hours at 20° C. Ion exchange and size exclusion chromatographic techniques were then used to purify the bioconjugate of unreacted polymer and antibody, respectively. Degree of labeling (indicated as p below) is determined via absorbance and a corrected 280 nm value. Flow Cytometry Analysis of Polymer Tandem Conjugate in Multicolor Experiment The resulting antiCD8 Tandem conjugate was evaluated on both compensation beads and whole blood samples on a flow cytometer. Anti mouse IgG compensation beads were used to capture the antibody and quantify signal spill over into detection channels (detectors with unique emission filters) other than that intended for the conjugate. FIG. 28 (left) shows the signal measured when the tandem conjugate was excited with a violet laser with emission detected using a 610 nm filter matched to the conjugates emission (labeled QDotA). Crosstalk into the flow cytometer's other channels paired with the violet excitation laser (DAPI-A and AmCyan-A) and two channels off the 488 nm laser (FITC-A and PE-A) are also shown in this panel of the figure. The data show minimal crosstalk in the 450/50 nm filter (DAPI-A) which specifically detects residual polymer (donor) emission. The significantly higher signal from the Cy3 reporter on the Tandem (610 nm filter) relative to the other channels above illustrates that minimal compensation (maximally no more than 6% in this example and case by case often much lower) is required. The Tandem anti CD8 conjugate was subsequently evaluated in a 4 color flow assay with other labeled antibodies (anti CD3 Pacific Blue, anti CD45 Phycoerythrin and anti CD4 fluorescein) on whole human blood from a healthy volunteer using staining and analysis protocols in accord and developed from Example 39. The data in FIG. 28 (right) clearly show the compatibility of the Tandem label with common multicolour flow cytometry instrumentation, reagents and protocols. Specifically, intense and specific staining of CD8 positive lymphocytes is observed and within the CD4 positive subset ready discrimination of CD8 expressive and non expressive cells is clear Collectively the data highlight the viability of the polymer-dye Tandem conjugates in multicolor flow assays as described in the disclosed invention (See, e.g., FIG. 20 and FIG. 22). Example 50: Validation of Non-Ionic Polymer Side Chains for Water Solubility and Flow Cytometry Application A series of different polyfluorene polymers were produced to investigate the interaction of water soluble conjugated polymers with cells. This was done by first synthesizing a range of monomers substituted with different solublizing side chains (e.g., PEG-, sulfonate-, quaternary amine-, zwitterion-substituted) which were then polymerized using Suzuki coupling. The purpose was to determine what influence the side chains had on both non-specific cell binding and polymer solubility in typical buffers used in biological assays, particularly those used in flow cytometry (e.g. PBS and DPBS). The number and property diversity of polymer candidates synthesized made it impractical to produce purified conjugates of each for flow cytometry testing. Thus, a system was developed to score each candidate polymer based on its contribution to non-specific binding to cells. Such a system enabled ranking of polymers, with predictive value on whether they would perform sufficiently once conjugated. A Non-specific Binding (NSB) “Index” was developed around a Jurkat cell model (lymphocyte cell line). In this, cells were incubated with a fixed concentration of each polymer, washed, and analyzed by flow. FIG. 33 displays the outcome following such analysis, and illustrates the wide variation in signal generated by each polymer type. The polymers in FIG. 33 were evaluated with a phtalamide protecting group on the pendant amine with the exception of P9. The data ranks these polymers in terms of signal generated purely by NSB. More accurate assessment of relative NSB was enabled by adjusting further normalizing the flow signal by differences in fluorescence efficiency (crude assessment of quantum yield) of each form of polymer when assayed independently in stain buffer using 405 nm excitation on a fluorometer and monitoring emission in the range of 420-460 nm (to estimate a 440/40 nm filter in the cytometer). Representative polymers P5, P2, P9 and P12 showed increasing NSB relative to unstained cells (far left curve, intensity represented on x-axis). The data in FIG. 34 go on to highlight the difference in polymers produced with neutral, non-ionic PEG side chains (designated P20) verses those which also incorporate anionic side chains (designated P4). The data are histograms collected from flow cytometry analysis (405 nm excitation in a BD LSR-II cytometer) using a Jurkat cell line as in FIG. 33. The panel on the left shows unstained cells and a negative control (cells treated with a non-specific Pacific Blue labeled conjugate) which are the two curves on the far left. Little if any non-specific staining is observed for the Pacific Blue control. In this same panel, however, curve on the right represents cells treated with the anionic P4 polymer and has a clear off set in signal (x-axis) as shown. Conversely the neutral polymer P20 showed almost no off set from the untreated cells which is in line with the Pacific Blue control. The panel in the middle represents a range of different polymer and polymer side chain combinations tested on the same cells. The data highlighted the advantage of neutral side chains. This advantage has also translated to other assay formats including plate based immunoassays and cytometric bead arrays (data not shown). The neutral side chains also unexpectedly resulted in a significant increase in the solubility of the conjugated polymers in aqueous solutions relative to those made previously with ionic side chains. This was particularly true in buffers containing even moderate ionic strength (such as those used in basic cell protocols). The solution quantum yields were also seen to increase, possibly due to the higher aqueous solubility (and less aggregation). The poor solubility in buffers also made protein conjugation more difficult and streptavidin conjugates produced from P4 showed signs of aggregation in typical assay buffers such as phosphate buffered saline (PBS). This was not true of polymers and conjugates produced in other examples disclosed herein. Example 51: Purification and Characterization of Polymer-Avidin Conjugates Gel Analysis of Polymer-Avidin Conjugates To verify successful conjugation to avidin (AvDN), an agarose gel electrophoresis method was developed and used to assess the relative mobility of AvDN as a function of the degree of conjugation with polymer (FIG. 35). Prior to gel loading, the conjugation reaction was stained with biotinyl-fluorescein, which bound polymer-AvDN conjugate and free AvDN. Electrophoresis was performed in 0.8% agarose gels, poured and run in a buffer of 10 mM Sodium Borate, pH 11. The gel was visualized under UV illumination (to visualize the polymer) and by 532 nm excitation (to visualize fluorescein) to assess the degree of conjugation. Under UV illumination, a single band was observed for polymer. Under 532 nm excitation, bands were observed for unbound biotinyl-fluorescein, unreacted AvDN, and polymer-AvDN conjugate which coincided with the free polymer band, indicating that unreacted polymer co-eluted with polymer-AvDN conjugate (FIG. 35). Conjugation was confirmed by the intensity of the conjugate band. The key at the top of the gel images (FIG. 35) indicates which components were included in the conjugation reaction, as well as whether the samples were pre-incubated with biotinyl fluorescein prior to loading and electrophoresis. The image on left visualizes polymer by UV-excitation, whereas the image on right captures the result of fluorescein excitation. On the right image, biotinylated fluorescein can be seen associating with polymer when conjugation was performed in the presence, but not in the absence, of hetero-bifunctional NHS-ethoxy-maleimide linkers (linkers were used to functionalize the polymer amine, while protein amines were partially converted to thiols using Traut's reagent, prior to the maleimide-thiol coupling). Abbreviations: AvDN=avidin DN, AA1=polymer, Linker=hetero-bifunctional NHS-Maleimide linker included in the reaction, Biot-F=biotinyl fluorescein pre-staining before electrophoresis. Purification: Removal of Unreacted Avidin by SEC Chromatography The crude conjugate mixture was fractionated on a Superdex 200 size exclusion column, while fractions were monitored by UV absorbance (FIG. 36, top). To validate the method, fractions were analyzed by agarose gel electrophoresis. As described above, this method of electrophoresis made it possible to visualize the degree to which avidin was attached to polymer, and in this case to analyze the composition of each fraction from the column. Selected fractions were incubated with biotinyl-fluorescein (1 molar equivalent relative to avidin) prior to gel loading, with biotinyl-fluorescein loaded separately as a marker (leftmost lane, FIG. 36, bottom). Electrophoresis was performed in 0.8% agarose gels, poured and run in a buffer of 10 mM Sodium Borate, pH 11. The gel was visualized by 532 nm excitation. Retardation of fluorescein-visualized bands for fractions C2-C6 indicates purified polymer-avidin conjugate, while the two bands observed for fraction C8 indicate a mixture of polymer-avidin conjugate and free avidin. Fractions C10-D2 show only free avidin. Evaluation of Conjugation Efficiency by Gel Analysis In order to determine the best ratio of polymer to streptavidin in conjugation reactions, the molar equivalents of polymer to streptavidin were varied from 0-24 equivalents. Post conjugation, the conjugation products were incubated with biotinyl-fluorescein prior to electrophoresis. The gel was visualized by UV illumination and 532 nm excitation (FIG. 37). At 0 molar equivalents of polymer to streptavidin, free streptavidin is observed as a band with relatively high mobility. As the molar equivalents for polymer are increased from 3 equivalents to 12 equivalents, the free streptavidin band decreases in intensity while the polymer-streptavidin conjugate band increases in intensity. At 24 equivalents of polymer, only the conjugate band is observed by 532 nm excitation. Impact of Purification on Conjugate Performance on Cell Analysis by Flow Cytometry Purification of polymer streptavidin conjugates (polymer structure exemplified in Example 9, denoted P30 in FIG. 38) was performed to determine the impact on flow cytometry performance. Cation-exchange chromatography was implemented in purification to improve removal of excess free polymer. Uncharged polymer eluted in the flow-through while protonated amines on proteins were retained by the media. Thus, streptavidin, whether conjugated to polymer or unreacted, was retained. This ion exchange phase of purification was kept simple with a step gradient, which resulted in co-elution of conjugated and unreacted SA. Further fractionation was enabled by subsequent size-exclusion chromatography, which provided better resolution of conjugate from free SA. Performance benefits in flow cytometry of this new purification method were observed using Jurkat cells incubated with polymer-streptavidin conjugate which were analyzed by flow cytometry. Comparisons were made between crude samples (FIG. 38—top) and purified conjugates (FIG. 38 bottom). Commercially available Pacific Blue-streptavidin conjugates were used as a comparator for brightness, nonspecific binding, and stain index. An improvement in overall Stain Index of approximately 3-fold was shown for Jurkat cells, with similar NSB for both Polymer conjugates and PB-SA based on the histograms shown in FIG. 38. Testing in blood (data not shown) indicated a significant reduction in NSB to levels similar to PB-SA upon conjugate purification. In a separate experiment with a similar polymer (exemplified in Example 11), conjugates with varying polymer to streptavidin ratios were obtained by SEC. Those with the higher ratio provided flow performance relative to those with lower labeling. Ratios were determined based on a ratio of absorbance at 385 nm/280 nm. Relative performance to a Pacific Blue control showed an increase from 10.9 times higher stain index (385/280 ratio of 3.6) to a stain index 13.8 times that of Pacific Blue (A385/280 ratio of 4.7). While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby. | <SOH> BACKGROUND OF THE INVENTION <EOH>Fluorescent hybridization probes have developed into an important tool in the sequence-specific detection of DNA and RNA. The signals generated by the appended fluorescent labels (or dyes) can be monitored in real time and provide simple, rapid, and robust methods for the detection of biological targets and events. Utility has been seen in applications ranging from microarrays and real time PCR to fluorescence in situ hybridization (FISH). Recent work in the area of multichromophores, particularly regarding conjugated polymers (CPs) has highlighted the potential these materials have in significantly improving the detection sensitivity of such methods (Liu and Bazan, Chem. Mater., 2004). The light harvesting structures of these materials can be made water soluble and adapted to amplify the fluorescent output of various probe labels (See U.S. patent application Ser. No. 10/600,286, filed Jun. 20, 2003 and Gaylord, Heeger, and Bazan, Proc. Natl. Acad. Sci., 2002, both of which are incorporated herein by reference in their entirety). Results such as these indicate CPs to be highly promising in the field of nucleic acid diagnostics, particularly where sample quantities are scarce. However, there exist methods for the amplification (or replication) of nucleic acid targets, i.e., PCR. Comparatively, in the field of protein recognition, there are no such simple methods for amplifying the targeted materials. As such, signal enhancement arising from CP application is of high consequence in this area. Dye-labeled antibodies are regularly used for the detection of protein targets in applications such as immunohistochemistry, protein arrays, ELISA tests, and flow cytometry. Integrating CP materials into such methodologies promises to provide a dramatic boost in the performance of such assays, enabling detection levels previously unattainable with conventional fluorescent reporters (e.g., dyes). Beyond addition signal, one of the other key drivers in biological detection formats is the ability to detect multiple analytes in the same test or multiplexing. This is commonly achieved by using fluorescent reporters with operate at different, decernable wavelengths. CP materials are ideally suited to provide a platform for expanded multiplexing. This can be achieved by tuning the structure of different CPs to operate at different wavelengths or by incorporating a dye within the polymer-biomolecule conjugate. The material and methods to produce higher sentivity biological assays and increase multiplexing are highly desired in both molecular (nucleic acid) and immunoassay formats. | <SOH> SUMMARY OF THE INVENTION <EOH>Provided herein are water soluble conjugated polymers of Formula (I): wherein: each R is independently a non-ionic side group capable of imparting solubility in water in excess of 10 mg/mL; MU is a polymer modifying unit or band gap modifying unit that is evenly or randomly distributed along the polymer main chain and is optionally substituted with one or more optionally substituted substituents selected from halogen, hydroxyl, C 1 -C 12 alkyl, C 2 -C 12 alkene, C 2 -C 12 alkyne, C 3 -C 12 cycloalkyl, C 1 -C 12 haloalkyl, C 1 -C 12 alkoxy, C 2 -C 18 (hetero)aryloxy, C 2 -C 18 (hetero)arylamino, (CH 2 ) x′ (OCH 2 CH 2 ) y′ OCH 3 where each x′ is independently an integer from 0-20, y′ is independently an integer from 0 to 50, or a C 2 -C 18 (hetero)aryl group; each optional linker L 1 and L 2 are aryl or hetroaryl groups evenly or randomly distributed along the polymer main chain and are substituted with one or more pendant chains terminated with a functional group for conjugation to another substrate, molecule or biomolecule selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof; G 1 and G 2 are each independently selected from hydrogen, halogen, amine, carbamate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiol, optionally substituted aryl, optionally substituted heteroaryl, halogen substituted aryl, boronic acid substituted aryl, boronic ester substituted aryl, boronic esters, boronic acids, optionally substituted fluorene and aryl or hetroaryl substituted with one or more pendant chains terminated with a functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule; wherein the polymer comprises at least 1 functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, and thiols within G 1 , G 2 , L 1 or L 2 that allows, for functional conjugation to another molecule, substrate or biomolecule; each dashed bond, - - - - - - , is independently a single bond, triple bond or optionally substituted vinylene (—CR 5 ═CR 5 —) wherein each R 5 is independently hydrogen, cyano, C 1 -C 12 alkyl, C 2 -C 12 alkene, C 2 -C 12 alkyne, C 3 -C 12 cycloalkyl or a C 2 -C 18 (hetero)aryl group, wherein each C 1 -C 12 alkyl, C 2 -C 12 alkene, C 2 -C 12 alkyne, C 3 -C 12 cycloalkyl or a C 2 -C 18 (hetero)aryl group is optionally substituted with one or more halogen, hydroxyl, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl group, C 1 -C 12 alkoxy, or C 1 -C 12 haloalkyl; and n is an integer from 1 to about 10,000; and a, b, c and d define the mol % of each unit within the structure which each can be evenly or randomly repeated and where a is a mol % from 10 to 100%, b is a mol % from 0 to 90%, and each c and d are mol % from 0 to 25%. In one aspect, water soluble conjugated polymers of Formula (I) have the structure of Formula (Ia): wherein R, L 1 , L 2 , G 1 , G 2 , MU, a, b, c, d and n are described previously for formula (I). In some embodiments, each R is independently (CH 2 ) x (OCH 2 CH 2 ) y OCH 3 where each x is independently an integer from 0-20, each y is independently an integer from 0 to 50, or a benzyl optionally substituted with one or more halogen, hydroxyl, C 1 -C 12 alkoxy, or (OCH 2 CH 2 ) z OCH 3 where each z is independently an integer from 0 to 50. In some instances, each R is (CH 2 ) 3 (OCH 2 CH 2 ) 11 OCH 3 . In other embodiments, each R is a benzyl substituted with at least one (OCH 2 CH 2 ) 10 OCH 3 group. In some instances, the benzyl is substituted with two (OCH 2 CH 2 ) 10 OCH 3 groups. In other instances, the benzyl is substituted with three (OCH 2 CH 2 ) 10 OCH 3 groups. In some embodiments, optional linkers L 1 or L 2 have the structure: *=Site for covalent attachment to unsaturated backbone; wherein R 3 is independently hydrogen, halogen, alkoxy(C 1 -C 12 ), C 1 -C 12 alkyl, C 2 -C 12 alkene, C 2 -C 12 alkyne, C 3 -C 12 cycloalkyl or a C 2 -C 18 (hetero)aryl group, wherein each C 1 -C 12 alkyl, C 2 -C 12 alkene, C 2 -C 12 alkyne, C 3 -C 12 cycloalkyl or a C 2 -C 18 (hetero)aryl group is optionally substituted with one or more halogen, hydroxyl, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl group, C 1 -C 12 alkoxy, or C 1 -C 12 haloalkyl; and q is an integer from 0 to 4. In other embodiments, optional linkers L 1 or L 2 have the structure: *=site for covalent attachment to unsaturated backbone wherein A is a site for conjugation, chain extension or crosslinking and is —[O—CH 2 —CH 2 ] q —W, or (C 1 -C 12 )alkoxy-X or C 2 -C 18 (hetero)aryl, phenoxy, amido, amino, carbamate, carboxylate, carbonates, sulfide, disulfide, or imido groups terminated with a functional group selected from amine, carbamate, carboxylate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule; W is —OH or —COOH; X is —NH 2 , —NHCOOH, —NHCOOC(CH 3 ) 3 , —NHCO(C 3 -C 12 )cycloalkyl(C 1 -C 4 )alkyl-N-maleimide; or —NHCO[CH 2 —CH 2 —O] t NH 2 ; q is an integer from 1 to 20; and t is an integer from 1 to 8. In yet other embodiments, optional linkers L 1 or L 2 have the structure: *=site for covalent attachment to backbone wherein R 25 are each independently any one of or a combination of a bond, C 1 -C 20 alkyl, C 1 -C 20 alkoxy, C 2 -C 20 alkene, C 2 -C 20 alkyne, C 3 -C 20 cycloalkyl, C 1 -C 20 haloalkyl, (CH 2 ) x (OCH 2 CH 2 ) p (CH 2 ) x where each x is independently an integer from 0-20, p is independently an integer from 0 to 50, aryl, C 2 -C 18 (hetero)aryl, phenoxy, amido, amino, carbamate, carboxylate, carbonates, sulfide, disulfide, or imido groups; wherein at least one R 25 is terminated with a functional group selected from amine, carbamate, carboxylate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule. In further embodiments, optional linkers L 1 or L 2 have the structure: *=site for covalent attachment to unsaturated backbone; wherein R35 is any one of or a combination of a bond, C1-C20 alkyl, C1-C20 alkoxy, C2-C20 alkene, C2-C20 alkyne, C3-C20 cycloalkyl, C1-C20 haloalkyl, (CH2)x(OCH2CH2)p(CH2)x where each x is independently an integer from 0-20, p is independently an integer from 0 to 50, aryl, C2-C18(hetero)aryl, phenoxy, amido, amino, carbamate, carboxylate, carbonates, sulfide, disulfide, or imido groups terminated with a functional group selected from amine, carbamate, carboxylate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule. In further embodiments, optional linkers L 1 or L 2 are selected from the group consisting of a-h having the structures: *=site for covalent attachment to unsaturated backbone; wherein R′ is independently H, halogen, C 1 -C 12 alkyl, (C 1 -C 12 alkyl)NH 2 , C 2 -C 12 alkene, C 2 -C 12 alkyne, C 3 -C 12 cycloalkyl, C 1 -C 12 haloalkyl, C 2 -C 18 (hetero)aryl, C 2 -C 18 (hetero)arylamino, —[CH 2 —CH 2 ]r′—Z 1 , or (C 1 -C 12 )alkoxy-X 1 ; and wherein Z 1 is —OH or —COOH; X 1 is —NH 2 , —NHCOOH, —NHCOOC(CH 3 ) 3 , —NHCO(C3-C12)cycloalkyl(C1-C4)alkyl-N-maleimide; or —NHCO[CH 2 —CH 2 —O] s′ (CH 2 ) s′ NH 2 ; r′ is an integer from 1 to 20; and each s′ is independently an integer from 1 to 20, (CH 2 ) 3 (OCH 2 CH 2 ) x″ OCH 3 where x″ is independently an integer from 0 to 50, or a benzyl optionally substituted with one or more halogen, hydroxyl, C 1 -C 12 alkoxy, or (OCH 2 CH 2 ) y″ OCH 3 where each y″ is independently an integer from 0 to 50 and R′ is different from R; wherein k is 2, 4, 8, 12 or 24; wherein R 15 is selected from the group consisting of l-t having the structure: *=site for covalent attachment to backbone. In yet further embodiments, optional linkers L 1 or L 2 are In some embodiments, G 1 and G 2 are each independently selected from hydrogen, halogen, alkyne, optionally substituted aryl, optionally substituted heteroaryl, halogen substituted aryl, boronic acid substituted aryl, boronic ester substituted aryl, boronic esters, boronic acids, optionally substituted fluorine and aryl or hetroaryl substituted with one or more pendant chains terminated with a functional group, molecule or biomolecule selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule. In some embodiments, G 1 and G 2 each independently have the structure wherein R 11 is any one of or a combination of a bond, C 1 -C 20 alkyl, C 1 -C 20 alkoxy, C 2 -C 20 alkene, C 2 -C 20 alkyne, C 3 -C 20 cycloalkyl, C 1 -C 20 haloalkyl, (CH 2 ) x (OCH 2 CH 2 ) p (CH 2 ) x where each x is independently an integer from 0-20, p is independently an integer from 0 to 50, aryl, C 2 -C 18 (hetero)aryl, phenoxy, amido, amino, carbamate, carboxylate, carbonates, sulfide, disulfide, or imido groups terminated with a functional group selected from amine, carbamate, carboxylate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule. In other embodiments, G 1 and G 2 are each independently selected from the group consisting of 1-31 having the structures: *=site for covalent attachment to backbone wherein R 15 is selected from the group consisting of l-t having the structure: and k is 2, 4, 8, 12 or 24. In further embodiments, G 1 and G 2 are optionally substituted aryl or heteroaryl wherein the optional substituent is selected from halogen, amine, carbamate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiol, boronic acid, boronate radical, boronic esters and optionally substituted fluorene. In some embodiments, G 1 and G 2 are the same. In other embodiments, G 1 and G 2 are different. In further embodiments, the polymer contains a single conjugation site at only one terminus of the polymer chain G 1 or G 2 . In yet further embodiments, G 1 and G 2 is In some embodiments, MU is selected from the group consisting of a′-k′ having the structure: *=site for covalent attachment to unsaturated backbone wherein R is a non-ionic side group capable of imparting solubility in water in excess of 10 mg/mL. In some embodiments, the water soluble conjugated polymer has the structure of formula: wherein at least one of G 1 or G 2 comprises a functional conjugation site. In some embodiments, the water soluble conjugated polymer has the structure of formula: wherein L 1 comprises a functional conjugation site. In some embodiments, the water soluble conjugated polymer has the structure of formula: wherein at least one of G 1 or G 2 comprises a functional conjugation site. In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In some instances, a signaling chromophore is attached to the polymer via the NH 2 group. In certain instances, the signaling chromophore is Cy3 or Dylight 594 dye. In certain instances, the linker, is about 10% of the entire polymer. In other instances, the polymer is conjugated to a secondary dye reporter and an antibody. In some embodiments of conjugated polymers described herein, the polymer is further conjugated to additional molecules. In some embodiments, the polymer is conjugated to a streptavidin, antibody or nucleic acid and used as a direct fluorescent reporter. In certain embodiments, the polymer is conjugated to a streptavidin. In other embodiments, the polymer is conjugated to thiol groups at the hinge region of an antibody. In yet other embodiments, the polymer is conjugated to an amine group on a protein which is modified with a heterobifuntional linker. In further embodiments, the polymer is conjugated to a nucleic acid. In yet further embodiments, the polymer is conjugated to an antibody. In certain instances, the polymer is conjugated to a monoclonal antibody, a secondary antibody or a primary antibody. In other instances, a polymer antibody conjugate is excited at about 405 nm in a flow cytometry assay where the specific signal is at least 3 fold greater than the same antibody conjugated to Pacific Blue. In some embodiments of conjugated polymers described herein, the polymer is purified by ion exchange chromatography. In other embodiments, the polymer is >95% pure. In some embodiments of conjugated polymers described herein, the polymer is used in flow cytometry assays to identify different cell markers or cell types. In other embodiments, the polymer is used to sort cells. In yet other embodiments, the polymer is used to sort cells for use in therapeutics. In some embodiments of conjugated polymers described herein, the polymer is used for intracellular staining. In certain instances, the polymer is used in flow cytometry assays to identify different cell markers or cell types. In some embodiments of conjugated polymers described herein, the polymer comprises a minimum number average molecular weight of greater than 40,000 g/mol and a water solubility of greater than 50 mg/mL in pure water or a phosphate buffered saline solution. In some embodiments of conjugated polymers described herein, the polymer comprises at least two unique conjugation linkers which can conjugated to two unique materials. Also provided herein are assay methods comprising providing a sample that is suspected of containing a target biomolecule; providing a sensor protein conjugated to at least one signaling chromophore and is capable of interacting with the target biomolecule or a target-associated biomolecule; providing a water soluble conjugated polymer described herein; contacting the sample with the sensor protein and the conjugated polymer in a solution under conditions in which the sensor protein can bind to the target biomolecule or a target-associated biomolecule if present; applying a light source to the sample that can excite the conjugated polymer; and detecting whether light is emitted from the signaling chromophore. In some embodiments, the sensor protein is an antibody. In other embodiments, the sensor protein comprises a plurality of sensor proteins conjugated to a plurality of signaling chromophores, wherein at least two of the plurality of chromophores emit different wavelengths of light upon energy transfer from the multichromophore. Also provided herein are conjugated polymer complexes comprising a polymer coupled to at least one biomolecule selected from the group consisting of a sensor biomolecule, a bioconjugate and a target biomolecule wherein the polymer is covalently bound by at least one bioconjugation site pendant thereto, and the polymer comprises a signaling chromophore or a signaling chromophore optionally is covalently bound to the polymer or the sensor biomolecule; wherein the polymer comprises the structure of formula: wherein: each R is a non-ionic side group capable of imparting solubility in water in excess of 10 mg/mL; MU is a polymer modifying unit or band gap modifying unit that is evenly or randomly distributed along the polymer main chain and is optionally substituted with one or more optionally substituted substituents selected from halogen, hydroxyl, C 1 -C 12 alkyl, C 2 -C 12 alkene, C 2 -C 12 alkyne, C 3 -C 12 cycloalkyl, C 1 -C 12 haloalkyl, C 1 -C 12 alkoxy, C 2 -C 18 (hetero)aryloxy, C 2 -C 18 (hetero)arylamino, (CH 2 ) x′ (OCH 2 CH 2 ) y′ OCH 3 where each x′ is independently an integer from 0-20, y′ is independently an integer from 0 to 50, or a C 2 -C 18 (hetero)aryl group; each optional linker L 1 and L 2 are aryl or hetroaryl groups evenly or randomly distributed along the polymer main chain and are substituted with one or more pendant chains terminated with a functional group for conjugation to another molecule, substrate or biomolecule selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof; G 1 and G 2 are each independently selected from hydrogen, halogen, amine, carbamate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiol, optionally substituted aryl, optionally substituted heteroaryl, halogen substituted aryl, boronic acid substituted aryl, boronic ester substituted aryl, boronic esters, boronic acids, optionally substituted fluorene and aryl or hetroaryl substituted with one or more pendant chains terminated with a functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule; wherein the polymer comprises at least 1 functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, and thiols within G 1 , G 2 , L 1 or L 2 that allows, for functional conjugation to another molecule, substrate or biomolecule; n is an integer from 1 to about 10,000; and a, b, c and d define the mol % of each unit within the structure which each can be evenly or randomly repeated and where a is a mol % from 10 to 100%, b is a mol % from 0 to 90%, and each c and d are mol % from 0 to 25%. In some embodiments, the sensor biomolecule is selected from the group consisting of an avidin, streptavidin, neutravidin, avidinDN, and avidinD. In other embodiments, the conjugated polymer complex is further configured to bind to a complex selected from the group consisting of a biotin-labeled antibody, biotin-labeled protein, and biotin-labeled target biomolecule. In further embodiments, the sensor biomolecule is an antibody. In yet further embodiments, both the signaling chromophore and the sensor biomolecule are covalently linked to the multichromophore through a plurality of linkers. In some other embodiments, both the signaling chromophore and the sensor biomolecule are covalently linked to the polymer through a central linking site that covalently binds the polymer, the signaling chromophore and the sensor biomolecule. In yet other embodiments, the signaling chromophore, when covalently bound to the polymer or the sensor biomolecule, is an organic dye. Also provided herein are water soluble conjugated polymer having the structure of Formula (Ia): wherein: each R is independently (CH 2 ) x (OCH 2 CH 2 ) y OCH 3 where each x is independently an integer from 0-20, y is independently an integer from 0 to 50, or a benzyl optionally substituted with one or more halogen, hydroxyl, C 1 -C 12 alkoxy, or (OCH 2 CH 2 ) z OCH 3 where each z is independently an integer from 0 to 50; each optional linker L 1 or L 2 is selected from the group consisting of a-i having the structure *=site for covalent attachment to unsaturated backbone wherein R′ is independently H, halogen, C 1 -C 12 alkyl, (C 1 -C 12 alkyl)NH 2 , C 2 -C 12 alkene, C 2 -C 12 alkyne, C 3 -C 12 cycloalkyl, C 1 -C 12 haloalkyl, C 2 -C 18 (hetero)aryl, C 2 -C 18 (hetero)arylamino, —[CH 2 —CH 2 ] r′ —Z 1 , or (C 1 -C 12 )alkoxy-X 1 ; and wherein Z 1 is —OH or —COOH; X 1 is —NH 2 , —NHCOOH, —NHCOOC(CH 3 ) 3 , —NHCO(C3-C12)cycloalkyl(C1-C4)alkyl-N-maleimide; or —NHCO[CH 2 —CH 2 —O] s′ (CH 2 ) s′ NH 2 ; r′ is an integer from 1 to 20; and each s′ is independently an integer from 1 to 20, (CH 2 ) 3 (OCH 2 CH 2 ) x″ OCH 3 where x″ is independently an integer from 0 to 50, or a benzyl optionally substituted with one or more halogen, hydroxyl, C 1 -C 12 alkoxy, or (OCH 2 CH 2 ) y″ OCH 3 where each y″ is independently an integer from 0 to 50 and R′ is different from R; wherein R 15 is selected from the group consisting of l-t having the structure: and k is 2, 4, 8, 12 or 24; *=site for covalent attachment to backbone MU is a polymer modifying unit or band gap modifying unit that is selected from the group consisting of a′-k′ having the structure: *=site for covalent attachment to unsaturated backbone; wherein R is a non-ionic side group capable of imparting solubility in water in excess of 10 mg/mL; G 1 and G 2 are each independently selected from the group consisting of 1-31 having the structures: wherein the polymer comprises at least 1 functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, and thiols within G 1 , G 2 , L 1 or L 2 that allows, for functional conjugation to another molecule, substrate or biomolecule; n is an integer from 1 to about 10,000; and a, b, c and d define the mol % of each unit within the structure which each can be evenly or randomly repeated and where a is a mol % from 10 to 100%, b is a mol % from 0 to 90%, and each c and d are mol % from 0 to 25%. Also provided herein are water soluble conjugated polymer having the structure of Formula: wherein Ar is an aryl or heteroaryl and is optionally substituted with one or more optionally substituted substituents selected from halogen, hydroxyl, C 1 -C 12 alkyl, C 2 -C 12 alkene, C 2 -C 12 alkyne, C 3 -C 12 cycloalkyl, C 1 -C 12 haloalkyl, C 1 -C 12 alkoxy, C 2 -C 18 (hetero)aryloxy, C 2 -C 18 (hetero)arylamino, (CH 2 ) x′ (OCH 2 CH 2 ) y′ OCH 3 where each x′ is independently an integer from 0-20, y′ is independently an integer from 0 to 50; and dashed bonds, L 1 , L 2 , G 1 , G 2 , MU, a, b, c, d and n are described previously for formula (I). | G01N3358 | 20171031 | 20180419 | 86750.0 | G01N3358 | 1 | TRUONG, DUC | Novel Reagents for Directed Biomarker Signal Amplification | UNDISCOUNTED | 1 | CONT-ACCEPTED | G01N | 2,017 |
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15,800,482 | PENDING | METHOD FOR CONVERTING A TONER CARTRIDGE PRINTER TO A SUBLIMATION TONER PRINTER | A method of converting a standard CMYK color toner printer to a CMYK or CMYW sublimation color toner printer. Providing a standard CMYK color toner printer, comprising four toner printing cartridges: a cyan toner printing cartridge, a magenta toner printing cartridge, a yellow toner printing cartridge, and a black toner printing cartridge. Removing the four toner printing cartridges, such that four empty toner cartridge slots are created. Providing four sublimation toner printing cartridges: a cyan sublimation toner printing cartridge, a magenta sublimation toner printing cartridge, a yellow sublimation toner printing cartridge, and a black sublimation toner printing cartridge, or a white sublimation toner printer cartridge. Installing the four sublimation toner printing cartridges into the four empty toner cartridge slots. | 1. A method of converting a standard CMYK color toner printer to a CMYK sublimation color toner printer, comprising the steps: providing a standard CMYK color toner printer, comprising four toner printing cartridges: a cyan toner printing cartridge, a magenta toner printing cartridge, a yellow toner printing cartridge, and a black toner printing cartridge; removing said four toner printing cartridges, such that four empty toner cartridge slots are created: a cyan toner cartridge slot, a magenta toner cartridge slot, a yellow toner cartridge slot, and a black toner cartridge slot; providing four sublimation toner printing cartridges: a cyan sublimation toner printing cartridge, a magenta sublimation toner printing cartridge, a yellow sublimation toner printing cartridge; and a black sublimation toner printing cartridge; installing said cyan sublimation toner printing cartridge into said cyan toner cartridge slot; installing said magenta sublimation toner printing cartridge into said magenta toner cartridge slot; installing said yellow sublimation toner printing cartridge into said yellow toner cartridge slot; and installing said black sublimation toner printing cartridge into said black toner cartridge slot. 2. The method of claim 1, further comprising the steps: printing a print job onto a transfer material; and transferring said print job to a final print surface via a heat transfer. 3. The method of claim 1, wherein providing said four sublimation toner printing cartridges comprises the steps: disassembling said four removed toner printing cartridges; emptying and cleaning said four removed toner printing cartridges, such that four empty printing cartridges are created; filling said four empty printing cartridges with four sublimation toners: a cyan sublimation toner, a magenta sublimation toner, a yellow sublimation toner, and a black sublimation toner. 4. A method of converting a standard CMYK color toner printer to a CMYW sublimation color toner printer, comprising the steps: providing a standard CMYK color toner printer, comprising four toner printing cartridges: a cyan toner printing cartridge, a magenta toner printing cartridge, a yellow toner printing cartridge, and a black toner printing cartridge; removing said four toner printing cartridges, such that four empty toner cartridge slots are created: a cyan toner cartridge slot, a magenta toner cartridge slot, a yellow toner cartridge slot, and a black toner cartridge slot; wherein said black toner cartridge slot is a first or fourth toner cartridge slot; providing at least three sublimation toner printing cartridges: a cyan sublimation toner printing cartridge, a magenta sublimation toner printing cartridge, and a yellow sublimation toner printing cartridge; providing a white replacement toner printing cartridge; installing said cyan sublimation toner printing cartridge into said cyan toner cartridge slot; installing said magenta sublimation toner printing cartridge into said magenta toner cartridge slot; installing said yellow sublimation toner printing cartridge into said yellow toner cartridge slot; and installing said white replacement toner printing cartridge into said first or fourth toner cartridge slot. 5. The method of claim 4, further comprising the steps: providing raster image processor (RIP) software for printing cartridge remapping. 6. The method of claim 4, further comprising the steps: printing a print job onto a transfer material; and transferring said print job to a final print surface via a heat transfer. 7. The method of claim 4, wherein providing said four sublimation toner printing cartridges comprises the steps: disassembling said four removed toner printing cartridges; emptying and cleaning said four removed toner printing cartridges, such that four empty printing cartridges are created; filling three of said four empty printing cartridges with at least three sublimation toners: a cyan sublimation toner, a magenta sublimation toner, and a yellow sublimation toner; filling said fourth empty printing cartridge with a white replacement toner. 8. A method of converting a standard CMYK color toner printer to a CMYX sublimation color toner printer, comprising the steps: providing a standard CMYK color toner printer, comprising four toner printing cartridges: a cyan toner printing cartridge, a magenta toner printing cartridge, a yellow toner printing cartridge, and a black toner printing cartridge; removing said four toner printing cartridges, such that four empty toner cartridge slots are created: a cyan toner cartridge slot, a magenta toner cartridge slot, a yellow toner cartridge slot, and a black toner cartridge slot; wherein said black toner cartridge slot is a fourth toner cartridge slot; providing at least three sublimation toner printing cartridges: a cyan sublimation toner printing cartridge, a magenta sublimation toner printing cartridge, and a yellow sublimation toner printing cartridge; providing a non-standard toner printing cartridge; installing said cyan sublimation toner printing cartridge into said cyan toner cartridge slot; installing said magenta sublimation toner printing cartridge into said magenta toner cartridge slot; installing said yellow sublimation toner printing cartridge into said yellow toner cartridge slot; and installing said non-standard toner printing cartridge into said fourth toner cartridge slot. 9. The method of claim 8, further comprising the steps: providing raster image processor (RIP) software for printing cartridge remapping. 10. The method of claim 8, further comprising the steps: printing a print job onto a transfer material; and transferring said print job to a final print surface via a heat transfer. 11. The method of claim 8, wherein providing said three sublimation toner printing cartridges comprises the steps: disassembling said three removed toner printing cartridges; emptying and cleaning said three removed toner printing cartridges, such that three empty printing cartridges are created; filling said three empty printing cartridges with three sublimation toners: a cyan sublimation toner, a magenta sublimation toner, and a yellow sublimation toner. 12. The method of claim 11, further comprising the steps: wherein providing said non-standard toner printing cartridge comprises the steps: disassembling said black removed toner printing cartridge; emptying and cleaning said black toner printing cartridge, such that an empty printing cartridge is created; and filling said empty printing cartridge with a non-standard toner. 13. The method of claim 8, wherein said non-standard toner is selected from the group of non-standard toners consisting of: white, metallic, fluorescent, light, clear, clear fluorescent, ceramic, and sublimation. 14. A method of converting a standard CMYKW color toner printer to CMYKW sublimation color toner printer, comprising the steps: providing a standard CMYKW color toner printer, comprising five toner printing cartridges: a cyan toner printing cartridge, a magenta toner printing cartridge, a yellow toner printing cartridge, a black toner printing cartridge; and a white toner printing cartridge; removing said five toner printing cartridges, such that five empty toner cartridge slots are created: a cyan toner cartridge slot, a magenta toner cartridge slot, a yellow toner cartridge slot, a black toner cartridge slot, and a white toner cartridge slot; providing five sublimation toner printing cartridges: a cyan sublimation toner printing cartridge, a magenta sublimation toner printing cartridge, a yellow sublimation toner printing cartridge, a black sublimation toner printing cartridge, and a white sublimation toner printing cartridge; installing said cyan sublimation toner printing cartridge into said cyan toner cartridge slot; installing said magenta sublimation toner printing cartridge into said magenta toner cartridge slot; installing said yellow sublimation toner printing cartridge into said yellow toner cartridge slot; installing said black sublimation toner printing cartridge into said black toner cartridge slot; and installing said white sublimation toner printing cartridge into said white toner cartridge slot. 15. The method of claim 14, further comprising the steps: providing raster image processor (RIP) software for printing cartridge remapping. 16. The method of claim 13, further comprising the steps: printing a print job onto a transfer material; and transferring said print job from said transfer material to a final print surface via a heat transfer. 17. The method of claim 14, wherein the step of providing said five sublimation toner printing cartridges comprises said steps: disassembling said five removed toner printing cartridges; emptying and cleaning said five removed toner printing cartridges, such that five empty printing cartridges are created; filling said five empty printing cartridges with five sublimation toners: a cyan sublimation toner, a magenta sublimation toner, a yellow sublimation toner, a black sublimation toner, and a white sublimation toner. 18. The method of claim 15, further comprising the steps: printing a print job onto a transfer material; wherein a layer of white is overprinted on said print job in a single pass; transferring said print job from said transfer material to a final print surface via a heat transfer, such that said layer of white is under said print job on said final print surface. 19. A method of converting a standard CMYKX color toner printer to a CMYKX sublimation color toner printer, comprising the steps: providing a standard CMYKX color toner printer, comprising five toner printing cartridges: a cyan toner printing cartridge, a magenta toner printing cartridge, a yellow toner printing cartridge, a black toner printing cartridge; and a non-standard toner printing cartridge; removing said five toner printing cartridges, such that five empty toner cartridge slots are created: a cyan toner cartridge slot, a magenta toner cartridge slot, a yellow toner cartridge slot, a black toner cartridge slot, and a non-standard toner cartridge slot; providing at least four sublimation toner printing cartridges: a cyan sublimation toner printing cartridge, a magenta sublimation toner printing cartridge, a yellow sublimation toner printing cartridge, and a black sublimation toner printing cartridge, providing one non-standard toner printing cartridge; installing said cyan sublimation toner printing cartridge into said cyan toner cartridge slot; installing said magenta sublimation toner printing cartridge into said magenta toner cartridge slot; installing said yellow sublimation toner printing cartridge into said yellow toner cartridge slot; installing said black sublimation toner printing cartridge into said black toner cartridge slot; and installing said non-standard toner printing cartridge into said non-standard toner cartridge slot. 20. The method of claim 19, further comprising the steps: providing raster image processor (RIP) software for printing cartridge remapping. 21. The method of claim 19, further comprising the steps: printing a print job onto a transfer material; and transferring said print job from said transfer material to a final print surface via a heat transfer. 22. The method of claim 19, wherein the step of providing said four sublimation toner printing cartridges comprises said steps: disassembling said four removed toner printing cartridges; emptying and cleaning said four removed toner printing cartridges, such that four empty printing cartridges are created; filling said four empty printing cartridges with four sublimation toners: a cyan sublimation toner, a magenta sublimation toner, a yellow sublimation toner, and a black sublimation toner; 23. The method of claim 22, wherein the step of providing said non-standard toner printing cartridge comprises said steps: disassembling said removed non-standard toner printing cartridge; emptying and cleaning said removed non-standard toner printing cartridge, such that an empty non-standard printing cartridge is created; and filling said empty non-standard printing cartridge with a non-standard toner. 24. The method of claim 19, wherein said non-standard toner is selected from the group of non-standard toners consisting of: white, metallic, fluorescent, light, clear, clear fluorescent, ceramic, and sublimation. 25. A method of converting a standard CMYKW color toner printer to a CMYKW sublimation color toner printer, comprising the steps: providing a standard CMYKW color toner printer, comprising five toner printing cartridges: a cyan toner printing cartridge, a magenta toner printing cartridge, a yellow toner printing cartridge, a black toner printing cartridge; and a white toner printing cartridge; removing at least four toner printing cartridges, such that four empty toner cartridge slots are created: a cyan toner cartridge slot, a magenta toner cartridge slot, a yellow toner cartridge slot, and a black toner cartridge slot; providing at least four sublimation toner printing cartridges: a cyan sublimation toner printing cartridge, a magenta sublimation toner printing cartridge, a yellow sublimation toner printing cartridge, and a black sublimation toner printing cartridge; installing said cyan sublimation toner printing cartridge into said cyan toner cartridge slot; installing said magenta sublimation toner printing cartridge into said magenta toner cartridge slot; installing said yellow sublimation toner printing cartridge into said yellow toner cartridge slot; and installing said black sublimation toner printing cartridge into said black toner cartridge slot. 26. The method of claim 25, further comprising the steps: providing raster image processor (RIP) software for printing cartridge remapping. 27. The method of claim 25, further comprising the steps: printing a print job onto a transfer material; and transferring said print job from said transfer material to a final print surface via a heat transfer. 28. The method of claim 25, wherein the step of providing said four sublimation toner printing cartridges comprises said steps: disassembling said four removed toner printing cartridges; emptying and cleaning said four removed toner printing cartridges, such that four empty printing cartridges are created; filling said four empty printing cartridges with four sublimation toners: a cyan sublimation toner, a magenta sublimation toner, a yellow sublimation toner, and a black sublimation toner. 29. The method of claim 26, further comprising the steps: printing a print job onto a transfer material; wherein a layer of white is overprinted on said print job in a single pass; transferring said print job from said transfer material to a final print surface via a heat transfer, such that said layer of white is under said print job on said final print surface. 30. The method of claim 4, wherein said white replacement toner printing cartridge is a regular, non-sublimation specific white toner printing cartridge. 31. The method of claim 4, wherein said white replacement toner printing cartridge is a sublimation white toner printing cartridge. 32. The method of claim 7, wherein said white replacement toner printing cartridge is a regular, non-sublimation specific white toner printing cartridge. 33. The method of claim 7, wherein said white replacement toner printing cartridge is a sublimation white toner printing cartridge. | CROSS-REFERENCE TO RELATED APPLICATIONS This patent application takes priority from U.S. Provisional Patent Application No. 62/470,639, filed on Mar. 13, 2017, titled, Toner Cartridge Printer Devices, Systems, and Methods, by co-inventors Michael Raymond Josiah and Joseph Dovi, the contents of which are expressly incorporated herein by this reference as though set forth in their entirety and to which priority is claimed. This patent application is also a Continuation-in-Part of U.S. Non-Provisional patent application Ser. Nos.: (1) Ser. No. 15/408,186, filed on Jan. 17, 2017, titled, Toner Cartridge Printer Devices, Systems, and Methods For Over Printing and Under Printing, by co-inventors Michael Raymond Josiah and Joseph Dovi; (2) Ser. No. 15/286,998, filed on Oct. 6, 2016, titled, Method and System for Converting a Toner Cartridge Printer to a Double White Toner Printer, by co-inventors Michael Raymond Josiah and Joseph Dovi; (3) Ser. No. 15/286,943, filed on Oct. 6, 2016, titled Method And System For Converting A Toner Cartridge Printer To A White, Clear, Metallic, Fluorescent, Or Light Toner Printer, by co-inventors Michael Raymond Josiah and Joseph Dovi; the contents of all three of which are expressly incorporated herein by this reference as though set forth in their entirety and to which priority is claimed. U.S. Non-Provisional patent application Ser. No. 15/408,186 is a Continuation-in-Part Application of U.S. Non-Provisional patent application Ser. No. 15/286,875, filed on Oct. 6, 2016, titled, Method and System for Converting a Toner Cartridge Printer to a Metallic, Clear Fluorescent, or Light Toner Printer, by co-inventors Michael Raymond Josiah and Joseph Dovi, the contents of which are expressly incorporated herein by this reference as though set forth in their entirety and to which priority is claimed, U.S. Non-Provisional patent application Ser. No. 15/286,875 is a Continuation-in-Part of U.S. Non-Provisional patent application Ser. No. 14/879,548, now U.S. Pat. No. 9,488,932, filed on Oct. 9, 2015, titled, Method and System for Converting a Toner Cartridge Printer to a White, Clear, or Fluorescent Toner Printer, by co-inventors Michael Raymond Josiah and Joseph Dovi, the contents of which are expressly incorporated herein by this reference as though set forth in their entirety and to which priority is claimed. U.S. Non-Provisional patent application Ser. No. 14/879,548 is a Continuation-in-Part of U.S. Non-Provisional patent application Ser. No. 14/731,785, now U.S. Pat. No. 9,383,684, filed on Jun. 5, 2015, titled, Method and System for Converting a Toner Cartridge Printer to a White Toner Printer, by co-inventors Michael Raymond Josiah and Joseph Dovi, the contents of which are expressly incorporated herein by this reference as though set forth in their entirety and to which priority is claimed. The patent application is also a Continuation-in-Part Application. FIELD OF USE The present disclosure relates generally to printer cartridge replacement. More specifically, this disclosure relates to methods and systems of converting a standard toner cartridge printer to a printer that prints with sublimation toner. BACKGROUND Traditional Cyan (C), Magenta (M), Yellow (Y), and Black (K) (or CMYK) laser or Light Emitting Diode (LED) type printers come standard with Cyan, Magenta, Yellow, and Black toner and/or drum cartridges. However, traditional black toner printers and CMYK toner printers are generally used in surface printing of materials, including direct-to-fabric printing, but do not become part of the fabric like dye sublimation printings does. Dye sublimation printing works by heating a special type of solid ink. This is different from traditional printing techniques, such as traditional inkjet, CMYK laser, or LED type printers, which spray liquid ink onto a page or surface, staining it (as in the case of inkjet) or transferring a dry ink (toner) to a page or surface and heat pressing the toner into the page or surface. Instead, dye sublimation printing heats up the solid ink, causing it to turn into gas vapors. These vapors make their way into the target surface, where they then turn back into solid form. The target surface may be transfer paper, which is coupled to a piece of polyester or another synthetic fabric, and then fed through heated rollers that combine heat with pressure to expand the cells of the fabric and convert the dye to a gaseous state. The dye is sublimated into the open pores of the polymeric synthetic materials, and as it cools again, traps the sublimated dye within the cells of the fabric. Because the dye became gaseous, it does not create a dot pattern during the sublimation process like traditional printing techniques, rather it creates a continuous tone print that creates brighter and smoother color variations and transitions, and a superior overall look. Thus, there is a need for a method for converting or retrofitting a standard CMYK (four cartridge) or CMYKW (five cartridge) toner printer to print using sublimation toner. SUMMARY OF EMBODIMENTS To minimize the limitations in the cited references, and to minimize other limitations that will become apparent upon reading and understanding the present specification, the toner cartridge printer methods disclosed herein preferably allow a user to convert a standard printer into one that prints using sublimation toner. In various embodiments, the methods may be used to convert a traditional toner cartridge(s) and/or drum(s) printing machine to a printing machine that prints sublimation toner from one or more of the toner cartridge(s). One embodiment may be a method of converting a standard CMYK color toner printer to a CMYK sublimation color toner printer. A standard CMYK color toner printer may be provided and may comprise four toner printing cartridges. The four toner printing cartridges may comprise a cyan toner printing cartridge, a magenta toner printing cartridge, a yellow toner printing cartridge, and a black toner printing cartridge. The four toner printing cartridges may be removed such that four empty toner cartridge slots are created, and may comprise a cyan toner cartridge slot, a magenta toner cartridge slot, a yellow toner cartridge slot, and a black toner cartridge slot. Four sublimation toner printing cartridges may be provided and may comprise a cyan sublimation toner printing cartridge, a magenta sublimation toner printing cartridge, a yellow sublimation toner printing cartridge, and a black sublimation toner printing cartridge. The cyan sublimation toner printing cartridge may be installed into the cyan toner cartridge slot. The magenta sublimation toner printing cartridge may be installed into the magenta toner cartridge slot. The yellow sublimation toner printing cartridge may be installed into the yellow toner cartridge slot. The black sublimation toner printing cartridge may be installed into the black toner cartridge slot. A print job may be printed onto a transfer material and the print job may be transferred to a final print surface via a heat transfer. The four sublimation toner printing cartridges may comprise disassembling the four toner printing cartridges, emptying and cleaning the four toner printing cartridges, such that four empty printing cartridges may be created, and filling the four empty printing cartridges with four sublimation toners: a cyan sublimation toner, a magenta sublimation toner, a yellow sublimation toner, and a black sublimation toner. Another embodiment may be a method of converting a standard CMYK color toner printer to a CMYW sublimation color toner printer. A standard CMYK color toner printer may be provided and may comprise four toner printing cartridges. The four toner printing cartridges may comprise a cyan toner printing cartridge, a magenta toner printing cartridge, a yellow toner printing cartridge, and a black toner printing cartridge. The four toner printing cartridges may be removed such that four empty toner cartridge slots are created and may comprise a cyan toner cartridge slot, a magenta toner cartridge slot, a yellow toner cartridge slot, and a black toner cartridge slot. The black toner cartridge slot may be a fourth toner cartridge slot. Four sublimation toner printing cartridges may be provided and may comprise a cyan sublimation toner printing cartridge, a magenta sublimation toner printing cartridge, a yellow sublimation toner printing cartridge, and a white sublimation toner printing cartridge. The cyan sublimation toner printing cartridge may be installed into the cyan toner cartridge slot. The magenta sublimation toner printing cartridge may be installed into the magenta toner cartridge slot. The yellow sublimation toner printing cartridge may be installed into the yellow toner cartridge slot. The white sublimation toner printing cartridge may be installed into the fourth toner cartridge slot. Raster image processor (RIP) software may be provided for printing cartridge remapping. A print job may be printed onto a transfer material and the print job may be transferred to a final print surface via a heat transfer. The four sublimation toner printing cartridges may comprise disassembling the four toner printing cartridges, emptying and cleaning the four toner printing cartridges, such that four empty printing cartridges may be created, and filling the four empty printing cartridges with four sublimation toners: a cyan sublimation toner, a magenta sublimation toner, a yellow sublimation toner, and a white sublimation toner. Another embodiment may be a method of converting a standard CMYK color toner printer to a CMYX sublimation color toner printer. A standard CMYK color toner printer may be provided and may comprise four toner printing cartridges. The four toner printing cartridges may comprise a cyan toner printing cartridge, a magenta toner printing cartridge, a yellow toner printing cartridge, and a black toner printing cartridge. The four toner printing cartridges may be removed such that four empty toner cartridge slots are created and may comprise a cyan toner cartridge slot, a magenta toner cartridge slot, a yellow toner cartridge slot, and a black toner cartridge slot. The black toner cartridge slot may be a fourth toner cartridge slot. At least three sublimation toner printing cartridges may be provided and may comprise a cyan sublimation toner printing cartridge, a magenta sublimation toner printing cartridge, a yellow sublimation toner printing cartridge. A non-standard toner printing cartridge may also be provided. The cyan sublimation toner printing cartridge may be installed into the cyan toner cartridge slot. The magenta sublimation toner printing cartridge may be installed into the magenta toner cartridge slot. The yellow sublimation toner printing cartridge may be installed into the yellow toner cartridge slot. The non-standard toner printing cartridge may be installed into the fourth toner cartridge slot. Raster image processor (RIP) software may be provided for printing cartridge remapping. A print job may be printed onto a transfer material and the print job may be transferred to a final print surface via a heat transfer. The three sublimation toner printing cartridges may comprise disassembling the three toner printing cartridges, emptying and cleaning the three toner printing cartridges, such that three empty printing cartridges may be created, and filling the three empty printing cartridges with three sublimation toners: a cyan sublimation toner, a magenta sublimation toner, and a yellow sublimation toner. The non-standard toner printing cartridge may comprise disassembling the black toner printing cartridge, emptying and cleaning the black toner printing cartridge, such that an empty printing cartridges may be created, and filling the empty printing cartridges with a non-standard toner. The non-standard toner may be selected from the group of non-standard toners consisting of: white, metallic, fluorescent, light, clear, clear fluorescent, ceramic, and sublimation. Another embodiment may be a method of converting a standard CMYKW color toner printer to a CMYKW sublimation color toner printer. A standard CMYKW color toner printer may be provided and may comprise five toner printing cartridges. The five toner printing cartridges may comprise a cyan toner printing cartridge, a magenta toner printing cartridge, a yellow toner printing cartridge, a black toner printing cartridge, and a white toner printing cartridge. The five toner printing cartridges may be removed such that five empty toner cartridge slots are created and may comprise a cyan toner cartridge slot, a magenta toner cartridge slot, a yellow toner cartridge slot, a black toner cartridge slot, and a white toner cartridge slot. Five sublimation toner printing cartridges may be provided and may comprise a cyan sublimation toner printing cartridge, a magenta sublimation toner printing cartridge, a yellow sublimation toner printing cartridge, a black sublimation toner printing cartridge, and a white sublimation toner printing cartridge. The cyan sublimation toner printing cartridge may be installed into the cyan toner cartridge slot. The magenta sublimation toner printing cartridge may be installed into the magenta toner cartridge slot. The yellow sublimation toner printing cartridge may be installed into the yellow toner cartridge slot. The black sublimation toner printing cartridge may be installed into the black toner cartridge slot. The white sublimation toner printing cartridge may be installed into the white toner cartridge slot. Raster image processor (RIP) software may be provided for printing cartridge remapping. A print job may be printed onto a transfer material and the print job may be transferred to a final print surface via a heat transfer. The five sublimation toner printing cartridges may comprise disassembling the five toner printing cartridges, emptying and cleaning the five toner printing cartridges, such that five empty printing cartridges may be created, and filling the five empty printing cartridges with five sublimation toners: a cyan sublimation toner, a magenta sublimation toner, a yellow sublimation toner, a black sublimation toner, and a white sublimation toner. A print job may be printed onto a transfer material wherein a layer of white is overprinted on the print job in a single pass. The print job may be transferred from the transfer material to a final print surface via a heat transfer, such that the layer of white is under the print job on the final print surface. Another embodiment may be a method of converting a standard CMYKX color toner printer to a CMYKX sublimation color toner printer. A standard CMYKX color toner printer may be provided and may comprise five toner printing cartridges. The five toner printing cartridges may comprise a cyan toner printing cartridge, a magenta toner printing cartridge, a yellow toner printing cartridge, a black toner printing cartridge, and a non-standard toner printing cartridge. The five toner printing cartridges may be removed such that five empty toner cartridge slots are created and may comprise a cyan toner cartridge slot, a magenta toner cartridge slot, a yellow toner cartridge slot, a black toner cartridge slot, and a non-standard toner cartridge slot. At least four sublimation toner printing cartridges may be provided and may comprise a cyan sublimation toner printing cartridge, a magenta sublimation toner printing cartridge, a yellow sublimation toner printing cartridge, and a black sublimation toner printing cartridge. A non-standard toner cartridge may also be provided. The cyan sublimation toner printing cartridge may be installed into the cyan toner cartridge slot. The magenta sublimation toner printing cartridge may be installed into the magenta toner cartridge slot. The yellow sublimation toner printing cartridge may be installed into the yellow toner cartridge slot. The black sublimation toner printing cartridge may be installed into the black toner cartridge slot. The non-standard toner printing cartridge may be installed into the non-standard toner cartridge slot. Raster image processor (RIP) software may be provided for printing cartridge remapping. A print job may be printed onto a transfer material and the print job may be transferred to a final print surface via a heat transfer. The four sublimation toner printing cartridges may comprise disassembling the four toner printing cartridges, emptying and cleaning the four toner printing cartridges, such that four empty printing cartridges may be created, and filling the four empty printing cartridges with four sublimation toners: a cyan sublimation toner, a magenta sublimation toner, a yellow sublimation toner, and a black sublimation toner. The non-standard toner printing cartridge may comprise disassembling the non-standard toner printing cartridge, emptying and cleaning the toner printing cartridge, such that an empty non-standard printing cartridge may be created, and filling the empty non-standard printing cartridge with a non-standard toner. The non-standard toner may be selected from the group of non standard toners consisting of: white, metallic, fluorescent, light, clear, clear fluorescent, ceramic, and sublimation. Another embodiment may be a method of converting a standard CMYKW color toner printer to a CMYKW sublimation color toner printer. A standard CMYKW color toner printer may be provided and may comprise five toner printing cartridges. The five toner printing cartridges may comprise a cyan toner printing cartridge, a magenta toner printing cartridge, a yellow toner printing cartridge, a black toner printing cartridge, and a white toner printing cartridge. Four toner printing cartridges may be removed such that four empty toner cartridge slots are created and may comprise a cyan toner cartridge slot, a magenta toner cartridge slot, a yellow toner cartridge slot, and a black toner cartridge slot. Four sublimation toner printing cartridges may be provided and may comprise a cyan sublimation toner printing cartridge, a magenta sublimation toner printing cartridge, a yellow sublimation toner printing cartridge, and a black sublimation toner printing cartridge. The cyan sublimation toner printing cartridge may be installed into the cyan toner cartridge slot. The magenta sublimation toner printing cartridge may be installed into the magenta toner cartridge slot. The yellow sublimation toner printing cartridge may be installed into the yellow toner cartridge slot. The black sublimation toner printing cartridge may be installed into the black toner cartridge slot. Raster image processor (RIP) software may be provided for printing cartridge remapping. A print job may be printed onto a transfer material and the print job may be transferred to a final print surface via a heat transfer. The four sublimation toner printing cartridges may comprise disassembling the four toner printing cartridges, emptying and cleaning the four toner printing cartridges, such that four empty printing cartridges may be created, and filling the four empty printing cartridges with four sublimation toners: a cyan sublimation toner, a magenta sublimation toner, a yellow sublimation toner, and a black sublimation toner. A print job may be printed onto a transfer material wherein a layer of white is overprinted on the print job in a single pass. The print job may be transferred from the transfer material to a final print surface via a heat transfer, such that the layer of white may be under the print job on the final print surface. Additional embodiments of the invention will be understood from the detailed description of the illustrative embodiments. BRIEF DESCRIPTION OF THE DRAWINGS The drawings are of illustrative embodiments. They do not illustrate all embodiments. Other embodiments may be used in addition or instead. Details which may be apparent or unnecessary may be omitted to save space or for more effective illustration. Some embodiments may be practiced with additional components or steps and/or without all of the components or steps, which are illustrated. When the same numeral appears in different drawings, it refers to the same or like components or steps. FIG. 1 is a flow block diagram of one embodiment of a method of converting a standard CMYK color toner printer to a CMYK sublimation color toner printer. FIG. 2 is a flow block diagram of one embodiment of a method of converting a standard CMYK color toner printer to a CMYW sublimation color toner printer. FIG. 3 is a flow block diagram of one embodiment of a method of converting a standard CMYK color toner printer to a CMYX sublimation color toner printer. FIG. 4 is a flow block diagram of one embodiment of a method of converting a standard CMYKW color toner printer to a CMYKW sublimation color toner printer. FIG. 5 is a flow block diagram of one embodiment of a method of converting a standard CMYKX color toner printer to a CMYKX sublimation color toner printer. FIG. 6 is a flow block diagram of another embodiment of a method of converting a standard CMYKW color toner printer to a CMYKW sublimation color toner printer. DETAILED DESCRIPTION OF THE ILLUSTRATIVE EMBODIMENTS In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of various aspects of one or more embodiments. However, these embodiments may be practiced without some or all of these specific details. In other instances, well-known methods, procedures, and/or components have not been described in detail so as not to unnecessarily obscure aspects of embodiments. While multiple embodiments are disclosed, still other embodiments will become apparent to those skilled in the art from the following detailed description. As will be realized, these embodiments are capable of modifications in various obvious aspects, all without departing from the spirit and scope of protection. Accordingly, the screen shots, figures, and the detailed descriptions thereof, are to be regarded as illustrative in nature and not restrictive. Also, the reference or non-reference to a particular embodiment shall not be interpreted to limit the scope of protection. In the following description, certain terminology is used to describe certain features of one or more embodiments. For purposes of the specification, unless otherwise specified, the term “substantially” refers to the complete or nearly complete extent or degree of an action, characteristic, property, state, structure, item, or result. For example, in one embodiment, an object that is “substantially” located within a housing would mean that the object is either completely within a housing or nearly completely within a housing. The exact allowable degree of deviation from absolute completeness may in some cases depend on the specific context. However, generally speaking, the nearness of completion will be so as to have the same overall result as if absolute and total completion were obtained. The use of “substantially” is also equally applicable when used in a negative connotation to refer to the complete or near complete lack of an action, characteristic, property, state, structure, item, or result. As used herein, the terms “approximately” and “about” generally refer to a deviance of within 15% of the indicated number or range of numbers. In one embodiment, the term “approximately” and “about”, refer to a deviance of between 0.0001-40% from the indicated number or range of numbers. The present specification discloses methods for converting a toner cartridge printer to a sublimation toner printer. The methods for converting a toner cartridge printer to a sublimation toner printer preferably require no special or dedicated printer drivers. In the following description, certain terminology is used to describe certain features of one or more embodiments. For purposes of the specification, unless otherwise specified, the term “printing cartridge(s)” generally refers to a toner cartridge, a laser toner cartridge, a LEI) toner cartridge, a drum cartridge, and/or a combined toner and drum cartridge. As used herein, the term “toner” generally refers to a powder, particulate, or dry ink that is used in laser printers, printers, and printing machines to form the printed text and images on the medium being printed. Generally, toner particles are melted by the heat of a fuser, and bound to the media. Regarding a CMYK printer, the letter “K” preferably stands for black. Regarding a CMYKW printer, the letter “W” preferably stands for white, but may also refer to a non-standard toner or toner color, such as white, clear, clear fluorescent, and/or metallic. Regarding a CMYKX printer, the letter “X” refers to a non-standard toner or toner color, such as white, metallic, fluorescent, light, clear, clear fluorescent, ceramic, and/or sublimation. The term transfer material may typically refer to a polyurethane media that accepts the toner print job and then allows the print job to be transferred to a final print surface via heat transfer. The transfer material may also be constructed from any suitable material, such as a specially coated paper or even just plain paper. The final print surface is preferably plastic or polymer, such as, for example, a polyester shirt or product. FIG. 1 is a flow block diagram of one embodiment of a method of converting a standard CMYK color toner printer to a CMYK sublimation color toner printer. As shown in FIG. 1, the method 100 of converting a standard CMYK color toner printer to a CMYK sublimation color toner printer, may comprise providing a standard CMYK color toner printer with four toner printing cartridges: a cyan toner printing cartridge, a magenta toner printing cartridge, a yellow toner printing cartridge, and a black toner printing cartridge 105. Preferably, the CMYK printer is a LED printer. The CMYK printer provided may have the following configurations: Configuration 1: Black—First Yellow—Second Magenta—Third Cyan—Fourth Configuration 2: Cyan—First Magenta-Section Yellow—Third Black—Fourth In this configuration, the toner is transferred to the transfer belt first and then to the media. Configuration 3: Yellow—First Magenta—Second Cyan—Third Black—Fourth In various embodiments, any one of the cartridges may be in any of the four cartridge slots. In various embodiments, the black toner printing cartridge may be in the fourth toner cartridge slot or the first toner cartridge slot. The cartridges and slots may also be referred to by their position: a first toner cartridge, a second toner cartridge, a third toner cartridge, and a fourth toner cartridge; and a first toner cartridge slot, a second toner cartridge slot, a third toner cartridge slot, and a fourth toner cartridge slot. The method 100 may further comprise removing the four toner printing cartridges, such that four empty toner cartridge slots are created: a cyan toner cartridge slot, a magenta toner cartridge slot, a yellow toner cartridge slot, and a black toner cartridge slot 110. Four sublimation toner printing cartridges may be provided. Preferably, the four sublimation toner printing cartridges comprise: a cyan sublimation toner printing cartridge, a magenta sublimation toner printing cartridge, a yellow sublimation toner printing cartridge, and a black sublimation toner printing cartridge 115. The cyan sublimation toner printing cartridge may be installed into the cyan toner cartridge slot, the magenta sublimation toner printing cartridge may be installed into the magenta toner cartridge slot, the yellow sublimation toner printing cartridge may be installed into the yellow toner cartridge slot, and the black sublimation toner printing cartridge may be installed into the black toner cartridge slot 120. The method 100 may further comprise printing a print job onto a transfer material 125. The transfer material may comprise a polyurethane media that accepts the toner print job and then allows the print job to be transferred to a final print surface via heat transfer 130. The final print surface is preferably plastic or polymer, such as, for example, a polyester shirt or product. In some embodiments, the print job may be directly printed onto the final print surface without the need for an intermediate transfer material. In some embodiments, the steps of providing the four sublimation toner printing cartridges may further comprise: disassembling the four removed toner printing cartridges; emptying and cleaning the four removed toner printing cartridges, such that four empty printing cartridges may be created. The four empty printing cartridges may be filled with four sublimation color toners. Preferably, the four sublimation toners may comprise: a cyan sublimation toner, a magenta sublimation toner, a yellow sublimation toner, and a black sublimation toner 135. The modified printer may be converted back to a traditional CMYK printer by removing the sublimation toner printing cartridges and/or drum cartridges from the four slots in the CMYK printer and re-installing the regular cyan, yellow, magenta, and black toner printing cartridges and/or drum cartridge into their original positions. FIG. 2 is a flow block diagram of one embodiment of a method of converting a standard CMYK color toner printer to a CMYW sublimation color toner printer. As shown in FIG. 2, the method 200 of converting a standard CMYK color toner printer to a CMYW sublimation color toner printer, may comprise providing a standard CMYK color toner printer with four toner printing cartridges: a cyan toner printing cartridge, a magenta toner printing cartridge, a yellow toner printing cartridge, and a black toner printing cartridge 205. In some embodiments, the CMYK printer may be a LED printer. The CMYK printer provided may have the following configurations: Configuration 1: Black—First Yellow—Second Magenta—Third Cyan—Fourth Configuration 2: Cyan—First Magenta—Section Yellow—Third Black—Fourth In this configuration, the toner is transferred to the transfer belt first and then to the media. Configuration 3: Yellow—First Magenta—Second Cyan—Third Black—Fourth In various embodiments, the black toner printing cartridge may be in the fourth toner cartridge slot or the first toner cartridge slot. The cartridges and slots may also be referred to by their position: a first toner cartridge, a second toner cartridge, a third toner cartridge, and a fourth toner cartridge; and a first toner cartridge slot, a second toner cartridge slot, a third toner cartridge slot, and a fourth toner cartridge slot. The method 200 may further comprise removing the four toner printing cartridges, such that four empty toner cartridge slots are created: a cyan toner cartridge slot, a magenta toner cartridge slot, a yellow toner cartridge slot, and a black toner cartridge slot 210. In one embodiment, the black toner printing cartridge may be in the fourth toner cartridge slot or the first toner cartridge slot. Three or four sublimation toner printing cartridges may be provided. Preferably, three of the sublimation toner printing cartridges comprise: a cyan sublimation toner printing cartridge, a magenta sublimation toner printing cartridge, and a yellow sublimation toner printing cartridge; the fourth toner printing cartridge may be a white replacement toner printing cartridge 215. In some embodiments, the white replacement toner printing cartridge is regular, non-sublimation specific toner. In other embodiments, the white replacement toner printing cartridge is white sublimation toner. The cyan sublimation toner printing cartridge may be installed into the cyan toner cartridge slot, the magenta sublimation toner printing cartridge may be installed into the magenta toner cartridge slot, the yellow sublimation toner printing cartridge may be installed into the yellow toner cartridge slot, and the white replacement toner printing cartridge may be installed into the first or fourth toner cartridge slot 220 (depending on the configuration of the printer being converted). The method 200 may further comprise providing raster image processor (RIP) software for printing cartridge remapping 222 and printing a print job onto a transfer material 225. The transfer material may comprise a polyurethane media that accepts the toner print job and then allows the print job to be transferred to a final print surface via heat transfer 230. In some embodiments, the print job may be directly printed/sublimated onto the final print surface without the need for an intermediate transfer material. In some embodiments, the steps of providing the four sublimation toner printing cartridges may comprise: disassembling the four removed toner printing cartridges; emptying and cleaning the four removed toner printing cartridges, such that four empty printing cartridges may be created. The four empty printing cartridges may be filled with four sublimation toners. The four sublimation toners may comprise: a cyan sublimation toner, a magenta sublimation toner, a yellow sublimation toner, and a white sublimation toner 235. Alternatively, and preferably, three sublimation toners and one regular toner may be put into the four empty cartridge slots: a cyan sublimation toner, a magenta sublimation toner, a yellow sublimation toner, and a white non-sublimation toner Regarding the RIP software, the RIP software utilizes printing cartridge mapping to enable the ability to move, change or swap printing cartridge locations in the printer. This allows white under printing or over printing in a single pass. The RIP software may also add a customizable separate layer of white either on top or underneath the image depending on the cartridge configuration and printing needs. This fully customizable feature in the software (RIP) allows you to completely reconfigure the printer to get almost any desired effect. However, in a preferred embodiment, a white toner foreground layer may be printed when the white toner is place in the last printing cartridge position. The RIP software may also be configured to allow the user to print in full color, CMY black, and white, such that the white prints with the other colors at the same time in a single layer. Preferably, the single layer is put down in a single pass. Black may be printed by combining all three of the color print colors. FIG. 3 is a flow block diagram of one embodiment of a method of converting a standard CMYK color toner printer to a CMYX sublimation color toner printer. As shown in FIG. 3, the method 300 of converting a standard CMYK color toner printer to a CMYX sublimation color toner printer, may comprise providing a standard CMYK color toner printer with four toner printing cartridges: a cyan toner printing cartridge, a magenta toner printing cartridge, a yellow toner printing cartridge, and a black toner printing cartridge 305. In one embodiment, the CMYK printer may be a LED printer. The method 300 may further comprise removing the four toner printing cartridges, such that four empty toner cartridge slots are created: a cyan toner cartridge slot, a magenta toner cartridge slot, a yellow toner cartridge slot, and a black toner cartridge slot 310. In one embodiment, the black toner printing cartridge may be in the fourth toner cartridge slot. At least three sublimation toner printing cartridges may be provided. Preferably, the three sublimation toner printing cartridges comprise: a cyan sublimation toner printing cartridge, a magenta sublimation toner printing cartridge, and a yellow sublimation toner printing cartridge 315. A non-standard toner printing cartridge may also be provided. The cyan sublimation toner printing cartridge may be installed into the cyan toner cartridge slot, the magenta sublimation toner printing cartridge may be installed into the magenta toner cartridge slot, the yellow sublimation toner printing cartridge may be installed into the yellow toner cartridge slot, and the non-standard toner printing cartridge may be installed into the fourth toner cartridge slot 320. The method 300 may further comprise providing raster image processor (RIP) software for printing cartridge remapping 322 and printing a print job onto a transfer material 325. The transfer material may comprise a polyurethane media that accepts the toner print job and then allows the print job to be transferred to a final print surface via heat transfer 330. In some embodiments, the print job may be directly printed/sublimated onto the final print surface without the need for an intermediate transfer material. In some embodiments, the steps of providing the three sublimation toner printing cartridges 335 may comprise: disassembling the three removed toner printing cartridges; emptying and cleaning the three removed toner printing cartridges, such that three empty printing cartridges may be created. The three empty printing cartridges may be filled with three sublimation toners. Preferably, the three sublimation toners may comprise: a cyan sublimation toner, a magenta sublimation toner, and a yellow sublimation toner. The steps of providing the non-standard toner printing cartridge 335 may comprise: disassembling the removed black toner printing cartridges; emptying and cleaning the removed black toner printing cartridges, such that an empty printing cartridge may be created. The empty printing cartridge may be filled with a non-standard toner. Preferably, the non-standard toner may comprise a non-sublimation toner, such as a white toner, a metallic toner, a fluorescent toner, a light toner, a clear toner, a clear fluorescent toner, or a ceramic toner. In one embodiment, the original black toner cartridge that was removed may be put back in along with the three new sublimation toner cartridges. In some embodiments, the CMYK toner printer provided may be a CMYX toner printer, wherein the X is a non-standard cartridge (as original manufactured, or as previously modified), and X can be white, fluorescent, clear, metallic, ceramic, or a different sublimation. The present disclosure covers taking any existing four or five printer toner cartridges (standard and/or non-standard) and converting it to use other types of printing cartridges (standard and/or non-standard). FIG. 4 is a flow block diagram of one embodiment of a method of converting a standard CMYKW color toner printer to a CMYKW sublimation color toner printer. As shown in FIG. 4, the method 400 of converting a standard CMYKW color toner printer to a CMYKW sublimation color toner printer, may comprise providing a standard CMYKW color toner printer with five toner printing cartridges: a cyan toner printing cartridge, a magenta toner printing cartridge, a yellow toner printing cartridge, a black toner printing cartridge, and a white toner printing cartridge 405. In one embodiment, the CMYKW printer may be a LED printer. The method 400 may further comprise removing five toner printing cartridges, such that five empty toner cartridge slots are created: a cyan toner cartridge slot, a magenta toner cartridge slot, a yellow toner cartridge slot, a black toner cartridge slot, and a white toner cartridge slot 410. In one embodiment, the black toner printing cartridge may be in the fourth toner cartridge slot. Five sublimation toner printing cartridges may be provided. Preferably, the five sublimation toner printing cartridges comprise: a cyan sublimation toner printing cartridge, a magenta sublimation toner printing cartridge, a yellow sublimation toner printing cartridge, a black sublimation toner printing cartridge, and a white sublimation toner printer cartridge 415. The cyan sublimation toner printing cartridge may be installed into the cyan toner cartridge slot, the magenta sublimation toner printing cartridge may be installed into the magenta toner cartridge slot, the yellow sublimation toner printing cartridge may be installed into the yellow toner cartridge slot, the black sublimation toner printing cartridge may be installed into the black toner cartridge slot, and the white sublimation toner printing cartridge may be installed into the white toner cartridge slot 420. The method 400 may further comprise providing raster image processor (RIP) software for printing cartridge remapping 422 (which may be used for over (or even under) printing with white in a single pass). The method 400 may further comprise printing a print job onto a transfer material 425. The transfer material may comprise a polyurethane media that accepts the toner print job and then allows the print job to be transferred to a final print surface via heat transfer 430. In some embodiments, the print job may be directly printed/sublimated onto the final print surface without the need for an intermediate transfer material. In some embodiments, the steps of providing the five sublimation toner printing cartridges may comprise: disassembling the five removed toner printing cartridges; emptying and cleaning the five removed toner printing cartridges, such that five empty printing cartridges may be created. The five empty printing cartridges may be filled with five sublimation toners. Preferably, the five sublimation toners may comprise: a cyan sublimation toner, a magenta sublimation toner, a yellow sublimation toner, a black sublimation toner, and a white sublimation toner 435. Another embodiment may be a CMYKW printer that underprints in a single pass, or overprints in a single pass, and/or does both and can be switched back and forth. Overprint printers are useful in providing a clear or white background to an image that is heat transferred to a final surface from a transfer material. Underprint printers are useful in providing a clear or white background to an image that is printed on a non-standard or dark material/surface. The overprint of clear or white may then be the background layer after the image is transferred/sublimated to the final media. FIG. 5 is a flow block diagram of one embodiment of a method of converting a standard CMYKX color toner printer to a CMYKX sublimation color toner printer. As shown in FIG. 5, the method 500 of converting a standard CMYKX color toner printer to a CMYKX sublimation color toner printer, may comprise providing a standard CMYKX color toner printer with five toner printing cartridges: a cyan toner printing cartridge, a magenta toner printing cartridge, a yellow toner printing cartridge, a black toner printing cartridge, and a non-standard toner printing cartridge 505. In one embodiment, the CMYKX printer may be a LED printer. The method 500 may further comprise removing five toner printing cartridges, such that five empty toner cartridge slots are created: a cyan toner cartridge slot, a magenta toner cartridge slot, a yellow toner cartridge slot, a black toner cartridge slot, and a non-standard toner cartridge slot 510. In one embodiment, the black toner printing cartridge may be in the fourth toner cartridge slot. At least four sublimation toner printing cartridges may be provided. Preferably, the four sublimation toner printing cartridges comprise: a cyan sublimation toner printing cartridge, a magenta sublimation toner printing cartridge, a yellow sublimation toner printing cartridge, and a black sublimation toner printing cartridge 515, A non-standard toner printing cartridge may also be provided to go in the fifth toner cartridge slot. The cyan sublimation toner printing cartridge may be installed into the cyan toner cartridge slot, the magenta sublimation toner printing cartridge may be installed into the magenta toner cartridge slot, the yellow sublimation toner printing cartridge may be installed into the yellow toner cartridge slot, the black sublimation toner printing cartridge may be installed into the black toner cartridge slot, and the non-standard, but non-sublimation, toner printing cartridge may be installed into the non-standard toner cartridge slot 520. The method 500 may further comprise providing raster image processor (RIP) software for printing cartridge remapping 522 (which may be used for over (or even under) printing with white in a single pass). The method 500 may also comprise printing a print job onto a transfer material 525. The transfer material may comprise a polyurethane media that accepts the toner print job and then allows the print job to be transferred to a final print surface via heat transfer 530. In some embodiments, the print job may be directly printed/sublimated onto the final print surface without the need for an intermediate transfer material. In some embodiments, the steps of providing the four sublimation toner printing cartridges 535 may comprise: disassembling the four removed toner printing cartridges; emptying and cleaning the four removed toner printing cartridges, such that four empty printing cartridges may be created. The four empty printing cartridges may be filled with four sublimation color toners. Preferably, the four sublimation toners may comprise: a cyan sublimation toner, a magenta sublimation toner, a yellow sublimation toner, and a black sublimation toner. The steps of providing a non-standard toner printing cartridge 535 may comprise: disassembling the removed non-standard toner printing cartridge; emptying and cleaning the removed non-standard toner printing cartridge, such that an empty non-standard printing cartridge may be created. The empty non-standard printing cartridge may be filled with a non-standard toner color. Preferably; the non-standard toner color may comprise: a white toner, a metallic toner, a fluorescent toner, a light toner, a clear toner, a clear fluorescent toner, a sublimation non-standard toner, and/or a ceramic toner. In one embodiment, the original white toner printing cartridge may be put back into place in the fifth toner cartridge slot. In some embodiments, the X non-standard toner may be in the first, fourth, or fifth toner printing cartridge slot and the black sublimation toner printing cartridge may be in the first, fourth, or fifth toner printing cartridge slot and whichever is not being used by the non-standard toner cartridge. In another embodiment, the X non-standard toner may be in the first, second, third, fourth; or fifth toner printing cartridge slot and the black sublimation toner printing cartridge may be in the first, second, third, fourth, or fifth toner printing cartridge slot. Another embodiment may be a CMYKX printer that underprints in a single pass, or overprints in a single pass, and/or does both and can be switched back and forth. Overprint printers are useful in providing a clear or white background to an image that is heat transferred to a final surface from a transfer material. Underprint printers are useful in providing a clear or white background to an image that is printed on a non-standard or dark material/surface. The overprint of clear or white may then be the background layer after the image is transferred/sublimated to the final media. FIG. 6 is a flow block diagram of one embodiment of a method of converting a standard CMYKW color toner printer to a CMYKW sublimation color toner printer. As shown in FIG. 6, the method 600 of converting a standard CMYKW color toner printer to a CMYKW sublimation color toner printer, may comprise providing a standard CMYKW color toner printer with five toner printing cartridges: a cyan toner printing cartridge, a magenta toner printing cartridge, a yellow toner printing cartridge, a black toner printing cartridge, and a white toner printing cartridge 605. In one embodiment, the CMYKW printer may be a LED printer. The method 600 may further comprise removing four toner printing cartridges, such that four empty toner cartridge slots are created: a cyan toner cartridge slot, a magenta toner cartridge slot, a yellow toner cartridge slot, and a black toner cartridge slot 610. Preferably, the white toner cartridge is not removed, unless it is remapped into another slot. In one embodiment, the black toner printing cartridge may be in the fourth toner cartridge slot. Four sublimation toner printing cartridges may be provided. Preferably, the four sublimation toner printing cartridges comprise: a cyan sublimation toner printing cartridge, a magenta sublimation toner printing cartridge, a yellow sublimation toner printing cartridge, and a black sublimation toner printing cartridge 615. The cyan sublimation toner printing cartridge may be installed into the cyan toner cartridge slot, the magenta sublimation toner printing cartridge may be installed into the magenta toner cartridge slot, the yellow sublimation toner printing cartridge may be installed into the yellow toner cartridge slot, and the black sublimation toner printing cartridge may be installed into the black toner cartridge slot 620. The method 600 may further comprise providing raster image processor (RIP) software for printing cartridge remapping 622 and printing a print job onto a transfer material 625. The transfer material may comprise a polyurethane media that accepts the toner print job and then allows the print job to be transferred to a final print surface via heat transfer 630. In some embodiments, the print job may be directly printed onto the final print surface without the need for an intermediate transfer material. In some embodiments, the steps of providing the four sublimation toner printing cartridges 635 may comprise: disassembling the four removed toner printing cartridges; emptying and cleaning the four removed toner printing cartridges, such that four empty printing cartridges may be created. The four empty printing cartridges may be filled with four sublimation toners. Preferably, the four sublimation toners may comprise: a cyan sublimation toner, a magenta sublimation toner, a yellow sublimation toner, and a black sublimation toner. In some embodiments, the X non-standard toner may be in the first, fourth, or fifth toner printing cartridge slot and the black toner printing cartridge may be in the first; fourth, or fifth toner printing cartridge slot and whichever is not being used by the non-standard toner cartridge. Another embodiment may be a CMYKX printer that underprints in a single pass, or overprints in a single pass, and/or does both and can be switched back and forth. Overprint printers are useful in providing a clear or white background to an image that is heat transferred to a final surface from a transfer material. Underprint printers are useful in providing a clear or white background to an image that is printed on a non-standard or dark material/surface. The overprint of white may then be the background layer after the image is transferred/sublimated to the final media. Unless otherwise stated, all measurements, values, ratings, positions, magnitudes, sizes, locations, and other specifications, which set forth in this specification, including in the claims that follow, are approximate, not exact. They are intended to have a reasonable range, which is consistent with the functions to which they relate and with what is customary in the art to which they pertain. The foregoing description of the preferred embodiment has been presented for the purposes of illustration and description. While multiple embodiments are disclosed, still other embodiments will become apparent to those skilled in the art from the above detailed description, which shows and describes the illustrative embodiments. As will be realized, these embodiments are capable of modifications in various obvious aspects, all without departing from the spirit and scope of the present disclosure. Accordingly; the detailed description is to be regarded as illustrative in nature and not restrictive. Also, although not explicitly recited, one or more additional embodiments may be practiced in combination or conjunction with one another. Furthermore, the reference or non-reference to a particular embodiment shall not be interpreted to limit the scope of protection. It is intended that the scope of protection not be limited by this detailed description, but by the claims and the equivalents to the claims that are appended hereto. Except as stated immediately above, nothing which has been stated or illustrated is intended or should be interpreted to cause a dedication of any component, step, feature, object, benefit, advantage, or equivalent to the public, regardless of whether it is or is not recited in the claims. | <SOH> BACKGROUND <EOH>Traditional Cyan (C), Magenta (M), Yellow (Y), and Black (K) (or CMYK) laser or Light Emitting Diode (LED) type printers come standard with Cyan, Magenta, Yellow, and Black toner and/or drum cartridges. However, traditional black toner printers and CMYK toner printers are generally used in surface printing of materials, including direct-to-fabric printing, but do not become part of the fabric like dye sublimation printings does. Dye sublimation printing works by heating a special type of solid ink. This is different from traditional printing techniques, such as traditional inkjet, CMYK laser, or LED type printers, which spray liquid ink onto a page or surface, staining it (as in the case of inkjet) or transferring a dry ink (toner) to a page or surface and heat pressing the toner into the page or surface. Instead, dye sublimation printing heats up the solid ink, causing it to turn into gas vapors. These vapors make their way into the target surface, where they then turn back into solid form. The target surface may be transfer paper, which is coupled to a piece of polyester or another synthetic fabric, and then fed through heated rollers that combine heat with pressure to expand the cells of the fabric and convert the dye to a gaseous state. The dye is sublimated into the open pores of the polymeric synthetic materials, and as it cools again, traps the sublimated dye within the cells of the fabric. Because the dye became gaseous, it does not create a dot pattern during the sublimation process like traditional printing techniques, rather it creates a continuous tone print that creates brighter and smoother color variations and transitions, and a superior overall look. Thus, there is a need for a method for converting or retrofitting a standard CMYK (four cartridge) or CMYKW (five cartridge) toner printer to print using sublimation toner. | <SOH> SUMMARY OF EMBODIMENTS <EOH>To minimize the limitations in the cited references, and to minimize other limitations that will become apparent upon reading and understanding the present specification, the toner cartridge printer methods disclosed herein preferably allow a user to convert a standard printer into one that prints using sublimation toner. In various embodiments, the methods may be used to convert a traditional toner cartridge(s) and/or drum(s) printing machine to a printing machine that prints sublimation toner from one or more of the toner cartridge(s). One embodiment may be a method of converting a standard CMYK color toner printer to a CMYK sublimation color toner printer. A standard CMYK color toner printer may be provided and may comprise four toner printing cartridges. The four toner printing cartridges may comprise a cyan toner printing cartridge, a magenta toner printing cartridge, a yellow toner printing cartridge, and a black toner printing cartridge. The four toner printing cartridges may be removed such that four empty toner cartridge slots are created, and may comprise a cyan toner cartridge slot, a magenta toner cartridge slot, a yellow toner cartridge slot, and a black toner cartridge slot. Four sublimation toner printing cartridges may be provided and may comprise a cyan sublimation toner printing cartridge, a magenta sublimation toner printing cartridge, a yellow sublimation toner printing cartridge, and a black sublimation toner printing cartridge. The cyan sublimation toner printing cartridge may be installed into the cyan toner cartridge slot. The magenta sublimation toner printing cartridge may be installed into the magenta toner cartridge slot. The yellow sublimation toner printing cartridge may be installed into the yellow toner cartridge slot. The black sublimation toner printing cartridge may be installed into the black toner cartridge slot. A print job may be printed onto a transfer material and the print job may be transferred to a final print surface via a heat transfer. The four sublimation toner printing cartridges may comprise disassembling the four toner printing cartridges, emptying and cleaning the four toner printing cartridges, such that four empty printing cartridges may be created, and filling the four empty printing cartridges with four sublimation toners: a cyan sublimation toner, a magenta sublimation toner, a yellow sublimation toner, and a black sublimation toner. Another embodiment may be a method of converting a standard CMYK color toner printer to a CMYW sublimation color toner printer. A standard CMYK color toner printer may be provided and may comprise four toner printing cartridges. The four toner printing cartridges may comprise a cyan toner printing cartridge, a magenta toner printing cartridge, a yellow toner printing cartridge, and a black toner printing cartridge. The four toner printing cartridges may be removed such that four empty toner cartridge slots are created and may comprise a cyan toner cartridge slot, a magenta toner cartridge slot, a yellow toner cartridge slot, and a black toner cartridge slot. The black toner cartridge slot may be a fourth toner cartridge slot. Four sublimation toner printing cartridges may be provided and may comprise a cyan sublimation toner printing cartridge, a magenta sublimation toner printing cartridge, a yellow sublimation toner printing cartridge, and a white sublimation toner printing cartridge. The cyan sublimation toner printing cartridge may be installed into the cyan toner cartridge slot. The magenta sublimation toner printing cartridge may be installed into the magenta toner cartridge slot. The yellow sublimation toner printing cartridge may be installed into the yellow toner cartridge slot. The white sublimation toner printing cartridge may be installed into the fourth toner cartridge slot. Raster image processor (RIP) software may be provided for printing cartridge remapping. A print job may be printed onto a transfer material and the print job may be transferred to a final print surface via a heat transfer. The four sublimation toner printing cartridges may comprise disassembling the four toner printing cartridges, emptying and cleaning the four toner printing cartridges, such that four empty printing cartridges may be created, and filling the four empty printing cartridges with four sublimation toners: a cyan sublimation toner, a magenta sublimation toner, a yellow sublimation toner, and a white sublimation toner. Another embodiment may be a method of converting a standard CMYK color toner printer to a CMYX sublimation color toner printer. A standard CMYK color toner printer may be provided and may comprise four toner printing cartridges. The four toner printing cartridges may comprise a cyan toner printing cartridge, a magenta toner printing cartridge, a yellow toner printing cartridge, and a black toner printing cartridge. The four toner printing cartridges may be removed such that four empty toner cartridge slots are created and may comprise a cyan toner cartridge slot, a magenta toner cartridge slot, a yellow toner cartridge slot, and a black toner cartridge slot. The black toner cartridge slot may be a fourth toner cartridge slot. At least three sublimation toner printing cartridges may be provided and may comprise a cyan sublimation toner printing cartridge, a magenta sublimation toner printing cartridge, a yellow sublimation toner printing cartridge. A non-standard toner printing cartridge may also be provided. The cyan sublimation toner printing cartridge may be installed into the cyan toner cartridge slot. The magenta sublimation toner printing cartridge may be installed into the magenta toner cartridge slot. The yellow sublimation toner printing cartridge may be installed into the yellow toner cartridge slot. The non-standard toner printing cartridge may be installed into the fourth toner cartridge slot. Raster image processor (RIP) software may be provided for printing cartridge remapping. A print job may be printed onto a transfer material and the print job may be transferred to a final print surface via a heat transfer. The three sublimation toner printing cartridges may comprise disassembling the three toner printing cartridges, emptying and cleaning the three toner printing cartridges, such that three empty printing cartridges may be created, and filling the three empty printing cartridges with three sublimation toners: a cyan sublimation toner, a magenta sublimation toner, and a yellow sublimation toner. The non-standard toner printing cartridge may comprise disassembling the black toner printing cartridge, emptying and cleaning the black toner printing cartridge, such that an empty printing cartridges may be created, and filling the empty printing cartridges with a non-standard toner. The non-standard toner may be selected from the group of non-standard toners consisting of: white, metallic, fluorescent, light, clear, clear fluorescent, ceramic, and sublimation. Another embodiment may be a method of converting a standard CMYKW color toner printer to a CMYKW sublimation color toner printer. A standard CMYKW color toner printer may be provided and may comprise five toner printing cartridges. The five toner printing cartridges may comprise a cyan toner printing cartridge, a magenta toner printing cartridge, a yellow toner printing cartridge, a black toner printing cartridge, and a white toner printing cartridge. The five toner printing cartridges may be removed such that five empty toner cartridge slots are created and may comprise a cyan toner cartridge slot, a magenta toner cartridge slot, a yellow toner cartridge slot, a black toner cartridge slot, and a white toner cartridge slot. Five sublimation toner printing cartridges may be provided and may comprise a cyan sublimation toner printing cartridge, a magenta sublimation toner printing cartridge, a yellow sublimation toner printing cartridge, a black sublimation toner printing cartridge, and a white sublimation toner printing cartridge. The cyan sublimation toner printing cartridge may be installed into the cyan toner cartridge slot. The magenta sublimation toner printing cartridge may be installed into the magenta toner cartridge slot. The yellow sublimation toner printing cartridge may be installed into the yellow toner cartridge slot. The black sublimation toner printing cartridge may be installed into the black toner cartridge slot. The white sublimation toner printing cartridge may be installed into the white toner cartridge slot. Raster image processor (RIP) software may be provided for printing cartridge remapping. A print job may be printed onto a transfer material and the print job may be transferred to a final print surface via a heat transfer. The five sublimation toner printing cartridges may comprise disassembling the five toner printing cartridges, emptying and cleaning the five toner printing cartridges, such that five empty printing cartridges may be created, and filling the five empty printing cartridges with five sublimation toners: a cyan sublimation toner, a magenta sublimation toner, a yellow sublimation toner, a black sublimation toner, and a white sublimation toner. A print job may be printed onto a transfer material wherein a layer of white is overprinted on the print job in a single pass. The print job may be transferred from the transfer material to a final print surface via a heat transfer, such that the layer of white is under the print job on the final print surface. Another embodiment may be a method of converting a standard CMYKX color toner printer to a CMYKX sublimation color toner printer. A standard CMYKX color toner printer may be provided and may comprise five toner printing cartridges. The five toner printing cartridges may comprise a cyan toner printing cartridge, a magenta toner printing cartridge, a yellow toner printing cartridge, a black toner printing cartridge, and a non-standard toner printing cartridge. The five toner printing cartridges may be removed such that five empty toner cartridge slots are created and may comprise a cyan toner cartridge slot, a magenta toner cartridge slot, a yellow toner cartridge slot, a black toner cartridge slot, and a non-standard toner cartridge slot. At least four sublimation toner printing cartridges may be provided and may comprise a cyan sublimation toner printing cartridge, a magenta sublimation toner printing cartridge, a yellow sublimation toner printing cartridge, and a black sublimation toner printing cartridge. A non-standard toner cartridge may also be provided. The cyan sublimation toner printing cartridge may be installed into the cyan toner cartridge slot. The magenta sublimation toner printing cartridge may be installed into the magenta toner cartridge slot. The yellow sublimation toner printing cartridge may be installed into the yellow toner cartridge slot. The black sublimation toner printing cartridge may be installed into the black toner cartridge slot. The non-standard toner printing cartridge may be installed into the non-standard toner cartridge slot. Raster image processor (RIP) software may be provided for printing cartridge remapping. A print job may be printed onto a transfer material and the print job may be transferred to a final print surface via a heat transfer. The four sublimation toner printing cartridges may comprise disassembling the four toner printing cartridges, emptying and cleaning the four toner printing cartridges, such that four empty printing cartridges may be created, and filling the four empty printing cartridges with four sublimation toners: a cyan sublimation toner, a magenta sublimation toner, a yellow sublimation toner, and a black sublimation toner. The non-standard toner printing cartridge may comprise disassembling the non-standard toner printing cartridge, emptying and cleaning the toner printing cartridge, such that an empty non-standard printing cartridge may be created, and filling the empty non-standard printing cartridge with a non-standard toner. The non-standard toner may be selected from the group of non standard toners consisting of: white, metallic, fluorescent, light, clear, clear fluorescent, ceramic, and sublimation. Another embodiment may be a method of converting a standard CMYKW color toner printer to a CMYKW sublimation color toner printer. A standard CMYKW color toner printer may be provided and may comprise five toner printing cartridges. The five toner printing cartridges may comprise a cyan toner printing cartridge, a magenta toner printing cartridge, a yellow toner printing cartridge, a black toner printing cartridge, and a white toner printing cartridge. Four toner printing cartridges may be removed such that four empty toner cartridge slots are created and may comprise a cyan toner cartridge slot, a magenta toner cartridge slot, a yellow toner cartridge slot, and a black toner cartridge slot. Four sublimation toner printing cartridges may be provided and may comprise a cyan sublimation toner printing cartridge, a magenta sublimation toner printing cartridge, a yellow sublimation toner printing cartridge, and a black sublimation toner printing cartridge. The cyan sublimation toner printing cartridge may be installed into the cyan toner cartridge slot. The magenta sublimation toner printing cartridge may be installed into the magenta toner cartridge slot. The yellow sublimation toner printing cartridge may be installed into the yellow toner cartridge slot. The black sublimation toner printing cartridge may be installed into the black toner cartridge slot. Raster image processor (RIP) software may be provided for printing cartridge remapping. A print job may be printed onto a transfer material and the print job may be transferred to a final print surface via a heat transfer. The four sublimation toner printing cartridges may comprise disassembling the four toner printing cartridges, emptying and cleaning the four toner printing cartridges, such that four empty printing cartridges may be created, and filling the four empty printing cartridges with four sublimation toners: a cyan sublimation toner, a magenta sublimation toner, a yellow sublimation toner, and a black sublimation toner. A print job may be printed onto a transfer material wherein a layer of white is overprinted on the print job in a single pass. The print job may be transferred from the transfer material to a final print surface via a heat transfer, such that the layer of white may be under the print job on the final print surface. Additional embodiments of the invention will be understood from the detailed description of the illustrative embodiments. | G03G211676 | 20171101 | 20180222 | 82418.0 | G03G1500 | 3 | ELEY, JESSICA L | METHOD FOR CONVERTING A TONER CARTRIDGE PRINTER TO A SUBLIMATION TONER PRINTER | SMALL | 1 | CONT-ACCEPTED | G03G | 2,017 |
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15,802,341 | PENDING | Enalapril Formulations | Provided herein are stable enalapril oral liquid formulations. Also provided herein are methods of using enalapril oral liquid formulations for the treatment of certain diseases including hypertension, heart failure and asymptomatic left ventricular dysfunction. | 1. A stable oral liquid formulation, comprising: (i) about 0.6 to about 1.2 mg/ml enalapril or a pharmaceutically acceptable salt or solvate thereof; (ii) a buffer comprising about 0.8 to about 3.5 mg/ml citric acid and about 0.1 to about 0.8 mg/ml sodium citrate; (iii) about 0.7 to about 1.2 mg/ml sodium benzoate; and (iv) water; wherein the formulation is stable at about 5±3° C. for at least 12 months; and wherein the stable oral liquid formulation has about 95% w/w or greater of the initial enalapril amount and about 5% w/w or less total impurity or related substances at the end of the given storage period. 2. The stable oral liquid formulation of claim 1 further comprising about 0.5 to about 0.9 mg/ml sucralose. 3. The stable oral liquid formulation of claim 1 further comprising a flavoring agent. 4. The stable oral liquid formulation of claim 1, wherein the formulation does not contain mannitol. 5. The stable oral liquid formulation of claim 1, wherein the formulation does not contain silicon dioxide. 6. The stable oral liquid formulation of claim 1, wherein the pH of the stable oral liquid formulation is less than about 3.5. 7. The stable oral liquid formulation of claim 1, wherein the pH of the stable oral liquid formulation is between about 3 and about 3.5. 8. The stable oral liquid formulation of claim 1, wherein the pH of the stable oral liquid formulation is about 3.3. 9. The stable oral liquid formulation of claim 1, wherein the formulation is stable at about 5±3° C. for at least 18 months. 10. The stable oral liquid formulation of claim 1, wherein the formulation is stable at about 5±3° C. for at least 24 months. 11. A stable oral liquid formulation, comprising: (i) about 10% to about 25% (w/w of solids) enalapril or a pharmaceutically acceptable salt or solvate thereof; (ii) a buffer comprising about 17% to about 47% (w/w of solids) citric acid and about 1% to about 11% (w/w of solids) sodium citrate; (iii) about 3% to about 25% (w/w of solids) sodium benzoate; and (iv) water; wherein the formulation is stable at about 5±3° C. for at least 12 months; and wherein the stable oral liquid formulation has about 95% w/w or greater of the initial enalapril amount and about 5% w/w or less total impurity or related substances at the end of the given storage period. 12. The stable oral liquid formulation of claim 11 further comprising about 8% to about 18% (w/w of solids) sucralose. 13. The stable oral liquid formulation of claim 11 further comprising a flavoring agent. 14. The stable oral liquid formulation of claim 11, wherein the formulation does not contain mannitol. 15. The stable oral liquid formulation of claim 11, wherein the formulation does not contain silicon dioxide. 16. The stable oral liquid formulation of claim 11, wherein the pH of the stable oral liquid formulation is less than about 3.5. 17. The stable oral liquid formulation of claim 11, wherein the pH of the stable oral liquid formulation is between about 3 and about 3.5. 18. The stable oral liquid formulation of claim 11, wherein the pH of the stable oral liquid formulation is about 3.3. 19. The stable oral liquid formulation of claim 11, wherein the formulation is stable at about 5±3° C. for at least 18 months. 20. The stable oral liquid formulation of claim 11, wherein the formulation is stable at about 5±3° C. for at least 24 months. | CROSS-REFERENCE OF RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser. No. 15/613,622, filed Jun. 5, 2017, which is a continuation of U.S. patent application No. 15/081,603, filed Mar. 25, 2016 (now U.S. Pat. No. 9,669,008, issued Jun. 06, 2017), which claims the benefit of U.S. Provisional Patent Application No. 62/310,198, filed Mar. 18, 2016, all of which are incorporated herein by reference in their entirety. BACKGROUND OF THE INVENTION Hypertension, or high blood pressure, is a serious health issue in many countries. According to the National Heart Blood and Lung Institute, it is thought that about 1 in 3 adults in the U.S. alone have hypertension. Left unchecked, hypertension is considered a substantial risk factor for cardiovascular and other diseases including coronary heart disease, myocardial infarction, congestive heart failure, stroke and kidney failure. Hypertension is classified as primary (essential) hypertension or secondary hypertension. Primary hypertension has no known cause and may be related to a number of environmental, lifestyle and genetic factors such as stress, obesity, smoking, inactivity and sodium intake. Secondary hypertension can be caused by drug or surgical interventions, or by abnormalities in the renal, cardiovascular or endocrine system. A number of antihypertensive drugs are available for treating hypertension. Various therapeutic classes of antihypertensive drugs include alpha-adrenergic blockers, beta-adrenergic blockers, calcium-channel blockers, hypotensives, mineralcorticoid antagonists, central alpha-agonists, diuretics and rennin-angiotensin-aldosterone inhibitors which include angiotensin II receptor antagonists (ARB) and angiotensin-converting enzyme (ACE) inhibitors. Angiotensin-converting enzyme (ACE) inhibitors inhibit angiotensin-converting enzyme (ACE), a peptydyl dipeptidase that catalyzes angiotension I to angiotension II, a potent vasoconstrictor involved in regulating blood pressure. Enalapril is a prodrug belonging to the angiotensin-converting enzyme (ACE) inhibitor of medications. It is rapidly hydrolyzed in the liver to enalaprilat following oral administration. Enalaprilat acts as a potent inhibitor of ACE. The structural formulae of enalapril and enalaprilat are as follows: Enalapril is currently administered in the form of oral tablets, (e.g., Vasotec®) or in the form of liquid formulations obtained by reconstitution of enalapril powder formulations. In addition to the treatment of hypertension, enalapril tablets have been used for symptomatic congestive heart failure, and asymptomatic left ventricular dysfunction. SUMMARY OF THE INVENTION Provided herein are enalapril oral liquid formulations. In one aspect, the enalapril oral liquid formulation, comprises (i) enalapril or a pharmaceutically acceptable salt or solvate thereof; (ii) a sweetener that is sucralose (iii) a buffer comprising citric acid; (iv) a preservative that is sodium benzoate; and (v) water; wherein the pH of the formulation is less than about 3.5; and wherein the formulation is stable at about 5±3° C. for at least 12 months. In some embodiments, the enalapril is enalapril maleate. In some embodiments, the formulation further comprises a flavoring agent. In some embodiments, the buffer in the formulation further comprises sodium citrate dihydrate. In some embodiments, the amount of enalapril or a pharmaceutically acceptable salt or solvate thereof is about 0.6 to about 1.2 mg/ml. In some embodiments, the amount of sucralose is about 0.5 to about 0.9 mg/ml. In some embodiments, the amount of citric acid in the buffer is about 0.8 to about 3.5 mg/ml. In some embodiments, the amount of sodium citrate dihydrate in the buffer is about 0.1 to about 0.80 mg/ml. In some embodiments, the amount of the sodium benzoate is about 0.2 to about 1,2 mg/ml. In some embodiments, the amount of enalapril or a pharmaceutically acceptable salt or solvate thereof is about 10 to about 25% (w/w of solids). In some embodiments, the amount of sucralose is about 8 to about 18 (w/w of solids). In some embodiments, the amount of citric acid in the buffer is about 17 to about 47% (w/w of solids). In some embodiments, the amount of sodium citrate dihydrate in the buffer is about 1 to about 11% (w/w of solids). In some embodiments, the amount of sodium benzoate is about 12 to about 25% (w/w of solids). In some embodiments, the pH of the formulation is between about 3 and about 3.5. In some embodiments, the pH of the formulation is about 3.3. In some embodiments, the citrate concentration in the buffer is about 5 nM to about 20 mM. In some embodiments, the citrate concentration in the buffer is about 10 mM. In some embodiments, the formulation is stable at about 5±3° C. for at least 18 months. In some embodiments, the formulation is stable at about 5±3° C. for at least 24 months. In some embodiments, the formulation does not contain mannitol. In some embodiments, the formulation does not contain silicon dioxide. In one aspect, the enalapril oral liquid formulation, comprises (i) about 1 mg/ml enalapril maleate; (ii) about 0.70 mg/ml of a sweetener that is sucralose; (iii) a buffer comprising about 1.82 mg/ml citric acid; (iv) about 1 mg/ml of a preservative that is sodium benzoate; and (v) water; wherein the pH of the formulation is less than about 3.5; and wherein the formulation is stable at about 5±3° C. for at least 12 months. In some embodiments, the formulation further comprises a flavoring agent. In some embodiments, the buffer further comprises about 0.15 mg/mL sodium citrate dihydrate. In some embodiments, the pH of the formulation is between about 3 and about 3.5. In some embodiments, the pH of the formulation is about 3.3. In some embodiments, the citrate concentration in the buffer is about 5 mM to about 20 mM. In some embodiments, the citrate concentration in the buffer is about 10 mM. In some embodiments, the formulation is stable at about 5±3° C. for at least 18 months. In some embodiments, the formulation is stable at about 5±3° C. for at least 24 months. In some embodiments, the formulation does not contain mannitol. In some embodiments, the formulation does not contain silicon dioxide. In one aspect, the enalapril oral liquid formulation comprises (i) about 19.3% (w/w of solids) enalapril maleate; (ii) about 13.5% (w/w of solids) of a sweetener that is sucralose; (iii) a buffer comprising about 35.2% (w/w of solids) citric acid; (iv) about 19.3% (w/w of solids) of a preservative that is sodium benzoate; and (v) water; wherein the pH of the formulation is less than about 3.5; and wherein the formulation is stable at about 5±3° C. for at least 12 months. In some embodiments, the formulation further comprises a flavoring agent. In some embodiments, the buffer further comprises about 2.9% (w/w of solids) sodium citrate dihydrate. In some embodiments, the pH of the formulation is between about 3 and about 3.5. In some embodiments, the pH of the formulation is about 3.3. In some embodiments, the citrate concentration in the buffer is about 5 mM to about 20 mM. In some embodiments, the citrate concentration in the buffer is about 10 mM. In some embodiments, the formulation is stable at about 5±3° C. for at least 18 months. In some embodiments, the formulation is stable at about 5±3° C. for at least 24 months. In some embodiments, the formulation does not contain mannitol. In some embodiments, the formulation does not contain silicon dioxide. In one aspect, the enalapril oral liquid formulation consists essentially of (i) about 1 mg/ml enalapril maleate; (ii) about 0.70 mg/ml of a sweetener that is sucralose; (iii) a buffer comprising about 1.82 mg/ml citric acid and about 0.15 mg/ml sodium citrate dihydrate; (iv) about 1 mg/ml of a preservative that is sodium benzoate; (v) a flavoring agent; and (vi) water; wherein the pH of the formulation is less than about 3.5 adjusted by sodium hydroxide or hydrochloric acid; and wherein the formulation is stable at about 5±3° C. for at least 12 months. Also provided herein are methods of treating hypertension in a subject comprising administering to that subject a therapeutically effective amount of enalapril oral liquid formulation comprising (i) about 1 mg/ml enalapril maleate; (ii) about 0.7 mg/ml sucralose; (iii) a buffer comprising about 1.82 mg/ml citric acid and about 0.15 mg/ml sodium citrate dihydrate; (iv) about 1 mg/ml of a preservative that is sodium benzoate; and (v) water, wherein the pH of the formulation is less than about 3.5; and wherein the formulation is stable at about 5±3° C. for at least 12 months. In some embodiments, the formulation does not contain mannitol. In some embodiments, the formulation does not contain silicon dioxide. In some embodiments, the hypertension is primary (essential) hypertension. In some embodiments, the hypertension is secondary hypertension. In some embodiments, the subject has blood pressure values greater than or equal to 140/90 mmm Hg. In some embodiments, the subject is an adult. In some embodiments, the subject is elderly. In some embodiments, the subject is a child. In some embodiments, the formulation is administered to the subject in a fasted state. In some embodiments, the formulation is administered to the subject in a fed state. In some embodiments, the formulation is further administered in combination with an agent selected from the group consisting of diuretics, beta blockers, alpha blockers, mixed alpha and beta blockers, calcium channel blockers, angiotensin II receptor antagonists, ACE inhibitors, aldosterone antagonists, and alpha-2 agonists. Also provided herein are methods of treating prehypertension in a subject comprising administering to that subject a therapeutically effective amount of enalapril oral liquid formulation comprising (i) about 1 mg/ml enalapril maleate; (ii) about 0,7 mg/ml of a sweetener that is sucralose; (ii) a buffer comprising about 1.82 mg/ml citric acid and about 0.15 mg/ml sodium citrate dihydrate; (iv) about 1 mg/ml of a preservative that is sodium benzoate; and (v) water; wherein the pH of the formulation is less than about 3.5; and wherein the formulation is stable at about 5±3° C. for at least 12 months. In some embodiments, the formulation does not contain mannitol. In some embodiments, the formulation does not contain silicon dioxide. In some embodiments, the subject has blood pressure values of about 120-139/80-89 mm Also provided herein are methods of treating heart failure in a subject comprising administering to that subject a therapeutically effective amount of enalapril oral liquid formulation comprising (i) about 1 mg/ml enalapril maleate; (ii) about 0.70 mg/ml of a sweetener that is sucralose; a buffer comprising about 1.82 mg/ml citric acid and about 0.15 mg/ml sodium citrate dihydrate; (iv) about 1 mg/ml of a preservative that is sodium benzoate; and (v) water; wherein the pH of the formulation is less than about 3.5; and wherein the formulation is stable at about 5±3° C. for at least 12 months. In some embodiments, the formulation does not contain mannitol. In some embodiments, the formulation does not contain silicon dioxide. Also provided herein are methods of treating left ventricular dysfunction in a subject comprising administering to that subject a therapeutically effective amount of enalapril oral liquid formulation comprising (i) about 1 mg/ml enalapril maleate; (ii) about 0.7 mg/ml of a sweetener that is sucralose; (iii) a buffer comprising about 1.82 mg/ml citric acid and about 0.15 mg/ml sodium citrate dihydrate; (iv) about 1 mg/ml of a preservative that is sodium benzoate; and (v) water; wherein the pH of the formulation is less than about 3.5; and wherein the formulation is stable at about 5±3° C. for at least 12 months. In some embodiments, the formulation does not contain mannitol. In some embodiments, the formulation does not contain silicon dioxide. INCORPORATION BY REFERENCE All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which: FIG. 1: Effect of pH on degradant formation after 8 weeks of storage of various enalapril solution formulations at 5° C. FIG. 2: Effect of pH on degradant formation after 8 weeks of storage of various enalapril solution formulations at room temperature (19-22° C.). DETAILED DESCRIPTION OF THE INVENTION Provided herein are stable enalapril oral liquid formulations. Also provided herein are stable enalapril powder formulations for reconstitution for oral liquid administration. These enalapril formulations described herein are useful for the treatment of hypertension, prehypertension, heart failure as well as ventricular dysfunction. The formulations are advantageous over conventional solid dosage administration of enalapril ranging from ease of administration, accuracy of dosing, accessibility to additional patient populations such as to children and the elderly, and an increased patient compliance to medication. It is generally known that certain segments of the population have difficulty ingesting and swallowing solid oral dosage forms such as tablets and capsules. As many as a quarter of the total population has this difficulty. Often, this leads to non-compliance with the recommended medical therapy with the solid dosage forms, thereby resulting in rending the therapy ineffective. Further, solid dosage forms are not recommended for children or elderly due to increased risk in choking. Furthermore, the dose of enalapril to be given to children is calculated according to the child's weight. When the calculated dose is something other than the amount present in one or more intact solid dosage forms, the solid dosage form must be divided to provide the correct dose. This leads to inaccurate dosing when solid dosages forms, such as tablets, are compounded to prepare other formulations for children. For enalapril, one solution to overcoming the use of the tablet form is for a compounding pharmacist to pulverize and crush the enalapril tablet(s) into a powder via mortar and pestle and reconstitute the powder in some liquid form. However forming a enalapril oral liquid in this fashion has significant drawbacks including large variability in the actual dosage, incomplete solubilizing of the enalapril tablet in the liquid, rapid instability, inconsistent formulation methods per compounding pharmacy, and a number of other potential issues. The crushed tablet liquid formulation may also be potentially unsafe due to contamination with residual drugs and other substances from the mortar and pestle or other crushing agent. Alternatively, enalapril is formulated as enalapril powder compositions for reconstitution as oral liquids as described in U.S. Pat. No. 8,568,747. The powder compositions as described in this patent require mannitol and colloidal silicon dioxide for stability and dissolution. While these powder compositions are an improvement over crushing tablets, they still require a step of mixing with a diluent. The stable enalapril oral liquid formulations described herein require no extra steps or manipulation prior to administration to a subject. Further, the stable enalapril oral liquid formulations described herein do not require or need mannitol or colloidal silicon dioxide for stability and dissolution. The present embodiments described herein provide a safe and effective oral administration of enalapril for the treatment of hypertension and other disorders. In particular, the embodiments provide stable enalapril oral liquid formulations as well as alternatively enalapril powder formulations for oral liquid administration. As used herein, “enalapril” refers to enalapril base, its salt, or solvate or derivative or isomer or polymorph thereof. Suitable compounds include the free base, the organic and inorganic salts, isomers, isomer salts, solvates, polymorphs, complexes etc. U.S. Pat. Nos. 4,374,829; 4,472,380 and 4,510,083 disclose exemplary methods in the preparation of enalapril. In some embodiments, the enalapril used in the formulations described herein is an enalapril salt. In some instances, the enalapril salt is enalapril maleate. In other instances, the enalapril salt is in the form of enalapril sodium. Other ACE inhibitors are contemplated in the formulations within and include but are not limited to quinapril, indolapril, ramipril, perindopril, lisinopril, benazepril, imidapril, zofenopril, trandolapril, fosinopril, captopril, and their salts, solvates, derivatives, polymorphs, or complexes, thereof. Enalapril Oral Liquid Formulations Oral liquids include, but are not limited to, solutions (both aqueous and nonaqueous), suspensions, emulsions, syrups, slurries, juices, elixirs, dispersions, and the like. It is envisioned that solution/suspensions are also included where certain components described herein are in a solution while other components are in a suspension. In one aspect, the enalapril liquid formulations described herein comprise enalapril, a preservative, a sweetening agent, a buffer, and water. In one embodiment, the sweetening agent is sucralose. In one embodiment, the sweetening agent is xylitol. In one embodiment, the sweetening agent is not mannitol. In another embodiment, the preservative is sodium benzoate. In some embodiments, the preservative is a paraben. In some embodiments, the preservative is a mixture of parabens. In yet another embodiment, the buffer comprises citric acid. In some embodiments, the buffer further comprises sodium citrate. In one aspect, the enalapril liquid formulation described herein comprises enalapril, sucralose, sodium benzoate, citric acid, sodium citrate, and water. In some embodiments, the enalapril liquid formulation herein further comprises a flavoring agent. In some embodiments, the enalapril liquid formulation is not obtained from crushing enalapril tablet and dissolving the powder in a suitable vehicle for oral administration. In some embodiments, the enalapril liquid formulation does not contain silicon dioxide. In some embodiments, the enalapril liquid formulation does not contain mannitol. In some embodiments, the enalapril liquid formulation does not contain lactose. In some embodiments, the enalapril liquid formulation does not contain magnesium stearate. In some embodiments, the enalapril liquid formulation does not contain sodium bicarbonate. In some embodiments, the enalapril liquid formulation does not contain iron oxides. In some embodiments, enalapril or a pharmaceutically acceptable salt thereof, is present in about 0.6 to about 1.2 mg/ml in the oral liquid formulation. In other embodiments, enalapril or a pharmaceutically acceptable salt thereof, is present in about 0.6 mg/ml, about 0.61 mg/ml, about 0.62 mg/ml, about 0.63 mg/ml, about 0.64 mg/ml, about 0.65 mg/ml, about 0.66 mg/ml, about 0.67 mg/ml, about 0.68 mg/ml, about 0.69 mg/ml, about 0.7 mg/ml, about 0.71 mg/ml, about 0.72 mg/ml, about 0.73 mg/ml, about 0.74 mg/ml, about 0.75 mg/ml, about 0.76 mg/ml, about 0.77 mg/ml, about 0.78 mg/ml, about 0.79 mg/ml, about 0.8 mg/ml, about 0.81 mg/ml, about 0.82 mg/ml, about 0.83 mg/ml, about 0.84 mg/ml, about 0.85 mg/ml, about 0.86 mg/ml, about 0.87 mg/ml, about 0.88 mg/ml, about 0.89 mg/ml, about 0.9 mg/ml, about 0.91 mg/ml, about 0.92 mg/ml, about 0.93 mg/ml, about 0.94 mg/ml, about 0.95 mg/ml, about 0.96 mg/ml, about 0.97 mg/ml, about 0.98 mg/ml, about 0.99 mg/ml, about 1 mg/ml, about 1.01 mg/ml, about 1.02, mg/ml, about 1.03 mg/ml, about 1.04 mg/ml, about 1.05 mg/ml, about 1.06 mg/ml, about 1.07 mg/ml, about 1.08 mg/ml, about 1.09 mg/ml, about 1.1 mg/ml, about 1.11 mg/ml, about 1.12, mg/ml, about 1.13 mg/ml, about 1.14 mg/ml, about 1.15 mg/ml, about 1.16 mg/ml, about 1.17 mg/ml, about 1.18 mg/ml, about 1.19 mg/ml, or about 1.2 mg/ml in the liquid oral formulation. In some embodiments, enalapril is present in about 0.76 mg/ml in the oral liquid formulation. In some embodiments, enalapril maleate is present in about 1 mg/ml in the oral liquid formulation. In some embodiments, the formulation contains enalapril or another pharmaceutically acceptable salt of enalapril in a molar concentration equivalent to 1 mg/ml, enalapril maleate. In some embodiments, the formulation contains enalapril or another pharmaceutically acceptable salt of enalapril in a molar concentration equivalent to 0.76 mg/mL enalapril. In some embodiments, enalapril or a pharmaceutically acceptable salt thereof, is present in about 0.5% w/w to about 30% w/w of the solids in the oral liquid formulation. In other embodiments, enalapril or a pharmaceutically acceptable salt thereof, is present in about 0.5% w/w, about 1% w/w, about 1.5% w/w, about 2% w/w, about 2.5% w/w, about 3% w/w, about 3.5% w/w, about 4% w/w, about 4.5% w/w, about 5% w/w, about 5.5% w/w, about 6% w/w, about 6.5% w/w, about 7% w/w, about 7.5% w/w, about 8% w/w, about 8.5% w/w, about 9% w/w, about 9.5% w/w, about 10% w/w, about 10.5% w/w, about 11% w/w, about 11.5% w/w, about 12% w/w, about 12.5% w/w, about 13% w/w, about 13.5% w/w, about 14% w/w, about 14.5% w/w, about 15% w/w, about 15.1% w/w, about 15.2% w/w, about 15.3% w/w, about 15.4% w/w, about 15.5% w/w, about 15.6% w/w, about 15.7% w/w, about 15.8% w/w, about 15.9% w/w, about 16% w/w, about 16.1% w/w, about 16.2% w/w, about 16.3% w/w, about 16.4% w/w, about 16.5% w/w, about 16.6% w/w, about 16.7% w/w, about 16.8% w/w, about 16.9% w/w, about 17% w/w, about 17.1% w/w, about 17.2% w/w, about 17.3% w/w, about 17.4 w/w, about 17.5% w/w, about 17.6% w/w, about 17.7% w/w, about 17.8% w/w, about 17.9% w/w, about 18% w/w, about 18.1% w/w, about 18.2% w/w, about 18.3% w/w, about 18.4% w/w, about 18.5 w/w, about 18.6% w/w, about 18.7% w/w, about 18.8% w/w, about 18.9% w/w, about 19% w/w, about 19.1% w/w, about 19.2% w/w, about 19.3% w/w, about 19.4% w/w, about 19.5% w/w, about 19.6% w/w, about 19.7% w/w, about 19.8% w/w, about 19.9% w/w, about 20% w/w, about 20.1% w/w, about 20.2% w/w, about 20.3% w/w, about 20.4% w/w, about 20.5% w/w, about 20.6% w/w, about 20.7% w/w, about 20.8% w/w, about 20.9% w/w, about 21% w/w, about 21.1% w/w, about 21.2 w/w, about 21.3% w/w, about 21.4% w/w, about 21.5% w/w, about 21.6% w/w, about 21.7% w/w, about 21.8% w/w, about 21.9% w/w, about 22% w/w, about 22.5% w/w, about 23% w/w, about 23.5% w/w, about 24% w/w, about 24.5% w/w, about 25% w/w, about 25.5% w/w, about 26% w/w, about 26.5% w/w, about 27% w/w, about 27.5% w/w, about 28% w/w, about 28.5% w/w, about 29% w/w, about 29.5% w/w, or about 30% w/w of the solids in the oral liquid formulation. In some embodiments, enalapril or a pharmaceutically acceptable salt thereof, is present in about 10% w/w to about 25% w/w of the solids in the oral liquid formulation. In some embodiments, enalapril is present in about 10.5% w/w of the solids in the oral liquid formulation. In some embodiments, enalapril is present in about 15% w/w of the solids in the oral liquid formulation. In some embodiments, enalapril is present in about 18.2 w/w of the solids in the oral liquid formulation. In some embodiments, enalapril maleate is present in about 13.5% w/w of the solids in the oral liquid formulation. In some embodiments, enalapril maleate is present in about 19.3% w/w of the solids in the oral liquid formulation. In some embodiments, enalapril maleate is present in about 24.5% w/w of the solids in the oral liquid formulation. In some embodiments, enalapril or a pharmaceutically acceptable salt thereof, is present in about 0.1% w/w to about 1% w/w of the solids in the oral liquid formulation. In other embodiments, enalapril or a pharmaceutically acceptable salt thereof, is present in about 0.1% w/w, about 0.15% w/w, about 0.2% w/w, about 0.25% w/w, about 0.3% w/w, about 0.35% w/w, about 0.4% w/w, about 0.45% w/w, about 0.5% w/w, about 0.55% w/w, about 0.6% w/w, about 0.65% w/w, about 0.7% w/w, about 0.75% w/w, about 0.8% w/w, about 0.85% w/w, about 0.9% w/w, about 0.95% w/w, or about 1% w/w of the solids in the oral liquid formulation. In some embodiments, enalapril or a pharmaceutically acceptable salt thereof, is present in about 0.4% w/w to about 0.7% w/w of the solids in the oral liquid formulation. In some embodiments, enalapril is present in about 0.4% w/w of the solids in the oral liquid formulation. In some embodiments, enalapril is present in about 0.5% w/w of the solids in the oral liquid formulation. In some embodiments, enalapril maleate is present in about 0.5% w/w of the solids in the oral liquid formulation. In some embodiments, enalapril maleate is present in about 0.6% w/w of the solids in the oral liquid formulation. Sweetener in the Enalapril Oral Liquid Formulations Sweeteners or sweetening agents include any compounds that provide a sweet taste. This includes natural and synthetic sugars, natural and artificial sweeteners, natural extracts and any material that initiates a sweet sensation in a subject. In some embodiments, a solid/powder sweetener is used in the oral liquid formulation described herein. In other embodiments, a liquid sweetener is used in the oral liquid formulation described herein. Sugars illustratively include glucose, fructose, sucrose, xylitol, tagatose, sucralose, maltitol, isomaltulose, Isomalt™ (hydrogenated isomaltulose), lactitol, sorbitol, erythritol, trehalose, maltodextrin, polydextrose, and the like. Other sweeteners illustratively include glycerin, inulin, erythritol, maltol, acesulfame and salts thereof, e.g., acesulfame potassium, alitame, aspartame, neotame, sodium cyclamate, saccharin and salts thereof, e.g., saccharin sodium or saccharin calcium, neohesperidin dihydrochalcone, stevioside, thaumatin, and the like. Sweeteners can be used in the form of crude or refined products such as hydrogenated starch hydrolysates, maltitol syrup, high fructose corn syrup, etc., and as branded products, e.g., Sweet Am™ liquid (Product Code 918.003-propylene glycol, ethyl alcohol, and proprietary artificial flavor combination, Flavors of North America) and Sweet Am™ powder (Product Code 918.005—maltodextrin, sorbitol, and fructose combination and Product Code 918.010—water, propylene glycol, sorbitol, fructose, and proprietary natural and artificial flavor combination, Flavors of North America), ProSweet™ (1-10% proprietary plant/vegetable extract and 90-99% dextrose combination, Viriginia Dare), Maltisweet™ (maltitol solution, Ingredion), Sorbo™ (sorbitol and sorbitol/xylitol solution, SPI Polyols), Invertose™ (high fructose corn syrup, Ingredion), Rebalance M60 and X60 (sucralose and maltodextrin, Tate and Lyle), and Ora-Sweet® sugar-free flavored syrup (Paddock Laboratories, Inc.). Sweeteners can be used singly or in combinations of two or more. Suitable concentrations of different sweeteners can be selected based on published information, manufacturers’ data sheets and by routine testing. In some embodiments, the enalapril oral liquid formulation described herein comprises a sweetening agent. In some embodiments, the sweetening agent is sucralose. In some embodiments, the sweetening agent is xylitol. In some embodiments, the sweetener is not mannitol. In some embodiments, the enalapril oral liquid formulation described herein comprises sucralose. In some embodiments, sucralose is present in about 0.5 to about 0.9 mg/ml in the oral liquid formulation. In other embodiments, sucralose is present in about 0.51 mg/ml, about 0.52 mg/ml, about 0.53 mg/ml, about 0.54 mg/ml, about 0.55 mg/ml, about 0.56 mg/ml, about 0.57 mg/ml, about 0.58 mg/ml, about 0.59 mg/ml, about 0.60 mg/ml, about 0.61 mg/ml, about 0.62 mg/ml, about 0.63 mg/ml, about 0.64 mg/ml, about 0.65 mg/ml, about 0.66 mg/ml, about 0.67 mg/ml, about 0.68 mg/ml, about 0.69 mg/ml, about 0.70 mg/ml, about 0.71 mg/ml, about 0.72 mg/ml, about 0.73 mg/ml, about 0.74 mg/ml, about 0.75 mg/ml, about 0.76 mg/ml, about 0.77 mg/ml, about 0.78 mg/ml, about 0.79 mg/ml, about 0.80 mg/ml, about 0.81 mg/ml, about 0.82 mg/ml, about 0.83 mg/ml, about 0.84 mg/ml, about 0.85 mg/ml, about 0.86 mg/ml, about 0.87 mg/ml, about 0.88 mg/ml, about 0.89 mg/ml, or about 0.90 mg/ml in the oral liquid formulation. In some embodiments, sucralose is present in about 0.7 mg/ml in the oral liquid formulation. In some embodiments, sucralose is present in about 1% w/w to about 30% w/w of the solids in the oral liquid formulation. In some embodiments, sucralose is present in about 1% w/w, about 1.5% w/w, about 2% w/w, about 2.5% w/w, about 3% w/w, about 3.5% w/w, about 4% w/w, about 4.5% w/w, about 5% w/w, about 5.5% w/w, about 6% w/w, about 6.5% w/w, about 7% w/w, about 7.5% w/w, about 8% w/w, about 8.5% w/w, about 9% w/w, about 9.5% w/w, about 10% w/w, about 10.5% w/w, about 11% w/w, about 11.5% w/w, about 12% w/w, about 12.5% w/w, about 13% w/w, about 13.5% w/w, about 14% w/w, about 14.5% w/w, about 15% w/w, about 15.5% w/w, about 16% w/w, about 16.5% w/w, about 17% w/w, about 17.5% w/w, about 18% w/w, about 18.5% w/w, about 19% w/w, about 19.5% w/w, about 20% w/w, about 20.5% w/w, about 21% w/w, about 21.5% w/w, about 22% w/w, about 22.5% w/w, about 23% w/w, about 23.5% w/w, about 24% w/w, about 24.5% w/w, about 25% w/w, about 25.5% w/w, about 26% w/w, about 26.5% w/w, about 27% w/w, about 27.5% w/w, about 28% w/w, about 28.5% w/w, about 29% w/w, about 29.5% w/w, or about 30% w/w of the solids in the oral liquid formulation. In some embodiments, sucralose is present in about 8% w/w to about 18% w/w of the solids in the oral liquid formulation. In some embodiments, sucralose is present in about 9.5% w/w of the solids in the oral liquid formulation. In some embodiments, sucralose is present in about 13.5% w/w of the solids in the oral liquid formulation. In some embodiments, sucralose is present in about 16.5% w/w of the solids in the oral liquid formulation. In some embodiments, the enalapril oral liquid formulation described herein comprises xylitol. In some embodiments, xylitol is present in about 140 mg/ml to about 210 mg/ml in the oral liquid formulation. In some embodiments, xylitol is present in about 140 mg/ml, about 145 mg/ml, about 150 mg/ml, about 155 mg/ml, about 160 mg/ml, about 165 mg/ml, about 170 mg/ml, about 175 mg/ml, about 180 mg/ml, about 185 mg/ml, about 190 mg/ml, about 195 mg/ml, about 200 mg/ml, about 205 mg/ml, or about 210 mg/ml of the oral liquid formulation. In some embodiments, xylitol is present in about 150 mg/ml in the oral liquid formulation. In some embodiments, xylitol is present in about 200 mg/ml in the oral liquid formulation. In some embodiments, xylitol is present in about 80% w/w to about 99% w/w of the solids in the oral liquid formulation. In other embodiments, xylitol is present in about 80% w/w, about 81% w/w, about 82% w/w, about 83% w/w, about 84% w/w, about 85% w/w, about 86% w/w, about 87% w/w, about 88% w/w, about 89% w/w, about 90% w/w, about 91% w/w, about 92% w/w, about 93% w/w, about 94% w/w, about 95% w/w, about 96% w/w, about 97% w/w, about 98% w/w, or about 99% w/w of the solids in the oral liquid formulation. In some embodiments, xylitol is present in about 96% w/w to about 98% w/w of the solids in the oral liquid formulation. In some embodiments, xylitol is present in about 96% w/w of the solids in the oral liquid formulation. Preservative in the Enalapril Oral Liquid Formulations Preservatives include anti-microbials, anti-oxidants, and agents that enhance sterility. Exemplary preservatives include ascorbic acid, ascorbyl palmitate, BHA, BHT, citric acid, EDTA and its salts, erythorbic acid, fumaric acid, malic acid, propyl gallate, sodium ascorbate, sodium bisulfate, sodium metabisulfite, sodium sulfite, parabens (such as methylparaben, ethylparaben, propylparaben, butylparaben and their salts), benzoic acid, sodium benzoate, potassium sorbate, vanillin, and the like. In some embodiments, the enalapril oral liquid formulation described herein comprises a preservative. In some embodiments, the preservative is a paraben and the sweetener is not a sugar (such as, but not limited to glucose, fructose, sucrose, lactose, maltose) or a sugar alcohol (such as, but not limited to xylitol, mannitol, lactitol, maltitol, sorbitol). In some embodiments, the preservative is sodium benzoate. In some embodiments, modulation of the pH is desired to provide the best antimicrobial activity of the preservative, sodium benzoate. In some embodiments, the antimicrobial activity of sodium benzoate drops when the pH is increased above 5. In some embodiments, the pH of the enalapril oral liquid formulation described herein is less than about 4. In some embodiments, the pH of the enalapril oral liquid formulation described herein is less than about 3.5. In some embodiments, the pH of the enalapril oral liquid formulation described herein is between about 3 and about 4. In some embodiments, the pH of the enalapril oral liquid formulation described herein is between about 3 and about 3.5. In some embodiments, the pH of the enalapril oral liquid formulation described herein is about 3, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, or about 4. In some embodiments, the pH of the enalapril oral liquid formulation described herein is about 3.3. In some embodiments, sodium benzoate is present in about 0.2 to about 1.2 mg/ml in the oral liquid formulation. In other embodiments, sodium benzoate is present in about 0.2 mg/ml, about 0.21 mg/ml, about 0.22 mg/ml, about 0.23 mg/ml, about 0.24 mg/ml, about 0.25 mg/ml, about 0.26 mg/ml, about 0.27 mg/ml, about 0.28 mg/ml, about 0.29 mg/ml, about 0.3 mg/ml, about 0.31 mg/ml, about 0.32 mg/ml, about 0.33 mg/ml, about 0.34 mg/ml, about 0.35 mg/ml, about 0.36 mg/ml, about 0.37 mg/ml, about 0.38 mg/ml, about 0.39 mg/ml, about 0.4 mg/ml, about 0.41 mg/ml, about 0.42 mg/ml, about 0.43 mg/ml, about 0.44 mg/ml, about 0.45 mg/ml, about 0.46 mg/ml, about 0.47 mg/ml, about 0.48 mg/ml, about 0.49 mg/ml, about 0.5 mg/ml, about 0.51 mg/ml, about 0.52 mg/ml, about 0.53 mg/ml, about 0.54 mg/ml, about 0.55 mg/ml, about 0.56 mg/ml, about 0.57 mg/ml, about 0.58 mg/ml, about 0.59 mg/ml, about 0.6 mg/ml, about 0.61 mg/ml, about 0.62 mg/ml, about 0.63 mg/ml, about 0.64 mg/ml, about 0.65 mg/ml, about 0.66 mg/ml, about 0.67 mg/ml, about 0.68 mg/ml, about 0.69 mg/ml, about 0.7 mg/ml, about 0.71 mg/ml, about 0.72 mg/ml, about 0.73 mg/ml, about 0.74 mg/ml, about 0.75 mg/ml, about 0.76 mg/ml, about 0.77 mg/ml, about 0.78 mg/ml, about 0.79 mg/ml, about 0.8 mg/ml, about 0.81 mg/ml, about 0.82 mg/ml, about 0.83 mg/ml, about 0.84 mg/ml, about 0.85 mg/ml, about 0.86 mg/ml, about 0.87 mg/ml, about 0.88 mg/ml, about 0.89 mg/ml, about 0.9 mg/ml, about 0.91 mg/ml, about 0.92 mg/ml, about 0.93 mg/ml, about 0.94 mg/ml, about 0.95 mg/ml, about 0.96 mg/ml, about 0.97 mg/ml, about 0.98 mg/ml, about 0.99 mg/ml, about 1 mg/ml, about 1.01 mg/ml, about 1.02, mg/ml, about 1.03 mg/ml, about 1.04 mg/ml, about 1.05 mg/ml, about 1.06 mg/ml, about 1.07 mg/ml, about 1.08 mg/ml, about 1.09 mg/ml, about 1.1 mg/ml, about 1.11 mg/ml, about 1.12, mg/ml, about 1.13 mg/ml, about 1.14 mg/ml, about 1.15 mg/ml, about 1.16 mg/ml, about 1.17 mg/ml, about 1.18 mg/ml, about 1.19 mg/ml, or about 1.2 mg/ml in the liquid oral formulation. In some embodiments, sodium benzoate is present in about 1 mg/ml in the oral liquid formulation. In some embodiments, sodium benzoate is present in about 1% w/w to about 30% w/w of the solids in the oral liquid formulation. In other embodiments, sodium benzoate is present in about 1% w/w, about 1.5% w/w, about 2% w/w, about 2.5% w/w, about 3% w/w, about 3.5% w/w, about 4% w/w, about 4.5% w/w, about 5% w/w, about 5.5% w/w, about 6% w/w, about 6.5% w/w, about 7% w/w, about 7.5% w/w, about 8% w/w, about 8.5% w/w, about 9% w/w, about 9.5% w/w, about 10% w/w, about 10.5% w/w, about 11% w/w, about 11.5% w/w, about 12% w/w, about 12.5% w/w, about 13% w/w, about 13.5% w/w, about 14% w/w, about 14.5% w/w, about 15% w/w, about 15.1% w/w, about 15.2% w/w, about 15.3% w/w, about 15.4% w/w, about 15.5% w/w, about 15.6% w/w, about 15.7% w/w, about 15.8% w/w, about 15.9% w/w, about 16% w/w, about 16.1% w/w, about 16.2% w/w, about 16.3% w/w, about 16.4% w/w, about 16.5% w/w, about 16.6% w/w, about 16.7% w/w, about 16.8% w/w, about 16.9% w/w, about 17% w/w, about 17.1% w/w, about 17.2% w/w, about 17.3% w/w, about 17.4% w/w, about 17.5% w/w, about 17.6% w/w, about 17.7% w/w, about 17.8% w/w, about 17.9% w/w, about 18% w/w, about 18.1% w/w, about 18.2% w/w, about 18.3% w/w, about 18.4% w/w, about 18.5% w/w, about 18.6% w/w, about 18.7% w/w, about 18.8% w/w, about 18.9% w/w, about 19% w/w, about 19.1% w/w, about 19.2% w/w, about 19.3% w/w, about 19.4% w/w, about 19.5% w/w, about 19.6% w/w, about 19.7% w/w, about 19.8% w/w, about 19.9% w/w, about 20% w/w, about 20.1% w/w, about 20.2% w/w, about 20.3% w/w, about 20.4% w/w, about 20.5% w/w, about 20.6% w/w, about 20.7% w/w, about 20.8% w/w, about 20.9% w/w, about 21% w/w, about 21.1% w/w, about 21.2% w/w, about 21.3% w/w, about 21.4% w/w, about 21.5% w/w, about 21.6% w/w, about 21.7% w/w, about 21.8% w/w, about 21.9% w/w, about 22% w/w, about 22.5% w/w, about 23% w/w, about 23.5% w/w, about 24% w/w, about 24.5% w/w, about 25% w/w, about 25.5% w/w, about 26% w/w, about 26.5% w/w, about 27% w/w, about 27.5% w/w, about 28% w/w, about 28.5% w/w, about 29% w/w, about 29.5% w/w, or about 30% w/w of the solids in the oral liquid formulation. In some embodiments, sodium benzoate is present in about 10% w/w to about 25% w/w of the solids in the oral liquid formulation. In some embodiments, sodium benzoate is present in about 13.5% w/w of the solids in the oral liquid formulation. In some embodiments, sodium benzoate is present in about 19.3% w/w of the solids in the oral liquid formulation. In some embodiments, sodium benzoate is present in about 23.5% w/w of the solids in the oral liquid formulation. In some embodiments, sodium benzoate is present in about 0.1% w/w to about 1% w/w of the solids in the oral liquid formulation. In other embodiments, sodium benzoate is present in about 0.1% w/w, about 0.15% w/w, about 0.2% w/w, about 0.25% w/w, about 0.3% w/w, about 0.35% w/w, about 0.4% w/w, about 0.45% w/w, about 0.5% w/w, about 0.55% w/w, about 0.6% w/w, about 0.65% w/w, about 0.7% w/w, about 0.75% w/w, about 0.8% w/w, about 0.85% w/w, about 0.9% w/w, about 0.95% w/w, or about 1% w/w of the solids in the oral liquid formulation. In some embodiments, sodium benzoate is present in about 0.4% w/w to about 0.7% w/w of the solids in the oral liquid formulation. In some embodiments, sodium benzoate is present in about 0.45% w/w of the solids in the oral liquid formulation. In some embodiments, sodium benzoate is present in about 0.6% w/w of the solids in the oral liquid formulation. In some embodiments, sodium benzoate is present in an amount sufficient to provide antimicrobial effectiveness to the enalapril oral liquid formulation described herein. (See Table G-1). In some embodiments, the preservative is a paraben. In some embodiments, the preservative is a mixture of parabens. In some embodiments, the paraben or mixture of parabens is present in about 0.1 mg/ml to about 2 mg/ml in the oral liquid formulation. In other embodiments, the paraben or mixture of parabens is present in about 0.1 mg/ml, about 0.2 mg/ml, about 0.3 mg/ml, about 0.4 mg/ml, about 0.5 mg/ml, about 0.6 mg/ml, about 0.7 mg/ml, about 0.8 mg/ml, about 0.9 mg/ml, about 1 mg/ml, about 1.1 mg/ml, about 1.2 mg/ml, about 1.3 mg/ml, about 1.4 mg/ml, or about 1.5 mg/ml, about 1.6 mg/ml, about 1.7 mg/ml, about 1.8 mg/ml, about 1.9 mg/ml, or about 2 mg/ml in the liquid oral formulation. In some embodiments, the paraben or mixture of parabens is present in about 1.6 mg/ml to about 2 mg/ml in the oral liquid formulation. In some embodiments, the paraben or mixture of parabens is present in about 1.6 mg/ml to about 1.8 mg/ml in the oral liquid formulation. In some embodiments, the paraben or mixture of parabens is present in about 0.1 mg/ml to about 0.5 mg/ml in the oral liquid formulation. In some embodiments, the paraben or mixture of parabens is present in about 2% w/w to about 30% w/w of the solids in the oral liquid formulation. In other embodiments, the paraben or mixture of parabens is present in about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w, about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w, about 10% w/w, about 11% w/w, about 12% w/w, about 13% w/w, about 14% w/w, about 15% w/w, about 16% w/w, about 17% w/w, about 18% w/w, about 19% w/w, about 20% w/w, about 21% w/w, about 22% w/w, about 23% w/w, about 24% w/w, about 25% w/w, about 26% w/w, about 27% w/w, about 28% w/w, about 29% w/w, or about 30% w/w of the solids in the oral liquid formulation. In some embodiments, the paraben or mixture of parabens is present in about 2% w/w to about 3% w/w of the solids in the oral liquid formulation. In some embodiments, the paraben or mixture of parabens is present in about 23% w/w to about 26% w/w of the solids in the oral liquid formulation. In some embodiments, the paraben or mixture of parabens is present in about 26% w/w to about 30% w/w of the solids in the oral liquid formulation. Sweetener and preservative incompatibility Paraben preservatives (especially methylparaben) can react with selected sugars (glucose, fructose, sucrose, lactose, maltose) and sugar alcohols (xylitol, mannitol, lactitol, maltitol, sorbitol) to form transesterification reaction products. This can be undesirable from a formulation and stability standpoint as the transesterification creates additional degradants. In some embodiments, the enalapril oral liquid formulation described herein does not comprise a paraben preservative. In further embodiments, the enalapril oral liquid formulation described herein does not comprise a paraben preservative when the formulation also comprises a sugar or sugar alcohol. pH of Enalapril Oral Liquid Formulations Buffering agents maintain the pH of the liquid enalapril formulation. Non-limiting examples of buffering agents include, but are not limited to sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium glucomate, aluminum hydroxide, aluminum hydroxide/sodium bicarbonate co-precipitate, mixture of an amino acid and a buffer, a mixture of aluminum glycinate and a buffer, a mixture of an acid salt of an amino acid and a buffer, and a mixture of an alkali salt of an amino acid and a buffer. Additional buffering agents include citric acid, sodium citrate, sodium tartarate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogenphosphate, dipotassium hydrogenphosphate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate, and other calcium salts. Some buffering agents also impart effervescent qualities when a powder is reconstituted in a solution. In some embodiments, the buffering agent is not sodium bicarbonate. In some embodiments, the oral liquid formulation comprises a buffer. In some embodiments, the buffer in the enalapril oral liquid formulation described herein comprises citric acid. In some embodiments, the buffer in the enalapril oral liquid formulation described herein comprises citric acid and sodium citrate. In some embodiments, the buffer in the enalapril oral liquid formulation described herein comprises citric acid and sodium citrate dihydrate or an equivalent molar amount of sodium citrate anhydrous. hi some embodiments, the sodium citrate is monosodium citrate. In some embodiments, the sodium citrate is disodium citrate. In some embodiments, the sodium citrate is trisodium citrate. In some embodiments, the buffer in the enalapril oral liquid formulation described herein comprises phosphoric acid. In some embodiments, the buffer in the enalapril oral liquid formulation described herein comprises sodium phosphate. In some embodiments, modulation of the pH is desired to provide a lowered impurity profile. In the exemplary stability studies, the main enalapril degradants are enalapril diketopiperazine and enalaprilat: In some embodiments, the percentage of enalaprilat formation is increased when the pH is above 3.5. (See table C-2 and FIG. 1 and FIG. 2). In some embodiments, the percentage of enalapril diketopiperazine formation is slightly increased as the pH is below 4. In some embodiments, the pH of the enalapril oral liquid formulation described herein is less than about 4. In some embodiments, the pH of the enalapril oral liquid formulation described herein is less than about 3.5. In some embodiments, the pH of the enalapril oral liquid formulation described herein is between about 3 and about 4. In some embodiments, the pH of the enalapril oral liquid formulation described herein is between about 3 and about 3.5. In some embodiments, the pH of the enalapril oral liquid formulation described herein is about 3, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, or about 4. In some embodiments, the pH of the enalapril oral liquid formulation described herein is about 3.3. In some embodiments, the formation of degradants is dependent on the buffer concentration. In some embodiments, the buffer concentration impacts the taste of the enalapril oral liquid formulation. In some embodiments, the buffer concentration is between about 5 mM and about 20 mM. In some embodiments, the buffer concentration is about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 11 mM, about 12 mM, about 13 mM, about 14 mM, about 15 mM, about 16 mM, about 17 mM, about 18 mM, about 19 mM, or about 20 mM. In some embodiments, the buffer concentration is about 5 mM. In some embodiments, the buffer concentration is about 10 mM. In some embodiments, the buffer concentration is about 20 mM. In some embodiments, citric acid is present in about 0.7 to about 2 mg/ml in the oral liquid formulation. In other embodiments, citric acid is present in about 0.7 mg/ml, about 0.71 mg/ml, about 0.72 mg/ml, about 0.73 mg/ml, about 0.74 mg/ml, about 0.75 mg/ml, about 0.76 mg/ml, about 0.77 mg/ml, about 0.78 mg/ml, about 0.79 mg/ml, about 0.8 mg/ml, about 0.81 mg/ml, about 0.82 mg/ml, about 0.83 mg/ml, about 0.84 mg/ml, about 0.85 mg/ml, about 0.86 mg/ml, about 0.87 mg/ml, about 0.88 mg/ml, about 0.89 mg/ml, about 0.9 mg/mL, about 0.91 mg/mL, about 0.92 mg/mL, about 0.93 mg/mL, about 0.94 mg/mL, about 0.95 mg/mL, about 0.96 mg/mL, about 0.97 mg/mL, about 0.98 mg/mL, about 0.99 mg/mL, about 1 mg/mL, about 1.11 mg/ml, about 1.12 mg/ml, about 1.13 mg/ml, about 1.14 mg/ml, about 1.15 mg/ml, about 1.16 mg/ml, about 1.17 mg/ml, about 1.18 mg/ml, about 1.19 mg/ml, about 1.2 mg/ml, about 1.21 mg/ml, about 1.22 mg/ml, about 1.23 mg/ml, about 1.24 mg/ml, about 1.25 mg/ml, about 1.26 mg/ml, about 1.27 mg/ml, about 1.28 mg/ml, about 1.29 mg/ml, about 1.3 mg/mL, about 1.31 mg/mL, about 1.32 mg/mL, about 1.33 mg/mL, about 1.34 mg/mL, about 1.35 mg/mL, about 1.36 mg/mL, about 1.37 mg/mL, about 1.38 mg/mL, about 1.39 mg/mL, about 1.4 mg/ml, about 1.41 mg/ml, about 1.42 mg/ml, about 1.43 mg/ml, about 1.44 mg/ml, about 1.45 mg/ml, about 1.46 mg/ml, about 1.47 mg/ml, about 1.48 mg/ml, about 1.49 mg/ml, about 1.5 mg/ml, about 1.51 mg/ml, about 1.52 mg/ml, about 1.53 mg/ml, about 1.54 mg/ml, about 1.55 mg/ml, about 1.56 mg/ml, about 1.57 mg/ml, about 1.58 mg/ml, about 1.59 mg/ml, about 1.6 mg/mL, about 1.61 mg/mL, about 1.62 mg/mL, about 1.63 mg/mL, about 1.64 mg/mL, about 1.65 mg/mL, about 1.66 mg/mL, about 1.67 mg/mL, about 1.68 mg/mL, about 1.69 mg/mL, about 1.7 mg/ml, about 1.71 mg/ml, about 1.72 mg/ml, about 1.73 mg/ml, about 1.74 mg/ml, about 1.75 mg/ml, about 1.76 mg/ml, about 1.77 mg/ml, about 1.78 mg/ml, about 1.79 mg/ml, about 1.8 mg/ml, about 1.81 mg/ml, about 1.82 mg/ml, about 1.83 mg/ml, about 1.84 mg/ml, about 1.85 mg/ml, about 1.86 mg/ml, about 1.87 mg/ml, about 1.88 mg/ml, about 1.89 mg/ml, about 1.9 mg/mL, about 1.91 mg/mL, about 1.92 mg/mL, about 1.93 mg/mL, about 1.94 mg/mL, about 1.95 mg/mL, about 1.96 mg/mL, about 1.97 mg/mL, about 1.98 mg/mL, about 1.99 mg/mL, or about 2 mg/mL in the oral liquid formulation. In some embodiments, citric acid is present in about 1.65 mg/ml in the oral liquid formulation. In some embodiments, citric acid is present in about 1.82 mg/ml in the oral liquid formulation. In some embodiments, citric acid is present in about 0.82 mg/ml in the oral liquid formulation. In some embodiments, citric acid is present in about 2 to about 3.5 mg/ml in the oral liquid formulation. In other embodiments, citric acid is present in about 2 mg/mL, about 2.05 mg/mL, about 2.1 mg/mL, about 2.15 mg/mL, about 2.2 mg/mL, about 2.25 mg/mL, about 2.3 mg/mL, about 2.35 mg/mL, about 2.4 mg/mL, about 2.45 mg/mL, about 2.5 mg/mL, about 2.55 mg/mL, about 2.6 mg/mL, about 2.65 mg/mL, about 2.7 mg/mL, about 2.75 mg/mL, about 2.8 mg/mL, about 2.85 mg/mL, about 2.9 mg/mL, about 2.95 mg/mL, about 3 mg/mL, about 3.05 mg/ml, about 3.1 mg/mL, about 3.15 mg/mL, about 3.2 mg/mL, about 3.25 mg/mL, about 3.3 mg/mL, about 3.35 mg/mL, about 3.4 mg/mL, about 3.45 mg/mL, or about 3.5 mg/mL in the oral liquid formulation. In some embodiments, citric acid is present in about 3.3 mg/ml in the oral liquid formulation. In some embodiments, citric acid is present in about 10% w/w to about 50% w/w of the solids in the oral liquid formulation. In other embodiments, citric acid is present in about 10% w/w, about 11% w/w, about 12% w/w, about 13% w/w, about 14% w/w, about 15% w/w, about 16% w/w, about 17% w/w, about 18% w/w, about 19% w/w, about 20% w/w, about 21% w/w, about 22% w/w, about 23% w/w, about 24% w/w, about 25% w/w, about 26% w/w, about 27% w/w, about 28% w/w, about 29% w/w, about 30% w/w, about 31% w/w, about 32% w/w, about 33% w/w, about 34% w/w, about 35% w/w, about 36% w/w, about 37% w/w, about 38% w/w, about 39% w/w, about 40% w/w, about 41% w/w, about 42% w/w, about 43% w/w, about 44% w/w, about 45% w/w, about 46% w/w, about 47% w/w, about 48% w/w, about 49% w/w, about 50% w/w of the solids in the oral liquid formulation. In some embodiments, citric acid is present in about 45% w/w of the solids in the oral liquid formulation. In some embodiments, citric acid is present in about 31% w/w of the solids in the oral liquid formulation. In some embodiments, citric acid is present in about 35% w/w of the solids in the oral liquid formulation. In some embodiments, citric acid is present in about 19% w/w of the solids in the oral liquid formulation. In some embodiments, citric acid is present in about 1% w/w to about 5% w/w of the solids in the oral liquid formulation. In other embodiments, citric acid is present in about 1% w/w, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about 2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w, about 3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6% w/w, about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, or about 5% w/w of the solids in the oral liquid formulation. In some embodiments, citric acid is present in about 2.1% w/w of the solids in the oral liquid formulation. In some embodiments, citric acid is present in about 1.6% w/w of the solids in the oral liquid formulation. In some embodiments, sodium citrate dihydrate is present in about 0.1 to about 0.8 mg/ml in the oral liquid formulation. In other embodiments, sodium citrate dihydrate is present in the oral liquid formulation is about 0.1 mg/mL, about 0.11 mg/mL, about 0.12 mg/mL, about 0.13 mg/mL, about 0.14 mg/mL, about 0.15 mg/ml, about 0.16 mg/mL, about 0.17 mg/mL, about 0.18 mg/mL, about 0.19 mg/mL, about 0.2 mg/ml, about 0.21 mg/ml, about 0.22 mg/ml, about 0.23 mg/ml, about 0.24 mg/ml, about 0.25 mg/ml, about 0.26 mg/ml, about 0.27 mg/ml, about 0.28 mg/ml, about 0.29 mg/ml, about 0.3 mg/ml, about 0.31 mg/ml, about 0.32 mg/ml, about 0.33 mg/ml, about 0.34 mg/ml, about 0.35 mg/ml, about 0.36 mg/ml, about 0.37 mg/ml, about 0.38 mg/ml, about 0.39 mg/ml, about 0.4 mg/ml, about 0.41 mg/ml, about 0.42 mg/ml, about 0.43 mg/ml, about 0.44 mg/ml, about 0.45 mg/ml, about 0.46 mg/ml, about 0.47 mg/ml, about 0.48 mg/ml, about 0.49 mg/ml, about 0.5 mg/ml, about 0.51 mg/ml, about 0.52 mg/ml, about 0.53 mg/ml, about 0.54 mg/ml, about 0.55 mg/ml, about 0.56 mg/ml, about 0.57 mg/ml, about 0.58 mg/ml, about 0.59 mg/ml, about 0.6 mg/ml, about 0.61 mg/ml, about 0.62 mg/ml, about 0.63 mg/ml, about 0.64 mg/ml, about 0.65 mg/ml, about 0.66 mg/ml, about 0.67 mg/ml, about 0.68 mg/ml, about 0.69 mg/ml, about 0.7 mg/ml, about 0.71 mg/ml, about 0.72 mg/ml, about 0.73 mg/ml, about 0.74 mg/ml, about 0.75 mg/ml, about 0.76 mg/ml, about 0.77 mg/ml, about 0.78 mg/ml, about 0.79 mg/ml, or about 0.8 mg/ml in the oral liquid formulation. In some embodiments, sodium citrate dihydrate is present in about 0.75 mg/ml in the oral liquid formulation. In some embodiments, sodium citrate dihydrate is present in about 0.35 mg/ml in the oral liquid formulation. In some embodiments, sodium citrate dihydrate is present in about 0.2 mg/ml in the oral liquid formulation. In some embodiments, sodium citrate dihydrate is present in about 0.15 mg/ml in the oral liquid formulation. In some embodiments, sodium citrate dihydrate is present in about 1% w/w to about 15% w/w of the solids in the oral liquid formulation. In other embodiments, sodium citrate dihydrate is present in about 1% w/w, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about 2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w, about 3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.5% w/w, about 5% w/w, about 5.5% w/w, about 6% w/w, about 6.5% w/w, about 7% w/w, about 7.5% w/w, about 8% w/w, about 8.5% w/w, about 9% w/w, about 9.5% w/w, about 10% w/w, about 10.5% w/w, about 11% w/w, about 11.5% w/w, about 12% w/w, about 12.5% w/w, about 13% w/w, about 13.5% w/w, about 14% w/w, about 14.5% w/w, about 15% w/w of the solids in the oral liquid formulation. In some embodiments, sodium citrate dihydrate is present in about 10.5% w/w of the solids in the oral liquid formulation. In some embodiments, sodium citrate dihydrate is present in about 7.5% w/w of the solids in the oral liquid formulation. In some embodiments, sodium citrate dihydrate is present in about 4.5% w/w of the solids in the oral liquid formulation. In some embodiments, sodium citrate dihydrate is present in about 2.9% w/w of the solids in the oral liquid formulation. In other embodiments, sodium citrate dihydrate is not added to the formulation. Additional Excipients In further embodiments, the enalapril liquid formulation described herein comprises additional excipients including, but not limited to, glidants, flavoring agents, coloring agents and thickeners. Additional excipients such as bulking agents, tonicity agents and chelating agents are within the scope of the embodiments. Glidants are substances that improve flowability of a powder. Suitable glidants include, but are not limited to, calcium phosphate tribasic, calcium silicate, cellulose (powdered), colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, silicon dioxide, starch, talc and the like. In some embodiments, the enalapril powder formulations described herein comprise a glidant. In some embodiments the glidant is not colloidal silicon dioxide. In another embodiment, the enalapril liquid formulation comprises a flavoring agent or flavorant to enhance the taste or aroma of the formulation in liquid form. Suitable natural or synthetic flavoring agents can be selected from standard reference books, for example Fenaroli's Handbook of Flavor Ingredients, 3rd edition (1995). Non-limiting examples of suitable natural flavors, some of which can readily be simulated with synthetic agents or combinations thereof, include almond, anise, apple, apricot, bergamot, blackberry, blackcurrant, blueberry, cacao, caramel, cherry, cinnamon, clove, coffee, coriander, cranberry, cumin, dill, eucalyptus, fennel, fig, ginger, grape, grapefruit, guava, hop, lemon, licorice, lime, malt, mandarin, molasses, nutmeg, mixed berry, orange, peach, pear, peppermint, pineapple, raspberry, rose, spearmint, strawberry, tangerine, tea, vanilla, wintergreen, etc. Also useful, particularly where the formulation is intended primarily for pediatric use, is tutti-frutti or bubblegum flavor, a compounded flavoring agent based on fruit flavors. Presently preferred flavoring agents include anise, cinnamon, cacao, orange, peppermint, cherry (in particular wild cherry), grape, bubblegum, vanilla, and mixed berry. In some embodiments, the enalapril liquid formulation described herein comprises a mixed berry flavoring agent. Flavoring agents can be used singly or in combinations of two or more. In further embodiments, the enalapril liquid formulation comprises a coloring agent for identity and/or aesthetic purposes. Suitable coloring agents illustratively include FD&C Red No. 3, FD&C Red No. 20, FD&C Red No. 40, FD&C Yellow No. 6, FD&C Blue No. 2, FD&C Green No. 5, FD&C Orange No. 5, caramel, ferric oxide and mixtures thereof. Thickeners impart viscosity or weight to the resultant liquid forms from the enalapril formulation described herein. Exemplary thickeners include dextrin, cellulose derivatives (carboxymethylcellulose and its salts, ethylcellulose, hydroxyethyl cellulose, methylcellulose, hypromellose, and the like) starches, pectin, polyethylene glycol, polyethylene oxide, trehalose and certain gums (xanthan gum, locust bean gum, etc.). In certain embodiments, the enalapril liquid formulation comprises a thickener. Additional excipients are contemplated in the enalapril liquid formulation embodiments. These additional excipients are selected based on function and compatibility with the enalapril liquid formulations described herein and may be found, for example in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, (Easton, Pa.: Mack Publishing Co 1975); Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms (New York, N.Y.: Marcel Decker 1980); and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed (Lippincott Williams & Wilkins 1999), herein incorporated by reference in their entirety. Stability The main enalapril degradants are enalapril diketopiperazine and enalaprilat. The enalapril oral liquid formulations described herein are stable in various storage conditions including refrigerated, ambient and accelerated conditions. Stable as used herein refers to enalapril oral liquid formulations having about 95% or greater of the initial enalapril amount and about 5% w/w or less total impurities or related substances at the end of a given storage period. The percentage of impurities is calculated from the amount of impurities relative to the amount of enalapril. Stability is assessed by HPLC or any other known testing method. In some embodiments, the stable enalapril oral liquid formulations have about 5% w/w, about 4% w/w, about 3% w/w, about 2.5% w/w, about 2% w/w, about 1.5% w/w, about 1% w/w, or about 0.5% w/w total impurities or related substances. In other embodiments, the stable enalapril oral liquid formulations have about 5% w/w total impurities or related substances. In yet other embodiments, the stable enalapril oral liquid formulations have about 4% w/w total impurities or related substances. In yet other embodiments, the stable enalapril oral liquid formulations have about 3% w/w total impurities or related substances. In yet other embodiments, the stable enalapril oral liquid formulations have about 2% w/w total impurities or related substances. In yet other embodiments, the stable enalapril oral liquid formulations have about 1% w/w total impurities or related substances. At refrigerated condition,the enalapril oral liquid formulations described herein are stable for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, at least 30 months and at least 36 months. In some embodiments, refrigerated condition is 5±3° C. In some embodiments, refrigerated condition is about 2° C., about 2.1° C., about 2.2° C., about 2.3° C., about 2.4° C., about 2.5° C., about 2.6° C., about 2.7 ° C., about 2.8° C., about 2.9° C., about 3° C., about 3.1° C., about 3.2° C., about 3.3° C., about 3.4° C., about 3.5° C., about 3.6° C., about 3.7° C., about 3.8° C., about 3.9° C., about 4° C., about 4.1° C., about 4.2° C., about 4.3° C., about 4.4° C., about 4.5° C., about 4.6° C., about 4.7° C., about 4.8° C., about 4.9° C., about 5° C., about 5.1° C., about 5.2° C., about 5.3° C., about 5.4° C., about 5.5° C., about 5.6° C., about 5.7° C., about 5.8° C., about 5.9° C., about 6° C., about 6.1° C., about 6.2° C., about 6.3° C., about 6.4° C., about 6.5° C., about 6.6° C., about 6.7° C., about 6.8° C., about 6.9° C., about 7° C., about 7.1° C., about 7.2° C., about 7.3° C., about 7.4° C., about 7.5° C., about 7.6° C., about 7.7° C., about 7.8° C., about 7.9° C., or about 8° C. At accelerated conditions, the enalapril oral liquid formulations described herein are stable for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months or at least 12 months. Accelerated conditions for the enalapril oral liquid formulations described herein include temperature and/or relative humidity (RH) that are at or above ambient levels (e.g. 25±5° C.; 55±10% RH). In some instances, an accelerated condition is at about 25° C., about 30° C., about 35° C., about 40° C., about 45° C., about 50° C., about 55° C. or about 60° C. In other instances, an accelerated condition is above 55% RH, about 65% RH, about 70% RH, about 75% RH or about 80% RH. In further instances, an accelerated condition is about 40° C. or 60° C. at ambient humidity. In yet further instances, an accelerated condition is about 40° C. at 75±5% RH humidity. Enalapril Oral Powder Formulation In another aspect, enalapril oral liquid formulations described herein are prepared from the reconstitution of an enalapril powder formulation. In some embodiments, the enalapril powder formulation comprising enalapril, a sweetener, a preservative, and optionally an excipient is dissolved in water, a buffer, other aqueous solvent, or a liquid to form an enalapril oral liquid formulation. In one embodiment, the sweetening agent is sucralose. In one embodiment, the sweetener is not mannitol. In one embodiment, the sweetening agent is xylitol. In another embodiment, the preservative is sodium benzoate. In one embodiment, the preservative is a paraben preservative. In one aspect, the enalapril powder formulation described herein comprises enalapril, sucralose, and sodium benzoate. In some embodiments, the enalapril powder formulation herein further comprises a flavoring agent. In some embodiments, the enalapril powder formulation herein further comprises one or more buffering agents. In some embodiments, enalapril or a pharmaceutically acceptable salt thereof, is present in about 0.5% w/w to about 30% w/w of the powder formulation. In other embodiments, enalapril or a pharmaceutically acceptable salt thereof, is present in about 0.5% w/w, about 1% w/w, about 1.5% w/w, about 2% w/w, about 2.5% w/w, about 3% w/w, about 3.5% w/w, about 4% w/w, about 4.5% w/w, about 5% w/w, about 5.5% w/w, about 6% w/w, about 6.5% w/w, about 7% w/w, about 7.5% w/w, about 8% w/w, about 8.5% w/w, about 9% w/w, about 9.5% w/w, about 10% w/w, about 10.5% w/w, about 11% w/w, about 11.5% w/w, about 12% w/w, about 12.5% w/w, about 13% w/w, about 13.5% w/w, about 14% w/w, about 14.5% w/w, about 15% w/w, about 15.5% w/w, about 16% w/w, about 16.5% w/w, about 17% w/w, about 17.5% w/w, about 18% w/w, about 18.5% w/w, about 19% w/w, about 19.5% w/w, about 20% w/w, about 20.5% w/w, about 21% w/w, about 21.5% w/w, about 22% w/w, about 22.5% w/w, about 23% w/w, about 23.5% w/w, about 24% w/w, about 24.5% w/w, about w/w, about 25.5% w/w, about 26% w/w, about 26.5% w/w, about 27% w/w, about 27.5% w/w, about 28% w/w, about 28.5% w/w, about 29% w/w, about 29.5% w/w, or about 30% w/w of the powder formulation. In some embodiments, enalapril or a pharmaceutically acceptable salt thereof, is present in about 10% w/w to about 25% w/w of the powder formulation. In some embodiments, enalapril maleate is present in about 13.5% w/w of the powder formulation. In some embodiments, enalapril maleate is present in about 19.5% w/w of the powder formulation. In some embodiments, enalapril maleate is present in about 24.5% w/w of the powder formulation. In some embodiments, enalapril is present in about 10.5% w/w of the powder formulation. In some embodiments, enalapril is present in about 14.5% w/w of the powder formulation. In some embodiments, enalapril is present in about 18% w/w of the powder formulation. In some embodiments, enalapril or a pharmaceutically acceptable salt thereof, is present in about 0.1% w/w to about 1% w/w of the powder formulation. In other embodiments, enalapril or a pharmaceutically acceptable salt thereof, is present in about 0.1% w/w, about 0.15% w/w, about 0.2% w/w, about 0.25% w/w, about 0.3% w/w, about 0.35% w/w, about 0.4% w/w, about 0.45% w/w, about 0.5% w/w, about 0.55% w/w, about 0.6% w/w, about 0.65% w/w, about 0.7% w/w, about 0.75% w/w, about 0.8% w/w, about 0.85% w/w, about 0.9% w/w, about 0.95% w/w, or about 1% w/w of the powder formulation. In some embodiments, enalapril or a pharmaceutically acceptable salt thereof, is present in about 0.4% w/w to about 0.7% w/w of the powder formulation. In some embodiments, enalapril maleate is present in about 0.45% w/w of the powder formulation. In some embodiments, enalapril maleate is present in about 0.6% w/w of the powder formulation. In some embodiments, enalapril is present in about 0.4% w/w of the powder formulation. In some embodiments, enalapril is present in about 0.5% w/w of the powder formulation. Various amounts and concentrations of other components (sweeteners, buffers, preservatives, and the like) in the enalapril powder formulations are found in the previous section describing the amounts and concentrations for the analogous enalapril oral liquid formulations. For example, in some embodiments where sucralose is present in about 1% w/w to about 30% w/w of the solids in the oral liquid formulation; in an analogous enalapril powder formulation, sucralose would be about 1% w/w to about 30% w/w in the powder formulation. In some embodiments where sodium benzoate is present in about 1% w/w to about 30% w/w of the solids in the oral liquid formulation, in an analogous enalapril powder formulation sodium benzoate is present in about 1% w/w to about 30% w/w in the powder formulation. Liquid vehicles suitable for the enalapril powder formulations to be reconstituted into an oral solution described herein are selected for a particular oral liquid formulation (solution, suspension, etc.) as well as other qualities such as clarity, toxicity, viscosity, compatibility with excipients, chemical inertness, palatability, odor, color and economy. Exemplary liquid vehicles include water, ethyl alcohol, glycerin, propylene glycol, syrup (sugar or other sweetener based, e.g., Ora-Sweet® SF sugar-free flavored syrup), juices (apple, grape, orange, cranberry, cherry, tomato and the like), other beverages (tea, coffee, soft drinks, milk and the like), oils (olive, soybean, corn, mineral, castor and the like), and combinations or mixtures thereof. Certain liquid vehicles, e.g., oil and water, can be combined together to form emulsions. In some embodiments, water is used for as a vehicle for a enalapril oral liquid formulation. In other embodiments, a syrup is used for as a vehicle for a enalapril oral liquid formulation. In yet other embodiments, a juice is used for as a vehicle for a enalapril oral liquid formulation. Buffering agents maintain the pH of the liquid enalapril formulation. Non-limiting examples of buffering agents include, but are not limited to sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate, aluminum hydroxide, aluminum hydroxide/sodium bicarbonate co precipitate, mixture of an amino acid and a buffer, a mixture of aluminum glycinate and a buffer, a mixture of an acid salt of an amino acid and a buffer, and a mixture of an alkali salt of an amino acid and a buffer. Additional buffering agents include citric acid, sodium citrate, sodium tartrate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogenphosphate, dipotassium hydrogenphosphate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate, and other calcium salts. Some buffering agents also impart effervescent qualities when a powder is reconstituted in a solution. In some embodiments, the reconstituted oral liquid formulation comprises a buffer. In some embodiments, the buffer comprises citric acid and sodium citrate. In further embodiments, the enalapril powder formulation described herein comprises additional excipients including, but not limited to, glidants, flavoring agents, coloring agents and thickeners. Additional excipients such as bulking agents, tonicity agents and chelating agents are within the scope of the embodiments. Glidants are substances that improve flowability of a powder. Suitable glidants include, but are not limited to, calcium phosphate tribasic, calcium silicate, cellulose (powdered), colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, silicon dioxide, starch, talc and the like. In some embodiments, the enalapril powder formulations described herein comprise a glidant. In another embodiment, the enalapril powder formulation described herein comprises a flavoring agent or flavorant to enhance the taste or aroma of the formulation in liquid form. Suitable natural or synthetic flavoring agents can be selected from standard reference books, for example Fenaroli's Handbook of Flavor Ingredients, 3rd edition (1995). Non-limiting examples of suitable natural flavors, some of which can readily be simulated with synthetic agents or combinations thereof, include almond, anise, apple, apricot, bergamot, blackberry, blackcurrant, blueberry, cacao, caramel, cherry, cinnamon, clove, coffee, coriander, cranberry, cumin, dill, eucalyptus, fennel, fig, ginger, grape, grapefruit, guava, hop, lemon, licorice, lime, malt, mandarin, molasses, nutmeg, mixed berry, orange, peach, pear, peppermint, pineapple, raspberry, rose, spearmint, strawberry, tangerine, tea, vanilla, wintergreen, etc. Also useful, particularly where the formulation is intended primarily for pediatric use, is tutti-frutti or bubblegum flavor, a compounded flavoring agent based on fruit flavors. Presently preferred flavoring agents include anise, cinnamon, cacao, orange, peppermint, cherry (in particular wild cherry), grape, bubblegum, vanilla, and mixed berry. Flavoring agents can be used singly or in combinations of two or more. In further embodiments, the enalapril powder formulation described herein comprises a coloring agent for identity and/or aesthetic purposes. Suitable coloring agents illustratively include FD&C Red No. 3, FD&C Red No. 20, FD&C Red No. 40, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, caramel, ferric oxide and mixtures thereof In further embodiments, the enalapril powder formulation described herein comprises a thickener. Thickeners impart viscosity or weight to the resultant liquid forms from the enalapril formulation described herein. Exemplary thickeners include dextrin, cellulose derivatives (carboxymethylcellulose and its salts, ethylcellulose, hydroxyethyl cellulose, methylcellulose, hypromellose, and the like) starches, pectin, polyethylene glycol, polyethylene oxide, trehalose and certain gums (xanthan gum, locust bean gum, etc.). Additional excipients are contemplated in the enalapril powder formulation embodiments. These additional excipients are selected based on function and compatibility with the the enalapril powder formulation described herein and may be found, for example in Remington: The Science and Practice of Pharmacy, Nineteeth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, (Easton, Pa.: Mack Publishing Co 1975); Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms (New York, N.Y.: Marcel Decker 1980); and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed (Lippincott Williams & Wilkins 1999), herein incorporated by reference in their entirety. In some embodiments, the enalapril oral liquid formulation prepared from the powder formulations described herein are homogenous. Homogenous liquids as used herein refer to those liquids that are uniform in appearance, identity, consistency and drug concentration per volume. Non-homogenous liquids include such liquids that have varied coloring, viscosity and/or aggregation of solid particulates, as well as non-uniform drug concentration in a given unit volume. Homogeneity in liquids are assessed by qualitative identification or appearance tests and/or quantitative HPLC testing or the like. The mixing methods and excipients described herein are selected to impart a homogenous quality to a resultant enalapril oral liquid formulation. Mixing methods encompass any type of mixing that result in a homogenous enalapril oral liquid formulation. In some embodiments, a quantity of an enalapril powder formulation is added to a liquid vehicle and then mixed by a stirring, shaking, swirling, agitation element or a combination thereof. In certain instances, a fraction of a enalapril powder formulation (i.e., one-half, one-third, one-fourth, etc.) is added to a liquid vehicle, mixed by stirring, shaking, swirling, agitation or a combination thereof, and the subsequent powder fraction(s) is added and mixed. In other embodiments, a liquid vehicle is added to an enalapril powder formulation in a container, for example, a bottle, vial, bag, beaker, syringe, or the like. The container is then mixed by stirring, shaking, swirling, agitation, inversion or a combination thereof. In certain instances, a fractional volume of the liquid vehicle (i.e., one-half, one-third, one-fourth volume, etc.) is added to a enalapril powder formulation in a container, mixed by stirring, shaking, swirling, agitation, inversion or a combination thereof; and the subsequent liquid fraction(s) is added and mixed. In certain instances, a one-half fractional volume of the liquid vehicle is added to an enalapril powder formulation in a container and mixing by shaking; the other one-half fractional volume of the liquid vehicle is then subsequently added and mixed. In any of the above embodiments, mixing (i.e., stirring, shaking, swirling, agitation, inversion or a combination thereof) occurs for a certain time intervals such as about 10 seconds, about 20 seconds, about 30 seconds, about 45 seconds, about 60 seconds, about 90 seconds, about 120 seconds, about 2.5 minutes, about 3 minutes, about 3.5 minutes, about 4 minutes, or about 5 minutes. In embodiments, where there are two or more mixing steps, the time intervals for each mixing can be the same (e.g., 2×10 seconds) or different (e.g., 10 seconds for first mixing and 20 seconds for second mixing) In any of the above embodiments, a enalapril oral liquid formulation is allowed to stand for a period of time such as about 10 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours or about 2 hours, to allow any air bubbles resultant from any of the mixing methods to dissipate. Stability of Enalapril Powder Formulation The enalapril powder formulations described herein are stable in various storage conditions including refrigerated, ambient and accelerated conditions. Stable as used herein refer to enalapril powder formulations having about 95% or greater of the initial enalapril amount and 5% w/w or less total impurities or related substances at the end of a given storage period. The percentage of impurities is calculated from the amount of impurities relative to the amount of enalapril. Stability is assessed by HPLC or any other known testing method. In some embodiments, the stable enalapril powder formulations have about 5% w/w, about 4% w/w, about 3% w/w, about 2.5% w/w, about 2% w/w, about 1.5% w/w, about 1% w/w, or about 0.5% w/w total impurities or related substances. In other embodiments, the stable enalapril powder formulations have about 5% w/w total impurities or related substances. In yet other embodiments, the stable enalapril powder formulations have about 4% w/w total impurities or related substances. In yet other embodiments, the stable enalapril powder formulations have about 3% w/w total impurities or related substances. In yet other embodiments, the stable enalapril powder formulations have about 2% w/w total impurities or related substances. In yet other embodiments, the stable enalapril powder formulations have about 1% w/w total impurities or related substances. At refrigerated and ambient conditions, in some embodiments, the enalapril powder formulations described herein are stable for at least 1 week, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 16 weeks, 20 weeks, at least 24 weeks, at least 30 weeks, or at least 36 weeks. At accelerated conditions, in some embodiments, the enalapril powder formulations described herein are stable for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks or at least 12 weeks. Accelerated conditions for the enalapril powder formulations described herein include temperature and/or relative humidity (RH) that are above ambient levels (e.g. 25±4° C.; 55±10% RH). In some instances, an accelerated condition is at about 30° C., about 35° C., about 40° C., about 45° C., about 50° C., about 55° C. or about 60° C. In other instances, an accelerated condition is above 65% RH, about 70% RH, about 75% RH or about 80% RH. In further instances, an accelerated condition is about 40° C. or 60° C. at ambient humidity. In yet further instances, an accelerated condition is about 40° C. at 75±5% RH humidity. Kits and Articles of Manufacture For the enalapril powder and liquid formulations described herein, kits and articles of manufacture are also described. Such kits can comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein including an enalapril powder or liquid formulation. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers can be formed from a variety of materials such as glass or plastic. A kit will typically may comprise one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user standpoint for an enalapril powder or liquid formulation described herein. Non-limiting examples of such materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and package inserts with instructions for use associated with an enalapril powder or liquid formulation. A set of instructions will also typically be included. A label can be on or associated with the container. A label can be on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label can be associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. A label can be used to indicate that the contents are to be used for a specific therapeutic application. The label can also indicate directions for use of the contents, such as in the methods described herein. Methods Provided herein, in one aspect, are methods of treatment comprising administration of the enalapril oral liquid formulations described herein to a subject. In some embodiments, the enalapril oral liquid formulations described herein treat hypertension in a subject. Hypertension as used herein includes both primary (essential) hypertension and secondary hypertension. In certain instances, hypertension is classified in cases when blood pressure values are greater than or equal to 140/90 (systolic/diastolic) mm Hg in a subject. In certain instances, the enalapril oral liquid formulations described herein treat a subject having a blood pressure values are greater than or equal to 140/90 mm Hg. In certain instances, the enalapril oral liquid formulations described herein treat primary (essential) hypertension in a subject. In other instances, the enalapril oral liquid formulations described herein treat secondary hypertension in a subject. In other embodiments, the enalapril oral liquid formulations described herein treat prehypertension in a subject. Prehypertension as used herein refers to cases where a subject's blood pressure is elevated above normal but not to the level considered to be hypertension. In some instances, prehypertension is classified in cases when blood pressure values are 120-139/80-89 mm Hg. In certain instances, the enalapril oral liquid formulations described herein treat a subject having blood pressure values of 120-139/80-89 mm Hg. In yet other embodiments, the enalapril oral liquid formulations described herein are prophylactically administered to subjects suspected of having, predisposed to, or at risk of developing hypertension. In some embodiments, the administration of enalapril oral liquid formulations described herein allow for early intervention prior to onset of hypertension. In certain embodiments, upon detection of a biomarker, environmental, genetic factor, or other marker, the enalapril oral liquid formulations described herein are prophylactically administered to subjects. In further embodiments, the enalapril oral liquid formulations described herein treat heart failure (e.g., symptomatic congestive), asymptomatic left ventricular dysfunction, myocardial infarction, diabetic nephropathy and chronic renal failure. In certain instances, the enalapril oral liquid formulations described herein treat symptomatic congestive heart failure. In other instances, the enalapril oral liquid formulations described herein treat asymptomatic left ventricular dysfunction. In further instances, the enalapril oral liquid formulations described herein treat myocardial infarction. In yet further instances, the enalapril oral liquid formulations described herein treat diabetic nephropathy. In yet further instances, the enalapril oral liquid formulations described herein treat chronic renal failure. Dosing In one aspect, the enalapril oral liquid formulations are used for the treatment of diseases and conditions described herein. In addition, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of enalapril oral liquid formulations in therapeutically effective amounts to said subject. Dosages of enalapril oral liquid formulations described can be determined by any suitable method. Maximum tolerated doses (MTD) and maximum response doses (MRD) for enalapril and/or enalaprilat can be determined via established animal and human experimental protocols as well as in the examples described herein. For example, toxicity and therapeutic efficacy of enalapril and/or enalaprilat can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50. Enalapril dosages exhibiting high therapeutic indices are of interest. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. Additional relative dosages, represented as a percent of maximal response or of maximum tolerated dose, are readily obtained via the protocols. In some embodiments, the amount of a given enalapril oral liquid formulation that corresponds to such an amount varies depending upon factors such as the particular enalapril salt or form, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but can nevertheless be determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the liquid composition type, the condition being treated, and the subject or host being treated. In some embodiments, the enalapril oral liquid formulations described herein are provided in a dose per day from about 0.01 mg to 100 mg, from about 0.1 mg to about 80 mg, from about 1 to about 60, from about 2 mg to about 40 mg of enalapril. In certain embodiments, the enalapril oral liquid formulations described herein are provided in a daily dose of about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.4 mg, about 0.6 mg, about 0.8 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 76, mg, about 80 mg, about 85 mg, about 90 mg or about 100 mg, or any range derivable therein. In certain instances, the enalapril oral liquid formulations described herein are provided in a dose per day of about 1 mg. In certain instances, the enalapril oral liquid formulations described herein are provided in a dose per day of about 2 mg. In certain instances, the enalapril oral liquid formulations described herein are provided in a dose per day of about 3 mg. In certain instances, the enalapril oral liquid formulations described herein are provided in a dose per day of about 4 mg. In certain instances, the enalapril oral liquid formulations described herein are provided in a dose per day of about 5 mg. In certain instances, the enalapril oral liquid formulations described herein are provided in a dose per day of about 6 mg. In certain instances, the enalapril oral liquid formulations described herein are provided in a dose per day of about 7 mg. In certain instances, the enalapril oral liquid formulations described herein are provided in a dose per day of about 8 mg. In certain instances, the enalapril oral liquid formulations described herein are provided in a dose per day of about 9 mg. In certain instances, the enalapril oral liquid formulations described herein are provided in a dose per day of about 10 mg. In certain instances, the enalapril oral liquid formulations described herein are provided in a dose per day of about 11 mg. In certain instances, the enalapril oral liquid formulations described herein are provided in a dose per day of about 12 mg. The dose per day described herein can be given once per day or multiple times per day in the form of sub-doses given b.i.d., t.i.d., q.i.d., or the like where the number of sub-doses equal the dose per day. In further embodiments, the daily dosages appropriate for the enalapril oral liquid formulations described herein are from about 0.01 to about 1.0 mg/kg per body weight. In one embodiment, the daily dosages appropriate for the enalapril oral liquid formulations are from about 0.02 to about 0.8 mg/kg enalapril per body weight. In another embodiment, the daily dosage appropriate for the enalapril oral liquid formulations are from about 0.05 to about 0.6 mg/kg per body weight. In another embodiment, the daily dosage appropriate for the enalapril oral liquid formulations is about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about 0.10 mg/kg, about 0.15 mg/kg, about 0.20 mg/kg, about 0.25 mg/kg, about 0.30 mg/kg, about 0.40 mg/kg, about 0.50 mg/kg, or about 0.60 mg/kg. In other embodiments the enalapril oral liquid formulations are provided at the maximum tolerated dose (MTD) for enalapril and/or enalaprilat. In other embodiments, the amount of the enalapril oral liquid formulations administered is from about 10% to about 90% of the maximum tolerated dose (MTD), from about 25% to about 75% of the MTD, or about 50% of the MTD. In particular embodiments, the amount of the enalapril oral liquid formulations administered is from about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or higher, or any range derivable therein, of the MTD for enalapril and/or enalaprilat. In further embodiments, the enalapril oral liquid formulations are provided in a dosage that is similar, comparable or equivalent to a dosage of a known enalapril tablet formulation. In other embodiments, the enalapril oral liquid formulations are provided in a dosage that provides a similar, comparable or equivalent pharmacokinetic parameters (e.g., AUC, Cmax, Tmax, Cmin, T1/2) as a dosage of a known enalapril tablet formulation. Similar, comparable or equivalent pharmacokinetic parameters, in some instances, refer to within 80% to 125%, 80% to 120%, 85% to 125%, 90% to 110%, or increments therein, of the given values. It should be recognized that the ranges can, but need not be symmetrical, e.g., 85% to 105%. Administration Administration of an enalapril oral liquid formulation is at a dosage described herein or at other dose levels and formulations determined and contemplated by a medical practitioner. In certain embodiments, the enalapril oral liquid formulations described herein are administered for prophylactic and/or therapeutic treatments. In certain therapeutic applications, the enalapril oral liquid formulations are administered to a patient already suffering from a disease, e.g., hypertension, in an amount sufficient to cure the disease or at least partially arrest or ameliorate the symptoms, e.g., lower blood pressure. Amounts effective for this use depend on the severity of the disease, previous therapy, the patient's health status, weight, and response to the enalapril formulations, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation clinical trial. In prophylactic applications, the enalapril oral liquid formulations described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, e.g., hypertension. Such an amount is defined to be a “prophylactically effective amount or dose.” In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in a patient, effective amounts for this use will depend on the risk or susceptibility of developing the particular disease, previous therapy, the patient's health status and response to the enalapril formulations, and the judgment of the treating physician. In certain embodiments wherein the patient's condition does not improve, upon the doctor's discretion the administration of an enalapril oral liquid formulations described herein are administered chronically, that is, for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disease. In other embodiments, administration of an enalapril oral liquid formulation continues until complete or partial response of a disease. In certain embodiments wherein a patient's status does improve, the dose of an enalapril oral liquid formulation being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”). In specific embodiments, the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, and 365 days. The dose reduction during a drug holiday is, by way of example only, by 10%400%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%. In some embodiments, enalapril oral liquid formulations described herein are administered chronically. For example, in some embodiments, an enalapril oral liquid formulation is administered as a continuous dose, i.e., administered daily to a subject. In some other embodiments, enalapril oral liquid formulations described herein are administered intermittently (e.g. drug holiday that includes a period of time in which the formulation is not administered or is administered in a reduced amount). In some embodiments an enalapril oral liquid formulation is administered to a subject who is in a fasted state. A fasted state refers to a subject who has gone without food or fasted for a certain period of time. General fasting periods include at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 14 hours and at least 16 hours without food. In some embodiments, an enalapril oral liquid formulation is administered orally to a subject who is in a fasted state for at least 8 hours. In other embodiments, an enalapril oral liquid formulation is administered to a subject who is in a fasted state for at least 10 hours. In yet other embodiments, an enalapril oral liquid formulation is administered to a subject who is in a fasted state for at least 12 hours. In other embodiments, an enalapril oral liquid formulation is administered to a subject who has fasted overnight. In other embodiments an enalapril oral liquid formulation is administered to a subject who is in a fed state. A fed state refers to a subject who has taken food or has had a meal. In certain embodiments, an enalapril oral liquid formulation is administered to a subject in a fed state 5 minutes post-meal, 10 minutes post-meal, 15 minutes post-meal, 20 minutes post-meal, 30 minutes post-meal, 40 minutes post-meal, 50 minutes post-meal, 1 hour post-meal, or 2 hours post-meal. In certain instances, an enalapril oral liquid formulation is administered to a subject in a fed state 30 minutes post-meal. In other instances, an enalapril oral liquid formulation is administered to a subject in a fed state 1 hour post-meal. In yet further embodiments, an enalapril oral liquid formulation is administered to a subject with food. In further embodiments described herein, an enalapril oral liquid formulation is administered at a certain time of day for the entire administration period. For example, an enalapril oral liquid formulation can be administered at a certain time in the morning, in the evening, or prior to bed. In certain instances, an enalapril oral liquid formulation is administered in the morning. In other embodiments, an enalapril oral liquid formulation can be administered at different times of the day for the entire administration period. For example, an enalapril oral liquid formulation can be administered on 8:00 am in the morning for the first day, 12 pm noon for the next day or administration, 4 pm in the afternoon for the third day or administration, and so on. Further Combinations The treatment of certain diseases or conditions (e.g., hypertension, heart failure, myocardial infarction and the like) in a subject with an enalapril oral liquid formulation described herein encompass additional therapies and treatment regimens with other agents in some embodiments. Such additional therapies and treatment regimens can include another therapy, e.g., additional anti-hypertensives, for treatment of the particular disease or condition in some embodiments. Alternatively, in other embodiments, additional therapies and treatment regimens include other agents used to treat adjunct conditions associated with the disease or condition or a side effect from the enalapril oral liquid formulation in the therapy. Additional agents for use in combination with an enalapril oral liquid formulation described herein include, but are not limited to, diuretics (loop, thiazide, potassium-sparing, and the like), beta blockers (metoprolol, propanolol, pronethalol, and the like), alpha blockers (phentolamine, phenoxybenzamine, tamsulosin, prazosin, and the like), mixed alpha and beta blockers (bucindolol, carvedilol, labetalol), calcium channel blockers (dihydropyridines such as nifedipine, amlodipine, etc., dilitazem, verapamil and the like), angiotensin II receptor antagonists (saralasin, lsartan, eprosartin, irbesartan, valsartan, and the like), other ACE inhibitors (captopril, quinapril, ramipril, lisinopril, zofenopril, and the like), aldosterone antagonists (eplerenone, spironolactone and the like), vasodilators (hydralazine and the like) and alpha-2 agonists (clonidine, moxonidine, guanabenz and the like). Certain Definitions Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments described herein, certain preferred methods, devices, and materials are now described. As used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural reference unless the context clearly dictates otherwise. Thus, for example, reference to “an excipient” is a reference to one or more excipients and equivalents thereof known to those skilled in the art, and so forth. The term “about” is used to indicate that a value includes the standard level of error for the device or method being employed to determine the value. The use of the term “or” in the claims is used to mean “and/or” unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and to “and/or.” The terms “comprise,” “have” and “include” are open-ended linking verbs. Any forms or tenses of one or more of these verbs, such as “comprises,” “comprising,” “has,” “having,” “includes” and “including,” are also open-ended. For example, any method that “comprises,” “has” or “includes” one or more steps is not limited to possessing only those one or more steps and also covers other unlisted steps. “Optional” or “optionally” may be taken to mean that the subsequently described structure, event or circumstance may or may not occur, and that the description includes instances where the events occurs and instances where it does not. As used herein, the term “therapeutic” means an agent utilized to treat, combat, ameliorate, prevent or improve an unwanted condition or disease of a patient. In some embodiments, a therapeutic agent such as enalapril is directed to the treatment and/or the amelioration of, reversal of, or stabilization of the symptoms of hypertension described herein. “Administering” when used in conjunction with a therapeutic means to administer a therapeutic systemically or locally, as directly into or onto a target tissue, or to administer a therapeutic to a patient whereby the therapeutic positively impacts the tissue to which it is targeted. Thus, as used herein, the term “administering”, when used in conjunction with an enalapril formulation, can include, but is not limited to, providing an enalapril formulation into or onto the target tissue; providing an enalapril formulation systemically to a patient by, e.g., oral administration whereby the therapeutic reaches the target tissue or cells. “Administering” a formulation may be accomplished by injection, topical administration, and oral administration or by other methods alone or in combination with other known techniques. The term “animal” as used herein includes, but is not limited to, humans and non-human vertebrates such as wild, domestic and farm animals. As used herein, the terms “patient,” “subject” and “individual” are intended to include living organisms in which certain conditions as described herein can occur. Examples include humans, monkeys, cows, sheep, goats, dogs, cats, mice, rats, and transgenic species thereof. In a preferred embodiment, the patient is a primate. In certain embodiments, the primate or subject is a human. In certain instances, the human is an adult. In certain instances, the human is child. In further instances, the human is 12 years of age or younger. In certain instances, the human is elderly. In other instances, the human is 60 years of age or older. Other examples of subjects include experimental animals such as mice, rats, dogs, cats, goats, sheep, pigs, and cows. The experimental animal can be an animal model for a disorder, e.g., a transgenic mouse with hypertensive pathology. A patient can be a human suffering from hypertension, or its variants or etiological forms. By “pharmaceutically acceptable”, it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The term “pharmaceutical composition” shall mean a composition comprising at least one active ingredient, whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human). Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan. A “therapeutically effective amount” or “effective amount” as used herein refers to the amount of active compound or pharmaceutical agent that elicits a biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease, (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology), and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology). As such, a non-limiting example of a “therapeutically effective amount” or “effective amount” of a formulation of the present disclosure may be used to inhibit, block, or reverse the activation, migration, or proliferation of cells or to effectively treat hypertension or ameliorate the symptoms of hypertension. The terms “treat,” “treated,” “treatment,” or “treating” as used herein refers to both therapeutic treatment in some embodiments and prophylactic or preventative measures in other embodiments, wherein the object is to prevent or slow (lessen) an undesired physiological condition, disorder or disease, or to obtain beneficial or desired clinical results. For the purposes described herein, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. A prophylactic benefit of treatment includes prevention of a condition, retarding the progress of a condition, stabilization of a condition, or decreasing the likelihood of occurrence of a condition. As used herein, “treat,” “treated,” “treatment,” or “treating” includes prophylaxis in some embodiments. EXAMPLES Example A Effect of pH on the Formation of Degradants in Enalapril Formulations at 60° C. Formulations were prepared containing enalapril maleate according to Table A-1. The pH of each solution was recorded. Five milliliters of each formulation were transferred to each of four 3-dram glass screw-capped vials with Teflon inserts in the caps. The vials were placed into a 60° C. heating chamber then one vial removed and analyzed by HPLC at times of zero, ˜97 and ˜180 hours. TABLE A-1 Formulation (in mg/mL) of Enalapril Formulations at Varying pH and Citrate Buffer Concentration Formulation (mM citrate) Component A1 (50) A2 (50) A3 (50) A4 (50) A5 (50) A6 (25) Enalapril maleate 1.0 1.0 1.0 1.0 1.0 1.0 Mannitol 50 50 50 50 6.0 Xylitol 50 Citric acid, anhydrous 7.35 5.05 2.55 5.05 5.05 2.76 Sodium citrate, dihydrate 3.45 7.0 10.8 7.0 7.0 3.15 Sodium benzoate 1 1 1 1 1 Methylparaben sodium 1.75 0.335 Propylparaben sodium 0.095 Potassium sorbate 1 Sucralose 0.75 0.75 0.75 0.75 0.75 0.75 Silicon dioxide 0.075 Mixed berry flavor (powdered) 0.5 0.5 0.5 0.5 0.5 0.5 Water qs qs qs qs qs qs pH 3.4 4.4 5.2 4.4 4.5 4.4 qs = sufficient quantity The results of the HPLC analysis for the two main degradants in the samples, enalapril diketopiperazine and enalaprilat, are provided in Table A-2. TABLE A-2 Primary Degradants Present in the Formulations (% w/w of enalapril maleate) Formulation Hours at 60° C. A1 A2 A3 A4 A5 A6 Enalapril Diketopiperazine 0 0.04 0.03 0.03 0.03 0.03 0.03 97 3.10 0.88 0.33 0.86 0.70 0.53 180 6.21 1.77 0.75 1.73 1.43 1.07 Enalaprilat 0 0.09 0.15 0.29 0.14 0.16 0.12 97 5.20 16.9 47.4 16.1 20.3 15.6 180 9.94 34.8 113 33.5 42.2 31.7 Example B Effect of Buffer Concentration on the Formation of Degradants in Enalapril Formulations at 60° C. Formulations were prepared containing enalapril maleate according to Table B-1. The pH of each solution was measured and adjusted as needed to pH 3.3 with ˜1N HCl or ˜0.5N NaOH. Five milliliters of each formulation were transferred to each of six 3-dram glass screw-capped vials with Teflon inserts in the caps. The vials were placed into a 60° C. heating chamber then two vials were removed and analyzed by HPLC at times of zero, ˜66 and ˜139 hours. TABLE B-1 Formulation (in mg/mL) of Enalapril Maleate Formulations at Varying Citrate Buffer Concentrations Formulation B1 (5 mM B2 (10 mM B3 (20 mM Component citrate) citrate) citrate) Enalapril maleate 1.0 1.0 1.0 Citric acid, anhydrous 0.82 1.65 3.29 Sodium citrate, anhydrous 0.19 0.38 0.75 Sodium benzoate 1.0 1.0 1.0 Sucralose 0.7 0.7 0.7 Mixed berry flavor (powdered) 0.5 0.5 0.5 Water qs qs qs pH 3.3 3.3 3.3 qs = sufficient quantity The results of the HPLC analysis for the two main degradants in the samples, enalapril diketopiperazine and enalaprilat, are provided in Table B-2. TABLE B-2 Primary Degradants Present in the Formulations (% w/w of enalapril maleate) Formulation B2 Hours at 60° C. B1 (5 mM citrate) (10 mM citrate) B3 (20 mM citrate) Enalapril Diketopiperazine 0 0.01 0.01 0.01 66 1.57 1.63 1.79 139 3.70 3.94 4.24 Enalaprilat 0 0.00 0.00 0.00 66 2.98 2.88 3.19 139 5.28 5.23 5.69 Example C Stability of Enalapril Maleate Formulations Containing Paraben Preservatives Powder formulations were prepared according to Table C-1. All components in each formulation except mannitol or xylitol were added to a 2.5 liter polypropylene screw capped bottle. The bottle was mixed by inversion in a Turbula° mixer for 5 minutes. The mannitol or xylitol was then added and the components mixed for 5 minutes, then the other half of the mannitol or xylitol was added and a final mix of 5 minutes was completed. One liter of solution formulation was prepared for each formulation by adding an appropriate amount of each powdered formulation to a 1 liter volumetric flask and adding about 500 mL water. The powder was dissolved with mixing then the contents of the flask were brought to 1 liter with additional water. The amount of powder to add was determined such that the final concentration of enalapril maleate was 1.0 mg/mL. Fifty milliliter aliquots of each formulation were placed into HDPE bottles. The bottles were screw-capped and placed into storage at 5° C.±3° C., at room temperature (19-23° C.) and at 40° C.±2° C. At various times, bottles were removed from the storage condition and analyzed. TABLE C-1 Composition of Enalapril Maleate Formulations Component C1 C2 C3 C4 C5 Powder Formulation (grams) Enalapril maleate 12.3 12.3 8.86 2.16 2.16 Mannitol 74.4 74.4 394.0 Xylitol 96.6 93.7 Citric acid, anhydrous 28.6 35.6 28.4 5.40 5.40 Sodium citrate, 24.5 14.7 7.73 4.10 4.10 anhydrous Sodium methylparaben 4.17 4.17 8.86 2.16 2.16 Sodium propylparaben 1.10 1.10 Potassium sorbate 12.3 12.3 Sodium benzoate 8.86 2.16 2.16 Xanthan Gum 1.62 Colloidal silicon dioxide 0.859 0.859 4.43 1.08 Sucralose 9.20 9.20 6.64 1.62 1.62 Mixed berry flavor 6.13 6.13 4.43 1.08 1.08 Total solids 173.5 170.7 472.3 115.2 115.2 Liquid Formulations (mg/mL) Enalapril maleate 1.00 1.00 1.00 1.00 1.00 Mannitol 6.07 6.07 44.5 Xylitol 44.7 43.4 Citric acid, anhydrous 2.33 2.90 3.21 2.50 2.50 Sodium citrate, 2.00 1.20 0.87 1.90 1.90 anhydrous Sodium methylparaben 0.34 0.34 1.00 1.00 1.00 Sodium propylparaben 0.09 0.09 1.00 Potassium sorbate 1.00 1.00 Sodium benzoate 1.00 1.00 1.00 Xanthan Gum 0.75 Colloidal silicon dioxide 0.07 0.07 0.50 0.50 Sucralose 0.75 0.75 0.75 0.75 0.75 Mixed berry flavor 0.50 0.50 0.50 0.50 0.50 pH (measured) 4.4 3.8 3.7 4.4 4.6 The results of the HPLC analysis for the diketopiperazine and enalaprilat degradants in the samples are provided in Table C-2. TABLE C-2 Degradant Content After Storage (% w/w of enalapril maleate) Storage Formulation ° C. Weeks C1 C2 C3 C4 C5 Liquid Formulations Diketopiperazine 5 0 0.03 0.04 0.04 0.02 0.02 4 0.02 0.03 0.03 0.03 0.02 8 0.03 0.04 0.04 19-23 0 0.03 0.04 0.04 0.02 0.02 4 0.05 0.09 0.11 0.05 0.04 8 0.08 0.17 0.19 40 0 0.03 0.04 0.04 0.02 0.02 4 0.35 0.91 1.10 0.31 0.21 8 0.65 1.80 2.05 Enalaprilat 5 0 0.18 0.14 0.12 0.13 0.19 4 0.18 0.15 0.12 0.43 0.53 8 0.55 0.38 0.34 19-23 0 0.18 0.14 0.12 0.13 0.19 4 1.35 0.83 0.80 1.75 2.29 8 3.34 2.06 1.98 40 0 0.18 0.14 0.12 0.13 0.19 4 10.49 6.08 6.11 12.30 16.14 8 24.37 14.12 14.22 Example D Stability of Enalapril Maleate Formulations Containing Benzoate Preservative Powder formulations were prepared according to Table D-1. All components in each formulation except enalapril maleate and mannitol or xylitol were blended with a mortar and pestle. The enalapril maleate was then triturated with the blend. The xylitol or mannitol was then triturated into the blend using a geometric dilution technique. One liter of solution formulation was prepared for each formulation by adding an appropriate amount of each powdered formulation to a 1 liter volumetric flask and adding about 500 mL water. The powder was dissolved with mixing then the contents of the flask were brought to 1 liter with additional water. The amount of powder to add was determined such that the final concentration of enalapril maleate was 1.0 mg/mL. Fifty milliliter aliquots of each formulation were placed into HDPE bottles. The bottles were screw-capped and placed into storage at 5° C.±3° C., at room temperature (19-23° C.) and at 40° C.±2° C. At various times, bottles were removed from the storage condition and analyzed. TABLE D-1 Composition of Enalapril Maleate Formulations Component D1 D2 D3 D4 D5 D6 Powder Formulation (grams) Enalapril maleate 3.63 3.63 3.63 3.63 8.86 2.16 Xylitol 537.2 176.1 537.2 Mannitol 319.4 401.2 98.9 Citric acid, anhydrous 11.9 11.9 11.9 10.4 26.6 6.48 Sodium citrate, anhydrous 2.72 2.72 2.72 4.86 11.3 2.76 Sodium benzoate 3.63 3.63 3.63 3.63 8.86 2.16 Rebalance X60 (sucralose and maltodextrin) 10.9 Sucralose 6.64 1.62 Saccharin sodium 7.26 Colloidal silicon dioxide 4.43 Mixed berry flavor 1.82 1.82 1.82 1.82 4.43 1.08 Total solids 561 211 350. 561 472.3 115.2 Liquid Formulations (mg/mL) Enalapril maleate 1.00 1.00 1.00 1.00 1.00 1.00 Xylitol 148.0 48.5 148.0 Mannitol 88.0 45.3 45.8 Citric acid, anhydrous 3.29 3.29 3.29 2.85 3.00 3.00 Sodium citrate, anhydrous 0.75 0.75 0.75 1.34 1.28 1.28 Sodium benzoate 1.00 1.00 1.00 1.00 1.00 1.00 Rebalance X60 (sucralose and maltodextrin) 3.00 Sucralose 0.75 0.75 Saccharin sodium 2.00 Colloidal silicon dioxide 0.50 Mixed berry flavor 0.50 0.50 0.50 0.50 0.50 0.50 pH (measured) 3.2 3.2 3.4 3.7 3.6 3.6 The results of the HPLC analysis for the diketopiperazine and enalaprilat degradants in the samples are provided in Table D-2. TABLE D-2 Degradant Content After Storage (% w/w of enalapril maleate) Storage Formulation ° C. Weeks D1 D2 D3 D4 D5 D6 Liquid Formulations Diketopiperazine 5 0 0.04 0.02 0.03 0.03 0.04 0.04 4 0.07 0.03 0.05 0.05 0.03 8 0.11 0.06 0.08 0.08 0.05 12 0.08 0.04 0.06 0.06 26 0.11 0.07 0.09 0.07 19-23 0 0.04 0.02 0.03 0.03 0.04 0.04 4 0.27 0.21 0.24 0.16 0.12 0.12 8 0.50 0.41 0.47 0.30 0.21 0.22 12 0.62 0.52 0.58 0.35 26 1.39 1.20 1.33 0.76 40 0 0.04 0.02 0.03 0.03 0.04 0.04 4 2.87 2.32 2.73 1.57 1.21 1.13 8 5.13 4.42 5.44 2.97 2.23 2.16 12 6.86 5.90 6.90 3.91 26 13.63 12.18 13.56 7.74 Enalaprilat 5 0 0.03 0.02 0.03 0.03 0.13 0.14 4 0.15 0.12 0.06 0.17 0.13 8 0.22 0.19 0.22 0.27 0.34 12 0.20 0.17 0.19 0.22 8 0.32 0.30 0.30 0.39 19-23 0 0.03 0.02 0.03 0.03 0.13 0.14 4 0.69 0.66 0.69 0.86 0.74 0.76 8 1.38 1.33 1.41 1.68 1.83 1.82 12 1.71 1.68 1.73 2.15 26 3.63 3.61 3.59 4.55 40 0 0.03 0.02 0.03 0.03 0.13 0.14 4 4.76 4.42 4.76 6.45 5.55 5.24 8 8.95 8.64 9.61 12.94 12.73 12.18 12 11.01 10.64 11.41 16.16 26 17.18 17.11 18.30 27.36 Example E Stability of Solution Formulations of Enalapril Maleate Solution formulations were prepared according to Table E-1. Thirty milliliter aliquots of each formulation were placed into HDPE bottles. The bottles were screw-capped and placed into storage at 5° C.±3° C., at room temperature (19-23° C.) and at 40° C.±2° C. At various times, bottles were removed from the storage condition and analyzed. Composition of Enalapril Maleate Formulations (mg/mL) Component E1 E2 E3 E4 E5 E6 Enalapril maleate 1.00 1.00 1.00 1.00 1.00 1.00 Xylitol 150 200 150 Citric acid anhydrous 3.29 3.29 3.29 3.29 1.65 0.82 Sodium citrate 0.75 0.75 0.75 0.75 0.38 0.19 anhydrous Sodium benzoate 1.00 1.00 1.00 1.00 1.00 1.00 Sucralose 0.70 0.70 0.70 Mixed berry flavor 0.50 0.50 0.50 0.50 0.50 Water qs qs qs qs qs qs pH (measured) 3.3 3.3 3.3 3.4 3.3 3.3 qs = sufficient quantity The results of the HPLC analysis for the diketopiperazine and enalaprilat degradants in the samples are provided in Table E-2. TABLE E-2 Degradant Content After Storage (% w/w of enalapril maleate) Storage Formulation ° C. Weeks E1 E2 E3 E4 E5 E6 Diketopiperazine 5 0 0.01 0.01 0.01 0.01 0.01 0.01 4 0.04 0.04 0.05 0.04 0.03 0.03 8 0.04 0.04 0.04 0.04 0.03 0.03 12 0.05 0.05 0.04 0.05 0.04 0.04 26 0.07 0.06 0.05 0.06 0.05 0.05 52 0.15 0.14 62 0.18 0.18 0.16 0.14 19-23 0 0.01 0.01 0.01 0.01 0.01 0.01 4 0.22 0.23 0.21 0.20 0.16 0.15 8 0.35 0.35 0.32 0.31 0.29 0.28 12 0.58 0.59 0.53 0.51 0.48 0.45 26 1.10 1.10 1.00 0.95 0.97 0.92 52 2.30 2.15 62 3.02 3.04 2.75 2.64 40 0 0.01 0.01 0.01 0.01 0.01 0.01 4 2.65 2.71 2.60 2.42 1.76 1.68 8 4.02 3.99 3.99 3.62 3.37 3.13 12 6.72 6.42 6.47 6.00 5.53 5.29 Enalaprilat 5 0 0.00 0.00 0.01 0.02 0.00 0.00 4 0.07 0.09 0.10 0.11 0.07 0.08 8 0.12 0.14 0.10 0.13 0.09 0.08 12 0.16 0.15 0.15 0.17 0.14 0.11 26 0.31 0.30 0.29 0.31 0.27 0.24 52 0.54 0.46 62 0.75 0.75 0.74 0.71 19-23 0 0.00 0.00 0.01 0.02 0.00 0.00 4 0.65 0.65 0.68 0.70 0.50 0.46 8 1.17 1.19 1.20 1.23 1.03 0.95 12 1.67 1.69 1.72 1.80 1.30 1.21 26 3.36 3.38 3.42 3.57 3.07 2.90 52 6.32 5.88 62 7.99 8.02 8.04 8.57 40 0 0.00 0.00 0.01 0.02 0.00 0.00 4 4.85 4.93 5.19 5.42 3.33 3.25 8 8.08 8.06 8.56 9.01 6.65 6.35 12 10.70 10.48 11.01 11.97 8.14 7.96 Example F Effect of pH on the Formation of Degradants in Enalapril Formulations at 5° C. and 19-23° C. The content of enalapril diketopiperazine and enalaprilat that were formed after 8 weeks of storage for formulations C1-C3 and D1-D5 are plotted in FIG. 1 (5° C.±3° C.) and FIG. 2 (19-23° C. storage). These formulations all contained 20mM total citrate buffer content, but with varying pH. The general effects of formulation pH on the formation of the two main enalapril degradants are shown. Example G Antimicrobial Effectiveness Testing of Enalapril Maleate Formulations at pH 3.3 Enalapril formulations were prepared containing differing amounts of the antimicrobial preservative, sodium benzoate. The formulations were then tested for antimicrobial effectiveness (AET) according to the procedures in the 2014 United States Pharmacopeia 37, Chapter <51> for category 3 products. The formulation of the formulations and the AET results are included in Table G-1. TABLE G-1 Formulation and AET Testing Results Formulation G1 G2 G3 G4 G5 Formulation (mg/mL) Enalapril maleate 1.00 1.00 1.00 1.00 1.00 Xylitol 150 150 150 150 Sucralose 0.70 Citric acid, anhydrous 1.64 1.64 1.64 1.64 1.80 Sodium citrate, anhydrous 0.322 0.322 0.322 0.322 Sodium citrate, dihydrate 0.165 Sodium benzoate 1.00 0.80 0.60 0.40 1.0 Mixed berry flavor 0.50 0.50 0.50 0.50 0.50 Water q.s. q.s. q.s. q.s. q.s. HCl/NaOH as need to achieve pH Measured pH 3.3 3.3 3.3 3.3 3.3 AET Results USP <51> Pass Pass Pass Pass Pass qs = sufficient quantity Example H Clinical Trial: Bioavailability Study of 10mg Enalapril Maleate Oral Solution vs. 10mg Epaned® Powder for Oral Solution (Reconstituted) Under Fasted Conditions The objective of this open-label, randomized, two-period, two-treatment, two-way crossover study was to compare the oral bioavailability of a test formulation of 10 mL of enalapril maleate oral solution, 1 mg/mL (formulation E-5), to an equivalent oral dose of the commercially available comparator product, Epaned® (enalapril maleate) Powder for Oral Solution, 1 mg/mL, when administered under fasted conditions in healthy adults. Study design: Thirty-two healthy adult subjects received a single 10 mL dose of enalapril maleate oral solution, 1 mg/mL, formulation E-5 (Treatment A), in one period and a separate single dose of Epaned Powder for Oral Solution (reconstituted with the supplied Ora-Sweet SF), 1 mg/mL (Treatment B) in another period. Each treatment was administered after an overnight fast of at least 10 hours, followed by a 4-hour fast postdose. Each treatment was administered via a 10 mL oral dosing syringe and followed with 240 mL of room temperature tap water. Each drug administration was separated by a washout period of at least 7 days. During each study period, meals were the same and scheduled at approximately the same times relative to dose. In addition, during each period, blood samples were obtained prior to and following each dose at selected times through 72 hours postdose. Pharmacokinetic samples were analyzed for enalapril and its metabolite enalaprilat using a validated analytical method; appropriate pharmacokinetic parameters were calculated for each formulation using non-compartmental methods. Blood was also drawn and urine collected for clinical laboratory testing at screening and at the end of the study. Statistical Methods: The concentration-time data were analyzed using noncompartmental methods in Phoenix™ WinNonlin® (Version 6.3, Pharsight Corporation). Concentration-time data that were below the limit of quantitation (BLQ) were treated as zero in the data summarization and descriptive statistics. In the pharmacokinetic analysis, BLQ concentrations were treated as zero from time-zero up to the time at which the first quantifiable concentration was observed; embedded and/or terminal BLQ concentrations were treated as “missing”. Actual sample times were used for all pharmacokinetic and statistical analyses. Analysis of variance (ANOVA) and the Schuirmann's two one-sided t-test procedures at the 5% significance level were applied to the log-transformed pharmacokinetic exposure parameters, Cmax, AUClast, and AUCinf. The 90% confidence interval for the ratio of the geometric means (Test/Reference) was calculated. Bioequivalence was declared if the lower and upper confidence intervals (CIs) of the log-transformed parameters were within 80% to 125% for enalapril and enalaprilat. Results: A total of 32 subjects participated in the study and 29 of these subjects completed both study periods. Based on the geometric mean ratios of enalapril and enalaprilat AUCs (AUClast and AUCinf), the bioavailability of the enalapril maleate oral solution (formulation E-5) relative to the Epaned Powder for Oral Solution (reconstituted) was approximately 105% to 110%. The geometric mean ratios of enalapril and enalaprilat Cmax were approximately 115% and 109%, respectively. The 90% CI for comparing the maximum exposure to enalapril and enalaprilat, based on ln (Cmax), was within the accepted 80% to 125% limits. The 90% CIs for comparing total systemic exposure to enalapril and enalaprilat, based on ln (AUClast) and ln (AUCinf), was within the accepted 80% to 125% limits. Therefore, the test formulation of enalapril maleate oral solution, 1 mg/mL, is bioequivalent to the reference product, Epaned Powder for Oral Solution (reconstituted), 1 mg/mL, under fasted conditions. While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby. | <SOH> BACKGROUND OF THE INVENTION <EOH>Hypertension, or high blood pressure, is a serious health issue in many countries. According to the National Heart Blood and Lung Institute, it is thought that about 1 in 3 adults in the U.S. alone have hypertension. Left unchecked, hypertension is considered a substantial risk factor for cardiovascular and other diseases including coronary heart disease, myocardial infarction, congestive heart failure, stroke and kidney failure. Hypertension is classified as primary (essential) hypertension or secondary hypertension. Primary hypertension has no known cause and may be related to a number of environmental, lifestyle and genetic factors such as stress, obesity, smoking, inactivity and sodium intake. Secondary hypertension can be caused by drug or surgical interventions, or by abnormalities in the renal, cardiovascular or endocrine system. A number of antihypertensive drugs are available for treating hypertension. Various therapeutic classes of antihypertensive drugs include alpha-adrenergic blockers, beta-adrenergic blockers, calcium-channel blockers, hypotensives, mineralcorticoid antagonists, central alpha-agonists, diuretics and rennin-angiotensin-aldosterone inhibitors which include angiotensin II receptor antagonists (ARB) and angiotensin-converting enzyme (ACE) inhibitors. Angiotensin-converting enzyme (ACE) inhibitors inhibit angiotensin-converting enzyme (ACE), a peptydyl dipeptidase that catalyzes angiotension I to angiotension II, a potent vasoconstrictor involved in regulating blood pressure. Enalapril is a prodrug belonging to the angiotensin-converting enzyme (ACE) inhibitor of medications. It is rapidly hydrolyzed in the liver to enalaprilat following oral administration. Enalaprilat acts as a potent inhibitor of ACE. The structural formulae of enalapril and enalaprilat are as follows: Enalapril is currently administered in the form of oral tablets, (e.g., Vasotec®) or in the form of liquid formulations obtained by reconstitution of enalapril powder formulations. In addition to the treatment of hypertension, enalapril tablets have been used for symptomatic congestive heart failure, and asymptomatic left ventricular dysfunction. | <SOH> SUMMARY OF THE INVENTION <EOH>Provided herein are enalapril oral liquid formulations. In one aspect, the enalapril oral liquid formulation, comprises (i) enalapril or a pharmaceutically acceptable salt or solvate thereof; (ii) a sweetener that is sucralose (iii) a buffer comprising citric acid; (iv) a preservative that is sodium benzoate; and (v) water; wherein the pH of the formulation is less than about 3.5; and wherein the formulation is stable at about 5±3° C. for at least 12 months. In some embodiments, the enalapril is enalapril maleate. In some embodiments, the formulation further comprises a flavoring agent. In some embodiments, the buffer in the formulation further comprises sodium citrate dihydrate. In some embodiments, the amount of enalapril or a pharmaceutically acceptable salt or solvate thereof is about 0.6 to about 1.2 mg/ml. In some embodiments, the amount of sucralose is about 0.5 to about 0.9 mg/ml. In some embodiments, the amount of citric acid in the buffer is about 0.8 to about 3.5 mg/ml. In some embodiments, the amount of sodium citrate dihydrate in the buffer is about 0.1 to about 0.80 mg/ml. In some embodiments, the amount of the sodium benzoate is about 0.2 to about 1,2 mg/ml. In some embodiments, the amount of enalapril or a pharmaceutically acceptable salt or solvate thereof is about 10 to about 25% (w/w of solids). In some embodiments, the amount of sucralose is about 8 to about 18 (w/w of solids). In some embodiments, the amount of citric acid in the buffer is about 17 to about 47% (w/w of solids). In some embodiments, the amount of sodium citrate dihydrate in the buffer is about 1 to about 11% (w/w of solids). In some embodiments, the amount of sodium benzoate is about 12 to about 25% (w/w of solids). In some embodiments, the pH of the formulation is between about 3 and about 3.5. In some embodiments, the pH of the formulation is about 3.3. In some embodiments, the citrate concentration in the buffer is about 5 nM to about 20 mM. In some embodiments, the citrate concentration in the buffer is about 10 mM. In some embodiments, the formulation is stable at about 5±3° C. for at least 18 months. In some embodiments, the formulation is stable at about 5±3° C. for at least 24 months. In some embodiments, the formulation does not contain mannitol. In some embodiments, the formulation does not contain silicon dioxide. In one aspect, the enalapril oral liquid formulation, comprises (i) about 1 mg/ml enalapril maleate; (ii) about 0.70 mg/ml of a sweetener that is sucralose; (iii) a buffer comprising about 1.82 mg/ml citric acid; (iv) about 1 mg/ml of a preservative that is sodium benzoate; and (v) water; wherein the pH of the formulation is less than about 3.5; and wherein the formulation is stable at about 5±3° C. for at least 12 months. In some embodiments, the formulation further comprises a flavoring agent. In some embodiments, the buffer further comprises about 0.15 mg/mL sodium citrate dihydrate. In some embodiments, the pH of the formulation is between about 3 and about 3.5. In some embodiments, the pH of the formulation is about 3.3. In some embodiments, the citrate concentration in the buffer is about 5 mM to about 20 mM. In some embodiments, the citrate concentration in the buffer is about 10 mM. In some embodiments, the formulation is stable at about 5±3° C. for at least 18 months. In some embodiments, the formulation is stable at about 5±3° C. for at least 24 months. In some embodiments, the formulation does not contain mannitol. In some embodiments, the formulation does not contain silicon dioxide. In one aspect, the enalapril oral liquid formulation comprises (i) about 19.3% (w/w of solids) enalapril maleate; (ii) about 13.5% (w/w of solids) of a sweetener that is sucralose; (iii) a buffer comprising about 35.2% (w/w of solids) citric acid; (iv) about 19.3% (w/w of solids) of a preservative that is sodium benzoate; and (v) water; wherein the pH of the formulation is less than about 3.5; and wherein the formulation is stable at about 5±3° C. for at least 12 months. In some embodiments, the formulation further comprises a flavoring agent. In some embodiments, the buffer further comprises about 2.9% (w/w of solids) sodium citrate dihydrate. In some embodiments, the pH of the formulation is between about 3 and about 3.5. In some embodiments, the pH of the formulation is about 3.3. In some embodiments, the citrate concentration in the buffer is about 5 mM to about 20 mM. In some embodiments, the citrate concentration in the buffer is about 10 mM. In some embodiments, the formulation is stable at about 5±3° C. for at least 18 months. In some embodiments, the formulation is stable at about 5±3° C. for at least 24 months. In some embodiments, the formulation does not contain mannitol. In some embodiments, the formulation does not contain silicon dioxide. In one aspect, the enalapril oral liquid formulation consists essentially of (i) about 1 mg/ml enalapril maleate; (ii) about 0.70 mg/ml of a sweetener that is sucralose; (iii) a buffer comprising about 1.82 mg/ml citric acid and about 0.15 mg/ml sodium citrate dihydrate; (iv) about 1 mg/ml of a preservative that is sodium benzoate; (v) a flavoring agent; and (vi) water; wherein the pH of the formulation is less than about 3.5 adjusted by sodium hydroxide or hydrochloric acid; and wherein the formulation is stable at about 5±3° C. for at least 12 months. Also provided herein are methods of treating hypertension in a subject comprising administering to that subject a therapeutically effective amount of enalapril oral liquid formulation comprising (i) about 1 mg/ml enalapril maleate; (ii) about 0.7 mg/ml sucralose; (iii) a buffer comprising about 1.82 mg/ml citric acid and about 0.15 mg/ml sodium citrate dihydrate; (iv) about 1 mg/ml of a preservative that is sodium benzoate; and (v) water, wherein the pH of the formulation is less than about 3.5; and wherein the formulation is stable at about 5±3° C. for at least 12 months. In some embodiments, the formulation does not contain mannitol. In some embodiments, the formulation does not contain silicon dioxide. In some embodiments, the hypertension is primary (essential) hypertension. In some embodiments, the hypertension is secondary hypertension. In some embodiments, the subject has blood pressure values greater than or equal to 140/90 mmm Hg. In some embodiments, the subject is an adult. In some embodiments, the subject is elderly. In some embodiments, the subject is a child. In some embodiments, the formulation is administered to the subject in a fasted state. In some embodiments, the formulation is administered to the subject in a fed state. In some embodiments, the formulation is further administered in combination with an agent selected from the group consisting of diuretics, beta blockers, alpha blockers, mixed alpha and beta blockers, calcium channel blockers, angiotensin II receptor antagonists, ACE inhibitors, aldosterone antagonists, and alpha-2 agonists. Also provided herein are methods of treating prehypertension in a subject comprising administering to that subject a therapeutically effective amount of enalapril oral liquid formulation comprising (i) about 1 mg/ml enalapril maleate; (ii) about 0,7 mg/ml of a sweetener that is sucralose; (ii) a buffer comprising about 1.82 mg/ml citric acid and about 0.15 mg/ml sodium citrate dihydrate; (iv) about 1 mg/ml of a preservative that is sodium benzoate; and (v) water; wherein the pH of the formulation is less than about 3.5; and wherein the formulation is stable at about 5±3° C. for at least 12 months. In some embodiments, the formulation does not contain mannitol. In some embodiments, the formulation does not contain silicon dioxide. In some embodiments, the subject has blood pressure values of about 120-139/80-89 mm Also provided herein are methods of treating heart failure in a subject comprising administering to that subject a therapeutically effective amount of enalapril oral liquid formulation comprising (i) about 1 mg/ml enalapril maleate; (ii) about 0.70 mg/ml of a sweetener that is sucralose; a buffer comprising about 1.82 mg/ml citric acid and about 0.15 mg/ml sodium citrate dihydrate; (iv) about 1 mg/ml of a preservative that is sodium benzoate; and (v) water; wherein the pH of the formulation is less than about 3.5; and wherein the formulation is stable at about 5±3° C. for at least 12 months. In some embodiments, the formulation does not contain mannitol. In some embodiments, the formulation does not contain silicon dioxide. Also provided herein are methods of treating left ventricular dysfunction in a subject comprising administering to that subject a therapeutically effective amount of enalapril oral liquid formulation comprising (i) about 1 mg/ml enalapril maleate; (ii) about 0.7 mg/ml of a sweetener that is sucralose; (iii) a buffer comprising about 1.82 mg/ml citric acid and about 0.15 mg/ml sodium citrate dihydrate; (iv) about 1 mg/ml of a preservative that is sodium benzoate; and (v) water; wherein the pH of the formulation is less than about 3.5; and wherein the formulation is stable at about 5±3° C. for at least 12 months. In some embodiments, the formulation does not contain mannitol. In some embodiments, the formulation does not contain silicon dioxide. | A61K31401 | 20171102 | 20180301 | 95061.0 | A61K31401 | 6 | SPRINGER, STEPHANIE K | Enalapril Formulations | UNDISCOUNTED | 1 | CONT-ACCEPTED | A61K | 2,017 |
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15,802,384 | PENDING | INTERACTION TRACKING AND ORGANIZING SYSTEM | A server that cross-references a first user's device location with registered members in a spatial proximity of the first user's device and returns the results by disclosing personal user attributes including pictures and names of all members in the spatial proximity of the first user's device. The first user who initiated the inquiry may select from the results returned any discovered user he/she wishes to connect with and send a form of invitation to connect using network available tools such as email, SMS, text or any customized invitation form. The invitation to connect to the inquiring user includes his/her personal attributes including a picture and name. The discovered member who received the invitation may accept, ignore, or decline connecting with the inquiring user. The first user may also receive an invitation from the server to accept, ignore, or decline connecting with the discovered member. | 1. A server configured to: communicate with a first communication device of a first user and a second communication device of a second user over communication links comprising a cellular network; store in a database a first profile associated with the first user and a second profile associated with a second user, both the first and the second profile comprising at least a picture and a name of their respective users; automatically determine based on wireless communication that the first communication device and the second communication device are coincidently located within a spatial proximity to one another; responsive at least to the first communication device and the second communication device coincidently located in a spatial proximity, send to the first communication device a first information about the second profile and send to the second communication device a second information about the first profile, wherein the first communication device displays on a first screen a first invitation comprising at least a picture and name from the second profile and the second communication device displays on a second screen a second invitation comprising at least picture and name from the first profile, wherein the first communication device is configured to receive a first input from the first user if he is willing to accept the first invitation and the second communication device is configured to receive a second input from the second user if he is willing to accept the second invitation; receive a first response from the first communication device representing the first input; receive a second response from the second communication device representing the second input; and responsive to both the first and the second input being positive, store information in the database that the first and the second users are now contacts of each other, and if such information is stored in the database, enable the first user and the second user to communicate using the first and the second communication devices. 2. The server of claim 1, configured to provide to communication device associated with users who are contacts with the first user information about the first user beyond information in the first invitation. 3. The server of claim 1, wherein the server is to communicate with a networking device, and wherein the networking device is to provide social networking services that operates independently of the server. 4. The server of claim 3, wherein the server is to receive profile related information from the networking device. 5. The server of claim 1, wherein the server is to connect with a contact exchanging application executing on the first and second communication devices to execute services and features available with the server. 6. The server of claim 5, wherein the contact exchanging application is to store updated contact information and profiles of user contacts including pictures. 7. The server of claim 5, wherein the server is to utilize the contact exchanging application of the first communication device to discover the second communication device present within the spatial proximity thereof, and to present a picture and name of the second user associated with the second communication device on a user interface of the first communication device before the first user deciding to send an invite to connect. 8. The server of claim 5, wherein the contact exchanging application is to present the second user with an option to accept or reject the invitation sent by the first user by sending to the server the acceptance or rejection response of the second user, and allowing the server to communicate the acceptance or rejection response to the first user. 9. A method comprising: communicating a server with a first communication device of a first user and a second communication device of a second user over communication links comprising a cellular network; storing, in the database, a first profile associated with the first user and a second profile associated with a second user, wherein both the first and the second profiles comprise at least a picture and a name of their respective users; automatically determine based on wireless communication that the first communication device and the second communication device are coincidently located within a spatial proximity to one another; responsive at least to the first communication device and the second communication device coincidently located within a spatial proximity, transmitting, from the server, a first information about the second profile to the first communication device and a second information about the first profile to the second communication device, wherein the first communication device displays on a first screen a first invitation comprising at least picture and name from the second profile and the second communication device displays on a second screen a second invitation comprising at least picture and name from the first profile, and wherein the first communication device is configured to receive a first input from the first user if the first user is willing to accept the first invitation, and the second communication device is configured to receive a second input from the second user if the second user is willing to accept the second invitation; receiving, at the server, a first response from the first communication device representing the first input; receiving, at the server, a second response from the second communication device representing the second input; responsive to both the first and the second input being positive, storing connectivity information in the database, wherein the connectivity information represents that the first and second users are enabled to communicate using the first and second communication devices; and establishing a connection between the first and second communication devices for enabling the first user and the second user to communicate. 10. The method of claim 9, further comprising providing the first and second communication devices with the profile related information beyond the first and second user information comprised in the first and second invitations. 11. The method of claim 9, further comprising receiving profile related information from a networking device. 12. The method of claim 9, further comprising receiving profile related information from a networking device in communication with the server. 13. The method of claim 9, further comprising connecting the server with a contact exchanging application executing on the first and second communication devices to execute services and features available with the server on the first and second communication devices. 14. The method of claim 13, further comprising discovering, using the contact exchanging application of the first communication device, the second communication device present within the spatial proximity of one another, and presenting a picture and name of the second communication device on user interface of the first communication device before the first user deciding to send an invite to connect. 15. The method of claim 13, further comprising presenting, by the contact exchanging application, an option to the second user to accept or reject the invitation sent by the first user, sending to the server the acceptance or rejection response of the second user, and allowing the server to communicate the acceptance or rejection response to the first user. 16. A server configured to communicate with a first communication device of a first user and a second communication device of a second user over communication links comprising a cellular network, wherein the server comprises a processor configured to: store in a data storage device a first profile associated with the first user and a second profile associated with a second user, both the first and the second profile comprises at least a picture and a name of their respective users, and able to associate each member profile with unique hardware identification associated with the member device; identify a unique ID of a second member in the vicinity and spatial proximity of the first member and provide the first member with the profile of the second member comprising a picture and name to facilitate invitation and connection between both members; send the second member the profile of the first member including picture and name upon first member initiating an invite to the second member to connect over the service; inform the first member if the second member has accepted or rejected the invite to connect initiated by the first member; and once the second member accepts the invite of the first member, store the connectivity between both members in data base and facilitates chat feature between them using respective devices connected to the server. 17. The server of claim 16, further comprising a context information retrieval module, which when executed by the one or more processors, provides the first and second communication devices with the profile related information beyond the first and second user information comprised in first and second invitations. 18. The server of claim 16, wherein the server is to communicate with a second server, and wherein the second server is to provide social networking services that operate independently of the server. 19. The server of claim 18, wherein the server is to receive profile related information from the second server. 20. The server of claim 18, wherein the server is to connect with a contact exchanging application executing on the first and second communication devices to execute services and features available with the server. 21. The server of claim 20, wherein the contact exchanging application is to store updated contacts information and profiles of user contacts including pictures. 22. The server of claim 20, wherein the server is to utilize the contact exchanging application of the first communication device to discover the second communication device present within the spatial proximity, and to present a picture and name of the second user associated with the second communication device on user interface of the first communication device before the first user deciding to send an invite to connect. 23. The server of claim 20, wherein the contact exchanging application is to present the second user with an option to accept or reject the invitation sent by the first user by sending to the server the acceptance or rejection response of the second user, and allowing the server to communicate the acceptance or rejection response to the first user. 24. A method for communicating a server with a first communication device of a first user and a second communication device of a second user over communication links comprising a cellular network, the method comprising: storing, in a data storage device of the server, a first profile associated with the first user and a second profile associated with the second user, wherein both the first and second profiles comprise at least a picture and a name of their respective users, and able to associate each user profile with a unique hardware identifier associated with the users' devices; identifying a unique hardware identifier of the second communication device within a spatial proximity of the first communication device; based on the identification of the unique identifier, transmitting the second profile of the second user to the first communication device as an invitation to connect with the second communication device; transmitting the first profile of the first user to the second communication device as an invitation to connect with the first communication device; notifying the first communication device when the second user has accepted or rejected the invitation to connect the second communication device with the first communication device; and in response to the acceptance of the invitation by the second user, storing the connectivity information between both the first and second communication devices in the data storage device and facilitates chat feature between the first and second users using the respective communication devices connected to the server. 25. The method of claim 24, further comprising providing the first and second communication devices with the profile related information beyond the first and second user information comprised in the first and second invitations. 26. The method of claim 24, further comprising receiving profile related information from a networking server. 27. The method of claim 24, further comprising receiving profile related information from a networking server present in communication with the server. 28. The method of claim 24, further comprising connecting with a contact exchanging application executing on the first and second communication devices to execute services and features available with the server on the first and second communication devices. 29. The method of claim 28, further comprising discovering, using the contact exchanging application of the first communication device, the second communication device present within the spatial proximity, and presenting picture and name of the second communication device on user interface of the first communication device before the first user deciding to send an invite to connect. 30. The method of claim 28, further comprising presenting, by the contact exchanging application, an option to the second user to accept or reject the invitation sent by the first user, sending to the server the acceptance or rejection response of the second user, and letting the server communicate the acceptance or rejection response to the first user. | CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of U.S. application Ser. No. 15/136,842, filed on Apr. 22, 2016, which is a continuation of U.S. application Ser. No. 15/000,960, filed on Jan. 19, 2016, now U.S. Pat. No. 9,357,352, issued on May 31, 2016, which is a continuation-in-part of U.S. application Ser. No. 14/570,779, filed on Dec. 15, 2014, now U.S. Pat. No. 9,264,875, issued on Feb. 16, 2016, which is a continuation-in-part of U.S. application Ser. No. 12/351,654, filed on Jan. 9, 2009, now U.S. Pat. No. 8,914,024, issued on Dec. 16, 2014, which claims the benefit to U.S. Provisional Application No. 61/010,891 filed on Jan. 10, 2008, the complete disclosures of which, in their entireties, are herein incorporated by reference. BACKGROUND Technical Field The embodiments herein generally relate to an interaction tracking and organizing system and, in particular, to the establishment of social connections and exchange of electronic coordinates card (also known as contact information card) via the short-range wireless communications. Description of the Related Art The usage or access of the social networks on the communication devices has increased tremendously. With such increase in the use of communication devices for accessing social networks, the users of the communication devices are feeling a need of exchanging contact information, including pictures, social network profiles, emails, and phone numbers, for enhancing social interaction. SUMMARY In view of the foregoing, an embodiment herein provides a server configured to communicate with a first communication device of a first user and a second communication device of a second user over communication links comprising a cellular network; store in a database a first profile associated with the first user and a second profile associated with a second user, both the first and the second profile comprising at least a picture and a name of their respective users; automatically determine based on wireless communication that the first communication device and the second communication device are coincidently located within a spatial proximity to one another; responsive at least to the first communication device and the second communication device coincidently located in a spatial proximity, send to the first communication device a first information about the second profile and send to the second communication device a second information about the first profile, wherein the first communication device displays on a first screen a first invitation comprising at least a picture and name from the second profile and the second communication device displays on a second screen a second invitation comprising at least picture and name from the first profile, wherein the first communication device is configured to receive a first input from the first user if he is willing to accept the first invitation and the second communication device is configured to receive a second input from the second user if he is willing to accept the second invitation; receive a first response from the first communication device representing the first input; receive a second response from the second communication device representing the second input; and responsive to both the first and the second input being positive, store information in the database that the first and the second users are now contacts of each other, and if such information is stored in the database, enable the first user and the second user to communicate using the first and the second communication devices. The server may be configured to provide to communication device associated with users who are contacts with the first user information about the first user beyond information in the first invitation. The server may communicate with a networking device, and wherein the networking device is to provide social networking services that operates independently of the server. The server may receive profile related information from the networking device. The server may connect with a contact exchanging application executing on the first and second communication devices to execute services and features available with the server. The contact exchanging application may store updated contact information and profiles of user contacts including pictures. The server may utilize the contact exchanging application of the first communication device to discover the second communication device present within the spatial proximity thereof, and to present a picture and name of the second user associated with the second communication device on a user interface of the first communication device before the first user deciding to send an invite to connect. The contact exchanging application may present the second user with an option to accept or reject the invitation sent by the first user by sending to the server the acceptance or rejection response of the second user, and allowing the server to communicate the acceptance or rejection response to the first user. Another embodiment provides a method comprising communicating a server with a first communication device of a first user and a second communication device of a second user over communication links comprising a cellular network; storing, in the database, a first profile associated with the first user and a second profile associated with a second user, wherein both the first and the second profiles comprise at least a picture and a name of their respective users; automatically determine based on wireless communication that the first communication device and the second communication device are coincidently located within a spatial proximity to one another; responsive at least to the first communication device and the second communication device coincidently located within a spatial proximity, transmitting, from the server, a first information about the second profile to the first communication device and a second information about the first profile to the second communication device, wherein the first communication device displays on a first screen a first invitation comprising at least picture and name from the second profile and the second communication device displays on a second screen a second invitation comprising at least picture and name from the first profile, and wherein the first communication device is configured to receive a first input from the first user if the first user is willing to accept the first invitation, and the second communication device is configured to receive a second input from the second user if the second user is willing to accept the second invitation; receiving, at the server, a first response from the first communication device representing the first input; receiving, at the server, a second response from the second communication device representing the second input; responsive to both the first and the second input being positive, storing connectivity information in the database, wherein the connectivity information represents that the first and second users are enabled to communicate using the first and second communication devices; and establishing a connection between the first and second communication devices for enabling the first user and the second user to communicate. The method may further comprise providing the first and second communication devices with the profile related information beyond the first and second user information comprised in the first and second invitations. The method may further comprise receiving profile related information from a networking device. The method may further comprise receiving profile related information from a networking device in communication with the server. The method may further comprise connecting the server with a contact exchanging application executing on the first and second communication devices to execute services and features available with the server on the first and second communication devices. The method may further comprise discovering, using the contact exchanging application of the first communication device, the second communication device present within the spatial proximity of one another, and presenting a picture and name of the second communication device on user interface of the first communication device before the first user deciding to send an invite to connect. The method may further comprise presenting, by the contact exchanging application, an option to the second user to accept or reject the invitation sent by the first user, sending to the server the acceptance or rejection response of the second user, and allowing the server to communicate the acceptance or rejection response to the first user. Another embodiment provides a server configured to communicate with a first communication device of a first user and a second communication device of a second user over communication links comprising a cellular network, wherein the server comprises a processor configured to store in a data storage device a first profile associated with the first user and a second profile associated with a second user, both the first and the second profile comprises at least a picture and a name of their respective users, and able to associate each member profile with unique hardware identification associated with the member device; identify a unique ID of a second member in the vicinity and spatial proximity of the first member and provide the first member with the profile of the second member comprising a picture and name to facilitate invitation and connection between both members; send the second member the profile of the first member including picture and name upon first member initiating an invite to the second member to connect over the service; inform the first member if the second member has accepted or rejected the invite to connect initiated by the first member; and once the second member accepts the invite of the first member, store the connectivity between both members in data base and facilitates chat feature between them using respective devices connected to the server. The server may further comprise a context information retrieval module, which when executed by the one or more processors, provides the first and second communication devices with the profile related information beyond the first and second user information comprised in first and second invitations. The server may communicate with a second server, and wherein the second server is to provide social networking services that operate independently of the server. The server may receive profile related information from the second server. The server may connect with a contact exchanging application executing on the first and second communication devices to execute services and features available with the server. The contact exchanging application may store updated contacts information and profiles of user contacts including pictures. The server may utilize the contact exchanging application of the first communication device to discover the second communication device present within the spatial proximity, and to present a picture and name of the second user associated with the second communication device on user interface of the first communication device before the first user deciding to send an invite to connect. The contact exchanging application may present the second user with an option to accept or reject the invitation sent by the first user by sending to the server the acceptance or rejection response of the second user, and allowing the server to communicate the acceptance or rejection response to the first user. Another embodiment provides a method for communicating a server with a first communication device of a first user and a second communication device of a second user over communication links comprising a cellular network, the method comprising storing, in a data storage device of the server, a first profile associated with the first user and a second profile associated with the second user, wherein both the first and second profiles comprise at least a picture and a name of their respective users, and able to associate each user profile with a unique hardware identifier associated with the users' devices; identifying a unique hardware identifier of the second communication device within a spatial proximity of the first communication device; based on the identification of the unique identifier, transmitting the second profile of the second user to the first communication device as an invitation to connect with the second communication device; transmitting the first profile of the first user to the second communication device as an invitation to connect with the first communication device; notifying the first communication device when the second user has accepted or rejected the invitation to connect the second communication device with the first communication device; and in response to the acceptance of the invitation by the second user, storing the connectivity information between both the first and second communication devices in the data storage device and facilitates chat feature between the first and second users using the respective communication devices connected to the server. The method may further comprise providing the first and second communication devices with the profile related information beyond the first and second user information comprised in the first and second invitations. The method may further comprise receiving profile related information from a networking server. The method may further comprise receiving profile related information from a networking server present in communication with the server. The method may further comprise connecting with a contact exchanging application executing on the first and second communication devices to execute services and features available with the server on the first and second communication devices. The method may further comprise discovering, using the contact exchanging application of the first communication device, the second communication device present within the spatial proximity, and presenting picture and name of the second communication device on user interface of the first communication device before the first user deciding to send an invite to connect. The method may further comprise presenting, by the contact exchanging application, an option to the second user to accept or reject the invitation sent by the first user, sending to the server the acceptance or rejection response of the second user, and letting the server communicate the acceptance or rejection response to the first user. BRIEF DESCRIPTION OF THE DRAWINGS The embodiments herein will be better understood from the following detailed description with reference to the drawings, in which: FIG. 1 illustrates an exemplary architecture implementing a server in accordance with the embodiments herein; FIG. 2A illustrates a sample EC file in accordance with the embodiments herein; FIG. 2B illustrates a window-in-window viewer in accordance with the embodiments herein; FIG. 2C illustrates an exemplary representation of a web-based portal of the server in accordance with the embodiments herein; FIG. 3 illustrates an exemplary architecture implementing the server in accordance with the embodiments herein; FIG. 4 illustrates various components of a server in accordance with the embodiments herein; FIG. 5 illustrates an exemplary architecture implementing the server in accordance with the embodiments herein; FIG. 6 illustrates another exemplary architecture implementing the server in accordance with the embodiments herein; FIG. 7 illustrates an example of the notification of an invitation to connect, in accordance with the embodiments herein; FIG. 8 illustrates another example of the notification of an invitation to connect, in accordance with the embodiments herein; FIG. 9 an exemplary flow diagram illustrating a first method, in accordance with the embodiments herein; and FIG. 10 illustrates an exemplary flow diagram illustrating a second method, in accordance with the embodiments herein. DETAILED DESCRIPTION The embodiments herein and the various features and advantageous details thereof are explained more fully with reference to the non-limiting embodiments that are illustrated in the accompanying drawings and detailed in the following description. Descriptions of well-known components and processing techniques are omitted so as to not unnecessarily obscure the embodiments herein. The examples used herein are intended merely to facilitate an understanding of ways in which the embodiments herein may be practiced and to further enable those skilled in the art to practice the embodiments herein. Accordingly, the examples should not be construed as limiting the scope of the embodiments herein. As used herein, the terms “a” or “an” are used, as is common in patent documents, include one or more than one. In this document, the term “or” is used to refer to a “nonexclusive or” unless otherwise indicated. The embodiments herein provide a system and a method to ascertain authenticity of the data shared over a network service. The embodiments herein provide a system and method that allows disseminating flow of data unit over an un-trusted network. The embodiments herein a system and a method to ascertain authenticity of the data based on the reputation or identity information of the owner of the data in addition to the content of the data shared over a network service. The embodiments herein provide a system and a method to disseminate the flow of data over an un-trusted network. Referring now to the drawings, and more particularly to FIGS. 1 through 10, where similar reference characters denote corresponding features consistently throughout the figures, there are shown exemplary embodiments. The embodiments herein provide a system and a method to establish a connection between at least two communication devices to share electronic coordinate (EC) files over short-range wireless communication. The embodiments herein provide a system and a method to allow user's communication device to regularly update a local EC file with an updated online EC file. The embodiments herein provide a system and a method to ascertain the presence of communication devices within a range of the short-range wireless communication using a common application executing on the communication devices. The embodiments herein provide a system and a method for providing a secure and authenticated operation of sharing or exchanging EC files between communication devices. The embodiments herein provide a system and a method of maintaining and storing user's contact files in a database of on an online platform. The embodiments herein provide a system and a method of facilitating a chat feature between users having profiles or accounts over different networking platforms. The embodiments herein may utilize communication devices, a system (server) and a method implemented in accordance with the descriptions herein. The communication devices generally include a short-range wireless transceiver, such as Bluetooth® or near field communication (NFC) transceiver, targeted towards peer-to-peer wireless communication. The communication devices may further include at least one supplementary wireless communication adapter, which preferably supports longer range and/or higher data rates than the short-range transceiver. Non-limiting examples of the supplementary adapters include a GSM (Global System for Mobile Communications) transceiver and a WLAN (Wireless LAN, wireless local area network) transceiver. The supplementary adapter may be such that it is configured to co-operate with a predetermined communications network (infrastructure) such as the adapters listed above. The communications network may further connect to other networks and provide versatile switching means for establishing circuit switched and/or packet switched connections between the communication devices. In an aspect, when a first communication device may be brought, by a user thereof, into the spatial proximity; i.e., within the range of the short-range wireless transceiver of remote or second communication device, the communication device may receive notification (including at least picture and name of user of the communication device) from a server herein about profile associated with user of the second communication device. Similar notifications about a profile associated with the user of the first mobile device may be received on the second communication device from the server. In an example, the notification about the profile may include at a picture and a name of respective user. Also, the notification may ask for confirmation (acceptance/rejection) from respective users that whether they want to exchange electronic coordinate (EC) file (also referred to herein as a contact information card) via the short-range wireless communication link. The EC file may include information about the users beyond the information shared along with notification. For example, the EC file may include, but is not limited to, a picture or graphic, phone number, fax number, social network profile identification number, and other encrypted or non-encrypted information. Upon receiving an affirmative response from both the users, a connection may be established by the server between the first and second communication devices of both the users, for exchanging the EC files. In an aspect, the first and second communication devices may exchange the EC files simultaneously or in a serial sequence. In an aspect, transmission and reception of various data, such as notifications and/or EC files, relative to communication devices and/or system(s)/server(s) connecting the communication devices, may take place directly or via a common client-side application executing on both the communication devices. In an example, in case the transmission and reception of various data takes place using the common client-side application or app, the communication devices may search for another communication devices having same and common client-side application for implementation of the subject matter described in the embodiments herein. In an aspect, the first communication device may wirelessly send and address notifications to/from remote parties, such as a server arrangement according to the embodiments herein, for storage and further distribution of the exchanged or received EC files from the remote/second communication device, directly to and through the common client-side application installed on the first communication device. Accordingly, in an embodiment, a server of establishing a communication link for exchanging profile related information between communication devices is provided. In an example, the server may be implemented as, or within, a server for implementing the various functionalities of the embodiments herein. The server may include a non-transitory storage device having embodied therein one or more routines, and one or more processors coupled to the non-transitory storage device and operable to execute the one or more routines. In an aspect, the one or more routines may include a registration module, a detection and notification module, and a communication establishment module. The registration module may communicate with a first communication device of a first user and a second communication device of a second user over communication links including a cellular network. Upon communicating with the first and second communication devices, the registration module may store, in its database, a first profile associated with the first user and a second profile associated with a second user, where both the first and the second profiles may include at least a picture and a name of their respective users. In another example, the first and the second profiles may be stored in a common app (client-side application) executing on the first and second communication devices. In an aspect, when both the first and second communication devices are implementing the common client-side application and are connected through the same server, the first and second communication devices may be considered as users or members of the server connecting them. Following the storage of the first and second profiles by the registration module, the detection and notification module may continuously track the locations of the first communication device and the second communication device so as to detect whether the first communication device and the second communication device are coincidently located within a spatial proximity. In an example, the range of spatial proximity may be defined based on the range of a standard short-range wireless communications link. In an example, the detection and notification module may locate the communication devices using the common app (client-side application) installed in accordance with the embodiments herein on both the communication devices. In response to at least the first communication device and the second communication device coincidently located within the spatial proximity, the detection and notification module may transmit a first information about the second profile to the first communication device and a second information about the first profile to the second communication device. Upon transmission or reception of the information about the profiles, the first communication device may display a first invitation including at least the picture and name of the second profile, and the second communication device may display a second invitation including at least the picture and name of the first profile. Also, in an example, the first communication device may be configured to receive a first input from the first user if the first user is willing to accept the first invitation and the second communication device may be configured to receive a second input from the second user if the second user is willing to accept the second invitation. Upon receipt of the invitations, the connection establishment module may receive a first response from the first communication device representing the first input, and a second response from the second communication device representing the second input. In an example, the common app (client-side application) running on both the first and second communication devices may provide the first and second users with an option to accept or reject the invitation sent by the other respective user. In case both the first and the second inputs are positive towards acceptance of invitation, the connection establishment module may store connectivity information in the database that the first and the second users are now contacts of each other, followed by establishing a communication between the first and second communication devices. In an aspect, once the communication is established between the first and second communication devices, the first and second users may access or receive user information beyond information received in the first and second invitations. The user information may include, but is not limited to, a picture or graphic, phone number, fax number, social network profile identification number, and other encrypted or non-encrypted information. In an example, the information may collectively referred to as electronic coordinates (EC) of user and accessed/received in the form of a digital file called as EC file. Based on the information received from the first and second communication devices, the server may communicate with a networking server. The networking server may be operating independently of the server. Further, the networking server may be a server providing social networking services such as Facebook®, Twitter®, Instagram®, MySpace®, LinkedIn®, and the like. Once the server communicates with the networking server, the server may be able to use contact information, or profile related information, of first or second users to update the user information received from the first or second communication devices. In an aspect, the server may establish a connection or communication with the contact exchanging applications executing on the first and second communication devices to execute its services and features on the first and second communication devices. In an aspect, the contact exchanging applications may be used to store updated contacts information and profiles of user contacts including pictures on a respective communication device for facilitating instant access to user. The embodiments herein further provide a method comprising communicating a server with a first communication device of a first user and a second communication device of a second user over communication links comprising a cellular network; storing, in a database of the server, a first profile associated with the first user and a second profile associated with a second user, where both the first and the second profiles comprise at least a picture and a name of their respective users; responsive at least to the first communication device and the second communication device coincidently located within a spatial proximity, transmitting a first information about the second profile to the first communication device and a second information about the first profile to the second communication device, where the first communication device displays on a first screen a first invitation including at least picture and name from the second profile and the second communication device displays on a second screen a second invitation comprising at least picture and name from the first profile, and the first communication device may be configured to receive a first input from the first user if the first user is willing to accept the first invitation, and the second communication device is configured to receive a second input from the second user if the second user is willing to accept the second invitation; receiving a first response from the first communication device representing the first input; receiving a second response from the second communication device representing the second input; responsive to both the first and the second input being positive, storing connectivity information in the database, wherein the connectivity information represents that the first and second users are enabled to communicate using the first and second communication devices; and establishing a connection between the first and second communication devices for enabling the first user and the second user to communicate. The embodiments herein further provide a server for communicating with a first communication device of a first user and a second communication device of a second user over communication links including a cellular network. In an aspect, the server may include a non-transitory storage device having embodied therein one or more routines, and one or more processors coupled to the non-transitory storage device and operable to execute the one or more routines. The one or more routines may include a registration module, a detection and notification module, and a connection establishment module. The registration module may store, in a database, a first profile associated with the first user and a second profile associated with the second user. In an example, both the first and second profiles comprise at least a picture and a name of their respective users, and are able to associate each user profile with a unique hardware identifier associated with the users' devices. For example, each user profile may be associated with device's identification number. Once the first and second profiles are stored, the detection and notification module may identify a unique hardware identifier of the second communication device within a spatial proximity of the first communication device. In an example, the range of the spatial proximity of the first communication device may be defined using the range of the short-range wireless communication. Based on the identification of the unique identifier, the detection and notification module may transmit the second profile of the second user to the first communication device as an invitation to connect with the second communication device, and the first profile of the first user to the second communication device as an invitation to connect with the first communication device. Thereafter, the detection and notification module notifies the first communication device when the second user has accepted or rejected the invitation to connect the second communication device with the first communication device. Following the receipt of the acceptance of the notification, the connection establishment module may store the connectivity information between both the first and second communication devices in the database and facilitate chat feature between the first and second users using the respective communication devices connected to the server. Based on the information received from the first and second communication devices, the server may communicate with a networking server. The networking server may be operating independently of the server. Further, the networking server may be a server providing social networking services such as Facebook®, Twitter®, Instagram®, MySpace®, LinkedIn®, and the like. Once the server communicates with the networking server, the server may be able to use contact information, or profile related information, of first or second users to update the user information received from the first or second communication devices. In an aspect, the server may establish a connection or communication with the contact exchanging applications executing on the first and second communication devices to execute its services and features on the first and second communication devices. In an aspect, the contact exchanging applications may be used to store updated contacts information and profiles of user contacts including pictures on a respective communication device for facilitating instant access to user. The embodiments herein further include a method for communicating a server with a first communication device of a first user and a second communication device of a second user over communication links comprising a cellular network. The method may include storing, in a database of the server, a first profile associated with the first user and a second profile associated with the second user, where both the first and second profiles comprise at least a picture and a name of their respective users, and able to associate each user profile with a unique hardware identifier associated with the users' devices; identifying a unique hardware identifier of the second communication device within a spatial proximity of the first communication device; based on the identification of the unique identifier, transmitting the second profile of the second user to the first communication device as an invitation to connect with the second communication device; transmitting the first profile of the first user to the second communication device as an invitation to connect with the first communication device; notifying the first communication device when the second user has accepted or rejected the invitation to connect the second communication device with the first communication device; and in response to the acceptance of the invitation by the second user, storing the connectivity information between both the first and second communication devices in the database and facilitates chat feature between the first and second users using the respective communication devices connected to the server. In operation, when the first user associated with the first communication device and the second user associated with the second communication device wish to create an account with a server herein, the server communicates with the first and second devices over communication links including cellular network. Once the communication is established, the server may ask the users of the first and second device to install an app; e.g., a client-side application, on their respective devices. Upon installation of the client-side application, the users may log in and create a new user profile by selecting which information he/she wishes to exchange as part of electronic coordinates (EC). Also, the users may select information about the profile which they want to transmit along with an invitation to connect. For example, the information about the user profile may include at least a picture and a name of the user. Once the user profiles are created, these user profiles are stored on in a web database of the server. While storing the user profiles, the users may also store their contacts or EC files stored on the devices or other networking servers in the web database. For example, the users may synchronize their device contacts, or EC files, with the web database to update the contacts on the web database. In an example, the users may save their user IDs and passwords of other networking servers in encrypted form on the server, so as to allow the server to import contacts or ECs from these other networking servers. In one example, the server may periodically synchronize the information related to user profile and contacts from the communication devices and the other networking servers, for ensuring that the updated information is stored in the web database of the server. As described herein, the web database may also be interchangeably referred to as Electronic Coordinates (EC) master database. Once the user profiles and the user contacts are stored and updated, the server may continuously monitor the locations of the devices associated/member with the server. In an example, the server may continuously monitor the locations using the app; e.g., a client-side application, installed on the devices. In the example, the app may search for similar or the same app installed on other communication devices present within a spatial proximity. The range of the spatial proximity may correspond to range of a short-range wireless communication standard of the communication devices. Once the app that is installed on first communication device determines that the second communication device with same app is within a spatial proximity of the first communication device, the server may transmit information about a user profile associated with the first communication device to the second communication device, and also transmits other information about a user profile associated with the second communication device to the first communication device. In one example, the information about the profile may be transmitted and presented as an invitation to connect with the other communication device. In the example, the invitation may present at least a user picture, a user name, and an option to accept/reject the invitation. Once both the users accept the invitation to connect, the server may store connectivity information in the web database that from now onwards the users of the first and second communication devices are contacts of each other, and then establish a communication between the app implemented on the first and second communication devices to exchange the EC files or contact information. In one example, the app implemented on the first and second communication devices may be a Bluetooth® app or a web app. In an example, in case of a Bluetooth® app, the first and second communication devices may exchange EC files or contact information over a Bluetooth® communication link. In another example, in the case of a web app, the first and second communication devices may exchange or update EC files or contact information over web based services facilitated via cellular services. Further, once the EC files or the contact information is exchanged between the first and second communication devices, the server may facilitate a universal chat tool. Such a tool may facilitate the users of the first and second communication devices to communicate with each other using messages with their accounts maintained at different networking servers/portals. Thus, with the servers (systems) and methods, users having accounts maintained at disparate networking servers may communicate with each other over the universal chat tool. Accordingly, the servers (systems) and methods provided by the embodiments herein enable the users to exchange EC files over short-range wireless communication link, allow the users to add the contact information (EC files) from other networking servers/portals to EC master database of the system, allow for the ability to link the online maintained contact information of EC files with a universal chat tool, and allow users to chat across the disparate networking servers/portals. FIG. 1 illustrates an exemplary architecture 100 for creation, sharing, and exchange of an electronic coordinate (EC) file (e.g., a contact information card) via a short-range wireless communication link in accordance with the embodiments herein. The EC file may include user information having, but is not limited to, a picture or graphic, phone number, fax number, social network profile identification number, and other encrypted or non-encrypted information. Apart from creation, sharing, and exchange of the EC file, the architecture 100 may also facilitate the services including registration with a server, view newly created social card/profile on a server, edit profile including adding multiple pictures, obtain user location dynamically based on standard mobile communication protocols, search for network members in spatial vicinity, access additional features provided by social network such as chat with members, view members who discovered the user, accept or reject invitations to connect, and access any features provided by a social network facilitate by the server. In an aspect, the architecture 100 may include a plurality of communication devices 102-1, 102-2, . . . , 102-N, hereinafter collectively referred to as communication devices 102 (or simply, devices 102) and individually as communication device 102 (or simply, device 102). Examples of the communication devices 102 may include, but are not limited to, mobile phones, smart phones, personal computers (“PCs”), laptops, and other network-enabled devices which let users to surf the web to access sources of information and entertainment, send e-mails and instant messages. Further, the communication devices 102 may communicate with each other and a server 104 over a cellular network 108 facilitated by at least one base transceiver station (BTS) 106. In an example, the server 104 may be a networking server, a network server, a web server, or a data server. In an example, the server 104 may facilitate a web-based networking service which allows members or users of that service to interact with their contacts associated or linked to other disparate social networks (e.g., Facebook®, LinkedIn®, Twitter®, etc.), micro-blogs (e.g., Pinterest®, Tumblr®, Instagram®, etc.), blogs, e-commerce sites, and other social networks that support the creation, introduction, sharing, purchase, licensing, renting, and consumption of data. The cellular network of the BTS 106 may facilitate bi-directional communication links between the communication devices 102 and the server 104 through a communication standard that provides separate facilities for transmission of digital data. In an aspect, the BTS 106 may establish a communication network 108 between the communication devices 102 and the server 104, and may facilitate communication according to packet-based telecommunications protocol such as 3G, 4G, LTE, or any similar data technology. In an example, the communication network 108 may be a wireless network, a wired network or a combination thereof. The communication network may be implemented as one of the different types of networks, such as intranet, Local Area Network (LAN), Wide Area Network (WAN), the Internet, and the like. The communication network may either be a dedicated network or a shared network. The shared network represents an association of the different types of networks that use a variety of protocols, for example, Hypertext Transfer Protocol (HTTP), Transmission Control Protocol/Internet Protocol (TCP/IP), Wireless Application Protocol (WAP), and the like, to communicate with one another. Further, the communication network may include a variety of network devices, including routers, bridges, servers, communication devices, storage devices, and the like. When a user of communication device 102-1 wishes to join or become member of the server 104 herein, the user may sign-up or register with a service of the server 104 through website or using the communication device 102-1. In an example, the user may access the service website by browsing a uniform resource locator (URL) address of the website. Once the user lands on the service website of the server 104, the user may register with the server 104 by creating a new account by submitting basic information, including name and picture. For ease of registration, the user may optionally sign-up using other existing social network credentials and import pictures from these other existing social network(s) for creation of the new account with the server 104, if the other existing social network allows transferring and/or access of users' information and personal attributes such as picture(s) and name. In an aspect, the creation of the user profile may be performed by selectively submitting the profile related information which the user may wish to exchange with other users while establishing communication for the first time. Such selective profile related information may include, but is not limited to, a picture and name of the user. In addition to the selective information, the user information may include, but is not limited to, a picture or graphic, phone number, age, e-communication address, fax number, social network profile identification number, device's identification number, and other encrypted or non-encrypted information. Additional aspects of the registration process may include creating a social electronic coordinates (EC) card or profile, which is intended to be shared with other members or be discovered by other members of the server 104. An example of an EC card 202 generated is shown in FIG. 2A, with reference to FIG. 1. In an aspect, the user's or a member's profiles may be available for members present in a spatial proximity to the user's communication device 102-1 to view, via a mobile data connection to internet or direct internet connection from the communication device 102-1 to a local wireless network. In an embodiment, signing-up or registration through the communication device 102-1 may require the user of that communication device 102-1 to download a CSA (Client-side Application) from either a third-party application provider or request from the service website to send to his/her communication device 102-1 a link allowing the download of the CSA. Once the CSA is downloaded on the communication device 102-1, the user may provide information by filling out, including uploading graphics or pictures, an on-line profile through a web based interface or interface of the CSA. Further, the CSA residing on the communication device 102-1 may facilitate the user to communicate directly with the service website of the server 104, through a provided internet connection, to synchronize/update contacts and to manage communication with contacts or potential new contacts, access account information via username/password, or phone ID, send search requests for information about users in the spatial proximity, transmit invitations for accepting/denying exchange requests for exchange of contact information, obtain instances of the server addresses, allow the user to edit his/her own profile, and update photos or information or add additional photos or information, etc. In an example, the CSA may connect to the server 104 through internet connection provided by the communication device 102-1. In an example, the CSA may obtain a mobile device unique identifier upon completion of the sign-up process from the communication device 102-1 or upon first access from the communication device 102-1. The obtained unique identifier may then be submitted to the server 104 for associating with user account of the user associated with the communication device 102-1, so that the unique identifier may be used to authenticate the communication device 102 for providing access to the user. Further, personal and other user information, including hobbies, business associations, or personal information as examples, may also be added by way of the CSA for storage on the server 104. In order to take advantage of the functionalities offered by the server 104, the member of the server's service may have a communication device that provides separate facilities for transmitting digital data. This allows the communication device to act like any other computer over the Internet, including sending and receiving data via the Internet Protocol. In a further aspect, the service offered by the server 104 may be part of a social network. Accordingly, following the creation or registration of the new account with the server 104, the server 104 or the CSA may prompt the user to enter the login credentials for other social networks in case the user wishes to link his/her other social networks with the service offered by the server 104 herein. The user may then provide his/her login credentials for other social networks, which in turn allows the user to view multiple social networks of his/her choice into a window-in-window viewer 204 (as shown in FIG. 2B, with reference to FIGS. 1 and 2A) of the service. With the window-in-window viewer 204, the user may access anyone or all the social networks at a single service of the server 104 herein. In an aspect, from the other social networks linked onto the service of the server 104, the server 104 may import contacts into an EC master database maintained for the user of the communication device 102-1. Such imported contacts may be synchronized regularly or periodically with the updated profile related information from the linked other social networks, so as to maintain an up-to-date EC master database of EC files or cards. FIG. 2C, with reference to FIGS. 1 through 2B, illustrates an example of a service website 200 associated with the server 104. The service website 200 may provide a user with a network-based storage for personal contact information, creation of a custom social EC cards to send to discovered, or discovering, users who are also members of the service, for the purpose of providing personal contact information including personal attributes such as picture(s) to other users/member and for accessing personal contact information including personal attributes such as picture(s) of other users/members of the service. Further, as may be seen from FIG. 2C, the service website 200 may include a universal chat tool 206. The universal chat tool 206 may have the ability to login with multiple user IDs over various other social networks chat. For instance, a user may chat with users or contacts using Google®, AIM®, Yahoo!® services and other chat applications. In one example, the universal chat in accordance with the embodiments herein may be performed between the members of the service offered or managed by the server 104 herein. FIG. 3, with reference to FIGS. 1 through 2C, illustrates an architecture 300 implementing the server 104 in accordance with an exemplary embodiment. As shown in FIG. 3, the architecture 300 may include the communication device 102-1 communicating with the server 104 over the communication network 108. As described above, the communication device 102-1 may include a CSA 302. The CSA 302 may reside on any communication device, and is not limited to smartphone applications, which means that the CSA 302 would be able to provide support to multiple operating systems. The CSA 302 may be configured to collect characteristics, such as the device identification number, from the communication device 102-1 for the purpose of associating the communication device 102-1 with a user account 304 maintained at the server 104. This association between the unique identifier, such as the device identification number, and the user account 304 may be used to report the location of the communication device 102-1 to the server 104 dynamically and authenticate the user with communication device 102-1 used. In order to completely utilize the communication device's features provided by the service including dynamic search of members in spatial proximity, the user may have to install the CSA 302 to the communication device 102-1. The CSA 302 associated with the server 104 may enable the user to update, replace, and revise the social profile or personal attribute information, modify, hide or publish profile information (at the server) as contained in the user's contact information; e.g., the information contained in the user's profile which may be transmitted when the user initiates discovery process. Furthermore, the CSA 302 may allow the user to indicate interest in connecting with a member, or the user is discovered by other members searches and communicate to other members though features such as SMS, chat, text, and other features. In accordance with the embodiments herein, the server 104 may associate each communication device 102 with a member account 304 of the service using a unique identifier such as an identification number. The device identification number may be used for future location reporting and authentication for secure and future log in, if needed. In an aspect, the member account 304 may store or maintain the profile information related to user's EC card 306. In addition to the user's or member's EC card 306, the member account 304 may include an EC master database 308 for storing or maintaining the EC cards/files of the users/members which at in contact with the user. Further, the member account 304 may include storage 310 for storing data temporarily during processing or execution of various tools and/or applications of the service offered by the server 104. In addition to the member account 304, the server 104 may include other member accounts 312 as shown in FIG. 3. Further, the server 104 may include contents 314 that may be purchased and billed to the user of the communication devices 102 associated with the service of the server 104. Further, in an aspect, the member account 304 may be associated with a link tool 306 allowing the server 104 to link and navigate the window-in-window viewer 204 from one social network window to another social network window, and may be associated with the universal chat tool 206 allowing the user to chat with other members/users having messenger accounts of different social networks. With such an architecture 300 in place, the user of the communication device 102-1 may communicate with the server 104 to create his/her membership/user account 304 and then maintain the EC master database 308 for utilizing various services of the server 104. Once the user of the communication device 102-1 has created his/her membership account and associated profile on the service website of the server 104, the user may connect with the server 104 using CSA 302 to enquire about other members in the spatial proximity of the communication device 102-1. In an example, the range of the spatial proximity may correspond to the range of standard short-range wireless communication. The server 104, after receiving an inquiry on members in the spatial proximity, may transmit an invitation to connect with list of members, including name and picture of the members, to the requesting communication device 102-1, which is then displayed on screen of the communication device 102-1. Thus, the server 104, not only provides a list of members, but also provides names and pictures of the members for easy identification. Once the requesting user receives the list of pictures and names, the user may select from the communication device 102-1 for exchange of EC cards or contact information. Once the user selects any one or more member(s) from the received list of members, the server 104 may transmit an invitation to connect the requesting user/member with the selected member(s). At this point, when the server 104 receives an acceptance for exchange of EC cards from the selected member and the requesting member, the server 104 may establish a communication between the requesting user and the selected member to exchange the EC cards or contact information. The detailed working and operation of the server is further explained with reference to FIG. 4. FIG. 4, with reference to FIGS. 1 through 3, illustrates various components of a server 104. In an example, the server 104 may be implemented to facilitate service accessible through a website or a client-side application. The server 104 may be in communication with one or more communication devices 102 through the communication network 108 as discussed above. In an example implementation, the communication devices 102 may be configured as mobile phones, smart phones, laptops, notepads, or any other network-enabled devices. In an example, the communication devices 102 may include a client-side application (CSA) 302 to access the service of the server 104. As an example, the CSA 320 may be a web application or Bluetooth® application. In an aspect, the server 104 may include one or more processor(s) 402. The one or more processor(s) 402 may be implemented as one or more microprocessors, microcomputers, microcontrollers, digital signal processors, central processing units, logic circuitries, and/or any devices that manipulate data based on operational instructions. Among other capabilities, the one or more processor(s) 402 are configured to fetch and execute computer-readable instructions stored in a memory 404 of the server 104. The memory 404 may store one or more computer-readable instructions or routines, which may be fetched and executed to create or share the data units over a network service. The memory 404 may include any non-transitory data storage device including, for example, volatile memory such as RAM, or non-volatile memory such as EPROM, flash memory, and the like. The server 104 may also include an interface(s) 406. The interface(s) 406 may include a variety of interfaces, for example, interfaces for data input and output devices, referred to as I/O devices, storage devices, and the like. The interface(s) 406 may facilitate communication of the server 104 with various communication devices 102 coupled to the server 104. The interface(s) 406 may also provide a communication pathway for one or more components of the server 104. Examples of such components include, but are not limited to, module(s) 408 and data 410. The module(s) 408 may be implemented as a combination of hardware and programming (for example, programmable instructions) to implement one or more functionalities of the module(s) 408. In examples described herein, such combinations of hardware and programming may be implemented in several different ways. For example, the programming for the module(s) 408 may be processor executable instructions stored on a non-transitory machine-readable storage medium and the hardware for the module(s) 408 may include a processing resource (for example, one or more processors), to execute such instructions. In some examples, the machine-readable storage medium may store instructions that, when executed by the processing resource, implement the module(s) 408. In such examples, the server 104 may include the machine-readable storage medium storing the instructions and the processing resource to execute the instructions, or the machine-readable storage medium may be separate but accessible to server 104 and the processing resource. In other examples, the module(s) 408 may be implemented by electronic circuitry. In an example, the module(s) 408 may include a registration module 412, a detection and notification module 414, a connection establishment module 416, and other module(s) 418. The other module(s) 418 may implement functionalities that supplement applications or functions performed by the server 104 or the module(s) 408. The data 410 may include data that is either stored or generated as a result of functionalities implemented by any of the components of the module(s) 408. In one example, the data 410 may include a server database 420 to store any contact information exchanged and synchronized with the communication devices 102. In operation, when s first user associated with a first communication device 102-1 and a second user associated with a second communication device 102-2 wish to create an account with a service offered by the server 104 herein, the users of these devices 102-1, 102-2 may install a client-side application (CSA) 302 on their respective devices 102-1, 102-2 to establish a communication with the server 104. In an alternate example, the users may directly access the service website of the server 104 to create an account. Once the user accesses the server 104 via CSA or service website, the users may create their respective accounts by creating respective first and second profiles using the registration module 412. Each of the first and second profiles may include a picture and name of a respective user. Once the user profiles are created, the registration module 412 may store these user profiles in the web database of the server 104. While storing the user profiles, the registration module 412 may prompt the users to store their contacts already stored on their respective devices or other networking servers, in the web database. For example, the registration module 412 may ask the users to allow synchronization of their device contacts with the web database to update the contacts on the web database. In an alternative example, the registration module 412 may prompt the users to save their user IDs and passwords of other networking servers in the encrypted form on the server 104, so as to allow the server 104 to import contacts from these other networking servers. In one example, the registration module 104 may periodically synchronize the information related to the user profile and contacts from the communication device and the other networking servers, to ensure that the updated information is stored in the web database, or Electronic Coordinates (EC) master database, of the server 104. Once the user profiles and the user contacts are stored and updated, the detection and notification module 414 may continuously monitor the locations of the devices associated/member with the service of the server 104. In an example, the detection and notification module 414 may trigger the monitoring upon receiving a request from a user of one of the first and second communication devices. Further, the detection and notification module 414 may continuously monitor the locations of the first and second devices using dynamic locations obtained from GPS, etc. Once the detection and notification module 414 locates the second communication device in the spatial proximity of the first communication device, the detection and notification module 414 may transmit information about a user profile associated with the first communication device 102-1 to the second communication device 102-2, and also transmits another information about a user profile associated with the second communication device 102-2 to the first communication device 102-2. In one example, the information about the first and second profiles may be transmitted and presented as an invitation to connect with other communication device. In an example, the invitation may present at least a user picture, a user name, and an option to accept/reject the invitation. Once both the users accept the invitation to connect through the detection and notification module 414, the connection establishment module 416 may store a connectivity information in the web database that from now onwards the users of the first and second communication devices 102-1, 102-2 are contacts of each other, and then establish a communication between the CSA 302 implemented on the first and second communication devices 102-1, 102-2 to exchange the EC files or contact information. In one example, the CSA 302 implemented on the first and second communication devices 102-1, 102-2 may be either a Bluetooth® app or a web app. In an example, in the case of a Bluetooth® app, the first and second communication devices 102-1, 102-2 may exchange EC files or contact information over a Bluetooth® communication link. In another example, in the case of a web app, the first and second communication devices 102-1, 102-2 may exchange or update EC files or contact information over service website facilitated via cellular services by the server 104. Further, once the EC files or the contact information are exchanged between the first and second communication devices 102-1, 102-2, the server 104 may facilitate the universal chat tool 206. The tool 206 may facilitate the users of the first and second communication devices 102-1, 102-2 to communicate with each other using message tools with their accounts maintained at different networking servers. Thus, with the servers (systems) and methods, users having accounts maintained at disparate networking servers may communicate with each other. Accordingly, the servers (systems) and methods as provided by the embodiments herein enable the users to exchange EC files over a short-range wireless communication link, allow the users to add the contact information from other networking servers/portals to EC master database of the system, allow the ability to link the online maintained contact information of EC files with a universal chat tool, and allow users to chat across the disparate networking servers/portals. The operation of the server 104 is further described in connection with FIGS. 5 through 8, with reference to FIGS. 1 through 4. In an exemplary implementation, upon creating a user account with the service of the server 104, a text message may be sent on the number associated with the communication device 102. The text message may include a link that once clicked will result into installation of client-side application (CSA) 302 on the communication device 102. In some examples, the CSA 302 implemented on the first and second communication devices 102-1, 102-2 may be either a Bluetooth® app, an NFC app, or a web app. Upon installation of the CSA 302, the user may utilize the CSA 302 to update the online profile with the new contacts in various ways. In an example, the communication devices 102-1, 102-2 may include application interface management software (AIMS) 502, 504 which facilitates the storage of newly exchanged or acquired EC files in a temporary or permanent storage library 506, 508. Further, once the newly exchanged or acquired EC files are stored in the temporary or permanent storage library 506, 508, the CSA 302 may update the online profile using cellular signals, or hardware connection that allows the communication device to be plugged into a computer. For example, as shown in FIGS. 5 and 6, the first communication device 102-1 may include the AIMS 502, which may decide based on the available network conditions that whether the communication device 102-1 may be connected through web database hardware interface 510 or cellular network 512 for synchronizing or updating the web database with the newly exchanged or acquired EC files. In an example, after complete update or synchronization of the user profile, the user may download and store his/her contacts on the communication device 102-1 in case the communication device 102-1 has required storage capacity in the temporary or permanent storage library 506, 508. Once the contacts at the communication device 102-1 and the web database are synchronized, the user of the communication device 102-1 may request the server 104 to detect or locate another communication device in spatial proximity of the communication device 102-1. Upon receipt of the request, the server 104 may perform a detection to search another communication device in the spatial proximity of the requesting communication device 102-1 using the Bluetooth® or Short range connection 514 of the requesting communication device 102-1 and presents the user profile (picture and name of user) associated with the detected communication device 102-2 to the requesting communication device 102-1. If the user of the requesting communication device 102-1 accepts the request to connect with the detected communication device 102-2, the user of the requesting communication device 102-1 may indicate this and the process of informing/notifying the other member associated with the detected communication device 102-2 is managed by the server 104 over cellular network 512. Thus, no direct contact occurs between users (of different communication devices) at this point and will not unless both the users elect to exchange personal information such as device numbers to connect outside of provided service and features. This managed communication by the server 104 may ensure privacy and allows users to reject connections or terminate conversations without having to worry about direct connections potential issues. FIG. 7, with reference to FIGS. 1 through 6, illustrates a further example of notification to the detected users alerting them to exchange request. The notification or invitation may include the users' profile including the users' name and picture, along with an option to accept or reject. For instance, referring to FIG. 7, when a user BOB of a requesting device 102-1 transmits an invitation to connect with a user JOHN (whose device 102-2 is found to be in spatial proximity of the BOB's device 102-1), BOB's device 102-1 may present a message that “JOHN's device 102-2 has CSA 302 and therefore would you wish to exchange EC?”. Similarly, John's device 102-2 may present a message that “BOB would like to exchange EC”. The invitation to connect includes at least a picture and name of the users, and does not include the contact details such as the device numbers or addresses of the users. Once the users (BOB and John) provide a positive feedback in response to the message displayed on their devices, their devices 102-1 and 102-2 may establish a short-range wireless connection to exchange contact details or EC. FIG. 8, with reference to FIGS. 1 through 7, shows an alternative example of a notification when the detected device 102-2 of JOHN does not have a CSA installed thereon. In such a scenario, the server 104 may transmit a SMS (short message service) message with a link that once clicked/accepted by JOHN may divert the JOHN to service website of the server, to accept or reject the invitation. Also, acceptance of the invitation may facilitate the download of the CSA 302 on JOHN's device 102-2 to exchange contact information or EC with device 102-1 of BOB. Also, in the scenario represented in FIG. 8, the requesting device 102-1 of BOB may be provided with a notification that the detected device 102-2 of JOHN does not have the required CSA 302 and therefore would BOB like to share his EC cards without receiving acceptance from the detected device 102-2, and invite JOHN to join his network over service website facilitated by the server 104. In the examples shown in FIGS. 7 and 8, the user (JOHN) of the detected device 102-2 may have the option of accepting the invitation, ignoring/declining or engage in services provided by the server 104, so as to chat or SMS with or without accepting connection with the user of the requesting device 102-1. Since all of the communications between members/users is managed by the server 104, the server database 420 may store any contact information exchanged and add it through a synchronization method with the CSA 302 as well as keep the history of any conversations/SMS between the members/users. Further, the CSA 302 may include features such as storing edits to profiles or communication between the members/users and synchronizes to the server database 420 for storage once connection between the CSA 302 and server 104 is established. This dual storage feature allows the user to restore communication between users on a new device if the device in use is lost or damaged as well as restoring all account information. In the case where a user switches or loses a device, all the user has to do is to install the CSA 302 on the new device and login with his/her credentials. Once an internet connection is established between the new device, the CSA 302 and server 104, and user credentials are verified; the server 104 synchronizes all stored information to the new device, and the new installed CSA 302 reports the new device unique hardware identification number for further services. Further, the server 104 facilitates communication between the two users' devices 102-1, 102-2 and may provide additional features such as the ability to chat via SMS or email service and other services with reference to FIGS. 1 through 8. FIGS. 9 and 10, with reference to FIGS. 1 through 8, illustrate example methods 900 and 1000, respectively, for establishing a connection between at least two communication devices 102-1, 102-2 for enabling the users of the devices 102-1, 102-2 to communicate with one another. The order in which the methods are described is not intended to be construed as a limitation, and any number of the described method blocks may be combined in any order to implement the methods, or an alternative method. Furthermore, methods 900 and 1000 may be implemented by processing resource or communication device(s) through any suitable hardware, non-transitory machine-readable instructions, or combinations thereof. It may also be understood that methods 900 and 1000 may be performed by programmed communication devices, such as communication device(s) 102 or server 104. Furthermore, the methods 900 and 1000 may be executed based on instructions stored in a non-transitory computer readable medium, as will be readily understood. The non-transitory computer readable medium may include, for example, digital memories, magnetic storage media, such as one or more magnetic disks and magnetic tapes, hard drives, or optically readable digital data storage media. The methods 900 and 1000 are described below with reference to communication device(s) 102 as described above; other suitable systems for the execution of these methods may also be utilized. Additionally, implementation of these methods 900, 1000 is not limited to such examples. In FIG. 9, with reference to FIGS. 1 through 8, at block 902, the method 900 may include communicating a server 104 with a first communication device 102-1 of a first user and a second communication device 102-2 of a second user over communication links comprising a cellular network 108. At block 904, the method 900 may include storing, in a database 420 of the server 104, a first profile associated with the first user and a second profile associated with a second user, wherein both the first and the second profiles comprise at least a picture and a name of their respective users. At block 906, responsive at least to the first communication device 102-1 and the second communication device 102-2 coincidently located within a spatial proximity of one another, the method 900 may include transmitting, from the server 104, first information about the second profile to the first communication device 102-1 and second information about the first profile to the second communication device 102-2. In an example, the first communication device 102-1 may display a first invitation comprising at least a picture and name from the second profile, and the second communication device 102-2 may display a second invitation comprising at least a picture and name from the first profile. Further, the first communication device 102-1 may be configured to receive a first input from the first user if the first user is willing to accept the first invitation, and the second communication device 102-2 may be configured to receive a second input from the second user if the second user is willing to accept the second invitation. At block 908, the method 900 may include receiving, at the server 104, a first response from the first communication device 102-1 representing the first input. At block 910, the method 900 may include receiving, at the server 104, a second response from the second communication device 102-2 representing the second input. At block 912, the method 900 may include storing connectivity information in the database 420 in response to both the first and the second input being positive. In an example, the connectivity information may represent that the first and second users are enabled to communicate using the first and second communication devices 102-1, 102-2. At block 914, the method 900 may include establishing a connection between the first and second communication devices 102-1, 102-2 for enabling the first user and the second user to communicate with one another. FIG. 10, with reference to FIGS. 1 through 9, provides another example method 1000 for establishing a connection between at least two communication devices 102-1, 102-2 for enabling the users of the devices 102-1, 102-2 to communicate with one another. At block 1002, the method 1000 may include storing, in a database 420 of the server 104, a first profile associated with the first user and a second profile associated with the second user. In an example, both the first and second profiles comprise at least a picture and a name of their respective users, and are able to associate each user profile with a unique hardware identifier associated with the users' devices 102-1, 102-2. At block 1004, the method 1000 may include identifying a unique hardware identifier of the second communication device 102-2 within a spatial proximity of the first communication device 102-1. At block 1006, the method 1000 may include transmitting the second profile of the second user to the first communication device 102-1 as an invitation to connect with the second communication device 102-2, based on the identification of the unique identifier. At block 1008, the method 1000 may include transmitting the first profile of the first user to the second communication device 102-2 as an invitation to connect with the first communication device 102-1. At block 1010, the method 1000 may include notifying the first communication device 102-1 when the second user has accepted or rejected the invitation to connect the second communication device 102-2 with the first communication device 102-1. At block 1012, the method 1000 may include, in response to the acceptance of the invitation by the second user, storing the connectivity information between both the first and second communication devices 102-1, 102-2 in the database 420 and facilitates a chat feature between the first and second users using the respective communication devices 102-1, 102-2 connected to the server 104. Thus, the embodiments herein allow for the locating of devices 102 and the ability to communicate amongst the devices 102 by associating personal attributes to each device 102 such that when a search is performed, a face picture is found rather than a hardware ID number (e.g., device identification number). Associating personal attributes such as pictures and personal attributes allow users to identify other members and select members whom they wish to exchange contacts with or connect with through the social network. Further, the systems and methods described herein may be used for meeting people including discovering people; e.g., viewing their pictures, names, or other personal information, and selecting one or more people to send an invitation to. The invitation may take the form of a social card, EC card, or other manner of engaging another person in a social atmosphere like quick SMS or flag that there is interest of connecting, or even a business setting such as a meeting, trade show, conference, and the like. The embodiments herein provide a server 104 that cross-references a location of a first user's device 102-1 with registered members in a spatial proximity of the first user's device 102-1 and returns the results by disclosing personal user attributes including pictures and names of all members in the spatial proximity of the first user's device 102-1. The first user who initiated the inquiry may select from the results returned any discovered user he/she wishes to connect with and send a form of invitation to connect using network available tools such as email, SMS, text or any customized invitation form. The invitation to connect to the inquiring user would include his/her personal attributes including picture and name. The discovered member who received invitation may accept, ignore or decline connecting with the inquiring user. At the same point of time, the first user may also receive an invitation from the server 104 to accept, ignore or decline connecting with the discovered member. Upon receipt of a positive acceptance response from both users, the server 104 establishes a connection to exchange the user EC cards. The communication between requesting and discovered users may then proceed through services provided by the social network server 104, thereby bypassing the limitations of communication over one protocol, network limitation/fees, or incompatibility for different types of devices. As an example, one member may be connected to the service of the social network and the communication device through internet service over a cellular signal while the other person may be connected to the same service through a WiFi® signal that provides internet access. The exemplary embodiment also relates to a system/device for performing the operations discussed above. This system/apparatus/device may be specially constructed for the required purposes, or it may comprise a general-purpose computer selectively activated or reconfigured by a computer program stored in the computer. Such a computer program may be stored in a computer readable storage medium, such as, but is not limited to, any type of disk including floppy disks, optical disks, CD-ROMs, and magnetic-optical disks, read-only memories (ROMs), random access memories (RAMs), EPROMs, EEPROMs, magnetic or optical cards, or any type of media suitable for storing electronic instructions, and each coupled to a computer system bus. The foregoing description of the specific embodiments will so fully reveal the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. | <SOH> BACKGROUND <EOH> | <SOH> SUMMARY <EOH>In view of the foregoing, an embodiment herein provides a server configured to communicate with a first communication device of a first user and a second communication device of a second user over communication links comprising a cellular network; store in a database a first profile associated with the first user and a second profile associated with a second user, both the first and the second profile comprising at least a picture and a name of their respective users; automatically determine based on wireless communication that the first communication device and the second communication device are coincidently located within a spatial proximity to one another; responsive at least to the first communication device and the second communication device coincidently located in a spatial proximity, send to the first communication device a first information about the second profile and send to the second communication device a second information about the first profile, wherein the first communication device displays on a first screen a first invitation comprising at least a picture and name from the second profile and the second communication device displays on a second screen a second invitation comprising at least picture and name from the first profile, wherein the first communication device is configured to receive a first input from the first user if he is willing to accept the first invitation and the second communication device is configured to receive a second input from the second user if he is willing to accept the second invitation; receive a first response from the first communication device representing the first input; receive a second response from the second communication device representing the second input; and responsive to both the first and the second input being positive, store information in the database that the first and the second users are now contacts of each other, and if such information is stored in the database, enable the first user and the second user to communicate using the first and the second communication devices. The server may be configured to provide to communication device associated with users who are contacts with the first user information about the first user beyond information in the first invitation. The server may communicate with a networking device, and wherein the networking device is to provide social networking services that operates independently of the server. The server may receive profile related information from the networking device. The server may connect with a contact exchanging application executing on the first and second communication devices to execute services and features available with the server. The contact exchanging application may store updated contact information and profiles of user contacts including pictures. The server may utilize the contact exchanging application of the first communication device to discover the second communication device present within the spatial proximity thereof, and to present a picture and name of the second user associated with the second communication device on a user interface of the first communication device before the first user deciding to send an invite to connect. The contact exchanging application may present the second user with an option to accept or reject the invitation sent by the first user by sending to the server the acceptance or rejection response of the second user, and allowing the server to communicate the acceptance or rejection response to the first user. Another embodiment provides a method comprising communicating a server with a first communication device of a first user and a second communication device of a second user over communication links comprising a cellular network; storing, in the database, a first profile associated with the first user and a second profile associated with a second user, wherein both the first and the second profiles comprise at least a picture and a name of their respective users; automatically determine based on wireless communication that the first communication device and the second communication device are coincidently located within a spatial proximity to one another; responsive at least to the first communication device and the second communication device coincidently located within a spatial proximity, transmitting, from the server, a first information about the second profile to the first communication device and a second information about the first profile to the second communication device, wherein the first communication device displays on a first screen a first invitation comprising at least picture and name from the second profile and the second communication device displays on a second screen a second invitation comprising at least picture and name from the first profile, and wherein the first communication device is configured to receive a first input from the first user if the first user is willing to accept the first invitation, and the second communication device is configured to receive a second input from the second user if the second user is willing to accept the second invitation; receiving, at the server, a first response from the first communication device representing the first input; receiving, at the server, a second response from the second communication device representing the second input; responsive to both the first and the second input being positive, storing connectivity information in the database, wherein the connectivity information represents that the first and second users are enabled to communicate using the first and second communication devices; and establishing a connection between the first and second communication devices for enabling the first user and the second user to communicate. The method may further comprise providing the first and second communication devices with the profile related information beyond the first and second user information comprised in the first and second invitations. The method may further comprise receiving profile related information from a networking device. The method may further comprise receiving profile related information from a networking device in communication with the server. The method may further comprise connecting the server with a contact exchanging application executing on the first and second communication devices to execute services and features available with the server on the first and second communication devices. The method may further comprise discovering, using the contact exchanging application of the first communication device, the second communication device present within the spatial proximity of one another, and presenting a picture and name of the second communication device on user interface of the first communication device before the first user deciding to send an invite to connect. The method may further comprise presenting, by the contact exchanging application, an option to the second user to accept or reject the invitation sent by the first user, sending to the server the acceptance or rejection response of the second user, and allowing the server to communicate the acceptance or rejection response to the first user. Another embodiment provides a server configured to communicate with a first communication device of a first user and a second communication device of a second user over communication links comprising a cellular network, wherein the server comprises a processor configured to store in a data storage device a first profile associated with the first user and a second profile associated with a second user, both the first and the second profile comprises at least a picture and a name of their respective users, and able to associate each member profile with unique hardware identification associated with the member device; identify a unique ID of a second member in the vicinity and spatial proximity of the first member and provide the first member with the profile of the second member comprising a picture and name to facilitate invitation and connection between both members; send the second member the profile of the first member including picture and name upon first member initiating an invite to the second member to connect over the service; inform the first member if the second member has accepted or rejected the invite to connect initiated by the first member; and once the second member accepts the invite of the first member, store the connectivity between both members in data base and facilitates chat feature between them using respective devices connected to the server. The server may further comprise a context information retrieval module, which when executed by the one or more processors, provides the first and second communication devices with the profile related information beyond the first and second user information comprised in first and second invitations. The server may communicate with a second server, and wherein the second server is to provide social networking services that operate independently of the server. The server may receive profile related information from the second server. The server may connect with a contact exchanging application executing on the first and second communication devices to execute services and features available with the server. The contact exchanging application may store updated contacts information and profiles of user contacts including pictures. The server may utilize the contact exchanging application of the first communication device to discover the second communication device present within the spatial proximity, and to present a picture and name of the second user associated with the second communication device on user interface of the first communication device before the first user deciding to send an invite to connect. The contact exchanging application may present the second user with an option to accept or reject the invitation sent by the first user by sending to the server the acceptance or rejection response of the second user, and allowing the server to communicate the acceptance or rejection response to the first user. Another embodiment provides a method for communicating a server with a first communication device of a first user and a second communication device of a second user over communication links comprising a cellular network, the method comprising storing, in a data storage device of the server, a first profile associated with the first user and a second profile associated with the second user, wherein both the first and second profiles comprise at least a picture and a name of their respective users, and able to associate each user profile with a unique hardware identifier associated with the users' devices; identifying a unique hardware identifier of the second communication device within a spatial proximity of the first communication device; based on the identification of the unique identifier, transmitting the second profile of the second user to the first communication device as an invitation to connect with the second communication device; transmitting the first profile of the first user to the second communication device as an invitation to connect with the first communication device; notifying the first communication device when the second user has accepted or rejected the invitation to connect the second communication device with the first communication device; and in response to the acceptance of the invitation by the second user, storing the connectivity information between both the first and second communication devices in the data storage device and facilitates chat feature between the first and second users using the respective communication devices connected to the server. The method may further comprise providing the first and second communication devices with the profile related information beyond the first and second user information comprised in the first and second invitations. The method may further comprise receiving profile related information from a networking server. The method may further comprise receiving profile related information from a networking server present in communication with the server. The method may further comprise connecting with a contact exchanging application executing on the first and second communication devices to execute services and features available with the server on the first and second communication devices. The method may further comprise discovering, using the contact exchanging application of the first communication device, the second communication device present within the spatial proximity, and presenting picture and name of the second communication device on user interface of the first communication device before the first user deciding to send an invite to connect. The method may further comprise presenting, by the contact exchanging application, an option to the second user to accept or reject the invitation sent by the first user, sending to the server the acceptance or rejection response of the second user, and letting the server communicate the acceptance or rejection response to the first user. | H04W4023 | 20171102 | 20180308 | 91849.0 | H04W402 | 7 | GENACK, MATTHEW W | INTERACTION TRACKING AND ORGANIZING SYSTEM | SMALL | 1 | CONT-ACCEPTED | H04W | 2,017 |
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15,802,390 | PENDING | STABLE LIQUID FORMULATION OF AMG 416 (ETELCALCETIDE) | A liquid formulation comprising a peptide agonist of the calcium sensing receptor and method of preparing and using the formulation are provided. | 1. A pharmaceutical formulation comprising AMG 416 hydrochloride in aqueous solution, wherein the formulation has a pH of 2.0 to 5.0. 2. The formulation of claim 1, wherein the formulation has a pH of 2.5 to 4.5. 3. The formulation of claim 1, wherein the formulation has a pH of 2.5 to 4.0. 4. The formulation of claim 1, wherein the formulation has a pH of 3.0 to 3.5. 5. The formulation of claim 1, wherein the pH is maintained by a pharmaceutically acceptable buffer. 6. The formulation of claim 5, wherein the buffer is succinate. 7. The formulation of claim 1, wherein the AMG 416 hydrochloride is present in the formulation at a concentration of 0.1 mg/mL to 20 mg/mL 8. The formulation of claim 1, wherein the AMG 416 hydrochloride is present in the formulation at a concentration of 1 mg/mL to 15 mg/mL. 9. The formulation of claim 1, wherein the AMG 416 hydrochloride is present in the formulation at a concentration of 2.5 mg/mL to 10 mg/mL. 10. The formulation of claim 1, further comprising a pharmaceutically acceptable tonicity modifier. 11. The formulation of claim 10, wherein the tonicity modifier is present in the formulation at a concentration wherein the formulation is approximately isotonic. 12. The formulation of claim 10, wherein the tonicity modifier is NaCl. 13. The formulation of claim 1, wherein the formulation has less than 10% degradation when stored at 2-8° C. for 2 years. 14. The formulation of claim 1, wherein the formulation has less than 10% degradation when stored at room temperature for 2 years. 15. A formulation comprising 2 mg/mL to 20 mg/mL of AMG 416 hydrochloride in aqueous solution, a succinate buffer that maintains the formulation at a pH of about 3.0 to 3.5, and a concentration of sodium chloride wherein the formulation is approximately isotonic. | CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. application Ser. No. 14/908,481, filed Jan. 23, 2016, now allowed, which is a U.S. National Stage of International Patent Application No. PCT/US2014/044622, filed Jun. 27, 2014, which claims the benefit of U.S. Provisional Application No. 61/840,618, filed Jun. 28, 2013, the contents of each is incorporated herein by reference in its entirety. FIELD OF THE INVENTION The present disclosure relates to a liquid formulation comprising a peptide agonist of the calcium sensing receptor, particularly to such a formulation that remains stable after storage for an extended period. The disclosure is also directed to methods of preparing and using the formulation. BACKGROUND OF THE INVENTION A variety of compounds having activity for lowering parathyroid hormone levels have been described. See International Publication No. WO 2011/014707. In one embodiment, the compound may be represented as follows: The main chain has 7 amino acids, all in the D-configuration and the side-chain cysteine residue is in the L-configuration. The amino terminal is acetylated and the carboxyl-terminal is amidated. This compound (“AMG-416”) has utility for the treatment of secondary hyperparathyroidism (SHPT) in hemodialysis patients. A liquid formulation comprising AMG-416 may be administered to a subject intravenously. The hydrochloride salt of AMG-416 may be represented as follows: Therapeutic peptides pose a number of challenges with respect to their formulation. Peptides in general, and particularly those that contain a disulfide bond, typically have only moderate or poor stability in aqueous solution. Peptides are prone to amide bond hydrolysis at both high and low pH. Disulfide bonds can be unstable even under quite mild conditions (close to neutral pH). In addition, disulfide containing peptides that are not cyclic are particularly prone to dimer formation. Accordingly, therapeutic peptides are often provided in lyophilized form, as a dry powder or cake, for later reconstitution. A lyophilized formulation of a therapeutic peptide has the advantage of providing stability for long periods of time, but is less convenient to use as it requires the addition of one or more diluents and there is the potential risk for errors due to the use of an improper type or amount of diluent, as well as risk of contamination. In addition, the lyophilization process is time consuming and costly. Accordingly, there is a need for an aqueous liquid formulation comprising a peptide agonist of the calcium sensing receptor, such as AMG 416. It would be desirable for the liquid formulation to remain stable over a relevant period of time under suitable storage conditions and to be suitable for administration by intravenous or other parenteral routes. SUMMARY OF THE INVENTION A liquid formulation comprising a peptide agonist of the calcium sensing receptor, such as AMG 416 is provided. In one embodiment, the formulation has a pH of about 2.0 to about 5.0. In another embodiment, the formulation has a pH of 2.5 to 4.5. In another embodiment, the formulation has a pH of 2.5 to 4.0. In another embodiment, the formulation has a pH of 3.0 to 3.5. In another embodiment, the formulation has a pH of 3.0 to 4.0. In another embodiment, the formulation has a pH of 2.8 to 3.8. In another embodiment, the pH of the formulation is maintained by a pharmaceutically acceptable buffer. Such buffers include, without limitation, succinate buffers, acetate buffers, citrate buffers and phosphate buffers. In another embodiment, the buffer is succinate buffer. The pH of the formulation may be adjusted as needed with an acid or base, such as HCl or NaOH. In another embodiment, the peptide agonist of the calcium sensing receptor is present at a concentration of 0.1 mg/mL to 20 mg/mL. In another embodiment, the peptide is present at a concentration of 1 mg/mL to 15 mg/mL. In another embodiment, the peptide is present at a concentration of 2.5 mg/mL to 10 mg/mL. In another embodiment, the peptide is present at a concentration of about 1 mg/mL, about 5 mg/mL or about 10 mg/mL. In another embodiment, AMG 416 is present at a concentration of about 0.1 mg/mL to about 20 mg/mL. In one embodiment, AMG 416 is present at a concentration of about 1 mg/mL to about 15 mg/mL. In another embodiment, AMG 416 is present at a concentration of about 2.5 mg/mL to about 10 mg/mL. In another embodiment, AMG 416 is present at a concentration of about 1 mg/mL, about 2.5 mg/mL, about 5 mg/mL or about 10 mg/mL. In another embodiment, AMG 416 is present at a concentration of 0.1 mg/mL to 20 mg/mL. In one embodiment, AMG 416 is present at a concentration of 1 mg/mL to 15 mg/mL. In another embodiment, AMG 416 is present at a concentration of 2.5 mg/mL to 10 mg/mL. In another embodiment, AMG 416 is present at a concentration of 1 mg/mL to 5 mg/mL. In another embodiment, AMG 416 is present at a concentration of 5 mg/mL to 10 mg/mL. In another embodiment, AMG 416 is present at a concentration of 0.5 to 1.5 mg/mL, 2.0 to 3.0 mg/mL, 4.5 to 5.5 mg/mL or 9.5 to about 10.5 mg/mL In another embodiment, the formulation further comprises a pharmaceutically acceptable tonicity modifier or mixture of pharmaceutically acceptable tonicity modifiers. In another embodiment, the tonicity modifier (or mixture of tonicity modifiers) is present at a concentration sufficient for the formulation to be approximately isotonic with bodily fluids (e.g., human blood). In another aspect, the tonicity modifier is NaCl. In another embodiment, the formulation comprises a therapeutically effective amount of a peptide agonist of the calcium sensing receptor. In a preferred embodiment, the formulation comprises a therapeutically effective amount of AMG 416. In another embodiment, the formulation has less than 10% degradation when stored at 2-8° C. for up to 2 years. In another embodiment, the formulation has less than 10% degradation when stored at 2-8° C. for up to 3 years. In another embodiment, the formulation has less than 10% degradation when stored at 2-8° C. for up to 4 years. In another embodiment, the formulation has less than 8% degradation when stored at 2-8° C. for up to 2 years. In another embodiment, the formulation has less than 8% degradation when stored at 2-8° C. for up to 3 years. In another embodiment, the formulation has less than 8% degradation when stored at 2-8° C. for up to 4 years. In another embodiment, the formulation has less than 10% degradation when stored at room temperature for 3 months. In another embodiment, the formulation has less than 10% degradation when stored at room temperature for up to 6 months. In another embodiment, the formulation has less than 10% degradation when stored at room temperature for up to 1 year. In another embodiment, a formulation comprising 0.5 mg/mL to 20 mg/mL of a peptide agonist of the calcium sensing receptor (e.g., AMG 416) in aqueous solution, a succinate buffer that maintains the formulation at a pH of about 3.0 to about 3.5, and a sufficient concentration of sodium chloride for the formulation to be approximately isotonic with human blood is provided. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a series of graphs plotting purity (%) as a function of time (days) for AMG 416 solutions in succinate-buffered saline (pH 4.5) at room temperature (RT). FIG. 1A shows the stability of AMG 416 solutions having concentrations of 200, 66, 20, 6.7, 2.2 and 0.67 mg/mL of AMG 416. In FIG. 1B, the scale is expanded to more clearly illustrate the degradation pattern at concentrations of 20 mg/mL and below. FIG. 2 is a graph plotting purity (%) as a function of time (days) for AMG 416 solutions in succinate-buffered saline (pH 4.5) at 40° C. having concentrations in the range of 20, 6.7, 2.2 and 0.67 mg/mL of AMG 416. FIG. 3 is a series of graphs plotting purity (%) as a function of time (days) for AMG 416 solutions in succinate-buffered saline (pH 2, 3, 4, 5 and 6) at 40° C. In FIG. 3A, the concentration of AMG 416 is 10 mg/mL and in FIG. 3B the concentration of AMG 416 is 2.5 mg/mL. FIG. 4 is a series of graphs plotting purity (%) at 28 days as a function of pH for AMG 416 solutions in succinate-buffered saline at 2-8° C., RT and 40° C. In FIG. 4A, the concentration of AMG 416 is 10 mg/mL and in FIG. 4B the concentration of AMG 416 is 2.5 mg/mL. FIG. 5 is a series of HPLC chromatograms. The HPLC trace in FIG. 5A is for a AMG 416 solution (5 mg/mL, pH 2.25) stored for 27 days at 40° C. (87.8% purity). In FIG. 5B, the scale is expanded to more clearly illustrate the peaks. FIG. 6 is a series of HPLC chromatograms. The HPLC trace in FIG. 6A is for a AMG 416 solution (5 mg/mL, pH 3.5) stored for 27 days at 40° C. (91.7% purity). In FIG. 6B, the scale is expanded to more clearly illustrate the peaks. FIG. 7 is a graph plotting purity (%) as a function of time (days) for a series of AMG 416 solutions (5 mg/mL) in succinate-buffered saline (pH 2.25, 2.5, 3.0 and 3.5) at 2-8° C. FIG. 8 is a graph plotting purity (%) as a function of time (days) for a series of AMG 416 solutions (5 mg/mL) in succinate-buffered saline (pH 2.25, 2.5, 3.0 and 3.5) at RT. FIG. 9 is a graph plotting purity (%) as a function of time (days) for a series of AMG 416 solutions (5 mg/mL) in succinate-buffered saline (pH 2.25, 2.5, 3.0 and 3.5) at 40° C. FIG. 10 is a series of graphs plotting degradant (%) as a function of time (days) for a series of AMG 416 solutions (5 mg/mL) in succinate-buffered saline (pH 2.25, 2.5, 3.0 and 3.5). The time-course of C-terminal deamidation is shown at 2-8° C. (FIG. 10A), RT (FIG. 10B) and at 40° C. (FIG. 10C). Note that the scale of the y-axis is different in each graph. FIG. 11 is a series of graphs plotting degradant (%) as a function of time (days) for a series of AMG 416 solutions (5 mg/mL) in succinate-buffered saline ((pH 2.25, 2.5, 3.0 and 3.5). The time-course of homodimer formation is shown at 2-8° C. (FIG. 11A), RT (FIG. 11B) and at 40° C. (FIG. 11C). Note that the scale of the y-axis of FIG. 11C is different from that in FIGS. 11A and 11B. FIG. 12 is a series of graphs plotting purity (%) as a function of pH (2.8-3.8), AMG 416 concentration (4-6 mg/mL) and NaCl (0.7-1.0%) for a series of solutions in succinate-buffered saline stored at 2-8° C. (FIG. 12A), 25° C. (FIG. 12B) and 40° C. (FIG. 12C). FIG. 13 is a series of graphs plotting purity (%) as a function of time (months) for a series of AMG 416 solutions (3.4 mg/mL) in succinate-buffered saline (pH 2.5, 3.0, 3.5) stored at 2-8° C. (FIG. 13A), 25° C. (FIG. 13B) and 40° C. (FIG. 13C). DETAILED DESCRIPTION OF THE INVENTION The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. Unless otherwise defined herein, scientific and technical terms used in connection with the present application shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Generally, nomenclatures used in connection with, and techniques of, molecular biology and protein chemistry described herein are those well known and commonly used in the art. The methods and techniques of the present application are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification unless otherwise indicated. See, e.g., Laszlo, Peptide-Based Drug Design: Methods and Protocols, Humana Press (2008); Benoiton, Chemistry of Peptide Synthesis, CRC Press (2005); Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates (1992), which are incorporated herein by reference for any purpose. Purification techniques are performed according to manufacturer's specifications, as commonly accomplished in the art or as described herein. The terminology used in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well known and commonly used in the art. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. It should be understood that this disclosure is not limited to the particular methodology, protocols, and reagents, etc., described herein and as such may vary. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the disclosed, which is defined solely by the claims. As used herein, the term “about” in the context of a given value or range refers to a value or range that is within 20%, preferably within 10%, and more preferably within 5% of the given value or range I. General Definitions Following convention, as used herein “a” and “an” mean “one or more” unless specifically indicated otherwise. The term “AMG 416” refers to the compound having the chemical name: N-acetyl-D-cysteinyl-D-alanyl-D-arginyl-D-arginyl-D-arginyl-D-alanyl-D-arginamide disulfide with L-cysteine, which may be represented as: The terms “AMG 416 hydrochloride” or “AMG 416 HCl” are interchangeable and refer to the compound having the chemical name: N-acetyl-D-cysteinyl-D-alanyl-D-arginyl-D-arginyl-D-arginyl-D-alanyl-D-arginamide disulfide with L-cysteine hydrochloride, which may be represented as: As used herein, the terms “amino acid” and “residue” are interchangeable and, when used in the context of a peptide or polypeptide, refer to both naturally occurring and synthetic amino acids, as well as amino acid analogs, amino acid mimetics and non-naturally occurring amino acids that are chemically similar to the naturally occurring amino acids. The term “treating” refers to any indicia of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of signs or symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being. The treatment or amelioration of signs or symptoms can be based on objective or subjective parameters; including the results of a physical examination, for example, the treatment of SHPT by decreasing elevated levels of parathyroid hormone (PTH). The terms “therapeutically effective dose” and “therapeutically effective amount,” as used herein, means an amount that elicits a biological or medicinal response in a tissue system, animal, or human being sought by a researcher, physician, or other clinician, which includes alleviation or amelioration of the signs or symptoms of the disease or disorder being treated, for example, an amount of AMG 416 that elicits a desired reduction in elevated PTH level. The term “room temperature” as used herein refers to a temperature of about 25° C. Storage under “refrigerated conditions” as used herein refers to storage at a temperature of 2-8° C. The terms “peptide”, “polypeptide” and “protein” are interchangeable and refer to a polymer of amino acids, typically joined together through peptide or disulfide bonds. The terms also apply to amino acid polymers in which one or more amino acid residues is an analog or mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers. The terms can also encompass amino acid polymers that have been modified, e.g., by the addition of carbohydrate residues to form glycoproteins, or phosphorylated. Peptides, polypeptides and proteins can be produced by a liquid-phase synthesis or solid phase synthesis or by a genetically-engineered or recombinant cell. A “variant” of a peptide or polypeptide comprises an amino acid sequence wherein one or more amino acid residues are inserted into, deleted from and/or substituted into the amino acid sequence relative to another polypeptide sequence. Variants include fusion proteins. A “derivative” of a peptide or polypeptide is a peptide or polypeptide that has been chemically modified in some manner distinct from insertion, deletion, or substitution variants, e.g., via conjugation to another chemical moiety. Such modification can include the covalent addition of a group to the amino and/or carboxy termini of the peptide or polypeptide, e.g., acetylation of the amino terminus and/or amidation of the carboxy terminus of a peptide or polypeptide. The term “amino acid” includes its normal meaning in the art. The twenty naturally-occurring amino acids and their abbreviations follow conventional usage. See, Immunology—A Synthesis, 2nd Edition, (E. S. Golub and D. R. Green, eds.), Sinauer Associates: Sunderland, Mass. (1991), which is incorporated herein by reference for any purpose. Stereoisomers (e.g., d-amino acids) of the 19 conventional amino acids (except glycine), unnatural amino acids such as [alpha]-, [alpha]-disubstituted amino acids, N-alkyl amino acids, and other unconventional amino acids may also be suitable components for polypeptides and are included in the phrase “amino acid.” Examples of unconventional amino acids include: homocysteine, ornithine, 4-hydroxyproline, [gamma]-carboxyglutamate, [epsilon]-N,N,N-trimethyllysine, [epsilon]-N-acetyllysine, O-phosphoserine, N-acetylserine, N-formylmethionine, 3-methylhistidine, 5-hydroxylysine, [sigma]-N-methylarginine, and other similar amino acids and imino acids (e.g., 4-hydroxyproline). In the polypeptide notation used herein, the amino terminal is to the left and the carboxyl-terminal is to the right, in accordance with standard usage and convention. A “subject” or “patient” as used herein can be any mammal. In a typical embodiment, the subject or patient is a human. A “buffer” as used herein refers to a composition, wherein the composition comprises a weak acid and its conjugate base (usually as a conjugate base salt), a weak base and its conjugate acid, or mixtures thereof. Those skilled in the art would readily recognize a variety of buffers that could be used in the formulations used in the invention. Typical buffers include, but are not limited to pharmaceutically acceptable weak acids, weak bases, or mixtures thereof. Exemplary pharmaceutically acceptable buffers include acetate (e.g., sodium acetate), succinate (e.g., sodium succinate). The phrase “weak acid” is a chemical acid that does not fully ionize in aqueous solution; that is, if the acid is represented by the general formula HA, then in aqueous solution A− forms, but a significant amount of undissociated HA still remains. The acid dissociation constant (Ka) of a weak acid varies between 1.8×10-16 and 55.5. The phrase “weak base” is a chemical base that does not fully ionize in aqueous solution; that is, if the base was represented by the general formula B, then in aqueous solution BH+ forms, but a significant amount of unprotonated B still remains. The acid dissociation constant (Ka) of the resultant conjugate weak acid BH+ varies between 1.8×10-16 and 55.5. The phrase “conjugate acid” is the acid member, HX+, of a part of two compounds (HX+, X) that transform into each other by gain or loss of a proton. The phrase “conjugate base” is the base member, X−, of a pair of two compounds (HX, X−) that transform into each other by gain or loss of a proton. The phrase “conjugate base salt” is the ionic salt comprising a conjugate base, X−, and a positively charged counterion. The phrase “buffer system” means a mixture containing at least two buffers. The term “q.s.” means adding a quantity sufficient to achieve a desired function, e.g., to bring a solution to the desired volume (i.e., 100%). The phrase “tonicity modifier” means a pharmaceutically acceptable inert substance that can be added to the formulation to adjust the tonicity of the formulation. Tonicity modifiers suitable for this invention include, but are not limited to, sodium chloride, potassium chloride, mannitol or glycerin and other pharmaceutically acceptable tonicity modifier. II. Embodiments The present disclosure relates to liquid formulations comprising a peptide agonist of the calcium sensing receptor, wherein the formulation has a pH of about 2.0 to about 5.0. In a preferred embodiment, the present disclosure relates to a liquid formulation comprising AMG 416, wherein the formulation has a pH of about 2.0 to about 5.0. AMG 416 and its preparation are described in International Pat. Publication No. WO 2011/014707. For example, AMG 416 may be assembled by solid-phase synthesis from the corresponding Fmoc-protected D-amino acids. After cleavage from the resin, the material may be treated with Boc-L-Cys(NPyS)—OH to form the disulfide bond. The Boc group may then be removed with trifluoroacetic acid (TFA) and the resulting product purified by reverse-phase high pressure liquid chromatography (HPLC) and isolated as the TFA salt form by lyophilization. The TFA salt can be converted to a pharmaceutically acceptable salt by carrying out a subsequent salt exchange procedure. Such procedures are well known in the art and include, e.g., an ion exchange technique, optionally followed by purification of the resultant product (for example by reverse phase liquid chromatography or reverse osmosis). The formulations disclosed herein are described primarily in terms of the therapeutic peptide, AMG 416, as the active ingredient. However, as the skilled artisan will readily appreciate, the present disclosure also extends to variants and derivatives of AMG 416. For example, in one embodiment, the disclosed formulations also may be used with: N-acetyl-D-cysteinyl-D-alanyl-D-arginyl-D-arginyl-D-arginyl-D-alanyl-D-arginamide disulfide with D-cysteine. In another embodiment, the disclosed formulation may also be used with N-acetyl-D-cysteinyl-D-alanyl-D-arginyl-D-arginyl-D-arginyl-D-alanyl-D-arginamide disulfide with N-acetyl-D-cysteine. In another embodiment, the disclosed formulations also may be used with: N-acetyl-D-cysteinyl-D-alanyl-D-arginyl-D-arginyl-D-arginyl-D-alanyl-D-arginamide disulfide with N-acetyl-L-cysteine. In another embodiment, the disclosed formulations also may be used with: N-acetyl-l-cysteinyl-l-alanyl-l-arginyl-l-arginyl-l-arginyl-l-alanyl-l-arginamide disulfide with d-cysteine. In another embodiment, the disclosed formulations also may be used with: N-acetyl-l-cysteinyl-l-alanyl-l-arginyl-l-arginyl-l-arginyl-l-alanyl-l-arginamide disulfide with l-cysteine. In another embodiment, the disclosed formulations also may be used with: N-acetyl-l-cysteinyl-l-alanyl-l-arginyl-l-arginyl-l-arginyl-l-alanyl-l-arginamide disulfide with N-acetyl-d-cysteine. In another embodiment, the disclosed formulations also may be used with: N-acetyl-l-cysteinyl-l-alanyl-l-arginyl-l-arginyl-l-arginyl-l-alanyl-l-arginamide disulfide with N-acetyl-l-cysteine. In another embodiment, the disclosed formulations also may be used with: N-acetyl-d-cysteinyl-d-arginyl-d-arginyl-d-alanyl-d-arginyl-d-alanyl-d-arginamide disulfide with d-cysteine. In another embodiment, the disclosed formulations also may be used with: N-acetyl-d-cysteinyl-d-arginyl-d-arginyl-d-alanyl-d-arginyl-d-alanyl-d-arginamide disulfide with l-cysteine. In another embodiment, the disclosed formulations also may be used with: N-acetyl-d-cysteinyl-d-arginyl-d-arginyl-d-alanyl-d-arginyl-d-alanyl-d-arginamide disulfide with N-acetyl-d-cysteine. In another embodiment, the disclosed formulations also may be used with: N-acetyl-d-cysteinyl-d-arginyl-d-arginyl-d-alanyl-d-arginyl-d-alanyl-d-arginamide disulfide with N-acetyl-l-cysteine. In another embodiment, the disclosed formulations also may be used with: N-acetyl-l-cysteinyl-l-arginyl-l-arginyl-l-alanyl-l-arginyl-l-alanyl-l-arginamide disulfide with d-cysteine. In another embodiment, the disclosed formulations also may be used with: N-acetyl-l-cysteinyl-l-arginyl-l-arginyl-l-alanyl-l-arginyl-l-alanyl-l-arginamide disulfide with l-cysteine. In another embodiment, the disclosed formulations also may be used with: N-acetyl-l-cysteinyl-l-arginyl-l-arginyl-l-alanyl-l-arginyl-l-alanyl-l-arginamide disulfide with N-acetyl-d-cysteine. In another embodiment, the disclosed formulations also may be used with: N-acetyl-l-cysteinyl-l-arginyl-l-arginyl-l-alanyl-l-arginyl-l-alanyl-l-arginamide disulfide with N-acetyl-l-cysteine. In another embodiment, the disclosed formulations also may be used with one or more of the compounds provided in Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, Table 9 and/or Table 10 of International Pat. Publication No. WO 2011/014707. In another embodiment, the disclosed formulations may also be used with one or more of the compounds described in International Pat. Publication No. WO 2011/014707. In some embodiments, the formulation contains a therapeutically effective amount of the active ingredient (e.g., AMG 416). A therapeutically effective amount of the active ingredient in any given embodiment of the formulation of the present disclosure will depend upon the volume of the formulation to be delivered to a given subject, as well as the age and weight of the subject, and the nature of the illness or disorder being treated. Depending on the dosage form, in some instances a therapeutically effective amount may be provided to the patient in one administration while in other instances a plurality of administrations may be required. The liquid formulation of the present disclosure is a pharmaceutical composition suitable for administration by intravenously, intra-arterially, intramuscularly, and subcutaneously. In a preferred embodiment, the liquid formulation is suitable for administration by intravenous or other parenteral routes. Preferably, the liquid formulation is a sterile, aqueous solution. Typically, the solvent is injectable grade water or a mixture of water and one or more other water-miscible solvents(s), such as propylene glycol, polyethylene glycol, and ethanol. The use of sterile, deionized water as solvent is preferred. Other solvents which are suitable and conventional for pharmaceutical preparations can, however, be employed. The formulation typically contains about 0.1 mg/mL to about 100 mg/mL of the active ingredient (e.g., AMG 416), about 0.1 mg/mL to about 20 mg/mL of the active ingredient, about 0.5 mg/mL to about 15 mg/mL of the active ingredient, about 1 mg/mL to about 10 mg/mL of the active ingredient, or about 2 mg/mL to about 5 mg/mL of the active ingredient. In some embodiments, the formulation contains about 1 mg/mL of the active ingredient, about 2 mg/mL of the active ingredient, about 2.5 mg/mL of the active ingredient, about 5 mg/mL of the active ingredient, about 10 mg/mL of the active ingredient or about 20 mg/mL of the active ingredient. In another embodiment, the formulation contains 0.1 mg/mL to 100 mg/mL of the active ingredient, 0.1 mg/mL to 20 mg/mL of the active ingredient, 0.5 mg/mL to 15 mg/mL of the active ingredient, or 1 mg/mL to 10 mg/mL of the active ingredient, or 2 mg/mL to 5 mg/mL of the active ingredient. In a preferred embodiment, the formulation contains 1 mg/mL to 10 mg/mL of the active ingredient. In another preferred embodiment, the formulation contains 2 mg/mL to 5 mg/mL of the active ingredient. The formulation typically has a pH of about 2.0 to about 5.0, a pH of about 2.5 to about 4.5, a pH of about 2.5 to about 4.0, a pH of about 3.0 to about 3.5 or a pH of about 3.0 to about 3.6. In some embodiments, the formulation has a pH of about 2, a pH of about 2.5, a pH of about 3.0, a pH or about 3.3, a pH of about 3.5 or a pH of about 4.0. In some embodiments, the formulation has a pH of 2.0 to 5.0, a pH of 2.5 to 4.5, a pH of 2.5 to about 4.0, a pH of 3.0 to 3.5 or a pH of 3.0 to 3.6. As described more fully in the examples, the stability of AMG 416 depends on the pH of the solution. The present inventors have found that the two major degradants are the result of C-terminal deamidation and homodimer formation. In addition, the present inventors have found that the time course of degradation by these pathways is a function of pH. See Example 6. At low pH, degradation by C-terminal deamidation predominates (see FIG. 10) while at higher pH, degradation by homodimer formation predominates (see FIG. 11). Thus, formation of the two major degradants have the opposite relationship between pH and extent of degradation. These opposing trends underlie the overall stability data over the range of pH values and support the identification of about pH 3.0 to 3.5 as the pH of maximum stability of AMG 416 solutions. Typically, the formulation contains a physiologically acceptable buffering agent that maintains the pH of the formulation in the desired range. In one embodiment, the buffer maintains a pH of about 2.0 to about 5.0, a pH of about 2.5 to about 4.5, a pH of about 2.5 to about 4.0, a pH of about 3.0 to about 3.5 or a pH of about 3.0 to about 3.6. In some embodiments, the buffer maintains a pH of about 2, a pH of about 2.5, a pH of about 3.0, a pH of about 3.3, a pH of about 3.5 or a pH of about 4.0. In some embodiments, the buffer maintains a pH of 2.0 to 5.0, a pH of 2.5 to 4.5, a pH of 2.5 to about 4.0, a pH of 3.0 to 3.5 or a pH of 3.0 to 3.6. Any buffer that is capable of maintaining the pH of the formulation at any pH or within any pH range provided above is suitable for use in the formulations of the present disclosure, provided that it does not react with other components of the formulation, cause visible precipitates to form, or otherwise cause the active ingredient to become chemically destabilized. The buffer used in the present formulation typically comprises a component selected from the group consisting of succinate, citrate, malate, edentate, histidine, acetate, adipate, aconitate, ascorbate, benzoate, carbonate, bicarbonate, maleate, glutamate, lactate, phosphate, and tartarate, or a mixture of these buffers. In a preferred embodiment, the buffer comprises succinate, e.g., sodium succinate. The concentration of the buffer is selected so that pH stabilization as well as sufficient buffering capacity is provided. In one embodiment, the buffer is present in the formulation at a concentration of from about 0.5 to about 100 mmol/L, from about 0.75 to about 50 mmol/L, from about 1 to about 20 mmol/L, or from about 10 to about 20 mmol/L. In other embodiments, the buffer is present at about 5 mmol/L, at about 10 mmol/L, at about 15 mmol/L or about 20 mmol/L. In other embodiments, the buffer is present in the formulation at a concentration of from 0.5 to 100 mmol/L, from 0.75 to 50 mmol/L, from 1 to 20 mmol/L, or from 10 to 20 mmol/L. In a preferred embodiment, the buffer is present at about 10 mmol/L. In another preferred embodiment, the buffer is succinate present at about 10 mmol/L. From the point of view of compatibility of the liquid formulation with intravenous administration, it would be desirable for the pH of the liquid formation to be as near as possible to the physiological pH. Liquid formulations that have a pH that is far from physiological pH or that are strongly buffered can cause pain or discomfort when administration. As has been discussed, liquid formulations of AMG 416 at physiological pH or higher would not remain stable over an extended period of time. Therefore, in a preferred embodiment, the liquid formulation of the present disclosure is weakly buffered so that the quantity injected is quickly neutralized by physiological fluids of the body of the subject. It is surprising that good stability and good control of pH is maintained with the low buffer concentration. In a preferred embodiment, the HCl salt of AMG 416 is used in the preparation of the liquid formulation to minimize buffer capacity. Because HCl is a strong acid, it does not act as a buffer. This provides an advantage over the use of a weaker acid, such as an acetic acid. Using the acetate salt of AMG 416, for example, would itself provide some buffering capacity and allow less flexibility to set the buffering capacity of the formulation and may result in a formulation which is more resistant to neutralization within the body and therefore less well tolerated. Because AMG 416 is a polycationic peptide, the effect would be enhanced compared to most peptides which have a more neutral character. It is generally desirable for a formulation to be administered by intravenous or other parenteral route to be isotonic with bodily fluids. In some embodiments, the formulation of the present disclosure contains a physiologically acceptable tonicity modifier. Tonicity modifiers useful in the present disclosure may include sodium chloride, mannitol, sucrose, dextrose, sorbitol, potassium chloride, or mixtures thereof. In a preferred embodiment, the tonificier is sodium chloride. When a tonicity agent is present, it is preferably present in an amount sufficient to make the liquid formulation approximately isotonic with bodily fluids (i.e., about 270 to about 300 mOsm/L) and suitable for parenteral injection into a mammal, such as a human subject, into dermal, subcutaneous, or intramuscular tissues or IV. Isotonicity can be measured by, for example, using a vapor pressure or ice-freezing type osmometer. Depending upon the concentrations of the other components in the formulation, sodium chloride is present in the formulation at a concentration of about 7.0 to about 10 mg/mL, about 7.5 to about 9.5 mg/mL, or about 8.0 to about 9.0 mg/mL. In a one embodiment, sodium chloride is present in the formulation at a concentration of about 8.5 mg/mL. In other embodiments, sodium chloride is present in the formulation at a concentration of 7.0 to 10 mg/mL, 7.5 to 9.5 mg/mL, or 8.0 to 9.0 mg/mL. The formulations of the present disclosure may include other conventional pharmaceutical carriers, excipients or adjuvants. For example, the formulations of the present invention may include stabilizing agents (e.g., EDTA and/or sodium thiosulfate) or preservatives (e.g., benzyl alcohol). In addition, the formulations of the present disclosure may including additional medicinal and/or pharmaceutical agents. For example, in methods of treating treat SHPT in hemodialysis patients with CKD-MBD, AMG 416 can be coadministered with one or more active agents in renal osteodystrophy, such as a vitamin D therapy (e.g., paricalcitol) which is an established treatment for SHPT. In one embodiment, the formulation has less than 5% degradation when stored at about 2-8° C. for 1 year. In another embodiment, the formulation has less than 5% degradation when stored at room temperature for 1 year. In another embodiment, the formulation has less than 10% degradation when stored at about 2-8° C. for 1 year. In another embodiment, the formulation has less than 10% degradation when stored at room temperature for 1 year. In another embodiment, the formulation has less than 5% degradation when stored at about 2-8° C. for 2 years. In another embodiment, the formulation has less than 5% degradation when stored at room temperature for 2 years. In another embodiment, the formulation has less than 10% degradation when stored at about 2-8° C. for 2 years. In another embodiment, the formulation has less than 10% degradation when stored at room temperature for 2 years. In one embodiment, the liquid formulation comprises 0.1 mg/mL to 20 mg/mL of the therapeutic peptide, a buffer that maintains the formulation at a pH of 2.0 to 5.0, and a sufficient concentration of sodium chloride for the formulation to be approximately isotonic is provided. In another embodiment, the liquid formulation comprises 1 mg/mL to 15 mg/mL of the therapeutic peptide, a buffer that maintains the formulation at a pH of 2.5 to 4.5, and a sufficient concentration of sodium chloride for the formulation to be approximately isotonic is provided. In another embodiment, the liquid formulation comprises 2.5 mg/mL to 10 mg/mL of the therapeutic peptide, a buffer that maintains the formulation at a pH of 2.5 to 4.0, and a sufficient concentration of sodium chloride for the formulation to be approximately isotonic is provided. In another embodiment, the liquid formulation comprises 2.5 mg/mL to 5 mg/mL of the therapeutic peptide, a buffer that maintains the formulation at a pH of 2.5 to 3.5, and a sufficient concentration of sodium chloride for the formulation to be approximately isotonic is provided. In another embodiment, the formulation comprises 2 mg/mL to 20 mg/mL of the therapeutic peptide in aqueous solution, a succinate buffer that maintains the formulation at a pH of about 3.0 to 3.5, and a sufficient concentration of sodium chloride for the formulation to be approximately isotonic is provided. In one embodiment, the liquid formulation comprises 0.1 mg/mL to 20 mg/mL of AMG 416, a buffer that maintains the formulation at a pH of 2.0 to 5.0, and a sufficient concentration of sodium chloride for the formulation to be approximately isotonic is provided. In another embodiment, the liquid formulation comprises 1 mg/mL to 15 mg/mL of AMG 416, a buffer that maintains the formulation at a pH of 2.5 to 4.5, and a sufficient concentration of sodium chloride for the formulation to be approximately isotonic is provided. In another embodiment, the liquid formulation comprises 2.5 mg/mL to 10 mg/mL of AMG 416, a buffer that maintains the formulation at a pH of 2.5 to 4.0, and a sufficient concentration of sodium chloride for the formulation to be approximately isotonic is provided. In another embodiment, the liquid formulation comprises 2.5 mg/mL to 5 mg/mL of AMG 416, a buffer that maintains the formulation at a pH of 2.5 to 3.5, and a sufficient concentration of sodium chloride for the formulation to be approximately isotonic is provided. In another embodiment, the formulation comprises 2 mg/mL to 20 mg/mL of AMG 416 in aqueous solution, a succinate buffer that maintains the formulation at a pH of about 3.0 to 3.5, and a sufficient concentration of sodium chloride for the formulation to be approximately isotonic is provided. In a preferred embodiment, the formulations of the present disclosure are prepared by placing an amount of buffer calculated to generate the desired pH into a suitable vessel and dissolving it with water for injection (WFI), adding an amount of material (e.g., the hydrochloride salt of AMG 416) sufficient to achieve the desired concentration of the active ingredient (e.g., AMG 416), adding an amount of tonicity modifier (or mixture of tonicity modifiers) calculated to render the resulting formulation isotonic with body fluids, and adding the amount of WFI necessary to bring the total volume to the desired concentration. After the ingredients are mixed, the pH is adjusted to about 3.0 to about 3.5, and the components are again mixed. If an adjustment is required in order to achieve the desired pH range, the pH value may be adjusted by means of suitable solutions; with acidic solutions if a reduction of the pH value is indicated and with alkaline solution if an increase of pH value is indicated. Non-limiting examples of suitable acidic solutions are, e.g., hydrochloric acid, phosphoric acid, citric acid and sodium or potassium hydrogen phosphate. Non-limiting examples of suitable alkaline solutions are alkali and alkali earth hydroxides, alkali carbonates, alkali acetates, alkali citrates and dialkali hydrogen phosphates, e.g., sodium hydroxide, sodium acetate, sodium carbonate, sodium citrate, disodium or dipotassium hydrogen phosphate, or ammonia. The procedure is typically carried out at a temperature from about 2-8° C. to about 50° C., and at atmospheric pressure. The resulting formulation may then be transferred to unit dosage or multi-dosage containers (such as bottles, vials, ampoules or prefilled syringes) for storage prior to use. The formulations can be prepared and administered as described above. Alternatively, the formulations can be administered after dissolving, dispersing, etc. the formulation (prepared as described above) in a carrier, such as, for example, an infusion fluid or in the blood/fluid returned to the patient during hemodialysis (e.g., during rinse-back). The preparation of liquid formulations according to the present disclosure are known, or will be apparent, to those skilled in the art, for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 17th edition, 1985. EXAMPLES The following examples, including the experiments conducted and the results achieved, are provided for illustrative purposes only and are not to be construed as limiting the scope of the appended claims. Example 1 Solubility of AMG 416 in Succinate Buffered Saline In this study, the solubility of AMG 416 in succinate buffered-saline was investigated. AMG 416 HCl (103 mg powder, 80 mg peptide) was dissolved in 200 μL of sodium succinate buffered saline (25 mM succinate, 0.9% saline, pH 4.5). After briefly vortexing, a clear solution was obtained with a nominal concentration of 400 mg/mL. Because expansion of the solution volume was not determined, the solubility of AMG 416 can be conservatively stated as at least 200 mg/mL. Although the maximal solubility was not determined in this experiment, AMG 416 is soluble in pH 4.5 succinate buffered saline to concentrations of at least 200 mg/mL. Example 2 Concentration Dependent Stability Study In this study, the stability of AMG 416 over a range of concentrations in succinate-buffered saline (pH 4.5) was investigated. The solution of 200 mg/mL AMG 416 from Example 1, supra, was diluted further with 200 μL of succinate-buffered saline (pH 4.5) to a nominal concentration of 200 mg/mL, which was serially diluted with succinate-buffered saline (pH 4.5) to 66, 20, 6.7, 2.2 and 0.67 mg/mL. The samples were kept at room temperature (i.e., about 25° C.) and aliquots were analyzed by HPLC at intervals up to 29 days. A second series of AMG 416 samples covering the concentration range 20 to 0.67 mg/mL were incubated at 40° C. and analyzed in the same manner. The purity at the 29-day time point for samples at room temperature and 40° C. is provided in Tables 1 and 2, respectively. The results provide a stability profile of AMG 416 as a function of concentration and temperature. TABLE 1 RT Stability of AMG 416 in 25 mM succinate-buffered saline (pH 4.5) Concentration Purity at Time (Days) (mg/ml) 0 1 2 5 13 29 200 99.8 99.6 98.4 96.4 89.0 63.8 66 99.6 99.4 99.0 98.1 97.7 91.5 20 99.6 99.7 99.7 99.6 99.3 98.7 6.7 99.4 99.6 99.5 99.5 99.3 98.9 2.2 99.3 99.2 99.3 99.4 99.3 99.1 0.67 99.4 99.5 99.5 99.7 99.5 99.3 TABLE 2 40° C. Stability of AMG 416 in 25 mM succinate-buffered saline (pH 4.5) Concentration Purity at Time (Days) (mg/ml) 0 1 2 5 13 29 20 99.6 99.1 98.1 n.d. 90.5 72.9 6.7 99.4 99.1 98.7 n.d. 95.2 90.0 2.2 99.3 99.3 99.0 98.4 97.0 94.3 0.67 99.4 99.4 99.3 99.0 97.2 94.4 The time course of AMG 416 degradation as a function of concentration at room temperature is shown in FIG. 1A. In FIG. 1B, the scale is expanded to more clearly illustrate the degradation pattern at drug concentrations of 20 mg/mL and below. The time course of AMG 416 degradation as a function of concentration at 40° C. is shown in FIG. 2. The data show that AMG 416 solution stability is related to concentration in the study range from 0.67 mg/mL to 200 mg/mL. The data also shows that AMG 416 solution stability is related to temperature of incubation. Table 3 shows predictions of extent of degradation for solutions of various concentrations of AMG 416 at room temperature, based on extent of degradation at 29 days, room temperature storage in pH 4.5 SBS. The room temperature 29-day data from Table 1 was extrapolated to the stated time period by assuming linear degradation kinetics. Room temperature data was extrapolated to 5° C. A 20° C. difference was assumed, equivalent to a 4-fold lower rate of degradation. Extrapolations were carried out using a simple application of the Arrhenius equation, where at 10° C. rise in temperature provides a 2-fold increase in reaction rate, assuming the same reaction mechanism and that activation energy for each relevant reaction is around 50 kJ/mol. Bolded values indicate concentration/storage conditions which have less than 10% degradation, which may be preferable for a liquid formulation. TABLE 3 Stability Predictions for Velcalcetide Solutions Concentration Predicted extent of degradation at: (mg/mL) 2 yr RT 1 yr RT 2 yr 5° C. 1 yr 5° C. 66 >100 >100 50.1 25.0 20 20.9 10.4 5.2 2.6 6.7 13.9 7.0 3.5 1.7 2.2 5.2 2.6 1.3 0.7 0.67 2.7 1.4 0.7 0.3 Comparison of the data shown in Tables 1 and 2 allows assessment of temperature increase as a tool to predict the long-term stability of AMG 416 solutions. The data from 0.67 to 20 mg/mL is presented in Table 4, infra, and shows acceleration of degradation at 40° C., which is markedly higher than that predicted by Arrhenius (with the assumptions described, supra). This suggests that accelerated stability data will predict a greater extent of degradation than will be observed at the actual storage temperature. TABLE 4 Temperature and Concentration Dependence of AMG 416 Degradation in pH 4.5 Solution Con- Degradation Degradation Acceleration Predicted centration at 29 days, at 29 days, 40 C. RT ->40 C. acceleration (mg/mL) RT (%) (%) (fold) (fold) 20 0.9 26.7 29.7 4 6.7 0.5 9.4 18.8 4 2.2 0.2 5.0 25.0 4 0.67 0.1 5.0 50.0 4 Example 3 Stability of Liquid Formulations of AMG 416 Over Range of pH In this study, the stability of liquid formulations of AMG 416, at a concentration of 10 mg/mL, was determined over a range of pH in succinate-buffered saline. AMG 416 HCl (257 mg powder) was dissolved in 20 ml of pH 4.5 succinate buffered saline to provide 10.0 mg/ml peptide concentration (adjusted for peptide content of powder). The solution was divided evenly into five 4 mL portions which were adjusted to pH 2, 3, 4, 5 and 6, respectively, with NaOH and HCl as needed. Three 1 mL solutions were aliquoted from each portion and incubated at 2-8° C., room temperature (about 25° C.), and 40° C., respectively. The remaining 1 mL solution in each aliquot was diluted with pH 4.5 succinate buffered saline to 4 mL of 2.5 mg/mL peptide concentration, pH adjusted, and incubated in the same manner. Samples were retrieved according to schedule and diluted with deionized water to 1.0 mg/mL for HPLC analysis. The purity at the 28 day time point for all samples tested is provided in Table 5 (note: the starting purity value was 99.3% for this study). The results provide a stability profile as a function of pH, temperature and concentration. TABLE 5 Purity at 28-Day Time Point for AMG 416 Solutions. 10 mg/mL 2.5 mg/mL 2-8° C. RT 40° C. 2-8° C. RT 40° C. pH 2 99.1 98.7 94.0 98.9 98.7 89.8 pH 3 99.4 99.1 98.2 99.1 99.0 97.2 pH 4 99.4 98.6 85.0 99.2 98.9 92.2 pH 5 99.0 93.8 64.4 98.9 96.1 73.0 pH 6 96.9 71.8 53.6 97.0 80.0 52.9 The time course of AMG 416 degradation as a function of pH is shown in FIG. 3. In both the 10 mg/mL (FIG. 3A) and the 2.5 mg/mL (FIG. 3B) solutions, the least degradation is observed at pH 3. In both solutions, degradation at pH 6 proceeds most rapidly with purity approaching 50% by the 29 day point. HPLC analysis showed that the major degradant at pH 2 different than that observed at pH greater than 3. At lower pH, the degradation is predominantly by deamidation by hydrolysis and at higher pH, the degradation is predominantly formation of the homodimer. The stability profile as a function of pH at the 28 day point is shown in FIG. 4. It can be seen again in both the 10 mg/mL (FIG. 4A) and 2.5 mg/mL (FIG. 4B) that in this set of experiments, the pH of least degradation is approximately 3.0. In addition, the decreases in purity are related to the temperature at all pH levels, with the least degradation observed in the samples incubated at 2-8° C., and the most degradation observed in the samples incubated at 40° C. Based on the extent of degradation at 28 days, predictions of the extent of degradation were calculated as described, supra. The predictions for the 10 mg/mL solution are provided in Table 6 and the predictions for the 2.5 mg/mL are provided in Table 7. Bolded values indicate conditions which show less than 10% degradation, and which may be preferred for a liquid formulation. Conditions where the sample at 28 days show slightly higher purity than the initial data are presented as 0.0% for all projections. These extrapolations suggest less than 10% degradation after 2 years at room temperature for 2.5 or 10 mg/mL solutions at pH 3. In general, higher temperature data predicts greater degradation at 2 years than the lower temperature data. Thus, for the 10 mg/mL studies (Table 6), while pH 3 is predicted to be less than 10% degradation from all temperature data, the 2-8° C. data predicts a lower extent of degradation than the higher temperatures, and in fact at 2-8° C., the pH 4 data is also supportive of less than 10% degradation. Similarly, at 2.5 mg/mL, a pH range from 2-4 is predicted to have less than 10% degradation over 2 years at RT when extrapolated from the 2-8° C. data. TABLE 6 Stability Predictions for AMG 416 10 mg/mL Solutions Based on Extent of Degradation at 28 days. Observed Calculated Degradation degradation at 360 d at 1 y at 2 y at 2 y RT at 28 days (%) (%) RT (%) 5° C. (%) (%) 2-8° C. pH = 2 0.3 3.8 15.4 7.7 30.7 pH = 3 −0.2 0.0 0.0 0.0 0.0 pH = 4 −0.1 0.0 0.0 0.0 0.0 pH = 5 0.3 3.5 13.8 6.9 27.6 pH = 6 1.9 23.9 95.7 47.8 >100 RT pH = 2 0.6 8.1 8.1 4.0 16.1 pH = 3 0.2 2.6 2.6 1.3 5.1 pH = 4 0.7 8.6 8.6 4.3 17.1 pH = 5 5.6 71.4 71.4 35.7 >100 pH = 6 26.9 >100 >100 >100 >100 40° C. pH = 2 5.3 68.4 17.1 8.6 34.2 pH = 3 1.1 14.1 3.5 1.8 7.0 pH = 4 14.3 >100 45.8 22.9 91.7 pH = 5 34.9 >100 >100 55.9 >100 pH = 6 45.1 >100 >100 72.2 >100 TABLE 7 Stability Predictions for AMG 416 2.5 mg/mL Solutions Based on Extent of Degradation at 28 days. Observed degradation Calculated Degradation (%) at 28 days (%) 1 y 2-8° C. 1 y RT 2 y 2-8° C. 2 y RT 2-8° C. pH = 2 0.0 0.0 0.0 0.0 0.0 pH = 3 0.0 0.0 0.0 0.0 0.0 pH = 4 −0.1 0.0 0.0 0.0 0.0 pH = 5 0.2 2.9 11.8 5.9 23.5 pH = 6 0.8 10.7 43.0 21.5 86.0 RT pH = 2 0.6 7.9 7.9 4.0 15.9 pH = 3 0.0 0.0 0.0 0.0 0.0 pH = 4 0.3 3.6 3.6 1.8 7.2 pH = 5 2.9 37.7 37.7 18.9 75.5 pH = 6 18.1 231.0 231.0 115.5 462.1 40° C. pH = 2 9.1 116.5 29.1 14.6 58.3 pH = 3 1.8 22.5 5.6 2.8 11.3 pH = 4 6.9 88.7 22.2 11.1 44.3 pH = 5 26.1 333.6 83.4 41.7 166.8 pH = 6 45.0 575.7 143.9 72.0 287.8 Table 8 presents the temperature acceleration effect for these data in a similar way to Table 4, supra. This again indicates that temperature elevation tends to provide greater acceleration of degradation than is expected by extrapolation based on simple application of Arrhenius principles. TABLE 8 Temperature acceleration as a function of pH. Acceleration: 10 mg/mL data 28 d Deg 10 mg/mL RT/ 40 C./ 40 C./ 2-8° C. RT 40° C. 2-8 predicted 2-8 predicted RT predicted pH 2 0.2 0.6 5.3 3 4 28 16 9 4 pH 3 −0.1 0.2 1.1 >2 4 >10 16 6 4 pH 4 −0.1 0.7 14.3 >7 4 >100 16 22 4 pH 5 0.3 5.6 34.9 19 4 116 16 6 4 pH 6 2.4 27.5 45.7 12 4 19 16 2 4 At each pH value, the degradation data for each of three temperatures is compared to data from the other two temperatures to calculate the observed acceleration. The predicted acceleration is by simple application of Arrhenius principles as described above. As described, infra, HPLC analysis shows that the predominant degradation mechanism at pH less than about 3 is different than that observed at pH greater than about 3. Example 4 Effect of Tonicifying Excipients on Stability In this study, the effects of various pharmaceutical excipients on the stability of AMG 416 in liquid formulation were determined. A 10 mg/mL solution of AMG 416 and stock solutions of mannitol, glycine, arginine, NaCl and Na2SO4 at 2× isotonic concentrations were prepared. The pH of the AMG 416 solution and the five excipient solutions and deionized water separately were adjusted to pH 3.5 using HCl/NaOH. 500 μL aliquots of each of the six solutions were added to glass vials and 500 μL of the AMG 416 solution was added to the same vials and mixed well. This was performed in triplicate to provided eighteen sample vials, each containing 5 mg/mL AMG 416 and an isotonic concentration of the excipient (or deionized water). This was repeated with a set of solutions adjusted to pH 4.5, providing a further eighteen sample vials. The samples were incubated and removed for HPLC analysis at relevant time points. The stability data at the 56-day time point is shown in Table 9. A range of stability behavior was observed as a function of excipient. Under most conditions tested, NaCl formulations showed the least amount of degradation. The exceptions are for the 2-8° C. data at pH 3.5 and 4.5. More variability was observed for other excipients, although arginine appeared to be deleterious in the 40° C. samples and in the pH 4.5 sample at room temperature (about 25° C.), and sodium sulfate appeared to be deleterious in the pH 4.5 samples at room temperature and at 40° C. TABLE 9 Extent of degradation (%) at 56 days for 5 mg/mL AMG 416 Solution Temp 2-8° C. RT 40° C. pH 3.5 4.5 3.5 4.5 3.5 4.5 DI Water 0.0 0.7 1.0 3.6 8.2 24 Mannitol 0.0 0.5 0.5 2.2 4.9 23 Gly 0.0 0.6 0.6 6.4 17 28 Arg 0.0 0.5 0.6 29 28 67 NaCl 0.1 1.1 0.3 1.8 3.0 18 Na2SO4 0.0 0.4 0.4 51 9.4 30 Table 10 extrapolates the data to 2 years at room temperature storage, and a similar trend is seen as discussed, supra, in that higher temperature storage generally predicts more rapid degradation than is expected by simple application of Arrhenius principles. TABLE 10 Predicted extent of degradation (%) for 5 mg/mL AMG 416 Solutions After 2 Year Storage at Room Temperature. Temp 2-8° C. RT 40° C. pH 3.5 4.5 3.5 4.5 3.5 4.5 DI Water 1 35 13 47 27 77 Mannitol 0 28 7 28 16 75 Gly 3 31 8 83 55 90 Arg 2 27 7 >100 90 >100 NaCl 4 56 4 24 10 58 Na2SO4 2 22 5 >100 31 98 The data shows that sodium chloride may be a suitable tonicity modifier for AMG 416 solution formulations. Example 5 Solution Stability in Different Buffers In this study, the stability of liquid formulations of AMG 416 was evaluated in four different buffers over 9 days. Buffered saline solutions were prepared at 25 mM concentration, pH 4.5, for four different anionic buffers in the sodium salt form: acetate, citrate, lactate and succinate. AMG 416 HCl (powder) was dissolved in each buffered solution to provide a 2.5 mg/mL solution and the pH was adjusted to 4.5 with HCl/NaOH. The solutions were diluted further with pH 4.5 buffer to 1.0 mg/mL and 0.25 mg/mL. Each of the resulting solutions was split to two glass HPLC vials, one stored at 2-8° C. and one at room temperature (about 25° C.). HPLC analysis was conducted at 0, 4 and 9 days for determination of potency and purity. The purity of AMG 416 in most samples at all time points was 100%, with the exception of a few small peaks for the citrate sample at 9 days which may be attributed to baseline variation. In all buffers tested, AMG 416 showed good stability during the 9 day study. Example 6 Stability in Buffered Solutions at pH 2.25, 2.5 3.0 and 3.5 In this study, the stability of a liquid formulation of AMG 416 under low pH conditions was investigated. Succinate-buffered saline (10 mM, pH 3.5) was prepared by dissolving 59 mg of succinic acid in 45 ml of lab processed (deionized) water and adjusting the pH to 3.5 using 1N HCl and 1N NaOH as needed, and q.s. to 50 ml. In the same way, a 10 mM, pH 3.5 sodium lactate (56 mg/50 mL) buffer solution was prepared. AMG 416 HCl (128 mg powder) was dissolved in 20 mL of succinate buffer to provide a 5 mg/mL AMG 416 solution which was split into two equal 10 mL portions. NaCl (90 mg) was added to one portion and mannitol (500 mg) was added to the other. Each 10 mL portion was split again into two equal 5 mL portions and the pH was adjusted to 2.25 and 3.5, respectively, with 1N HCl and 1N NaOH. In the same way, four 5 mL solutions were prepared using lactate buffer. 1.0 mL of each of the (eight) resulting solutions was added to 3 serum sample vials. In addition, the remaining pH 2.25, succinate-buffered AMG 416 solution containing NaCl was adjusted to pH 2.5 and 0.5 mL aliquots were added to 3 serum sample vials and the remaining pH 3.5 succinate buffered solution with NaCl was adjusted to pH 3.0 and 0.5 mL aliquots were added to 3 serum sample vials. See Table 11. At each time point (0, 2, 8, 12 and 24 weeks) all 30 samples were retrieved from storage, equilibrated to room temperature (about 25° C.), and a 100 μL aliquot was diluted to 0.5 mg/mL with water for RP-HPLC analysis. The remaining samples were resealed and returned to their respective storage conditions. TABLE 11 Description of Sample Numbers pH 2.25 3.5 2.5 3.0 Buffer Lactate Succinate Lactate Succinate Succinate Excipient NaCl Mann NaCl Mann NaCl Mann NaCl Mann NaCl NaCl 2-8° C. 1 2 3 4 5 6 7 8 25 28 RT 9 10 11 12 13 14 15 16 26 29 40° C. 17 18 19 20 21 22 23 24 27 30 Representative HPLC data for the study are shown in FIGS. 5 and 6. The HPLC trace shown in FIG. 5 is a pH 2.25 sample stored for 67 days at 40° C. (5 mg/mL, 87.8% purity). FIG. 5B shows a different scale to see at the impurities. FIG. 6 illustrates the effect of increasing pH to 3.5 for the otherwise equivalent formulation (pH 3.5, 40° C., 5 mg/mL, 67 days, 91.7% purity). FIG. 6B shows a different scale to see the impurities. As in the prior study, a notable difference is seen in the degradant profile as pH changes. AMG 416 purity as a function of time is presented in Table 12 (10 mM buffer concentration: L=lactate; S=succinate. tonicity modifier: N=0.9% NaCl; M=5% mannitol). Note that the lot used contained 3.4% dimer at time 0. The 14 day time point for sample 26 was omitted due to an error in sample preparation. Selected data trends are represented in graphical form in FIGS. 7-9. TABLE 12 Stability of AMG 416 Solution at 5 mg/mL to 67 days in Buffered Solution Purity (%) at Time (Days) Sample pH Temp Buffer Tonic. 0 14 27 49 67 1 2.25 5 L N 96.8 96.4 97.0 95.7 95.7 2 2.25 5 L M 96.8 96.4 95.9 96.0 95.7 3 2.25 5 S N 95.6 95.1 95.1 94.6 93.8 4 2.25 5 S M 95.4 95.1 95.4 94.0 94.0 5 3.5 5 L N 96.9 96.6 96.4 95.8 96.2 6 3.5 5 L M 96.8 96.9 96.9 96.0 94.5 7 3.5 5 S N 95.3 95.7 95.5 95.0 95.0 8 3.5 5 S M 95.4 95.2 95.1 95.1 94.4 9 2.25 25 L N 96.9 96.4 95.2 94.0 92.8 10 2.25 25 L M 96.9 96.6 95.6 93.2 94.9 11 2.25 25 S N 95.3 94.2 93.9 91.7 90.6 12 2.25 25 S M 95.6 94.5 94.1 92.5 92.1 13 3.5 25 L N 96.6 96.3 96.3 94.7 95.2 14 3.5 25 L M 96.5 96.2 95.3 94.8 93.3 15 3.5 25 S N 95.3 95.1 94.8 93.4 93.3 16 3.5 25 S M 95.8 95.3 94.7 93.5 93.6 17 2.25 40 L N 96.7 91.9 87.8 83.5 79.4 18 2.25 40 L M 96.5 93.8 89.5 86.6 83.0 19 2.25 40 S N 95.3 89.9 86.9 80.4 76.3 20 2.25 40 S M 95.4 91.8 89.6 85.3 82.9 21 3.5 40 L N 96.7 94.3 91.7 89.5 86.2 22 3.5 40 L M 96.6 92.2 85.9 79.5 77.3 23 3.5 40 S N 95.3 92.3 89.3 86.8 84.2 24 3.5 40 S M 95.6 91.6 88.5 84.2 80.3 25 2.5 5 S N 95.4 94.9 95.2 94.8 94.4 26 2.5 25 S N 95.2 ND 94.5 93.2 93.2 27 2.5 40 S N 95.3 92.3 90.3 85.0 82.4 28 3.0 5 S N 95.4 95.4 94.9 94.7 94.9 29 3.0 25 S N 95.6 94.9 95.0 93.9 94.2 30 3.0 40 S N 95.3 92.5 90.0 86.9 85.2 FIG. 7 provides solution stability of AMG 416 (5 mg/mL) in succinate-buffered saline as a function of pH under refrigerated conditions (2-8° C.). FIG. 8 provides solution stability of AMG 416 (5 mg/mL) in succinate-buffered saline as a function of pH after storage at room temperature. FIG. 9, provide solution stability of AMG 416 (5 mg/mL) in succinate-buffered saline as a function of pH after storage at 40° C. The degradant profile at the latest time point is presented in Table 13, and the time course of appearance of the two major degradants (C-terminal deamidation and homodimer formation) is shown in Tables 14 and 15. FIGS. 10 and 11 present the time course of degradation to these individual products (C-terminal deamidation and homodimer formation, respectively) as a function of pH for selected formulations (those formulations for which a complete set of pH conditions are available, i.e., those containing NaCl and succinate, but not lactate or mannitol). FIG. 10 indicates a clear pH dependency for deamidation, with significantly greater degradation by this pathway at pH 2.25 than at higher pH, and a direct correspondence between pH and amount of deamidation. In contrast, homodimer formation presented in FIG. 11 shows the opposite relationship between pH and extent of degradation. These opposing trends underlie the overall stability data presented in FIGS. 7-9, and Maximal stability for AMG 416 solutions in this set of experiments was observed at pH of 3.0±0.5. The correlation between stability and excipient composition is less clear. Regarding the buffer selection (succinate vs. lactate), inspection of the data in Tables 12-14 shows no clear pattern of preference for either buffer with respect to any of the major degradants at pH 2.25 or 3.5. All samples with succinate buffer showed lower purity at time 0 than the corresponding lactate-buffered samples, due to the larger integration of the homodimer peak. The reason for this is unclear, but may indicate a change in the relative absorbance for the parent and dimer as a function of buffer. However, as noted above, subsequent incubation provides essentially identical rate of degradation in the presence of either buffer. Regarding the choice of tonicity modifier (NaCl or mannitol), sodium chloride appears to enhance the rate of deamidation at pH 2.25 (see Table 13, samples 9-12 at 25° C. and especially samples 17-20 at 40° C.). However, NaCl appears to suppress (compared to mannitol) the degradation to the homodimer at pH 3.5 (Table 14, samples 13-16 at 25° C. and especially samples 21-24 at 40° C.). TABLE 13 Degradant Profile for AMG 416 (5 mg/mL) Solution after 67 Days Major Impurities (% total area) t = 67 Days Acid Dimer Dimer Trisulfide Deacetyl Trisulfide pH Temp Buffer Tonic. 8.1 mins 9.3 mins 9.5 7.4 mins 8.2 mins 2.25 5 L N 0.8 0.4 2.25 5 L M 0.5 0.6 2.25 5 S N 0.8 0.8 2.25 5 S M 1.1 0.1 3.5 5 L N 0.1 3.5 5 L M 1.2 1.6 3.5 5 S N 0.2 0.1 3.5 5 S M 0.7 −0.1 2.25 25 L N 2.5 0.3 0.3 0.9 2.25 25 L M 1.2 0.4 0.3 2.25 25 S N 3.1 0.4 0.4 2.25 25 S M 1.6 0.9 3.5 25 L N 1.4 3.5 25 L M 3.1 3.5 25 S N 0.2 1.8 3.5 25 S M 2.1 0.1 2.25 40 L N 13.9 0.4 0.7 2.9 2.25 40 L M 8.7 1.6 0.6 2.0 0.3 2.25 40 S N 14.2 0.0 0.2 3.1 2.25 40 S M 8.9 2.4 0.6 2.5 0.3 3.5 40 L N 1.4 7.4 1.0 0.7 3.5 40 L M 0.5 17.0 0.5 1.0 3.5 40 S N 1.0 8.1 0.6 0.1 0.6 3.5 40 S M 1.0 11.7 0.7 1.3 2.5 5 S N 0.5 0.5 2.5 25 S N 1.5 0.2 0.4 2.5 40 S N 8.4 1.1 0.4 1.9 3.0 5 S N 0.2 0.4 3.0 25 S N 1.3 0.1 3.0 40 S N 2.4 5.5 0.6 0.6 0.5 10 mM buffer concentration: L = Lactate; S = succinate. Tonicity modifier: N = 0.9% NaCl; M = 5% mannitol). Value for dimer % reflects increase in degradant after subtracting starting value. TABLE 14 Deamidation in AMG 416 (5 mg/mL) Solution at Time Points up to 67 Days % Degradant at Time (Days) Sample pH Temp Buffer Tonic. 0 14 27 49 67 1 2.25 5 L N 0.1 0.7 0.8 2 2.25 5 L M 0.9 0.8 0.5 3 2.25 5 S N 0.4 0.8 0.8 4 2.25 5 S M 0.3 1.1 5 3.5 5 L N 0.3 0.4 6 3.5 5 L M 1.2 7 3.5 5 S N 0.2 8 3.5 5 S M 0.7 9 2.25 25 L N 1.3 1.6 2.5 10 2.25 25 L M 1.2 1.2 1.2 11 2.25 25 S N 1.1 1.4 2.0 3.1 12 2.25 25 S M 0.7 1.0 1.3 1.6 13 3.5 25 L N 14 3.5 25 L M 15 3.5 25 S N 0.2 16 3.5 25 S M 17 2.25 40 L N 3.4 6.6 10.2 13.9 18 2.25 40 L M 2.5 4.8 7.0 8.7 19 2.25 40 S N 3.9 6.6 11.0 14.2 20 2.25 40 S M 2.3 4.2 6.4 8.9 21 3.5 40 L N 0.9 0.9 1.4 22 3.5 40 L M 0.5 0.6 0.5 23 3.5 40 S N 1.0 1.0 1.0 24 3.5 40 S M 0.4 0.3 1.0 25 2.5 5 S N 0.5 26 2.5 25 S N 0.7 1.3 1.5 27 2.5 40 S N 2.0 3.3 6.7 8.4 28 3.0 5 S N 29 3.0 25 S N 0.3 30 3.0 40 S N 1.0 2.2 2.4 10 mM buffer concentration: L = Lactate; S = succinate. Tonicity modifier: N = 0.9% NaCl; M = 5% mannitol). Maximal stability for AMG 416 solutions in this set of experiments was observed at pH of 3.0±0.5. The rate of total degradation at pH 2.5 and 3.5 is similar, but the degradant profile is different. Stability at pH 2.25 is inferior due to the greater quantities of deamidation observed. While some effect of excipient can be observed on the stability profile, the data does not indicate an overall preference among the excipient systems studied, when formulated at pH 3.0. TABLE 15 AMG 416 Degradation to Homodimer in 5 mg/mL Solution at Time Points up to 67 Days Dimer (% Increase) Sample pH Temp Buffer Tonic. 0 14 27 49 67 1 2.25 5 L N 0.0 0.5 −0.1 0.5 0.4 2 2.25 5 L M 0.0 0.4 0.0 0.0 0.6 3 2.25 5 S N 0.0 0.5 0.1 0.1 0.8 4 2.25 5 S M 0.0 0.3 0.0 0.2 0.1 5 3.5 5 L N 0.0 0.2 0.1 0.2 0.1 6 3.5 5 L M 0.0 −0.1 0.0 0.2 1.6 7 3.5 5 S N 0.0 −0.4 −0.2 0.0 0.1 8 3.5 5 S M 0.0 0.2 0.1 −0.1 −0.1 9 2.25 25 L N 0.0 0.5 0.4 0.5 0.3 10 2.25 25 L M 0.0 0.3 0.1 0.5 0.4 11 2.25 25 S N 0.0 −0.1 0.0 0.0 0.4 12 2.25 25 S M 0.0 0.5 0.5 0.2 0.9 13 3.5 25 L N 0.0 0.3 0.3 0.9 1.4 14 3.5 25 L M 0.0 0.4 0.3 1.5 3.1 15 3.5 25 S N 0.0 0.2 0.5 1.1 1.8 16 3.5 25 S M 0.0 0.5 1.0 1.4 2.1 17 2.25 40 L N 0.0 0.6 0.8 0.5 0.4 18 2.25 40 L M 0.0 0.0 0.3 0.6 1.6 19 2.25 40 S N 0.0 0.5 0.4 0.8 0.0 20 2.25 40 S M 0.0 0.6 0.6 1.3 2.4 21 3.5 40 L N 0.0 2.4 3.7 5.5 7.4 22 3.5 40 L M 0.0 4.1 9.5 15.0 17.0 23 3.5 40 S N 0.0 2.8 4.6 6.3 8.1 24 3.5 40 S M 0.0 3.7 6.6 9.0 11.7 25 2.5 5 S N 0.0 0.4 0.2 0.0 0.5 26 2.5 25 S N 0.0 0.1 0.5 0.2 27 2.5 40 S N 0.0 0.6 0.6 1.5 1.1 28 3.0 5 S N 0.0 0.0 0.5 0.2 0.2 29 3.0 25 S N 0.0 0.6 0.6 0.9 1.3 30 3.0 40 S N 0.0 1.6 3.2 4.8 5.5 (10 mM buffer concentration: L = Lactate; S = succinate. Tonicity modifier: N = 0.9% NaCl; M = 5% mannitol). Note that degradation is expressed as an increase in dimer content (not total dimer) as the API used for the experiment contained appreciable quantity of dimer. Maximal stability for AMG 416 solutions in this set of experiments was observed at pH of 3.0±0.5. Analysis of solutions formulated at pH 2.5 or 3.5 show different degradation profiles, with C-terminal amide hydrolysis being the largest degradant at low pH whereas homodimer formation was larger at higher pH. Liquid formulations at pH 3.0 have predicted total degradation of 2-4% over 2 years under refrigerated conditions. Example 7 Robustness Study In this study, the stability of a liquid formulation of AMG 416 under a variety of manufacturing and analytical conditions was investigated. Fourteen formulation testing groups were prepared, each having a different combination of pH (2.7, 3.3 or 3.9), peptide concentration (4, 5 or 6 mg/mL) and salt concentration (0.7, 0.85 or 1.0%). The osmolality of each formulation was kept the same (succinate 10 mM). See Table 16. TABLE 16 Formulation Testing Groups Succinate Peptide NaCl Sample pH (mM) (mg/mL) (%) 1 3.3 10 5 0.85 2 3.9 10 4 1.0 3 2.7 10 4 0.85 4 3.9 10 6 0.7 5 3.3 10 4 0.7 6 3.9 10 6 1.0 7 3.3 10 5 1.0 8 3.3 10 5 0.85 9 3.9 10 5 0.85 10 3.3 10 6 0.85 11 2.7 10 6 0.85 12 2.7 10 5 1.0 13 2.7 10 5 0.7 14 3.9 10 4 0.7 Samples (2.1 mL) of each of the formulation testing groups were dispensed into 3 mL Type 1B glass vials (Schott, Germany) and sealed (rubber stopper). Sets of the vials were stored upright for three months at temperatures of 4° C., 25° C. or 40° C. Changes in the pH, osmolality, percent AMG 416, and degradants were assessed over three months. The time-dependent response surface defined by the three factors (pH, % peptide and % NaCl) was estimated by fitting a statistical model that describes such surface to the data for each HPLC response and at each temperature (JMP® statistical discovery software, SAS). Monte Carlo simulation was used to generate the distributions of the predicted HPLC responses at the set point (pH=3.3, peptide=5% and NaCl=8.5%) as a function of the random variation of factors around the set point and the random noise. No significant change in pH and osmolality with time were noted. At 4° C. and 25° C., purity remained 92% or greater, deamidation was 4% or less and homodimer formation was 4% or less over the entire length of the study. At 40° C., purity, deamidation and homodimer formation was seen beginning at 1 month. However, deamidation and homodimer formation were decreased as the pH range narrowed around 3.3, indicating that pH has a significant impact on the formation of these degradants. Based on this data, it is possible to provide a prediction of the purity profile over a range of pH from 2.8 to 3.8. As shown in FIG. 12, the purity at each temperature is strongly dependent on pH, and less dependent on peptide concentration and NaCl within the range tested. Under refrigerated conditions, the effect of pH is less significant at values above pH 3.3, but at room temperature (about 25° C.), higher pH values are associated with more rapid degradation. Formulations for therapeutic use may be subject to long term storage under refrigerated conditions. In addition, consideration should also be given to potential exposure of the formulation to higher temperatures during manufacturing, packaging, labeling and clinical use. Thus, in this set of experiments, it was observed that a pH value in the tested range of 2.8 to 3.8 (3.3±0.5) would be suitable for AMG 416 formulations. Example 8 Long Term Stability of Liquid Formulations of AMG 416 Over Range of pH In this study, the long term stability of a liquid formulation of AMG 416, at a concentration of 3.4 mg/mL, was determined over a range of pH in succinate-buffered saline. USP purified water (1200 mL) was dispensed into a glass beaker. Sodium succinate (4.05 g) and sodium chloride (13.5 g) were added and stirred to dissolve. The pH was adjusted to 2.5 with 1N NaOH and/or 1N HCl as required. AMG 416 HCl (5.5 g powder weight) was added, stirred to dissolve, and q.s. to 1500 mL with purified water to provide 3.4 mg/mL solution (AMG 416). The solution was divided into three portions and the pH for each portion was adjusted to 2.5, 3.0 and 3.5, respectively. Each solution was filtered separately through 0.22 micron PVDF filter and dispense 2 mL to 5-cc vials. After being stoppered, sealed, and labeled, the vials were place in designated stability chambers at 5° C.±3, 25° C.±2, and 40° C.±2. Samples were retrieved according to schedule and diluted with deionized water to 1.0 mg/mL for HPLC analysis. The purity at months 0, 1, 2, 3, 5, 12 and 24 is provided in Table 17 (note: the starting purity value was 99.2% for this study). The results provide a long term stability profile of a 3.4 mg/mL liquid formulation of AMG 416 as a function of pH and temperature. TABLE 17 Purity at Time Point up to 24 Months for AMG 416 Solutions. Purity (%) at Time (Months) pH Temp (° C.) 0 1 2 3 5 12 24 Degradation at 2 y 2.5 25 99.2 96.9 95.2 93.4 89.3 80.9 68.5 30.7 40 99.2 88.8 81.9 75.3 60.9 39.1 20.4 78.8 5 99.2 99.1 99.1 99.2 98.7 98.3 97.7 1.5 3 25 99.2 98.2 97.5 96.7 95.0 91.1 84.6 14.6 40 99.2 93.7 90.2 86.4 78.9 61.6 39.2 60.0 5 99.2 99.2 99.2 99.2 98.8 98.6 98.3 0.9 3.5 25 99.2 98.6 98.1 97.6 96.2 93.4 89.2 10.0 40 99.2 94.6 91.5 88.7 83.1 67.5 46.1 53.1 The time course of AMG 416 liquid formulation purity at each pH level is shown in FIG. 13. At all temperatures, the greatest purity was observed at pH 3.5 while the most degradation was observed at pH 2.5. Furthermore, at all temperatures, the purity at pH 3.0 and 3.5 was significantly greater than the purity at pH 2.5. Thus, for example, for the refrigerated samples, the purity at 24 months was 98.3 and 97.7 for the solutions at pH 3.5 and 3.0, respectively, but only 94.8 for the solution at pH 2.5. In addition, the decrease in purity was seen to be related to temperature at all pH levels, with the least degradation observed in the samples incubated at 2-8° C. and the most degradation observed in the samples incubated at 40° C. The major degradant observed at pH 2.5 was the deamidated product and at pH 3.5 the homodimer was observed. These data confirm that the described formulations are able to maintain adequate stability of AMG 416 over at least a two year shelf-life under refrigerated conditions. The observed degradation is linear in all cases and supports the conclusions based on data extrapolation from earlier experiments. From this data, the optimal pH lies between 3.0 and 3.5 based on the balance between different degradation pathways. All publications, patents and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims. | <SOH> BACKGROUND OF THE INVENTION <EOH>A variety of compounds having activity for lowering parathyroid hormone levels have been described. See International Publication No. WO 2011/014707. In one embodiment, the compound may be represented as follows: The main chain has 7 amino acids, all in the D-configuration and the side-chain cysteine residue is in the L-configuration. The amino terminal is acetylated and the carboxyl-terminal is amidated. This compound (“AMG-416”) has utility for the treatment of secondary hyperparathyroidism (SHPT) in hemodialysis patients. A liquid formulation comprising AMG-416 may be administered to a subject intravenously. The hydrochloride salt of AMG-416 may be represented as follows: Therapeutic peptides pose a number of challenges with respect to their formulation. Peptides in general, and particularly those that contain a disulfide bond, typically have only moderate or poor stability in aqueous solution. Peptides are prone to amide bond hydrolysis at both high and low pH. Disulfide bonds can be unstable even under quite mild conditions (close to neutral pH). In addition, disulfide containing peptides that are not cyclic are particularly prone to dimer formation. Accordingly, therapeutic peptides are often provided in lyophilized form, as a dry powder or cake, for later reconstitution. A lyophilized formulation of a therapeutic peptide has the advantage of providing stability for long periods of time, but is less convenient to use as it requires the addition of one or more diluents and there is the potential risk for errors due to the use of an improper type or amount of diluent, as well as risk of contamination. In addition, the lyophilization process is time consuming and costly. Accordingly, there is a need for an aqueous liquid formulation comprising a peptide agonist of the calcium sensing receptor, such as AMG 416. It would be desirable for the liquid formulation to remain stable over a relevant period of time under suitable storage conditions and to be suitable for administration by intravenous or other parenteral routes. | <SOH> SUMMARY OF THE INVENTION <EOH>A liquid formulation comprising a peptide agonist of the calcium sensing receptor, such as AMG 416 is provided. In one embodiment, the formulation has a pH of about 2.0 to about 5.0. In another embodiment, the formulation has a pH of 2.5 to 4.5. In another embodiment, the formulation has a pH of 2.5 to 4.0. In another embodiment, the formulation has a pH of 3.0 to 3.5. In another embodiment, the formulation has a pH of 3.0 to 4.0. In another embodiment, the formulation has a pH of 2.8 to 3.8. In another embodiment, the pH of the formulation is maintained by a pharmaceutically acceptable buffer. Such buffers include, without limitation, succinate buffers, acetate buffers, citrate buffers and phosphate buffers. In another embodiment, the buffer is succinate buffer. The pH of the formulation may be adjusted as needed with an acid or base, such as HCl or NaOH. In another embodiment, the peptide agonist of the calcium sensing receptor is present at a concentration of 0.1 mg/mL to 20 mg/mL. In another embodiment, the peptide is present at a concentration of 1 mg/mL to 15 mg/mL. In another embodiment, the peptide is present at a concentration of 2.5 mg/mL to 10 mg/mL. In another embodiment, the peptide is present at a concentration of about 1 mg/mL, about 5 mg/mL or about 10 mg/mL. In another embodiment, AMG 416 is present at a concentration of about 0.1 mg/mL to about 20 mg/mL. In one embodiment, AMG 416 is present at a concentration of about 1 mg/mL to about 15 mg/mL. In another embodiment, AMG 416 is present at a concentration of about 2.5 mg/mL to about 10 mg/mL. In another embodiment, AMG 416 is present at a concentration of about 1 mg/mL, about 2.5 mg/mL, about 5 mg/mL or about 10 mg/mL. In another embodiment, AMG 416 is present at a concentration of 0.1 mg/mL to 20 mg/mL. In one embodiment, AMG 416 is present at a concentration of 1 mg/mL to 15 mg/mL. In another embodiment, AMG 416 is present at a concentration of 2.5 mg/mL to 10 mg/mL. In another embodiment, AMG 416 is present at a concentration of 1 mg/mL to 5 mg/mL. In another embodiment, AMG 416 is present at a concentration of 5 mg/mL to 10 mg/mL. In another embodiment, AMG 416 is present at a concentration of 0.5 to 1.5 mg/mL, 2.0 to 3.0 mg/mL, 4.5 to 5.5 mg/mL or 9.5 to about 10.5 mg/mL In another embodiment, the formulation further comprises a pharmaceutically acceptable tonicity modifier or mixture of pharmaceutically acceptable tonicity modifiers. In another embodiment, the tonicity modifier (or mixture of tonicity modifiers) is present at a concentration sufficient for the formulation to be approximately isotonic with bodily fluids (e.g., human blood). In another aspect, the tonicity modifier is NaCl. In another embodiment, the formulation comprises a therapeutically effective amount of a peptide agonist of the calcium sensing receptor. In a preferred embodiment, the formulation comprises a therapeutically effective amount of AMG 416. In another embodiment, the formulation has less than 10% degradation when stored at 2-8° C. for up to 2 years. In another embodiment, the formulation has less than 10% degradation when stored at 2-8° C. for up to 3 years. In another embodiment, the formulation has less than 10% degradation when stored at 2-8° C. for up to 4 years. In another embodiment, the formulation has less than 8% degradation when stored at 2-8° C. for up to 2 years. In another embodiment, the formulation has less than 8% degradation when stored at 2-8° C. for up to 3 years. In another embodiment, the formulation has less than 8% degradation when stored at 2-8° C. for up to 4 years. In another embodiment, the formulation has less than 10% degradation when stored at room temperature for 3 months. In another embodiment, the formulation has less than 10% degradation when stored at room temperature for up to 6 months. In another embodiment, the formulation has less than 10% degradation when stored at room temperature for up to 1 year. In another embodiment, a formulation comprising 0.5 mg/mL to 20 mg/mL of a peptide agonist of the calcium sensing receptor (e.g., AMG 416) in aqueous solution, a succinate buffer that maintains the formulation at a pH of about 3.0 to about 3.5, and a sufficient concentration of sodium chloride for the formulation to be approximately isotonic with human blood is provided. | F04D250606 | 20171102 | 20180322 | 64611.0 | F04D2506 | 3 | HA, JULIE | STABLE LIQUID FORMULATION OF AMG 416 (ETELCALCETIDE) | UNDISCOUNTED | 1 | CONT-ACCEPTED | F04D | 2,017 |
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15,802,782 | ACCEPTED | WEARABLE CAMERA SYSTEM | A wearable camera systems according to examples of the present disclosure may include a camera and a mobile charging unit. The camera may include onboard power, memory and control for capturing and storing an image without being connected to the mobile charging unit and the camera body may have a width or a height that is smaller than the length of the camera body. The camera body may include a trigger for initiating image capture. The wearable camera may be attachable to an eyewear temple and the mobile charging unit is configured to recharge the wearable camera without being connected to an external power source. | 1. A wearable camera system, wherein the wearable camera system includes a wearable camera and a mobile charging unit, wherein the camera has a camera body having a width or a height that is smaller than a length of the camera body, wherein the camera body is devoid of a view finder, and wherein the camera body comprises on board power, memory and control for capturing and storing an image without being connected to the mobile charging unit, wherein the camera body comprises a trigger configured to initiate image capture, wherein the wearable camera is attachable to an eyewear temple, wherein the mobile charging unit is not attached to the eyewear temple and wherein the mobile charging unit is configured to recharge the wearable camera while the mobile charging unit is not connected to an external power source. 2. The camera of claim 1, wherein the camera magnetically attaches to the eyewear temple. 3. The camera of claim 1, wherein the camera comprises an additional securing mechanism for securing the camera to the temple. 4. The camera of claim 1, wherein the camera weighs 10 grams or less. 5. The camera of claim 1, wherein the camera is configured to capture an image responsive to motion detected by the camera. 6. The camera of claim 1, wherein the camera has a height between 8 mm and 15 mm or a width between 8 mm and 14 mm or a length between 8 mm and 50 mm. 7. The camera of claim 1, wherein the camera has a volume of 6,000 cubic millimeters or less. 8. The camera of claim 1, wherein the camera is water resistant. 9. The camera of claim 1, wherein the camera is configured to notify another individual that his or her image is being captured by the camera and wherein the notification is accomplished by one or more lights configured to illuminate or a sound communicated when an image is being captured. 10. The camera of claim 1, wherein the camera is configured to be wirelessly charged. 11. The camera of claim 1, wherein the camera is configured to be inductively charged. 12. The camera of claim 1, wherein the camera is configured to down load data to the mobile charging unit. 13. The camera of claim 1, wherein the camera is configured to transfer an image to the mobile charging unit and wherein the mobile charging unit is configured to transfer the image to a separate mobile computing system. 14. The camera of claim 1, wherein its memory and battery is less than that of the mobile charging unit. 15. A wearable camera system comprising a camera and a mobile charging unit, wherein the camera body has a length greater than a width of the camera body and greater than a height of the camera body, wherein the wearable camera is configured to removably attach directly to an outside side of an eyewear temple via magnetic attraction, wherein the camera body comprises on board power, memory and control for capturing and storing an image, wherein the camera comprises a magnetic attachment mechanism configured to movably attach the camera to a temple of the eyewear such that camera is positionable in multiple positions relative to a forward-most portion of the eyewear including a position in which the camera is aligned with or ahead of the forward-most portion of the eyewear and wherein the mobile charging unit is configured to recharge the camera when the mobile charging unit is not connected to an external power source. 16. The camera of claim 15, wherein the camera comprises an additional securing mechanism for securing the camera to the temple. 17. The camera of claim 15, wherein the camera weighs 10 grams or less. 18. The camera of claim 15, wherein the camera is configured to capture an image responsive to motion detected by the camera. 19. The camera of claim 15, wherein the camera is configured to transfer an image to the mobile charging unit and whereby the mobile charging unit is configured to enhance the image. 20. The camera of claim 15, wherein the camera has a height between 8 mm and 15 mm or a width between 8 mm and 14 mm or a length between 8 mm and 50 mm. 21. The camera of claim 15, wherein the camera has a volume of 6,000 cubic millimeters or less. 22. The camera of claim 15, wherein the camera is water resistant. 23. The camera of claim 15, wherein the camera is configured to notify another individual that his or her image is being captured by the camera and wherein the notification is accomplished by one or more lights configured to illuminate or a sound communicated when an image is being captured. 24. The camera of claim 15, wherein the camera is configured to be wirelessly charged. 25. The camera of claim 15, wherein the camera is configured to be inductively charged. 26. The camera of claim 15, wherein the camera is configured to down load data to the mobile charging unit. 27. The camera of claim 15, wherein the camera is configured to down load data to the mobile charging unit wirelessly. 28. The camera of claim 15, wherein the camera is configured to transfer an image to the mobile charging unit and wherein the mobile charging unit is configured to transfer the image to a separate mobile computing device. 29. The camera of claim 15, wherein the camera is configured to wirelessly transmit an image to a mobile computing system. 30. The camera of claim 15, wherein its memory and battery is less than that of the mobile charging unit. | CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of pending U.S. application Ser. No. 15/423,315 filed Feb. 2, 2017, which application is a continuation of U.S. application Ser. No. 14/757,753, filed Dec. 23, 2015 and issued as U.S. Pat. No. 9,628,707 on Apr. 18, 2017. The aforementioned applications and issued patent are hereby incorporated by reference in their entirety, for any purpose. U.S. application Ser. No. 14/757,753 claims the benefit under 35 U.S.C. 119 of the earlier filing date of U.S. Provisional Application 62/095,920 entitled “CAMERA SYSTEM COMPRISING WIRELESS POWER AND DATA TRANSFER”, filed Dec. 23, 2014. The aforementioned provisional application is hereby incorporated by reference in its entirety, for any purpose. U.S. application Ser. No. 14/757,753 claims the benefit under 35 U.S.C. 119 of the earlier filing date of U.S. Provisional Application 62/104,418 entitled “ENHANCED CAMERA SYSTEM COMPRISING WIRELESS POWER AND DATA TRANSFER”, filed Jan. 16, 2015. The aforementioned provisional application is hereby incorporated by reference in its entirety, for any purpose. U.S. application Ser. No. 14/757,753 claims the benefit under 35 U.S.C. 119 of the earlier filing date of U.S. Provisional Application 62/113,573 entitled “ENHANCED CAMERA SYSTEM COMPRISING HIGHLY RESONANT COUPLING”, filed Feb. 9, 2015. The aforementioned provisional application is hereby incorporated by reference in its entirety, for any purpose. U.S. application Ser. No. 14/757,753 claims the benefit under 35 U.S.C. 119 of the earlier filing date of U.S. Provisional Application 62/116,648 entitled “FURTHER ENHANCED CAMERA SYSTEM COMPRISING HIGH RESONANT COUPLING”, filed Feb. 16, 2015. The aforementioned provisional application is hereby incorporated by reference in its entirety, for any purpose. U.S. application Ser. No. 14/757,753 claims the benefit under 35 U.S.C. 119 of the earlier filing date of U.S. Provisional Application 62/127,622 entitled “HIGHLY RESONANT COUPLED CAMERA SYSTEM”, filed Mar. 3, 2015. The aforementioned provisional application is hereby incorporated by reference in its entirety, for any purpose. U.S. application Ser. No. 14/757,753 claims the benefit under 35 U.S.C. 119 of the earlier filing date of U.S. Provisional Application 62/128,362 entitled “CAMERA EYEWEAR SYSTEM”, filed Mar. 4, 2015. The aforementioned provisional application is hereby incorporated by reference in its entirety, for any purpose. U.S. application Ser. No. 14/757,753 claims the benefit under 35 U.S.C. 119 of the earlier filing date of U.S. Provisional Application 62/153,999 entitled “CAMERA SYSTEM CAPABLE OF WIRELESS ENERGY TRANSFER”, filed Apr. 28, 2015. The aforementioned provisional application is hereby incorporated by reference in its entirety, for any purpose. U.S. application Ser. No. 14/757,753 claims the benefit under 35 U.S.C. 119 of the earlier filing date of U.S. Provisional Application 62/154,019 entitled “CAMERA EYEWEAR SYSTEM”, filed Apr. 28, 2015. The aforementioned provisional application is hereby incorporated by reference in its entirety, for any purpose. U.S. application Ser. No. 14/757,753 claims the benefit under 35 U.S.C. 119 of the earlier filing date of U.S. Provisional Application 62/167,739 entitled “FURTHER ENHANCED CAMERA SYSTEM CAPABLE OF WIRELESS ENERGY TRANSFER”, filed May 28, 2015. The aforementioned provisional application is hereby incorporated by reference in its entirety, for any purpose. U.S. application Ser. No. 14/757,753 claims the benefit under 35 U.S.C. 119 of the earlier filing date of U.S. Provisional Application 62/173,788 entitled “ROBUST CAMERA SYSTEM CAPABLE OF WIRELESS ENERGY TRANSFER”, filed Jun. 10, 2015. The aforementioned provisional application is hereby incorporated by reference in its entirety, for any purpose. U.S. application Ser. No. 14/757,753 claims the benefit under 35 U.S.C. 119 of the earlier filing date of U.S. Provisional Application 62/180,199 entitled “WIRELESS ENERGY TRANSFER CAMERA SYSTEM”, filed Jun. 16, 2015. The aforementioned provisional application is hereby incorporated by reference in its entirety, for any purpose. U.S. application Ser. No. 14/757,753 claims the benefit under 35 U.S.C. 119 of the earlier filing date of U.S. Provisional Application 62/186,341 entitled “WIRELESS ENERGY TRANSFER CAMERA SYSTEM”, filed Jun. 29, 2015. The aforementioned provisional application is hereby incorporated by reference in its entirety, for any purpose. U.S. application Ser. No. 14/757,753 claims the benefit under 35 U.S.C. 119 of the earlier filing date of U.S. Provisional Application 62/189,916 entitled “WIRELESS ENERGY TRANSFER CAMERA SYSTEM COMPRISING ENERGY HARVESTING”, filed Jul. 8, 2015. The aforementioned provisional application is hereby incorporated by reference in its entirety, for any purpose. TECHNICAL FIELD The present disclosure relates to camera systems and more specifically to wearable camera systems. BACKGROUND The number and types of commercially available electronic wearable devices continues to expand. Forecasters are predicting that the electronic wearable devices market will more than quadruple in the next ten years. Some hurdles to realizing this growth remain. Two major hurdles are the cosmetics/aesthetics of existing electronic wearable devices and their limited battery life. Consumers typically desire electronic wearable devices to be small, less noticeable, and require less frequent charging. Typically, consumers are unwilling to compromise functionality to obtain the desired smaller form factor and extended battery life. The desire for a small form factor yet a longer battery life are goals which are in direct conflict with one another and which conventional devices are struggling to address. Further solutions in this area may thus be desirable. SUMMARY A camera according to some examples of the present disclosure may include an image capture device, a receiver configured to receive power wirelessly from a distance separated transmitting coil of a wireless power transfer system which includes a base unit, a rechargeable battery coupled to the receiver for storing wirelessly received power, and a memory configured to store images captured with the image capture device. In some examples, the another computing device may be the base unit of the wireless power transfer system. The camera may be configured to transfer data including one or more images captured with the image capture device to another computing device. In some examples, the camera may be a wearable camera. In some examples, the camera may be waterproof. In some examples, the camera may be devoid of a view finder. In some examples, the camera's receiver may include a receiving coil having a magnetic core. In some examples, the magnetic core may include a ferrite core. In some examples, the receiving coil is configured to receive power from the transmitting coil regardless of orientation between the receiving and transmitting coils. In some examples, at least the image capture device, the receiving coil, the processor, and the memory are enclosed in a housing configured to be movably coupled to a wearable article. In some examples, the housing includes a guide comprising one or more magnets for magnetically attaching the wearable camera to eyewear. In some examples, the housing may include a first opening and an optically transparent material spanning the first opening, and a second opening and an acoustically transparent material spanning the second opening. In some examples, the camera may include a microphone. In some examples, the camera may be configured to detect an audible command and capture an image responsive to the audible command. In some examples, the camera may include a transmitter configured to transmit one or more of the images stored in the memory to the wireless power transfer system. In some examples, the camera may be configured to broadcast a proximity signal for detecting the wireless power receiver in proximity. In some examples, the camera may include at least one user control for receiving user input. In some examples, the at least one user control may include a capacitive switch. In some examples, the camera may include a status indicator, a privacy indicator, or combinations thereof. In some examples, the camera may include an aperture for engaging with a securing ring. In further examples, the camera may include a guide configured to engage a temple guide in an eyewear frame, and wherein a plane of a diameter of the aperture is parallel with a longitudinal direction of the guide. In some examples, the securing ring may be made of a transparent plastic material. In some examples, the securing ring may include a core diameter greater than 0.01 mm and less than 2 mm. In some examples, the core diameter may be less than 1 mm. A system according to the present disclosure may include a base unit which includes a transmitter configured for wireless power delivery and a battery coupled to the transmitter, wherein the transmitter includes a transmitting coil having a magnetic core. The system may further include a camera, which may be a wearable camera, separated from the base unit, the camera including a receiver inductively coupled to the transmitter to receive power from the base unit while the camera remains within a charging distance from the base unit, wherein the receiver includes a receiving coil having a magnetic core, and wherein a dimension of the transmitting coil is at least twice a dimension of the receiving coil. In some examples, the dimension of the transmitting coil may be a diameter of the transmitting coil, a length or a diameter of a wire forming windings of the transmitting coil, a number of windings of the transmitting coil, or a length, a diameter or a surface area of the core of the transmitting coil, and the dimension of the receiving coil may respectively be a diameter of the receiving coil, a length or a diameter of a wire forming windings of the receiving coil, a number of windings of the receiving coil, or a length, a diameter or a surface area of the core of the receiving coil. In some examples, the transmitter and receiver may be configured for operation with a Q value less than 100. In some examples, the transmitter and receiver may be configured to operate at a frequency within the range of 50 kHz or 500 kHz, wherein the transmitter and receiver are configured to operate in weak resonance, and wherein the system is configured to operate using an amount of guided flux. In some examples, the base unit may be mechanically coupled to a portable communication device. In some examples, the transmitter may include an omnidirectional antenna configured to transmit power to one or more electronic devices including the camera regardless of orientation of the electronic devices with respect to the base unit. In some examples, the camera, which may be a wearable camera, may be configured to be magnetically attached to eyewear. A method according to some examples may include placing a base unit proximate a wearable camera, the base unit comprising a transmitting coil configured to inductively couple with a receiving coil in the wearable camera to wirelessly transmit power to the wearable camera, detecting the wearable camera with the base unit, and wirelessly transmitting power from the base unit to the wearable camera while the electronic device remains within a charging range of the base unit or until a charge state signal of the wearable camera corresponds to a fully charged state of the wearable camera. In some examples, the method may further include capturing an image responsive to an audible command detected by the wearable camera. In some examples, the method may further include wirelessly transmitting an image captured by the camera to the base unit. In some examples, the detecting the wearable camera includes automatically detecting a signal from the wearable camera, the signal broadcast by the wearable camera or transmitted to the base unit responsive to an interrogation signal from the base unit. In some examples, the wirelessly transmitting power from the base unit includes broadcasting power signals at a body-safe level. In some examples, the wirelessly transmitting power from the base unit includes broadcasting power signals at a frequency within the range of 50 kHz or 500 kHz. BRIEF DESCRIPTION OF THE DRAWINGS Features, aspects and attendant advantages of the present invention will become apparent from the following detailed description of various embodiments, including the best mode presently contemplated of practicing the invention, when taken in conjunction with the accompanying drawings, in which: FIG. 1 illustrates an isometric view of a camera in accordance with some examples herein; FIG. 2 illustrates a cross-sectional view of the camera in FIG. 1 taken at line 2-2; FIGS. 3A and 3B illustrate exploded views of the camera in FIG. 1; FIGS. 4A-4G illustrate isometric, top, bottom, front, back, left and right side views, respectively, of the camera in FIG. 1; FIG. 5 illustrates a block diagram of a wireless power transfer system according to examples of the present disclosure: FIG. 6 illustrates examples of electronic devices attached to eyewear in accordance with the present disclosure: FIG. 7 illustrates an example of a receiving coil for an electronic device such as the camera in FIG. 1, and a transmitting coil for a base unit in accordance with the present disclosure; FIG. 8 illustrates a block diagram of a base unit implemented in the form of a mobile phone case form factor according to examples of the present disclosure; FIGS. 9A and 9B illustrate isometric and exploded isometric views of a base unit implemented as a mobile phone case according to further examples of the present disclosure: FIG. 10 illustrates a flow chart of a process according to some examples herein: FIG. 11 illustrates a typical use scenario of a base unit with a wearable camera in accordance with the present disclosure; FIG. 12A-F illustrate views of a camera in accordance with further examples herein; FIG. 13 illustrates an isometric view of a camera in accordance with yet further examples herein; FIG. 14 illustrates a flow diagram of a process for automatic processing of an image captured by a camera in accordance with some examples herein: FIG. 15 illustrates a system for automatic processing of images in accordance some examples herein. DETAILED DESCRIPTION Systems, methods and apparatuses for wirelessly powering electronic devices, for example a camera such as a wearable camera, are described. According to some examples, an electronic device, for example a wearable camera, may be configured to receive power wirelessly from a distance separated transmitter of a base unit, which may be part of a wireless power transfer system. The base unit and/or wearable electronic device may be part of an ecosystem which may include any number of energy transmitting devices (e.g., base units) and any number of energy receiving devices (e.g., wearable electronic devices). The electronic device (e.g., camera) may be placed within a charging zone (e.g., hotspot) of the base unit and configured to receive power wirelessly from the base unit while the electronic device remains within the hotspot. The electronic device may include a receiver (e.g., a receiving coil) and the base unit may include a transmitter (e.g., transmitting coil). The receiver of the wearable electronic device and the transmitter of the base unit may be inductively coupled to enable the wearable electronic device to receive power wirelessly from the base unit. The transmitter and receiver may be configured to operate at a body safe frequency. For example, the transmitter and receiver may be configured to operate at a frequency within the range of about 50 kHz or about 500 kHz. In some examples, the transmitter and receiver may be configured to operate at a frequency within the range of about 75 kHz to about 175 kHz. In some examples, the transmitter and receiver may be configured to operate in weak resonance. In some examples, the transmitter and receiver may be configured for operation with a Q value less than 100. In some examples, the wireless power transfer system may operate using an amount of guided flux. As described, the electronic device according to some examples herein may be a camera. FIGS. 1-4 show views of a camera 1200 in accordance with some examples of the present disclosure. The camera 1200 may be configured to record audiovisual data. The camera 1200 may include an image capture device 1210, a battery 1220, a receiver 1230, a memory 1240, and a controller 1250. The image capture device 1210 may include an image sensor 1212 and an optical component (e.g., camera lens 1214). The image capture device may be configured to capture a variety of visual data, such as image stills, video, etc. Thus, images or image data may interchangeably be used to refer to any images (including video) captured by the camera 1200. In some examples, the camera 1200 may be configured to record audio data. For example, the camera 1200 may include a microphone 1268 operatively coupled to the memory 1240 for storing audio detected by the microphone 1268. The controller 1250 may be implemented in hardware and/or software. For example, the controller 1250 may be implemented using one or more application specific integrated circuits (ASICs). In some examples, some or all of the functionality of the controller 1250 may be implemented in processor-executable instructions, which may be stored in memory onboard the camera (e.g., memory 1240). In some examples the camera may wirelessly receive instructions for performing certain functions of the camera, e.g., initiating image/video capture, initiating data transfer, setting parameters of the camera, and the like. The processor-executable instructions, when executed by a processor 1252 onboard the camera 1200 may program the camera 1200 to perform functions, as described further below. Any combination of hardware and/or software components may be used to implement the functionality of a camera according to the present disclosure (e.g., camera 1200). The battery 1220 may be a rechargeable battery such as a Nickel-Metal Hydride (NiMH), a Lithium ion (Li-ion), or a Lithium ion polymer (Li-ion polymer) battery. The battery 1220 may be operatively coupled to the receiver to store power received wirelessly from a distance separated wireless power transfer system. In some example, the battery may be coupled to energy generator (e.g., an energy harvesting device) onboard the camera. Energy harvesting devices may include, but are not limited to, kinetic-energy harvesting devices, solar cells, thermoelectric generators, or radio-frequency harvesting devices. The receiver 1230 may include a receiving coil 1232 configured to couple inductively with a distance separated transmitting coil (e.g., Tx coil 112, Tx coil 312), which may be part of a base unit (e.g., base unit 100, 300) in a wireless power transfer system (e.g., system 10). The receiving coil 1232 may include a magnetic core 1234 with conductive windings 1236. The windings may include copper wire (also referred to as copper windings). In some examples, the copper wire may be monolithic copper wire (e.g., single-strand wire). In some examples, the copper wire may be multi-strand copper wire (e.g., Litz wire), which may reduce resistivity due to skin effect in some examples, which may improve the power transfer between the receiving coil and transmitting coil. In some examples, the magnetic core 1234 may be a ferrite core (interchangeably referred to as ferrite rod). The ferrite core may comprise a medium permeability ferrite, for example 78 material supplied by Fair-Rite Corporation. In some examples, the ferrite core may comprise a high permeability material, such as Vitroperm 500F supplied by Vacuumschmelze in Germany. Ferrite cores comprising other ferrite materials may be used. In some examples, the ferrite may have a medium permeability of micro-i (μ) of about 2300. In some examples, the ferrite may have permeability of micro-i (μ) ranging from about 200 to about 5000. In some examples, different magnetic material may be used for the magnetic core. In some examples, the receiver 1230 may be configured to loosely inductively couple to a transmitter (e.g., a transmitter 110 of base unit 100). For example, the receiving coil 1232 may be configured to loosely inductively couple to a transmitting coil of the base unit. As will be further described below, the transmitting coil may include a magnetic core with windings. Similar materials may be used for the core and windings of the transmitting coil; however the receiving and transmitting coils may differ significantly in size, e.g., as illustrated in FIG. 7 and as will be further described. In some examples, the receiving coil may be configured to receive power from the transmitting coil regardless of relative orientation between the receiving and transmitting coils. Generally, a transmitting coil of a base unit according to the examples herein may utilize a magnetic core, which may in some examples shape the field provided by the transmitting coil, as the field lines may preferentially go through the magnetic core and in this manner a partially guided flux may be used where a portion of the flux is guided by the magnetic core. In some examples, the receiving coil 1232 of the electronic device may be configured to resonantly inductively couple to the transmitting coil. In some examples, the memory 1240 of the camera may store processor-executable instructions for performing functions of the camera described herein. In such examples, a micro-processor may be operatively coupled to the memory and configured to execute the processor-executable instruction to cause the camera to perform functions, such as cause power to be selectively received upon detection of the wireless power receiver in proximity, cause images to be captured upon receiving an image capture command, and/or cause images to be stored in the memory. In some examples, the memory 1240 may be configured to store user data including image data (e.g., images captured with the camera 1200). In some examples, the user data may include configuration parameters. Although certain electronic components, such as the memory 1240 and processor 1252 are discussed in the singular, it will be understood that the camera may include any number of memory devices and any number of processors and other appropriately configured electronic components. The memory 1240 and processor 1252 may be connected to a main circuit board 1260 (e.g., main PCB). The main circuit board 1260 may support one or more additional components, such as a wireless communication device (e.g., a Wi-Fi or Bluetooth chip), microphone and associated circuitry 1268, and others. In some examples, one or more of these components may be supported by separate circuit boards (e.g., auxiliary board 1264) operatively coupled to the main circuit board 1260. In some examples, some of the functionality of the camera may be incorporated in a plurality of separate IC chips or integrated into a single processing unit. The electronic components of camera 1200 may be packaged in a housing 1280, which may be made from a variety of rigid plastic materials known in the consumer electronics industry. In some examples, a thickness of the camera housing 1280 may range from about 0.3 mm to about 1 mm. In some examples, the thickness may be about 0.5 mm. In some examples, the thickness may exceed 1 mm. A camera according to the present disclosure may be a miniaturized self-contained electronic device, e.g., a miniaturized point-and-shoot camera. The camera 1200 may have a length of about 8 mm to about 50 mm. In some examples, the camera 1200 may have a length from about 12 mm to about 42 mm. In some examples, the camera 1200 may have a length not exceeding 42 mm. In some examples the camera 1200 may be about 12 mm long. The camera 1200 may have a width of about 8 mm to about 12 mm. In some examples, the camera 1200 may be about 9 mm wide. In some example, the camera 1200 may have a width not exceeding about 10 mm. In some example, the camera 1200 may have a height of about 8 mm to about 15 mm. In some examples, the camera 1200 may be about 9 mm high. In some examples, the camera 1200 may have a height not exceeding about 14 mm. In some examples, the camera 1200 may weigh from about 5 grams to about 10 grams. In some examples the camera 1200 may weigh be about 7 grams or less. In some examples, the camera 1200 may have a volume of about 6,000 cubic millimeters or less. In some examples, the camera 1200 may be a waterproof camera. In some examples, the camera may include a compliant material, e.g., forming or coating at least a portion of an exterior surface of the camera 1200. This may provide functionality (e.g., accessibility to buttons through a waterproof enclosure) and/or comfort to the user. The electronic components may be connected to the one or more circuit boards (e.g., main PCB 1260, auxiliary circuit board 1264) and electrical connection between the boards and/or components thereon may be formed using known techniques. In some examples, circuitry may be provided on a flexible circuit board, or a shaped circuit board, such as to optimize the use of space and enable packaging of the camera within a small form factor. For example, a molded interconnect device 1266 may be used to provide connectivity between one or more electronic components on the one or more boards. The electronic components may be stacked and/or arranged within the housing for optimal fit within a miniaturized enclosure. For example, the main circuit board 1260 may be provided adjacent another component (e.g., the battery 1220) and attached thereto via an adhesive layer 1265. In some examples, the main PCB may support IC chips on both sides of the board in which case the adhesive layer may attach to packaging of the IC chips, a surface of a spacing structure provided on the main PCB and/or a surface of the main PCB. In other examples, the main PCB and other circuit boards may be attached via other conventional mechanical means, such as fasteners. In some examples, the camera 1200 may be waterproof. The housing 1280 may provide a waterproof enclosure for the internal electronics (e.g., the image capture device 1210, battery 1220, receiver 1230, and circuitry). After the internal components are assembled into the housing 1280, a cover 1282 may be irremovably attached, such as via gluing or laser welding, for example. In the illustrated example, the cover 1282 is provided on the back side 1289 of the camera. In other examples, the cover may be located elsewhere, such as along the base 1283 or sidewall 1287 of the camera. In some examples, the cover 1282 may be removable (e.g., for replacement of the battery and/or servicing of the internal electronics) and may include one or more seals. In some examples, the housing 1280 may include one or more openings for optically and/or acoustically coupling internal components to the ambiance. In some examples, the camera may include a first opening 1284 on a front side 1281 of the camera 1200. An optically transparent (or nearly optically transparent) material 1285 may be provided across the first opening 1284 thereby defining a camera window 1231 for the image capture device 1210. The camera window 1231 may be sealingly integrated with the housing 1280, for example by an overmolding process in which the optically transparent material 1285 is overmolded with the plastic material forming the housing 1280. The image capture device 1210 may be positioned behind the camera window 1231 with the lens 1214 of the image capture device 1210 facing forward through the optically transparent material 1285. In some examples, an alignment or orientation of the image capture device 1210 may be adjustable. A second opening 1286 may be provided along a sidewall 1287 of the housing 1280. The second opening 1286 may be arranged to acoustically couple the microphone 1268 with the ambiance. A substantially acoustically transparent material 1288 may be provided across the second opening 1286 to serve as a microphone protector plug 1233 (e.g., to protect the microphone from being soiled or damaged by water or debris) without substantially interfering with the operation of the microphone. The acoustically transparent material 1288 may be configured to prevent or reduce water ingress through the second opening 1286. For example, the acoustically transparent material 1288 may comprise a water impermeable mesh. The mesh may be a micro-mesh sized with a mesh density selected to prevent water from passing through the mesh. In some examples, the mesh may include (e.g., formed of, or coated with) an hydrophobic material. The microphone 1268 may be configured to detect sounds, such as audible commands, which may be used to control certain operations of the camera 1200. In some examples, the camera 1200 may be configured to capture an image responsive to an audible command. In some examples, the audible command may be a spoken word or it may be a non-speech sound such as the click of teeth, the click of a tongue, or smack of lips. The camera 1200 may detect the audible command (e.g., in the form of an audible sound) and perform an action, such as capture an image, transfer data, or others. In some examples, the camera 1200 may be configured to transfer data wirelessly to another electronic device, for example a base unit of the wireless power transfer system. For example, the camera 1200 may transfer images captured by the image capture device for processing and/or storage elsewhere such as on the base unit and/or another computing device (e.g., personal computer, laptop, mobile phone, tablet, or a remote storage device such as cloud storage). Images captured with the camera 1200 may be processed (e.g., batch processed) by the other computing device, as will be further described. Data may be transferred from the camera 1200 to the other electronic device (e.g., base unit, a personal computing device, the cloud) via a separate wireless communication device (e.g., Wi-Fi or Bluetooth enabled device) or via the receiver/transmitter of the camera 1200, which in such instances would be configured to also transmit signals in addition to receiving signals (e.g., power signals). In other words, in some examples, the receiver 1230 may in some examples be also configured as a transmitter such that the receiver 1230 is operable in transmit mode as well as receive mode. In other examples, a separate transmitter (e.g., separate transmitting coil that includes a magnetic core and conductive windings) may alternatively or additionally be provided. The camera 1200 may be a wearable camera. In this regard the camera 1200 may be configured to be attached to a wearable article, such as eyewear (e.g., as shown in FIG. 11). In some examples, the camera may be removably attached to a wearable article. That is, the camera may be attachable to the wearable article (e.g., eyewear), detachable from the wearable article (e.g., eyewear), and may be further configured to be movable on the wearable article while attached thereto. In some examples, the wearable article may be any article worn by a user, such as by way of example only, a ring, a band (e.g., armband, wrist band, etc.), a bracelet, a necklace, a hat or other headgear, a belt, a purse strap, a holster, or others. The term eyewear includes all types of eyewear, including and without limitation eyeglasses, safety and sports eyewear such as goggles, or any other type of aesthetic, prescription, or safety eyewear. In some examples, the camera 1200 may be configured to be movably attached to a wearable article, such as eyewear, for example via a guide 1290 configured to engage a corresponding guide on the eyewear, e.g., track 6 in FIG. 6. The guide 1290 on the camera may be configured to slidably engage the guide on the eyewear. In some examples, the guide on the eyewear may be provided on the eyewear frame, e.g., on a temple of the eyewear. The camera 1200 may be configured to be attachable, detachable, and re-attachable to the eyewear frame. In some examples, the guide 1290 may be configured for magnetically attaching the camera 1200 to the eyewear. In this regard, one or more magnets may be embedded in the guide 1290. The guide 1290 may be provided along a bottom side 1283 (also referred to as a base 1283) of the camera 1200. The guide 1290 may be implemented as a protrusion (also referred to as male rail or simply rail) which is configured for a cooperating sliding fit with a groove (also referred to as female track or simply track) on the eyewear. The one or more magnets may be provided on the protrusion or at other location(s) along the base 1283. The eyewear may include a metallic material (e.g., along a temple of the eyewear) for magnetically attracting the one or more magnets on the camera. The camera may be configured to couple to the eyewear in accordance with any of the examples described in U.S. patent application Ser. No. 14/816,995, filed Aug. 3, 2015, and titled “Wearable Camera Systems and Apparatus and Method for Attaching Camera Systems or Other Electronic Device to Wearable Article.” which application is incorporated herein in its entirety for any purpose. As described, the camera 1200 may be configured to receive power wirelessly, e.g., from a base unit of a wireless power system. An example of a wireless power transfer system is illustrated and described further with reference to FIGS. 5-11. FIG. 5 shows a block diagram of a system for wirelessly powering one or more electronic devices according to some examples of the present disclosure. The system 10 includes a base unit 100 and one or more electronic devices 200. The base unit 100 is configured to wirelessly provide power to one or more of the electronic devices 200, which may be separated from the base unit by a distance. The base unit 100 is configured to provide power wirelessly to an electronic device 200 while the electronic device remains within a threshold distance (e.g., a charging range or charging zone 106) of the base unit 100. The base unit 100 may be configured to selectively transmit power wirelessly to any number of electronic devices (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 although a greater number than 10 devices may be charged in some examples) detected to be within a proximity (e.g., within the charging range) of the base unit 100. Although the electronic device 200 may typically be charged (e.g., coupled to the base unit for charging) while being distance-separated from the base unit 100, it is envisioned and within the scope of this disclosure that the base unit 100 may operate to provide power wirelessly to an electronic device 200 when the electronic device 200 is adjacent to or in contact with the base unit 100. The base unit 100 includes a transmitter 110, a battery 120, and a controller 130. The transmitter 110 includes at least one transmitting coil 112 (interchangeably referred to as Tx coil). The transmitting coil 112 may include a magnetic core with conductive windings. The windings may include copper wire (also referred to as copper windings). In some examples, the copper wire may be monolithic copper wire (e.g., single-strand wire). In some examples, the copper wire may be multi-strand copper wire (e.g., Litz, wire), which may reduce resistivity due to skin effect in some examples, which may allow for higher transmit power because resistive losses may be lower. In some examples, the magnetic core may be a ferrite core (interchangeably referred to as ferrite rod). The ferrite core may comprise a medium permeability ferrite, for example 78 material supplied by Fair-Rite Corporation. In some examples, the ferrite core may comprise a high permeability material, such as Vitroperm 500F supplied by Vacuumschmelze in Germany. Ferrite cores comprising other ferrite materials may be used. In some examples, the ferrite may have a medium permeability of micro-i (μ) of about 2300. In some examples, the ferrite may have permeability of micro-i (μ) ranging from about 200 to about 5000. In some examples, different magnetic material may be used for the magnetic core. Generally, transmitting coils described herein may utilize magnetic cores which may in some examples shape the field provided by the transmitting coil, as the field lines preferentially go through the magnetic core, in this manner, partially guided flux may be used where a portion of the flux is guided by the magnetic core. The transmitting coil 112 is configured to inductively couple to a receiving coil 212 in the electronic device 200. In some examples, the transmitter 110 may be additionally configured as a receiver and may thus be interchangeably referred to as transmitter/receiver. For example, the transmitting coil of the transmitter/receiver may additionally be configured as a receiving coil. In some examples, the transmitter/receiver may additionally include a receiving coil. In yet further examples, the base unit may include a separate receiver 140 comprising a receiving coil. The transmitter/receiver or separate receiver of the base unit may be configured to wirelessly receive power (102) and/or data (104) as will be further described below. In some examples, the transmitter 110 may include a single transmitting coil 112. The transmitting coil 112 may be placed in an optimal location and/or orientation to provide an optimum charging zone 106. In some examples, the transmitting coil may be placed in a location within the base unit selected to provide a large number of charging opportunities during a typical use of the device. For example, the transmitting coil 112 may be placed near a side of the base unit which most frequently comes in proximity to an electronic device (e.g., a top side of a base unit implemented as a mobile phone case as illustrated in the example in FIG. 9). In some examples, the transmitter 110 includes a plurality of transmitting coils 112. The transmitting coils 112 may be arranged in virtually any pattern. For example, the base unit may include a pair of coils which are angled to one another. In some examples, the coils may be arranged at angles smaller than 90 degrees, for example ranging between 15-75 degrees. In some examples, the coils may be arranged at 45 degrees relative to one another. Other combinations and arrangements may be used, examples of some of which will be further described below. In some examples, the transmitting coils may be arranged to provide a nearly omnidirectional charging zone 106 (also referred to as charging sphere or hotspot). The charging zone 106 of the base unit may be defined by a three dimensional space around the base unit which extends a threshold distance from the base unit in all three directions (e.g., the x, y, and z directions). Although a three dimensions (3D) space corresponding to a charging range of the base unit may be referred to herein as a sphere, it will be understood that the three dimensions (3D) space corresponding to a charging range need not be strictly spherical in shape. In some examples, the charging sphere may be an ellipsoid or a different shape. Efficiency of wireless power transfer within the charging zone 106 may be variable, for example, depending on a particular combination of transmitting and receiving coils and/or a particular arrangement of the coils or relative arrangements of the coils in the base unit and electronic device(s). The one or more transmitting coils 112 may be arranged within a housing of the base unit in a manner which improves the omni-directionality of the charging zone 106 and/or improves the efficiency of power transmission within the zone 106. In some examples, one or more transmitting coils 112 may be arranged within the housing in a manner which increases the opportunities for charging during typical use of the base unit. For example, the transmitting coil(s) may extend, at least partially, along one or more sides of the base unit which are most brought near an electronic device (e.g., the top or sides of a mobile phone case base unit which may frequently be moved in proximity with a wearable electronic device such as eyewear camera or a digital wrist watch). In some examples, the base unit may be placed on a surface (e.g., a table or desk) during typical use and electronic devices may be placed around the base unit. In such examples, the transmitting coil(s) may be arranged along a perimeter of the base unit housing. In some examples, the base unit may be attached to a mobile phone via an attachment mechanism such as adhesive attachment, an elastic attachment, a spring clamp, suction cup(s), mechanical pressure, or others. In some examples, the base unit may be enclosed or embedded in an enclosure (also referred to as housing), which may have a generally planar shape (e.g., a rectangular plate). An attachment mechanism may be coupled to the housing such that the base unit may be removably attached to a mobile phone, a table, or other communication device. In an example, the attachment mechanism may be a biasing member, such as a clip, which is configured to bias the mobile phone towards the base unit in the form of, by way of example only, a rectangular plate. For example, a clip may be provided proximate a side of the base unit and the base unit may be attached to (e.g., clipped to) the mobile phone via the clip in a manner similar to attaching paper or a notebook/notepad to a clip board. In some examples, the base unit may be adhesively or elastically attached to the communication device and/or to a case of the communication device. In further examples, the base unit may be separate from the communication device. In yet further examples, the base unit may be incorporated into (e.g., integrated into) the communication device. For example, the transmitter 110 may be integrated with other components of a typical mobile phone. The controller 130 may be a separate IC in the mobile phone or its functionality may be incorporated into the processor and/or other circuitry of the mobile phone. Typical mobile phones include a rechargeable battery which may also function as the battery 120 of the base unit. In this manner, a mobile phone may be configured to provide power wirelessly to electronic devices, such as separated electronic wearable devices. As previously noted, the base unit 100 may include a battery 120. The battery 120 may be a rechargeable battery, such as a Nickel-Metal Hydride (NiMH), a Lithium ion (Li-ion), or a Lithium ion polymer (Li-ion polymer) battery. The battery 120 of the base unit 100 may include larger amount of energy capacity as compared to a battery of the electronic device 200. That is, the battery 120 may store more power, and in some examples, significantly more power than a battery onboard the electronic device (e.g., the battery 1220 of wearable camera 1200). The electronic device, which may be a wearable device, may have a significantly smaller form factor than the base unit 100 and accordingly, may be able to accommodate a much smaller battery. Periodic wireless transfer of power from the base unit to the electronic device (e.g., when the electronic device is within the charging range of the base unit) may enable a small form factor suitable for a wearable electronic device without significant sacrifice in performance. The battery 120 may be coupled to other components to receive power. For example, the battery 120 may be coupled to an energy generator 150. The energy generator 150 may include an energy harvesting device which may provide harvested energy to the battery for storage and use in charging the electronic device(s). Energy harvesting devices may include, but not be limited to, kinetic-energy harvesting devices, solar cells, thermoelectric generators, or radio-frequency harvesting devices. In some examples, the battery 120 may be coupled to an input/output connector 180 such as a universal serial bus (USB) port. It will be understood that the term USB port herein includes any type of USB interface currently known or later developed, for example mini and micro USB type interfaces. Other types of connectors, currently known or later developed, may additionally or alternatively be used. The I/O connector 180 (e.g., USB port) may be used to connect the base unit 100 to an external device, for example an external power source or a computing device (e.g., a personal computer, laptop, tablet, or a mobile phone). The transmitter 110 is operatively coupled to the battery 120 to selectively receive power from the battery and wirelessly transmit the power to the electronic device 200. As described herein, in some examples, the transmitter may combine the functionality of transmitter and receiver. In such examples, the transmitter may also be configured to wirelessly receive power from an external power source. It will be understood that during transmission, power may be wirelessly broadcast by the transmitter and may be received by any receiving devices within proximity (e.g., within the broadcast distance of the transmitter). The transmitter 110 may be weakly-coupled to a receiver in the electronic device 200 in some examples. There may not be a tight coupling between the transmitter 110 and the receiver in the electronic device 200. Highly resonant coupling may be considered tight coupling. The weak (or loose) coupling may allow for power transmission over a distance (e.g. from a base unit in or on a mobile phone to a wearable device on eyewear or from a base unit placed on a surface to a wearable device placed on the surface in a neighborhood of, but not on, the base unit). So, for example, the transmitter 110 may be distance separated from the receiver. The distance may be greater than 1 mm in some examples, greater than 10 mm in some examples, greater than 100 mm in some examples, and greater than 1000 mm in some examples. Other distances may be used in other examples, and power may be transferred over these distances. The transmitter 110 and the receiver in the electronic device 200 may include impedance matching circuits each having an inductance, capacitance, and resistance. The impedance matching circuits may function to adjust impedance of the transmitter 110 to better match impedance of a receiver under normal expected loads, although in examples described herein the transmitter and receiver may have transmit and receive coils, respectively, with different sizes and/or other characteristics such that the impedance of the receiver and transmitter may not be matched by the impedance matching circuits, but the impedance matching circuits may reduce a difference in impedance of the transmitter and receiver. The transmitter 110 may generally provide a wireless power signal which may be provided at a body-safe frequency, e.g. less than 500 kHz in some examples, less than 300 kHz in some examples, less than 200 kHz in some examples, 125 kHz in some examples, less than 100 kHz in some examples, although other frequencies may be used. Transmission/broadcasting of power may be selective in that a controller controls when power is being broadcast. The base unit may include a controller 130 coupled to the battery 120 and transmitter 110. The controller 130 may be configured to cause the transmitter 110 to selectively transmit power, as will be further described. A charger circuit may be connected to the battery 120 to protect the battery from overcharging. The charger circuit may monitor a level of charge in the battery 120 and turn off charging when it detects that the battery 120 is fully charged. The functionality of the charger circuit may, in some examples, be incorporated within the controller 130 or it may be a separated circuit (e.g., separate IC chip). In some examples, the base unit may include a memory 160. The memory 160 may be coupled to the transmitter 110 and/or any additional transmitters and/or receivers (e.g., receiver 140) for storage of data transmitted to and from the base unit 100. For example, the base unit 100 may be configured to communicate data wirelessly to and from the electronic device 200, e.g., receive images acquired with an electronic device in the form of a wearable camera, or transmit executable instructions, configuration data, or other data to the electronic device. The base unit 100 may include larger amount of memory as compared to the electronic device 200. That is, the memory 160 may be configured to store more data, and in some examples, significantly more data than a memory device onboard the electronic device (e.g., the memory 1240 of wearable camera 1200). The electronic device, which may be a wearable device, may have a significantly smaller form factor than the base unit and accordingly, may be able to accommodate a much smaller memory device. Periodic wireless transfer of data from the electronic device to the base unit (e.g., when the electronic device is within range of the base unit such as during charging) may enable a small form factor suitable for a wearable electronic device without significant sacrifice in performance. The base unit may include one or more sensors 170, which may be operatively coupled to the controller. A sensor 170 may detect a status of the base unit such that the transmitter may provide power selectively and/or adjustably under control from controller 130. The electronic device 200 may be configured to provide virtually any functionality, for example an electronic device configured as a camera (e.g., camera 1200). In this regard, the electronic device 200 may include circuitry associated with wireless charging. For example, the electronic device 200 may include a receiving which may include at least one receiving coil 212. As described, the receiving coil 212 may be coupled to a rechargeable power cell onboard the electronic device 200. Frequent charging in a manner that is non-invasive or minimally invasive to the user during typical use of the electronic device may be achieved via wireless coupling between the receiving and transmitting coils in accordance with the examples herein. In some examples, the electronic device may be a wearable electronic device, which may interchangeably be referred to herein as electronic wearable devices (e.g., wearable camera). The electronic device may have a sufficiently small form factor to make it easily portable by a user. The electronic device 200 may be attachable to clothing or an accessory worn by the user, for example eyewear. For example, the electronic device 200 may be attached to eyewear using a guide 6 (e.g., track) incorporated in the eyewear, e.g., as illustrated in FIG. 6 (only a portion of eyewear, namely the temple, is illustrated so as not to clutter the drawing). FIG. 6 shows examples of electronic devices 200 which may be configured to receive power wirelessly in accordance with the present disclosure. In some examples, the electronic device 200 may be a miniaturized camera system which may, in some examples, be attached to eyewear. In other examples, the electronic device may be any other type of an electronic system attached to eyewear, such as an image display system, an air quality sensor, a UV/HEV sensor, a pedometer, a night light, a blue tooth enabled communication device such as blue tooth headset, a hearing aid or an audio system. In some examples, the electronic device may be worn elsewhere on the body, for example around the wrist (e.g., an electronic watch or a biometric device, such as a pedometer). The electronic device 200 may be another type of electronic device other than the specific examples illustrated. The electronic device 200 may be virtually any miniaturized electronic device, for example and without limitation a camera, image capture device, IR camera, still camera, video camera, image sensor, repeater, resonator, sensor, sound amplifier, directional microphone, eyewear supporting an electronic component, spectrometer, directional microphone, microphone, camera system, infrared vision system, night vision aid, night light, illumination system, sensor, pedometer, wireless cell phone, mobile phone, wireless communication system, projector, laser, holographic device, holographic system, display, radio, GPS, data storage, memory storage, power source, speaker, fall detector, alertness monitor, geo-location, pulse detection, gaming, eye tracking, pupil monitoring, alarm. CO sensor, CO detector, CO2 sensor, CO2 detector, air particulate sensor, air particulate meter, UV sensor, UV meter, IR sensor IR meter, thermal sensor, thermal meter, poor air sensor, poor air monitor, bad breath sensor, bad breath monitor, alcohol sensor, alcohol monitor, motion sensor, motion monitor, thermometer, smoke sensor, smoke detector, pill reminder, audio playback device, audio recorder, speaker, acoustic amplification device, acoustic canceling device, hearing aid, assisted hearing assisted device, informational earbuds, smart earbuds, smart ear-wearables, video playback device, video recorder device, image sensor, fall detector, alertness sensor, alertness monitor, information alert monitor, health sensor, health monitor, fitness sensor, fitness monitor, physiology sensor, physiology monitor, mood sensor, mood monitor, stress monitor, pedometer, motion detector, geo-location, pulse detection, wireless communication device, gaming device, eyewear comprising an electronic component, augmented reality system, virtual reality system, eye tracking device, pupil sensor, pupil monitor, automated reminder, light, alarm, cell phone device, phone, mobile communication device, poor air quality alert device, sleep detector, doziness detector, alcohol detector, thermometer, refractive error measurement device, wave front measurement device, aberrometer, GPS system, smoke detector, pill reminder, speaker, kinetic energy source, microphone, projector, virtual keyboard, face recognition device, voice recognition device, sound recognition system, radioactive detector, radiation detector, radon detector, moisture detector, humidity detector, atmospheric pressure indicator, loudness indicator, noise indicator, acoustic sensor, range finder, laser system, topography sensor, motor, micro motor, nano motor, switch, battery, dynamo, thermal power source, fuel cell, solar cell, kinetic energy source, thermo electric power source, smart band, smart watch, smart earring, smart necklace, smart clothing, smart belt, smart ring, smart bra, smart shoes, smart footwear, smart gloves, smart hat, smart headwear, smart eyewear, and other such smart devices. In some examples, the electronic device 200 may be a smart device. In some examples, the electronic device 200 may be a micro wearable device or an implanted device. The electronic device 200 may include a receiver (e.g., Rx coil 212) configured to inductively couple to the transmitter (e.g. Tx coil 112) of the base unit 100. The receiver may be configured to automatically receive power from the base unit when the electronic device and thus the receiver is within proximity of the base unit (e.g., when the electronic device is a predetermined distance, or within a charging range, from the base unit). The electronic device 200 may store excess power in a power cell onboard the electronic device. The power cell onboard the electronic device may be significantly smaller than the battery of the base unit. Frequent recharging of the power cell may be effected by virtue of the electronic device frequently coming within proximity of the base unit during normal use. For example, in the case of a wearable electronic device coupled to eyewear and a base unit in the form of a cell phone case, during normal use, the cell phone may be frequently brought to proximity of the user's head to conduct phone calls during which times recharging of the power cell onboard the wearable electronic device may be achieved. In some examples, in which the wearable electronic device comprises an electronic watch or biometric sensor coupled to a wrist band or an arm band, the wearable electronic device may be frequently recharged by virtue of the user reaching for their cellphone and the base unit in the form of a cell phone case coming within proximity to the wearable electronic device. In some examples, the electronic device may include an energy harvesting system. In some examples, the electronic device 200 may not include a battery and may instead be directly powered by wireless power received from the base unit 100. In some examples, the electronic device 200 may include a capacitor (e.g., a supercapacitor or an ultracapacitor) operatively coupled to the Rx coil 212. Typically in existing systems which apply wireless power transfer, transmitting and receiving coils may have the same or substantially the same coil ratios. However, given the smaller form factor of miniaturized electronic devices according to the present disclosure, such implementation may not be practical. In some examples herein, the receiving coil may be significantly smaller than the transmitting coils, e.g., as illustrated in FIG. 7. In some examples, the Tx coil 112 may have a dimension (e.g., a length of the wire forming the windings 116, a diameter of the wire forming the windings 116, a diameter of the coil 112, a number of windings 116, a length of the core 117, a diameter of the core 117, a surface area of the core 117) which is greater, for example twice or more, than a respective dimension of the Rx coil 212 (e.g., a length of the wire forming the windings 216, a diameter of the coil 212, a number of windings 216, a length of the core 217, a surface area of the core 217). In some examples, a dimension of the Tx coil 112 may be two times or greater, five times or greater, 10 times or greater, 20 times or greater, or 50 times or greater than a respective dimension of the Rx coil 212. In some examples, a dimension of the Tx coil 112 may be up to 100 times a respective dimension of the Rx coil 212. For example, the receiving coil 212 (Rx coil) may comprise conductive wire having wire diameter of about 0.2 mm. The wire may be a single strand wire. The Rx coil in this example may have a diameter of about 2.4 mm and a length of about 13 mm. The Rx coil may include a ferrite rod having a diameter of about 1.5 mm and a length of about 15 mm. The number of windings in the Rx coil may be, by way of example only, approximately 130 windings. The transmitting coil 112 (Tx coil) may comprise a conductive wire having a wire diameter of about 1.7 mm. The wire may be a multi-strand wire. The Tx coil in this example may have a diameter of about 14.5 mm and a length of about 67 mm. The Tx coil may include a ferrite rod having a diameter of about 8 mm and a length of about 68 mm. Approximately 74 windings may be used for the Tx coil. Other combinations may be used for the Tx and Rx coils in other examples, e.g., to optimize power transfer efficiency even at distances in excess of approximately 30 cm or more. In some examples, the transfer distance may exceed 12 inches. In some examples herein, the Tx and Rx coils may not be impedance matched, as may be typical in conventional wireless power transfer systems. Thus, in some examples, the Tx and Rx coils of the base unit and electronic device, respectively, may be referred to as being loosely-coupled. According to some examples, the base unit is configured for low Q factor wireless power transfer. For example, the base unit may be configured for wireless power transfer at Q factors less than 500 in some examples, less than 250 in some examples, less than 100 in some examples, less than 80 in some examples, less than 60 in some examples, and other Q factors may be used. While impedance matching is not required, examples in which the coils are at least partially impedance matched are also envisioned and within the scope of this disclosure. While the Tx and Rx coils in wireless powers transfer systems described herein may be typically loosely coupled, the present disclosure does not exclude examples in which the Tx and Rx coils are impedance matched. The receiving coil (e.g., Rx coil 212) may include conductive windings, for example copper windings. Conductive materials other than copper may be used. In some examples, the windings may include monolithic (e.g., single-strand) or multi-strand wire. In some examples, the core may be a magnetic core which includes a magnetic material such as ferrite. The core may be shaped in the form of a rod. The Rx coil may have a dimension that is smaller than a dimension of the Tx coil, for example a diameter, a length, a surface area, and/or a mass of the core (e.g., rod) may be smaller than a diameter, a length, a surface area, and/or a mass of the core (e.g., rod) of the Tx coil. In some examples, the magnetic core (e.g., ferrite rod) of the Tx coil may have a surface area that is two times greater or more than a surface area of the magnetic core (e.g., ferrite rod) of the Rx coil. In some examples, the Tx coil may include a larger number of windings and/or a greater length of wire in the windings when unwound than the number or length of wire of the windings of the Rx coil. In some examples, the length of unwound wire of the Tx coil may be at least two times the length of unwound wire of the Rx coil. In some examples, an Rx coil 212 may have a length from about 10 mm to about 90 mm and a radius from about 1 mm to about 15 mm. In one example, the performance of an Rx coil 212 having a ferrite rod 20 mm in length and 2.5 mm in diameter with 150 conductive windings wound thereupon was simulated with a Tx coil 112 configured to broadcast power at frequency of about 125 KHz. The Tx coil 112 included a ferrite rod having a length of approximately 67.5 mm and a diameter of approximately 12 mm. Up to 20% transmission efficiency was obtained in the aligned orientation at distances of up to 200 mm between the coils. Some improvement was observed in the performance when the coils were arranged in a parallel orientation, in which the Rx coil continued to receive transmitted power until a distance of about 300 mm. Examples of a wireless energy transfer system according to the present disclosure were compared with efficiency achievable by a system configured in accordance with the Qi 1.0 standard. The size of the Tx coil in one simulated system was 52 mm×52 mm×5.6 mm and a size of one Rx coil simulated was 48.2 mm×32.2 mm×1.1 mm, and load impedance was 1 KOhm. Referring now also to FIGS. 8-9, a base unit 300, which may be incorporated in a mobile phone case form factor as shown in FIGS. 9A and 9B, will be described. The base unit 300 may include some or all of the components of base unit 100 described above with reference to FIG. 5. For example, the base unit 300 may include a transmitting coil 312 (also referred to as Tx coil). The transmitting coil 312 is coupled to an electronics package 305, which includes circuitry configured to perform the functions of a base unit in accordance with the present disclosure, including selectively and/or adjustably providing wireless power to one or more electronic devices. In some examples, the electronic device may be an electronic device which is separated from the base unit (e.g., camera 1200). In some examples, the electronic device may be the mobile phone 20, to which the base unit 300 in the form of a case is attached. The base unit 300 may provide a mobile wireless hotspot (e.g., charging sphere 106) for wirelessly charging electronic devices that are placed or come into proximity of the base unit (e.g., within the charging sphere). As will be appreciated, the base unit 300 when implemented in the form of a mobile phone case may be attached to a mobile phone and carried by the user, thus making the hotspot of wireless power mobile and available to electronic devices wherever the user goes. In examples, the base unit may be integrated with the mobile phone. The hotspot of wireless power by virtue of being connected to the user's mobile phone, which the user often or always carries with him or her, thus advantageously travels with the user. As will be further appreciated, opportunities for recharging the power cell on an electronic device worn by the user are frequent during the normal use of the mobile phone, which by virtue of being use may frequently be brought into the vicinity of wearable devices (e.g., eyewear devices when the user is making phone calls, wrist worn devices when the user is browsing or using other function of the mobile phone). The Tx coil 312 and electronics (e.g., electronics package 305) may be enclosed in a housing 315. The housing 315 may have a portable form factor. In this example, the housing is implemented in the form of an attachment member configured to be attached to a communication device such as a mobile phone (e.g., a mobile phone, a cellular phone, a smart phone, a two-way radio, a walkie-talkie, and the like), a tablet or the like. In this regard, the housing 315 of the base unit may be implemented as a mobile phone/tablet case or cover. The housing 315 may include features for mechanically engaging the communication device (e.g., mobile phone 20). In further examples, the housing of the base unit may be implemented as an attachment member adapted to be attached to an accessory, such as a handbag, a belt, or others. Other form factors may be used. The base unit 300 may power an electronic device other than the communication device to which it is connected, for example the camera 1200. In the examples in FIGS. 8 and 9, the base unit 300 includes a transmitting coil 312. The transmitting coil 312 includes a magnetic core 317 with conductive windings 316. The core 317 may be made of a ferromagnetic material (e.g., ferrite), a magnetic metal, or alloys or combinations thereof, collectively referred to herein as magnetic material. For example, a magnetic material such as ferrite and various alloys of iron and nickel may be used. The coil 312 includes conductive windings 316 provided around the core 317. It will be understood in the context of this disclosure that the windings 316 may be, but need not be, provided directly on the core 317. In other words, the windings 316 may be spaced from the core material which may be placed within a space defined by the windings 316. In some examples, improved performance may be achieved by the windings being wound directly onto the core as in the present example. The core 317 may be shaped as an elongate member and may have virtually any cross section, e.g., rectangular or circular cross section. An elongate core may interchangeably be referred to as a rod 314, e.g., a cylindrical or rectangular rod. The term rod may be used to refer to an elongate core in accordance with the present application, regardless of the particular cross sectional shape of the core. The core may include a single rod or any number of discrete rods (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or any other number greater than 10) arranged in patterns as will be described. In the examples in FIGS. 8 and 9, without limitation, the transmitting coil comprises a single cylindrical rod positioned at least partially along a first side (e.g., top side 321) of the housing 315. In other examples, one or more coils may alternatively or additionally be positioned along other sides, e.g., a bottom side 323, the left side 325 and/or right sides 327 of the housing 315. The electronics package 305 (interchangeably referred to as electronics or circuitry) may be embedded in the housing 315 or provided behind a cover 307. In some examples, the cover 307 may be removable. In some examples, it may be advantageous to replace the battery 320. In such examples, the battery 320 may be a separable component from the remaining circuitry. The battery 320 may be accessed by removing the cover 307. In some examples, the electronics package 305 may include a battery for storing energy from an external power source. In some examples, the base unit 300 may alternatively or additionally receive power from the mobile phone when powering the distance separated electronic device. In some examples, the base unit may not require a battery, and even smaller form factors may thus be achieved. The base unit may be provided with one or more I/O devices 380. I/O devices may be used to receive and/or transmit power and/or data via a wired connection between the base unit and another device. For example, the base unit may include an I/O device 380 in the form of a USB connector. The I/O device 380 (e.g., USB connector) may include a first connection side 382 (e.g., a female port) for coupling the base unit to external devices (e.g., a power source such as the power grid and/or another electronic device). The I/O device 380 may include a second connection side 384 (e.g., a male connector) for coupling the base unit to the mobile phone, e.g., via a USB port of the mobile phone. One or more of the signal lines 385 of the I/O device may be coupled to power, ground, and/or data lines in the base unit circuitry. For example, if a USB connector with 5 lines is used, 2 lines may be used for data, 2 lines may be used for power, and 1 line may be coupled to ground or used for redundancy. The signal lines 385 of the first and second connection sides may be coupled to the base unit circuitry via a connector circuit 386 (e.g., USB chip). It will be understood that any other type of connectors may be used, for example, and without limitation, an APPLE Lightning connector. The base unit 300 may include a controller 330. The controller 330 may include functionality for controlling operations of the base unit 300, for example controlling detection of electronic devices (e.g., a camera 1200) within proximity, selective transmission of wireless power upon detection of an electronic device, determination of status of the base unit, and selection of transmission mode depending on the status of the base unit. These functions may be implemented in computer readable media or hardwired into an ASIC or other processing hardware. The controller 330 may interchangeably be referred to as base unit processor. The base unit may include one or more memory devices 360. The base unit may include volatile memory 362 (e.g., RAM) and non-volatile memory 364 (e.g., EEPROM, flash or other persistent electronic storage). The base unit may be configured to receive data (e.g. user data, configuration data) through wired or wireless connection with external electronic devices and may store the data on board the base unit (e.g., in one or more of the memory devices 360). The base unit may be configured to transmit data stored onboard the base unit to external electronic devices as may be desired. In addition to user data, the memory devices may store executable instructions which, when executed by a processor (e.g., processor 360), cause the base unit to perform functions described herein. The base unit 300 may include a charger circuit 332, which may be configured to protect the battery 320 from overcharging. The charger circuit may be a separate chip or may be integrated within the controller 330. The base unit may include a separate transmitter/receiver circuitry 340 in addition to the Tx coil 312 used for wireless power transmission. The transmitter/receiver circuitry 340 may include a receiving/transmitting coil 342. e.g., an RF coil. The transmitter/receiver circuitry 340 may further include driver circuitry 344 for transmission (e.g., RF driver circuit) and sense circuitry 346 for reception of signals (e.g., RF sensing circuit). The base unit 300 may include additional circuitry for wireless communication (e.g., communication circuit 388). The communication circuit 388 may include circuitry configured for Bluetooth or WiFi communication. In some examples, the base unit 300 may include one or more sensor 370 and/or one or more energy generators 350 as described herein. Additional circuitry providing additional functionality may be included. For example, the base unit 300 may include an image processor for processing and/or enhancement of images received from a wearable camera (e.g., eyewear camera). The image processing functionality may be provided in a separate IC (e.g., a DaVinci chip set) or it may be incorporated in a processor which implements the functions of controller 330. In some examples, the housing may be configured to be mechanically coupled to a communication device, such as a mobile phone. For example, the housing 315 may be configured to provide the functionality of a mobile phone case. The housing 315 may have a shape corresponding to a shape of a communication device (e.g., a mobile phone). For example, the housing 315 may be generally rectangular in shape and may be sized to receive, at least partially, or enclose, at least partially, the communication device. In some examples, the housing 315 may be configured to cover only one side of the communication device. In some examples, the housing 315 may cover at least partially two or more sides of the communication device. The housing 315 may include a receptacle 309 configured to receive and/or retain the mobile phone at least partially therein. The receptacle 309 may be on a front side of the housing 315. The base unit electronics may be provided proximate an opposite side of the receptacle. The coils may be placed around the perimeter of the housing, e.g. along any of the top, bottom, or left and right sides. In some examples, the transmitter includes a plurality of discrete Tx coils (for example 2, 3, 4, 5, 6, 7, 8, 9 or 10 coils), each having a magnetic core with conductive windings wound thereon. At least some of the Tx coils may be at an angle to one another, for example at 20 degrees or more, 30 degrees or more, 45 degrees or more, 75 degrees or more relative to one another. In some examples, the Tx coils may be generally perpendicular to one another. In some examples, two or more Tx coils may be generally parallel to one another. In some examples, two or more Tx coils may be disposed along a same edge of the housing. A diameter ø of the Tx coils may range from about 5 mm to about 20 mm. In some examples, the diameter ø of the Tx coils may be between 8 mm to 15 mm. In some examples, the diameter ø of the Tx coils may be 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, or 14 mm. Different diameters for the coils may be used. In some examples, the magnetic core may be an elongate cylindrical rod made from a magnetic material. In some examples, the rods may be arranged around the perimeter of the base unit's housing. In some examples, the rods may extend substantially along the full length of a top side, bottom side, left and/or right sides of the housing. Lengths (l), widths (w), and thicknesses (t) of the housing may vary depending on dimensions of the communication device, which the housing is configured to attach to. In some examples, the housing may range from about 150 mm-180 mm, 80-95 mm, and 15-25 mm, respectively. Other lengths, widths, and thicknesses may be used. e.g., to accommodate a given communication device (e.g. smartphone) and/or accommodate a particular coil size. In some examples, the housing may be configured to attach to an IPHONE brand mobile phone or a SAMSUNG brand mobile phone. For example, a housing configured to attach to an IPHONE 6 mobile phone may be about 160 mm long, about 84 mm wide, and about 19 mm thick and accommodate Tx coils having a diameter of about 9 mm. In another example, the housing may have a length of about 165 mm, a width of about 94 mm, and a thickness of about 21 mm accommodating a coil having a diameter of about 14 mm. In some examples, the housing may be configured to attach to an IPAD brand tablet or a SAMSUNG brand tablet. In some examples, the housing may be configured to engage one, two, three and/or all of the perimeter sides of the communication device. In some examples, the base unit housing may be configured to cover or partially cover one or more of the communication devices' major sides (e.g., the display side or the back side) of the communication device. FIG. 10 shows a flow diagram of a process in accordance with the present disclosure. The process 1000 may include placing a base unit (e.g., base unit 100) proximate a camera (e.g., camera 1200), as show in block 1005. The camera may be a wearable camera, which may be attached to eyewear 4, for example via a guide on the camera engaging a track on the eyewear 4, as illustrated in FIG. 11. The base unit (e.g., base unit 100) may be attached to a communication device, such as a mobile phone. The base unit may include a transmitting coil configured to inductively couple with a receiving coil in the camera to wirelessly transmit power to the wearable camera. The process 1000 may further include detecting the wearable camera with the base unit. For example, the base unit may detect a proximity signal of the camera, as shown in block 1010. In some examples, the base unit may alternatively or additionally detect a charge status signal of the camera, as further shown in block 1010. The charge status signal may be indicative of a charge status of the camera's power cell (e.g., battery 1220 of camera 1200). The process 1000 may also include wirelessly transmitting power from the base unit to the camera, as shown in block 1015. The wireless transfer of power may continue while the camera remains within a charging range of the base unit (e.g., based on a detected proximity signal) or until a charge state signal of the camera corresponds to a fully charged state of the camera. In some examples, the base unit may be configured to broadcast wireless power only if a charge status of an electronic device in proximity indicates a less than full charge of the electronic device's onboard battery. To that end, the base unit may monitor the proximity and/or charge status of the camera, as shown in block 1020. In some examples, the camera may be configured to selectively receive power. In other words, circuitry associated with wireless power charging may be selectively activated responsive to an indication of proximity of an appropriately tuned wireless power transmitter. The base unit may be configured to broadcast power and the camera may be configured to receive power broadcast at body-safe levels. The base unit may be configured to broadcast power and the camera may be configured to receive power broadcast at a frequency within the range of 50 kHz or 500 kHz. The camera may broadcast a signal (e.g., proximity signal, charge status signal), which may be detected by the base unit. Upon detecting of the camera in proximity the base unit may begin broadcasting power signals and the camera may activate circuitry associated with wireless power reception (e.g., a charging circuit of the camera). In some examples, the camera may broadcast a signal (e.g., proximity signal, charge status signal) responsive to an interrogation signal from the base unit and the base unit may automatically detect the broadcast signal from the camera and/or automatically initiate power transmission upon the detection of the signal from the camera. In some examples, the process 1000 may include capturing an image with the camera and/or transfer data (e.g., images) wirelessly, as shown in block 1025. Images may be captured responsive to a command, which may be generated responsive to manual user input (e.g., via a trigger button on the camera). In some examples, images may be captured responsive to a command generated by the controller responsive to an audible command detected by the camera. For example, the camera may include a microphone (e.g., microphone 1268), which is configured to detect an audible command, which may include a voice command or other speech or non-speech sounds (a click of the user's teeth). The camera may be configured to capture images while receiving wireless power, e.g., as shown in block 1030. Captured images may be stored onboard the camera (e.g., in a memory 1240) or transferred to another electronic device, such as the base unit or a computer system 1410. Images or other data may be transferred wirelessly from the camera to the base unit or to another computing device (e.g., computer system 1410 in FIG. 14) automatically or responsive to user input. To that end, the camera may include wireless communication devices (e.g., Wi-Fi, Bluetooth, or the like). In some examples, the wireless receiver of the camera (e.g., receiver 1230) may also be configured as a transmitter operable to transmit data (e.g., images) from the camera to the base unit or another computing device. Referring now also to FIGS. 12-13, additional features of cameras in accordance with the present disclosure will be described. As described, the camera 1200′, 1200″ may be a wearable camera and may include a guide 1290. The guide 1290 may include one or more magnets 1292 for magnetically attaching the camera to the eyewear. The one or more magnets may be embedded in the guide 1290. The guide 1290 may be provided along a bottom side 1283 (also referred to as a base 1283) of the camera 1200′, 1200″. The guide 1290 may be implemented as a protrusion (also referred to as male rail or simply rail) which is configured for a cooperating sliding fit with a groove (also referred to as female track or simply track) on the eyewear. The one or more magnets may be provided on the protrusion or at other location(s) along the base 1283. In examples, the magnets may be positioned below the bottom surface of the guide. In some examples, the magnets may be substantially flush with the bottom surface of the guide. A coating or protective layer may be provided on the contact surface of the magnets to prevent the guide from scratching any exterior/aesthetic surfaces of the eyewear as may otherwise result from slidable engagement between the camera guide and the eyewear guide. The camera 1200′ may include one or more user controls 1294. The user controls 1294 may be implemented in the form of buttons, switches, or the like. To maintain waterproof characteristics of the camera, in some examples, such buttons or switches may be provided below a flexible portion of the housing. That is, one or more portions of the housing 1280 may be formed of a resilient material such as rubber, silicon, or the like, such that that portion of the housing may be deflected to operate a button located below the flexible portion. In some examples, the user controls 1294 may be implemented using one or more capacitive surfaces. For example, a capacitive switch 1295, which may include a smooth or textured surface, may be provided along a sidewall of the camera. The capacitive surface may be molded with the housing to provide an integral, water-tight user control. The capacitive switch 1295 may function as a trigger for capturing an image. In some examples, the same user control (e.g., capacitive switch 1295) may be configured to perform different functions depending on the manipulation of the user control. For example, a single input via the user control (e.g., single touch or click) may correspond with one function (e.g., capture an image), a double input (e.g., two consecutive touches or double clicks) may correspond with another function (e.g., initiate image transfer), a continuous input (e.g., a touch/click and hold) may correspond with yet another function (e.g., configuring a setting or a parameter of the camera, powering the camera on or off). These specific examples of functions or types of manipulations of the user control are illustrative only and other combinations of functions and/or manipulations of the user control(s) may be used. User controls may be provided along one or more sides of the housing, for example along the sidewall, as shown in FIG. 12 or along a back wall 1289′, as shown in FIG. 13. The camera may also include one or more securing features 1297. The camera may be configured to engage a securing ring which may be connected to the eyewear. The securing ring may be configured to provide an additional attachment means for ensuring that the camera remains connected to the eyewear even if the magnetic attachment fails. The securing ring may be made from a clear plastic material (e.g., clear rubber or silicon) and may have a diameter of the core ranging between 0.01 mm to about 2 mm. The camera may include a securing feature 1297 which may be in the form of a securing pin, as shown in FIG. 12 or a securing aperture, as shown in FIG. 13 for engaging the securing ring. In the example in FIG. 13, the securing aperture may be arranged such that a plane of a diameter of the aperture is generally perpendicular to the back wall 1289′ and/or base of the camera. In some examples, the plane of the diameter of the aperture may be generally parallel with the longitudinal direction of the guide 1290. The camera may include one or more indicators 1296. The indicators 1296 may be provided along one or more sides of the camera 1200′, 1200″, for example along a top side of the camera, as in the example in FIG. 12 or on the back wall 1289′ of the camera, as in FIG. 13. The indicators may be implemented in the form of one or more white or colored LEDs, which based on a color, duration or pattern of illumination may provide indication as to different functions or states of the camera or components thereof. The indicators may include a charge status indicator, a power On/Off indicator, a privacy indicator, or others. For example, a privacy indicator may comprise one or more LEDs which may illuminate when an image (e.g., a still image or video) is being captured. The illumination may notify others that an image is being captured. In some examples, audible, vibrational, or other tactile feedback may be used for the one or more indicators. In some examples, the camera may be configured to provide audible feedback sounds to the user. For example, the camera may include a vibration source, a speaker, a buzzer, or other audio generating device and the indication may be provided by tactile or audible means. In some examples, the camera may be devoid of a view finder. Commercially available cameras typically include a view finder, which in the case of digital cameras is typically in the form of a display. The view finder allows the user to visualize the image that will be captured by the image sensor thereby giving the user an opportunity to adjust the direction in which the camera is pointing so as to capture the desired image. A view finder however significantly increases the overall size of the camera because an additional display device has to be added in the case of digital camera to provide a view finder. Such a size increase may be undesirable or impractical in some examples, such as for a wearable or other small or miniaturized form factor cameras according to the present disclosure. In some examples, the camera does not include a view finder and the user may not be able to preview the image to be captured prior to capturing it. Configuration parameters for auto-alignment and/or auto-centering of images captured by a camera of the present disclosure may be developed in accordance with further examples herein. An example system and process for automatic processing of an image is described further with reference to FIGS. 14 and 15. As shown in blocks 1405 and 1410 of FIG. 14, a process 1400 may include the steps of capturing a first image with a camera (e.g., camera 1500 in FIG. 15), and wirelessly transmitting the first image to a computing system (e.g., computing system 1 in FIG. 15). The camera 1500 may include an image sensor 1502 and, a memory 1504. The camera 1500 may be configured to receive power wirelessly in accordance with the examples herein. In this regard, the camera 1500 may include some or all of the components of cameras described herein (e.g., camera 1200, 1200′, 1200″) thus for brevity the description of these components will not be repeated. The camera 1500 may be configured to communicate wirelessly with one or more computing systems. The camera 1500 may include a wireless communication device 1506, such as a Wi-Fi enabled or Bluetooth enabled receiver/transmitter or a receiver/transmitter configured additionally for wireless power reception, as described herein. In some examples, the camera may be devoid of a view finder thus the captured first image may not have been previewed prior to capture. The computing system may be a personal computer, laptop, or a smart device such as a tablet or a mobile phone. The computing system (e.g., computing system 1) may include a memory 1530, a processor 1522, a display 1524, and a wireless communication device 1526 (e.g., Wi-Fi enabled or Bluetooth enabled receiver/transmitter and/or a receiver transmitter configured to also broadcast wireless power and/or receive data). In some examples, the computing system 1 may be the base unit or a communication device to which the base unit is attached. The memory may be configured to store processor-executable instructions, data (e.g., images 1534 received from the camera), and one or more configuration parameters 1536 associated with the camera. The first image captured by camera 1500 may be used as a set-up or reference image. The first image may be displayed on a display of the computing system (e.g., display 1524 of computing system 1), as shown in block 1415 of FIG. 14. The user may modify the first image, for example by changing the center of the image, or changing an orientation of the image. This user-directed modification to the first image may be received by the computing system as an indication of an adjustment to the location of the center of the first image or the orientation of the first image, as shown in block 1420. The computing system may generate configuration parameters 1536 corresponding to the adjustment, as shown in block 1425 and store the configuration parameters 1536 in memory (e.g., memory 1530). This may complete a configuration or set-up process. In subsequent steps, the user may capture additional images with the camera (e.g., camera 1500). The images may be transmitted to the computing system (e.g., computing system 1) for processing (e.g., batch processing). The computing system may retrieve the configuration parameter 1536 following receipt of a second image from the camera and may automatically modify the second image in accordance with the configuration parameters 1536, as shown in block 1430 in FIG. 14. For example, the computing system may automatically center or rotate the image by a corresponding amount as in the first image. This modification may be performed automatically (e.g., without further user input) and/or in batch upon receiving additional images from the camera, which may reduce subsequent processing steps that the user may need to perform to the images. In some examples, initial modification (e.g., as directed by user input) may include cropping the image, which may be reflected in the configuration parameter. Thus, in some examples, automatic modification of subsequent images may also include cropping a second image based on the configuration parameters 1536. In some examples, the camera may be operable to be communicatively coupled to two or more computing systems. For example, the camera may be configured to receive power and data from and/or transfer data to a second computing system (e.g., computing system 2). The second computing system may be a personal computer, laptop, a smart device. In some examples, the second computing system may be a base unit of a wireless power transfer system or a communication device to which such base unit is coupled. In some examples, the first computing system may be configured to transmit (e.g., wirelessly) the configuration parameters 1536 to the camera. The configuration parameters 1536 may be stored in memory onboard the camera (e.g., memory 1504) and may be transmitted to other computing devices different from the initial computing device which generated the configuration parameters. The configuration parameters 1536 may be transmitted to these other computing devices for example prior to or along with images transferred thereto, which may enable automatic processing/modification of images by additional computing device other than the computing device used in the initial set-up process. It will be appreciated that the designation of computing system as first or second is provided for clarity of illustrations and in examples, the set-up/configuration steps may be performed by the second computing system. It will be further understood that while two computing systems are illustrated in FIG. 15, embodiments according to the present disclosure may include any number of computing systems. In some examples, a process for auto-centering of an image may include the steps of capturing an image with a camera (e.g., camera 1500). The camera may be devoid of a view finder. The camera 1500 may wirelessly transmit the image to a computing system (e.g., computing system 1 or computing system 2). The computing system may include processor-executable instructions (e.g., instructions 1532) for processing the image, for example for auto-centering the image based on a number of objects in the image. For example, the computing system may include processor-executable instructions for identifying number of objects in the image. In some examples, the objects may be one or more heads, which may be human heads, or other objects such as buildings, or other natural or man-made structures. Following identification of the number of objects, the computing system may determine a middle object from the number of objects. For example, if the computing system determines that there are 5 heads in the image, the middle head, which may be the 3rd head, may be selected as the middle head, if the computing system determines that there are 7 heads, the 4th head may be determined as the middle head, and so on. In some examples, the computing system may include instructions for centering the image between two adjacent object. For example, if an even number of objects are identified, the computing system may be configured to split the difference between the middle two adjacent object and center the image there. In some examples, the computing system may refer to a look-up table which may identify the middle object(s) for any given number of objects. The computing system may then automatically center the image on the middle object or a midpoint between two adjacent middle objects. In other words, the computing system may be configured to count the number of heads in the captured image and center the captured image on the middle head or the midpoint between two adjacent middle objects. The computing system may store the modified image centered in accordance with the examples herein. The above detailed description of examples is not intended to be exhaustive or to limit the method and system for wireless power transfer to the precise form disclosed above. While specific embodiments of, and examples for, the method and systems for wireless power transfer are described above for illustrative purposes, various equivalent modifications are possible within the scope of the system, as those skilled in the art will recognize. For example, while processes or blocks are presented in a given order, alternative embodiments may perform routines having operations, or employ systems having blocks, in a different order, and some processes or blocks may be deleted, moved, added, subdivided, combined, and/or modified. While processes or blocks are at times shown as being performed in series, these processes or blocks may instead be performed in parallel, or may be performed at different times. It will be further appreciated that one or more components of base units, electronic devices, or systems in accordance with specific examples may be used in combination with any of the components of base units, electronic devices, or systems of any of the examples described herein. | <SOH> BACKGROUND <EOH>The number and types of commercially available electronic wearable devices continues to expand. Forecasters are predicting that the electronic wearable devices market will more than quadruple in the next ten years. Some hurdles to realizing this growth remain. Two major hurdles are the cosmetics/aesthetics of existing electronic wearable devices and their limited battery life. Consumers typically desire electronic wearable devices to be small, less noticeable, and require less frequent charging. Typically, consumers are unwilling to compromise functionality to obtain the desired smaller form factor and extended battery life. The desire for a small form factor yet a longer battery life are goals which are in direct conflict with one another and which conventional devices are struggling to address. Further solutions in this area may thus be desirable. | <SOH> SUMMARY <EOH>A camera according to some examples of the present disclosure may include an image capture device, a receiver configured to receive power wirelessly from a distance separated transmitting coil of a wireless power transfer system which includes a base unit, a rechargeable battery coupled to the receiver for storing wirelessly received power, and a memory configured to store images captured with the image capture device. In some examples, the another computing device may be the base unit of the wireless power transfer system. The camera may be configured to transfer data including one or more images captured with the image capture device to another computing device. In some examples, the camera may be a wearable camera. In some examples, the camera may be waterproof. In some examples, the camera may be devoid of a view finder. In some examples, the camera's receiver may include a receiving coil having a magnetic core. In some examples, the magnetic core may include a ferrite core. In some examples, the receiving coil is configured to receive power from the transmitting coil regardless of orientation between the receiving and transmitting coils. In some examples, at least the image capture device, the receiving coil, the processor, and the memory are enclosed in a housing configured to be movably coupled to a wearable article. In some examples, the housing includes a guide comprising one or more magnets for magnetically attaching the wearable camera to eyewear. In some examples, the housing may include a first opening and an optically transparent material spanning the first opening, and a second opening and an acoustically transparent material spanning the second opening. In some examples, the camera may include a microphone. In some examples, the camera may be configured to detect an audible command and capture an image responsive to the audible command. In some examples, the camera may include a transmitter configured to transmit one or more of the images stored in the memory to the wireless power transfer system. In some examples, the camera may be configured to broadcast a proximity signal for detecting the wireless power receiver in proximity. In some examples, the camera may include at least one user control for receiving user input. In some examples, the at least one user control may include a capacitive switch. In some examples, the camera may include a status indicator, a privacy indicator, or combinations thereof. In some examples, the camera may include an aperture for engaging with a securing ring. In further examples, the camera may include a guide configured to engage a temple guide in an eyewear frame, and wherein a plane of a diameter of the aperture is parallel with a longitudinal direction of the guide. In some examples, the securing ring may be made of a transparent plastic material. In some examples, the securing ring may include a core diameter greater than 0.01 mm and less than 2 mm. In some examples, the core diameter may be less than 1 mm. A system according to the present disclosure may include a base unit which includes a transmitter configured for wireless power delivery and a battery coupled to the transmitter, wherein the transmitter includes a transmitting coil having a magnetic core. The system may further include a camera, which may be a wearable camera, separated from the base unit, the camera including a receiver inductively coupled to the transmitter to receive power from the base unit while the camera remains within a charging distance from the base unit, wherein the receiver includes a receiving coil having a magnetic core, and wherein a dimension of the transmitting coil is at least twice a dimension of the receiving coil. In some examples, the dimension of the transmitting coil may be a diameter of the transmitting coil, a length or a diameter of a wire forming windings of the transmitting coil, a number of windings of the transmitting coil, or a length, a diameter or a surface area of the core of the transmitting coil, and the dimension of the receiving coil may respectively be a diameter of the receiving coil, a length or a diameter of a wire forming windings of the receiving coil, a number of windings of the receiving coil, or a length, a diameter or a surface area of the core of the receiving coil. In some examples, the transmitter and receiver may be configured for operation with a Q value less than 100. In some examples, the transmitter and receiver may be configured to operate at a frequency within the range of 50 kHz or 500 kHz, wherein the transmitter and receiver are configured to operate in weak resonance, and wherein the system is configured to operate using an amount of guided flux. In some examples, the base unit may be mechanically coupled to a portable communication device. In some examples, the transmitter may include an omnidirectional antenna configured to transmit power to one or more electronic devices including the camera regardless of orientation of the electronic devices with respect to the base unit. In some examples, the camera, which may be a wearable camera, may be configured to be magnetically attached to eyewear. A method according to some examples may include placing a base unit proximate a wearable camera, the base unit comprising a transmitting coil configured to inductively couple with a receiving coil in the wearable camera to wirelessly transmit power to the wearable camera, detecting the wearable camera with the base unit, and wirelessly transmitting power from the base unit to the wearable camera while the electronic device remains within a charging range of the base unit or until a charge state signal of the wearable camera corresponds to a fully charged state of the wearable camera. In some examples, the method may further include capturing an image responsive to an audible command detected by the wearable camera. In some examples, the method may further include wirelessly transmitting an image captured by the camera to the base unit. In some examples, the detecting the wearable camera includes automatically detecting a signal from the wearable camera, the signal broadcast by the wearable camera or transmitted to the base unit responsive to an interrogation signal from the base unit. In some examples, the wirelessly transmitting power from the base unit includes broadcasting power signals at a body-safe level. In some examples, the wirelessly transmitting power from the base unit includes broadcasting power signals at a frequency within the range of 50 kHz or 500 kHz. | H04N523241 | 20171103 | 20180327 | 20180301 | 68659.0 | H04N5232 | 1 | COLEMAN, STEPHEN P | WEARABLE CAMERA SYSTEM | UNDISCOUNTED | 1 | CONT-ACCEPTED | H04N | 2,017 |
15,803,021 | PENDING | Method, Apparatus, And Computer-Readable Medium For Stitching | Presented are a method, apparatus, and computer-readable medium for stitching. The method includes sensing, by a first sensor, a movement of a work piece relative to a sewing head. The method further includes sensing, by a second sensor, a movement of the work piece relative to the sewing head. The method includes determining, by a processor, a translational and rotational movement of the work piece relative to the sewing head based on the sensed movement of the first sensor and the second sensor. The method also includes altering, by the processor, a speed of a reciprocating needle in response to the determined translational and rotational movement. | 1. A method of stitching, the method comprising: (a) sensing, by a first sensor, a movement of a work piece relative to a sewing head; (b) sensing, by a second sensor, a movement of the work piece relative to the sewing head; (c) determining, by a processor, a translational and rotational movement of the work piece relative to the sewing head based on the sensed movement of the first sensor and the second sensor; and (d) altering, by the processor, a speed of a reciprocating needle in response to the determined translational and rotational movement. 2. The method according to claim 1, the method further comprising manipulating, by the processor, the sensed movement of the work piece relative to the sewing head by the first sensor and the second sensor to account for missensing by at least one of the first sensor and the second sensor. 3. The method according to claim 2, wherein the first sensor and the second sensor are optical sensors. 4. An apparatus for stitching, the apparatus comprising: a sewing head including a reciprocating needle; a first and a second sensor for sensing a movement of a work piece relative to the sewing head; a memory including computer program instructions; and a processor, wherein the sewing head including the reciprocating needle, the first sensor, the second sensor, the memory and the processor are configured to cause the apparatus to at least: sense, by the first sensor, a movement of a work piece relative to the sewing head; sense, by the second sensor, a movement of the work piece relative to the sewing head; determine, by the processor, a translational and rotational movement of the work piece relative to the sewing head based on the sensed movement of the first sensor and the second sensor; and alter, by the processor, a speed of a reciprocating needle in response to the determined translational and rotational movement. 5. The apparatus according to claim 4, the apparatus further configured to manipulate the sensed movement of the work piece relative to the sewing head by the first sensor and the second sensor to account for missensing by at least one of the first sensor and the second sensor. 6. The apparatus according to claim 5, wherein the first sensor and the second sensor are optical sensors. 7. A non-transitory computer-readable medium tangibly comprising computer program instructions which when executed on a processor of an apparatus causes the apparatus to at least: sense, by a first sensor, a movement of a work piece relative to a sewing head; sense, by a second sensor, a movement of the work piece relative to the sewing head; determine, by the processor, a translational and a rotational movement of the work piece relative to the sewing head based on the sensed movement of the first sensor and the second sensor; and alter, by the processor, a speed of a reciprocating needle in response to the determined translational and rotational movement. 8. The non-transitory computer-readable medium according to claim 7, wherein the computer program instructions with the processor further cause the apparatus to manipulate, by the processor, the sensed movement of the work piece relative to the sewing head by the first sensor and the second sensor, to account for missensing by at least one of the first sensor and the second sensor. 9. The non-transitory computer-readable medium according to claim 8, wherein the first sensor and the second sensor are optical sensors. | FIELD OF THE INVENTION Exemplary embodiments of the present disclosure relate to a method, apparatus and computer-readable medium for sensing movement. The present disclosure relates more specifically to sensing movement of a work piece relative to a sewing head or a sewing head relative to a work piece. BACKGROUND OF THE INVENTION Machine quilting is quilting made through the use of a sewing machine to stitch in rows or patterns using select techniques to stitch through layers of fabric and batting in the manner of old-style hand-quilting. Free motion quilting is a process used to stitch the layers of a quilt together using a domestic sewing machine. The operator controls the stitch length as well as the direction of the stitching line by moving the quilt with their hands. The stitching can be made in any direction to produce curvilinear lines or straight patterns. Each design, whether drawn on the quilt top or held in the imagination of the quilter, is formed with a line of stitching that is guided by the movement of the quilt under the machine needle. The length of each stitch is determined by the distance the quilt has been moved since the previous stitch. Machine quilting is the process of using a home sewing machine or a long arm machine to sew the layers together. With the home sewing machine, the layers are tacked together before quilting. This involves laying the top, batting, and backing out on a flat surface and either pinning (using large safety pins) or tacking the layers together. Longarm Quilting involves placing the layers to be quilted on a special frame. The frame has bars on which the layers are rolled, keeping these together without the need for tacking or pinning. These frames are used with a sewing machine mounted on a moveable platform. The platform rides along tracks so that the sewing machine can move across the layers on the frame. In contrast, a sit down quilting machine provides a stationary sewing machine attached to a flat surface for retaining a work piece. The user moves the work piece underneath the needle of the stationary sewing head of the quilting machine while operating a foot pedal that controls a reciprocating needle that creates a desired quilt or pattern. SUMMARY OF THE INVENTION In view of the foregoing, it is an object of the present disclosure to provide a method, apparatus, and computer-readable medium for stitching. A first exemplary embodiment of the present disclosure provides a method for stitching. The method includes sensing, by a first sensor, a movement of a work piece relative to a sewing head and sensing, by a second sensor, a movement of the work piece relative to the sewing head. The method further includes determining, by a processor, a translational and rotational movement of the work piece relative to the sewing head based on the sensed movement of the first sensor and the second sensor and altering, by the processor, a speed of a reciprocating needle in response to the determined translational and rotational movement. A second exemplary embodiment of the present disclosure provides an apparatus for stitching. The apparatus includes a sewing head including a reciprocating needle, a first and a second sensor for sensing a movement of a work piece relative to the sewing head, a memory including computer program instructions, and a processor. The sewing head including the reciprocating needle, the first sensor, the second sensor, the memory including computer program instructions and the processor are configured to cause the apparatus to at least sense, by the first sensor, a movement of the work piece relative to the sewing head. The apparatus is further configured to at least sense, by the second sensor, a movement of the work piece relative to the sewing head and determine, by the processor, a translational and rotational movement of the work piece relative to the sewing head based on the sensed movement of the first sensor and the second sensor. The apparatus is further configured to at least alter, by the processor, a speed of the reciprocating needle in response to the determined translational and rotational movement. A third exemplary embodiment of the present disclosure provides a non-transitory computer-readable medium tangibly comprising computer program instructions which when executed on a processor of an apparatus causes the apparatus to at least sense, by a first sensor, a movement of a work piece relative to a sewing head. The computer-readable medium comprising computer program instructions and the processor further cause the apparatus to at least sense, by a second sensor, a movement of the work piece relative to the sewing head and determine, by the processor, a translational and rotational movement of the work piece relative to the sewing head based on the sensed movement of the first sensor and the second sensor. The computer-readable medium comprising computer program instructions and the processor further cause the apparatus to at least alter, by the processor, a speed of a reciprocating needle in response to the determined translational and rotational movement. The following will describe embodiments of the present invention, but it should be appreciated that the present disclosure is not limited to the described embodiments and various modifications of the invention are possible without departing from the basic principles. The scope of the present disclosure is therefore to be determined solely by the appended claims. BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S) FIG. 1 is a perspective view of a configuration of a device suitable for use in practicing exemplary embodiments of this disclosure. FIG. 2 is a logic flow diagram in accordance with a method, apparatus, and computer-readable medium for performing exemplary embodiments of this disclosure. FIG. 3 is a simplified block diagram of a device suitable for use in practicing exemplary embodiments of this disclosure. FIG. 4 is a perspective view of an alternative configuration of a device suitable for practicing exemplary embodiments of this disclosure. FIG. 5a is a close up view of another configuration of a device suitable for practicing exemplary embodiments of this disclosure. FIG. 5b is a close up view of another configuration of a device suitable for practicing exemplary embodiments of this disclosure. DETAILED DESCRIPTION OF THE INVENTION In free motion quilting, the location as well as the movement of the needle relative to a location on a work piece is determined by a user. That is, the user moves the sewing head of the quilting machine in whichever direction they please to create the pattern in the quilt. Hence, each stitch in free motion quilting is determined by the user and not preprogrammed by a computer. One difficulty that arises during free motion quilting is the ability to maintain a uniform stitch length while the user moves the sewing head or the work piece in multiple directions and at different speeds. One solution that overcomes this difficulty is for the reciprocating speed of the needle to remain constant as the user moves the sewing head or the work piece at a continuous constant rate. This solution however, still leaves open the likely possibility that the user will move the sewing head or the fabric at different speeds and thus create different stitch lengths. Therefore, rather than rely on the user to move the sewing head or the fabric at a continuous constant rate, it is ideal to provide a way to accurately track the movement of the sewing head or the quilt and modify the reciprocating speed of the needle in response to the tracked movement. Some quilting machine manufacturers have developed quilting machines that use a sensor to observe the translational velocity of the sewing head or the quilt and in turn controls the stitching motor speed as needed. Yet, this solution still falls short of providing a complete answer because they are not able to monitor both translational and rotational movement. Exemplary embodiments of the present disclosure allow for the reciprocating speed of a needle to be adjusted or modified based on both the translational and rotational movement of a sewing head relative to a work piece or the work piece relative to the sewing head. Exemplary embodiments of the present disclosure provide for a quilting or sewing machine that has a two photo sensor mechanism. The two photo sensor mechanism can be located on the head of the quilting or sewing machine or underneath the work piece or fabric that is laid out underneath the sewing head of the quilting machine or sewing machine. The two photo sensors stream position data of the work piece or fabric to a sensor controller or processor. The sensor controller or processor manipulates the data to account for translational and rotational movement as well as to account for misreading or missensing by one of the sensors. Once the rotations and misreads are accounted for, the sensor controller or processor creates two simulated encoder outputs to represent movement in X and Y Cartesian coordinates. XA/XB are the equivalent X encoder signals and YA/YB are the equivalent Y encoder signals. These signals are provided to the controller that is operating the sewing head or needle position to maintain uniform stitch length. These two sets of channels allow either the internal or the external processor to determine an array of information. First, the channels provide a means to detect position of the work piece relative to the needle or the position of the needle relative to the work piece as opposed to the position of the needle in a reciprocating cycle. The total number of output pulses in the X and Y direction are recorded. The two channels allow the external or internal processors to add or subtract position values. The total sum of pulses in the X and Y direction from the encoder multiplied by a calibration factor gives the relative position of the sensed work piece or fabric. The calibration factor is a value equal to pulses per linear distance for the given system. Since the pulses XA/XB and YA/YB are outputs created from the reading of the sensors, the frequency of the pulses is controlled by how fast the work piece is moved over the sensors. Second, the channels provide a means to detect the velocity of the sewing head or the work piece. The sensor controller which includes a processor using the Pythagorean Theorem can manipulate data pulses of the two photo sensors containing movement in the X and Y direction. A sample of the pulses for the X and Y direction are taken over a small period of time. The square root of the sum of the squares of the total pulses in the X direction and the total pulses in the Y direction multiplied by the calibration factor gives a linear distance. The linear distance is divided by the period of time in which the sample pulses were taken. This value is the velocity of the sensed product over the period of time. It should be noted that in order to detect velocity, it is not necessary to be able to detect position. In other words, all data pulses, XA/XB and YA/YB, are additions. Only a consistent stream of pulses that varies based on motion of the product is needed. In other exemplary embodiments, these two sets of channels allow other computer systems to manipulate the data in other ways. For instance, the position data can be calculated and tracked on a Cartesian coordinate system to maintain a cursor position on a screen. In this example, the movement information of the work piece relative to the needle would be tracked. Based on the tracked movement, a cursor on a screen would move proportionally in the same direction and speed as to the sensed movement of the work piece. Referring to FIG. 1, provided is a perspective view of a quilting machine 100 suitable for use in practicing exemplary embodiments of the present disclosure. It can be appreciated that embodiments of the present disclosure are not limited to the particular configurations of quilting machine 100. The term quilting machine 100 incorporates any device for the stitching or embroidery of a work piece or fabric. The term quilting machine 100 also includes quilting machines able to stitch together multiple layers, such as a filler layer between a top and bottom textile layer, as well as an embroidery machine. The term work piece or fabric incorporates any article of manufacture or fabric made by weaving, felting, knitting, crocheting, compressing natural or synthetic fibers. In one configuration, a work piece or fabric is a quilt. In the construction of a quilt, it is common to refer to or identify a quilt block. A quilt block is a small part of a quilt top. A number of quilt blocks together make a quilt. The blocks can be the same, or different from each other. Quilt blocks can be pieced or appliqued or represent a given portion of the quilt. Quilting machine 100 includes a support frame 102, a sewing machine 104, table top 106 for supporting or retaining a work piece or fabric, a sewing head 108, a reciprocating needle 110, a first sensor 112, a second sensor 114, and a motor 116. Quilting machine 100 further includes a controller 118 operably connected to the sewing head 108 and an encoder 120. The controller 118 can include a computer processor 122 (not shown) and memory 124 (not shown) for storing computer program instructions. The computer program instructions when executed on the computer processor 122 allow for quilting machine 100 to perform the operations described below. The support frame 102 can be arranged in any variety of configurations. For example, the support frame 102 depicted in FIG. 1 can include struts or supports for engaging components described herein. The support frame 102 can be composed of any variety of materials or combinations of materials, such as metals, metal alloys, aluminum alloys, plastics, composites or wood. Sewing machine 104 includes sewing head 108 having a portion above table top 106 and a second portion below or within table top 106. A passage is provided in table top 106 such that a portion of the reciprocating needle 110 can pass through a work piece or fabric placed on top of table top 106 and selectively engaging the passage of a length of thread through the work piece or fabric. Table top 106 provides a flat surface area for a work piece or fabric to be placed while sewing machine 104 is sewing or operating on the work piece or fabric. Sewing head 108 includes reciprocating needle 110. Exemplary embodiments of reciprocating needle 110 provide that it can operably move in an up and down motion such that a portion of reciprocating needle 110 can pierce a work piece or fabric that lies on table top 106. First sensor 112 and second sensor 114 are located on table top 106 and are optimally located on opposite sides of the drop location of the reciprocating needle 110. The first sensor 112 and the second sensor 114 in exemplary embodiments can be optical sensors, motion sensors or any type of sensor capable of monitoring the movement of the work piece relative to the sewing head 108. An optical sensor operates by using a tiny camera that takes upward of 1,500 pictures every second. The images are compared with one another such that over a sequence of images it can be determined when movement occurs. An exemplary optical sensor in the marketplace is found in a commercially sold optical mouse for a computer. In other exemplary embodiments of quilting machine 100, the first sensor 112 and the second sensor 114 are located on sewing head 108 such that they can monitor the movement of the work piece relative to the sewing head 108. Thus the sensors may be located below the work piece or above the work piece. The controller 118 can include a display and input, such as a touch screen, keyboard, keypad, and/or mouse. The controller 118 can be physically connected to the main frame 102 or the sewing machine 104. Alternatively, the controller 118 can be a stand-alone device, which communicates with the sewing machine 104 and the encoder 120 through a wired or wireless connection. Although the present disclosure is set forth in terms of a quilting machine 100 that has a stationary sewing head and a work piece that is moved during stitching, it is understood that the sewing head 108 can move relative to a fixed work piece. Alternatively, both the sewing head 108 and work piece can be simultaneously moved. Encoder 120 is operably able to communicate with the controller 118 as well as computer processor 122 and memory 124. Encoder 120 receives the movement information determined by the computer processor 122 and memory 124. Encoder 120 then translates or converts the movement information into a format readable by motor 116, such that motor 116 operates reciprocating needle 110 in a manner that maintains a uniform stitch length. In one exemplary embodiment as the work piece is moved along table top 106 relative to sewing head 108, the first sensor 112 and the second sensor 114 sense the direction and speed of the movement of the work piece. This data is communicated to the encoder 120, the computer processor 122, and memory 124. The speed and direction of movement of the work piece is determined by the computer processor 122. Encoder 120 then converts the movement information determined by the computer processor 122 into a format readable by motor 116, which then directs the motor 116 to operate at a certain rate controlling the up and down speed of reciprocating needle 110. That is, motor 116 drives the cycle frequency of the reciprocating needle 110. In order to provide a uniform stitch length, as the velocity of the work piece relative to sewing machine 106 is increased so is the speed of motor 116 and the cycle frequency of reciprocating needle 110. Likewise, as the velocity and distance moved of the work piece is decreased so is the speed of motor 116 and the cycle frequency of the reciprocating needle 110. In another exemplary embodiment the work piece could be rotated about an axis that aligns either on or more closely to the first sensor or the second sensor. In this instance, the sensor that is located either close to or at the center of the axis of rotation will not sense that there is any movement by the work piece or sense less movement of the work piece than the other sensor. The other sensor will be able to sense the movement of the work piece. The encoder 120, the computer processor 122, and memory 124 will determine based on the difference between the information received from the first sensor and the second sensor the rate of rotation of the work piece and adjust the speed of the motor 116 and the reciprocating needle 110 accordingly in order to maintain a uniform stitch length. This will be performed by the computer processor 122 continuously comparing the data received from the two sensors. The data received from the two sensors will be added together to produce an improved response to the movement of the work piece. If the sum of the sensed movement of the two sensors is a positive or negative number then it is known that the work piece is moving in one linear direction. If the sensed movement is in opposite directions because of rotation of the work piece, the sum of the two sensors will cancel each other out. In yet another exemplary embodiment, if a work piece is rotating and moving translationally relative to the sewing head, one of the two sensors may misread or missense some or all of the movement of the work piece. In this instance, the encoder 120, the computer processor 122, and memory 124 will receive correct information from one of the sensors and the other sensor will either not send any information or will send information that is incorrect. The encoder 120, the computer processor 122, and memory 124 will adjust the information from the sensor that either provides no information or incorrect information in conjunction with the information from the sensor that is sensing correctly to create correct movement information of the work piece. One exemplary embodiment of this process begins with the computer processor 122 detecting that one of the sensors is either no longer sending movement information or updating with invalid movement information. The computer processor 122 will then assume that the sensor is no longer sensing the work piece and will double the information from the sensor still providing information. The processor 122 through encoder 120 will then communicate with motor 116 and adjust the reciprocating speed of the reciprocating needle 110 to produce a uniform stitch length. FIG. 2 presents a summary of the above teachings for stitching. Block 202 presents sensing, by a first sensor, a movement of a work piece relative to a sewing head; sensing, by a second sensor, a movement of the work piece relative to the sewing head; determining, by a processor, a translational and rotational movement of the work piece relative to the sewing head based on the sensed movement of the first sensor and the second sensor; and altering, by the processor, a speed of a reciprocating needle in response to the determined translational and rotational movement. Then block 204 specifies further comprising manipulating, by the processor, the sensed movement of the work piece relative to the sewing head by the first sensor and the second sensor to account for missensing by at least one of the first sensor and the second sensor. Some of the non-limiting implementations detailed above are also summarized at FIG. 2 following block 204. Block 206 relates to wherein the first sensor and the second sensor are optical sensors. The present system thus varies the cycle frequency of the reciprocating needle corresponding to the user imparted velocity, distance and rotation moved of the work piece relative to the sewing head. In other exemplary embodiments, the present system can vary the cycle frequency of the reciprocating needle corresponding to the user imparted velocity, distance and rotation moved of the sewing head relative to the work piece. The logic diagram of FIG. 2 may be considered to illustrate the operation of a method, a result of execution of computer program instructions stored in a computer-readable medium. The logic diagram of FIG. 2 may also be considered a specific manner in which components of the device are configured to cause that device to operate, whether such a device is a quilting machine or some other device, or one or more components thereof. The various blocks shown in FIG. 2 may also be considered as a plurality of coupled logic circuit elements constructed to carry out the associated function(s), or specific result of strings of computer program instructions or code stored in a memory. Various embodiments of the computer-readable medium include any data storage technology type which is suitable to the local technical environment, including but not limited to semiconductor based memory devices, magnetic memory devices and systems, optical memory devices and systems, fixed memory, removable memory, disc memory, flash memory, dynamic random-access memory (DRAM), static random-access memory (SRAM), electronically erasable programmable read-only memory (EEPROM) and the like. Various embodiments of the processor include but are not limited to general purpose computers, special purpose computers, microprocessors, digital signal processors and multi-core processors. Reference is now made to FIG. 3 for illustrating a simplified block diagram of the various elements of a device suitable for use in practicing the exemplary embodiments of this disclosure. In FIG. 3, device 302 is adapted for stitching a work piece. Device 302 may be any quilting or sewing machine or device suitable for stitching together two or more pieces of fabric. Device 302 includes processing means such as a controller 304 which includes at least one data processor 306, storing means such as at least one computer-readable memory 308 storing at least one computer program 310. Controller 304, the at least one data processor 306, and the at least one computer-readable memory 308 with the at least one computer program 310 provide a mechanism to interpret and determine the movement of a work piece. The device 302 also includes sensor 312 and sensor 314 for sensing the movement of the work piece. Sensors 312 and 314 are operably connected to controller 304 such that sensors 312 and 314 are able to transmit their sensor information to controller 304 and data processor 306. Device 302 further includes motor 316 operably connected to controller 304 and reciprocating needle 318. Reciprocating needle 318 is operably connected to controller 304. The cycle frequency of reciprocating needle 318 is controlled by motor 316, which is in turn determined by controller 304. Device 302 also includes encoder 320 to encode the sensed movement information determined by the data processor 306 such that it can be read by motor 316. Encoder 320 is operably connected to sensors 312 and 314 as well as controller 304, data processor 306, and motor 316. Device 302 includes an operational on/off switch 320 for selectively operating controller 304, motor 316, sensors 312 and 314, reciprocating needle 318, and encoder 320. In some exemplary embodiments, on/off switch 320 is a foot pedal that can be pressed to operate device 302. In other exemplary embodiments, on/off switch 320 is a physical switch located on device 302 that can be operated by hand. The at least one of computer program 310 in device 320 in exemplary embodiments is a set of program instructions that, when executed by the associated data processor 306, enable the device 302 to operate in accordance with the exemplary embodiments of this disclosure, as detailed above. In these regards, the exemplary embodiments of this disclosure may be implemented at least in part by a computer software stored in computer-readable memory 308, which is executable by the data processor 306. Devices implementing these aspects of the disclosure need not be the entire device as depicted in FIG. 3 or may be one or more components of same such as the above described tangibly stored software, hardware, and data processor. Referring to FIG. 4, provided is an alternative arrangement of a device suitable for practicing exemplary embodiments of this disclosure. FIG. 4 provides a device 402 for quilting or sewing. Device 402 includes a sewing head 404 with reciprocating needle 406. Reciprocating needle 406 is operable to move in an up and down motion. Device 402 is stationary and maintained on table 416. Within table 416 and underneath reciprocating needle 406 is space 408. Space 408 provides an opening such that when reciprocating needle 406 is in a fully extended down position, reciprocating needle 406 does not touch table 416. FIG. 4 also provides sensors 410 and 412 for sensing movement of a work piece that are placed on sewing head 404. Sensors 410 and 412 are stationary and in this embodiment are located on either side of reciprocating needle 406. It should be appreciated that sensors 410 and 412 can be located in many different arrangements with respect to reciprocating needle 406. Ideally, sensors 410 and 412 are located on opposite sides of reciprocating needle 406. Sensors 410 and 412 in exemplary embodiments are optical sensors, motion sensors or any type of sensor capable of monitoring the movement of a work piece relative to the sewing head 404. The sensed movement from sensors 410 and 412 is communicated either through a wired or wireless connection to a controller (not shown), a processor (not shown), and an encoder (not shown). The processor in conjunction with the encoder determines the movement of the work piece and operates a motor that controls that cycle frequency of reciprocating needle 406 in order to create a uniform stitch length. Exemplary embodiments of the configuration provided in FIG. 4 include different arrangements of sensors 410 and 412 relative to reciprocating needle 406. Sensors 410 and 412 are preferably located on opposite sides of reciprocating needle 406 and relatively close to reciprocating needle 406. While sewing or quilting, the area of a work piece immediately surrounding the drop location of reciprocating needle 406, which is within space 408 typically, has an increased tension when compared to other areas of the work piece. This increased tension helps prevent the possibility of the work piece folding on itself and the reciprocating needle 406 from stitching two portions of the work piece together that were not meant to be sewn together. Additionally, the increased tension helps in the creation of a uniform stitch length. Due to this increased tension in the work piece, it is preferred that sensors 410 and 412 be relatively close to the drop location of reciprocating needle 406 and within the area of tension of the work piece. Since the area of tension of the work piece is in most cases the flattest and most uniform area of the work piece, this area is also the portion of the work piece that will provide the most accurate data for sensing movement. It can also be appreciated that sensors 410 and 412 are preferably spaced a given distance from one another such that when the work piece is rotated about an axis that aligns with one of the two sensors, the other sensor is able to sense the movement of the work piece. If sensors 410 and 412 are located too closely to one another, neither sensor will be able to detect any movement even though the work piece is in fact rotating. This is true for whether the sensors are located on the sewing head 404 or on table 416. FIG. 5a provides an alternative configuration of a device suitable for practicing exemplary embodiments of this disclosure. FIG. 5a illustrates a sewing or quilting machine 502 with reciprocating needle 504, space 506, and two sensors 508 and 510. Reciprocating needle 504 is operably able to move up and down. Space 506 provides an opening in the surface of the table to which sewing or quilting machine 502 is affixed. Space 506 also provides an opening for reciprocating needle 504 to extend into when it is in the fully extended in the down position. In this embodiment, sensors 508 and 510 for sensing movement of a work piece are located on opposite sides of spacer 506 and align with the body of sewing or quilting machine 502. FIG. 5b provides another alternative configuration of a device suitable for practicing exemplary embodiments of this disclosure. FIG. 5b again illustrates sewing or quilting machine 502 with reciprocating needle 504, space 506, and two sensors 508 and 510. Reciprocating needle 504 is operably able to move up and down. Space 506 provides an opening in the surface of the table that sewing or quilting machine 502 rests. Space 506 also provides an opening for reciprocating needle 504 to extend into when it is in the down position. In this embodiment, sensors 508 and 510 for sensing movement are located on adjacent sides of space 506. It can be appreciated that sensors 508 and 510 can be located in many different arrangements and variations without departing from the basic principles described above. | <SOH> BACKGROUND OF THE INVENTION <EOH>Machine quilting is quilting made through the use of a sewing machine to stitch in rows or patterns using select techniques to stitch through layers of fabric and batting in the manner of old-style hand-quilting. Free motion quilting is a process used to stitch the layers of a quilt together using a domestic sewing machine. The operator controls the stitch length as well as the direction of the stitching line by moving the quilt with their hands. The stitching can be made in any direction to produce curvilinear lines or straight patterns. Each design, whether drawn on the quilt top or held in the imagination of the quilter, is formed with a line of stitching that is guided by the movement of the quilt under the machine needle. The length of each stitch is determined by the distance the quilt has been moved since the previous stitch. Machine quilting is the process of using a home sewing machine or a long arm machine to sew the layers together. With the home sewing machine, the layers are tacked together before quilting. This involves laying the top, batting, and backing out on a flat surface and either pinning (using large safety pins) or tacking the layers together. Longarm Quilting involves placing the layers to be quilted on a special frame. The frame has bars on which the layers are rolled, keeping these together without the need for tacking or pinning. These frames are used with a sewing machine mounted on a moveable platform. The platform rides along tracks so that the sewing machine can move across the layers on the frame. In contrast, a sit down quilting machine provides a stationary sewing machine attached to a flat surface for retaining a work piece. The user moves the work piece underneath the needle of the stationary sewing head of the quilting machine while operating a foot pedal that controls a reciprocating needle that creates a desired quilt or pattern. | <SOH> SUMMARY OF THE INVENTION <EOH>In view of the foregoing, it is an object of the present disclosure to provide a method, apparatus, and computer-readable medium for stitching. A first exemplary embodiment of the present disclosure provides a method for stitching. The method includes sensing, by a first sensor, a movement of a work piece relative to a sewing head and sensing, by a second sensor, a movement of the work piece relative to the sewing head. The method further includes determining, by a processor, a translational and rotational movement of the work piece relative to the sewing head based on the sensed movement of the first sensor and the second sensor and altering, by the processor, a speed of a reciprocating needle in response to the determined translational and rotational movement. A second exemplary embodiment of the present disclosure provides an apparatus for stitching. The apparatus includes a sewing head including a reciprocating needle, a first and a second sensor for sensing a movement of a work piece relative to the sewing head, a memory including computer program instructions, and a processor. The sewing head including the reciprocating needle, the first sensor, the second sensor, the memory including computer program instructions and the processor are configured to cause the apparatus to at least sense, by the first sensor, a movement of the work piece relative to the sewing head. The apparatus is further configured to at least sense, by the second sensor, a movement of the work piece relative to the sewing head and determine, by the processor, a translational and rotational movement of the work piece relative to the sewing head based on the sensed movement of the first sensor and the second sensor. The apparatus is further configured to at least alter, by the processor, a speed of the reciprocating needle in response to the determined translational and rotational movement. A third exemplary embodiment of the present disclosure provides a non-transitory computer-readable medium tangibly comprising computer program instructions which when executed on a processor of an apparatus causes the apparatus to at least sense, by a first sensor, a movement of a work piece relative to a sewing head. The computer-readable medium comprising computer program instructions and the processor further cause the apparatus to at least sense, by a second sensor, a movement of the work piece relative to the sewing head and determine, by the processor, a translational and rotational movement of the work piece relative to the sewing head based on the sensed movement of the first sensor and the second sensor. The computer-readable medium comprising computer program instructions and the processor further cause the apparatus to at least alter, by the processor, a speed of a reciprocating needle in response to the determined translational and rotational movement. The following will describe embodiments of the present invention, but it should be appreciated that the present disclosure is not limited to the described embodiments and various modifications of the invention are possible without departing from the basic principles. The scope of the present disclosure is therefore to be determined solely by the appended claims. | D05B1914 | 20171103 | 20180222 | 72572.0 | D05B1914 | 1 | WORRELL JR, LARRY D | Method, Apparatus, And Computer-Readable Medium For Stitching | SMALL | 1 | CONT-ACCEPTED | D05B | 2,017 |
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15,804,451 | PENDING | INVOICELESS TRADING AND SETTLEMENT METHOD AND SYSTEM | Methods and systems consistent with the present invention overcome the shortcomings of existing trading systems by providing an invoiceless trading system that creates incentives for customers to pay suppliers within a predetermined period of time, such as a settlement period. Specifically, the invoiceless trading system enables a customer to obtain a discount on orders placed with suppliers in return for an immediate payment (e.g., within 24 hours) by the customer. The supplier receives payment within the predetermined period of time, and the customer receives additional cash benefits by providing an early payment to the supplier. To communicate with and transfer funds between customers and suppliers, the invoiceless trading system may use an electronic gateway and a settlement bank. In addition to creating an incentive to embrace e-commerce, both customers and suppliers avoid the need to manually process orders and use invoices to complete transactions. | 1.-39. (canceled) 40. A computer implemented method, the method comprising: receiving, on an authorization date and by a server, an electronic authorization, the electronic authorization relating to an invoice between a customer and a supplier, the electronic authorization authorizing payment for the invoice, the invoice comprising an invoice amount and an invoice due date, the invoice due date being after the authorization date; based on the electronic authorization, a funds provider electronically transferring to a supplier account, on an early payment date, the early payment date being before the invoice due date, a discounted payment amount for settlement of the invoice, the discounted payment amount discounted from the invoice amount based at least on: one or more fiscal attributes of the customer; and a credit period, the credit period being an amount of time between the early payment date and the invoice due date; and after the credit period, electronically debiting a customer payment from an account associated with the customer, wherein the customer payment is at least the discounted payment amount. 41. The method of claim 40, further comprising storing a record of an agreement between a bank and the customer, wherein the record comprises information related to the customer. 42. The method of claim 40, further comprising storing a record of an agreement between a bank and the customer, wherein the record comprises information related to the one or more fiscal attributes of the customer. 43. The method of claim 40, further comprising storing a record of an agreement between a bank and the customer, wherein the agreement enables the bank to transfer the discounted payment amount to the supplier as payment of the invoice. 44. The method of claim 40, wherein the discounted payment amount is transferred upon confirmation of the invoice, wherein one or more of: the confirmation is provided by the customer, the confirmation confirms contents of the invoice, the confirmation is an ASN confirmation, the ASN confirmation confirms that an ASN is identical to the invoice, and the ASN confirmation confirms that an ASN matches the invoice. 45. The method of claim 40, wherein the customer payment is one of: no more than the invoice amount, no more than the face value plus any applicable fees, or not less than the early payment plus the interest amount plus any applicable fees. 46. The method of claim 40, wherein the one or more fiscal attributes of the customer include one or more of: an interest rate of the customer, a cost of funds of the customer, a credit rating of the customer, and an assessed strength of the customer's balance sheet. 47. The method of claim 40, further comprising providing services of a settlement bank, wherein the settlement bank and the funds provider are one of: associated with the same institution or associated with different institutions. 48. The method of claim 40, wherein an electronic network is used to communicate at least one message between at least two of: one or more computers associated with the customer, one or more computers associated with the supplier, and one or more computers associated with one or more of: the funds provider and a settlement bank. 49. The method of claim 40, wherein the invoice comprises a shortened settlement period and wherein the discounted payment amount is further based on the shortened settlement period. 50. The method of claim 40, further comprising logging, at an electronic gateway, the invoice and the electronic authorization. 51. A system comprising: an electronic gateway that receives and logs, on an authorization date, an electronic authorization, the electronic authorization relating to an invoice between a customer and a supplier, the electronic authorization authorizing payment for the invoice, the invoice comprising an invoice amount and an invoice due date, the invoice due date being after the authorization date; and a banking interface for, based on the electronic authorization, electronically transferring to a supplier account, on an early payment date, the early payment date being before the invoice due date, a discounted payment amount for settlement of the invoice, the discounted payment amount discounted from the invoice amount based at least on: one or more fiscal attributes of the customer; and a credit period, the credit period being an amount of time between the early payment date and the invoice due date; and a server, electronically receiving, after the credit period, a customer payment from an account associated with the customer, wherein the customer payment is at least the discounted payment amount. 52. The system of claim 51, further comprising storage to store a record of an agreement between a bank and the customer, wherein the record comprises information related to the customer. 53. The system of claim 51, further comprising storage to store a record of an agreement between a bank and the customer, wherein the record comprises information related to the one or more fiscal attributes of the customer. 54. The system of claim 51, the electronic gateway further logging a record of an agreement between the funds provider and the customer, wherein the agreement enables the funds provider to transfer the discounted payment amount to the supplier as payment of the invoice. 55. The system of claim 51, wherein the discounted payment amount is transferred upon confirmation of the invoice, wherein one or more of: the confirmation is provided by the customer, the confirmation confirms contents of the invoice, the confirmation is an ASN confirmation, the ASN confirmation confirms that an ASN is identical to the invoice, and the ASN confirmation confirms that an ASN matches the invoice. 56. The system of claim 51, wherein the customer payment is one of: no more than the invoice amount, no more than the face value plus any applicable fees, or not less than the early payment plus the interest amount plus any applicable fees. 57. The system of claim 51, wherein the one or more fiscal attributes of the customer include one or more of: an interest rate of the customer, a cost of funds of the customer, a credit rating of the customer, and an assessed strength of the customer's balance sheet. 58. The system of claim 51, wherein the system allows to be provided services of a settlement bank, wherein the settlement bank and the funds provider are one of: associated with the same institution or associated with different institutions. 59. The system of claim 51, further comprising an electronic network to communicate at least one message between at least two of: one or more computers associated with the customer, one or more computers associated with the supplier, and one or more computers associated with one or more of: the funds provider and a settlement bank. 60. The system of claim 51, wherein the invoice comprises a shortened settlement period and wherein the discounted payment amount is further based on the shortened settlement period. 61. A system comprising: an electronic gateway that receives and logs, on an authorization date, an electronic authorization, the electronic authorization relating to an invoice between a customer and a supplier, the electronic authorization authorizing payment for the invoice, the invoice comprising an invoice amount and an invoice due date, the invoice due date being after the authorization date; a banking interface that, based on the electronic authorization, electronically transfers to a supplier account, on an early payment date, the early payment date being before the invoice due date, a discounted payment amount for settlement of the invoice, the discounted payment amount discounted from the invoice amount based at least on: one or more fiscal attributes of the customer; and a credit period, the credit period being an amount of time between the early payment date and the invoice due date; and a server electronically debiting, after the credit period, a customer payment from an account associated with the customer, wherein the customer payment is at least the discounted payment amount. 62. The system of claim 61, further comprising storage that stores a record of an agreement between a bank and the customer, wherein the record comprises information related to the customer. 63. The system of claim 61, further comprising storage that stores a record of an agreement between a bank and the customer, wherein the record comprises information related to the one or more fiscal attributes of the customer. 64. The system of claim 61, further comprising storage that stores a record of an agreement between a bank and the customer, wherein the agreement enables the bank to transfer the discounted payment amount to the supplier as payment of the invoice. 65. The system of claim 61, wherein the discounted payment amount is transferred upon confirmation of the invoice, wherein one or more of: the confirmation is provided by the customer, the confirmation confirms contents of the invoice, the confirmation is an ASN confirmation, the ASN confirmation confirms that an ASN is identical to the invoice, and the ASN confirmation confirms that an ASN matches the invoice. 66. The system of claim 61, wherein the customer payment is one of: no more than the invoice amount, no more than the face value plus any applicable fees, or not less than the early payment plus the interest amount plus any applicable fees. 67. The system of claim 61, wherein the one or more fiscal attributes of the customer include one or more of: an interest rate of the customer, a cost of funds of the customer, a credit rating of the customer, and an assessed strength of the customer's balance sheet. 68. The system of claim 61, wherein the system allows to be provided services of a settlement bank, wherein the settlement bank and the funds provider are one of: associated with the same institution or associated with different institutions. 69. The system of claim 61, further comprising an electronic network to communicate at least one message between at least two of: one or more computers associated with the customer, one or more computers associated with the supplier, and one or more computers associated with one or more of: the funds provider and a settlement bank. 70. The system of claim 61, wherein the invoice comprises a shortened settlement period and wherein the discounted payment amount is further based on the shortened settlement period. 71. The system of claim 61, wherein the electronic gateway further logs the invoice and the electronic authorization. | RELATED APPLICATIONS This application is a continuation of U.S. application Ser. No. 11/653,306, filed Jan. 16, 2007, which is a divisional of U.S. application Ser. No. 09/561,990, filed May 2, 2000, now U.S. Pat. No. 7,266,525. The entire disclosures of each of these references are expressly incorporated by reference herein. BACKGROUND OF THE INVENTION A. Field of the Invention This invention relates generally to data processing systems, and more particularly, to electronic trading and settlement systems. B. Description of the Related Art Conventional trading and settlement systems generally involve large corporate customers, commercial suppliers, and large financial institutions (e.g., settlement banks). These systems trade using large amounts of paper. That is, conventional trading and settlement systems create“paper trails” that serve to lengthen a business transaction from the initial order to the final payment. For example, a customer may place an order (e.g., a purchase order) with a supplier. Once the supplier receives the order, the supplier creates a packing slip, and ships the order to the customer. With the shipment of the order, the supplier includes an invoice for the order. The invoice generally requires payment within a standard time period set by the supplier (e.g., 30 days). In practice, however, many customers may take up to 60 days to settle their outstanding accounts with suppliers. Thus, it may take over two months from the time a customer places an order and it is shipped to the time the supplier receives a payment. Aside from the reduced cash flow and/or credit risk born by the supplier before receipt of payment, the customer must process (either manually or electronically) each invoice and account with the supplier. In response to the inherent problems with conventional trading and settlement systems, more and more suppliers and/or customers are switching to the Internet, and trading and settling “online.” That is, systems such as supply side trading systems that use normal trading terms (e.g., remit payment 30 days) offered by business solution firms, such as ORACLE, COMMERCE ONE, or ARIBA. Although these electronic trading and settlement systems create an electronic marketplace that enables both customers and suppliers to trade online, the trading system does so at a high price. That is, unless all parties (e.g., customers, suppliers, settlement banks) are “wired,” the benefits of electronic trading and settling is not realized. In other words, it may be that the customer has built a large infrastructure capable of complete automated ordering, however, unless the supplier has reciprocal functionality, the customer must resort to more conventional ordering (e.g., paper purchase orders) to engage the supplier. Although the benefits are obvious, nevertheless, both customers and suppliers have been slow to adopt electronic trading and settling. Thus, there is a need to for a system that encourages both suppliers and customers to adopt electronic trading and settlement capabilities. Therefore, there exists a need to improve existing trading and settlement systems by enabling electronic invoiceless trading and settlement systems that provide incentives for both customers and suppliers to trade and settle electronically. Such a system should not only offer a tangible incentive to both customers and suppliers, but also it should place little to no risk on the settlement bank. SUMMARY OF THE INVENTION Methods and systems consistent with the present invention overcome the shortcomings of existing trading systems by providing an invoiceless trading system that creates incentives for customers to pay suppliers within a predetermined period of time, such as a settlement period. Specifically, the invoiceless trading system enables a customer to obtain a discount on orders placed with suppliers in return for an immediate payment (e.g., within 24 hours) by the customer. The supplier receives payment within the predetermined period of time, and the customer receives additional cash benefits by providing an early payment to the supplier. To communicate with and transfer funds between customers and suppliers, the invoiceless trading system may use an electronic gateway and a settlement bank. In addition to creating an incentive to embrace e-commerce, both customers and suppliers avoid the need to manually process orders and use invoices to complete transactions. BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate an implementation of the invention and, together with the description, serve to explain the advantages and principles of the invention. In the drawings, FIG. 1A depicts an invoiceless trading system suitable for practicing methods and systems consistent with the present invention; FIG. 1B depicts another embodiment of an invoiceless trading system suitable for practicing methods and systems consistent with the present invention. FIG. 2A depicts a more detailed diagram of the customer computer depicted in FIG. 1; FIG. 2B depicts a more detailed diagram of the supplier computer depicted in FIG. 1; FIG. 3 depicts a more detailed diagram of the settlement bank server depicted in FIG. 1; and FIG. 4 depicts a flow chart of the steps performed by the invoiceless trading system consistent with the principles of the present invention. DETAILED DESCRIPTION The following detailed description of the invention refers to the accompanying drawings. Although the description includes exemplary implementations, other implementations are possible, and changes may be made to the implementations described without departing from the spirit and scope of the invention. The following detailed description does not limit the invention. Instead, the scope of the invention is defined by the appended claims. Wherever possible, the same reference numbers will be used throughout the drawings and the following description to refer to the same or like parts. Overview Methods and systems consistent with the present invention provide an invoiceless trading system that provides incentives for customers to pay suppliers within a predetermined period of time, such as a settlement period. The customer and supplier prenegotiate an incentive amount to apply to each order. The invoiceless trading system draws an amount equivalent to the full face value of an order placed by the customer and filled by the supplier from a bank account associated with the customer. Periodically, the trading system rebates to the customer the prenegotiated amount. Such methods and systems provide discounts as an incentive to the customer so that the customer pays the supplier within a predetermined settlement period (e.g., one day). The invoiceless trading and settlement system comprises a number of components, such as a customer bank, a settlement bank, a supplier bank, and an electronic gateway connecting a customer and a supplier. A customer (e.g., corporation or governmental entity) places an order using an electronic gateway to purchase products from a supplier. Products are broadly defined as commodities, services, physical objects or goods, or any other item a supplier might sell to a customer. An order may be an electronic message delivered in any well-known financial communications format, such as HTTP, FTP, EDI, SMTP. A supplier offers products to a plurality of customers. To entice the customer to promptly pay within a settlement date, the supplier offers an incentive to the customer, such as discounts, bonuses, prizes, and the like. To ensure accuracy of an order, the supplier immediately transmits an electronic message to the customer using the electronic gateway. A supplier may fill customer orders by any traditional means. For example, the supplier may “scan-pack” (described below). In addition to scan-packing, the supplier may transmit an electronic confirmation message (e.g., Advanced Shipping Notice, ASN) to the customer using the electronic gateway. The ASN is further described below. A settlement bank, such as a corporate bank or any similar financial institution, pays the supplier at a time agreed in advance between the customer and the supplier. Once a customer transmits an authorization to the settlement bank to pay the supplier through the electronic gateway, the settlement bank lodges cleared funds for a specified amount (e.g., a discounted amount) in a supplier's bank. Cleared funds may be obtained from a customer's bank as a loan to the customer, withdrawal from a customer's deposit account, or the like. An electronic gateway may be an independent entity or specific to the type of products being bought and sold. For example, in the case of a private network, an electronic gateway may include an administrator that exchanges, logs and translates messages between subscribing customers and subscribing suppliers. In the case of an open network, the electronic gateway may be the Internet. To provide security in an open network, a firewall or VPN may be used when connecting the customer, supplier, their respective banks, and the settlement bank. In addition, the electronic gateway may include translation, logging, and forwarding services to ensure the accuracy of all orders, payments, and notices. An example of an electronic gateway suitable for practicing methods and systems consistent with the present invention is the AT&T INTERCOMMERCE gateway, available from AT&T. Invoiceless trading systems provide a number of benefits over traditional trading and settlement systems. First, invoiceless trading systems provide both customers and suppliers a tangible incentive to embrace e-commerce. Customers can generate additional profits by receiving a cash benefit for improving the cashflow to the supplier by authorizing the settlement bank to transfer an early payment to a supplier's bank accounts. The supplier may receive payment of an outstanding customer account within a short period, such as one business day of the settlement bank receiving instructions from the customer to settle the account. Second, invoiceless trading systems significantly reduce the cost associated with supply chain trading for both customer and suppliers. By using an electronic gateway, not only does a supplier not have to produce invoices, followup on outstanding accounts, or process payments, but also the supplier can almost instantly receive funds since the settlement bank directly deposits the funds into the supplier's bank. Moreover, remittance advice can automatically be lodged into the supplier's accounting software. Customers may have access to electronic catalogs located on a supplier's system, and the customer may also receive automated and immediate confirmation of shipment. Finally, the invoiceless trading system creates additional profits for both suppliers and customers. That is, the customer's balance sheet is used to generate additional profits for the customer through supplier discounts. It is the strength of the customer's balance sheet that enables suppliers to receive immediate payment and therefore have the incentive to use the invoiceless trading system. The customer's balance sheet is not adversely affected by paying its suppliers early as borrowed funds are used to discharge trade creditors, thus canceling out the additional liability of the borrowing. Thus, the balance sheet improves marginally as the net borrowing is less than the face value of the trade creditors discharged. Moreover, the invoiceless trading system creates additional profits for the customer by providing a rebate from the settlement bank. Since the customer is generally a larger and stronger party than the supplier, the customer has a lower cost of funds. Thus, the difference between the cost and availability of funds to the customer and supplier largely determine the size of the supplier incentive (discount), and therefore the size of the rebate from the settlement bank. As part of their incentive from the supplier, the customer receives a rebate from the settlement bank based on the strength of the customer's balance sheet and credit rating. System Components FIG. 1A depicts an exemplary invoiceless trading system 100 suitable for practicing methods and systems consistent with the present invention. Invoiceless trading system 100 comprises a customer computer 102, a supplier computer 104, and a settlement bank server 106, all connected via an electronic gateway 120, such as the Internet. Also included in invoiceless trading system 100 are a customer bank computer 108 and a supplier bank computer 110. Bank computers 108, 110 may be directly connected to bank server 106, directly connected to customer 102 and supplier 104, or connected to both through electronic gateway 120. A customer may use customer computer 102 to place an order with a supplier for products. A supplier may use supplier computer 104 to receive and process orders and electronically transmit shipping notices to a customer computer 102. Although only one customer computer 102, and supplier computer 104 are depicted in system 100, one skilled in the art will appreciate that many more customers' and/or suppliers' computers may be connected into system 100. FIG. 1B depicts another exemplary invoiceless trading system 150 for practicing methods and systems consistent with the present invention. Invoiceless trading system 150 comprises customer computer 102, supplier computer 104, a settlement bank 112, and a funds provider 114. In system 150, customer 102 may obtain an early payment discount for an order from supplier 104 by paying the supplier by a funds provider 114 via a settlement bank 112. In one embodiment, customer 102 may establish a settlement bank agreement with settlement bank 112 for settling orders placed by customer 102 by paying suppliers using funds provided by the funds provider 114. Customer 102 may also establish a funding agreement with funds provider 114, including, for example, a service fee and a rate of interest to be paid by customer 102 to funds provider 114. When customer 102 transmits an order message to supplier 104 with an order for an item, the customer 102 may then receive a shipping notification from supplier 104 indicating that the order has been filled. After the shipping notification is received by customer 102 from supplier 104, customer 102 may transmit a payment message to settlement bank 112 to make a discounted payment to supplier 104 for the order on a first date using funds from funds provider 114. In one example, the discounted payment may be equal to a cost for the order less an early payment discount agreed upon between customer 102 and supplier 104 based on supplier 104 receiving payments for the order with a predetermined period of time. After the first date, customer 102 may pay a negotiated payment, e.g., equal to the discounted payment plus the service fee and an interest amount, to funds provider 114. For example, the interest rate may be calculated based on a time period between the first date and the date on which the customer pays funds provider 114. FIG. 2A depicts a more detailed diagram of customer computer 102, which contains a memory 210, a secondary storage device 220, a central processing unit (CPU) 230, an input device 240, and a video display 250. Memory 210 includes browser 212 that allows customers to interact with computer 104 and banks 106, 108 by transmitting and receiving files, such as Web pages. A Web page may include images or textual information to provide an interface to receive requests for products from a user using hypertext markup language (HTML), Java or other techniques. Examples of browsers suitable for use with methods and systems consistent with the present invention are the Netscape Navigator browser, from Netscape Communications Corp., and the Internet Explorer browser, from Microsoft Corp. As shown in FIG. 2B, supplier computer 104 includes a memory 260, a secondary storage device 270, a CPU 280, an input device 290, and a video display 292. Memory 260 includes accounting software 262 that processes received orders and creates ASNs for the customer. An ASN is a message sent to a customer upon shipment of goods. In addition, accounting software 262 contains a user interface (not shown) to communicate with computer 102 and bank servers 106, 110. The user interface may be a Web page, Application Program Interface (API), e-mail program, or other input interface. An API is a set of routines, protocols, or tools for communicating with software applications. APIs provide efficient access to accounting software 262 without the need for additional software to interface with the software. Web software, such as the APACHE Web software, or e-mail program, such as the Sendmail e-mail software, may also be included as a user interface to transmit and receive information. Secondary storage device 270 contains a database 272 that contains information relating to accounts receivables and accounts payables. As shown in FIG. 3, settlement bank server 106 includes a memory 310, a secondary storage device 320, a CPU 330, an input device 340, and a video display 350. Memory 310 includes settlement software 312 and a banking interface 314. Settlement software 312 dispatches funds to an account associated with the supplier in supplier bank 110 and debits funds from an account associated with the customer in customer bank 108. Settlement software 312 may communicate with computers 102, 104 and banks 108, 110 using banking interface 314. A banking interface is a payment gateway for a bank. Invoiceless Trading Process FIG. 4 depicts a flow chart of the steps performed by invoiceless trading system 100 when providing invoiceless trading among customers and suppliers. The first step is for a customer using customer computer 102 to transmit an order to a supplier computer 104 through electronic gateway 120 (step 402). As explained earlier, electronic gateway 120 may translate the customer's order to a format understandable by supplier computer 104 and forward the order to accounting software 262 in supplier computer 104. For example, a supplier may use a Web interface and/or email to provide access to accounting software 262, however the customer may not have email or Web capability and, instead, may have only facsimile capability. The customer may fax a purchase order to a facsimile server (not shown) in electronic gateway 120. Gateway 120 then converts the facsimile to an e-mail and forwards the e-mail to supplier computer 104. Electronic gateway 120 may also maintain a log of all orders placed by the customer in a centralized database for accounting and/or auditing purposes. If a customer's order contains multiple products from multiple suppliers, (e.g., product A from one supplier, and product B from another supplier), then electronic gateway 120 may create and forward order messages containing appropriate products for each supplier 104. Next, supplier computer 104 processes the order and transmits a response to customer computer 102 including the status of the order (step 404). The supplier may first send a confirmation message to customer computer 102 indicating that the order can be filled (e.g., the supplier has the product in stock). The supplier may process the order using a “scan-packing” technique. Scan-packing means first determining if the ordered products are available, and if so, scanning the barcodes of the ordered products, creating a packing slip, a delivery label and an ASN immediately prior to shipment of the products. The ASN message is sent to the customer as confirmation that the goods have been shipped, and confirmation of the contents of the shipment. The scan-packing technique ensures customer order integrity and accountability since the technique creates the bar code packing slip, delivery label as well as the ASN message. At the time of actual shipment (e.g., UPS, Federal Express), the supplier may forward the ASN message to customer computer 102 through electronic gateway 120. Similarly to the customer order in step 402, electronic gateway 120 may transform the electronic message in a format selected by supplier 104 (e.g., e-mail, HTTP request). Electronic gateway 120 translates the ASN to a format understandable by the customer, logs the ASN, and delivers the ASN to customer computer 102. Once customer computer 102 receives the ASN message, the customer may confirm that the contents of the ASN are identical to the order. And if so, the customer may use customer computer 102 to transmit a payment instruction to settlement software 312 located at settlement bank server 106 (step 406). The customer may use electronic gateway 120, or any other communication means, such as facsimile, to instruct bank server 106 to pay the supplier. The payment instruction may include supplier details (e.g., name, address, bank account number), amount of purchase, discounted amount, and the like. If the customer transmits the payment instruction using electronic gateway 120, electronic gateway 120 may translate the payment instruction into a format understandable by settlement bank server 106, and deliver the instruction to banking interface 314 in bank server 106. For example, if the customer transmits a payment instruction as an e-mail, and settlement bank server 106 requires an Electronic Data Interchange (EDI) format, electronic gateway 120 may translate the payment instruction to an EDI format before forwarding the message to banking interface 314. The customer may transmit the payment instruction regardless of whether or not the actual products have been received. Alternatively, the customer may transmit a payment instruction once the products have been received and/or scan-packed by the customer, or after some other prearranged event, such as issuance of a delivery tracking number by a shipping company. Regardless of the method used to transmit the payment instruction to settlement bank server 106, once received, settlement software 312 processes the payment instruction (step 408). That is, settlement software 312 first determines the amount to discount the payment and transfers cleared funds (e.g., customer loan, direct deposit) to the supplier's deposit account located at supplier bank 110. Settlement software 312 may determine the amount to discount from the payment instruction received from the customer. To deposit the funds with supplier bank 110, settlement software 312 may use banking interface 314 to wire transfer, prepare a check, or use any other well-known banking network, such as the EDI banking network. In addition, settlement software 312 may issue a remittance advice (e.g., electronic message, facsimile, e-mail) to the supplier by transmitting a notification though electronic gateway 120 to accounting software 262 (though a user interface). If the supplier can not accept an automated remittance, settlement bank 106 may forward the remittance notice in another format, such as facsimile, or mail. As mentioned before, the discounted payment is prearranged and may be different for each customer and supplier based on a negotiated contract. For example, a supplier may offer a large customer a higher discount, or a supplier may offer a customer that pays within a shorter period of time (e.g., 24 hours of receiving the ASN) a higher discount. Settlement bank server 106 may obtain cleared funds from the customer by providing a loan, or direct withdrawal from the customer's bank account at customer bank 108. One skilled in the art will appreciate that other accounting-exercises between a customer and a supplier may exist, such as the customer and the supplier negotiating a price based on an immediate payment from the customer to the supplier, such that the payment includes a discount. In this case, settlement bank 106 may pay the supplier a full amount without any deduction. After a credit period measured from the time at which settlement software 312 transfers the discounted funds to supplier bank 110 (e.g., one month), settlement software 312 debits the customer's account at customer bank 108 an amount equivalent to the face value of the payment before any discount (step 410). One skilled in the art will appreciate that other accounting exercises between settlement bank 106 and the customer may exist, such as debiting the amount equivalent to the discounted amount plus any additional bank fees (e.g., wire transfer, handling fees). For example, if settlement software 312 directly debits the customer's bank account the full amount, a bank or an intermediary software developer may be entitled to a “facility fee” (described below), and/or a bank fee to process any supplier payment. In addition, if settlement bank 106 provides a loan to the customer, settlement bank 106 may also be entitled to an interest fee for the time the bank's funds are outstanding. Finally, settlement bank 106 periodically (e.g., month, quarterly) rebates to the customer the amount of the discount deducted from the supplier account, less the settlement bank interest on funds for the time outstanding, plus any applicable fees (step 412). Facility Fee Electronic gateway 120 may contain added functionality. That is, a software supplier of business to business e-commerce solutions may add various software to electronic gateway 120, such as additional security, additional auditing and/or database functionality, or any other software to enhance financial settlements. The software supplier may request an electronic gateway 120 owner to include a facility fee for each order that uses the suppliers software in electronic gateway 120. The software supplier may license the software to the owners of electronic gateway 120, and in return for the use of the software, electronic gateway 120 may pay a license fee based on a revenue share agreement, or a set percentage based on dollars transacted. This licensing agreement would therefore enable the software suppliers to charge a facility fee for their software. CONCLUSION As explained, systems consistent with the present invention overcome the shortcomings of existing trading systems by providing incentives for customers to pay suppliers within a shortened settlement period. The customer pays a reduced price and the supplier receives payment more quickly reducing the cost of financing its sales. Although aspects of the present invention are described as being stored in memory, one skilled in the art will appreciate that these aspects may be stored on or read from other computer readable media, such as secondary storage devices, like hard disks, floppy disks, and CD-ROM; a carrier wave received from a network, such as the Internet; or other forms of ROM or RAM. Additionally, although specific components and programs of computers 102, 104 and various bank servers have been described, one skilled in the art will appreciate that these may contain additional or different components or programs. The foregoing description of an implementation of the invention has been presented for purposes of illustration and description. It is not exhaustive and does not limit the invention to the precise form disclosed. Modifications and variations are possible in light of the above teachings or may be acquired from practicing of the invention. For example, other discounts, and/or incentives for the customer may apply. Moreover the described implementation includes software but the present invention may be implemented as a combination of hardware and software or in hardware alone. The invention may be implemented with both object-oriented and non-object-oriented programming systems. | <SOH> BACKGROUND OF THE INVENTION <EOH> | <SOH> SUMMARY OF THE INVENTION <EOH>Methods and systems consistent with the present invention overcome the shortcomings of existing trading systems by providing an invoiceless trading system that creates incentives for customers to pay suppliers within a predetermined period of time, such as a settlement period. Specifically, the invoiceless trading system enables a customer to obtain a discount on orders placed with suppliers in return for an immediate payment (e.g., within 24 hours) by the customer. The supplier receives payment within the predetermined period of time, and the customer receives additional cash benefits by providing an early payment to the supplier. To communicate with and transfer funds between customers and suppliers, the invoiceless trading system may use an electronic gateway and a settlement bank. In addition to creating an incentive to embrace e-commerce, both customers and suppliers avoid the need to manually process orders and use invoices to complete transactions. | G06Q2028 | 20171106 | 20180301 | 84047.0 | G06Q2028 | 1 | HOLLY, JOHN H | INVOICELESS TRADING AND SETTLEMENT METHOD AND SYSTEM | UNDISCOUNTED | 1 | CONT-ACCEPTED | G06Q | 2,017 |
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15,804,735 | PENDING | Dose Counter for Inhaler Having An Anti-Reverse Rotation Actuator | An inhaler includes a main body having a canister housing, a medicament canister retained in a central outlet port of the canister housing, and a dose counter having an actuation member for operation by movement of the medicament canister. The canister housing has an inner wall, and a first inner wall canister support formation extending inwardly from a main surface of the inner wall. The canister housing has a longitudinal axis X which passes through the center of the central outlet port. The first inner wall canister support formation, the actuation member, and the central outlet port lie in a common plane coincident with the longitudinal axis X such that the first inner wall canister support formation protects against unwanted actuation of the dose counter by reducing rocking of the medicament canister relative to the main body of the inhaler. | 1-22. (canceled) 23. An inhaler for inhaling medicament, the inhaler having: a body for retaining a medicament canister; and a dose counter, the dose counter having a moveable actuator and a chassis mounted on the body; wherein one of the body and the chassis includes a plurality of apertures for receiving one or more pins on the other of the body and the chassis, wherein either the pins or the apertures on the chassis are positioned on different sides of the chassis for stabilizing the chassis on the body, and wherein the chassis comprises at least one of a pin or aperture heat staked to a respective aperture or pin of the body to mount the chassis to the body. 24. The inhaler as claimed in claim 23, wherein the dose counter is positioned in a dose counter chamber that is formed in the body at a location beneath the medicament canister. 25. The inhaler as claimed in claim 24 further comprising a cover that is fixed to the body to conceal the dose counter chamber. 26. The inhaler as claimed in claim 23, wherein the medicament canister is movable relative to the dose counter. 27. The inhaler as claimed in claim 23, wherein the body has a canister housing and the medicament canister is moveable relative to the canister housing, wherein at least a portion of the movable actuator of the dose counter is located in the canister housing for operation by movement of the medicament canister. 28. The inhaler as claimed in claim 23, wherein either the pins or the apertures on the chassis are positioned on three different sides of the chassis for stabilizing the chassis on the body. | CROSS-REFERENCE TO RELATED APPLICATIONS This patent application is a continuation patent application of U.S. Non-Provisional patent application Ser. No. 14/103,324, filed Dec. 11, 2013, which is a divisional patent application of U.S. Non-Provisional patent application Ser. No. 13/110,532, filed May 18, 2011, now U.S. Pat. No. 8,978,966, issued Mar. 17, 2015, which claims priority to U.S. Provisional Patent Application No. 61/345,763, filed May 18, 2010, and U.S. Provisional Patent Application No. 61/417,659, filed Nov. 29, 2010, each of which is incorporated herein by reference in its entirety for any and all purposes. FIELD OF THE INVENTION The present invention relates to dose counters for inhalers, inhalers and methods of assembly thereof. The invention is particularly applicable to metered dose inhalers including dry power medicament inhalers, breath actuated inhalers and manually operated metered dose medicament inhalers. BACKGROUND OF THE INVENTION Metered dose inhalers can comprise a medicament-containing pressurised canister containing a mixture of active drug and propellant. Such canisters are usually formed from a deep-dawn aluminium cup having a crimped lid which carries a metering valve assembly. The metering valve assembly is provided with a protruding valve stem which, in use is inserted as a push fit into a stem block in an actuator body of an inhaler having a drug delivery outlet. In order to actuate a manually operable inhaler, the user applies by hand a compressive force to a closed end of the canister and the internal components of the metering valve assembly are spring loaded so that a compressive force of approximately 15 to 30N is required to activate the device in some typical circumstances. In response to this compressive force the canister moves axially with respect to the valve stem and the axial movement is sufficient to actuate the metering valve and cause a metered quantity of the drug and the propellant to be expelled through the valve stem. This is then released into a mouthpiece of the inhaler via a nozzle in the stem block, such that a user inhaling through the outlet of the inhaler will receive a dose of the drug. A drawback of self-administration from an inhaler is that it is difficult to determine how much active drug and/or propellant are left in the inhaler, if any, especially of the active drug and this is potentially hazardous for the user since dosing becomes unreliable and backup devices not always available. Inhalers incorporating dose counters have therefore become known. WO 98/028033 discloses an inhaler having a ratchet mechanism for driving a tape drive dose counter. A shaft onto which tape is wound has a friction clutch or spring for restraining the shaft against reverse rotation. EP-A-1486227 discloses an inhaler for dry powered medicament having a ratchet mechanism for a tape dose counter which is operated when a mouthpiece of the inhaler is closed. Due to the way in which the mouthpiece is opened and closed, and actuation pawl of the device which is mounted on a yoke, travels a known long stroke of consistent length as the mouthpiece is opened and closed. WO 2008/119552 discloses a metered-dose inhaler which is suitable for breath-operated applications and operates with a known and constant canister stroke length of 3.04 mm+/−0.255 mm. A stock bobbin of the counter, from which a tape is unwound, rotates on a shaft having a split pin intended to hold the stock bobbin taut. However, some dose counters do not keep a particularly reliable count, such as if they are dropped onto a hard surface. More recently, it has become desirable to improve dose counters further and, in particular, it is felt that it would be useful to provide extremely accurate dose counters for manually-operated canister-type metered dose inhalers. Unfortunately, in these inhalers, it has been found in the course of making the present invention that the stroke length of the canister is to a very large extent controlled on each dose operation by the user, and by hand. Therefore, the stroke length is highly variable and it is found to be extremely difficult to provide a highly reliable dose counter for these applications. The dose counter must not count a dose when the canister has not fired since this might wrongly indicate to the user that a dose has been applied and if done repeatedly the user would throw away the canister or whole device before it is really time to change the device due to the active drug and propellant reaching a set minimum. Additionally, the canister must not fire without the dose counter counting because the user may then apply another dose thinking that the canister has not fired, and if this is done repeatedly the active drug and/or propellant may run out while the user thinks the device is still suitable for use according to the counter. It has also been found to be fairly difficult to assembly some known inhaler devices and the dose counters therefor. Additionally, it is felt desirable to improve upon inhalers by making them easily usable after they have been washed with water. The present invention aims to alleviate at least to a certain extent one or more of the problems of the prior art. SUMMARY OF THE INVENTION According to a first aspect of the present invention there is provided a dose counter for an inhaler, the dose counter having a counter display arranged to indicate dosage information, a drive system arranged to move the counter display incrementally in a first direction from a first station to a second station in response to actuation input, wherein a regulator is provided which is arranged to act upon the counter display at the first station to regulate motion of the counter display at the first station to incremental movements. The regulator is advantageous in that it helps prevent unwanted motion of the counter display if the counter is dropped. According to a further aspect of the present invention, the regulator provides a resistance force of greater than 0.1 N against movement of the counter display. According to still a further aspect of the present invention, the resistance force is greater than 0.3 N. According to yet a further aspect of the present invention, the resistance force is from 0.3 to 0.4 N. Preferably, the counter comprises a tape. Preferably, the tape has dose counter indicia displayed thereon. The first station may comprise a region of the dose counter where tape is held which is located before a display location, such as a display window, for the counter indicia. The first station may comprise a first shaft, the tape being arranged on the first shaft and to unwind therefrom upon movement of the counter display. The first shaft may be mounted for rotation relative to a substantially rotationally fixed element of the dose counter. The regulator may comprise at least one projection which is arranged on one of the first shaft and the substantially rotationally fixed element and to engage incrementally with one or more formations on the other of the first shaft and the substantially rotationally fixed element. At least two said projections may be provided. Exactly two said projections maybe provided. Each projection may comprise a radiused surface. The at least one projection may be located on the substantially fixed element which may comprise a fixed shaft which is fixed to a main body of the dose counter, the first shaft being rotationally mounted to the fixed shaft. Preferably, the fixed shaft has at least two resiliently flexible legs (or forks). Each leg may have at least one said projection formed in an outwardly facing direction thereon, said one or more formations being formed on an inwardly facing engagement surface of the first shaft, said at least one projection being arranged to resiliently engage said one or more formations. Preferably, a series of said formations are provided. An even number of said formations may be provided. Eight to twelve of said formations may be provided. In one embodiment, ten said formations are provided. Each said formation may comprise a concavity formed on an engagement surface. Each concavity may comprise a radiused surface wall portion which preferably merges on at least one side thereof into a flat wall portion surface. The engagement surface may include a series of said concavities, and convex wall portions of the engagement surface may be formed between each adjacent two said concavities, each said convex wall portion comprising a convex radiused wall portion. Each convex radiused wall portion of each convex wall portion may be connected by said flat wall portion surfaces to each adjacent concavity. The fixed shaft may comprise a split pin with fork legs and each projection may be located on a said fork leg. The first shaft may comprise a substantially hollow bobbin. Said at least one formation may be located on an inner surface of the bobbin. In other embodiments it may be located on an outer surface thereof. Said engagement surface may extend partially along said bobbin, a remainder of the respective inner or outer surface having a generally smooth journal portion along at least a portion thereof. The drive system may comprise a tooth ratchet wheel arranged to act upon a second shaft which is located at the second station, the second shaft being rotatable to wind the tape onto the second shaft. The second shaft may be located on a main body of the dose counter spaced from and parallel to the first shaft. The ratchet wheel may be fixed to the second shaft is arranged to rotate therewith. The ratchet wheel may be secured to an end of the second shaft and aligned coaxially with the second shaft. The dose counter may include anti-back drive system which is arranged to restrict motion of the second shaft. The anti-back drive system may include a substantially fixed tooth arranged to act upon teeth of the ratchet wheel. According to a further aspect of the present invention, a dose counter includes an anti-back drive system which is arranged to restrict motion of the second shaft in a tape winding direction. According to a further aspect of the present invention there is provided a shaft for holding counter tape in a dose counter for an inhaler, the shaft having an engagement surface including incrementally spaced formations located around a periphery thereof, the formations comprising a series of curved concavities and convex portions. The shaft may comprise a hollow bobbin. The engagement surface may be a generally cylindrical inwardly directed surface. The engagement surface may include a flat surface wall portion joining each concavity and convex wall portion. Each concavity may comprise a radiused wall portion. Each convex wall portion may comprise a radiused wall portion. Said concavities may be regularly spaced around a longitudinal axis of the shaft. Said convex wall portions may be regularly spaced around a longitudinal axis of the shaft. In some embodiments there may be from eight to twelve said concavities and/or convex wall portions regularly spaced around a longitudinal axis thereof. One embodiment includes ten said concavities and/or convex wall portions regularly spaced around a longitudinal axis of the shaft. According to a further aspect of the present invention there is provided a shaft and counter tape assembly for use in a dose counter for an inhaler, the assembly comprising a rotatable shaft and a counter tape which is wound around the shaft and is adapted to unwind therefrom upon inhaler actuation, the shaft having an engagement surface which includes incrementally spaced formations located around a periphery thereof. According to a further aspect of the present invention there is provided an inhaler for the inhalation of medication and the like, the inhaler including a dose counter as in the first aspect of the present invention. A preferred construction consists of a manually operated metered dose inhaler including a dose counter chamber including a dose display tape driven by a ratchet wheel which is driven in turn by an actuator pawl actuated by movement of a canister, the tape unwinding from a stock bobbin during use of the inhaler, a rotation regulator being provided for the stock bobbin and comprising a wavelike engagement surface with concavities which engage against control elements in the form of protrusions on resilient forks of a split pin thereby permitting incremental unwinding of the stock bobbin yet resisting excessive rotation if the inhaler is dropped onto a hard surface. According to another aspect of the present invention there is provided a dose counter for a metered dose inhaler having a body arranged to retain a medicament canister of predetermined configuration for movement of the canister relative thereto; the dose counter comprising: an incremental counting system for counting doses, the incremental counting system having a main body, an actuator arranged to be driven in response to canister motion and to drive an incremental output member in response to canister motion, the actuator and incremental output member being configured to have predetermined canister fire and count configurations in a canister fire sequence, the canister fire configuration being determined by a position of the actuator relative to a datum at which the canister fires medicament and the count configuration being determined by a position of the actuator relative to the datum at which the incremental count system makes an incremental count, wherein the actuator is arranged to reach a position thereof in the count configuration at or after a position thereof in the canister fire configuration. This arrangement has been found to be highly advantageous since it provides an extremely accurate dose counter which is suitable for use with manually operated metered dose inhalers. It has been found that dose counters with these features have a failure rate of less than 50 failed counts per million full canister activation depressions. It has been found in the course of making the present invention that highly reliable counting can be achieved with the dose counter counting at or soon after the point at which the canister fires. It has been is covered by the present inventors that momentum and motion involved in firing the canister, and in some embodiments a slight reduction in canister back pressure on the user at the time of canister firing, can very reliably result in additional further motion past the count point. The actuator and incremental counting system may be arranged such that the actuator is displaced less than 1 mm, typically 0.25 to 0.75 mm, more preferably about 0.4 to 0.6 mm, relative to the body between its location in the count and fire configurations, about 0.48 mm being preferred. The canister, which can move substantially in line with the actuator, can reliably move this additional distance so as to achieve very reliable counting. The incremental count system may comprise a ratchet mechanism and the incremental output member may comprise a ratchet wheel having a plurality of circumferentially spaced teeth arranged to engage the actuator. The actuator may comprise an actuator pawl arranged to engage on teeth of the ratchet wheel. The actuator pawl may be arranged to be connected to or integral with an actuator pin arranged to engage and be depressed by a medicament canister bottom flange. The actuator pawl may be generally U-shaped having two parallel arms arranged to pull on a central pawl member arranged substantially perpendicular thereto. This provides a very reliable actuator pawl which can reliably pull on the teeth of the ratchet wheel. The incremental count system may include a tape counter having tape with incremental dose indicia located thereon, the tape being positioned on a tape stock bobbin and being arranged to unwind therefrom. The actuator and incremental output member may be arranged to provide a start configuration at which the actuator is spaced from the ratchet output member, a reset configuration at which the actuator is brought into engagement with the incremental output member during a canister fire sequence, and an end configuration at which the actuator disengages from the ratchet output during a canister fire sequence. The actuator may be arranged to be located about 1.5 to 2.0 mm, from its location in the fire configuration, when in the start configuration, about 1.80 mm being preferred. The actuator may be arranged to be located about 1.0 to 1.2 mm, from its location in the fire configuration, when in the reset configuration, about 1.11 mm being preferred. The actuator may be arranged to be located about 1.1 to 1.3 mm, from its location in the fire configuration, when in the end configuration, about 1.18 mm being preferred. These arrangements provide extremely reliable dose counting, especially with manually operated canister type metered dose inhalers. The main body may include a formation for forcing the actuator to disengage from the incremental output member when the actuator is moved past the end configuration. The formation may comprise a bumped up portion of an otherwise generally straight surface against which the actuator engages and along which it is arranged to slide during a canister firing sequence. The dose counter may include a counter pawl, the counter pawl having a tooth arranged to engage the incremental output member, the tooth and incremental output member being arranged to permit one way only incremental relative motion therebetween. When the incremental output member comprises a ratchet wheel, the tooth can therefore serve as an anti-back drive tooth for the ratchet wheel, thereby permitting only one way motion or rotation thereof. The counter pawl may be substantially fixedly mounted on the main body of the incremental count system and the counter pawl may be arranged to be capable of repeatedly engaging equi-spaced teeth of the incremental output member in anti-back drive interlock configurations as the counter is operated. The counter pawl may be positioned so that the incremental output member is halfway, or substantially halfway moved from one anti-back drive interlock configuration to the next when the actuator and incremental output member are in the end configuration thereof. This is highly advantageous in that it minimises the risk of double counting or non-counting by the dose counter. According to a further aspect of the invention there is provided an inhaler comprising a main body arranged to retain a medicament canister of predetermined configuration and a dose counter mounted in the main body. The inhaler main body may include a canister receiving portion and a separate counter chamber, the dose counter being located within the main body thereof, the incremental output member and actuator thereof inside the counter chamber, the main body of the inhaler having wall surfaces separating the canister-receiving portion and the counter chamber, the wall surfaces being provided with a communication aperture, an actuation member extending through the communication aperture to transmit canister motion to the actuator. According to a further aspect of the present invention there is a provided an inhaler for metered dose inhalation, the inhaler comprising a main body having a canister housing arranged to retain a medicament canister for motion therein, and a dose counter, the dose counter having an actuation member having at least a portion thereof located in the canister housing for operation by movement of a medicament canister, wherein the canister housing has an inner wall, and a first inner wall canister support formation located directly adjacent the actuation member. This is highly advantageous in that the first inner wall canister support formation can prevent a canister from rocking too much relative to the main body of the inhaler. Since the canister may operate the actuation member of the dose counter, this substantially improves dose counting and avoids counter errors. The canister housing may have a longitudinal axis which passes through a central outlet port thereof, the central outlet port being arranged to mate with an outer canister fire stem of a medicament canister, the inner wall canister support formation, the actuation member and the outlet port lying in a common plane coincident with the longitudinal axis. Accordingly, this construction may prevent the canister from rocking towards the position of the dose counter actuation member, thereby minimising errors in counting. The canister housing may have a further inner canister wall support formation located on the inner wall opposite, or substantially opposite, the actuation member. Accordingly, the canister may be supported against rocking motion away from the actuator member so as to minimise count errors. The canister housing may be generally straight and tubular and may have an arrangement in which each said inner wall support formation comprises a rail extending longitudinally along the inner wall. Each said rail may be stepped, in that it may have a first portion located towards a medicine outlet end or stem block of the canister housing which extends inwardly a first distance from a main surface of the inner wall and a second portion located toward an opposite end of the canister chamber which extends inwardly a second, smaller distance from the main surface of the inner wall. This may therefore enable easy insertion of a canister into the canister housing such that a canister can be lined up gradually in step wise function as it is inserted into the canister housing. The inhaler may include additional canister support rails which are spaced around an inner periphery of the inner wall of the canister housing and which extend longitudinally therealong. At least one of the additional rails may extend a constant distance inwardly from the main surface of the inner wall. At least one of the additional rails may be formed with a similar configuration to the first inner wall canister support formation. The dose counter may, apart from said at least a portion of the actuation member, be located in a counter chamber separate from the canister housing, the actuation member comprising a pin extending through an aperture in a wall which separates the counter chamber and the canister housing. According to a further aspect of the present invention there is provided an inhaler for inhaling medicaments having: a body for retaining a medicament store; the body including a dose counter, the dose counter having a moveable actuator and a return spring for the actuator, the return spring having a generally cylindrical and annular end; the body having a support formation therein for supporting said end of the return spring, the support formation comprising a shelf onto which said end is engageable and a recess below the shelf. This shelf and recess arrangement is highly advantageous since it allows a tool (such as manual or mechanical tweezers) to be used to place the return spring of the actuator onto the shelf with the tool then being withdrawn at least partially via the recess. The shelf may be U-shaped. The support formation may include a U-shaped upstanding wall extending around the U-shaped shelf, the shelf and upstanding wall thereby forming a step and riser of a stepped arrangement. The recess below the shelf my also be U-shaped. At least one chamfered surface may be provided at an entrance to the shelf. This may assist in inserting the actuator and return spring into position. A further aspect of the invention provides a method of assembly of an inhaler which includes the step of locating said end of said spring on the shelf with an assembly tool and then withdrawing the assembly tool at least partly via the recess. This assembly method is highly advantageous compared to prior art methods in which spring insertion has been difficult and in which withdrawal of the tool has sometimes accidentally withdrawn the spring again. The cylindrical and annular end of the spring may be movable in a direction transverse to its cylindrical extent into the shelf while being located thereon. According to a further aspect of the present invention there is provided an inhaler for inhaling medicament, the inhaler having a body for retaining a medicament store; and a dose counter, the dose counter having a moveable actuator and a chassis mounted on the body; the chassis being heat staked in position on the body. This is be highly advantageous in that the chassis can be very accurately positioned and held firmly in place, thereby further improving counting accuracy compared to prior art arrangements in which some movement of the chassis relative to the body may be tolerated in snap-fit connections. The chassis may have at least one of a pin or aperture heat staked to a respective aperture or pin of the body. The chassis may have a ratchet counter output member mounted thereon. The ratchet counter output member may comprise a ratchet wheel arranged to reel in incrementally a dose meter tape having a dosage indicia located thereon. According to a further aspect of the present invention there is provided a method of assembling an inhaler including the step of heat staking the chassis onto the body. The step of heat staking is highly advantageous in fixedly positioning the chassis onto the body in order to achieve highly accurate dose counting in the assembled inhaler. The method of assembly may include mounting a spring-returned ratchet actuator in the body before heat staking the chassis in place. The method of assembly may include pre-assembling the chassis with a dose meter tape prior to the step of heat staking the chassis in place. The method of assembly may include attaching a dose meter cover onto the body after the heat staking step. The cover may be welded onto the body or may in some embodiments be glued or otherwise attached in place. According to a further aspect of the present invention there is provided an inhaler for inhaling medicament and having a body, the body have a main part thereof for retaining a medicament store; and a dose counter, the dose counter being located in a dose counter chamber of the body which is separated from the main part of the body, the dose counter chamber of the body having a dosage display and being perforated so as to permit the evaporation of water or aqueous matter in the dose counter chamber into the atmosphere. This is high advantageous since it enables the inhaler to be thoroughly washed and the dose counting chamber can thereafter dry out fully. The display may comprise a mechanical counter display inside the dose counter chamber and a window for viewing the mechanical counter display. The mechanical counter display may comprise a tape. The perforated dose counter chamber may therefore enable reliable washing of the inhaler, if desired by the user, and may therefore dry out without the display window misting up. The dose counter chamber may be perforated by a drain hole formed through an outer hole of the body. The drain hole may be located at a bottom portion of the body of the inhaler, thereby enabling full draining of the inhaler to be encouraged after washing when the inhaler is brought into an upright position. According to a further aspect of the present invention there is provided a dose counter for an inhaler, the dose counter having a display tape arranged to be incrementally driven from a tape stock bobbin onto an incremental tape take-up drive shaft, the bobbin having an internal bore supported by and for rotation about a support shaft, at least one of the bore and support shaft having a protrusion which is resiliently biased into frictional engagement with the other of the bore and support shaft with longitudinally extending mutual frictional interaction. This arrangement may provide good friction for the bobbin, thereby improving tape counter display accuracy and preventing the bobbin from unwinding undesirably for example if the inhaler is accidentally dropped. The support shaft may be forked and resilient for resiliently biasing the support shaft and bore into frictional engagement. The support shaft may have two forks, or more in some cases, each having a radially extending protrusion having a friction edge extending therealong parallel to a longitudinal axis of the support shaft for frictionally engaging the bore of the support shaft with longitudinally extending frictional interaction therebetween. The bore may be a smooth circularly cylindrical or substantially cylindrical bore. Each of the above inhalers in accordance with aspects of the present invention may have a medicament canister mounted thereto. The canister may comprise a pressurised metered dose canister having a reciprocally movable stem extending therefrom and movable into a main canister portion thereof for releasing a metered dose of medicament under pressure, for example by operating a metered dose valve inside the canister body. The canister may be operable by pressing by hand on the main canister body. In cases in which one or more support rails or inner wall support formations are provided, the canister may at all times when within the canister chamber have a clearance of about 0.25 to 0.35 mm from the first inner wall support formation. The clearance may be almost exactly 0.3 mm. This clearance which may apply to the canister body itself or to the canister once a label has been applied, is enough to allow smooth motion of the canister in the inhaler while at the same time preventing substantial rocking of the canister which could result in inaccurate counting by a dose counter of the inhaler, especially when lower face of the canister is arranged to engage an actuator member of the dose counter for counting purposes. According to a further aspect of the invention, a method of assembling a dose counter for an inhaler comprises the steps of providing a tape with dosing indicia thereon; providing tape positioning indicia on the tape; and stowing the tape while monitoring for the tape positioning indicia with a sensor. The method advantageously permits efficient and accurate stowing of the tape, e.g. by winding. The dosing indicia may be provided as numbers, the tape positioning indicia may be provided as one or more lines across the tape. The stowing step comprises winding the tape onto a bobbin or shaft, and, optionally, stopping winding when the positioning indicia are in a predetermined position. The tape may be provided with pixelated indicia at a position spaced along the tape from the positioning indicia. The tape may also be provided with a priming dot. According to a further aspect of the invention, a tape system for a dose counter for an inhaler has a main elongate tape structure, and dosing indicia and tape positioning indicia located on the tape structure. The tape positioning indicia may comprise at least one line extending across the tape structure. The tape system may comprise pixelated indicia located on the tape structure and spaced from the positioning indicia. The tape system may comprise a priming dot located on the tape structure. The positioning indicia may be located between the timing dot and the pixelated indicia. The main elongate tape structure may have at least one end thereof wound on a bobbin or shaft. A further aspect of the invention provides a method of designing an incremental dose counter for an inhaler comprising the steps of calculating nominal canister fire and dose counter positions for a dose counter actuator of the inhaler; calculating a failure/success rate for dose counters built to tolerance levels for counting each fire of inhalers in which the dose counter actuators may be applied; and selecting a tolerance level to result in said failure/success rate to be at or below/above a predetermined value. This is highly advantageous in that it allows an efficient and accurate prediction of the reliability of a series of inhaler counters made in accordance with the design. The method of designing may include selecting the failure/success rate as a failure rate of no more than one in 50 million. The method of designing may include setting an average count position for dose counters built to the tolerances to be at or after an average fire position thereof during canister firing motion. The method of designing may include setting the average count position to be about 0.4 to 0.6 mm after the average fire position, such as about 0.48 mm after. The method of designing may include setting tolerances for the standard deviation of the fire position in dose counters built to the tolerances to be about 0.12 to 0.16 mm, such as about 0.141 mm. The method of designing may include setting tolerances for the standard deviation of the count positions in dose counters built to the tolerances to be about 0.07 to 0.09 mm, such as about 0.08 mm. A further aspect of the invention provides a computer implemented method of designing an incremental dose counter for an inhaler which includes the aforementioned method of designing. A further aspect of the invention provides a method of manufacturing in a production run a series of incremental dose counters for inhalers which comprises manufacturing the series of dose counters in accordance with the aforementioned method of designing. A further aspect of the invention provides a method of manufacturing a series of incremental dose counters for inhalers, which comprises manufacturing the dose counters with nominal canister fire and dose count positions of a dose counter actuator relative to a dose counter chassis (or inhaler main body), and which includes building the dose counters with the average dose count position in the series being, in canister fire process, at or after the average canister fire position in the series. According to a further aspect of the invention, the method provides fitting each dose counter in the series of incremental dose counters to a corresponding main body of an inhaler. These aspects advantageously provide for the production run of a series of inhalers and dose counters which count reliably in operation. According to a further aspect of the invention, an incremental dose counter for a metered dose inhaler has a body arranged to retain a canister for movement of the canister relative thereto, the incremental dose counter having a main body, an actuator arranged to be driven and to drive an incremental output member in a count direction in response to canister motion, the actuator being configured to restrict motion of the output member in a direction opposite to the count direction. This advantageously enables an inhaler dose counter to keep a reliable count of remaining doses even if dropped or otherwise jolted. The output member may comprise a ratchet wheel. The actuator may comprise a pawl and in which the ratchet wheel and pawl are arranged to permit only one-way ratcheting motion of the wheel relative to the pawl. The dose counter may include an anti-back drive member fixed to the main body. In a rest position of the dose counter, the ratchet wheel is capable of adopting a configuration in which a back surface of one tooth thereof engages the anti-back drive member and the pawl is spaced from an adjacent back surface of another tooth of the ratchet wheel without positive drive/blocking engagement between the pawl and wheel. BRIEF DESCRIPTION OF THE DRAWINGS The present invention may be carried out in various ways and preferred embodiment of a dose counter, inhaler and methods of assembly, design and manufacture will now be described with reference to the accompanying drawings in which: FIG. 1 is an isometric view of a main body of an embodiment of an inhaler related to the invention together with a mouthpiece cap therefor; FIG. 2 is a top plan view of the components as shown in FIG. 1; FIG. 3A is a section on the plane 3A-3A in FIG. 2; FIG. 3B is a view corresponding to FIG. 3A but with a dose counter fitted to the main body of the inhaler; FIG. 4A is an exploded view of the inhaler main body, mouthpiece cap, dose counter and a dose counter window; FIG. 4B is a view in the direction 4B in FIG. 4C of a spring retainer of the dose counter; FIG. 4C is a top view of the spring retainer of FIG. 4B; FIG. 5 is a bottom view of the assembled inhaler main body, mouthpiece cap, dose counter and dose counter window; FIGS. 6A, 6B, 6C, 6D, 6E, 6F, 6G and 6H are various views of dose counter components of the inhaler; FIGS. 7A and 7B are sectional views showing canister clearance inside the main body of the inhaler; FIG. 7C is a further sectional view similar to that of FIG. 7B but with the canister removed; FIG. 7D is a top plan view of the inhaler main body; FIGS. 8A, 8B, 8C and 8D show the inhaler main body and dose counter components during assembly thereof; FIG. 9 shows a sectional side view of a datum line for an actuator pawl of the dose counter; FIGS. 10A, 10B, 10C, 10D, 10E and 10F show various side views of positions and configurations of the actuator pawl, a ratchet wheel, and a count pawl; FIG. 11 shows distributions for tolerances of start, reset, fire, count and end positions for the actuator of the dose counter; FIG. 12 is an enlarged version of part of FIG. 4A; FIG. 13 shows an end portion of a tape of the dose counter; FIG. 14 shows a computer system for designing the dose counter; FIG. 15 is an isometric view of a stock bobbin modified in accordance with the present invention for use in the dose counter of the inhaler of FIGS. 1 to 14; FIG. 16 shows an end view of the stock bobbin of FIG. 15; FIG. 17 is a section through a longitudinal axis of the stock bobbin of FIGS. 15 and 16; FIGS. 18A, 18B and 18C are views of the stock bobbin of FIGS. 15 to 17 mounted in the dose counter chassis of FIGS. 1 to 14, with the control elements of the forks of the second shaft (or split pin) having a profile slightly different to that in FIG. 6F, with the forks in a compressed configuration; FIGS. 19A, 19B and 19C are views equivalent to FIGS. 18A to 18C but with the forks in a more expanded configuration due to a different rotational position of the stock bobbin; FIG. 20 is an isometric view of the chassis assembled and including the stock bobbin of FIGS. 15 to 17 but excluding the tape for reasons of clarity; FIG. 21 is a view of a preferred embodiment of a dry powder inhaler in accordance with the present invention; FIG. 22 is an exploded view of the inhaler of FIG. 21; FIG. 23 is a view of a dose counter of the inhaler of FIG. 21; FIG. 24 is an exploded view of the dose counter shown in FIG. 23; FIG. 25 is an exploded view of parts of the inhaler of FIG. 21; and FIG. 26 is a view of a yoke of the inhaler of FIG. 21. DETAILED DESCRIPTION OF THE INVENTION FIG. 1 shows a main body 10 of a manually operated metered dose inhaler 12 in accordance with an embodiment related to the present invention and having a mouthpiece cap 14 securable over a mouthpiece 16 of the main body. The main body has a canister chamber 18 into which a canister 20 (FIG. 7A) is slideable. The canister 20 has a generally cylindrical main side wall 24, joined by a tapered section 26 to a head portion 28 having a substantially flat lower face 30 which has an outer annular drive surface 32 arranged to engage upon and drive an actuation pin 34 of a dose counter 36 as will be described. Extending centrally and axially from the lower face 30 is a valve stem 38 which is arranged to sealingly engage in a valve stem block 40 of the main body 10 of the inhaler 12. The valve stem block 40 has a passageway 42 leading to a nozzle 44 for directing the contents of the canister 20, namely active drug and propellant, towards an air outlet 46 of the inhaler main body 12. It will be appreciated that due to gaps 48 between the canister 20 and an inner wall 50 of the main body 10 of the inhaler 12 an open top 52 of the main body 10 forms an air inlet into the inhaler 12 communicating via air passageway 54 with the air outlet 46, such that canister contents exiting nozzle 44 mix with air being sucked by the user through the air passageway 54 in order to pass together through the air outlet and into the mouth of the user (not shown). The dose counter 36 will now be described. The dose counter 36 includes an actuation pin 34 biased upwardly from underneath by a return spring 56 once installed in the main body 10. As best shown in FIGS. 4A, 6H and 8A, the pin 34 has side surfaces 58, 60 arranged to slide between corresponding guide surfaces 62, 64 located in a dose counter chamber 66 of the main body 10, as well as an end stop surface 68 arranged to engage a corresponding end stop 70 formed in the dose counter chamber 66 to limit upward movement of the pin 34. The pin 34 has a top part 72 which is circularly cylindrical and extends through an aperture 74 formed through a separator wall 76 which separates the canister chamber 18 from the dose counter chamber 66. The top part 72 of the pin 34 has a flat top surface 78 which is arranged to engage the outer annular drive surface 32 of the canister 20. The actuation pin 34 is integrally formed with a drive or actuator pawl 80. The actuator pawl 80 has a generally inverted U-shape configuration, having two mutually spaced and parallel arms 82, 84 extending from a base portion of the actuation pin 34, each holding at respective distal ends 88 thereof opposite ends of a pawl tooth member 90 which extends in a direction substantially perpendicular to the arms 82, 84, so as to provide what may be considered a “saddle” drive for pulling on each of the 11 drive teeth 92 of a ratchet wheel 94 of an incremental drive system 96 or ratchet mechanism 96 of the dose counter 36. As shown for example in FIG. 10B, the pawl tooth member 90 has a sharp lower longitudinal side edge 98 arranged to engage the drive teeth 92, the edge-to-surface contact provided by this engagement providing very accurate positioning of the actuator pawl 80 and resultant rotational positioning of the ratchet wheel 94. The dose counter 36 also has a chassis preassembly 100 which, as shown in FIGS. 4A and 6A, includes a chassis 102 having a first shaft 104 receiving the ratchet wheel 94 which is secured to a tape reel shaft 106, and a second shaft (or split pin) 108 which is parallel to and spaced from the first shaft 104 and which slidably and rotationally receives a tape stock bobbin 110. As shown in FIG. 6B, when the inhaler has not been used at all, the majority of a tape 112 is wound on the tape stock bobbin 110 and the tape 112 has a series of regularly spaced numbers 114 displayed therealong to indicate a number of remaining doses in the canister 20. As the inhaler is repeatedly used, the ratchet wheel 94 is rotated by the actuator pawl 80 due to operation of the actuation pin 34 by the canister 20 and the tape 112 is incrementally and gradually wound on to the tape reel shaft 106 from the second shaft 108. The tape 112 passes around a tape guide 116 of the chassis 102 enabling the numbers 114 to be displayed via a window 118 in a dose counter chamber cover 120 having a dose marker 132 formed or otherwise located thereon. As shown in FIGS. 6A and 6D, the second shaft 108 is forked with two forks 124, 126. The forks 124, 126 are biased away from one another. The forks have located thereon at diametrically opposed positions on the second shaft 108 friction or control elements 128, 130, one on each fork. Each control element extends longitudinally along its respective fork 124, 126 and has a longitudinally extending friction surface 132, 134 which extends substantially parallel to a longitudinal axis of the second shaft and is adapted to engage inside a substantially cylindrical bore 136 inside the tape stock bobbin 110. This control arrangement provided between the bore 136 and the control elements 128, 130 provides good rotational control for the tape stock bobbin 110 such that it does not unwind undesirably such as when the inhaler is dropped. The tape force required to unwind the tape stock bobbin 110 and overcome this friction force is approximately 0.1 N. As can be seen in FIG. 6D, as well as FIGS. 6G and 10A to 10F, the chassis 102 is provided with an anti-back drive tooth 138 or count pawl 138 which is resiliently and substantially fixedly mounted thereto. As will be described below and as can be seen in FIGS. 10A to 10F, when the actuation pin 34 is depressed fully so as to fire the metered valve (not shown) inside the canister 20, the actuator pawl 80 pulls down on one of the teeth 92 of the ratchet wheel 94 and rotates the wheel 94 anticlockwise as shown in FIG. 6D so as to jump one tooth 92 past the count pawl 138, thereby winding the tape 112 a distance incrementally relative to the dose marker 122 on the dose counter chamber 120 so as to indicate that one dose has been used. With reference to FIG. 10B, the teeth of the ratchet wheel 94 have tips 143 which are radiused with a 0.1 mm radius between the flat surfaces 140, 142. The ratchet wheel 94 has a central axis 145 which is 0.11 mm above datum plane 220 (FIG. 9). A top/nose surface 147 of the anti-back drive tooth 138 is located 0.36 mm above the datum plane 220. The distance vertically (i.e. transverse to datum plane 220—FIG. 9) between the top nose surface 147 of the anti-back drive tooth is 0.25 mm from the central axis 145 of the wheel 94. Bump surface 144 has a lateral extent of 0.20 mm, with a vertical length of a flat 145′ thereof being 1 mm, the width of the bump surface being 1.22 mm (in the direction of the axis 145), the top 149 of the bump surface 144 being 3.02 mm vertically below the axis 145, and the flat 145′ being spaced a distance sideways (i.e. parallel to the datum plane 220) 2.48 mm from the axis 145. The top surface 78 of the pin 34 (FIG. 6H) is 11.20 mm above the datum plane 220 (FIG. 9) when the actuator pawl 80 and pin 34 are in the start configuration. The length of the valve stem 22 is 11.39 mm and the drive surface 32 of the canister 20 is 11.39 mm above the datum plane 220 when the canister is at rest waiting to be actuated, such that there is a clearance of 0.19 mm between the canister 20 and the pin 34 in this configuration. FIGS. 10A and 10B show the actuator pawl 80 and ratchet wheel 94 and count pawl 138 in a start position in which the flat top 78 of the pin 34 has not yet been engaged by the outer annular drive surface 32 of the canister 20 or at least has not been pushed down during a canister depression. In this “start” position, the count pawl 138 engages on a non-return back surface 140 of one of the teeth 92 of the ratchet wheel 94. The lower side edge 98 of the actuator pawl is a distance “D” (FIG. 9) 1.33 mm above datum plane 220 which passes through bottom surface or shoulder 41 of valve stem block 40, the datum plane 220 being perpendicular to a main axis “X” of the main body 10 of the inhaler 12 which is coaxial with the centre of the valve stem block bore 43 and parallel to a direction of sliding of the canister 20 in the main body 10 of the inhaler 12 when the canister is fired. As shown in FIG. 10B, an advantageous feature of the construction is that the pawl tooth/actuator 90 acts as a supplementary anti-back drive member when the inhaler 12 is not being used for inhalation. In particular, if the inhaler 12 is accidentally dropped, resulting in a jolt to the dose counter 36 then, if the wheel 94 would try to rotate clockwise (backwards) as shown in FIG. 10B, the back surface 140 of a tooth will engage and be blocked by the tooth member 90 of the pawl 80. Therefore, even if the anti-back drive tooth 138 is temporarily bent or overcome by such a jolt, undesirable backwards rotation of the wheel 94 is prevented and, upon the next canister firing sequence, the pawl 90 will force the wheel 94 to catch up to its correct position so that the dose counter 36 continues to provide correct dosage indication. FIG. 10C shows a configuration in which the actuator pawl 80 has been depressed with the pin 34 by the canister 20 to a position in which the side edge 98 of the pawl tooth member 90 is just engaged with one of the teeth 92 and will therefore upon any further depression of the pin 34 begin to rotate the wheel 94. This is referred to as a “Reset” position or configuration. In this configuration, the lower side edge 98 of the actuator 80 is 0.64 mm above the datum plane 220. FIG. 10D shows a configuration in which the actuator pawl 80 has been moved to a position lower than that shown in FIG. 10C and in which the metered dose valve (not shown) inside the canister has at this very position fired in order to eject active drug and propellant through the nozzle 44. It will be noted that in this configuration the count pawl 138 is very slightly spaced from the back surface 140 of the same tooth 92 that it was engaging in the configuration of FIG. 10D. The configuration shown in FIG. 10D is known as a “Fire” configuration. In this configuration the lower side edge 98 of the actuator 80 is 0.47 min below the datum plane 220. FIG. 10E shows a further step in the sequence, called a “Count” position in which the actuator pawl 80 has rotated the ratchet wheel 94 by the distance circumferentially angularly between two of the teeth 92, such that the count pawl 138 has just finished riding along a forward surface 142 of one of the teeth 92 and has resiliently jumped over the tooth into engagement with the back surface 140 of the next tooth. Accordingly, in this “Count” configuration, a sufficiently long stroke movement of the pin 34 has occurred that the tape 112 of the dose counter 36 will just have counted down one dose. In this configuration, the lower side edge 98 of the actuator is 0.95 mm below the datum plane 220. Accordingly, in this position, the actuator 80 generally, including edge 98, is 0.48 mm lower than in the fire configuration. It has been found that, although the count configuration happens further on than the fire configuration, counting is highly reliable, with less than 50 failed counts per million. This is at least partially due to momentum effects and to the canister releasing some back pressure on the user in some embodiments as its internal metering valve fires. In the configuration of FIG. 10F, the pawl 80 has been further depressed with the pin 34 by the canister 20 to a position in which it is just disengaging from one of the teeth 92 and the actuator pawl 80 is assisted in this disengagement by engagement of one of the arms 84 with a bump surface 144 on the chassis 102 (see FIG. 6G) and it will be seen at this point of disengagement, which is called an “End” configuration, the count pawl 138 is positioned exactly halfway or substantially halfway between two of the drive teeth 92. This advantageously means therefore that there is a minimum chance of any double counting or non-counting, which would be undesirable. In the end configuration, the side edge 98 of the actuator is 1.65 mm below the datum plane 220. It will be appreciated that any further depression of the actuator pawl 80 and pin 34 past the “End” configuration shown in FIG. 10F will have no effect on the position of the tape 112 displayed by the dose counter 36 since the actuator pawl 80 is disengaged from the ratchet wheel 94 when it is below the position shown in FIG. 10F. As shown in FIGS. 7C and 7D, the inner wall 50 of the main body 10 is provided with a two-step support rail 144 which extends longitudinally along inside the main body and is located directly adjacent the aperture 74. As shown in FIG. 7B a diametrically opposed two-step support rail 146 is also provided and this diametrically opposed in the sense that a vertical plane (not shown) can pass substantially directly through the first rail 144, the aperture 74, a central aperture 148 of the valve stem block 40 (in which canister stem 25 is located) and the second two-step support rail 146. As shown in FIG. 7A and schematically in FIG. 7B, the rails 144, 146 provide a maximum clearance between the canister 20 and the rails 144, 146 in a radial direction of almost exactly 0.3 mm, about 0.25 to 0.35 mm being a typical range. This clearance in this plane means that the canister 20 can only rock backwards and forwards in this plane towards away from the actuation pin 34. A relatively small distance and this therefore prevents the canister wobbling and changing the height of the actuation pin 34 a as to undesirably alter the accuracy of the dose counter 36. This is therefore highly advantageous. The inner wall 50 of the main body 10 is provided with two further two-step rails 150 as well as two pairs 152, 154 of rails extending different constant radial amounts inwardly from the inner wall 50, so as to generally achieve a maximum clearance of almost exactly 0.3 mm around the canister 20 for all of the rails 144, 146, 150, 152, 154 spaced around the periphery of the inner wall 50, in order to prevent undue rocking while still allowing canister motion freely inside the inhaler 12. It will be clear from FIG. 7C for example that the two-step rails have a first portion near an outlet end 156 of the canister chamber 18, the first portion having a substantially constant radial or inwardly-extending width, a first step 160 leading to a second portion 162 of the rail, the second portion 102 having a lesser radial or inwardly extending extent than the first portion 156, and finally a second step 164 at which the rail merges into the main inner wall 50 main surface. A method of assembling the inhaler 12 will now be described. With reference to FIG. 8A, the main body 10 of the inhaler 12 is formed by two or more plastics mouldings which have been joined together to the configuration shown. As shown in FIG. 8B, the actuator pawl 80 and pin 34 are translated forward into position into a pin receiving area 166 in the dose counter chamber 66 and the pin 34 and actuator 80 may then be raised until the pin 34 emerges through the aperture 74. Next, the return spring 56 may be inserted below the pin 34 and a generally cylindrical annular lower end 168 of the spring 56 may be moved by a tweezer or tweezer-like assembly tool (not shown) into engagement with a shelf 170 of a spring retainer 172 in the dose counter chamber 66. The spring retainer 172 is U-shaped and the shelf 170 is U-shaped and has a recess 174 formed below it. As shown in FIGS. 4B, 4C and 12 shelf 170 includes three chamfer surfaces 176, 178, 180 arranged to assist in moving the lower end of the spring 168 into position onto the shelf using the assembly tool (not shown). Once the lower end of the spring 168 is in place, the assembly tool (not shown) can easily be removed at least partly via the recess 174 below the lower end 168 of the spring 56. The tape 112 is attached at one end (not shown) to the tape stock bobbin 110 and is wound onto the bobbin by a motor 200 (FIG. 13) having a hexagonal output shaft 202 which engages in a hexagonal socket 204 (FIG. 6B) of the bobbin. During winding, the tape is monitored by a sensor 206, which may be in the form of a camera or laser scanner, which feeds data to a computer controller 205 for the motor 200. The controller 205 recognises three positioning markers 210 in the form of lines across the tape 112 and stops the motor 202 when the tape 112 is nearly fully wound onto the bobbin 110, such that the distal end 212 of the tape 112 can be secured, e.g. by adhesive, to the tape reel shaft 106. The controller 205 also recognises a pixelated tape size marker 214 observed by the sensor 206 and logs in a stocking system data store 217 details of the tape 112 such as the number of numbers 114 on the tape, such as one hundred and twenty or two hundred numbers 114. Next, the tape reel shaft is wound until an appropriate position of the lines 210 at which a priming dot 216 will, once the bobbin 110 and reel shaft 106 are slid onto the second shaft 108 and second shaft 104, be in a position to be located in the window 118 when the inhaler 12 is fully assembled. In the embodiments, the bobbin 110 and reel shaft 106 may be slid onto the shafts 108, 104 before the tape 112 is secured to the reel shaft 106 and the reel shaft may then be wound to position the priming dot 216. Next, the assembled dose counter components of the chassis preassembly 100 shown in FIG. 6B may as shown in FIG. 8C be inserted into the dose counter chamber 66, with pins 182, 184, 186 formed on the main body 10 in the dose counter chamber 66 passing through apertures or slots 188, 190, 192 formed on the chassis 102, such that the pins 182, 184, 186 extend through (or at least into) the apertures or slots 188, 190, 192. With the chassis 102 being relatively firmly pushed towards the main body 10, the pins 182, 184, 186 are then heat staked and the chassis 102 is therefore after this held very firmly in position in the main body and is unable to move, thereby assisting in providing great accuracy for the dose counter 36. Next, as shown in FIG. 8D, the dose counter chamber cover 120 may be fitted over the dose counter chamber 66 and may be secured in place such as by welding, with the priming dot 216 being displayed through the window. The user can, when readying the inhaler 12 for first use, prime the inhaler by depressing the canister 20 three times which will bring the first number 114 on the tape into display through the window 118 in place of the priming dot 216, the number 114 shown in FIG. 8D being “200”, thereby indicating that 200 doses are remaining to be dispensed from the canister 20 and inhaler 12. As shown in FIG. 8D, and in FIG. 5, an open drain hole 194 is provided at the bottom of the dose counter chamber 66 by a substantially semi-circular cut-out or recess formation 196 in a lower surface 198 of the main body 10 of the inhaler. Accordingly, if the user (not shown) should decide to wash the main body 10 of the inhaler, for example after encountering an unhygienic situation or simply as a matter of choice, the drain hole 194 allows initial draining of water from inside the dose counter chamber 66 and also thereafter evaporation of water or any aqueous matter in the dose counter chamber 66 so that the window 118 does not mist up undesirably. FIG. 14 shows a computer system 230 for designing the dose counter 36 and in particular for calculating distributions representative of average positions and standard deviations in a production series of inhalers of the start, reset, fire, count and end positions of the actuator lower side edge 98 relative to the datum plane 220 (FIG. 9) and therefore of the actuator pawl 80 generally relative to the ratchet wheel 94, chassis 102 and, when the inhaler 12 is fully assembled, the main body 10 of the inhaler 12. The computer system 230 includes a data store 232, a CPU 234, an input device 236 (such as a keyboard or communication port) and an output device 238 (such as a communications port, display screen and/or printer). A user may enter data via the input device 236 which may be used by the CPU 234 in a mathematical calculation to predict count failure rates when the various dose counters are to be built in a series with dose counter positions set with given averages and standard deviations and taking into account any momentum/inertia effects and metering valve user-back-pressure reduction effect which will occur upon canister firing of a given type of canister. The computer system 230 is thus mathematically used to design the distributions. For the inhaler 12 described herein with the dose counter 36 and canister 20, the distributions are designed as shown in FIG. 11. The x axis shows distance of the lower side surface 98 of the actuator 80 above the datum plane 220 and the y axis is representative of the distribution. Thus, curve 240 shows that the start configuration has an average 1.33 mm above the datum plane 200 (standard deviation is 0.1 mm), curve 242 shows that the reset configuration has an average of 0.64 mm above the datum plane 220 (standard deviation is 0.082 mm), curve 244 shows the fire configuration has an average 0.47 mm below the datum plane 220 (standard deviation is 0.141 mm), curve 246 shows the count configuration has an average 0.95 mm below the datum plane 220 (standard deviation is 0.080 mm), and curve 248 shows the end configuration has an average of 1.65 mm below the datum plane 220 (standard deviation is 0.144 mm). FIGS. 15 to 20 show a version of the inhaler modified in accordance with the present invention. In these drawings, the same reference numerals have been used to those in the earlier drawings to denote the equivalent components. The inhaler 12 is the same as that in FIGS. 1 to 14 apart from the following modifications. First, it can be seen that there is a modification in that the drive teeth 92 of the ratchet wheel 94 have a different profile to that in FIGS. 1 to 14. There are also only nine ratchet teeth 94 in this embodiment instead of eleven. Additionally, as shown in FIGS. 18C and 19C, the control elements 128, 130 on the forks 124, 126 of the second shaft 108 have a tapered profile which is different to the profile of the control elements 128, 130 shown in FIG. 6F. Either profile can be used in the embodiment of FIGS. 15 to 20 however. Furthermore, as shown in FIG. 15, the tape stock bobbin 110 has an inwardly facing generally cylindrical engagement surface 300 with a wavelike form extending partially therealong. The engagement surface 300 has a cross-section 301 perpendicular to the longitudinal length of the stock bobbin 110 which is constant therealong. This cross-section 301 can be seen in FIG. 16 and consists of a series of ten regularly spaced concavities 302 and ten convex wall portions 304. The convex wall portions 304 are equi-spaced between the concavities 302. Each concavity 302 has a radius of 0.2 mm. Each convex wall portion 304 also has a radius of 0.2 mm. Finally, the cross section 301 also includes flat wall portions 306 between all of the radiused wall portions of the concavities 302 and convex wall portions 304. The geometry of the cross-section 301 is therefore defined by the radii of the concavities 302 and convex wall portions 304, the flat wall portions 306 and the fact that there are ten concavities 302 and convex wall portions 304. The minor diameter of the engagement surface 300, i.e. between the tips of opposite convex wall portions 304, is 2.46 mm. The major diameter of the engagement surface 300, i.e. between the outermost portions of the concavities 302, is 2.70 mm. The undeformed tip to tip maximum diameter of the forks 124, 126 of the split pin (the second shaft) 108, i.e. in the region of the maximum radio extent of the control elements 128, 130, is 3.1 millimetres and it will therefore be appreciated that the forks 124, 126 are resiliently compressed once the stock bobbin 110 has been assembled onto the split pin 108 in all rotational configurations of the stock bobbin 110 relative to the split pin 108. The minimum gap between the forks 124, 126 in the plane of the cross sections of FIGS. 18C and 19C is 1 mm when the split pin 108 is in the undeformed, pre-inserted state. When the split pin 108 is at maximum compression, as shown in FIGS. 18A to 18C when the control elements 128, 130 are shown to be engaged on top of the convex wall portions 304, the gap 308 between the tips 310, 312 of the forks 124, 126 is 0.36 mm. On the other hand, when the split pin 108 is at minimum compression (once inserted into the stock bobbin) as shown in FIGS. 19A to 19C, when the control elements 128, 130 rest in the concavities 302, the gap between the tips 310, 312 of the forks 124, 126 is 0.6 mm. The control elements 128, 130 are outwardly radiused with a radius also of 0.2 mm such that they can just rest on the concavities 302 with full surface contact (at least at an axial location on the split pin where the tapered control elements are at their maximum radial extent), without rattling in, locking onto or failing to fit in the concavities 302. The radii of the control elements 128, 130 is therefore preferably substantially the same as the radii of the concavities 302 It will be appreciated that whereas FIGS. 18B and 19B are end views along the coaxial axis of the stock bobbin 110 and split pin 108, FIGS. 18A and 19A are cross-sections. FIG. 19A is a section on the plane A-A′ in FIG. 19C and FIG. 18A is a section at the same plane, but of course with the stock bobbin 110 rotated relative to the split pin 108. As the inhaler 12 is used and the ratchet wheel 94 rotates in order to count used doses, the stock bobbin rotates incrementally through rotational positions in which rotation is resisted, i.e. due to increasing compression of the split pin 108 at such rotational positions, and rotational positions in which rotation is promoted, i.e. due to decreasing compression of the split pin 108 at such rotational positions and this may involve a click forward of the stock bobbin 110 to the next position equivalent to that in FIGS. 19A to 19C in which the control elements 128, 130 of the split pin art located in the concavities 302. This functionality firstly allows the stock bobbin to unwind during use as required, but also prevents the tape 112 from loosening during transit if the inhaler 12 is dropped, such as onto a hard surface. This is highly advantageous, since the tape 11 is prevented from moving to a position in which it will give an incorrect reading regarding the number of doses in the canister. During compression and expansion of the forks in the radial direction between the two configurations shown in FIGS. 18C and 19C, the forks 124, 126 rotate about a point 316 on the split pin where the forks 124, 126 come together. This rotational action means that there is a camming action between the forks 124, 126 and the engagement surface 300 without significant friction but, nevertheless, the resilient forces provided by the regulator formed by the engagement surface 300 and forks 124, 126 are able to regulate unwinding of the tape such that it does not easily occur during transit or if the inhaler 12 is dropped. It has been found during testing that a force of 0.3 to 0.4 N needs to be applied to the tape 112 to overcome the regulator at the stock bobbin 110. 0.32 N is achieved with the control elements 128 having the profile shown in FIG. 19C and 0.38 N is achieved with the profile of the control elements 128 altered to be as shown as described with reference to FIG. 6F. These forces are substantially higher than the 0.1 N force mentioned above and undesirable movement of the tape is substantially avoided even if the inhaler is dropped onto a hard surface. The modified arrangement of FIGS. 15 to 20 does not provide this force “constantly” such that there is overall not an undesirably high friction of the tape 112 as it passes over the other components of the dose counter because, due to the incremental nature of the resilient forces at the regulator, the tape 112 can incrementally relax as it slides over the stationary chassis components. Instead of having ten concavities 302 and convex wall portions 304, other numbers may be used, such as 8 or 12. However, it is preferred to have an even number, especially since two control elements 128, 130 are provided, so that all of the control elements 128, 130 will expand and contract simultaneously. However, other arrangements are envisaged with 3 or more forks and the number of concavities/convex wall portions may be maintained as an integer divisible by the number of forks to maintain a system with simultaneous expansion/contraction. For example, the use of 9, 12 or 15 concavities/convex wall portions with 3 forks is envisaged. Instead of having the engagement surface 300 on the inside of the stock bobbin 110, it could be placed on the outside of the stock bobbin 110 so as to be engaged by flexible external legs/pawls or similar. It will be noted that the regulator provided by the engagement surface 300 and forks 124, 126 does not only allow rotation of the stock bobbin in one direction as is the case with the ratchet wheel 94. Rotation in both directions is possible, i.e. forwards and backwards. This means that during assembly, the stock bobbin 110 can be wound backwards during or after fitting the bobbin 100, shaft 106 and tape 112 onto the carriage 102, if desired. The stock bobbin 110 and the carriage 102 including the split pin 108 are both moulded of polypropylene material. It will be seen from FIG. 16 that the cross-sectional shape 301 is not symmetrical within the hexagonal socket 204. This has enabled the hexagonal socket 204 to be maintained at a useful size while still allowing the desired size and geometry of the cross section 301 to fit without interfering with the hexagonal shape of the hexagonal socket 204 and also permits moulding to work during manufacture. As shown in FIG. 17, the stock bobbin 110 has a series of four circumferential ribs 330 inside it and a spaced therealong. These hold the stock bobbin 110 on the correct side of the mould tool during moulding. FIGS. 21 and 22 show a preferred embodiment in accordance with the invention of an inhaler 510 for dispensing a dry-powdered medicament in metered doses for patient inhalation. The inhaler 510 is as disclosed in FIGS. 1 to 16 or EP-A-1330280, the contents of which are hereby fully incorporated herein by reference, but with the stock bobbin 110 and second shaft 108 of the dose counter 516 modified so as to be as in FIGS. 15 to 20 hereof. Thus, the dry powder inhaler 510 generally includes a housing 518, and an assembly 512 received in the housing (see FIG. 21). The housing 518 includes a case 520 having an open end 522 and a mouthpiece 524 (FIG. 25) for patient inhalation, a cap 526 secured to and closing the open end 522 of the case 520, and a cover 528 pivotally mounted to the case 520 for covering the mouthpiece 524. As shown in FIG. 22, the inhaler 510 also includes an actuation spring 569, first yoke 566 with opening 572, bellows 540 with crown 574, a reservoir 514, second yoke 568 with hopper 542 and dose counter 516 mounted thereto, and case 520 has transparent window 5130 thereon for viewing dose counter tape indicia 5128. The dose metering system also includes two cams 570 mounted on the mouthpiece cover 528 and movable with the cover 528 between open and closed positions. The cams 570 each include an opening 580 for allowing outwardly extending hinges 582 of the case 520 to pass therethrough and be received in first recesses 584 of the cover 528. The cams 570 also include bosses 586 extending outwardly and received in second recesses 588 of the cover 528, such that the cover 528 pivots about the hinges 582 and the cams 570 move with the cover 528 about the hinges 582. As described in EP-A-1330280, cams 570 act upon cam followers 578 to move second yoke 568 up and down and thereby operate dose counter by engagement of pawl 5138 on the second yoke 568 with teeth 5136. Remaining components of the inhaler are provided as, and operate as described, in EP-A-1330280. The dose counting system 516 therefore includes a ribbon or tape 5128 (FIGS. 23 & 24), having successive numbers or other suitable indicia printed thereon, in alignment with a transparent window 5130 provided in the housing 18 (see FIG. 22). The dose counting system 516 includes the rotatable stock bobbin 110 (as described above), an indexing spool 5134 rotatable in a single direction, and the ribbon 5128 rolled and received on the bobbin 110 and having a first end 5127 secured to the spool 5134, wherein the ribbon 5128 unrolls from the bobbin 110 so that the indicia are successively displayed as the spool 5134 is rotated or advanced. In FIGS. 23 and 24 the wavelike engagement surface 300 of the bobbin 110 is not shown for the purposes of clarity. The spool 134 is arranged to rotate upon movement of the yokes 566, 568 to effect delivery of a dose of medicament from reservoir 514, such that the number on the ribbon 5128 is advanced to indicate that another dose has been dispensed by the inhaler 510. The ribbon 5128 can be arranged such that the numbers, or other suitable indicia, increase or decrease upon rotation of the spool 5134. For example, the ribbon 5128 can be arranged such that the numbers, or other suitable indicia, decrease upon rotation of the spool 5134 to indicate the number of doses remaining in the inhaler 510. Alternatively, the ribbon 5128 can be arranged such that the numbers, or other suitable indicia, increase upon rotation of the spool 5134 to indicate the number of doses dispensed by the inhaler 10. The indexing spool 5134 includes radially extending teeth 5136, which are engaged by pawl 5138 extending from a cam follower 578 of the second yoke 568 upon movement of the yoke to rotate, or advance, the indexing spool 5134. More particularly, the pawl 5138 is shaped and arranged such that it engages the teeth 5136 and advances the indexing spool 5134 only upon the mouthpiece cover 528 being closed and the yokes 566, 568 moved back towards the cap 526 of the housing 518. The dose counting system 516 also includes a chassis 5140 that secures the dose counting system to the hopper 542 and includes shafts 108, 5144 for receiving the bobbin 110 and the indexing spool 5134. As described above with reference to FIGS. 1 to 20, the bobbin shaft 108 is forked and includes radially nubs 5146 for creating a resilient resistance to rotation of the bobbin 110 on the shaft 108 by engaging with the wavelike engagement surface 300 inside the bobbin 110. A clutch spring 5148 is received on the end of the indexing spool 5134 and locked to the chassis 5140 to allow rotation of the spool 5134 in only a single direction. Various modifications may be made to the embodiment shown without departing from the scope of the invention as defined by the accompanying claims as interpreted under patent law. | <SOH> BACKGROUND OF THE INVENTION <EOH>Metered dose inhalers can comprise a medicament-containing pressurised canister containing a mixture of active drug and propellant. Such canisters are usually formed from a deep-dawn aluminium cup having a crimped lid which carries a metering valve assembly. The metering valve assembly is provided with a protruding valve stem which, in use is inserted as a push fit into a stem block in an actuator body of an inhaler having a drug delivery outlet. In order to actuate a manually operable inhaler, the user applies by hand a compressive force to a closed end of the canister and the internal components of the metering valve assembly are spring loaded so that a compressive force of approximately 15 to 30N is required to activate the device in some typical circumstances. In response to this compressive force the canister moves axially with respect to the valve stem and the axial movement is sufficient to actuate the metering valve and cause a metered quantity of the drug and the propellant to be expelled through the valve stem. This is then released into a mouthpiece of the inhaler via a nozzle in the stem block, such that a user inhaling through the outlet of the inhaler will receive a dose of the drug. A drawback of self-administration from an inhaler is that it is difficult to determine how much active drug and/or propellant are left in the inhaler, if any, especially of the active drug and this is potentially hazardous for the user since dosing becomes unreliable and backup devices not always available. Inhalers incorporating dose counters have therefore become known. WO 98/028033 discloses an inhaler having a ratchet mechanism for driving a tape drive dose counter. A shaft onto which tape is wound has a friction clutch or spring for restraining the shaft against reverse rotation. EP-A-1486227 discloses an inhaler for dry powered medicament having a ratchet mechanism for a tape dose counter which is operated when a mouthpiece of the inhaler is closed. Due to the way in which the mouthpiece is opened and closed, and actuation pawl of the device which is mounted on a yoke, travels a known long stroke of consistent length as the mouthpiece is opened and closed. WO 2008/119552 discloses a metered-dose inhaler which is suitable for breath-operated applications and operates with a known and constant canister stroke length of 3.04 mm+/−0.255 mm. A stock bobbin of the counter, from which a tape is unwound, rotates on a shaft having a split pin intended to hold the stock bobbin taut. However, some dose counters do not keep a particularly reliable count, such as if they are dropped onto a hard surface. More recently, it has become desirable to improve dose counters further and, in particular, it is felt that it would be useful to provide extremely accurate dose counters for manually-operated canister-type metered dose inhalers. Unfortunately, in these inhalers, it has been found in the course of making the present invention that the stroke length of the canister is to a very large extent controlled on each dose operation by the user, and by hand. Therefore, the stroke length is highly variable and it is found to be extremely difficult to provide a highly reliable dose counter for these applications. The dose counter must not count a dose when the canister has not fired since this might wrongly indicate to the user that a dose has been applied and if done repeatedly the user would throw away the canister or whole device before it is really time to change the device due to the active drug and propellant reaching a set minimum. Additionally, the canister must not fire without the dose counter counting because the user may then apply another dose thinking that the canister has not fired, and if this is done repeatedly the active drug and/or propellant may run out while the user thinks the device is still suitable for use according to the counter. It has also been found to be fairly difficult to assembly some known inhaler devices and the dose counters therefor. Additionally, it is felt desirable to improve upon inhalers by making them easily usable after they have been washed with water. The present invention aims to alleviate at least to a certain extent one or more of the problems of the prior art. | <SOH> SUMMARY OF THE INVENTION <EOH>According to a first aspect of the present invention there is provided a dose counter for an inhaler, the dose counter having a counter display arranged to indicate dosage information, a drive system arranged to move the counter display incrementally in a first direction from a first station to a second station in response to actuation input, wherein a regulator is provided which is arranged to act upon the counter display at the first station to regulate motion of the counter display at the first station to incremental movements. The regulator is advantageous in that it helps prevent unwanted motion of the counter display if the counter is dropped. According to a further aspect of the present invention, the regulator provides a resistance force of greater than 0.1 N against movement of the counter display. According to still a further aspect of the present invention, the resistance force is greater than 0.3 N. According to yet a further aspect of the present invention, the resistance force is from 0.3 to 0.4 N. Preferably, the counter comprises a tape. Preferably, the tape has dose counter indicia displayed thereon. The first station may comprise a region of the dose counter where tape is held which is located before a display location, such as a display window, for the counter indicia. The first station may comprise a first shaft, the tape being arranged on the first shaft and to unwind therefrom upon movement of the counter display. The first shaft may be mounted for rotation relative to a substantially rotationally fixed element of the dose counter. The regulator may comprise at least one projection which is arranged on one of the first shaft and the substantially rotationally fixed element and to engage incrementally with one or more formations on the other of the first shaft and the substantially rotationally fixed element. At least two said projections may be provided. Exactly two said projections maybe provided. Each projection may comprise a radiused surface. The at least one projection may be located on the substantially fixed element which may comprise a fixed shaft which is fixed to a main body of the dose counter, the first shaft being rotationally mounted to the fixed shaft. Preferably, the fixed shaft has at least two resiliently flexible legs (or forks). Each leg may have at least one said projection formed in an outwardly facing direction thereon, said one or more formations being formed on an inwardly facing engagement surface of the first shaft, said at least one projection being arranged to resiliently engage said one or more formations. Preferably, a series of said formations are provided. An even number of said formations may be provided. Eight to twelve of said formations may be provided. In one embodiment, ten said formations are provided. Each said formation may comprise a concavity formed on an engagement surface. Each concavity may comprise a radiused surface wall portion which preferably merges on at least one side thereof into a flat wall portion surface. The engagement surface may include a series of said concavities, and convex wall portions of the engagement surface may be formed between each adjacent two said concavities, each said convex wall portion comprising a convex radiused wall portion. Each convex radiused wall portion of each convex wall portion may be connected by said flat wall portion surfaces to each adjacent concavity. The fixed shaft may comprise a split pin with fork legs and each projection may be located on a said fork leg. The first shaft may comprise a substantially hollow bobbin. Said at least one formation may be located on an inner surface of the bobbin. In other embodiments it may be located on an outer surface thereof. Said engagement surface may extend partially along said bobbin, a remainder of the respective inner or outer surface having a generally smooth journal portion along at least a portion thereof. The drive system may comprise a tooth ratchet wheel arranged to act upon a second shaft which is located at the second station, the second shaft being rotatable to wind the tape onto the second shaft. The second shaft may be located on a main body of the dose counter spaced from and parallel to the first shaft. The ratchet wheel may be fixed to the second shaft is arranged to rotate therewith. The ratchet wheel may be secured to an end of the second shaft and aligned coaxially with the second shaft. The dose counter may include anti-back drive system which is arranged to restrict motion of the second shaft. The anti-back drive system may include a substantially fixed tooth arranged to act upon teeth of the ratchet wheel. According to a further aspect of the present invention, a dose counter includes an anti-back drive system which is arranged to restrict motion of the second shaft in a tape winding direction. According to a further aspect of the present invention there is provided a shaft for holding counter tape in a dose counter for an inhaler, the shaft having an engagement surface including incrementally spaced formations located around a periphery thereof, the formations comprising a series of curved concavities and convex portions. The shaft may comprise a hollow bobbin. The engagement surface may be a generally cylindrical inwardly directed surface. The engagement surface may include a flat surface wall portion joining each concavity and convex wall portion. Each concavity may comprise a radiused wall portion. Each convex wall portion may comprise a radiused wall portion. Said concavities may be regularly spaced around a longitudinal axis of the shaft. Said convex wall portions may be regularly spaced around a longitudinal axis of the shaft. In some embodiments there may be from eight to twelve said concavities and/or convex wall portions regularly spaced around a longitudinal axis thereof. One embodiment includes ten said concavities and/or convex wall portions regularly spaced around a longitudinal axis of the shaft. According to a further aspect of the present invention there is provided a shaft and counter tape assembly for use in a dose counter for an inhaler, the assembly comprising a rotatable shaft and a counter tape which is wound around the shaft and is adapted to unwind therefrom upon inhaler actuation, the shaft having an engagement surface which includes incrementally spaced formations located around a periphery thereof. According to a further aspect of the present invention there is provided an inhaler for the inhalation of medication and the like, the inhaler including a dose counter as in the first aspect of the present invention. A preferred construction consists of a manually operated metered dose inhaler including a dose counter chamber including a dose display tape driven by a ratchet wheel which is driven in turn by an actuator pawl actuated by movement of a canister, the tape unwinding from a stock bobbin during use of the inhaler, a rotation regulator being provided for the stock bobbin and comprising a wavelike engagement surface with concavities which engage against control elements in the form of protrusions on resilient forks of a split pin thereby permitting incremental unwinding of the stock bobbin yet resisting excessive rotation if the inhaler is dropped onto a hard surface. According to another aspect of the present invention there is provided a dose counter for a metered dose inhaler having a body arranged to retain a medicament canister of predetermined configuration for movement of the canister relative thereto; the dose counter comprising: an incremental counting system for counting doses, the incremental counting system having a main body, an actuator arranged to be driven in response to canister motion and to drive an incremental output member in response to canister motion, the actuator and incremental output member being configured to have predetermined canister fire and count configurations in a canister fire sequence, the canister fire configuration being determined by a position of the actuator relative to a datum at which the canister fires medicament and the count configuration being determined by a position of the actuator relative to the datum at which the incremental count system makes an incremental count, wherein the actuator is arranged to reach a position thereof in the count configuration at or after a position thereof in the canister fire configuration. This arrangement has been found to be highly advantageous since it provides an extremely accurate dose counter which is suitable for use with manually operated metered dose inhalers. It has been found that dose counters with these features have a failure rate of less than 50 failed counts per million full canister activation depressions. It has been found in the course of making the present invention that highly reliable counting can be achieved with the dose counter counting at or soon after the point at which the canister fires. It has been is covered by the present inventors that momentum and motion involved in firing the canister, and in some embodiments a slight reduction in canister back pressure on the user at the time of canister firing, can very reliably result in additional further motion past the count point. The actuator and incremental counting system may be arranged such that the actuator is displaced less than 1 mm, typically 0.25 to 0.75 mm, more preferably about 0.4 to 0.6 mm, relative to the body between its location in the count and fire configurations, about 0.48 mm being preferred. The canister, which can move substantially in line with the actuator, can reliably move this additional distance so as to achieve very reliable counting. The incremental count system may comprise a ratchet mechanism and the incremental output member may comprise a ratchet wheel having a plurality of circumferentially spaced teeth arranged to engage the actuator. The actuator may comprise an actuator pawl arranged to engage on teeth of the ratchet wheel. The actuator pawl may be arranged to be connected to or integral with an actuator pin arranged to engage and be depressed by a medicament canister bottom flange. The actuator pawl may be generally U-shaped having two parallel arms arranged to pull on a central pawl member arranged substantially perpendicular thereto. This provides a very reliable actuator pawl which can reliably pull on the teeth of the ratchet wheel. The incremental count system may include a tape counter having tape with incremental dose indicia located thereon, the tape being positioned on a tape stock bobbin and being arranged to unwind therefrom. The actuator and incremental output member may be arranged to provide a start configuration at which the actuator is spaced from the ratchet output member, a reset configuration at which the actuator is brought into engagement with the incremental output member during a canister fire sequence, and an end configuration at which the actuator disengages from the ratchet output during a canister fire sequence. The actuator may be arranged to be located about 1.5 to 2.0 mm, from its location in the fire configuration, when in the start configuration, about 1.80 mm being preferred. The actuator may be arranged to be located about 1.0 to 1.2 mm, from its location in the fire configuration, when in the reset configuration, about 1.11 mm being preferred. The actuator may be arranged to be located about 1.1 to 1.3 mm, from its location in the fire configuration, when in the end configuration, about 1.18 mm being preferred. These arrangements provide extremely reliable dose counting, especially with manually operated canister type metered dose inhalers. The main body may include a formation for forcing the actuator to disengage from the incremental output member when the actuator is moved past the end configuration. The formation may comprise a bumped up portion of an otherwise generally straight surface against which the actuator engages and along which it is arranged to slide during a canister firing sequence. The dose counter may include a counter pawl, the counter pawl having a tooth arranged to engage the incremental output member, the tooth and incremental output member being arranged to permit one way only incremental relative motion therebetween. When the incremental output member comprises a ratchet wheel, the tooth can therefore serve as an anti-back drive tooth for the ratchet wheel, thereby permitting only one way motion or rotation thereof. The counter pawl may be substantially fixedly mounted on the main body of the incremental count system and the counter pawl may be arranged to be capable of repeatedly engaging equi-spaced teeth of the incremental output member in anti-back drive interlock configurations as the counter is operated. The counter pawl may be positioned so that the incremental output member is halfway, or substantially halfway moved from one anti-back drive interlock configuration to the next when the actuator and incremental output member are in the end configuration thereof. This is highly advantageous in that it minimises the risk of double counting or non-counting by the dose counter. According to a further aspect of the invention there is provided an inhaler comprising a main body arranged to retain a medicament canister of predetermined configuration and a dose counter mounted in the main body. The inhaler main body may include a canister receiving portion and a separate counter chamber, the dose counter being located within the main body thereof, the incremental output member and actuator thereof inside the counter chamber, the main body of the inhaler having wall surfaces separating the canister-receiving portion and the counter chamber, the wall surfaces being provided with a communication aperture, an actuation member extending through the communication aperture to transmit canister motion to the actuator. According to a further aspect of the present invention there is a provided an inhaler for metered dose inhalation, the inhaler comprising a main body having a canister housing arranged to retain a medicament canister for motion therein, and a dose counter, the dose counter having an actuation member having at least a portion thereof located in the canister housing for operation by movement of a medicament canister, wherein the canister housing has an inner wall, and a first inner wall canister support formation located directly adjacent the actuation member. This is highly advantageous in that the first inner wall canister support formation can prevent a canister from rocking too much relative to the main body of the inhaler. Since the canister may operate the actuation member of the dose counter, this substantially improves dose counting and avoids counter errors. The canister housing may have a longitudinal axis which passes through a central outlet port thereof, the central outlet port being arranged to mate with an outer canister fire stem of a medicament canister, the inner wall canister support formation, the actuation member and the outlet port lying in a common plane coincident with the longitudinal axis. Accordingly, this construction may prevent the canister from rocking towards the position of the dose counter actuation member, thereby minimising errors in counting. The canister housing may have a further inner canister wall support formation located on the inner wall opposite, or substantially opposite, the actuation member. Accordingly, the canister may be supported against rocking motion away from the actuator member so as to minimise count errors. The canister housing may be generally straight and tubular and may have an arrangement in which each said inner wall support formation comprises a rail extending longitudinally along the inner wall. Each said rail may be stepped, in that it may have a first portion located towards a medicine outlet end or stem block of the canister housing which extends inwardly a first distance from a main surface of the inner wall and a second portion located toward an opposite end of the canister chamber which extends inwardly a second, smaller distance from the main surface of the inner wall. This may therefore enable easy insertion of a canister into the canister housing such that a canister can be lined up gradually in step wise function as it is inserted into the canister housing. The inhaler may include additional canister support rails which are spaced around an inner periphery of the inner wall of the canister housing and which extend longitudinally therealong. At least one of the additional rails may extend a constant distance inwardly from the main surface of the inner wall. At least one of the additional rails may be formed with a similar configuration to the first inner wall canister support formation. The dose counter may, apart from said at least a portion of the actuation member, be located in a counter chamber separate from the canister housing, the actuation member comprising a pin extending through an aperture in a wall which separates the counter chamber and the canister housing. According to a further aspect of the present invention there is provided an inhaler for inhaling medicaments having: a body for retaining a medicament store; the body including a dose counter, the dose counter having a moveable actuator and a return spring for the actuator, the return spring having a generally cylindrical and annular end; the body having a support formation therein for supporting said end of the return spring, the support formation comprising a shelf onto which said end is engageable and a recess below the shelf. This shelf and recess arrangement is highly advantageous since it allows a tool (such as manual or mechanical tweezers) to be used to place the return spring of the actuator onto the shelf with the tool then being withdrawn at least partially via the recess. The shelf may be U-shaped. The support formation may include a U-shaped upstanding wall extending around the U-shaped shelf, the shelf and upstanding wall thereby forming a step and riser of a stepped arrangement. The recess below the shelf my also be U-shaped. At least one chamfered surface may be provided at an entrance to the shelf. This may assist in inserting the actuator and return spring into position. A further aspect of the invention provides a method of assembly of an inhaler which includes the step of locating said end of said spring on the shelf with an assembly tool and then withdrawing the assembly tool at least partly via the recess. This assembly method is highly advantageous compared to prior art methods in which spring insertion has been difficult and in which withdrawal of the tool has sometimes accidentally withdrawn the spring again. The cylindrical and annular end of the spring may be movable in a direction transverse to its cylindrical extent into the shelf while being located thereon. According to a further aspect of the present invention there is provided an inhaler for inhaling medicament, the inhaler having a body for retaining a medicament store; and a dose counter, the dose counter having a moveable actuator and a chassis mounted on the body; the chassis being heat staked in position on the body. This is be highly advantageous in that the chassis can be very accurately positioned and held firmly in place, thereby further improving counting accuracy compared to prior art arrangements in which some movement of the chassis relative to the body may be tolerated in snap-fit connections. The chassis may have at least one of a pin or aperture heat staked to a respective aperture or pin of the body. The chassis may have a ratchet counter output member mounted thereon. The ratchet counter output member may comprise a ratchet wheel arranged to reel in incrementally a dose meter tape having a dosage indicia located thereon. According to a further aspect of the present invention there is provided a method of assembling an inhaler including the step of heat staking the chassis onto the body. The step of heat staking is highly advantageous in fixedly positioning the chassis onto the body in order to achieve highly accurate dose counting in the assembled inhaler. The method of assembly may include mounting a spring-returned ratchet actuator in the body before heat staking the chassis in place. The method of assembly may include pre-assembling the chassis with a dose meter tape prior to the step of heat staking the chassis in place. The method of assembly may include attaching a dose meter cover onto the body after the heat staking step. The cover may be welded onto the body or may in some embodiments be glued or otherwise attached in place. According to a further aspect of the present invention there is provided an inhaler for inhaling medicament and having a body, the body have a main part thereof for retaining a medicament store; and a dose counter, the dose counter being located in a dose counter chamber of the body which is separated from the main part of the body, the dose counter chamber of the body having a dosage display and being perforated so as to permit the evaporation of water or aqueous matter in the dose counter chamber into the atmosphere. This is high advantageous since it enables the inhaler to be thoroughly washed and the dose counting chamber can thereafter dry out fully. The display may comprise a mechanical counter display inside the dose counter chamber and a window for viewing the mechanical counter display. The mechanical counter display may comprise a tape. The perforated dose counter chamber may therefore enable reliable washing of the inhaler, if desired by the user, and may therefore dry out without the display window misting up. The dose counter chamber may be perforated by a drain hole formed through an outer hole of the body. The drain hole may be located at a bottom portion of the body of the inhaler, thereby enabling full draining of the inhaler to be encouraged after washing when the inhaler is brought into an upright position. According to a further aspect of the present invention there is provided a dose counter for an inhaler, the dose counter having a display tape arranged to be incrementally driven from a tape stock bobbin onto an incremental tape take-up drive shaft, the bobbin having an internal bore supported by and for rotation about a support shaft, at least one of the bore and support shaft having a protrusion which is resiliently biased into frictional engagement with the other of the bore and support shaft with longitudinally extending mutual frictional interaction. This arrangement may provide good friction for the bobbin, thereby improving tape counter display accuracy and preventing the bobbin from unwinding undesirably for example if the inhaler is accidentally dropped. The support shaft may be forked and resilient for resiliently biasing the support shaft and bore into frictional engagement. The support shaft may have two forks, or more in some cases, each having a radially extending protrusion having a friction edge extending therealong parallel to a longitudinal axis of the support shaft for frictionally engaging the bore of the support shaft with longitudinally extending frictional interaction therebetween. The bore may be a smooth circularly cylindrical or substantially cylindrical bore. Each of the above inhalers in accordance with aspects of the present invention may have a medicament canister mounted thereto. The canister may comprise a pressurised metered dose canister having a reciprocally movable stem extending therefrom and movable into a main canister portion thereof for releasing a metered dose of medicament under pressure, for example by operating a metered dose valve inside the canister body. The canister may be operable by pressing by hand on the main canister body. In cases in which one or more support rails or inner wall support formations are provided, the canister may at all times when within the canister chamber have a clearance of about 0.25 to 0.35 mm from the first inner wall support formation. The clearance may be almost exactly 0.3 mm. This clearance which may apply to the canister body itself or to the canister once a label has been applied, is enough to allow smooth motion of the canister in the inhaler while at the same time preventing substantial rocking of the canister which could result in inaccurate counting by a dose counter of the inhaler, especially when lower face of the canister is arranged to engage an actuator member of the dose counter for counting purposes. According to a further aspect of the invention, a method of assembling a dose counter for an inhaler comprises the steps of providing a tape with dosing indicia thereon; providing tape positioning indicia on the tape; and stowing the tape while monitoring for the tape positioning indicia with a sensor. The method advantageously permits efficient and accurate stowing of the tape, e.g. by winding. The dosing indicia may be provided as numbers, the tape positioning indicia may be provided as one or more lines across the tape. The stowing step comprises winding the tape onto a bobbin or shaft, and, optionally, stopping winding when the positioning indicia are in a predetermined position. The tape may be provided with pixelated indicia at a position spaced along the tape from the positioning indicia. The tape may also be provided with a priming dot. According to a further aspect of the invention, a tape system for a dose counter for an inhaler has a main elongate tape structure, and dosing indicia and tape positioning indicia located on the tape structure. The tape positioning indicia may comprise at least one line extending across the tape structure. The tape system may comprise pixelated indicia located on the tape structure and spaced from the positioning indicia. The tape system may comprise a priming dot located on the tape structure. The positioning indicia may be located between the timing dot and the pixelated indicia. The main elongate tape structure may have at least one end thereof wound on a bobbin or shaft. A further aspect of the invention provides a method of designing an incremental dose counter for an inhaler comprising the steps of calculating nominal canister fire and dose counter positions for a dose counter actuator of the inhaler; calculating a failure/success rate for dose counters built to tolerance levels for counting each fire of inhalers in which the dose counter actuators may be applied; and selecting a tolerance level to result in said failure/success rate to be at or below/above a predetermined value. This is highly advantageous in that it allows an efficient and accurate prediction of the reliability of a series of inhaler counters made in accordance with the design. The method of designing may include selecting the failure/success rate as a failure rate of no more than one in 50 million. The method of designing may include setting an average count position for dose counters built to the tolerances to be at or after an average fire position thereof during canister firing motion. The method of designing may include setting the average count position to be about 0.4 to 0.6 mm after the average fire position, such as about 0.48 mm after. The method of designing may include setting tolerances for the standard deviation of the fire position in dose counters built to the tolerances to be about 0.12 to 0.16 mm, such as about 0.141 mm. The method of designing may include setting tolerances for the standard deviation of the count positions in dose counters built to the tolerances to be about 0.07 to 0.09 mm, such as about 0.08 mm. A further aspect of the invention provides a computer implemented method of designing an incremental dose counter for an inhaler which includes the aforementioned method of designing. A further aspect of the invention provides a method of manufacturing in a production run a series of incremental dose counters for inhalers which comprises manufacturing the series of dose counters in accordance with the aforementioned method of designing. A further aspect of the invention provides a method of manufacturing a series of incremental dose counters for inhalers, which comprises manufacturing the dose counters with nominal canister fire and dose count positions of a dose counter actuator relative to a dose counter chassis (or inhaler main body), and which includes building the dose counters with the average dose count position in the series being, in canister fire process, at or after the average canister fire position in the series. According to a further aspect of the invention, the method provides fitting each dose counter in the series of incremental dose counters to a corresponding main body of an inhaler. These aspects advantageously provide for the production run of a series of inhalers and dose counters which count reliably in operation. According to a further aspect of the invention, an incremental dose counter for a metered dose inhaler has a body arranged to retain a canister for movement of the canister relative thereto, the incremental dose counter having a main body, an actuator arranged to be driven and to drive an incremental output member in a count direction in response to canister motion, the actuator being configured to restrict motion of the output member in a direction opposite to the count direction. This advantageously enables an inhaler dose counter to keep a reliable count of remaining doses even if dropped or otherwise jolted. The output member may comprise a ratchet wheel. The actuator may comprise a pawl and in which the ratchet wheel and pawl are arranged to permit only one-way ratcheting motion of the wheel relative to the pawl. The dose counter may include an anti-back drive member fixed to the main body. In a rest position of the dose counter, the ratchet wheel is capable of adopting a configuration in which a back surface of one tooth thereof engages the anti-back drive member and the pawl is spaced from an adjacent back surface of another tooth of the ratchet wheel without positive drive/blocking engagement between the pawl and wheel. | A61M150078 | 20171106 | 20180301 | 79850.0 | A61M1500 | 2 | HESS, DANIEL A | Dose Counter for Inhaler Having An Anti-Reverse Rotation Actuator | UNDISCOUNTED | 1 | CONT-ACCEPTED | A61M | 2,017 |
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15,804,822 | PENDING | MOBILE TERMINAL DEVICE AND ASSOCIATED METHOD FOR OBTAINING UPLINK RESOURCES | A method of allocating radio resources for uplink transmissions in a wireless telecommunications system, the method including: a first terminal device communicating a request for an allocation of radio resources to a base station; the base station determining there is an association between the first terminal device and a second terminal device based on their having similar predicted traffic profiles for uplink data; and the base station establishing a radio resource allocation for the second terminal device based on the resources requested by the first terminal device, and consequently transmitting radio resource allocation messages to allocate radio resources to the first and the second terminal devices for respective uplink transmissions based on the request for an allocation of radio resources received from the first terminal device. | 1. A method of operating a terminal device that communicates with a base station in a wireless telecommunications system, the method comprising: determining when uplink data is waiting for transmission to the base station, whether to transmit a request for an allocation of radio resources to the terminal device for transmission of the uplink data to the base station; and waiting, when the uplink data is waiting for transmission to the base station, to receive a radio resource allocation message from the base station, the radio resource allocation message indicating radio resources to be used for transmissions associated with the uplink data. 2. The method according to claim 1, wherein determining whether to transmit the request for an allocation of radio resources comprises determining that the terminal device should not initiate a random access procedure of the wireless telecommunications system. 3. The method according to claim 2, wherein determining that the terminal device should not initiate the random access procedure of the wireless telecommunications system comprises determining that the terminal device should not make transmissions on a physical random access channel of the wireless telecommunications system. 4. The method according to claim 1, wherein determining whether to transmit the request for an allocation of radio resources is based on the terminal device receiving an indication that the terminal device should not transmit the request for an allocation of radio resources. 5. The method according to claim 4, wherein the indication indicates that another terminal device in the wireless telecommunications system has made a request for an allocation of radio resources. 6. The method according to claim 1, wherein determining whether to transmit the request for an allocation of radio resources is based on the terminal device having received an access request denial message from the base station. 7. The method according to claim 1, further comprising subsequently receiving the radio resource allocation message from the base station. 8. The method according to claim 7, further comprising transmitting the uplink data to the base station using radio resources derived from information in the radio resource allocation message received from the base station. 9. The method according to claim 8, further comprising: determining, at a later time after having transmitted the uplink data to the base station, that the terminal device has further uplink data waiting for transmission to the base station; and in response determining that the terminal device has the further uplink data, determining that the terminal device should transmit a second request for an allocation of radio resources on which to transmit the uplink data to the base station, and transmitting such a request. 10. The method according to claim 9, wherein determining that the terminal device should transmit the second request for the allocation of radio resources is based on the terminal device having received an access request allow message from the base station indicating that the terminal device is allowed to make the second request for an allocation of radio resources. 11. The method according to claim 7, further comprising: determining that the allocation of radio resources is not sufficient for the uplink data waiting for transmission to the base station; and transmitting to the base station an indication of a request for a further allocation of radio resources in response thereto. 12. The method according to claim 11, wherein the indication of a request for a further allocation of radio resources is transmitted to the base station using the allocated radio resources. 13. The method according to claim 1, further comprising transmitting a second request, for the allocation of radio resources on which to transmit the uplink data to the base station after waiting to receive the radio resource allocation message from the base station for a period of time without having received the radio resource allocation message from the base station. 14. The method according to claim 1, wherein the terminal device is a machine type communication (MTC), terminal device. 15. The method according to claim 1, wherein the wireless telecommunications system is associated with a radio interface spanning a system frequency bandwidth for supporting radio communications with a first type of terminal device and comprising a restricted frequency bandwidth for supporting radio communications with a second type of terminal device, wherein the restricted frequency bandwidth is narrower than and within the system frequency bandwidth, and wherein the terminal device is a terminal device of the second type. 16. A terminal device that communicates with a base station in a wireless telecommunications system, wherein the terminal device is configured to: determine, when uplink data is waiting for transmission to the base station, whether to transmit a request for an allocation of radio resources to the terminal device for transmission of the uplink data to the base station; and wait, when the uplink data is waiting for transmission to the base station, to receive a radio resource allocation message from the base station, the radio resource allocation message indicating radio resources to be used for transmissions associated with the uplink data. 17. The terminal device according to claim 16, wherein the terminal device is configured such that determining whether to transmit the request for an allocation of radio resources comprises determining that the terminal device should not initiate a random access procedure of the wireless telecommunications system. 18. The terminal device according to claim 17, wherein the terminal device is configured such that determining that the terminal device should not initiate the random access procedure of the wireless telecommunications system comprises determining that the terminal device should not make transmissions on a physical random access channel of the wireless telecommunications system. 19. The terminal device according to claim 16, wherein the terminal device is configured such that determining whether to transmit the request for an allocation of radio resources is based on the terminal device receiving an indication that the terminal device should not transmit a request for an allocation of radio resources. 20. (canceled) 21. A terminal device that communicates with a base station in a wireless telecommunications system, the terminal device comprising: processing circuitry configured to determine, then uplink data is waiting for transmission to the base station, whether to transmit a request for an allocation of radio resources to the terminal device for transmission of the uplink data to the base station; and wait, when the uplink data is waiting for transmission to the base station, to receive a radio resource allocation message from the base station, the radio resource allocation message indicating radio resources to be used for transmissions associated with the uplink data. | The present application is a continuation of U.S. application Ser. No. 14/434,335, filed Apr. 8, 2015, which is based on PCT/GB2013/052738 filed Oct. 21, 2013, and claims priority to British Patent Application 1222902.7, filed in the UK IPO Dec. 19, 2012, the entire contents of each of which being incorporated herein by reference. BACKGROUND OF THE INVENTION The present invention relates to methods, systems and apparatus for use in wireless (mobile) telecommunications systems. In particular, embodiments of the invention relate to communicating uplink allocations of radio resources from a base station to a terminal device in such systems. Third and fourth generation mobile telecommunication systems, such as those based on the 3GPP defined UMTS and Long Term Evolution (LTE) architectures, are able to support more sophisticated services than simple voice and messaging services offered by previous generations of mobile telecommunication systems. For example, with the improved radio interface and enhanced data rates provided by LTE systems, a user is able to enjoy high data rate applications such as mobile video streaming and mobile video conferencing that would previously only have been available via a fixed line data connection. The demand to deploy third and fourth generation networks is therefore strong and the coverage area needed of these networks, i.e. geographic locations where access to the networks is desired, is expected to increase rapidly. The anticipated widespread deployment of third and fourth generation networks has led to the parallel development of devices and applications which, rather than taking advantage of the high data rates available, instead take advantage of the robust radio interface and increasing ubiquity of the coverage area. Examples include so-called machine type communication (MTC) applications, which are typified by semi-autonomous or autonomous wireless communication devices (i.e. MTC devices) communicating small amounts of data on a relatively infrequent basis. Examples include so-called smart meters which, for example, are located in a customer's house and periodically transmit information back to a central MTC server relating to the customer's consumption of a utility such as gas, water, electricity and so on. Further information on characteristics of MTC-type devices can be found, for example, in the corresponding standards, such as ETSI TS 122 368 V10.530 (2011 July )/3GPP TS 22.368 version 10.5.0 Release 10) [1]. Some typical characteristics of MTC type terminal devices/MTC type data might include, for example, characteristics such as low mobility, high delay tolerance, small data transmissions, a level of predictability for traffic usage and timing (i.e. traffic profile), relatively infrequent transmissions and group-based features, policing and addressing. As a result of the increasing use of wireless telecommunications networks generally, and also the development of devices such as MTC devices with their potential for introducing large numbers of terminal devices into networks, there is a desire to provide for wireless telecommunications networks that can reliably support access by increasing numbers of devices. This desire to support more devices, however, gives rise to an increased potential for issues with network congestion and interference, particular in respect of the radio access interface. These issues may be particularly relevant in respect of those communications which are not centrally managed by a scheduler in a communication cell of a network, such as random access communications from terminal devices seeking to access the network before having been allocated dedicated radio resources for doing so. There is therefore a desire to provide for telecommunications apparatus and methods which can help reduce the potential for radio network congestion and interference in circumstances where there might be relatively large numbers of terminal devices seeking access to the network. SUMMARY OF THE INVENTION According to a first aspect of the invention there is provided a method of operating a base station for allocating radio resources for uplink transmissions in a wireless telecommunications system, the method comprising: receiving a request for an allocation of radio resources from a first terminal device; determining an association between the first terminal device and a second terminal device; and transmitting a radio resource allocation message to allocate radio resources to the second terminal device for an uplink transmission in response to receiving the request for an allocation of radio resources from the first terminal device. In accordance with some embodiments the request for an allocation of radio resources from the first terminal device is received on a random access channel of the wireless telecommunications system. In accordance with some embodiments the request for an allocation of radio resources from the first terminal device is associated with a random access procedure of the wireless telecommunications system. In accordance with some embodiments the radio resources allocated to the second terminal device correspond with an allocation of radio resources requested by the first terminal device. In accordance with some embodiments the association between the first terminal device and the second terminal device is established based on the first terminal device and the second terminal device having a common characteristic relating to their uplink transmissions. In accordance with some embodiments the association between the first terminal device and the second terminal device is established based on the first terminal device and the second terminal device being associated with a same terminal device classifier. In accordance with some embodiments the terminal device classifier is a quality class indicator of respective bearers associated with the respective terminal devices. In accordance with sonic embodiments the method further comprises transmitting an access request denial message to the second terminal device to instruct the second terminal device not to make its own request for an allocation of radio resources. In accordance with some embodiments the method further comprises transmitting a cease access request denial message to the second terminal device after having transmitted the access request denial message to instruct the second terminal device that it is now allowed to make its own request for an allocation of radio resources. In accordance with some embodiments the method further comprises transmitting an access request allow message to the first terminal device to instruct the first terminal device that it is allowed to make the request for the allocation of radio resources. In accordance with some embodiments the method further comprises selecting the first terminal device from a plurality of terminal devices as the terminal device to which the access request allow message is transmitted based on a transmission characteristic associated with respective ones of the plurality of terminal devices. In accordance with some embodiments the transmission characteristic is selected from the group comprising: a timing advance; a reference signal received power, a reference signal received quality, a sounding reference signal measurement at the base station, and a radio channel quality indicator. In accordance with some embodiments the method further comprises determining an association between the first terminal device and a further terminal device; and transmitting a radio resource allocation message to the further terminal device to allocate radio resources for an uplink transmission from the further terminal device based on the request for an allocation of radio resources from the first terminal device. In accordance with some embodiments the method further comprises determining an association between the first terminal device and a plurality of other terminal devices, transmitting an access request denial message to a subset of the plurality of other terminal devices to instruct the subset of the plurality of other terminal devices not to make their own requests for an allocation of radio resources, and transmitting radio resource allocation messages to the plurality of other terminal devices to allocate radio resources for respective uplink transmissions from respective ones of the plurality of other terminal devices based on the request for an allocation of radio resources from the first terminal device. In accordance with some embodiments the method further comprises receiving a transmission from the second terminal device using the radio resources allocated to the second terminal device. in accordance with some embodiments the transmission received from the second terminal device comprises an indication that the second terminal device does not require some or any of the allocated resources for uplink transmission. In accordance with some embodiments the transmission received from the second terminal device comprises an indication of a request for a further allocation of radio resources for a further uplink transmission from the second terminal device. In accordance with some embodiments the request for an allocation of radio resources received from the first terminal device comprises a request for an allocation of radio resources to allow the first terminal device to transmit a buffer status report to the base station. In accordance with some embodiments the first and second terminal devices are machine type communication, MTC, terminal devices. In accordance with some embodiments the wireless telecommunications system is associated with a radio interface spanning a system frequency bandwidth for supporting radio communications with a first type of terminal device and comprising a restricted frequency bandwidth for supporting radio communications with a second type of terminal device, wherein the restricted frequency bandwidth is narrower than and within the system frequency bandwidth, and wherein the first and second terminal devices are terminal devices of the second type. In accordance with a second aspect of the invention there is provided a base station configured to allocate radio resources for uplink transmissions in a wireless telecommunications system. the base station comprising: transceiver configured to receive a request for an allocation of radio resources from a first terminal device; and a controller unit configured to determine an association between the first terminal device and a second terminal device and to control the transceiver to transmit a radio resource allocation message to allocate radio resources to the second terminal device for an uplink transmission in response to receiving the request for an allocation of radio resources from the first terminal device. In accordance with some embodiments the base station is configured such that the request for an allocation of radio resources from the first terminal device is received on a random access channel of the wireless telecommunications system. In accordance with some embodiments the base station is configured such that the request for an allocation of radio resources from the first terminal device is associated with a random access procedure of the wireless telecommunications system. In accordance with some embodiments the base station is configured such that the radio resources allocated to the second terminal device correspond with an allocation of radio resources requested by the first terminal device. In accordance with some embodiments the base station is configured such that the association between the first terminal device and the second terminal device is established based on the first terminal device and the second terminal device having a common characteristic relating to their uplink transmissions. In accordance with some embodiments the base station is configured such that the association between the first terminal device and the second terminal device is established based on the first terminal device and the second terminal device being associated with a same terminal device classifier. In accordance with some embodiments the base station is configured such that the terminal device classifier is a quality class indicator of respective bearers associated with the respective terminal devices. In accordance with some embodiments the controller unit is further configured to control the transceiver to transmit an access request denial message to the second terminal device to instruct the second terminal device not to make its own request for an allocation of radio resources. In accordance with some embodiments the controller unit is further configured to control the transceiver to transmit a cease access request denial message to the second terminal device after having transmitted the access request denial message to instruct the second terminal device that it is now allowed to make its own request for an allocation of radio resources. In accordance with some embodiments the controller unit is further configured to control the transceiver to transmit an access request allow message to the first terminal device to instruct the first terminal device that it is allowed to make the request for the allocation of radio resources. In accordance with some embodiments the controller unit is further configured to select the first terminal device from a plurality of terminal devices as the terminal device to which the access request allow message is transmitted based on a transmission characteristic associated with respective ones of the plurality of terminal devices. In accordance with some embodiments the transmission characteristic is selected from the group comprising: a timing advance; a reference signal received power, a reference signal received quality, a sounding reference signal measurement at the base station, and a radio channel quality indicator. In accordance with some embodiments the controller unit is further configured to determine an association between the first terminal device and a further terminal device; and to cause the transceiver to transmit a radio resource allocation message to the further terminal device to allocate radio resources for an uplink transmission from the further terminal device based on the request for an allocation of radio resources from the first terminal device. In accordance with some embodiments the controller unit is further configured to determine an association between the first terminal device and a plurality of other terminal devices and to control the transceiver to transmit an access request denial message to a subset of the plurality of other terminal devices to instruct the subset of the plurality of other terminal devices not to make their own requests for an allocation of radio resources and to further transmit radio resource allocation messages to the plurality of other terminal devices to allocate radio resources for respective uplink transmissions from respective ones of the plurality of other terminal devices based on the request for an allocation of radio resources from the first terminal device. In accordance with some embodiments the transceiver is further configured to receive a transmission from the second terminal device using the radio resources allocated to the second terminal device. In accordance with some embodiments the transmission received from the second terminal device comprises an indication that the second terminal device does not require some or any of the allocated resources for uplink transmission. In accordance with some embodiments the transmission received from the second terminal device comprises an indication of a request for a further allocation of radio resources for a further uplink transmission from the second terminal device. In accordance with some embodiments the request for an allocation of radio resources received from the first terminal device comprises a request for an allocation of radio resources to allow the first terminal device to transmit a buffer status report to the base station. In accordance with some embodiments the first and second terminal devices are machine type communication, MTC, terminal devices. In accordance with some embodiments the wireless telecommunications system is associated with a radio interface spanning a system frequency bandwidth for supporting radio communications with a first type of terminal device and comprising a restricted frequency bandwidth for supporting radio communications with a second type of terminal device, wherein the restricted frequency bandwidth is narrower than and within the system frequency bandwidth, and wherein the first and second terminal devices are terminal devices of the second type. According to a third aspect of the invention there is provided a wireless telecommunications system comprising the base station of the second aspect of the invention and a terminal device. According to a fourth aspect of the invention there is provided a method of operating a terminal device for receiving an allocation of radio resources for transmission of uplink data to a base station in a wireless telecommunications system, the method comprising: determining that the terminal device has uplink data waiting for transmission to the base station; determining that the terminal device should not transmit a request for an allocation of radio resources for transmission of the uplink data to the base station, and waiting to receive a radio, resource allocation message from the base station to allocate radio resources to be used for transmissions associated with the uplink data waiting for transmission to the base station. In accordance with some embodiments determining that the terminal device should not transmit a request for an allocation of radio resources comprises determining that the terminal device should not initiate a random access procedure of the wireless telecommunications system. In accordance with some embodiments determining that the terminal device should not initiate a random access procedure of the wireless telecommunications system comprises determining that the terminal device should not make transmissions on a physical random access channel of the wireless telecommunications system. In accordance with some embodiments determining that the terminal device should not transmit a request for an allocation of radio resources is based on the terminal device receiving an indication that the terminal device should not transmit a request for an allocation of radio resources. In accordance with some embodiments the indication comprises an indication that another terminal device in the wireless telecommunications system has made a request for an allocation of radio resources. In accordance with some embodiments determining that the terminal device should not transmit a request for an allocation of radio resources is based on the terminal device having received an access request denial message from the base station. In accordance with some embodiments the method further comprises subsequently receiving the radio resource allocation message from the base station. In accordance with some embodiments the method further comprises transmitting the uplink data waiting for transmission to the base station using radio resources derived from information in the radio resource allocation message received from the base station. In accordance with some embodiments the method further comprises determining at a later time after having transmitted the uplink data to the base station that the terminal device has further uplink data waiting for transmission to the base station, and, in response thereto, determining that the terminal device should transmit a request for an allocation of radio resources on which to transmit the uplink data to the base station, and transmitting such a request, In accordance with some embodiments determining that the terminal device should transmit a request for an allocation of radio resources in response to determining that the terminal device has further uplink data waiting for transmission to the base station is based on the terminal device having received an access request allow message from the base station to indicate the terminal device is allowed to make a request for an allocation of radio resources. In accordance with some embodiments the method further comprises determining that the allocation of radio resources is not sufficient for the uplink data waiting for transmission to the base station and transmitting to the base station an indication of a request for a further allocation of radio resources in response thereto. In accordance with some embodiments the indication of a request for a further allocation of radio resources is transmitted to the base station using the allocated radio resources. in accordance with some embodiments the method further comprises transmitting a request for an allocation of radio resources on which to transmit the uplink data to the base station after waiting to receive a radio resource allocation message from the base station for a period of time without a radio resource allocation message being received from the base station. In accordance with some embodiments the terminal device is a machine type communication, MTC, terminal device. In accordance with some embodiments the wireless telecommunications system is associated with a radio interface spanning a system frequency bandwidth for supporting radio communications with a first type of terminal device and comprising a restricted frequency bandwidth for supporting radio communications with a second type of terminal device, Wherein the restricted frequency bandwidth is narrower than and within the system frequency bandwidth, and wherein the terminal device is a terminal device of the second type. According to a fifth aspect of the invention there is provided a terminal device arranged to receive an allocation of radio resources for transmission of uplink data to a base station in a wireless telecommunications system, wherein the terminal device is configured to: determine that the terminal device has uplink data waiting for transmission to the base station; determine that the terminal device should not transmit a request for an allocation of radio resources for transmission of the uplink data to the base station, and wait to receive a radio resource allocation message from the base station to allocate radio resources to be used for transmissions associated with the uplink data waiting for transmission to the base station. In accordance with some embodiments the terminal device is configured such that determining that the terminal device should not transmit a request for an allocation of radio resources comprises determining that the terminal device should not initiate a random access procedure of the wireless telecommunications system. In accordance with some embodiments the terminal device is configured such that determining that the terminal device should not initiate a random access procedure of the wireless telecommunications system comprises determining that the terminal device should not make transmissions on a physical random access channel of the wireless telecommunications system. In accordance with some embodiments the terminal device is configured such that determining that the terminal device should not transmit a request for an allocation of radio resources is based on the terminal device receiving an indication that the terminal device should not transmit a request for an allocation of radio resources. In accordance with some embodiments the indication comprises an indication that another terminal device in the wireless telecommunications system has made a request for an allocation of radio resources. In accordance with some embodiments the terminal device is configured such that determining that the terminal device should not transmit a request for an allocation of radio resources is based on the terminal device having received an access request denial message from the base station. In accordance with some embodiments the terminal device is further configured to subsequently receive the radio resource allocation message from the base station. In accordance with some embodiments the terminal device is further configured to transmit the uplink data waiting for transmission to the base station using radio resources derived from information in the radio resource allocation message received from the base station. In accordance with some embodiments the terminal device is further configured to determine at a later time after having transmitted the uplink data to the base station that the terminal device has further uplink data waiting for transmission to the base station, and, in response thereto, to determine that the terminal device should transmit a request for an allocation of radio resources on which to transmit the uplink data to the base station, and to transmit such a request. In accordance with some embodiments the terminal device is configured such that determining that the terminal device should transmit a request for an allocation of radio resources in response to determining that the terminal device has further uplink data waiting for transmission to the base station is based on the terminal device having received an access request allow message from the base station to indicate the terminal device is allowed to make a request for an allocation of radio resources. In accordance with some embodiments the terminal device is further configured to determine that the allocation of radio resources is not sufficient for the uplink data waiting for transmission to the base station and to transmit to the base station an indication of a request for a further allocation of radio resources in response thereto. In accordance with some embodiments the terminal device is configured such that the indication of a request for a further allocation of radio resources is transmitted to the base station using the allocated radio resources, In accordance with some embodiments the terminal device is further configured to transmit a request for an allocation of radio resources on which to transmit the uplink data to the base station after waiting to receive a radio resource allocation message from the base station for a period of time without a radio resource allocation message being received from the base station. In accordance with some embodiments the terminal device is a machine type communication, MTC, terminal device. In accordance with some embodiments the wireless telecommunications system is associated with a radio interface spanning a system frequency bandwidth for supporting radio communications with a first type of terminal device and comprising a restricted frequency bandwidth for supporting radio communications with a second type of terminal device, wherein the restricted frequency bandwidth is narrower than and within the system frequency bandwidth, and wherein the terminal device is a terminal device of the second type. According to a sixth aspect of the invention there is provided a wireless telecommunications system comprising the terminal device of the fifth aspect of the invention and a base station. It will be appreciated that features and aspects of the invention described above in relation to the first and other aspects of the invention are equally applicable to, and may be combined with, embodiments of the invention according to other aspects of the invention as appropriate, and not just in the specific combinations described above. BRIEF DESCRIPTION OF DRAWINGS Embodiments of the present invention will now be described by way of example only with reference to the accompanying drawings where like parts are provided with corresponding reference numerals and in which: FIG. 1 schematically represents an example of a conventional LTE-type wireless telecommunication network; FIG. 2 schematically represents a conventional random access procedure in a LIE-type wireless telecommunication network; FIG. 3 schematically represents some aspects of a conventional uplink radio frame structure a LTE-type wireless telecommunication network; FIG. 4 shows a table summarizing four potential formats in which a terminal device may transmit a random access preamble in accordance with a LTE-based network operating in a frequency division duplex (FDD) mode; FIG. 5 schematically represents an example of a LTE-type wireless telecommunication network according to an embodiment of the invention; and FIG. 6 schematically represents a scheme for allocating radio resources in a LTE-type wireless telecommunication network in accordance with an embodiment of the invention. DESCRIPTION OF EXAMPLE EMBODIMENTS FIG. 1 provides a schematic diagram illustrating some basic functionality of a wireless telecommunications network system 100 operating in accordance with LTE principles. Various elements of FIG. 1 and their respective modes of operation are well-known and defined in the relevant standards administered by the 3GPP® body and also described in many books on the subject, for example, Holma H. and Toskala A [2]. The network 100 includes a plurality of base stations 101 connected to a core network 102. Each base station provides a coverage area 103 (i.e. a cell) within which data can be communicated to and from terminal devices 104. Data is transmitted from base stations 101 to terminal devices 104 within their respective coverage areas 103 via a radio downlink. Data is transmitted from terminal devices 104 to the base stations 101 via a radio uplink. The radio downlink and radio uplink may together he considered to support the radio interface for the wireless telecommunications system. The core network 102 routes data between the respective base stations 101 and provides functions such as authentication, mobility management, charging and so on. As is well understood, terminal devices may also be referred to as mobile stations, user equipment (LTE), user terminal, mobile radio, and so forth, and base stations may also be referred to as transceiver stations/nodeBs e-NodeBs/eNBs, and so forth. In LTE-type networks scheduling decisions for both uplink (UL) and downlink (DL) transmissions are governed by a scheduler in the base station (eNodeB/eNB), For downlink, clearly the base station knows how much data is ready to be delivered to each terminal device. However, for uplink the base station is generally not initially aware of how much data needs to be communicated (and hence does not know how much radio resource needs to be allocated) because the data is buffered at the respective terminal devices. Consequently, in accordance with established LTE principles, terminal device are configured to communicate to their serving base station information regarding their buffer status (i.e. how much data the respective terminal devices have ready for uplink communication). This information is conventionally sent in a so-called Buffer Status Report (BSR) on an uplink shared channel (UL-SCH) which is physically transmitted on a physical uplink shared channel (PUSCH). Further information on BSRs can be found with reference to the relevant standards. See, for example, ETSI TS 136 321 V10.6.0 (2012 October)/3GPP TS 36.321 version 10.6.0 Release 10 [3] A BSR in a conventional LTE network is 6 bits long and a terminal device may send either one or four such BSRs at a time, reporting the number of bytes of data in either one group of logical channels or four groups of logical channels respectively. The 6 bits are quantized in the relevant specifications/standards to allow a terminal device to report buffer levels of between 0 and 150,000 bytes, or in the case of an extended BSR, between 0 and 3,000,000 bytes. A terminal device will have a Radio Resource Control (RRC) configuration determining whether it should send ordinary or extended BSRs. A BSR can be Regular, Periodic or Padding. A terminal device sends a Regular BSR when: a) Data arrives for a logical channel which has higher priority than the logical channels whose buffers previously contained data; b) Data becomes available for any logical channel when there was previously no data available for transmission; c) A ‘retxBSR’ timer expires and there is data available tier transmission. The retxBSR timer is used to alleviate the situation where the base station fails to receive BSR correctly but for some reason is not able successfully to inform the terminal device of this (perhaps because the BSR HACK is incorrectly decoded as ACK at the terminal device). Therefore, the retxBSR timer is reset each time an LT grant is received and BSR is transmitted when the timer expires. A Periodic BSR is sent when a periodicBSR timer expires and is used by RRC to control reporting. A Padding BSR is sent when there is space available in a Medium Access Control Protocol Data Unit (MAC PDU) that can accommodate a BSR. In accordance with conventional LTE principles, if a terminal device does not have a sufficient allocation of PUSCH resource to send a Regular BSR, it will instead attempt to send a one-bit Scheduling Request (SR) on a physical uplink control channel (PUCCH) in resources which can be allocated by RRC. If the terminal device does not have such an allocation, it will initiate a Random Access (RA) procedure in which it sends a SR to request an uplink (UL) grant of resources on PUSCH which are sufficient to send the BSR. Periodic and Padding BSR do not trigger SR (or RA). Random Access procedures in LTE-based networks can be contention based or non-contention based. A contention based RA procedure is triggered when a terminal device needing to send a BSR does not have a sufficient allocation of PUSCH resource to do so or any SR allocation on PUCCH. Random Access procedures generally involve accessing a random access transport channel (RACH in LTE terminology) with transmissions on an associated physical random access channel (PRACH in LTE terminology). To access RACH in a LTE-type network, a terminal device transmits a sequence, known as a preamble, using defined radio resources within the network's uplink radio frame structure (time-frequency resource grid). The base station is configured to monitor the defined resources for any of the preambles that a terminal device in the cell might transmit, and, on detecting such a preamble. responds in accordance with the defined RA procedure, which is summarized further below, In total, 838 preambles are defined in LTE, but currently a network operator configures each communication cell with only 64 preambles according to the characteristics of the cell. The preambles and the uplink resources for transmission of the preambles available for use in a particular communication cell are broadcast by the base station to the terminal devices with System Information Block (SIB) signaling, in particular, using SIB2. FIG. 2 is a ladder diagram schematically showing steps of a conventional LTE contention-based random access procedure in which a terminal device 104 (left-hand node in FIG. 2) seeks to access to a base station 101 (right-hand node in FIG. 2), For more details on LTE RA procedures see, for example, FBI TS 136 300 V10.8.0 (2012 July )/3GPP TS 36.300 version 10.8.0 Release 10 [4]. The steps of the contention-based RA procedure may be summarized as follows: Step 1. The terminal device 104 transmits a preamble from among the set configured for contention based RA in the communication cell served by the base station 101. Based on the radio resources used for the transmission the terminal device determines a RA-RNTI (Random Access Radio Network Temporary Identity) associated with the transmission. Step 2. The base station 101 sends a Random Access Response (RAR) addressed to RA-RNTI and containing the identity of the detected preamble, a timing alignment command and a temporary C-RNTI (Cell Radio Network Temporary Identity). Step 3. Assuming the terminal device receives the RAR from the base station within a specified time window after preamble transmission in Step 1, the terminal device transmits a so-called Message 3, which contains the appropriate RA procedure message. For example, the RA procedure message might be a scheduling request, a tracking area update or a RRC connection request. Step 4. On receiving Message 3 from Step 3, the base station sends a contention resolution message. The terminal device to which this message is addressed will transmit ACK/NACK response signaling in association with the defined HARQ (Hybrid Automatic Repeat request) procedures. Other contending terminal devices which successfully decode the message as a result of contention transmit no HARQ feedback and exit the RA procedure. The physical transmissions associated with the RA procedure in LTE-based networks are carried ort PRACH. This physical channel occupies a bandwidth of 1.08 MHz (falling within the width of 6 Resource blocks (RBs)) in the frequency domain and, unlike other aspects of LTE channels, employs a 1.25 kHz subcarrier spacing. The subframes of the uplink radio frame structure in which terminal devices are permitted to transmit PRACH are configurable per-cell by the network operator. PRACH is time- and frequency-multiplexed with PUSCH and PUCCH as schematically indicated in FIG. 3. FIG. 3 represents a time-frequency resource grid for a LTE-based uplink frame structure with a schematic indication of how PUSCH, PUCCH and TRACH are multiplexed. As can be seen from FIG. 3, PUCCH is associated with frequency resources towards the upper and lower edges of the system bandwidth; PUSCH is associated with frequency resources between the PUCCH regions; and PRACH is associated with discrete regions of resources within the PUSCH regions. The respective regions of time and frequency resources associated with PRACH occur once every PRACH slot period, and as noted above, have a bandwidth corresponding to 6 RBs. Whether PUSCH transmissions occur in PRACH slots is a matter for the base station scheduler. FIG. 4 is a table that summarizes the four potential formats in which a terminal device may transmit a RA preamble in Step 1 of FIG. 2 in accordance with a LTE-based network operating in a frequency division duplex (FDD) mode. The left-most column (“Preamble format”) lists the four potential preamble formats. The next column (“TCP”) lists the corresponding cyclic prefix duration in microseconds. The next column (“TSEQ”) lists the corresponding preamble sequence duration in microseconds. The next column (“TGT”) lists the corresponding guard time in microseconds. The right-most column (“PRACH slot duration”) lists the corresponding duration of each PRACH slot in subframes. A significant aspect of PRACH in LTE-type networks is that resources for PRACH transmissions extend for at least one subframe, and potentially longer for preamble formats 1 to 3, and occur at the same time as PUSCH and PUCCH transmissions. This means PRACH is a potential source of interference for PUSCH and PUCCH during times of overlapping transmissions, In accordance with some embodiments of the invention the potential for interference caused by PRACH transmissions may he reduced by providing for modified random access procedures as discussed further below. Interference associated with random access procedure transmissions can occur regardless of a wireless telecommunication's system bandwidth, but the issue can be expected to be relatively more significant in situations involving relatively narrow bandwidths. This is because the bandwidth of the PRACH channel can becomes a relatively larger part of the overall system bandwidth. In this respect, one area where PRACH transmissions could represent a particularly significant interference issue is in the use of the so-called virtual carrier networks, for example as discussed in co-pending UK patent applications numbered GB 1101970.0 [5], GB 1101981.7 [6], GB 1101966.8 [7], GB 1101983.3 [8], GB 1101853.8 [9], GB 1101982.5 [10], GB 1101980.9 [11], GB 1101972.6 [12], GB 1121767.6 [13] and GB 1121766.8 [14]. More information on virtual carriers can be found from these documents, but by way of a general overview, the concept underlying the virtual-carrier ideas is the use of a relatively narrow band of frequencies from within a wider host carrier bandwidth to support terminal devices operating within the narrower band. Thus, the narrower band within the host carrier may in some respects be considered as a separate carrier for supporting certain devices (i.e. virtual carrier). As noted above, certain classes of devices, such as MTC devices, support communication applications that can often be characterised by the transmission of small amounts of data at relatively infrequent intervals, and can thus operate with considerably less complexity than conventional LTE terminals. In many scenarios, providing low capability terminals such as those with a conventional high-performance LTE receiver unit capable of operating over a full system bandwidth can he overly complex for a device which only needs to communicate small amounts of data. This may therefore limit the practicality of a widespread deployment of low capability MTC type devices in a LTE network if the devices are required to support relatively complex transceivers. It is preferable instead to provide low capability terminals such as MTC devices with a simpler transceiver unit which is more proportionate with the amount of data likely to be transmitted to the terminal. In this regard, the provision of a relatively narrow band “virtual carrier” within the transmission resources of a conventional OFDM type downlink carrier (i.e. a “host carrier”) can allow devices with simpler transceivers to be accommodated. This is because data communicated on the virtual carrier can be received and decoded without needing to process the full bandwidth of the downlink host OFDM carrier. Accordingly, data communicated on the virtual carrier can be received and decoded using a reduced complexity transceiver unit, which, as noted above, is attractive for MTC type devices. One proposed bandwidth for virtual carrier operation is 1.4 MHz and this corresponds with the bandwidth for PRACH. Accordingly, it may be the case in a virtual carrier context that PRACH transmissions span, and hence potentially interfere with, the full bandwidth for PUSCH transmissions on the virtual carrier, possibly for up to 3 subframes (depending on preamble format), when a terminal device initiates a RA procedure. The PRACH transmissions may also interfere with PUCCH depending on scheduling. Accordingly, it is expected that narrow bandwidth carriers, such as virtual carriers operating within a wider bandwidth host carrier, may be most affected by PRACH transmissions associated with random access procedures resulting in a degradation in performance for PUSCH and PUCCH transmissions. Such a degradation in performance can be expected to result in increased need for retransmissions from terminal devices, thereby causing still further congestion and interference on the radio network, and consuming terminal device power reserves more quickly. Furthermore, as noted above, for MTC-type devices, where terminal devices may be more densely deployed, such PRACH to PUSCH PUCCH interference could arise even more frequently as a result of the terminal device density. Such MTC devices are designed to be low cost and may have limited battery life and transmit power, and be installed in inaccessible locations, and so it can be particularly desirable to minimize the need to retransmit PUSCH/PUCCH due to PRACH interference in respect of MTC-devices, and furthermore in respect of MTC-type devices operating on relatively narrow bandwidths, such as in a virtual carrier context. Nonetheless, it will be appreciated that PRACH to PUSCH/PUCCH interference issues can equally arise for more conventional types of terminal device operating on wider bandwidths. In addition to radio network interference, in situations where there is the potential for relatively large numbers of terminal devices to seek to access a network through random access procedures the limited number of available RA preambles may become an issue. This is because with more terminal devices seeking access around the same time there is an increased likelihood of two terminal devices choosing the same RA preamble and causing a collision on RACH. Such collisions also result in PRACH retransmissions from at least one of the colliding terminal devices, thereby causing more radio network interference and consuming additional power for the terminal device. With these issues in mind, certain embodiments of the invention are directed to schemes for controlling random access procedures for a plurality of terminal devices in a wireless telecommunications network with a view to reducing the overall number of PRACH transmissions occurring. In some examples this is achieved by a base station allocating uplink resources to one terminal device in response to a random access procedure initiated by another, different, terminal device. Correspondingly, in accordance with some embodiments a terminal device may receive an allocation of resources as a consequence of another terminal device initiating a random access procedure. FIG. 5 schematically shows a telecommunications system 500 according to an embodiment of the invention. The telecommunications system 500 in this example is based broadly on a LTE-type architecture. As such many aspects of the operation of the telecommunications system 500 are known and understood and are not described here in detail in the interest of brevity. Operational aspects of the telecommunications system 500 which are not specifically described herein may be implemented in accordance with known techniques, for example according to the established and published LTE-standards. The telecommunications system 500 comprises a core network part (evolved packet core) 501 coupled to a radio network part. The radio network part comprises a base station (evolved-NodeB/eNB) 502 adapted in accordance with an embodiment of the invention and arranged to communicate with a plurality of terminal devices. In this example, four terminal devices are shown, namely a terminal device 505 of a first type and three terminal devices 508A, 508B, 508C of a second type. Where it is not significant to distinguish between the three terminal devices 508A, 508B, 508C of the second type, these terminal devices may be referred to collectively as terminal devices 508. It will of course be appreciated that in practice the radio network part may comprise a plurality of base stations serving a larger number of terminal devices across various communication cells. However, only a single base station and four seminal devices are shown in FIG. 5 in the interests of simplicity. As with a conventional mobile radio network, the terminal devices 505, 508 are arranged to communicate data to and from the base station (transceiver station) 502. The base station is in turn communicatively connected to a serving gateway, S-GW, (not shown) in the core network part which is arranged to perform routing and management of mobile communications services to the terminal devices in the telecommunications system 500 via the base station 502. In order to maintain mobility management and connectivity, the core network part 501 also includes a mobility management entity (not shown) which manages the enhanced packet service, EPS, connections with the terminal devices 505, 508 operating in the communications system based on subscriber information stored in a home subscriber server, HSS. Other network components in the core network (also not shown for simplicity) include a policy charging and resource function, PCRF, and a packet data network gateway, PDN-GW, which provides a connection from the core network part 501 to an external packet data network, for example the Internet. As noted above, the operation of the various elements of the communications system 500 shown in FIG. 5 may be broadly conventional apart from where modified to provide functionality in accordance with embodiments of the invention as discussed herein. In this example, it is assumed the first terminal device 505 is a conventional smart-phone type terminal device communicating with the base station 502 in a conventional manner This first terminal device 505 comprises a transceiver unit 507 for transmission and reception of wireless signals and a controller unit 506 configured to control the smart phone 505. The controller unit 506 may comprise a processor unit which is suitably configured/programmed to provide the desired functionality using conventional programming/configuration techniques for equipment in wireless telecommunications systems. The transceiver unit 507 and the controller unit 506 are schematically shown in FIG. 5 as separate elements. However, it will be appreciated that the functionality of these units can be provided in various different ways, for example using a single suitably programmed integrated circuit. As will be appreciated the smart phone 505 will in general comprise various other elements associated with its operating functionality. In this example, it is assumed the terminal devices 508 the second type are all machine-type communication (MTC) terminal devices. As discussed above, these types of device may be typically characterised as semi-autonomous or autonomous wireless communication devices communicating small amounts of data. Examples include so-called smart meters which may be located in a customer's house and periodically transmit information back to a central MTC server data relating to the customer's consumption of a utility, such as gas, water, electricity and so on. As with the smart phone 505, the respective MTC devices 508A, 508B, 508C each comprise a transceiver unit 510A, 510B, 5100 for transmission and reception of wireless signals and a controller unit 509A, 509B, 509C configured to control the respective devices 508A, 508B, 508C. The controller units 509A, 509B, 509C may each comprise various sub-units for providing functionality in accordance with embodiments of the invention. For example, in accordance with some embodiments the respective terminal devices may comprise a data for uplink determining unit for determining the terminal device has uplink data waiting for transmission to the base station and a transmit request determining unit for determining the terminal device should not transmit a request for an allocation of radio resources for transmission of the uplink data to the base station and instead should wait to receive a radio resource allocation message from the base station configured to operate to provide functionality as described herein in accordance with embodiments of the invention. These sub-units may be implemented as discrete hardware elements or as appropriately configured functions of the controller unit. Thus the respective controller units 509A, 509B, 509C may comprise a processor unit which is suitably configured/programmed to provide the desired functionality described herein using conventional programming/configuration techniques for equipment in wireless telecommunications systems. The respective pairs of transceiver units 510A, 510B, 510C and controller units 509A, 509B, 509C for each device 508 are schematically shown in FIG. 5 as separate elements for ease of representation However, it will be appreciated that within each device the functionality of these units can he provided in various different ways following established practices in the art, for example using a single suitably programmed integrated circuit. It will be appreciated the MTC devices 508 will in general comprise various other elements associated with their operating functionality and these other elements may generally operate in accordance with conventional techniques. The base station 502 comprises a transceiver unit 503 for transmission and reception of wireless signals and a controller unit 504 configured to control the base station 502. The controller unit 504 may again comprise various sub-units for providing functionality in accordance with embodiments of the invention. For example, in accordance with some embodiments the base station may comprise: a request receiving unit for receiving a request for an allocation of radio resources from a first terminal device; an association determining unit for determining an association between the first terminal device and a second terminal device; and an allocation message transmitting unit for transmitting a radio resource allocation message to allocate radio resources to the second terminal device for an uplink transmission in response to receiving the request for an allocation of radio resources from the first terminal device configured to operate to provide functionality as described herein in accordance with embodiments of the invention. These sub-units may be implemented as discrete hardware elements or as appropriately configured functions of the controller unit/transceiver unit. Thus, the controller unit 504 may comprise a processor unit which is suitably configured/programmed to provide the desired functionality described herein using conventional programming/configuration techniques for equipment in wireless telecommunications systems. The transceiver unit 503 and the controller unit 504 are schematically shown in FIG. 5 as separate elements for ease of representation. However, it will be appreciated the functionality of these units can be provided in various different ways following established practices in the art, for example using a single suitably programmed integrated circuit. It will be appreciated the base station 502 will in general comprise various other elements associated with its operating functionality and these other elements may generally operate in accordance with conventional techniques. It is assumed here the base station 502 is configured to communicate with the smart phone 505 in accordance with the established principles of LTE-based communications and to communicate with the terminal devices 508 in accordance with embodiments of the invention as described herein. Certain embodiments of the invention are based on a recognition that certain types of terminal device in a wireless telecommunications network, such as the network 500 in FIG. 5, can be expected to have similar traffic profiles. For example, MTC-type terminal devices 508 associated with a given MTC application, such as smart metering on behalf of a particular gas supplier, might all be expected to be configured to uplink similar amounts of data at similar times, for example corresponding to a regular upload of information relating to a user's consumption of gas (or whatever it is that is being metered). In this regard, certain types of terminal device may be grouped according to their expected (or historically seen) traffic profiles. For example, the terminal devices might he grouped together based on an associated Quality of Service (QoS) Class Indicator (QCI) as specified in existing LTE standards (see, for example, ETSI TS 123 401 V10.8.0 (2012 July )/3GPP TS 23.401 version 10.8.0 Release 10 [15] and ETSI TS 123 203 V10.7.0 (2012 July )/3GPP TS 23.203 version 10.7.0 Release 10 [16]. In accordance with embodiments of the invention in which terminal devices are grouped based on QCI, it will be appreciated there may be some expansion of the currently specified QCI categories, for example to include categories relating to typical periodicity of uplink traffic, or burst parameters/statistics, Terminal devices may be grouped in other ways. For example, MTC devices associated with a common MTC application, for example smart metering on behalf of a particular gas supplier, may be considered to fall into a single traffic-profile group. Thus, in accordance with an embodiment of the invention, a plurality of terminal devices may be notionally categorized as belonging to a particular group having some common characteristics associated with the uplink traffic profiles. With reference to FIG. 5, it is assumed in this example the three MTC-type terminal devices 508A, 508B, 508C are categorized as forming a group of terminal devices with similar uplink traffic profiles. As noted above, this might be because all three MTC terminal devices are associated with a given MTC application. In the following description of various modes of operation in accordance with some embodiments of the invention it will be assumed the MTC devices are in a RRC_Connected state. In accordance with a first embodiment, it is assumed a base station maintains a record of the terminal devices in the same traffic profile group (for example based on a data record containing a list of identifiers for the respective terminal devices in the respective groups served by the base station). However, while the base station is aware of the relevant grouping information, in accordance with this example embodiment the individual terminal devices are not aware of the identities of other members of the group(s) to which they belong. Referring again to FIG. 5, it is assumed that at some point in time terminal device 508A finds itself with some data in its uplink buffer. This might be because the terminal device is associated with a smart meter and it is time to upload information relating to usage according to its operating schedule. In accordance with the conventional principles of LTE operation, such as described above, the terminal device 508A seeks to transmit a BSR to the base station 502 to request an uplink allocation on PUSCH to uplink the data in its buffer in the normal way. However, again as described above, it may be that the terminal device has no current uplink grant on PUSCH on which to send a BSR and insufficient resources on PUCCH to send a SR. Accordingly, the terminal device will fall back to seek to access the network via RACH and the RA procedure. In this respect, the terminal device may follow conventional principles to arrive at the situation in which the RA procedure may be invoked in accordance with the conventional operating principles of the network in which this example embodiment is implemented. FIG. 6 is a ladder diagram schematically showing signaling among the base station 502 and terminal devices 508A, 508B, 508C in FIG. 5 in accordance with an embodiment of the invention. The signaling represented in FIG. 6 starts from a point at which terminal device 508A has reached a state in which a desire to send a BSR has caused terminal device 580A to initiate a RA procedure. In accordance with this embodiment of the invention, the RA procedure in respect of terminal device 508A is configured to proceed as normal, for example as described above with reference to FIG. 2. Thus, in a first step the terminal device 508A sends a conventional RA preamble 601A to the base station 502 and, in a second step, the base station 502 responds by sending a conventional RAR 602A to the terminal device 508A. The terminal device 508A in turn transmits a Message 3 603A of the conventional RA procedure to the base station 502 in accordance with the principles discussed above with reference to FIG. 2. At this stage of the process represented in FIG. 6 the base station 502 therefore receives signaling corresponding to Message 3 in the conventional RA procedure which indicates the terminal device 508A is transmitting a SR to request PUSCH resources to transmit a Regular BSR. In accordance with certain embodiments of the invention, the base station 502 is configured to determine whether or not the terminal device 508A that has initiated a RA procedure is a member of a defined traffic profile group. hi this example this leads the base station to identify terminal devices 508B and 508C as being classified as having similar traffic profiles to terminal device 508A currently involved in the RA procedure. Because of their similar traffic profiles, it may be expected that, as with terminal device 508A, the terminal devices 508B and 508C will also be approaching a state in which they will wish to invoke their own RA procedures to request uplink resources to transmit their own BSRs. However, in accordance with some embodiments of the invention the base station 502 is configured to act to prevent terminal devices 508B, 508C from making such requests for uplink resources. This is done in this example by the base station 502 instructing the terminal devices 508B, 508C to not make any PRACH transmissions by transmitting explicit signaling comprising what may be referred to in accordance with embodiments of the invention as PRACH access denial (or access request denial) messages 604B, 604C. That is to say, once the base station receives PRACH transmissions associated with a RA procedure for one terminal device in a group of terminal devices deemed to have traffic profiles with some common characteristic(s), the base station is configured to send signaling to the other terminal devices in the group to indicate they are denied access to PRACH, at least temporarily, thereby preventing these other terminal devices in the group from initiating their own RA procedures. Thus, a terminal device receiving a PRAM access denial message according to an embodiment of the invention, such as the terminal devices 508B, 508C in FIG. 6, will not initiate its own random access procedure by sending a random access preamble, even if in accordance with the terminal device's normal operating procedures it would otherwise be ready to invoke a random access procedure. For example, if either one of the terminal devices 508B, 508C reach a state in which they are ready to initiate a random access procedure to request an uplink radio resource allocation to allow them to send a BSR to the base station, they will not do so if they have been denied PRACH access (e.g. through a PRACH access denial message 604B, 604C) if the denial has not yet been lifted. By way of example, the PRACH access denial signaling could be implemented by way of a flag asserted or message contained in a RRC (re)configuration transmitted via the usual means of a PDCCH addressed to the C-RNTI(s) of the relevant terminal device(s) for locating the RRC message on PDSCH. Alternatively, PRACH access denial messaging could be conveyed using an additional bit (flag) asserted or a field added in a DCI (Downlink Control Information) message carried on a PDCCH addressed to the relevant terminal devices' C-RNTIs. Thus, having received the respective PRACH access denial messages 604B, 604C, the terminal devices 508B, 508C do not initiate any RA procedures of their own, even if they would otherwise have done so. Instead the terminal devices 508B, 508C that have been denied. PRACH access wait to receive further communications from the base station, as described further below. Turning now to the communications between the base station 502 and the terminal device 508A which initiated the RA procedure, the base station 502 having received the scheduling request (SR) from the terminal device 508A in Message 3 603A proceeds to send a contention resolution message 605A to the terminal device 508A, again following conventional RA procedures in respect of the communications associated with the RA procedure initiated by the terminal device 508A. Again following the conventional LTE signaling procedures associated with the transmission of a BSR, the base station 502 proceeds to transmit to the terminal device 508A an uplink grant for BSR message 606A providing an uplink grant of radio resources on which the terminal device 508A is to transmit its buffer status report. Having received the uplink grant of radio resources for transmitting its BSR, the terminal device 508A proceeds to transmit a BSR message 607A comprising the BSR to the base station 502. On receiving the BSR message 607A from the terminal device 508A the base station 502, more particularly, a scheduler of the base station 502, determines an allocation of radio resources to grant to the terminal device 508A to allow the terminal device 508A to transmit the data it has buffered and ready for uplink to the base station 502, and communicates this uplink resource allocation to the terminal device 508A in a buffered data uplink grant message 608A. Subsequently, although not shown in FIG. 6, the terminal device 508A can transmit the buffered data to the base station 502 using the uplink radio resources allocated to the terminal device 508A through the buffered data uplink grant message 608A. Accordingly, the communications between the base station 502 and the terminal device 508A which initiated the RA procedure as represented in FIG. 6 can be generally conventional. For example, the various signaling messages between the terminal device 508A and the base station 502 may be made in accordance with the established principles of LTE-type network communications. For example, the uplink grant messages 605A, 607A may be made in the usual way using a physical downlink control channel (PDCCH). However, a significant aspect of the operation represented in. FIG. 6 in accordance with an embodiment of the invention which differs from conventional approaches is that the base station 502 is configured to also send uplink grant messages 608B, 608C to the terminal devices 508B, 508C which have not themselves requested uplink resources, and indeed have been denied PRACH access as discussed above to prevent them from being able to request resources. The amount of radio resources allocated to the terminal devices 508B, 508C in this way may correspond with the amount of radio resources allocated to the terminal device 508A which initiated the random access procedure according to the buffer status report received from that terminal device 508A. The uplink grant messages 608B, 608C may be sent to the terminal devices 508B, 508C in accordance with the established principles for granting uplink resources in LTE-type wireless telecommunications systems, for example using PDCCH signaling in the usual way, A scheduler in the base station 502 may operate to allocate the radio resources to the various terminal devices 508A, 508B, 508C in accordance with the established principles that would be applied had the base station received independent buffer status reports from the respective terminal devices. For example, uplink grant signaling 608A, 608B, 608C may be provided over a number of radio subframes, depending on the amount of data for uplink based on the BSR received from the first terminal device 508 in the BSR message 607A in FIG. 6 and the radio resource availability in the cell, etc. Thus, an underlying principle of this mode of operation is that the base station 502 has associated the terminal device 508A as being a member of a group of terminal devices previously identified as having similar traffic profiles, wherein the group in this example further includes terminal devices 50813, 508C. Thus, the base station allocates radio resources (“grants”) for subsequent uplink transmissions from the terminal devices 508B, 508C on the basis of having received a request for an allocation of resources for an uplink transmission from another terminal device 508A in the group. The principle here is that if the terminal device 508A has a particular amount of data to transmit to the base station, it may reasonable to expect other terminal devices 508B, 508C in the same group may have a similar amount of data to transmit to the base station. Accordingly, the base station can pre-emptively allocate resources to the terminal devices 508B, 508C without them having requested such resources. Indeed, in accordance with this embodiment of the invention, the terminal devices 508B, 508C are prevented from asking fur resources by virtue of the base station having told them not to through the PRACH access denial messages 604B, 604C discussed above. Accordingly, this approach in accordance with some embodiments of the invention provides a mechanism for a base station to provide resource allocations to multiple terminal devices in response to a resource request from a single terminal device. An advantage of this approach of predicting when certain terminal devices may have data for uplink based on requests for uplink resources received from another terminal device, and allocating radio resources accordingly, is a potential reduction in the number of requests for resources received by the base station. This can therefore help to reduce the potential for radio interference and congestion in the communication cell served by the base station, in particular in association with random access procedures. In some respects approaches in accordance with embodiments of the invention may thus be seen as providing for pre-emptive resource allocations in respect of terminal devices which have not requested resources, but which have been classified as having a common traffic profile characteristic with another terminal device which has requested uplink resources. The other terminal device which has requested uplink resources in accordance with this example embodiment is simply the first terminal device of the group to initiate a random access procedure through sending a random access preamble to the base station. In this respect, the first terminal within a group of terminal devices which initiates a random access procedure may in effect be considered to become the “master” terminal device or “delegate” terminal device for the group of terminal devices in respect of providing a buffer status report to the base station which the base station will treat as being applicable for all terminal devices in the group and allocate radio resources accordingly. Having received the uplink grant messages 608B, 608C, the respective terminal devices 508B, 508C may thus transmit any data they have in their buffers to the base station using the allocated resources. In some cases it may he that the amount of resources allocated to the terminal devices 508B, 508C directly match, or exceed, the amount of data the respective terminal devices have waiting in their buffers for uplink transmission. For example this might be the case if there is a close correspondence between the traffic profiles of the terminal device 508A initiating the random access procedure and the other terminal devices 508A, 508C in the group. For example, this might be expected in situations where the various terminal devices are performing corresponding tasks. For example if each terminal device is associated with a smart-meter configured to record usage data in the same way, and to report the usage data to a server application at roughly the same time, it may be expected that all terminal devices will have very similar amounts of data in the buffer at around the same times. In this case, the terminal devices 508B, 508C may proceed to uplink their buffered data using the resources they have been allocated in the usual way. However, in other cases, it may be that in fact one or more of the terminal devices 508B, 508C which have been pre-emptively allocated resources by the base station 502 do not currently have any buffered data for uplink. This can arise even within an identified group of terminal devices having generally similar traffic profiles, for example because the traffic profiles are not identical, or because the terminal device 508A initiating the random access procedure did so for a reason that does not apply to the other terminal devices. For example, the terminal device 508A in FIG. 6 may have initiated the random access procedure to transmit uplink data associated with a fault condition that has arisen rather than to uplink data associated with its normal traffic profile on the basis of which it has been classified as being grouped with the other terminal devices. In some other eases it may be that in fact one or more of the terminal devices 508B, 508C which have been pre-emptively allocated resources by the base station 502 require more resources than they have been allocated to transmit all the data they currently have buffered for uplink. When a terminal device is pre-emptively allocated uplink resources that either it does not need, or which are not sufficient for its needs, the terminal device may in accordance with some embodiments of the invention be configured to send a rejection/insufficiency indication message 609B, 609C to the base station 502 to indicate this fact. A rejection/insufficiency indication message 609B, 609C may be transmitted by the terminal device 508B, 508C using the resources it has been allocated for uplink through the uplink grant messages 608B, 608C previously received from the base station 502, for example. A base station 502 receiving a rejection/insufficiency indication message from a terminal device can take appropriate scheduling action. For example, in response to a rejection indication message (i.e. a message indicating the terminal device does not have any data for uplink and so in effect rejects the grant) the base station may avoid further scheduling for the terminal device. Conversely, for an insufficiency indication message, the base station may allocate further resources to the terminal device, for example to allow the terminal device to transmit a buffer status report so that further resources can be allocated accordingly, or the base station may simply allocate more uplink resources to the terminal device in one or more subsequent subframe(s) to allow the terminal device to empty its buffers. In this respect, it may be helpful in some implementations if a terminal device transmitting an insufficiency indication message is configured to communicate an indication of how much resource is currently desired. For example, the terminal device may be configured to transmit as an insufficiency indication message a buffer status report. Thus, a base station receiving a BSR on radio resources pre-emptively allocated to a terminal device may be configured to respond by recognising this is a request for more resources to be allocated, and allocate these resources accordingly. Once the base station has identified the extra resource allocation is requested, the allocation may be made in the usual way. In a variant of this approach a terminal device may instead of transmitting a conventional BSR, transmit what might be termed a differential BSR indicating a difference in an amount of resource between the amount that was allocated by the base station and a desired amount. In situations where a base station identifies a terminal device in a particular group does not require resources that it has been pre-emptively allocated on the basis of a request from another terminal device, or requires more resources than it has been pre-emptively allocated, the base station may be configured to take account of this and modify the terminal device groupings accordingly. For example, a terminal device which is found to repeatedly not require resources, or require more resources than its fellow group members, might be removed from the group on the basis that its traffic profile is not sufficiently similar to the traffic profile of other terminal devices in the group to merit the above-described approach of pre-emptive resource allocations. Such a terminal device may be moved to another group, or simply removed from any groups associated with pre-emptive resource allocation processes in accordance with embodiments of the invention. When the base station has allocated resources to all terminal devices in a group, including the allocation to the delegate terminal device 508A of the radio resources it has requested and the corresponding allocations to other terminal devices in the delegate terminal device's group, it may be appropriate for the bar on accessing PRACH placed on the terminal devices 508B, 508C by the PRACH access denial messages 604A, 604B discussed above to be lifted. This is so that any one of the terminal devices in the group which subsequently generates new data for uplink is able to initiate a random access procedure to request resources to transmit the new data to the base station 502. In this respect, whichever of the terminal devices in a group becomes the first terminal device to initiate a new random access procedure may in effect become the new delegate terminal device. Processing may then continue following the principles described above with reference to FIG. 6 (taking account of a potential change in which of the terminal devices is the delegate terminal device). If a terminal device should fail to use the allocated resources at all, perhaps because it has lost power or is otherwise not receiving downlink signaling or transmitting uplink signaling, then the base station will receive no uplink data transmission and no rejection or insufficiency indication. In some implementations this might cause the base station to assume a failure to receive correctly the transmissions the terminal device is expected to have made, and therefore to begin the use of HARQ procedures by sending a negative acknowledgement to the terminal device, Typically, this would repeat a number of times according to the base station's configuration. Eventually, the limit of attempts to receive the transmission from the terminal would be reached, when the base station might then recognize the terminal device is not active, and possibly remove the terminal device from the group to which it is assigned. Expiration of the PRACH access denial applied for non-delegate terminal devices may occur in a number of ways in different embodiments, For example, each terminal device may be configured to treat the PRACH access denial as being lifted expired in respect of its own transmissions after it has received its uplink grant 608B, 608C provided in response to another terminal device requesting resources. In other examples, the terminal devices may be configured to treat the PRACH access denial as having expired after a pre-determined period of time. In still other examples, terminal devices may be configured to treat the PRACH access denial as remaining in force until specific signaling is received from the base station to indicate the PRACH access denial is lifted. A message indicating the PRACH access denial is lifted may, for example, be sent from a base station to terminal devices in a manner corresponding to that in which the PRACH access denial message is sent. It will be appreciated that the processing represented in FIG. 6 may be modified in accordance with other embodiments of the invention. For example, in some cases the PRACH access denial messages 604B, 604C may be sent at a different time. For example, it may be considered appropriate in some implementations to send the PRACH access denial messages earlier to further reduce the likelihood of another terminal device independently initiating a RA procedure because it has data to upload before being instructed not to. For example, PRACH access denial messages could be sent by the base station to non-delegate terminal devices as soon as an RA preamble is received from another terminal device (which hence becomes the delegate terminal device) in a group with which the remaining non-delegate terminal devices are associated. In the event a terminal device independently initiates a RA procedure when another terminal device in its group has already initiated such a procedure, but before the base station has transmitted any associated PRACH access denial messaging, the base station may be configured to simply ignore the later-received PRACH transmissions. The terminal device whose PRACH transmissions are ignored in accordance with some embodiment of the invention may eventually receive a PRACH access denial message and hence be configured to cease any PRACH (re)transmissions it might otherwise have made. In accordance with some embodiments of the invention the base station 502 may transmit PRACH access denial messages 604B, 604C to all terminal devices in a group associated with a delegate terminal device which initiates a random access procedure. However, in some other embodiments the base station may send PRACH access denial messages 604B, 604C to only a subset of the terminal devices in a group associated with a delegate terminal device which initiates a random access procedure. Terminal devices which are not sent a PRACH access denial message are therefore still permitted to access PRACH in the usual way, but will nonetheless also be pre-emptively allocated resources in accordance with the principles described above. Terminal devices in a group which are not forbidden to access PRACH (i.e. not sent a PRACH access denial message) could include terminal devices which are classified as having a relatively high priority among the terminal devices in the group, for example. In other cases, however, it may be more appropriate for such terminals devices to be removed from the relevant grouping instead. In accordance with some embodiments a terminal device may have multiple different traffic profiles associated with multiple different types of data for uplink communication. That is to say, in accordance with some embodiments a terminal device may be associated with more than one traffic class simultaneously and may therefore be considered as being in in more than one group of terminal devices with related traffic profiles. In such cases any signaling to a terminal device denying it access to PRACH may also include an assignment of that denial to a particular traffic class (or classes), Accordingly, it may be that a terminal device is only barred from making PRACH transmissions with respect to those traffic classes, at least when they would normally result in PRACH access. Traffic classes associated with particularly high priority QCIs might be given such exceptions, for example, so that a terminal device can send a BSR overriding that provided by a terminal device which has acted as a group's delegate according to the principles described above with reference to FIG. 6. This could therefore allow a terminal device to provide its own BSR with respect to a particular traffic class faster than would be possible by waiting for the chance to send a rejection or insufficiency indicator as described above. In the above-described embodiments a base station configured to allocate resources to what might be termed a non-delegate terminal device based on a request for resources received from what might be termed a delegate terminal device is also configured to transmit PRACH access denial signaling to the non-delegate terminal device(s) to indicate the non-delegate terminal device(s) should not attempt to access PRACH, at least temporarily. In the above-described embodiments a terminal device may attempt to access PRACH in the usual manner if it has not previously received RACH access denial signaling (and hence may in fact become a delegate terminal device). However, in accordance with some other embodiments, terminal devices may be configured to determine themselves that they should not attempt to access PRACH resources (i.e. they should not initiate a random access procedure), at least for a period of time, in the expectation they will be allocated radio resources by the base station based on, a request for radio resources made by another terminal device. This may in some respects be referred to as PRACH self-denial on the part of the terminal device. For example, a terminal device may come to a state in accordance with its normal operation whereby it is ready to initiate a random access procedure. However, rather than doing so, the terminal device may decide instead to delay accessing PRACH in the expectation that another terminal device having a similar traffic profile, and hence classified as being grouped with the terminal device at the base station, will shortly initiate a random access procedure of its own. In effect, certain terminal devices may be configured to wait for another terminal device to become a delegate terminal device to allow the terminal device to receive radio resources without having to access PRACH (e.g. in accordance with the principles set out above with reference to FIG. 6). This approach can be advantageous for the self-denying terminal device as it will save battery power, for example. To avoid a self-denying terminal device waiting for an undue length of time for another terminal device to initiate a random access procedure, it may be configured to initiate its own random access procedure if another terminal device does not do so within a given time window. The time window adopted for different types of data may be different. For example, data which is considered to have higher priority may be associated with a smaller time window, perhaps even as low as zero time window, corresponding to the self-denying terminal device not denying itself access to PRACH for that particular class of data. In any case, the length and ability to use the self-denial (speculative) PRACH transmission delay window(s) by a terminal device can, for example, be an implementation choice of the terminal device manufacturer and/or configured by the base station via RRC signaling for all or some terminal devices. As already mentioned, the above-described embodiments primarily focus on implementations in which a base station is configured to transmit PRACH access denial signaling to non-delegate terminal devices to indicate they should not attempt to access PRACH. Thus, in accordance with these examples all terminal devices may assume they may access PRACH unless they are instructed otherwise through PRACH access denial signaling. However, in accordance with other embodiments, terminal devices may be configured to assume they should not attempt to access PRACH unless they are instructed that they may do. Thus, instead of simply allowing whichever terminal device first initiates each random access procedure to become the delegate terminal device, in some embodiments one or more terminal devices may be pre-defined as a delegate terminal device and instructed that they may access PRACH whilst other terminal devices may be configured to not access PRACH and to rely solely on pre-emptive resource allocations of the kind described above. A base station may select one or more terminal devices to be allowed PRACH access (and hence act as a delegate terminal device) for the terminal devices of a particular group of terminal devices with related traffic profiles randomly or systematically. For example, the selection of one or more potential delegate terminal devices from within a group of terminal devices may be made on the basis of radio channel quality information associated with the respective terminal devices. For example, terminal devices with higher quality radio channel communications with the base station, for example because they are nearer to the base station, may he selected as potential delegate terminal devices to help with the probability that PRACH transmissions arrive at the base station quickly, allowing any subsequent denial signaling to be sent as early as possible and for the received signal quality on the preamble to be as good as possible. Thus the selection may be based on calculations performed but at the base station taking account of parameters such as Timing Advance (TA) associated with the terminal devices in the group. Other metrics which might be used include the (filtered, layer 3) radio resource management (RRM) measurements based on RSRP (reference signal received power)/RSRQ (reference signal received quality), or SRS (sounding reference signal) measurements at the base station. In accordance with some other example embodiments, terminal devices operable in accordance with the principles described above might be provided with a configuration relevant to MBSFN (Multicast Broadcast Single Frequency Network) operation, wherein at the physical layer certain subframes within certain radio frames may be defined as for use only for multicast or broadcast data. To each group of terminal devices can be associated an MBMS (Multimedia Broadcast Multicast Service) service. Then, PRACH denial signaling might be multicast to a group of terminal devices using MBMS, thereby helping reduce the resources used for this signaling as compared to individual signaling to each of the potentially many access-denied (“barred”) terminal devices. Only terminal devices configured with the MBMS service for which the PRACH denial is sent might then act in response to it (by suppressing RACH accesses). In accordance with this approach the base station need not know how many terminal devices are presently in the group, allowing them to be switched on and off without informing the network or requiring a variable amount of resource to transmit TRACH denial signaling. In example implementations in accordance with embodiments of the invention, there are various ways in which terminal devices can be configured to only access PRACH if they are one of the pre-defined allowable dedicated terminal devices are selected by the base station. For example, in a system where terminal devices are configured to generally assume they are allowed to access PRACH, the base station may be configured to send PRACH denial signaling to all terminal devices, apart from the selected potential delegate terminal device(s), even if there is no currently on-going random access procedure from a terminal device in the associated group of terminal devices. Alternatively, in a system where terminal devices are configured to generally assume they are not allowed to access PRACH, the base station may be configured to send signaling to the selected potential delegate terminal device(s) to indicate they are allowed to access PRACH. In accordance with further embodiments of the invention, a wireless telecommunications system may operate in a device-to-device (D2D) mode whereby the terminal devices communicate directly with one another using the same cellular technology (or possibly a different wireless bearer) as they use to communicate with the infrastructure network/base station provided by the operator. Such D2D architectures can have various advantages known in the art, including but not limited to, network-side power reduction, RAN traffic load reduction, and terminal-side power reduction. Thus, terminal devices operating in a D2D mode and requiring an allocation of uplink resource can send a BSR (or actual uplink data depending on the specific D2D implementation) to one designated terminal device which collates them to generate a total group BSR and provides this to the network via RACH in accordance with broadly conventional techniques. Having sent their own BSR to the designated terminal device, the other terminal devices may be configured to regard themselves as being prohibited from accessing RACH/PRACH in their own right. In accordance with principle similar to those described above with regards to FIG. 6, the base station scheduler may then schedule the entire group of terminal devices and provide the relevant uplink grants on PDCCH. These may either be transmitted to each terminal device individually or to the delegate terminal device for onward D2D transmission to the individual terminal devices according to the specific D2D implementation at hand. The C-RNTIs of the terminal device in the D2D set are assumed to be known to the base station to support this downlink signaling of uplink grants. Thus, there has been described various ways in which a base station may conveniently allocate resources to one terminal device based on a request received from another terminal device where the two terminal devices are classified as being in a group on the basis of their expected traffic profiles, for example, taking account of predicted timings and amounts of data for uplink from the respective terminal devices. In doing this, it can be possible to schedule uplink resources for a plurality of terminal devices with less signaling associated with random access procedures than would otherwise be the case. The associations among terminal devices (i.e. the groupings) may be maintained (and potentially modified) by the base station, for example based on inherent characteristics of the devices, such as their operating functions, or based empirically on previous data transfer behaviour associated with the respective terminal devices. In general, the terminal devices do not need to be aware of what other terminal devices are in their group, and as such the associations between terminal devices may be maintained internally at the base station without communication to the terminal devices. Thus, embodiments of the invention can help reduce the potentially impact of PRACH to PUSCH interference, especially in the context of a narrowband LIE-type carrier, such has been proposed for so-called virtual carriers, and also in the context of MTC terminal devices which may be deployed more densely than other types of terminal device, and furthermore may be more predictable and similar in their traffic profiles. By reducing, potentially to one, the number of terminal devices in a traffic group that have permission to access PRACH for a given time, the potential interference to PUSCH can be correspondingly reduced. Furthermore, in accordance with some embodiments of the invention there may be an overall reduction in transmissions and retransmissions from terminal devices as compared to conventional systems because transmissions on PRACH are carried out only by the delegated terminal device(s) among a group. This can reduce power consumption for terminal devices, thus increasing their battery life. This can be particularly relevant for MTC devices. Furthermore, in accordance with some embodiments contention on RACH could be reduced by virtue of the delegation of the random access procedure to a restricted number of terminal devices, for example to the first terminal device to transmit PRACH among a group rather than continuing to allow them all to potentially contend. This could further reduce terminal device power consumption for most terminal devices in a group, and also help reduce the latency of RACH. Furthermore, in accordance with some embodiments there may be reduced uplink intercell interference because of the potential reduction in the amount of uplink PRACH transmissions. Some significant differences associated with certain embodiments of the invention as compared to conventional approaches include following: The concept of one terminal device acting as a random access delegate for a group of terminal devices is not known in conventional systems. For example, in a conventional LTE-type network each terminal device is responsible for its own scheduling requests, BSRs, and RACH procedures. Allowing a terminal device to remain connected to a cell but to be explicitly denied access to PRACH/RACH by downlink signaling is not available in conventional wireless telecommunications systems. Conventional wireless telecommunications system do not allow for a base station to allocate uplink resources to a terminal device which has not requested them. The concept of providing for a differential BSR to allow a terminal device to communicate a desired adjustment to an amount of resource it has been allocated is not available in conventional wireless telecommunications networks. Conventional wireless telecommunications networks do not allow for a terminal device to speculatively delay its own PRACH transmission in the hope that another terminal device may act as a group delegate is not previously disclosed (linked with the first bullet point). The network-based configuration version of this embodiment represents a departure from current LTE specifications where no such capability exists. It will be appreciated that various modifications can be made to the embodiments described above without departing from the scope of the present invention as defined in the appended claims. In particular although embodiments of the invention have been described with reference to a LTE mobile radio network, it will be appreciated that the present invention can be applied to other forms of network such as GSM, 3G/UMTS, CDMA2000, etc. The term user equipment (UE) as used herein can be replaced with other terms user equipment (UE), mobile communications device, terminal device etc. Furthermore, although the term base station has been used interchangeably with eNodeB it should be understood that there is no difference in functionality between these network entities. Thus, there has been described a method of allocating radio resources for uplink transmissions in a wireless telecommunications system, the method comprising: a first terminal device communicating a request for an allocation of radio resources to a base station; the base station determining there is an association between the first terminal device and a second terminal device based on their having similar predicted traffic profiles for uplink data; and the base station establishing a radio resource allocation for the second terminal device based on the resources requested by the first terminal device, and consequently transmitting radio resource allocation messages to allocate radio resources to the first and second terminal devices for respective uplink transmissions based on the request for an allocation of radio resources received from the first terminal device. Thus in some respects certain embodiments of the invention provide for schemes to help allow one UE to act as a delegate for a group of UEs with respect to accessing RACH and making transmissions on PRACH. The group of UEs may have something common about their expected traffic profiles, for example QCIs, so that when a buffer status report (BSR) is triggered at one UE, the eNB can assume that a similar BSR is likely to be about to be triggered at the other UEs in the group. Therefore, the eNB can conduct the uplink (UL) scheduling process with this assumption and signal to the other UEs in the traffic profile group a denial of permission to transmit PRACH for the time being. After providing a determined UL schedule to all UEs in the group via usual PDCCH DCI messages, some embodiments allow UEs to reject the scheduled grants or indicate that they are insufficient. Embodiments of the invention may therefore help reduce interference between PRACH and PUSCH/PUCCH by in effect reducing the number of UEs likely to be transmitting PRACH at any one time simultaneously and in a similar manner could help reduce the load on RACH and the probability of RACH contention. Further particular and preferred aspects of the present invention are set out in the accompanying independent and dependent claims. It will be appreciated that features of the dependent claims may be combined with features of the independent claims in combinations other than those explicitly set out in the claims. REFERENCES [1] ETSI TS 122 368 V10.530 (2011 July)/3GPP TS 22.368 version 10.5.0 Release 10 [2] Holma H. and Toskala A, “LTE for UMTS OFDMA and SC-FDMA based radio access”, John Wiley and Sons, 2009 [3] ETSI TS 136 321 V10.6.0 (2012 October)/3GPP TS 36.321 version 10.6.0 Release 10 [4] ETSI TS 136 300 V10.8.0 (2012 July)/3GPP TS 36.300 version 10.8.0 Release 10 [5] UK patent application GB 1101970.0 [6] UK patent application GB 1101981.7 [7] UK patent application GB 1101966.8 [8] UK patent application GB 1101983.3 [9] UK patent application GB 1101853.8 [10] UK patent application GB 1101982.5 [11] UK patent application GB 1101980.9 [12] UK patent application GB 1101972.6 [13] UK patent application GB 1121767.6 [14] UK patent application GB 1121766.8 [15] ETSI TS 123 401 V10.8.0 (2012 July)/3GPP TS 23.401 version 10.8.0 Release 10 [16] ETSI TS 123 203 V10.7.0 (2012 July)/3GPP TS 23.203 version 10.7.0 Release 10 The present application claims priority to British Patent Application 1222902.7, filed in the UK IPO 19 December 2012, the entire contents of which being incorporated herein by reference | <SOH> BACKGROUND OF THE INVENTION <EOH>The present invention relates to methods, systems and apparatus for use in wireless (mobile) telecommunications systems. In particular, embodiments of the invention relate to communicating uplink allocations of radio resources from a base station to a terminal device in such systems. Third and fourth generation mobile telecommunication systems, such as those based on the 3GPP defined UMTS and Long Term Evolution (LTE) architectures, are able to support more sophisticated services than simple voice and messaging services offered by previous generations of mobile telecommunication systems. For example, with the improved radio interface and enhanced data rates provided by LTE systems, a user is able to enjoy high data rate applications such as mobile video streaming and mobile video conferencing that would previously only have been available via a fixed line data connection. The demand to deploy third and fourth generation networks is therefore strong and the coverage area needed of these networks, i.e. geographic locations where access to the networks is desired, is expected to increase rapidly. The anticipated widespread deployment of third and fourth generation networks has led to the parallel development of devices and applications which, rather than taking advantage of the high data rates available, instead take advantage of the robust radio interface and increasing ubiquity of the coverage area. Examples include so-called machine type communication (MTC) applications, which are typified by semi-autonomous or autonomous wireless communication devices (i.e. MTC devices) communicating small amounts of data on a relatively infrequent basis. Examples include so-called smart meters which, for example, are located in a customer's house and periodically transmit information back to a central MTC server relating to the customer's consumption of a utility such as gas, water, electricity and so on. Further information on characteristics of MTC-type devices can be found, for example, in the corresponding standards, such as ETSI TS 122 368 V10.530 (2011 July )/3GPP TS 22.368 version 10.5.0 Release 10) [1]. Some typical characteristics of MTC type terminal devices/MTC type data might include, for example, characteristics such as low mobility, high delay tolerance, small data transmissions, a level of predictability for traffic usage and timing (i.e. traffic profile), relatively infrequent transmissions and group-based features, policing and addressing. As a result of the increasing use of wireless telecommunications networks generally, and also the development of devices such as MTC devices with their potential for introducing large numbers of terminal devices into networks, there is a desire to provide for wireless telecommunications networks that can reliably support access by increasing numbers of devices. This desire to support more devices, however, gives rise to an increased potential for issues with network congestion and interference, particular in respect of the radio access interface. These issues may be particularly relevant in respect of those communications which are not centrally managed by a scheduler in a communication cell of a network, such as random access communications from terminal devices seeking to access the network before having been allocated dedicated radio resources for doing so. There is therefore a desire to provide for telecommunications apparatus and methods which can help reduce the potential for radio network congestion and interference in circumstances where there might be relatively large numbers of terminal devices seeking access to the network. | <SOH> SUMMARY OF THE INVENTION <EOH>According to a first aspect of the invention there is provided a method of operating a base station for allocating radio resources for uplink transmissions in a wireless telecommunications system, the method comprising: receiving a request for an allocation of radio resources from a first terminal device; determining an association between the first terminal device and a second terminal device; and transmitting a radio resource allocation message to allocate radio resources to the second terminal device for an uplink transmission in response to receiving the request for an allocation of radio resources from the first terminal device. In accordance with some embodiments the request for an allocation of radio resources from the first terminal device is received on a random access channel of the wireless telecommunications system. In accordance with some embodiments the request for an allocation of radio resources from the first terminal device is associated with a random access procedure of the wireless telecommunications system. In accordance with some embodiments the radio resources allocated to the second terminal device correspond with an allocation of radio resources requested by the first terminal device. In accordance with some embodiments the association between the first terminal device and the second terminal device is established based on the first terminal device and the second terminal device having a common characteristic relating to their uplink transmissions. In accordance with some embodiments the association between the first terminal device and the second terminal device is established based on the first terminal device and the second terminal device being associated with a same terminal device classifier. In accordance with some embodiments the terminal device classifier is a quality class indicator of respective bearers associated with the respective terminal devices. In accordance with sonic embodiments the method further comprises transmitting an access request denial message to the second terminal device to instruct the second terminal device not to make its own request for an allocation of radio resources. In accordance with some embodiments the method further comprises transmitting a cease access request denial message to the second terminal device after having transmitted the access request denial message to instruct the second terminal device that it is now allowed to make its own request for an allocation of radio resources. In accordance with some embodiments the method further comprises transmitting an access request allow message to the first terminal device to instruct the first terminal device that it is allowed to make the request for the allocation of radio resources. In accordance with some embodiments the method further comprises selecting the first terminal device from a plurality of terminal devices as the terminal device to which the access request allow message is transmitted based on a transmission characteristic associated with respective ones of the plurality of terminal devices. In accordance with some embodiments the transmission characteristic is selected from the group comprising: a timing advance; a reference signal received power, a reference signal received quality, a sounding reference signal measurement at the base station, and a radio channel quality indicator. In accordance with some embodiments the method further comprises determining an association between the first terminal device and a further terminal device; and transmitting a radio resource allocation message to the further terminal device to allocate radio resources for an uplink transmission from the further terminal device based on the request for an allocation of radio resources from the first terminal device. In accordance with some embodiments the method further comprises determining an association between the first terminal device and a plurality of other terminal devices, transmitting an access request denial message to a subset of the plurality of other terminal devices to instruct the subset of the plurality of other terminal devices not to make their own requests for an allocation of radio resources, and transmitting radio resource allocation messages to the plurality of other terminal devices to allocate radio resources for respective uplink transmissions from respective ones of the plurality of other terminal devices based on the request for an allocation of radio resources from the first terminal device. In accordance with some embodiments the method further comprises receiving a transmission from the second terminal device using the radio resources allocated to the second terminal device. in accordance with some embodiments the transmission received from the second terminal device comprises an indication that the second terminal device does not require some or any of the allocated resources for uplink transmission. In accordance with some embodiments the transmission received from the second terminal device comprises an indication of a request for a further allocation of radio resources for a further uplink transmission from the second terminal device. In accordance with some embodiments the request for an allocation of radio resources received from the first terminal device comprises a request for an allocation of radio resources to allow the first terminal device to transmit a buffer status report to the base station. In accordance with some embodiments the first and second terminal devices are machine type communication, MTC, terminal devices. In accordance with some embodiments the wireless telecommunications system is associated with a radio interface spanning a system frequency bandwidth for supporting radio communications with a first type of terminal device and comprising a restricted frequency bandwidth for supporting radio communications with a second type of terminal device, wherein the restricted frequency bandwidth is narrower than and within the system frequency bandwidth, and wherein the first and second terminal devices are terminal devices of the second type. In accordance with a second aspect of the invention there is provided a base station configured to allocate radio resources for uplink transmissions in a wireless telecommunications system. the base station comprising: transceiver configured to receive a request for an allocation of radio resources from a first terminal device; and a controller unit configured to determine an association between the first terminal device and a second terminal device and to control the transceiver to transmit a radio resource allocation message to allocate radio resources to the second terminal device for an uplink transmission in response to receiving the request for an allocation of radio resources from the first terminal device. In accordance with some embodiments the base station is configured such that the request for an allocation of radio resources from the first terminal device is received on a random access channel of the wireless telecommunications system. In accordance with some embodiments the base station is configured such that the request for an allocation of radio resources from the first terminal device is associated with a random access procedure of the wireless telecommunications system. In accordance with some embodiments the base station is configured such that the radio resources allocated to the second terminal device correspond with an allocation of radio resources requested by the first terminal device. In accordance with some embodiments the base station is configured such that the association between the first terminal device and the second terminal device is established based on the first terminal device and the second terminal device having a common characteristic relating to their uplink transmissions. In accordance with some embodiments the base station is configured such that the association between the first terminal device and the second terminal device is established based on the first terminal device and the second terminal device being associated with a same terminal device classifier. In accordance with some embodiments the base station is configured such that the terminal device classifier is a quality class indicator of respective bearers associated with the respective terminal devices. In accordance with some embodiments the controller unit is further configured to control the transceiver to transmit an access request denial message to the second terminal device to instruct the second terminal device not to make its own request for an allocation of radio resources. In accordance with some embodiments the controller unit is further configured to control the transceiver to transmit a cease access request denial message to the second terminal device after having transmitted the access request denial message to instruct the second terminal device that it is now allowed to make its own request for an allocation of radio resources. In accordance with some embodiments the controller unit is further configured to control the transceiver to transmit an access request allow message to the first terminal device to instruct the first terminal device that it is allowed to make the request for the allocation of radio resources. In accordance with some embodiments the controller unit is further configured to select the first terminal device from a plurality of terminal devices as the terminal device to which the access request allow message is transmitted based on a transmission characteristic associated with respective ones of the plurality of terminal devices. In accordance with some embodiments the transmission characteristic is selected from the group comprising: a timing advance; a reference signal received power, a reference signal received quality, a sounding reference signal measurement at the base station, and a radio channel quality indicator. In accordance with some embodiments the controller unit is further configured to determine an association between the first terminal device and a further terminal device; and to cause the transceiver to transmit a radio resource allocation message to the further terminal device to allocate radio resources for an uplink transmission from the further terminal device based on the request for an allocation of radio resources from the first terminal device. In accordance with some embodiments the controller unit is further configured to determine an association between the first terminal device and a plurality of other terminal devices and to control the transceiver to transmit an access request denial message to a subset of the plurality of other terminal devices to instruct the subset of the plurality of other terminal devices not to make their own requests for an allocation of radio resources and to further transmit radio resource allocation messages to the plurality of other terminal devices to allocate radio resources for respective uplink transmissions from respective ones of the plurality of other terminal devices based on the request for an allocation of radio resources from the first terminal device. In accordance with some embodiments the transceiver is further configured to receive a transmission from the second terminal device using the radio resources allocated to the second terminal device. In accordance with some embodiments the transmission received from the second terminal device comprises an indication that the second terminal device does not require some or any of the allocated resources for uplink transmission. In accordance with some embodiments the transmission received from the second terminal device comprises an indication of a request for a further allocation of radio resources for a further uplink transmission from the second terminal device. In accordance with some embodiments the request for an allocation of radio resources received from the first terminal device comprises a request for an allocation of radio resources to allow the first terminal device to transmit a buffer status report to the base station. In accordance with some embodiments the first and second terminal devices are machine type communication, MTC, terminal devices. In accordance with some embodiments the wireless telecommunications system is associated with a radio interface spanning a system frequency bandwidth for supporting radio communications with a first type of terminal device and comprising a restricted frequency bandwidth for supporting radio communications with a second type of terminal device, wherein the restricted frequency bandwidth is narrower than and within the system frequency bandwidth, and wherein the first and second terminal devices are terminal devices of the second type. According to a third aspect of the invention there is provided a wireless telecommunications system comprising the base station of the second aspect of the invention and a terminal device. According to a fourth aspect of the invention there is provided a method of operating a terminal device for receiving an allocation of radio resources for transmission of uplink data to a base station in a wireless telecommunications system, the method comprising: determining that the terminal device has uplink data waiting for transmission to the base station; determining that the terminal device should not transmit a request for an allocation of radio resources for transmission of the uplink data to the base station, and waiting to receive a radio, resource allocation message from the base station to allocate radio resources to be used for transmissions associated with the uplink data waiting for transmission to the base station. In accordance with some embodiments determining that the terminal device should not transmit a request for an allocation of radio resources comprises determining that the terminal device should not initiate a random access procedure of the wireless telecommunications system. In accordance with some embodiments determining that the terminal device should not initiate a random access procedure of the wireless telecommunications system comprises determining that the terminal device should not make transmissions on a physical random access channel of the wireless telecommunications system. In accordance with some embodiments determining that the terminal device should not transmit a request for an allocation of radio resources is based on the terminal device receiving an indication that the terminal device should not transmit a request for an allocation of radio resources. In accordance with some embodiments the indication comprises an indication that another terminal device in the wireless telecommunications system has made a request for an allocation of radio resources. In accordance with some embodiments determining that the terminal device should not transmit a request for an allocation of radio resources is based on the terminal device having received an access request denial message from the base station. In accordance with some embodiments the method further comprises subsequently receiving the radio resource allocation message from the base station. In accordance with some embodiments the method further comprises transmitting the uplink data waiting for transmission to the base station using radio resources derived from information in the radio resource allocation message received from the base station. In accordance with some embodiments the method further comprises determining at a later time after having transmitted the uplink data to the base station that the terminal device has further uplink data waiting for transmission to the base station, and, in response thereto, determining that the terminal device should transmit a request for an allocation of radio resources on which to transmit the uplink data to the base station, and transmitting such a request, In accordance with some embodiments determining that the terminal device should transmit a request for an allocation of radio resources in response to determining that the terminal device has further uplink data waiting for transmission to the base station is based on the terminal device having received an access request allow message from the base station to indicate the terminal device is allowed to make a request for an allocation of radio resources. In accordance with some embodiments the method further comprises determining that the allocation of radio resources is not sufficient for the uplink data waiting for transmission to the base station and transmitting to the base station an indication of a request for a further allocation of radio resources in response thereto. In accordance with some embodiments the indication of a request for a further allocation of radio resources is transmitted to the base station using the allocated radio resources. in accordance with some embodiments the method further comprises transmitting a request for an allocation of radio resources on which to transmit the uplink data to the base station after waiting to receive a radio resource allocation message from the base station for a period of time without a radio resource allocation message being received from the base station. In accordance with some embodiments the terminal device is a machine type communication, MTC, terminal device. In accordance with some embodiments the wireless telecommunications system is associated with a radio interface spanning a system frequency bandwidth for supporting radio communications with a first type of terminal device and comprising a restricted frequency bandwidth for supporting radio communications with a second type of terminal device, Wherein the restricted frequency bandwidth is narrower than and within the system frequency bandwidth, and wherein the terminal device is a terminal device of the second type. According to a fifth aspect of the invention there is provided a terminal device arranged to receive an allocation of radio resources for transmission of uplink data to a base station in a wireless telecommunications system, wherein the terminal device is configured to: determine that the terminal device has uplink data waiting for transmission to the base station; determine that the terminal device should not transmit a request for an allocation of radio resources for transmission of the uplink data to the base station, and wait to receive a radio resource allocation message from the base station to allocate radio resources to be used for transmissions associated with the uplink data waiting for transmission to the base station. In accordance with some embodiments the terminal device is configured such that determining that the terminal device should not transmit a request for an allocation of radio resources comprises determining that the terminal device should not initiate a random access procedure of the wireless telecommunications system. In accordance with some embodiments the terminal device is configured such that determining that the terminal device should not initiate a random access procedure of the wireless telecommunications system comprises determining that the terminal device should not make transmissions on a physical random access channel of the wireless telecommunications system. In accordance with some embodiments the terminal device is configured such that determining that the terminal device should not transmit a request for an allocation of radio resources is based on the terminal device receiving an indication that the terminal device should not transmit a request for an allocation of radio resources. In accordance with some embodiments the indication comprises an indication that another terminal device in the wireless telecommunications system has made a request for an allocation of radio resources. In accordance with some embodiments the terminal device is configured such that determining that the terminal device should not transmit a request for an allocation of radio resources is based on the terminal device having received an access request denial message from the base station. In accordance with some embodiments the terminal device is further configured to subsequently receive the radio resource allocation message from the base station. In accordance with some embodiments the terminal device is further configured to transmit the uplink data waiting for transmission to the base station using radio resources derived from information in the radio resource allocation message received from the base station. In accordance with some embodiments the terminal device is further configured to determine at a later time after having transmitted the uplink data to the base station that the terminal device has further uplink data waiting for transmission to the base station, and, in response thereto, to determine that the terminal device should transmit a request for an allocation of radio resources on which to transmit the uplink data to the base station, and to transmit such a request. In accordance with some embodiments the terminal device is configured such that determining that the terminal device should transmit a request for an allocation of radio resources in response to determining that the terminal device has further uplink data waiting for transmission to the base station is based on the terminal device having received an access request allow message from the base station to indicate the terminal device is allowed to make a request for an allocation of radio resources. In accordance with some embodiments the terminal device is further configured to determine that the allocation of radio resources is not sufficient for the uplink data waiting for transmission to the base station and to transmit to the base station an indication of a request for a further allocation of radio resources in response thereto. In accordance with some embodiments the terminal device is configured such that the indication of a request for a further allocation of radio resources is transmitted to the base station using the allocated radio resources, In accordance with some embodiments the terminal device is further configured to transmit a request for an allocation of radio resources on which to transmit the uplink data to the base station after waiting to receive a radio resource allocation message from the base station for a period of time without a radio resource allocation message being received from the base station. In accordance with some embodiments the terminal device is a machine type communication, MTC, terminal device. In accordance with some embodiments the wireless telecommunications system is associated with a radio interface spanning a system frequency bandwidth for supporting radio communications with a first type of terminal device and comprising a restricted frequency bandwidth for supporting radio communications with a second type of terminal device, wherein the restricted frequency bandwidth is narrower than and within the system frequency bandwidth, and wherein the terminal device is a terminal device of the second type. According to a sixth aspect of the invention there is provided a wireless telecommunications system comprising the terminal device of the fifth aspect of the invention and a base station. It will be appreciated that features and aspects of the invention described above in relation to the first and other aspects of the invention are equally applicable to, and may be combined with, embodiments of the invention according to other aspects of the invention as appropriate, and not just in the specific combinations described above. | A47B870284 | 20171106 | 20180301 | 99861.0 | A47B8702 | 0 | PHILLIPS, MICHAEL K | MOBILE TERMINAL DEVICE AND ASSOCIATED METHOD FOR OBTAINING UPLINK RESOURCES | UNDISCOUNTED | 1 | CONT-PENDING | A47B | 2,017 |
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15,805,720 | PENDING | THERMAL REACTION DEVICE AND METHOD FOR USING THE SAME | A method for carrying out nucleic acid amplification reactions using a microfluidic device is described. Amplification primers and other amplification reagents are deposited at a plurality of reaction sites in the device, a sample solution containing amplifiable polynucleotides is introduced into the reaction sites, and amplification is carried out. | 1. (canceled) 2. A method for carrying out nucleic acid amplification reactions to detect the quantity, presence, or absence of a plurality of target polynucleotide sequences in a sample, the method comprising: (a) providing a microfluidic device comprising (i) an inlet, (ii) a first flow channel in fluid communication with the inlet, and (ii) a plurality of second channels in fluid communication with the first flow channel, wherein each second channel comprises an entrance and a dead end, wherein amplification primers, and optionally other amplification reagents, are non-covalently deposited at reaction sites at the dead ends of each second channel, and amplification primers deposited in different second channels amplify different target polynucleotide sequences, (b) introducing a sample solution comprising the sample through the inlet such that the sample solution flows through the first flow channel and into the plurality of second channels, wherein the sample comprises a plurality of polynucleotides, and wherein introduction of the sample solution into the second channels causes the deposited amplification primers to be dissolved into the sample solution, and (c) isolating the reaction sites from the first flow channel and from each other, (d) conducting polynucleotide amplification reactions in the reaction sites, and (e) detecting the quantity, presence or absence of polynucleotide amplification products in the reaction sites to determine the quantity, presence, or absence of said target polynucleotide sequences in the sample. 3. The method of claim 2, wherein the microfluidic device comprises at least 100 reaction sites. 4. The method of claim 3, wherein the microfluidic device comprises 100 to 1,000 reaction sites. 5. The method of claim 2, wherein said target polynucleotide sequences comprise viral or bacterial sequences. 6. The method of claim 2, wherein the target polynucleotide sequences are cDNA sequences. 7. The method of claim 2, wherein the quantity, presence or absence of polynucleotide amplification products is detected using an intercalation. 8. The method of claim 2 wherein primers suitable for multiplex amplifications are deposited in at least one of said reaction sites. 9. The method of claim 2, wherein the polynucleotide amplification reactions are polymerase chain reactions (PCR). 10. The method of claim 9, wherein the polynucleotide amplification reactions are real time quantitative polymerase chain reactions (quantitative RT-PCR). 11. A method for carrying out nucleic acid amplification reactions to detect the presence or absence of a plurality of different target viral or bacterial polynucleotide sequences in a biological sample obtained from a human patient, the method comprising: (a) providing a microfluidic device comprising (i) an inlet, (ii) a first flow channel in fluid communication with the inlet, and (iii) a plurality of second channels in fluid communication with the first flow channel, wherein each second channel comprises an entrance and a dead end, wherein amplification primers, and optionally other amplification reagents, are non-covalently deposited at a reaction site at the dead-ends of each second channel, and amplification primers deposited in different second channels amplify different target polynucleotide sequences; and wherein the different target polynucleotide sequences are viral or bacterial sequences, (b) introducing a sample solution comprising the sample through the inlet such that the sample solution flows through the first flow channel and into the plurality of second channels, wherein the sample comprises a plurality of polynucleotides, and wherein introduction of the sample solution into the second channels causes the deposited amplification primers to be dissolved into the sample solution, (c) isolating the reaction sites from the first flow channel and from each other, (d) conducting polynucleotide amplification reactions in the reaction sites, and (e) detecting the presence or absence of a polynucleotide amplification products in the reaction sites to determine the presence or absence of a viral or bacterial target polynucleotide sequence in the biological sample obtained from the human patient. | CROSS-REFERENCE TO RELATED APPLICATIONS This patent application is a continuation of U.S. patent application Ser. No. 14/873,958, filed on Oct. 2, 2015, which is a continuation of U.S. patent application Ser. No. 13/548,068, filed on Jul. 12, 2012, now U.S. Pat. No. 9,150,913, which is a continuation of U.S. patent application Ser. No. 12/579,347, filed on Oct. 14, 2009, now U.S. Pat. No. 8,247,178, which is a continuation of U.S. patent application Ser. No. 11/084,357, filed on Mar. 18, 2005, now U.S. Pat. No. 7,604,965, which is a continuation-in-part of U.S. patent application Ser. No. 10/876,046, filed Jun. 23, 2004, which is a continuation-in-part of U.S. patent application Ser. No. 10/837,835, filed on May 2, 2004, now U.S. Pat. No. 7,476,363, which is a continuation-in-part of U.S. patent application Ser. No. 10/818,642, filed on Apr. 5, 2004, now U.S. Pat. No. 7,666,361, which claims priority under 35 U.S.C. § 119(e) to U.S. provisional application No. 60/460,634, filed on Apr. 3, 2003, all of which are incorporated by reference in their entirety for all purposes and the specific purposes describe therein and herein. This application is related to U.S. non-provisional application Ser. No. 11/043,895, filed on Feb. 14, 2005, which is incorporated by reference in its entirety for all purposes. BACKGROUND Recently, there have been concerted efforts to develop and manufacture microfluidic systems to perform various chemical and biochemical analyses and syntheses, both for preparative and analytical applications. The goal to make such devices arises because of the significant benefits that can be realized from miniaturization with respect to analyses and syntheses conducted on a macro scale. Such benefits include a substantial reduction in time, cost and the space requirements for the devices utilized to conduct the analysis or synthesis. Additionally, microfluidic devices have the potential to be adapted for use with automated systems, thereby providing the additional benefits of further cost reductions and decreased operator errors because of the reduction in human involvement. Microfluidic devices have been proposed for use in a variety of applications, including, for instance, capillary electrophoresis, gas chromatography and cell separations. However, realization of these benefits has often been thwarted because of various complications associated with the microfluidic devices that have thus far been manufactured. For instance, many of the current microfluidic devices are manufactured from silica-based substrates; these materials are difficult and complicated to machine and devices made from such materials are fragile. Furthermore, transport of fluid through many existing microfluidic devices requires regulation of complicated electrical fields to transport fluids in a controlled fashion through the device. Thus, in view of the foregoing benefits that can be achieved with microfluidic devices but the current limitations of existing devices, there remains a need for microfluidic devices designed for use in conducting a variety of chemical and biochemical analyses. Because of its importance in modern biochemistry, there is a particular need for devices that can be utilized to conduct a variety of nucleic acid amplification reactions, while having sufficient versatility for use in other types of analyses as well. Devices with the ability to conduct nucleic acid amplifications would have diverse utilities. For example, such devices could be used as an analytical tool to determine whether a particular target nucleic acid of interest is present or absent in a sample. Thus, the devices could be utilized to test for the presence of particular pathogens (e.g., viruses, bacteria or fungi), and for identification purposes (e.g., paternity and forensic applications). Such devices could also be utilized to detect or characterize specific nucleic acids previously correlated with particular diseases or genetic disorders. When used as analytical tools, the devices could also be utilized to conduct genotyping analyses and gene expression analyses (e.g., differential gene expression studies). Alternatively, the devices can be used in a preparative fashion to amplify sufficient nucleic acid for further analysis such as sequencing of amplified product, cell-typing, DNA fingerprinting and the like. Amplified products can also be used in various genetic engineering applications, such as insertion into a vector that can then be used to transform cells for the production of a desired protein product. SUMMARY A variety of devices and methods for conducting microfluidic analyses are provided herein, including devices that can be utilized to conduct thermal cycling reactions such as nucleic acid amplification reactions. The devices differ from conventional microfluidic devices in that they include elastomeric components; in some instances, much or all of the device is composed of elastomeric material. Certain devices are designed to conduct thermal cycling reactions (e.g., PCR) with devices that include one or more elastomeric valves to regulate solution flow through the device. Thus, methods for conducting amplification reactions with devices of this design are also provided. Some of the devices include blind flow channels which include a region that functions as a reaction site. Certain such devices include a flow channel formed within an elastomeric material, and a plurality of blind flow channels in fluid communication with the flow channel, with a region of each blind flow channel defining a reaction site. The devices can also include one or more control channels overlaying and intersecting each of the blind flow channels, wherein an elastomeric membrane separates the one or more control channels from the blind flow channels at each intersection. The elastomeric membrane in such devices is disposed to be deflected into or withdrawn from the blind flow channel in response to an actuation force. The devices can optionally further include a plurality of guard channels formed within the elastomeric material and overlaying the flow channel and/or one or more of the reaction sites. The guard channels are designed to have fluid flow therethrough to reduce evaporation from the flow channels and reaction sites of the device. Additionally, the devices can optionally include one or more reagents deposited within each of the reaction sites. In certain devices, the flow channel is one of a plurality of flow channels, each of the flow channels in fluid communication with multiple blind flow channels which branch therefrom. Of devices of this design, in some instances the plurality of flow channels are interconnected with one another such that fluid can be introduced into each of the reaction sites via a single inlet. In other devices, however, the plurality of flow channels are isolated from each other such that fluid introduced into one flow channel cannot flow to another flow channel, and each flow channel comprises an inlet at one or both ends into which fluid can be introduced. Other devices include an array of reaction sites having a density of at least 50 sites/cm2 , with the reaction sites typically formed within an elastomeric material. Other devices have even higher densities such as at least 250, 500 or 1000 sites/cm2, for example. Still other device include a reaction site formed within an elastomeric substrate, at which a reagent for conducting a reaction is non-covalently immobilized. The reagent can be one or more reagents for conducting essentially any type of reaction. The reagent in some devices includes one reagents for conducting a nucleic acid amplification reaction. Thus, in some devices the reagent comprises a primer, polymerase and one or more nucleotides. In other devices, the reagent is a nucleic acid template. A variety of matrix or array-based devices are also provided. Certain of these devices include: (i) a first plurality of flow channels formed in an elastomeric substrate, (ii) a second plurality of flow channels formed in the elastomeric substrate that intersect the first plurality of flow channels to define an array of reaction sites, (iii) a plurality of isolation valves disposed within the first and second plurality of flow channels that can be actuated to isolate solution within each of the reaction sites from solution at other reaction sites, and (iv) a plurality of guard channels overlaying one or more of the flow channels and/or one or more of the reaction sites to prevent evaporation of solution therefrom. The foregoing devices can be utilized to conduct a number of different types of reactions, including those involving temperature regulation (e.g., thermocycling of nucleic acid analyses). Methods conducted with certain blind channel type devices involve providing a microfluidic device that comprises a flow channel formed within an elastomeric material; and a plurality of blind flow channels in fluid communication with the flow channel, with an end region of each blind flow channel defining a reaction site. At least one reagent is introduced into each of the reaction sites, and then a reaction is detected at one or more of the reaction sites. The method can optionally include heating the at least one reagent within the reaction site. Thus, for example, a method can involve introducing the components for a nucleic acid amplification reaction and then thermocycling the components to form amplified product. Other methods involve providing a microfluidic device comprising one or more reaction sites, each reaction site comprising a first reagent for conducting an analysis that is non-covalently deposited on an elastomeric substrate. A second reagent is then introduced into the one or more reaction sites, whereby the first and second reagents mix to form a reaction mixture. A reaction between the first and second reagents at one or more of the reaction sites is subsequently detected. Still other methods involve providing a microfluidic device comprising an array of reaction sites formed within a substrate and having a density of at least 50 sites/cm2. At least one reagent is introduced into each of the reaction sites. A reaction at one or more of the reaction sites is then detected. Yet other methods involve providing a microfluidic device comprising at least one reaction site which is formed within an elastomeric substrate and a plurality of guard channels also formed within the elastomeric substrate. At least one reagent is introduced into each of the reaction sites and then heated within the reaction sites. A fluid is flowed through the guard channels before or during heating to reduce evaporation from the at least one reaction site. A reaction within the at least one reaction site is subsequently detected. Additional devices designed to reduce evaporation of fluid from the device are also provided. In general, such devices comprise a cavity that is part of a microfluidic network formed in an elastomeric substrate; and a plurality of guard channels overlaying the cavity and separated from the cavity by an elastomeric membrane. The guard channel in such devices is sized (i) to allow solution flow therethrough, and (ii) such that there is not a substantial reduction in solution flow in, out or through the cavity due to deflection of the membrane(s) upon application of an actuation force to the guard channels. Other such devices include (i) one or more flow channels and/or one or more reaction sites; and (ii) a plurality of guard channels overlaying the microfluidic system and separated therefrom by elastomer, wherein the spacing between guard channels is between 1 μm to 1 mm. In other devices the spacing is between 5 μm and 500 μm, in other devices between 10 μm and 100 μm, and in still other devices between 40 μm and 75 μm. In other embodiments of the invention provide for a microfluidic device have one or more sample channels having a plurality of valves in communication therewith, wherein each sample channel, when filled with a sample, can be partitioned into sub-samples for conducting analysis, such as amplification, for example, but not limited to PCR, including TAQMAN™, and endpoint PCR, and isothermal amplification techniques, such as INVADER™. Such microfluidic devices may have some sample channels devoted to partition and analyze known control samples, while other sample channels may be used to partition and analyze one or more test samples. The arrangement of the separate sample channels may be interdigitated or laid out as plots among the device surface, the latter being preferred for optimizing conditions for conducting analysis on a routine basis. One advantage of partitioning a sample is to reduce the apparent concentration of a high background of wild type sample containing a low, such as one, two, three, four, five, or six orders of magnitude lower concentration of a mutant sample than the wild type sample. For example, when analyzing a sample containing a high concentration of wild-type DNA that contains a very small, several orders of magnitude, such as 10 less copies than the wild type. By partitioning the sample many fold, such as by 100, 1,000, 10,000, 100,000, or 1,000,000 fold, the ratio in each partition between wild type and mutant DNA is changed from the original ratio such that the likelihood of background PCR product that would be produced relative the amount of PCR product produced from the target mutant is minimized to yield a valid signal indicating the presence of the mutant DNA target in the particular partitioned chamber. There may also be benefits afforded by conducting the reaction in very small volumes that are obtainable in certain embodiments of the present invention, in that by conducting the reaction in a small volume raises the concentration of target to the volume of the total reaction. In another embodiment, the invention provides a method for analyzing the presence of a specific gene, for example but not limited to an oncogene point mutation in a patient suspected of having a tumor if the tumor releases genetic material into the body, in particular, the blood stream, even though other non-oncogenic genetic material may be present in the blood stream in great excess, including one, two, three, four, five, and six orders of magnitude greater excess than the target oncogenic target genetic material. For example, in the K-ras point mutation at codon 12 occurs in about 70 to 95% of the cells of this cancer, wherein some or all of the cells may release genetic material containing the K-ras point mutation at codon 12 which can be detected by the methods described herein using the devices herein. In yet another embodiment, a sample may contain whole cells that when analyzed, for example but not limited to, by PCR, the cells lyse and make their genetic material available for amplification. Other oncogenic point mutations and genetic diseases that produce amplifiable genetic material in low quantities relative to the background genetic material normally present Compositions for conducting nucleic acid analyses in reaction sites of certain microfluidic devices are also provided. Certain such compositions include one or more of the following: an agent that blocks protein binding sites on an elastomeric material and a detergent. The blocking agent is typically selected from the group consisting of a protein (e.g., gelatin or albumin, such as bovine serum albumin (BSA)). The detergent can be SDS or Triton, for example BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1A is a schematic representation of an exemplary device with a matrix design of intersecting vertical and horizontal flow channels. FIGS. 1B-E show enlarged views of a portion of the device shown in FIG. 1A and illustrates its operation. FIG. 1F is a schematic representation of another exemplary matrix design device that utilizes guard channels to reduce sample evaporation. FIG. 2 is a plan view of an exemplary blind channel device. FIG. 3A is a plan view of another exemplary blind channel device. FIG. 3B is a schematic representation of a more complex blind channel device based upon the unit of the general design depicted in FIG. 3A. FIG. 3C is an enlarged view of a region of the device shown in FIG. 3B, and illustrates the orientation of the guard flow channels in this particular design. FIG. 4 is a plan view of a device utilizing the hybrid design. FIG. 5 is a chart showing ramp up and down times to conduct a thermocycling reaction. FIG. 6 shows the location of spotted reagents within reaction sites in a blind channel type device illustrating proper alignment of the reagents within reaction sites at the corners of the device. FIGS. 7A and 7B respectively are a cross-sectional view and a schematic diagram of another hybrid type microfluidic device and represents the type of device used to conduct the experiments described in Examples 1-4. FIG. 8 is a bar graph in which the average FAM/PR1/Control ratios are plotted for six different β-actin TaqMan reactions. The reactions were thermocycled in the micro fluidic device (chip) shown in FIG. 7B (solid bars) and Macro TaqMan reactions (striped bars). The controls are the first and fourth bar sets that have no DNA. The error bars are the standard deviation of the ratios. FIG. 9 is a diagram depicting an exemplary pin spotting process. Reagents are picked up from a source (e.g., a microtiter plate) and then printed by bringing the loaded pin into contact with the substrate. The wash step consists of agitation in deionized water followed by vacuum drying. FIG. 10 is a bar graph depicting FAM signal strength for the microfluidic device (chip) described in Example 1 (see FIG. 7B) based on the experiments described in Example 2. The data are in the form of (FAM signal/PR1 signal) scaled by the FAM/PR1 ratio for the reference lanes. Error bars are the standard deviation along a lane. The “1.3×” and “1×” designations refer to the concentration of the spotted primers and probes, in relation to their nominal values. FIG. 11 is a bar graph showing average VIC/PF1/Control ratios for 9-10 wells for Macro TaqMan (striped bars), and TaqMan reactions in the microfluidic device (solid bars). Two negative controls (Control) and two samples with 100 pg/nl genomic DNA were thermocycled with reaction components as described above with 4× the standard amount of primer/probe. The error bars represent the standard deviation of the average ratios. FIG. 12 is a bar graph that shows FAM/PR1/Control ratios for each of 1 nl wells branching from a single flow channel of a microfluidic device (see FIG. 7B). The amount of genomic DNA was 0.25 pg/nl, which results in an average of one target copy per well. FIG. 13 is a bar graph depicting the average VIC/PR1/Control ratios for CYP2D6 SNP reactions using the microfluidic device shown in FIG. 7B. Allele 1 (AI-1) is the positive control for the VIC probe against the reference or wild type allele CYP2D6*1. Allele 2 (AI-2) is the positive control for the FAM probe against the variant or mutant allele, CYP2D6*3. The control has no DNA template. Genomic DNA was used at either 100 pg/nl or 20 pg/nl. The error bars are the standard deviation of the ratios. FIG. 14 is a bar graph showing the average FAM/PR1/Control ratios for CYP2D6 SNP reactions in the microfluidic device shown in FIG. 7B. The samples are the same as described with respect to FIG. 13 and in Example 3. FIGS. 15 is a schematic diagram of the microfluidic device used for the experiments in Example 4. FIG. 16 is a polyacrylamide gel containing PCR product from Macro PCR and PCR reactions in the microfluidic device shown in FIG. 7B. The results on the left show the approximate migration of different DNA base pair lengths. The lanes containing interspersed bands are molecular weight markers. The lanes labeled “Macro” are the PCR products from the Macro reactions at different dilutions. The lanes labeled “In chip” are PCR products generated in the chip. The lanes containing many bands throughout the gel are nonspecific background signals. FIGS. 17a-17d depict two preferred designs of a partitioning microfluidic device in a valve off and valve actuated state. FIGS. 18A and 18B depict images of a partitioning microfluidic devices after a thermocycling reaction was performed. FIG. 18A depicts the pattern representing a two color fluorescence image, and FIG. 18B depicts the pattern of the remaining fluorescence image after subtraction of the control red fluorescence. FIG. 19 depicts a graph of comparing the average number of copies per well to the number of positive wells. FIG. 20 depicts an isothermic amplification scheme—SCORPION FIG. 21A depicts an exemplary matrix microfluidic device plan view. FIG. 21B shows a perspective view of a portion (four unit cells) of an exemplary device also shown in planar view in FIG. 21A. DETAILED DESCRIPTION I. Definitions Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this invention belongs. The following references provide one of skill with a general definition of many of the terms used in this invention: Singleton et al., Dictionary Of Microbiology And Molecular Biology (2d ed. 1994); The Cambridge Dictionary Of Science And Technology (Walker ed., 1988); The Glossary Of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary Of Biology (1991). As used herein, the following terms have the meanings ascribed to them unless specified otherwise. A “flow channel” refers generally to a flow path through which a solution can flow. The term “valve” unless otherwise indicted refers to a configuration in which a flow channel and a control channel intersect and are separated by an elastomeric membrane that can be deflected into or retracted from the flow channel in response to an actuation force. A “blind channel” or a “dead-end channel” refers to a flow channel which has an entrance but not a separate exit. Accordingly, solution flow in and out of the blind channel occurs at the same location. The process of filling one or more blind channels is sometimes simply referred to as “blind fill.” An “isolated reaction site” generally refers to a reaction site that is not in fluid communication with other reactions sites present on the device. When used with respect to a blind channel, the isolated reaction site is the region at the end of the blind channel that can be blocked off by a valve associated with the blind channel. A “via” refers to a channel formed in an elastomeric device to provide fluid access between an external port of the device and one or more flow channels. Thus, a via can serve as a sample input or output, for example. The term “elastomer” and “elastomeric” has its general meaning as used in the art. Thus, for example, Allcock et al. (Contemporary Polymer Chemistry, 2nd Ed.) describes elastomers in general as polymers existing at a temperature between their glass transition temperature and liquefaction temperature. Elastomeric materials exhibit elastic properties because the polymer chains readily undergo torsional motion to permit uncoiling of the backbone chains in response to a force, with the backbone chains recoiling to assume the prior shape in the absence of the force. In general, elastomers deform when force is applied, but then return to their original shape when the force is removed. The elasticity exhibited by elastomeric materials can be characterized by a Young's modulus. The elastomeric materials utilized in the microfluidic devices disclosed herein typically have a Young's modulus of between about 1 Pa-1 TPa, in other instances between about 10 Pa-100 GPa, in still other instances between about 20 Pa-1 GPa, in yet other instances between about 50 Pa-10 MPa, and in certain instances between about 100 Pa-1 MPa. Elastomeric materials having a Young's modulus outside of these ranges can also be utilized depending upon the needs of a particular application. Some of the microfluidic devices described herein are fabricated from an elastomeric polymer such as GE RTV 615 (formulation), a vinyl-silane crosslinked (type) silicone elastomer (family). However, the present microfluidic systems are not limited to this one formulation, type or even this family of polymer; rather, nearly any elastomeric polymer is suitable. Given the tremendous diversity of polymer chemistries, precursors, synthetic methods, reaction conditions, and potential additives, there are a large number of possible elastomer systems that can be used to make monolithic elastomeric microvalves and pumps. The choice of materials typically depends upon the particular material properties (e.g., solvent resistance, stiffness, gas permeability, and/or temperature stability) required for the application being conducted. Additional details regarding the type of elastomeric materials that can be used in the manufacture of the components of the microfluidic devices disclosed herein are set forth in Unger et al. (2000) Science 288:113-116, and PCT Publications WO 02/43615, and WO 01/01025, which are incorporated herein by reference in their entirety for all purposes. The terms “nucleic acid,” “polynucleotide,” and “oligonucleotide” are used herein to include a polymeric form of nucleotides of any length, including, but not limited to, ribonucleotides or deoxyribonucleotides. There is no intended distinction in length between these terms. Further, these terms refer only to the primary structure of the molecule. Thus, in certain embodiments these terms can include triple-, double- and single-stranded DNA, as well as triple-, double- and single-stranded RNA. They also include modifications, such as by methylation and/or by capping, and unmodified forms of the polynucleotide. More particularly, the terms “nucleic acid,” “polynucleotide,” and “oligonucleotide,” include polydeoxyribonucleotides (containing 2-deoxy-D-ribose), polyribonucleotides (containing D-ribose), any other type of polynucleotide which is an N- or C-glycoside of a purine or pyrimidine base, and other polymers containing nonnucleotidic backbones, for example, polyamide (e.g., peptide nucleic acids (PNAs)) and polymorpholino (commercially available from the Anti-Virals, Inc., Corvallis, Oreg., as Neugene) polymers, and other synthetic sequence-specific nucleic acid polymers providing that the polymers contain nucleobases in a configuration which allows for base pairing and base stacking, such as is found in DNA and RNA. A “probe” is an nucleic acid capable of binding to a target nucleic acid of complementary sequence through one or more types of chemical bonds, usually through complementary base pairing, usually through hydrogen bond formation, thus forming a duplex structure. The probe binds or hybridizes to a “probe binding site.” The probe can be labeled with a detectable label to permit facile detection of the probe, particularly once the probe has hybridized to its complementary target. The label attached to the probe can include any of a variety of different labels known in the art that can be detected by chemical or physical means, for example. Suitable labels that can be attached to probes include, but are not limited to, radioisotopes, fluorophores, chromophores, mass labels, electron dense particles, magnetic particles, spin labels, molecules that emit chemiluminescence, electrochemically active molecules, enzymes, cofactors, and enzyme substrates. Probes can vary significantly in size. Some probes are relatively short. Generally, probes are at least 7 to 15 nucleotides in length. Other probes are at least 20, 30 or 40 nucleotides long. Still other probes are somewhat longer, being at least 50, 60, 70, 80, 90 nucleotides long. Yet other probes are longer still, and are at least 100, 150, 200 or more nucleotides long. Probes can be of any specific length that falls within the foregoing ranges as well. A “primer” is a single-stranded polynucleotide capable of acting as a point of initiation of template-directed DNA synthesis under appropriate conditions (i.e., in the presence of four different nucleoside triphosphates and an agent for polymerization, such as, DNA or RNA polymerase or reverse transcriptase) in an appropriate buffer and at a suitable temperature. The appropriate length of a primer depends on the intended use of the primer but typically is at least 7 nucleotides long and, more typically range from 10 to 30 nucleotides in length. Other primers can be somewhat longer such as 30 to 50 nucleotides long. Short primer molecules generally require cooler temperatures to form sufficiently stable hybrid complexes with the template. A primer need not reflect the exact sequence of the template but must be sufficiently complementary to hybridize with a template. The term “primer site” or “primer binding site” refers to the segment of the target DNA to which a primer hybridizes. The term “primer pair” means a set of primers including a 5′ “upstream primer” that hybridizes with the complement of the 5′ end of the DNA sequence to be amplified and a 3′ “downstream primer” that hybridizes with the 3′ end of the sequence to be amplified. A primer that is “perfectly complementary” has a sequence fully complementary across the entire length of the primer and has no mismatches. The primer is typically perfectly complementary to a portion (subsequence) of a target sequence. A “mismatch” refers to a site at which the nucleotide in the primer and the nucleotide in the target nucleic acid with which it is aligned are not complementary. The term “substantially complementary” when used in reference to a primer means that a primer is not perfectly complementary to its target sequence; instead, the primer is only sufficiently complementary to hybridize selectively to its respective strand at the desired primer-binding site. The term “complementary” means that one nucleic acid is identical to, or hybridizes selectively to, another nucleic acid molecule. Selectivity of hybridization exists when hybridization occurs that is more selective than total lack of specificity. Typically, selective hybridization will occur when there is at least about 55% identity over a stretch of at least 14-25 nucleotides, preferably at least 65%, more preferably at least 75%, and most preferably at least 90%. Preferably, one nucleic acid hybridizes specifically to the other nucleic acid. See M. Kanehisa, Nucleic Acids Res. 12:203 (1984). The term “label” refers to a molecule or an aspect of a molecule that can be detected by physical, chemical, electromagnetic and other related analytical techniques. Examples of detectable labels that can be utilized include, but are not limited to, radioisotopes, fluorophores, chromophores, mass labels, electron dense particles, magnetic particles, spin labels, molecules that emit chemiluminescence, electrochemically active molecules, enzymes, cofactors, enzymes linked to nucleic acid probes and enzyme substrates. The term “detectably labeled” means that an agent has been conjugated with a label or that an agent has some inherent characteristic (e.g., size, shape or color) that allows it to be detected without having to be conjugated to a separate label. A “polymorphic marker” or “polymorphic site” is the locus at which divergence occurs. Preferred markers have at least two alleles, each occurring at frequency of greater than 1%, and more preferably greater than 10% or 20% of a selected population. A polymorphic locus may be as small as one base pair. Polymorphic markers include restriction fragment length polymorphisms, variable number of tandem repeats (VNTR's), hypervariable regions, minisatellites, dinucleotide repeats, trinucleotide repeats, tetranucleotide repeats, simple sequence repeats, and insertion elements such as Alu. The first identified allelic form is arbitrarily designated as the reference form and other allelic forms are designated as alternative or variant alleles. The allelic form occurring most frequently in a selected population is sometimes referred to as the wildtype form. Diploid organisms may be homozygous or heterozygous for allelic forms. A diallelic polymorphism has two forms. A triallelic polymorphism has three forms. A “single nucleotide polymorphism” (SNP) occurs at a polymorphic site occupied by a single nucleotide, which is the site of variation between allelic sequences. The site is usually preceded by and followed by highly conserved sequences of the allele (e.g., sequences that vary in less than 1/100 or 1/1000 members of the populations). A single nucleotide polymorphism usually arises due to substitution of one nucleotide for another at the polymorphic site. A transition is the replacement of one purine by another purine or one pyrimidine by another pyrimidine. A transversion is the replacement of a purine by a pyrimidine or vice versa. Single nucleotide polymorphisms can also arise from a deletion of a nucleotide or an insertion of a nucleotide relative to a reference allele. A “reagent” refers broadly to any agent used in a reaction. A reagent can include a single agent which itself can be monitored (e.g., a substance that is monitored as it is heated) or a mixture of two or more agents. A reagent may be living (e.g., a cell) or non-living. Exemplary reagents for a nucleic acid amplification reaction include, but are not limited to, buffer, metal ions, polymerase, primers, template nucleic acid, nucleotides, labels, dyes, nucleases and the like. Reagents for enzyme reactions include, for example, substrates, cofactors, coupling enzymes, buffer, metal ions, inhibitors and activators. Reagents for cell-based reactions include, but are not limited to, cells, cell specific dyes and ligands (e.g., agonists and antagonists) that bind to cellular receptors. A “ligand” is any molecule for which there exists another molecule (i.e., an “antiligand”) that specifically or non-specifically binds to the ligand, owing to recognition of some portion of the ligand by the antiligand. II. Overview A number of different microfluidic devices (also sometimes referred to as chips) having unique flow channel architectures are provided herein, as well as methods for using such devices to conduct a variety of high throughput analyses. The devices are designed for use in analyses requiring temperature control, especially analyses involving thermocycling (e.g., nucleic acid amplification reactions). The microfluidic devices incorporate certain design features that: give the devices a significantly smaller footprint than many conventional microfluidic devices, enable the devices to be readily integrated with other instrumentation and provide for automated analysis. Some of the microfluidic devices utilize a design typically referred to herein as “blind channel” or “blind fill” are characterized in part by having a plurality of blind channels, which, as indicated in the definition section, are flow channels having a dead end or isolated end such that solution can only enter and exit the blind channel at one end (i.e., there is not a separate inlet and outlet for the blind channel). These devices require only a single valve for each blind channel to isolate a region of the blind channel to form an isolated reaction site. During manufacture of this type of device, one or more reagents for conducting an analysis are deposited at the reaction sites, thereby resulting in a significant reduction in the number of input and outputs. Additionally, the blind channels are connected to an interconnected network of channels such that all the reaction sites can be filled from a single, or limited number, of sample inputs. Because of the reduction in complexity in inputs and outputs and the use of only a single valve to isolate each reaction site, the space available for reaction sites is increased. Thus, the features of these devices means that each device can include a large number of reaction sites (e.g., up to tens of thousands) and can achieve high reaction site densities (e.g., over 1,000-4,000 reaction sites/cm2). Individually and collectively, these features also directly translate into a significant reduction in the size of these devices compared to traditional microfluidic devices. Other microfluidic devices that are disclosed herein utilize a matrix design. In general, microfluidic devices of this type utilize a plurality of intersecting horizontal and vertical flow channels to define an array of reaction sites at the points of intersection. Thus, devices of this design also have an array or reaction sites; however, there is a larger number of sample inputs and corresponding outputs to accommodate the larger number of samples with this design. A valve system referred to as a switchable flow array architecture enables solution be flowed selectively through just the horizontal or flow channels, thus allowing for switchable isolation of various flow channels in the matrix. Hence, whereas the blind channel devices are designed to conduct a large number of analyses under different conditions with a limited number of samples, the matrix devices are constructed to analyze a large number of sample under a limited number of conditions. Still other devices are hybrids of these two general design types. The microfluidic devices that are described are further characterized in part by utilizing various components such as flow channels, control channels, valves and/or pumps from elastomeric materials. In some instances, essentially the entire device is made of elastomeric material. Consequently, such devices differ significantly in form and function from the majority of conventional microfluidic devices that are formed from silicon-based material. The design of the devices enables them to be utilized in combination with a number of different heating systems. Thus, the devices are useful in conducting diverse analyses that require temperature control. Additionally, those microfluidic devices for use in heating applications can incorporate a further design feature to minimize evaporation of sample from the reaction sites. Devices of this type in general include a number of guard channels formed within the elastomeric device through which water can be flowed to increase the water vapor pressure within the elastomeric material from which the device is formed, thereby reducing evaporation of sample from the reaction sites. In another embodiment, a temperature cycling device may be used to control the temperature of the microfluidic devices. Preferably, the microfluidic device would be adapted to make thermal contact with the microfluidic device. Where the microfluidic device is supported by a substrate material, such as a glass slide or the bottom of a carrier plate, such as a plastic carrier, a window may be formed in a region of the carrier or slide such that the microfluidic device, preferably a device having an elastomeric block, may directly contact the heating/cooling block of the temperature cycling device. In a preferred embodiment, the heating/cooling block has grooves therein in communication with a vacuum source for applying a suction force to the microfluidic device, preferably the portion wherein the reactions are taking place. Alternatively, a rigid thermally conductive plate may be bonded to the microfluidic device that then mates with the heating and cooling block for efficient thermal conduction resulting. The array format of certain of the devices means the devices can achieve high throughput. Collectively, the high throughput and temperature control capabilities make the devices useful for performing large numbers of nucleic acid amplifications (e.g., polymerase chain reaction—PCR). Such reactions will be discussed at length herein as illustrative of the utility of the devices, especially of their use in any reaction requiring temperature control. However, it should be understood that the devices are not limited to these particular applications. The devices can be utilized in a wide variety of other types of analyses or reactions. Examples include analyses of protein-ligand interactions and interactions between cells and various compounds. Further examples are provided infra. III. General Structure of Microfluidic Devices A. Pumps and Valves The microfluidic devices disclosed herein are typically constructed at least in part from elastomeric materials and constructed by single and multilayer soft lithography (MSL) techniques and/or sacrificial-layer encapsulation methods (see, e.g., Unger et al. (2000) Science 288:113-116, and PCT Publication WO 01/01025, both of which are incorporated by reference herein in their entirety for all purposes). Utilizing such methods, microfluidic devices can be designed in which solution flow through flow channels of the device is controlled, at least in part, with one or more control channels that are separated from the flow channel by an elastomeric membrane or segment. This membrane or segment can be deflected into or retracted from the flow channel with which a control channel is associated by applying an actuation force to the control channels. By controlling the degree to which the membrane is deflected into or retracted out from the flow channel, solution flow can be slowed or entirely blocked through the flow channel. Using combinations of control and flow channels of this type, one can prepare a variety of different types of valves and pumps for regulating solution flow as described in extensive detail in Unger et al. (2000) Science 288:113-116, and PCT Publication WO/02/43615 and WO 01/01025. The devices provided herein incorporate such pumps and valves to isolate selectively a reaction site at which reagents are allowed to react. The reaction sites can be located at any of a number of different locations within the device. For example, in some matrix-type devices, the reaction site is located at the intersection of a set of flow channels. In blind channel devices, the reaction site is located at the end of the blind channel. If the device is to be utilized in temperature control reactions (e.g., thermocycling reactions), then, as described in greater detail infra, the elastomeric device is typically fixed to a support (e.g., a glass slide). The resulting structure can then be placed on a temperature control plate, for example, to control the temperature at the various reaction sites. In the case of thermocycling reactions, the device can be placed on any of a number of thermocycling plates. Because the devices are made of elastomeric materials that are relatively optically transparent, reactions can be readily monitored using a variety of different detection systems at essentially any location on the microfluidic device. Most typically, however, detection occurs at the reaction site itself (e.g., within a region that includes an intersection of flow channels or at the blind end of a flow channel). The fact that the device is manufactured from substantially transparent materials also means that certain detection systems can be utilized with the current devices that are not usable with traditional silicon-based microfluidic devices. Detection can be achieved using detectors that are incorporated into the device or that are separate from the device but aligned with the region of the device to be detected. B. Guard Channels To reduce evaporation of sample and reagents from the elastomeric microfluidic devices that are provided herein, a plurality of guard channels can be formed in the devices. The guard channels are similar to the control channels in that typically they are formed in a layer of elastomer that overlays the flow channels and/or reaction site. Hence, like control channels, the guard channels are separated from the underlying flow channels and/or reaction sites by a membrane or segment of elastomeric material. Unlike control channels, however, the guard channels are considerably smaller in cross-sectional area. In general, a membrane with smaller area will deflect less than a membrane with larger area under the same applied pressure. The guard channels are designed to be pressurized to allow solution (typically water) to be flowed into the guard channel. Water vapor originating from the guard channel can diffuse into the pores of the elastomer adjacent a flow channel or reaction site, thus increasing the water vapor concentration adjacent the flow channel or reaction site and reducing evaporation of solution therefrom. In general, the guard channels are sufficiently small such that when pressurized the membrane that separates the guard channel from the underlying flow channel or reaction site does not substantially restrict solution flow in, out, or through the flow channel or reaction site which the guard channel overlays. When used in this context, the term “substantially restrict” or other similar terms means that solution flow is not reduced in, out or through the flow channel or reaction site by more than 40%, typically less than 30%, usually less than 20%, and in some instances less than 10%, as compared to solution flow in, to or through the flow channel or reaction site under the same conditions, when the guard channel is not pressurized to achieve solution flow therethrough. Usually this means that the guard channels have a cross-sectional area of between 100 μm2 and 50,000 μm2, or any integral or non-integral cross-sectional area therebetween. Thus, for example, in some instances, the cross-sectional area is less than 50,000 m2, in other instances less than 10,000 m2, in still other instances less than 10,00 m2, and in yet other instances less than 100 m2. The guard channels can have any of a variety of shapes including, but not limited to, circular, elliptical, square, rectangular, hexagonal and octahedral shapes. The guard channels are designed to reduce the evaporation of sample and reagents from the device during the time and under the conditions that it takes to conduct a thermocycling reaction to less than 50%, in other instance less than 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5% or 1%. Thus, for example, a typical PCR reaction involving 40 cycles can be conducted within 120 minutes. The guard channel system is designed to reduce evaporation during approximately this time frame to the foregoing set of limits. To achieve this level of evaporation reduction, the guard channels are typically present at a density of at least 10 lines/cm2 to 1000 lines/cm2, or any integral density level therebetween. More specifically, the guard channels are generally at least 25 lines/cm2, in other instances at least 50 lines/cm2, in still other instances at least 100 lines/cm2, and in yet other instances at least 500 lines/cm2. To achieve this level of evaporation reduction, the guard channels are typically present at a spacing between 1 mm to 1 m as measured from the outer edge of one line to the nearest outer edge of adjacent line, or any integral density level therebetween. More specifically, the guard channels are generally spaced between 500 m to 5 m, in other instances between 100 m to 10 m, in still other instances between 75 m to 40 m. Thus, the spacing is typically at least 1 μm, but is less than 1 mm, in other instances less than 500 m, in still other instances less than 400 m, in yet other instances less than 300 m, in other instances less than 200 m, and in still other instances less than 100 m, 50 m or 25 m. The guard channels can be formed as a separate network of channels or can be smaller channels that branch off of the control channels. The guard channels can extend across the device or only a particular region or regions of the device. Typically, the guard channels are placed adjacent and over flow channels and reaction sites as these are the primary locations at which evaporation is the primary concern. Exemplary locations of guard channels on certain matrix devices are illustrated in FIG. 1C, and on certain blind channel devices in FIGS. 3B and 3C, and discussed in greater detail infra. The solution flowed through the guard channel includes any substance that can reduce evaporation of water. The substance can be one that increases the water vapor concentration adjacent a flow line and/or reaction site, or one that while not increasing the water vapor concentration nonetheless blocks evaporation of water from the flow line and/or reaction site (blocking agent). Thus, one option is to utilize essentially any aqueous solution in which case suitable solutions include, but are not limited to, water and buffered solution (e.g., TaqMan buffer solution, and phosphate buffered saline). Suitable blocking agents include, for example, mineral oil. Guard channels are typically formed in the elastomer utilizing the MSL techniques and/or sacrificial-layer encapsulation methods cited above. The following sections describe in greater detail a number of specific configurations that can be utilized to conduct a variety of analyses, including analyses requiring temperature control (e.g., nucleic acid amplification reactions). It should be understood, however, that these configurations are exemplary and that modifications of these systems will be apparent to those skilled in the art. IV. Matrix Design A. General Devices utilizing the matrix design generally have a plurality of vertical and horizontal flow channel that intersect to form an array of junctions. Because a different sample and reagent (or set of reagents) can be introduced into each of the flow channels, a large number of samples can be tested against a relatively large number of reaction conditions in a high throughput format. Thus, for example, if a different sample is introduced into each of M different vertical flow channels and a different reagent (or set of reagents) is introduced into each of N horizontal flow channels, then M×N different reactions can be conducted at the same time. Typically, matrix devices include valves that allow for switchable isolation of the vertical and horizontal flow channels. Said differently, the valves are positioned to allow selective flow just through the vertical flow channels or just through the horizontal flow channels. Because devices of this type allow flexibility with respect to the selection of the type and number of samples, as well as the number and type of reagents, these devices are well-suited for conducting analyses in which one wants to screen a large number of samples against a relatively large number of reaction conditions. The matrix devices can optionally incorporate guard channels to help prevent evaporation of sample and reactants. The invention provides for high-density matrix designs that utilize fluid communication vias between layers of the microfluidic device to weave control lines and fluid lines through the device. For example, by having a fluid line in each layer of a two layer elastomeric block, higher density reaction cell arrangements are possible. FIGS. 21A and 21B depict an exemplary matrix design wherein a first elastomeric layer 2110 (1st layer) and a second elastomeric layer 2120 (2d layer) each having fluid channels formed therein. For example, a reagent fluid channel 2105 in the first layer 2110 is connected to a reagent fluid channel 2105 in the second layer 2120 through a via 2130, while the second layer 2120 also has sample channels 2115 therein, the sample channels and the reagent channels terminating in sample and reagent chambers 2180, respectively. The sample and reagent chambers 2180 are in fluid communication with each other through an interface channel 2150 that has an interface valve 2140 associated therewith to control fluid communication between each of the chambers 2180 of a reaction cell 2160. In use, the interface is first closed, then reagent is introduced into the reagent channel from the reagent inlet and sample is introduced into the sample channel through the sample inlet, containment valves 2170 are then closed to isolate each reaction cell 2160 from other reaction cells 2160. Once the reaction cells 2160 are isolated, the interface valve 2140 is opened to cause the sample chamber and the reagent chamber to be in fluid communication with each other so that a desired reaction may take place. Accordingly, a preferred aspect of the invention provides for a microfluidic device for reacting M number of different samples with N number of different reagents comprising: a plurality of reaction cells, each reaction cell comprising a sample chamber and a reagent chamber, the sample chamber and the reagent chamber being in fluid communication through an interface channel having an interface valve associated therewith for controlling fluid communication between the sample chamber and the reagent chamber; a plurality of sample inlets each in fluid communication with the sample chambers; a plurality of reagent inlets each in fluid communication with the reagent chambers; wherein one of the sample inlets or reagent inlets is in fluid communication with one of the sample chambers or one of the reagent chambers, respectively, through a via. Certain embodiments include having the reaction cells be formed within an elastomeric block formed from a plurality of layers bonded together and the interface valve is deflectable membrane; having the sample inlets be in communication with the sample chamber through a sample channel and the reagent inlet is in fluid communication with the reagent chamber through a reagent channel, a portion of the sample channel and a portion of the reagent channel being oriented about parallel to each other and each having a containment valve associated therewith for controlling fluid communication therethrough; having the valve associated with the sample channel and the valve associated with the reagent channel are in operable communication with each other through a common containment control channel; having the containment common control channel located along a line about normal to one of the sample channel or the reagent channel Another aspect of the invention provides for a method for making a feature in an elastomeric block comprising the steps of: providing a first elastomeric layer; applying a photoresist layer upon a surface of the first elastomeric layer; applying a light pattern to the photoresist layer to form a pattern of reacted photoresist material; removing unreacted photoresist material leaving the pattern of reacted photoresist upon the surface of the first elastomeric layer; applying an etching reagent to the first elastomeric surface to etch the surface of the first elastomeric layer not covered by the pattern of reacted photoresist material thereby removing regions of the first elastomeric layer not covered by the pattern of reacted photoresist and leaving a pattern of the elastomeric layer corresponding to the pattern of reacted photoresist material. In certain preferred embodiments of the method include having a step of removing the pattern of reacted photoresist material; having the removing is caused by applying an adhesive tape to the surface of the elastomeric layer and the pattern of reacted photoresist material, then separating the adhesive tape from the elastomeric layer while some or all of the pattern of reacted photoresist material is removed from the surface of the elastomeric layer; having the photo resist be SU8; having the etching reagent comprises tetrabutylammoniumfluoride-trihydrate; having the feature be a via; having the elastomeric block comprise a plurality of elastomeric layers bonded together, wherein two or more elastomeric layers have recesses formed therein and one recess of one elastomeric layer is in communication with a recess of another elastomeric layer through the via. The microfluidic devices of the present invention may be further integrated into the carrier devices described in copending and co-owned U.S. patent application Ser. No. 60/557,715 by Unger filed on Mar. 29, 2004, which is herein incorporated for all purposes. The carrier of Unger provides on-board continuous fluid pressure to maintain valve closure away from a source of fluid pressure, e.g., house air pressure. Unger further provides for an automated system for charging and actuating the valves of the present invention as described therein. B. Exemplary Designs and Uses FIG. 1A provides an illustration of one exemplary matrix device. This device 100 comprises seven vertical flow channels 102 and seven horizontal flow channels 104 that intersect to form an array of 49 different intersections or reaction sites 106. This particular device thus enables seven samples to be reacted with seven different reagents or sets of reagents. Column valves 110 that regulate solution flow in the vertical direction can be controlled by control channels 118 that can all be actuated at a single inlet 114. Similarly, row valves 108 regulate solution flow in the horizontal direction; these are controlled by control channels 116 that are actuated by a single control inlet 112. As shown in FIG. 1A, the control channels 116 that regulate the row valves 108 vary in width depending upon location. When a control channel 116 crosses a vertical flow channel 102, the control channel 116 is sufficiently narrow that when it is actuated it does not deflect into the vertical flow channel 102 to reduce substantially solution flow therethrough. However, the width of the control channel 116 is increased when it overlays one of the horizontal flow channels 104; this makes the membrane of the control channel sufficiently large to block solution flow through the horizontal flow channel 104. In operation, reagents R1-R7 are introduced into their respective horizontal flow channels 104 and samples S1-S7 are injected into their respective vertical flow channels 102. The reagents in each horizontal flow channel 104 thus mix with the samples in each of the vertical flow channels 102 at the intersections 106, which in this particular device are in the shape of a well or chamber. Thus, in the specific case of a nucleic acid amplification reaction, for example, the reagents necessary for the amplification reaction are introduced into each of the horizontal flow channels 104. Different nucleic acid templates are introduced into the vertical flow channels 102. In certain analyses, the primer introduced as part of the reagent mixture that is introduced into each of the horizontal flow channels 104 might differ between flow channels. This allows each nucleic acid template to be reacted with a number of different primers. FIGS. 1B-E show enlarged plan views of adjacent reaction sites in the device depicted in FIG. 1A to illustrate more specifically how the device operates during an analysis. For the purposes of clarity, the intersections 106 are not shown in the form of reaction wells and control channels 116, 118 have been omitted, with just the column and row valves 110, 108 being shown (rectangular boxes). As shown in FIG. 1B, an analysis is commenced by closing column valves 110 and opening row valves 108 to allow solution flow through horizontal flow channel 104 while blocking flow through vertical flow channels 102. Reagent R1 is then introduced into horizontal flow channel 104 and flowed completely through the length of the horizontal flow channel 104 such that all the reaction sites 106 are filled. Solution flow through horizontal channel 104 can be achieved by an external pump, but more typically is achieved by incorporating a peristaltic pump into the elastomeric device itself as described in detail in Unger et al. (2000) Science 288:113-116, and PCT Publication WO 01/01025, for example. Once R1 has been introduced, row valves 108 are closed and column valves 102 opened (see FIG. 1C). This allows samples S1 and S2 to be introduced into vertical flow channels 102 and to flow through their respective flow channels. As the samples flow through the vertical flow channels 102, they expel R1 from the reaction sites 106, thus leaving sample at reaction sites 106. Then, as shown in FIG. 1D, row valves 108 are opened to allow S1 and S2 to diffuse and mix with R1. Thus, a mixture of sample and reactant (R1S1 and R1S2) is obtained in the region of each intersection or reaction site 106. After allowing a sufficient time for S1 and S2 to diffuse with R1, all row and column valves 108, 110 are closed to isolate S1 and S2 within the region of their respective reaction sites 106 and to prevent intermixing of S1 and S2 (see FIG. 1E). The mixtures are then allowed to react and the reactions detected by monitoring the intersection 106 or the cross-shaped region that includes the intersection 106. For analyses requiring heating (e.g., thermocycling during amplification reactions), the device is placed on a heater and heated while the samples remain isolated. A modified version of the device shown in FIG. 1A is shown in FIG. 1F. The general structure bears many similarities with that depicted in FIG. 1A, and common elements in both figures share the same reference numbers. The device 150 illustrated in FIG. 1F differs in that pairs of horizontal flow channels 104 are joined to a common inlet 124. This essentially enables duplicate sets of reagents to be introduced into two adjacent flow channels with just a single injection into inlet 124. The use of a common inlet is further extended with respect to the vertical flow channels 102. In this particular example, each sample is introduced into five vertical flow channels 102 with a single injection into sample inlet 120. Thus, with this particular device, there are essentially ten replicate reactions for each particular combination of sample and reagent. Of course, the number of replicate reactions can be varied as desired by altering the number of vertical and/or horizontal flow channels 102, 104 that are joined to a common inlet 120, 124. The device shown in FIG. 1F also includes a separate control channel inlet 128 that regulates control channel 130 that can be used to govern solution flow toward outlets 132 and another control channel inlet 132 that regulates control channel 134 that regulates solution flow to outlets 136. Additionally, device 150 incorporates guard channels 138. In this particular design, the guard channels 138 are formed as part of control channels 116. As indicated supra, the guard channels 138 are smaller than the row valves 108; consequently, the membranes of the guard channels 138 are not deflected into the underlying horizontal flow channels 104 such that solution flow is disrupted. Finally, the design shown in FIG. 1F differs in that reaction does not occur in wells at the intersection of the horizontal and vertical flow lines, but in the intersection itself. V. Blind Channel Designs A. General Devices utilizing a blind channel design have certain features. First, the devices include one or more flow channels from which one or more blind channels branch. As indicated above, the end region of such channels can serve as a reaction site. A valve formed by an overlaying flow channel can be actuated to isolate the reaction site at the end of the blind channel. The valves provide a mechanism for switchably isolating the reaction sites. Second, the flow channel network in communication with the blind channels is configured such that all or most of the reaction sites can be filled with a single or a limited number of inlets (e.g., less than 5 or less than 10). The ability to fill a blind flow channel is made possible because the devices are made from elastomeric material. The elastomeric material is sufficiently porous such that air within the flow channels and blind channels can escape through these pores as solution is introduced into the channels. The lack of porosity of materials utilized in other microfluidic devices precludes use of the blind channel design because air in a blind channel has no way to escape as solution is injected. A third characteristic is that one or more reagents are non-covalently deposited on a base layer of elastomer during manufacture (see infra for further details on the fabrication process) within the reaction sites. The reagent(s) are non-covalently attached because the reagents are designed to become dissolved when sample is introduced into the reaction site. To maximize the number of analyses, a different reactant or set of reactants is deposited at each of the different reaction sites. Certain blind channel devices are designed such that the reaction sites are arranged in the form of an array. Thus, in those blind channel devices designed for conducting nucleic acid amplification reactions, for example, one or more of the reagents required for conducting the extension reaction are deposited at each of the reaction sites during manufacture of the device. Such reagents include, for example, all or some of the following: primers, polymerase, nucleotides, cofactors, metal ions, buffers, intercalating dyes and the like. To maximize high throughput analysis, different primers selected to amplify different regions of DNA are deposited at each reaction site. Consequently, when a nucleic acid template is introduced into the reaction sites via inlet, a large number of extension reactions can be performed at different segments of the template. Thermocycling necessary for an amplification reaction can be accomplished by placing the device on a thermocycling plate and cycling the device between the various required temperatures. The reagents can be immobilized in a variety of ways. For example, in some instances one or more of the reagents are non-covalently deposited at the reaction site, whereas in other instances one or more of the reagents is covalently attached to the substrate at the reaction site. If covalently attached, the reagents can be linked to the substrate via a linker. A variety of linker types can be utilized such as photochemical/photolabile linkers, themolabile linkers, and linkers that can be cleaved enzymatically. Some linkers are bifunctional (i.e., the linker contains a functional group at each end that is reactive with groups located on the element to which the linker is to be attached); the functional groups at each end can be the same or different. Examples of suitable linkers that can be used in some assays include straight or branched-chain carbon linkers, heterocyclic linkers and peptide linkers. A variety of types of linkers are available from Pierce Chemical Company in Rockford, Ill. and are described in EPA 188,256; U.S. Pat. Nos. 4,671,958; 4,659,839; 4,414,148; 4,669,784; 4,680,338, 4,569, 789 and 4,589,071, and by Eggenweiler, H. M, Pharmaceutical Agent Discovery Today 1998, 3, 552. NVOC (6 nitroveratryloxycarbonyl) linkers and other NVOC-related linkers are examples of suitable photochemical linkers (see, e.g., WO 90/15070 and WO 92/10092). Peptides that have protease cleavage sites are discussed, for example, in U.S. Pat. No. 5,382,513. B. Exemplary Designs and Uses FIG. 2 is a simplified plan view of one exemplary device utilizing the blind channel design. The device 200 includes a flow channel 204 and a set of branch flow channels 206 branching therefrom that are formed in an elastomeric substrate 202. Each branch flow channel 206 terminates in a reaction site 208, thereby forming an array of reaction sites. Overlaying the branch flow channels 206 is a control channel 210 that is separated from the branch flow channels 206 by membranes 212. Actuation of control channel 210 causes membranes 212 to deflect into the branch flow channels 206 (i.e., to function as a valve), thus enabling each of the reaction sites 208 to be isolated from the other reaction sites. Operation of such a device involves injecting a test sample into flow channel 204 with solution subsequently flowing into each of branch channels 206. Once the sample has filled each branch channel 206, control channel 210 is actuated to cause activation of valves/membranes 212 to deflect into branch channels 206, thereby sealing off each of reaction sites 208. As the sample flows into and remains in reaction sites 208, it dissolves reagents previously spotted at each of the reaction sites 208. Once dissolved, the reagents can react with the sample. Valves 212 prevent the dissolved reagents at each reaction site 208 from intermixing by diffusion. Reaction between sample and reagents are then detected, typically within reaction site 208. Reactions can optionally be heated as described in the temperature control section infra. FIG. 3A illustrates an example of a somewhat more complex blind flow channel design. In this particular design 300, each of a set of horizontal flow channels 304 are connected at their ends to two vertical flow channels 302. A plurality of branch flow channels 306 extend from each of the horizontal flow channels 304. The branch flow channels 304 in this particular design are interleaved such that the branch channel 306 attached to any given horizontal flow channel 304 is positioned between two branch channels 306 joined to an immediately adjacent horizontal flow channel 304, or positioned between a branch flow channel 306 joined to an immediately adjacent flow channel 304 and one of the vertical flow channels 302. As with the design depicted in FIG. 3A, each branch flow channel 306 terminates in a reaction site 308. Also consistent with the design shown in FIG. 3A, a control channel 310 overlays each of the branch channels and is separated from the underlying branch channel by membrane 312. The control channel is actuated at port 316. The vertical and horizontal flow channels 302, 304 are interconnected such that injection of sample into inlet 314 allows solution to flow throughout the horizontal and vertical flow channel network and ultimately into each of the reaction sites 308 via the branch flow channels 306. Hence, in operation, sample is injected into inlet to introduce solution into each of the reaction sites. Once the reaction sites are filled, valves/membranes are actuated to trap solution within the reaction sites by pressurizing the control channels at port. Reagents previously deposited in the reaction sites become resuspended within the reaction sites, thereby allowing reaction between the deposited reagents and sample within each reaction site. Reactions within the reaction sites are monitored by a detector. Again, reactions can optionally be controllably heated according to the methods set forth in the temperature control section below. An even more complicated version of the general design illustrated in FIG. 3A is shown in FIG. 3B. The device shown in FIG. 3B is one in which the unit organization of the horizontal and branch flow channels 302 shown in FIG. 3A is repeated multiple times. The device shown in FIG. 3B further illustrates the inclusion of guard channels 320 in those devices to be utilized in applications that involve heating (e.g., thermocycling). An exemplary orientation of the guard channels 320 with respect to the flow channels 304 and branch channels 306 is shown in the enlarged view depicted in FIG. 3C. The guard channels 320 overlay the branch flow channels 306 and reaction sites 308. As discussed above, water is flowed through the guard channels 320 during heating of the device 300 to increase the local concentration of water in the device, thereby reducing evaporation of water from solution in the flow channels 306 and reaction sites 308. The features of blind channel devices discussed at the outset of this section minimizes the footprint of the device and enable a large number of reaction sites to be formed on the device and for high densities to be obtained. For example, devices of this type having 2500 reaction sites can readily be manufactured to fit on a standard microscope slides (25 mm×75 mm). The foregoing features also enable very high densities of reaction sites to be obtained with devices utilizing the blind channel design. For example, densities of at least 50, 60, 70, 80, 90 or 100 reaction sites/cm2 or any integral density value therebetween can be readily obtained. However, certain devices have even higher densities ranging, for example, between 100 to 4000 reaction sites/cm2, or any integral density value therebetween. For instance, some devices have densities of at least 100, 150, 200, 250, 300, 400, 500, 600, 700, 800, 900 or 1000 sites/cm2. Devices with very high densities of at least, 2000, 3000, or 4000 sites/cm2 are also obtainable. Such high densities directly translate into a very large number of reaction sites on the device. Devices utilizing the blind channel architecture typically have at least 10-100 reaction sites, or any integral number of sites therebetween. More typically, the devices have at least 100-1,000 reaction sites, or any integral number of sites therebetween. Higher density devices can have even more reaction sites, such as at least 1,000-100,000 reaction sites, or any integral number of sites therebetween. Thus, certain devices have at least 100; 500; 1,000; 2,000; 3,000; 4,000; 5,000; 6,000; 7,000; 8,000; 9,000; 10,000; 20,000; 30,000; 40,000; 50,000; or 100,000 reaction sites depending upon the overall size of the device. The large number of reaction sites and densities that can be obtained is also a consequence of the ability to fabricate very small wells or cavities. For example, the cavities or wells typically have a volume of less than 50 nL; in other instances less than 40 nL, 30 nL, 20 nL or 10 nL; and in still other instances less than 5 nL or 1 nL. As a specific example, certain devices have wells that are 300 microns long, 300 microns wide and 10 microns deep. The blind channel devices provided herein can utilize certain design features and methodologies discussed in PCT Applications PCT/US01/44549 (published as WO 02/43615) and PCT/US02/10875 (published as WO 02/082047), including, for example, strategies for filling dead-ended channels, liquid priming, pressurized outgas priming, as well as various strategies for displacing gas during the filling of microfluidic channels. Both of these PCT publications are incorporated herein by reference in their entirety for all purposes. VI. Hybrid Designs Still other devices are hybrids of the matrix and blind fill designs. The design of devices of this type is similar to the blind channel device shown in FIG. 3A, except that each horizontal flow channel is connected to its own sample inlet port(s) and the horizontal flow channels are not interconnected via vertical flow channels. Consequently, sample introduced into any given horizontal flow channel fills only that horizontal flow channel and reaction sites attached thereto. Whereas, in the blind flow channel device shown in FIG. 3A, sample can flow between the horizontal flow channels 304 via vertical flow channels 302. An example of devices of this general device is shown in FIG. 4. Device 400 comprises a plurality of horizontal flow channels 404, each of which has a plurality of branch flow channels 406 extending from it and its own sample inlet 414. A control channel 410 overlays each of the branch flow channels 406 and membrane (valve) 412 separates the control channel 410 from the underlying branch flow channel 406. As with the blind flow channel design, actuation of the control channel at inlet 416 causes deflection of membranes 412 into the branch flow channels 406 and isolation of reaction sites 408. In a variation of this design, each horizontal flow channel 404 can include an inlet 414 at each end, thus allowing sample to be introduced from both ends. In some instances, reagents are deposited at the reaction sites during manufacture of the device. This enables a large number of samples to be tested under a relatively large number of reaction conditions in a short period of time without requiring time-consuming additions of reagents as required with the matrix devices. Alternatively, reaction mixtures can be prepared prior to injection on the chip. Once the mixtures are injected, they can be analyzed or further treated (e.g., heated). By injecting different samples into each of the horizontal flow channels, a large number of samples can be rapidly analyzed. Assuming reagents have been previously deposited at the reaction sites, the presence of the same reagent at each reaction site associated with any given horizontal flow channel provides a facile way to conduct a number of replicate reactions with each sample. If instead, the reagent at the reaction sites differ for any given flow channel, then each sample is essentially simultaneously exposed to a variety of different reaction conditions. Thus, the devices provided herein are tailored for a variety of different types of investigations. If an investigation involves screening of a relatively large number of different samples under user controlled conditions (e.g., 100 samples against 100 user selected reagents), then the matrix devices provide a useful solution. If, however, the investigation involves analyzing one or a limited number of samples under a wide variety of reaction conditions (e.g., one sample against 10,000 reaction conditions), then the blind channel design is useful. Finally, if one wants to examine a relatively large number of samples against defined reaction conditions without having to inject reagents (e.g., 100 samples against 100 previously defined reagents), then the hybrid devices are useful. VII. Temperature Control A. Devices and Components A number of different options of varying sophistication are available for controlling temperature within selected regions of the microfluidic device or the entire device. Thus, as used herein, the term temperature controller is meant broadly to refer to a device or element that can regulate temperature of the entire microfluidic device or within a portion of the microfluidic device (e.g., within a particular temperature region or at one or more junctions in a matrix of blind channel-type microfluidic device). Generally, the devices are placed on a thermal cycling plate to thermal cycle the device. A variety of such plates are readily available from commercial sources, including for example the ThermoHybaid Px2 (Franklin, Mass.), MJ Research PTC-200 (South San Francisco, Calif.), Eppendorf Part #E5331 (Westbury, N.Y.), Techne Part #205330 (Princeton, N.J.). To ensure the accuracy of thermal cycling steps, in certain devices it is useful to incorporate sensors detecting temperature at various regions of the device. One structure for detecting temperature is a thermocouple. Such a thermocouple could be created as thin film wires patterned on the underlying substrate material, or as wires incorporated directly into the microfabricated elastomer material itself. Temperature can also be sensed through a change in electrical resistance. For example, change in resistance of a thermistor fabricated on an underlying semiconductor substrate utilizing conventional techniques can be calibrated to a given temperature change. Alternatively, a thermistor could be inserted directly into the microfabricated elastomer material. Still another approach to detection of temperature by resistance is described in Wu et al. in “MEMS Flow Sensors for Nano-fluidic Applications”, Sensors and Actuators A 89 152-158 (2001), which is hereby incorporated by reference in its entirety. This paper describes the use of doped polysilicon structures to both control and sense temperature. For polysilicon and other semiconductor materials, the temperature coefficient of resistance can be precisely controlled by the identity and amount of dopant, thereby optimizing performance of the sensor for a given application. Thermo-chromatic materials are another type of structure available to detect temperature on regions of an amplification device. Specifically, certain materials dramatically and reproducibly change color as they pass through different temperatures. Such a material could be added to the solution as they pass through different temperatures. Thermo-chromatic materials could be formed on the underlying substrate or incorporated within the elastomer material. Alternatively, thermo-chromatic materials could be added to the sample solution in the form of particles. Another approach to detecting temperature is through the use of an infrared camera. An infrared camera in conjunction with a microscope could be utilized to determine the temperature profile of the entire amplification structure. Permeability of the elastomer material to radiation would facilitate this analysis. Yet another approach to temperature detection is through the use of pyroelectric sensors. Specifically, some crystalline materials, particularly those materials also exhibiting piezoelectric behavior, exhibit the pyroelectric effect. This effect describes the phenomena by which the polarization of the material's crystal lattice, and hence the voltage across the material, is highly dependent upon temperature. Such materials could be incorporated onto the substrate or elastomer and utilized to detect temperature. Other electrical phenomena, such as capacitance and inductance, can be exploited to detect temperature in accordance with embodiments of the present invention. B. Verification of Accurate Thermocycling As described in greater detail in the fabrication section infra, blind channel devices have a base layer onto which reagents are placed. The structure comprising the two layers containing the flow channels and control channels is overlayed on the base layer such that the flow channels are aligned with the deposited reagents. The other side of the base layer is then placed upon a substrate (e.g., glass). Usually, the reaction site at which reaction occurs is about 100-150 microns above the substrate/glass interface. Using known equations for thermal diffusivity and appropriate values for the elastomers and glass utilized in the device, one can calculate the time required for the temperature within the reaction site to reach the temperature the controller seeks to maintain. The calculated values shown in Table 1 demonstrate that temperature can rapidly be reached, even using elastomer and glass layers considerably thicker than utilized in devices in which the reaction site is approximately 100-150 microns (i.e., the typical distance for the devices described herein). TABLE 1 Calculated heat diffusion lengths through PDMS and glass layers at the indicated time periods. 1 second 10 seconds 100 seconds PDMS 400 um 1.26 mm 4.0 mm Glass 640 um 2.0 mm 6.4 mm FIG. 5 illustrates the rapidity at which the desired temperature is achieved using a blind channel device. In another embodiment, temperature may be measured by using double stranded oligonucleotide polymers having known tms wherein an intercollating dye whose intercollation indicates the whether the oligonucleotide is hybridized or denatured, such as SYBR Green™ or ethidium bromide for example, wherein by introducing a solution containing the oligonucleotide with the dye into the chambers of the microfluidic device having an array of reaction chambers can be used to determine the extent to which the temperature of each chamber is consistent across the array. In this embodiment, as the temperature is raised above the tm, the intercolating dye changes its relation to the oligonucleotide upon it sdenataturation into a single stranded oligonucleotide. Alternatively, the if the temperature is above the tm and is lowered, an the intercollation of the dye into the now annealed oligonucleotide may be monitored. The use of the dye in essence provides for an “oligonucleotide thermometer” which changes a property, such as fluorescence, in response to a temperature change relative to the tm of the oligonucleotide. By designing or using oligonucleotides of a selected tm, the extent to which an array of reaction chambers change temperature in a similar manner can be determined. VIII. Detection A. General A number of different detection strategies can be utilized with the microfluidic devices that are provided herein. Selection of the appropriate system is informed in part on the type of event and/or agent being detected. The detectors can be designed to detect a number of different signal types including, but not limited to, signals from radioisotopes, fluorophores, chromophores, electron dense particles, magnetic particles, spin labels, molecules that emit chemiluminescence, electrochemically active molecules, enzymes, cofactors, enzymes linked to nucleic acid probes and enzyme substrates. Illustrative detection methodologies suitable for use with the present microfluidic devices include, but are not limited to, light scattering, multichannel fluorescence detection, UV and visible wavelength absorption, luminescence, differential reflectivity, and confocal laser scanning. Additional detection methods that can be used in certain application include scintillation proximity assay techniques, radiochemical detection, fluorescence polarization, fluorescence correlation spectroscopy (FCS), time-resolved energy transfer (TRET), fluorescence resonance energy transfer (FRET) and variations such as bioluminescence resonance energy transfer (BRET). Additional detection options include electrical resistance, resistivity, impedance, and voltage sensing. Detection occurs at a “detection section,” or “detection region.” These terms and other related terms refer to the portion of the microfluidic device at which detection occurs. As indicated above, with devices utilizing the blind channel design, the detection section is generally the reaction site as isolated by the valve associated with each reaction site. The detection section for matrix-based devices is usually within regions of flow channels that are adjacent an intersection, the intersection itself, or a region that encompasses the intersection and a surrounding region. The detection section can be in communication with one or more microscopes, diodes, light stimulating devices (e.g., lasers), photomultiplier tubes, processors and combinations of the foregoing, which cooperate to detect a signal associated with a particular event and/or agent. Often the signal being detected is an optical signal that is detected in the detection section by an optical detector. The optical detector can include one or more photodiodes (e.g., avalanche photodiodes), a fiber-optic light guide leading, for example, to a photomultiplier tube, a microscope, and/or a video camera (e.g., a CCD camera). Detectors can be microfabricated within the microfluidic device, or can be a separate element. If the detector exists as a separate element and the microfluidic device includes a plurality of detection sections, detection can occur within a single detection section at any given moment. Alternatively, scanning systems can be used. For instance, certain automated systems scan the light source relative to the microfluidic device; other systems scan the emitted light over a detector, or include a multichannel detector. As a specific illustrative example, the microfluidic device can be attached to a translatable stage and scanned under a microscope objective. A signal so acquired is then routed to a processor for signal interpretation and processing. Arrays of photomultiplier tubes can also be utilized. Additionally, optical systems that have the capability of collecting signals from all the different detection sections simultaneously while determining the signal from each section can be utilized. External detectors are usable because the devices that are provided are completely or largely manufactured of materials that are optically transparent at the wavelength being monitored. This feature enables the devices described herein to utilize a number of optical detection systems that are not possible with conventional silicon-based microfluidic devices. A particularly preferred detector uses a CCD camera and an optical path that provides for a large field of view and a high numerical aperture to maximize the amount of light collected from each reaction chamber. In this regard, the CCD is used as an array of photodetectors wherein each pixel or group of pixels corresponds to a reaction chamber rather than being used to produce an image of the array. Thus, the optics may be altered such that image quality is reduced or defocused to increase the depth of field of the optical system to collect more light from each reaction chamber. A detector can include a light source for stimulating a reporter that generates a detectable signal. The type of light source utilized depends in part on the nature of the reporter being activated. Suitable light sources include, but are not limited to, lasers, laser diodes and high intensity lamps. If a laser is utilized, the laser can be utilized to scan across a set of detection sections or a single detection section. Laser diodes can be microfabricated into the microfluidic device itself. Alternatively, laser diodes can be fabricated into another device that is placed adjacent to the microfluidic device being utilized to conduct a thermal cycling reaction such that the laser light from the diode is directed into the detection section. Detection can involve a number of non-optical approaches as well. For example, the detector can also include, for example, a temperature sensor, a conductivity sensor, a potentiometric sensor (e.g., pH electrode) and/or an amperometric sensor (e.g., to monitor oxidation and reduction reactions). A number of commercially-available external detectors can be utilized. Many of these are fluorescent detectors because of the ease in preparing fluorescently labeled reagents. Specific examples of detectors that are available include, but are not limited to, Applied Precision ArrayWoRx (Applied Precision, Issaquah, Wash.)). B. Detection of Amplified Nucleic Acids 1. Intercalation Dyes Certain intercalation dyes that only fluoresce upon binding to double-stranded DNA can be used to detect double-stranded amplified DNA. Examples of suitable dyes include, but are not limited to, SYBR™ and Pico Green (from Molecular Probes, Inc. of Eugene, Oreg.), ethidium bromide, propidium iodide, chromomycin, acridine orange, Hoechst 33258, Toto-1, Yoyo-1, and DAPI (4′,6-diamidino-2-phenylindole hydrochloride). Additional discussion regarding the use of intercalation dyes is provided by Zhu et al., Anal. Chem. 66:1941-1948 (1994), which is incorporated by reference in its entirety. 2. FRET Based Detection Methods Detection methods of this type involve detecting a change in fluorescence from a donor (reporter) and/or acceptor (quencher) fluorophore in a donor/acceptor fluorophore pair. The donor and acceptor fluorophore pair are selected such that the emission spectrum of the donor overlaps the excitation spectrum of the acceptor. Thus, when the pair of fluorophores are brought within sufficiently close proximity to one another, energy transfer from the donor to the acceptor can occur. This energy transfer can be detected. FRET and template extension reactions. These methods generally utilize a primer labeled with one member of a donor/acceptor pair and a nucleotide labeled with the other member of the donor/acceptor pair. Prior to incorporation of the labeled nucleotide into the primer during an template-dependent extension reaction, the donor and acceptor are spaced far enough apart that energy transfer cannot occur. However, if the labeled nucleotide is incorporated into the primer and the spacing is sufficiently close, then energy transfer occurs and can be detected. These methods are particularly useful in conducting single base pair extension reactions in the detection of single nucleotide polymorphisms (see infra) and are described in U.S. Pat. No. 5,945,283 and PCT Publication WO 97/22719. Quantitative RT-PCR. A variety of so-called “real time amplification” methods or “real time quantitative PCR” methods can also be utilized to determine the quantity of a target nucleic acid present in a sample by measuring the amount of amplification product formed during or after the amplification process itself. Fluorogenic nuclease assays are one specific example of a real time quantitation method which can be used successfully with the devices described herein. This method of monitoring the formation of amplification product involves the continuous measurement of PCR product accumulation using a dual-labeled fluorogenic oligonucleotide probe—an approach frequently referred to in the literature as the “TaqMan” method. The probe used in such assays is typically a short (ca. 20-25 bases) polynucleotide that is labeled with two different fluorescent dyes. The 5′ terminus of the probe is typically attached to a reporter dye and the 3′ terminus is attached to a quenching dye, although the dyes can be attached at other locations on the probe as well. The probe is designed to have at least substantial sequence complementarity with the probe binding site on the target nucleic acid. Upstream and downstream PCR primers that bind to regions that flank the probe binding site are also included in the reaction mixture. When the probe is intact, energy transfer between the two fluorophors occurs and the quencher quenches emission from the reporter. During the extension phase of PCR, the probe is cleaved by the 5′ nuclease activity of a nucleic acid polymerase such as Taq polymerase, thereby releasing the reporter from the polynucleotide-quencher and resulting in an increase of reporter emission intensity which can be measured by an appropriate detector. One detector which is specifically adapted for measuring fluorescence emissions such as those created during a fluorogenic assay is the ABI 7700 manufactured by Applied Biosystems, Inc. in Foster City, Calif. Computer software provided with the instrument is capable of recording the fluorescence intensity of reporter and quencher over the course of the amplification. These recorded values can then be used to calculate the increase in normalized reporter emission intensity on a continuous basis and ultimately quantify the amount of the mRNA being amplified. Additional details regarding the theory and operation of fluorogenic methods for making real time determinations of the concentration of amplification products are described, for example, in U.S. Pat No. 5,210,015 to Gelfand, U.S. Pat. No. 5,538,848 to Livak, et al., and U.S. Pat. No. 5,863,736 to Haaland, as well as Heid, C. A., et al., Genome Research, 6:986-994 (1996); Gibson, U. E. M, et al., Genome Research 6:995-1001 (1996); Holland, P. M., et al., Proc. Natl. Acad. Sci. USA 88:7276-7280, (1991); and Livak, K. J., et al., PCR Methods and Applications 357-362 (1995), each of which is incorporated by reference in its entirety. Thus, as the amplification reaction progresses, an increasing amount of dye becomes bound and is accompanied by a concomitant increase in signal. Intercalation dyes such as described above can also be utilized in a different approach to quantitative PCR methods. As noted above, these dyes preferentially bind to double stranded DNA (e.g., SYBR GREEN) and only generate signal once bound. Thus, as an amplification reaction progresses, an increasing amount of dye becomes bound and is accompanied by a concomitant increase in signal that can be detected. Molecular Beacons: With molecular beacons, a change in conformation of the probe as it hybridizes to a complementary region of the amplified product results in the formation of a detectable signal. The probe itself includes two sections: one section at the 5′ end and the other section at the 3′ end. These sections flank the section of the probe that anneals to the probe binding site and are complementary to one another. One end section is typically attached to a reporter dye and the other end section is usually attached to a quencher dye. In solution, the two end sections can hybridize with each other to form a hairpin loop. In this conformation, the reporter and quencher dye are in sufficiently close proximity that fluorescence from the reporter dye is effectively quenched by the quencher dye. Hybridized probe, in contrast, results in a linearized conformation in which the extent of quenching is decreased. Thus, by monitoring emission changes for the two dyes, it is possible to indirectly monitor the formation of amplification product. Probes of this type and methods of their use is described further, for example, by Piatek, A. S., et al., Nat. Biotechnol. 16:359-63 (1998); Tyagi, S. and Kramer, F. R., Nature Biotechnology 14:303-308 (1996); and Tyagi, S. et al., Nat. Biotechnol. 16:49-53 (1998), each of which is incorporated by reference herein in their entirety for all purposes. Invader: Invader assays (Third Wave Technologies, (Madison, Wis.)) are used for SNP genotyping and utilize an oligonucleotide, designated the signal probe, that is complementary to the target nucleic acid (DNA or RNA) or polymorphism site. A second oligonucleotide, designated the Invader Oligo, contains the same 5′ nucleotide sequence, but the 3′ nucleotide sequence contains a nucleotide polymorphism. The Invader Oligo interferes with the binding of the signal probe to the target nucleic acid such that the 5′ end of the signal probe forms a “flap” at the nucleotide containing the polymorphism. This complex is recognized by a structure specific endonuclease, called the Cleavase enzyme. Cleavase cleaves the 5′ flap of the nucleotides. The released flap binds with a third probe bearing FRET labels, thereby forming another duplex structure recognized by the Cleavase enzyme. This time the Cleavase enzyme cleaves a fluorophore away from a quencher and produces a fluorescent signal. For SNP genotyping, the signal probe will be designed to hybridize with either the reference (wild type) allele or the variant (mutant) allele. Unlike PCR, there is a linear amplification of signal with no amplification of the nucleic acid. Further details sufficient to guide one of ordinary skill in the art is provided by, for example, Neri, B. P., et al., Advances in Nucleic Acid and Protein Analysis 3826:117-125, 2000). Nasba: Nucleic Acid Sequence Based Amplification (NASBA) is a detection method using RNA as the template. A primer complementary to the RNA contains the sequence for the T7 promoter site. This primer is allowed to bind with the template RNA and Reverse Transcriptase (RT) added to generate the complementary strand from 3′ to 5′. RNase H is subsequently added to digest away the RNA, leaving single stranded cDNA behind. A second copy of the primer can then bind the single stranded cDNA and make double stranded cDNA. T7 RNA polymerase is added to generate many copies of the RNA from the T7 promoter site that was incorporated into the cDNA sequence by the first primer. All the enzymes mentioned are capable of functioning at 41° C. (See, e.g., Compton, J. Nucleic Acid Sequence-based Amplification, Nature 350: 91-91, 1991.) Scorpion. This method is described, for example, by Thelwell N., et al. Nucleic Acids Research, 28:3752-3761, 2000, which is hereby incorporated by reference in its entirety for all purposes, and which FIG. 20 depicts the scheme thereof, wherein Scorpion probing mechanism is as follows. Step 1: initial denaturation of target and Scorpion stem sequence. Step 2: annealing of Scorpion primer to target. Step 3: extension of Scorpion primer produces double-stranded DNA. Step 4: denaturation of double-stranded DNA produced in step 3. This gives a single-stranded target molecule with the Scorpion primer attached. Step 5: on cooling, the Scorpion probe sequence binds to its target in an intramolecular manner. This is favoured over the intermolecular binding of the complementary target strand.A Scorpion (as shown in FIG. 24) consists of a specific probe sequence that is held in a hairpin loop configuration by complementary stem sequences on the 5′ and 3′ sides of the probe. The fluorophore attached to the 5′-end is quenched by a moiety (normally methyl red) joined to the 3′-end of the loop. The hairpin loop is linked to the 5′-end of a primer via a PCR stopping sequence (stopper). After extension of the primer during PCR amplification, the specific probe sequence is able to bind to its complement within the same strand of DNA. This hybridization event opens the hairpin loop so that fluorescence is no longer quenched and an increase in signal is observed. The PCR stoping sequence prevents read-through, that could lead to opening of the hairpin loop in the absence of the specific target sequence. Such read-through would lead to the detection of non-specific PCR products, e.g. primer dimers or mispriming events. 3. Capacitive DNA Detection There is a linear relationship between DNA concentration and the change in capacitance that is evoked by the passage of nucleic acids across a 1-kHz electric field. This relationship has been found to be species independent. (See, e.g., Sohn, et al. (2000) Proc. Natl. Acad. Sci. U.S.A. 97:10687-10690). Thus, in certain devices, nucleic acids within the flow channel (e.g., the substantially circular flow channel of FIG. 1 or the reaction chambers of FIG. 2) are subjected to such a field to determine concentration of amplified product. Alternatively, solution containing amplified product is withdrawn and then subjected to the electric field. IX. Composition of Mixtures for Conducting Reactions Reactions conducted with the microfluidic devices disclosed herein are typically conducted with certain additives to enhance the reactions. So, for example, in the case of devices in which reagents are deposited, these additives can be spotted with one or more reactants at a reaction site, for instance. One set of additives are blocking reagents that block protein binding sites on the elastomeric substrate. A wide variety of such compounds can be utilized including a number of different proteins (e.g., gelatin and various albumin proteins, such as bovine serum albumin) and glycerol. A detergent additive can also be useful. Any of a number of different detergents can be utilized. Examples include, but are not limited to SDS and the various Triton detergents. In the specific case of nucleic acid amplification reactions, a number of different types of additives can be included. One category are enhancers that promote the amplification reaction. Such additives include, but are not limited to, reagents that reduce secondary structure in the nucleic acid (e.g., betaine), and agents that reduce mispriming events (e.g., tetramethylammonium chloride). It has also been found in conducting certain amplification reactions that some polymerases give enhanced results. For example, while good results were obtained with AmpliTaq Gold polymerase (Applied Biosystems, Foster City, Calif.) from Thermus aquaticus, improved reactions were in some instances obtained using DyNAzyme polymerase from Finnzyme, Espoo, Finland. This polymerase is from the thermophilic bacterium, Thermus brockianus. Other exemplary polymerases that can be utilized include, but are not limited to, rTH polymerase XL, which is a combination of Thermus thermophilus (Tth) and Thermococcus litoralis (Tli), hyperthermo-philic archaebacterium Pyrosoccus woesei (Pwo), and Tgo DNA Polymerase. Further details regarding additives useful in conducting reactions with certain of the devices disclosed herein, including nucleic acid amplification reactions, are provided in Example 1 infra. X. Exemplary Applications Because the microfluidic devices provided herein can be manufactured to include a large number of reaction sites, the devices are useful in a wide variety of screening and analytical methods. In general, the devices can be utilized to detect reactions between species that react to form a detectable signal, or a product that upon interaction with another species generates a detectable signal. In view of their use with various types of temperature control systems, the devices can also be utilized in a number of different types of analyses or reactions requiring temperature control. A. Nucleic Acid Amplification Reactions The devices disclosed herein can be utilized to conduct essentially any type of nucleic acid amplification reaction. Thus, for example, amplification reactions can be linear amplifications, (amplifications with a single primer), as well as exponential amplifications (i.e., amplifications conducted with a forward and reverse primer set). When the blind channel type devices are utilized to perform nucleic acid amplification reactions, the reagents that are typically deposited within the reaction sites are those reagents necessary to perform the desired type of amplification reaction. Usually this means that some or all of the following are deposited, primers, polymerase, nucleotides, metal ions, buffer, and cofactors, for example. The sample introduced into the reaction site in such cases is the nucleic acid template. Alternatively, however, the template can be deposited and the amplification reagents flowed into the reaction sites. As discussed supra, when the matrix device is utilized to conduct an amplification reaction, samples containing nucleic acid template are flowed through the vertical flow channels and the amplification reagents through the horizontal flow channels or vice versa. While PCR is perhaps the best known amplification technique. The devices are not limited to conducting PCR amplifications. Other types of amplification reactions that can be conducted include, but are not limited to, (i) ligase chain reaction (LCR) (see Wu and Wallace, Genomics 4:560 (1989) and Landegren et al., Science 241:1077 (1988)); (ii) transcription amplification (see Kwoh et al., Proc. Natl. Acad. Sci. USA 86:1173 (1989)); (iii) self-sustained sequence replication (see Guatelli et al., Proc. Nat. Acad. Sci. USA, 87:1874 (1990)); and (iv) nucleic acid based sequence amplification (NASBA) (see, Sooknanan, R. and Malek, L., BioTechnology 13: 563-65 (1995)). Each of the foregoing references are incorporated herein by reference in their entirety for all purposes. Detection of the resulting amplified product can be accomplished using any of the detection methods described supra for detecting amplified DNA. B. SNP Analysis and Genotyping 1. General Many diseases linked to genome modifications, either of the host organism or of infectious organisms, are the consequence of a change in a small number of nucleotides, frequently involving a change in a single nucleotide. Such single nucleotide changes are referred to as single nucleotide polymorphisms or simply SN Ps, and the site at which the SNP occurs is typically referred to as a polymorphic site. The devices described herein can be utilized to determine the identify of a nucleotide present at such polymorphic sites. As an extension of this capability, the devices can be utilized in genotyping analyses. Genotyping involves the determination of whether a diploid organism (i.e., an organism with two copies of each gene) contains two copies of a reference allele (a reference-type homozygote), one copy each of the reference and a variant allele (i.e., a heterozygote), or contains two copies of the variant allele (i.e., a variant-type homozygote). When conducting a genotyping analysis, the methods of the invention can be utilized to interrogate a single variant site. However, as described further below in the section on multiplexing, the methods can also be used to determine the genotype of an individual in many different DNA loci, either on the same gene, different genes or combinations thereof. Devices to be utilized for conducting genotyping analyses are designed to utilize reaction sites of appropriate size to ensure from a statistical standpoint that a copy of each of the two alleles for a diploid subject are present in the reaction site at a workable DNA concentrations. Otherwise, an analysis could yield results suggesting that a heterozygote is a homozygote simply because a copy of the second allele is not present at the reaction site. Table 2 below indicates the number of copies of the genome present in a 1 nl reaction volume at various exemplary DNA concentrations that can be utilized with the devices described herein. TABLE 2 Number of genome copies present in a 1 nL volume at the indicated DNA concentration. Volume (nL) [DNA] (ug/uL) N 1 0.33 100 1 0.10 32 1 0.05 16 1 0.01 3 1 0.003 1 As a general matter, due to stochastic proportioning of the sample, the copy number present before an amplification reaction is commenced determines the likely error in the measurement. Genotyping analyses using certain devices are typically conducted with samples having a DNA concentration of approximately 0.10 ug/uL, although the current inventors have run successful TaqMan reactions at concentrations in which there is a single genome per reaction site. 2. Methods Genotyping analyses can be conducted using a variety of different approaches. In these methods, it is generally sufficient to obtain a “yes” or “no” result, i.e., detection need only be able to answer the question whether a given allele is present. Thus, analyses can be conducted only with the primers or nucleotides necessary to detect the presence of one allele potentially at a polymorphic site. However, more typically, primers and nucleotides to detect the presence of each allele potentially at the polymorphic site are included. Examples of suitable approaches follow. Single Base Pair Extension (SBPE) Reactions. SBPE reactions are one technique specifically developed for conducting genotyping analyses. Although a number of SPBE assays have been developed, the general approach is quite similar. Typically, these assays involve hybridizing a primer that is complementary to a target nucleic acid such that the 3′ end of the primer is immediately 5′ of the variant site or is adjacent thereto. Extension is conducted in the presence of one or more labeled non-extendible nucleotides that are complementary to the nucleotide(s) that occupy the variant site and a polymerase. The non-extendible nucleotide is a nucleotide analog that prevents further extension by the polymerase once incorporated into the primer. If the added non-extendible nucleotide(s) is(are) complementary to the nucleotide at the variant site, then a labeled non-extendible nucleotide is incorporated onto the 3′ end of the primer to generate a labeled extension product. Hence, extended primers provide an indication of which nucleotide is present at the variant site of a target nucleic acid. Such methods and related methods are discussed, for example, in U.S. Pat. Nos. 5,846,710; 6,004,744; 5,888,819; 5,856,092; and 5,710,028; and in WO 92/16657. Detection of the extended products can be detected utilizing the FRET detection approach described for extension reactions in the detection section supra. Thus, for example, using the devices described herein, a reagent mixture containing a primer labeled with one member of a donor/acceptor fluorophore, one to four labeled non-extendible nucleotides (differentially labeled if more than one non-extendible nucleotide is included), and polymerase are introduced (or previously spotted) at a reaction site. A sample containing template DNA is then introduced into the reaction site to allow template extension to occur. Any extension product formed is detected by the formation of a FRET signal (see, e.g., U.S. Pat. No. 5,945,283 and PCT Publication WO 97/22719.). The reactions can optionally be thermocycled to increase signal using the temperature control methods and apparatus described above. Quantitative PCR. Genotyping analyses can also be conducted using the quantitative PCR methods described earlier. In this case, differentially labeled probes complementary to each of the allelic forms are included as reagents, together with primers, nucleotides and polymerase. However, reactions can be conducted with only a single probe, although this can create ambiguity as to whether lack of signal is due to absence of a particular allele or simply a failed reaction. For the typical biallelic case in which two alleles are possible for a polymorphic site, two differentially labeled probes, each perfectly complementary to one of the alleles are usually included in the reagent mixture, together with amplification primers, nucleotides and polymerase. Sample containing the target DNA is introduced into the reaction site. If the allele to which a probe is complementary is present in the target DNA, then amplification occurs, thereby resulting in a detectable signal as described in the detection above. Based upon which of the differential signal is obtained, the identity of the nucleotide at the polymorphic site can be determined. If both signals are detected, then both alleles are present. Thermocycling during the reaction is performed as described in the temperature control section supra. B. Gene Expression Analysis 1. General Gene expression analysis involves determining the level at which one or more genes is expressed in a particular cell. The determination can be qualitative, but generally is quantitative. In a differential gene expression analysis, the levels of the gene(s) in one cell (e.g., a test cell) are compared to the expression levels of the same genes in another cell (control cell). A wide variety of such comparisons can be made. Examples include, but are not limited to, a comparison between healthy and diseased cells, between cells from an individual treated with one drug and cells from another untreated individual, between cells exposed to a particular toxicant and cells not exposed, and so on. Genes whose expression levels vary between the test and control cells can serve as markers and/or targets for therapy. For example, if a certain group of genes is found to be up-regulated in diseased cells rather than healthy cells, such genes can serve as markers of the disease and can potentially be utilized as the basis for diagnostic tests. These genes could also be targets. A strategy for treating the disease might include procedures that result in a reduction of expression of the up-regulated genes. The design of the devices disclosed herein is helpful in facilitating a variety of gene expression analyses. Because the devices contain a large number of reaction sites, a large number of genes and/or samples can be tested at the same time. Using the blind flow channel devices, for instance, the expression levels of hundreds or thousands of genes can be determined at the same time. The devices also facilitate differential gene expression analyses. With the matrix design, for example, a sample obtained from a healthy cell can be tested in one flow channel, with a sample from a diseased cell run in an immediately adjacent channel. This feature enhances the ease of detection and the accuracy of the results because the two samples are run on the same device at the same time and under the same conditions. 2. Sample Preparation and Concentration To measure the transcription level (and thereby the expression level) of a gene or genes, a nucleic acid sample comprising mRNA transcript(s) of the gene(s) or gene fragments, or nucleic acids derived from the mRNA transcript(s) is obtained. A nucleic acid derived from an mRNA transcript refers to a nucleic acid for whose synthesis the mRNA transcript or a subsequence thereof has ultimately served as a template. Thus, a cDNA reverse transcribed from an mRNA, an RNA transcribed from that cDNA, a DNA amplified from the cDNA, an RNA transcribed from the amplified DNA, are all derived from the mRNA transcript and detection of such derived products is indicative of the presence and/or abundance of the original transcript in a sample. Thus, suitable samples include, but are not limited to, mRNA transcripts of the gene or genes, cDNA reverse transcribed from the mRNA, cRNA transcribed from the cDNA, DNA amplified from the genes, RNA transcribed from amplified DNA. In some methods, a nucleic acid sample is the total mRNA isolated from a biological sample; in other instances, the nucleic acid sample is the total RNA from a biological sample. The term “biological sample”, as used herein, refers to a sample obtained from an organism or from components of an organism, such as cells, biological tissues and fluids. In some methods, the sample is from a human patient. Such samples include sputum, blood, blood cells (e.g., white cells), tissue or fine needle biopsy samples, urine, peritoneal fluid, and fleural fluid, or cells therefrom. Biological samples can also include sections of tissues such as frozen sections taken for histological purposes. Often two samples are provided for purposes of comparison. The samples can be, for example, from different cell or tissue types, from different individuals or from the same original sample subjected to two different treatments (e.g., drug-treated and control). Any RNA isolation technique that does not select against the isolation of mRNA can be utilized for the purification of such RNA samples. For example, methods of isolation and purification of nucleic acids are described in detail in WO 97/10365, WO 97/27317, Chapter 3 of Laboratory Techniques in Biochemistry and Molecular Biology: Hybridization With Nucleic Acid Probes, Part I. Theory and Nucleic Acid Preparation, (P. Tijssen, ed.) Elsevier, N.Y. (1993); Chapter 3 of Laboratory Techniques in Biochemistry and Molecular Biology: Hybridization With Nucleic Acid Probes, Part 1. Theory and Nucleic Acid Preparation, (P. Tijssen, ed.) Elsevier, N.Y. (1993); and Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, N.Y., (1989); Current Protocols in Molecular Biology, (Ausubel, F.M. et al., eds.) John Wiley & Sons, Inc., New York (1987-1993). Large numbers of tissue samples can be readily processed using techniques known in the art, including, for example, the single-step RNA isolation process of Chomczynski, P. described in U.S. Pat. No. 4,843,155. In gene expression analyses utilizing the devices that are described, a significant factor affecting the results is the concentration of the nucleic acid in the sample. At low copy number, noise is related to the square root of copy number. Thus, the level of error that is deemed acceptable governs the copy number required. The required copy number in the particular sample volume gives the required DNA concentration. Although not necessarily optimal, quantitation reactions can be conducted with an error level of up to 50%, but preferably is less. Assuming a 1 nanoliter volume, the DNA concentrations required to achieve a particular error level are shown in Table 3. As can be seen, 1 nanoliter volumes such as used with certain of the devices have sufficient copies of gene expression products at concentrations that are workable with microfluidic devices. TABLE 3 Gene Expression - DNA Quantity Error (%) N (Copy No.) Volume (nL) [DNA] (10−12 M) 2 2500 1 4.2 10 100 1 0.17 25 16 1 0.027 50 4 1 0.0066 A further calculation demonstrates that the certain of the devices provided herein which utilize a 1 nanoliter reaction site contain sufficient DNA to achieve accurate expression results. Specifically, a typical mRNA preparation procedure yields approximately 10 ug of mRNA. It has been demonstrated that typically there are 1 to 10,000 copies of each mRNA per cell. Of the mRNAs that are expressed within any given cell, approximately the four most common messages comprise about 13% of the total mRNA levels. Thus, such highly expressed messages comprise 1.3 ug of mRNA (each is 4×10−12 mole or approximately 2.4×1012 copies). In view of the foregoing expression ranges, rare messages are expected to be present at a level of about 2×10−8 copies. If in a standard analysis the mRNA sample is dissolved in 10 ul, the concentration of a rare message is approximately 2×107 copies/ul; this concentration corresponds to 20,000 copies per 1 nl well (or 4×1011 M). 3. Methods Because expression analysis typically involves a quantitative analysis, detection is typically achieved using one of the quantitative real time PCR methods described above. Thus, if a TaqMan approach is utilized, the reagents that are introduced (or previously spotted) in the reaction sites can include one or all of the following: primer, labeled probe, nucleotides and polymerase. If an intercalation dye is utilized, the reagent mixture typically includes one or all of the following: primer, nucleotides, polymerase, and intercalation dye. D. Multiplexing The array-based devices described herein (see, e.g., FIGS. 1A, 1F, 2, 3A and 3B and accompanying text) are inherently designed to conduct a large number of amplification reactions at the same time. This feature, however, can readily be further expanded upon by conducting multiple analyses (e.g., genotyping and expression analyses) within each reaction site. Multiplex amplifications can even be performed within a single reaction site by, for example, utilizing a plurality of primers, each specific for a particular target nucleic acid of interest, during the thermal cycling process. The presence of the different amplified products can be detected using differentially labeled probes to conduct a quantitative RT-PCR reaction or by using differentially labeled molecular beacons (see supra). In such approaches, each differentially labeled probes is designed to hybridize only to a particular amplified target. By judicious choice of the different labels that are utilized, analyses can be conducted in which the different labels are excited and/or detected at different wavelengths in a single reaction. Further guidance regarding the selection of appropriate fluorescent labels that are suitable in such approaches include: Fluorescence Spectroscopy (Pesce et al., Eds.) Marcel Dekker, New York, (1971); White et al., Fluorescence Analysis: A Practical Approach, Marcel Dekker, New York, (1970); Berlman, Handbook of Fluorescence Spectra of Aromatic Molecules, 2nd ed., Academic Press, New York, (1971); Griffiths, Colour and Constitution of Organic Molecules, Academic Press, New York, (1976); Indicators (Bishop, Ed.). Pergamon Press, Oxford, 19723; and Haugland, Handbook of Fluorescent Probes and Research Chemicals, Molecular Probes, Eugene (1992). Multiple genotyping and expression analyses can optionally be conducted at each reaction site. If quantitative PCR methods such as TaqMan is utilized, then primers for amplifying different regions of a target DNA of interest are included within a single reaction site. Differentially labeled probes for each region are utilized to distinguish product that is formed. E. Non-Nucleic Acid Analyses While useful for conducting a wide variety of nucleic acid analyses, the devices can also be utilized in a number of other applications as well. As indicated earlier, the devices can be utilized to analyze essentially any interaction between two or more species that generates a detectable signal or a reaction product that can reacted with a detection reagent that generates a signal upon interaction with the reaction product. Thus, for example, the devices can be utilized in a number of screening applications to identify test agents that have a particular desired activity. As a specific example, the devices can be utilized to screen compounds for activity as a substrate or inhibitor of one or more enzymes. In such analyses, test compound and other necessary enzymatic assay reagents (e.g., buffer, metal ions, cofactors and substrates) are introduced (if not previously deposited) in the reaction site. The enzyme sample is then introduced and reaction (if the test compound is a substrate) or inhibition of the reaction (if the test compound is an inhibitor) is detected. Such reactions or inhibition can be accomplished by standard techniques, such as directly or indirectly monitoring the loss of substrate and/or appearance of product. Devices with sufficiently large flow channels and reaction sites can also be utilized to conduct cellular assays to detect interaction between a cell and one or more reagents. For instance, certain analyses involve determination of whether a particular cell type is present in a sample. One example for accomplishing this is to utilize cell-specific dyes that preferentially reaction with certain cell types. Thus, such dyes can be introduced into the reaction sites and then cells added. Staining of cells can be detected using standard microscopic techniques. As another illustration, test compounds can be screened for ability to trigger or inhibit a cellular response, such as a signal transduction pathway. In such an analysis, test compound is introduced into a site and then the cell added. The reaction site is then checked to detect formation of the cellular response. Further discussion of related devices and applications of such devices is set forth in copending and commonly owned U.S. Provisional application No. 60/335,292, filed Nov. 30, 2001, which is incorporated herein by reference in its entirety for all purposes. XI. Fabrication A. General Aspects As alluded to earlier, the microfluidic devices that are provided are generally constructed utilizing single and multilayer soft lithography (MSL) techniques and/or sacrificial-layer encapsulation methods. The basic MSL approach involves casting a series of elastomeric layers on a micro-machined mold, removing the layers from the mold and then fusing the layers together. In the sacrificial-layer encapsulation approach, patterns of photoresist are deposited wherever a channel is desired. These techniques and their use in producing microfluidic devices is discussed in detail, for example, by Unger et al. (2000) Science 288:113-116, by Chou, et al. (2000) “Integrated Elastomer Fluidic Lab-on-a-chip-Surface Patterning and DNA Diagnostics, in Proceedings of the Solid State Actuator and Sensor Workshop, Hilton Head, S.C.; and in PCT Publication WO 01/01025, each of which is incorporated herein by reference in their entirety for all purposes. In brief, the foregoing fabrication methods initially involve fabricating mother molds for top layers (e.g., the elastomeric layer with the control channels) and bottom layers (e.g., the elastomeric layer with the flow channels) on silicon wafers by photolithography with photoresist (Shipley SJR 5740). Channel heights can be controlled precisely by the spin coating rate. Photoresist channels are formed by exposing the photoresist to UV light followed by development. Heat reflow process and protection treatment is typically achieved as described by M. A. Unger, H.-P. Chou, T. Throsen, A. Scherer and S. R. Quake, Science (2000) 288:113, which is incorporated herein by reference in its entirety. A mixed two-part-silicone elastomer (GE RTV 615) is then spun into the bottom mold and poured onto the top mold, respectively. Here, too, spin coating can be utilized to control the thickness of bottom polymeric fluid layer. The partially cured top layer is peeled off from its mold after baking in the oven at 80° C. for 25 minutes, aligned and assembled with the bottom layer. A 1.5-hour final bake at 80° C. is used to bind these two layers irreversibly. Once peeled off from the bottom silicon mother mold, this RTV device is typically treated with HCL (0.1N, 30 min at 80° C.). This treatment acts to cleave some of the Si—O—Si bonds, thereby exposing hydroxy groups that make the channels more hydrophilic. The device can then optionally be hermetically sealed to a support. The support can be manufactured of essentially any material, although the surface should be flat to ensure a good seal, as the seal formed is primarily due to adhesive forces. Examples of suitable supports include glass, plastics and the like. The devices formed according to the foregoing method result in the substrate (e.g., glass slide) forming one wall of the flow channel. Alternatively, the device once removed from the mother mold is sealed to a thin elastomeric membrane such that the flow channel is totally enclosed in elastomeric material. The resulting elastomeric device can then optionally be joined to a substrate support. B. Devices Utilizing Blind Channel Design 1. Layer Formation Microfluidic devices based on the blind channel design in which reagents are deposited at the reaction sites during manufacture are typically formed of three layers. The bottom layer is the layer upon which reagents are deposited. The bottom layer can be formed from various elastomeric materials as described in the references cited above on MLS methods. Typically, the material is polydimethylsiloxane (PMDS) elastomer. Based upon the arrangement and location of the reaction sites that is desired for the particular device, one can determine the locations on the bottom layer at which the appropriate reagents should be spotted. Because PMDS is hydrophobic, the deposited aqueous spot shrinks to form a very small spot. The deposited reagents are deposited such that a covalent bond is not formed between the reagent and the surface of the elastomer because, as described earlier, the reagents are intended to dissolve in the sample solution once it is introduced into the reaction site. The other two layers of the device are the layer in which the flow channels are formed and the layer in which the control and optionally guard channels are formed. These two layers are prepared according to the general methods set forth earlier in this section. The resulting two layer structure is then placed on top of the first layer onto which the reagents have been deposited. A specific example of the composition of the three layers is as follows (ration of component A to component B): first layer (sample layer) 30:1 (by weight); second layer (flow channel layer) 30:1; and third layer (control layer) 4:1. It is anticipated, however, that other compositions and ratios of the elastomeric components can be utilized as well. During this process, the reaction sites are aligned with the deposited reagents such that the reagents are positioned within the appropriate reaction site. FIG. 6 is a set of photographs taken from the four corners of a device; these photographs demonstrate that the deposited reagents can be accurately aligned within the reaction sites utilizing the foregoing approach. These photographs show guard channels and reaction site located at the end of branch flow channel. The white circle indicates the location of the deposited reagent relative to the reaction site. As indicated, each reagent spot is well within the confines of the reaction site. 2. Spotting The reagents can be deposited utilizing any of a number of commercially available reagent spotters and using a variety of established spotting techniques. Examples of suitable spotter that can be utilized in the preparation of the devices include pin spotters, acoustic spotters, automated micropipettors, electrophoretic pumps, ink jet printer devices, ink drop printers, and certain osmotic pumps. Examples of commercially available spotters include: Cartesian Technologies MicroSys 5100 (Irvine, Calif.), Hitach SPBIO (Alameda, Calif.), Genetix Q-Array (United Kingdom), Affymetrix 417 (Santa Clara, Calif.) and Packard Bioscience SpotArray (Meriden, Conn.). In general, very small spots of reagents are deposited; usually spots of less than 10 nl are deposited, in other instances less than 5 nl, 2 nl or 1 nl, and in still other instances, less than 0.5 nl, 0.25 nl, or 0.1 nl. Arrays of materials may also be formed by the methods described in Foder, et al., U.S. Pat. No. 5,445,934: titled “Array of oligonucleotides on a solid substrate”, which is herein incorporated by reference, wherein oligonucleotide probes, such as SNP probes, are synthesized in situ using spatial light directed photolithography. Such arrays would be used as the substrate or base of the microfluidic devices of the present invention such that the regions of the substrate corresponding to the reaction sites, for example, blind fill chambers, would be contain one, or preferably more than one, oligonucleotide probes arrayed in known locations on the substrate. In the case of a partitioning microfluidic structure, such as the one depicted in FIG. 15 herein, the reaction sites, depicted as square boxes along the serpentine, fluid channel, would contain a plurality of different SNP probes, preferably a collection of SNP probes suitable for identifying an individual from a population of individuals, and preferably wherein a plurality of reaction sites along the serpentine fluid channel, such that if a fluid sample containing nucleic acid sequences from a plurality of individuals where introduced into the serpentine flow channel, and a plurality of valve in communication with the serpentine flow channel such that when actuated causes the serpentine flow channel to be partitioned thereby isolating each reaction site from one another to contain a fraction of the fluid sample in each reaction site. Amplification of the components of the sample may be performed to increase the number of molecules, for example nucleic acid molecules, for binding to the array of SNP probes located within each reaction site. In some embodiments, each of the reaction sites along the serpentine fluid channel would be the same array, that is, have the same SNP probes arrayed, and in other embodiments, two or more of the reaction sites along the serpentine t fluid channel would have a different set of SNP probes. Other partitioning fluid channel architectures could also be used, for example, branched and/or branched branch systems, and so forth. Other arraying techniques, such as spotting described herein, may likewise be used to form the arrays located within the partitionable reactions sites along a serpentine or common, such as in branched, fluid channel(s). The following examples are presented to further illustrate certain aspects of the devices and methods that are disclosed herein. The examples are not to be considered as limiting the invention. EXAMPLE 1 Signal Strength Evaluations I. Introduction The purpose of this set of experiments was to demonstrate that successful PCR reactions can be conducted with a microfluidic device of the design set forth herein with signal strength greater than 50% of the Macro TaqMan reaction. II. Microfluidic Device A three layer microfluidic device, fabricated using the MSL process, was designed and fabricated for conducting the experiments described in the following example. FIG. 7A shows a cross-sectional view of the device. As shown, the device 700 includes a layer 722 into which is formed the flow channels. This fluid layer 722 is sandwiched between an overlaying layer 720 that includes the control and guard layers and an underlying sealing layer 724. The sealing layer 724 forms one side of the flow channels. The resulting three-layer structure is affixed to a substrate 726 (in this example, a slide or coverslip), which provides structural stiffness, increases thermal conductivity, and helps to prevent evaporation from the bottom of microfluidic device 700. FIG. 7B shows a schematic view of the design of the flow channels in flow layer 722 and of the control channels and guard channel in control/guard layer 720. Device 700 consists of ten independent flow channels 702, each with its own inlet 708, and branching blind channels 704, each blind channel 704 having a 1 nl reaction site 706. Device 700 contains a network of control lines 712, which isolate the reaction sites 706 when sufficient pressure is applied. A series of guard channels 716 are also included to prevent liquid from evaporating out of the reaction sites 706; fluid is introduced via inlet 718. II. Experimental Setup A PCR reaction using -actin primers and TaqMan probe to amplify exon 3 of the -actin gene from human male genomic DNA (Promega, Madison Wis.) was conducted in device 700. The TaqMan reaction consists of the following components: 1× TaqMan Buffer A (50 mM KCl, 10 mM Tris-HCl, 0.01M EDTA, 60 nM Passive Reference1 (PR1), pH 8.3); 3.5-4.0 mM MgCl; 200 nM dATP, dCTP, dGTP, 400 nM dUTP; 300 nM -actin forward primer and reverse primer; 200 nM FAM-labeled -actin probe; 0.01 U/ul AmpEraseUNG (Applied Biosystems, Foster City, Calif.); 0.1-0.2 U/ul DyNAzyme (Finnzyme, Espoo, Finland); 0.5% Triton-x-100 (Sigma, St. Louis, Mo.); 0.8 ug/ul Gelatin (Calbiochem, San Diego, Calif.); 5.0% Glycerol (Sigma, St. Louis, Mo.); deionized H2O and male genomic DNA. The components of the reaction were added to produce a total reaction volume of 25. Negative controls (Control) composed of all the TaqMan reaction components, except target DNA were included in each set of PCR reactions. Once the TaqMan reaction samples and Control were prepared, they were injected into microfluidic device 700 by using a gel loading pipet tip attached to a 1 ml syringe. The pipet tip was filled with the reaction samples and then inserted into the fluid via 708. The flow channels 702 were filled by manually applying backpressure to the syringe until all the entire blind channels 704 and reaction sites 706 were filled. Control lines 712 were filled with deionized water and pressurized to 15-20 psi after all of the samples were loaded into the flow lines 702, 704. The pressurized control lines 712 were actuated to close the valves and isolate the samples in the 1 nl wells 706. The guard channels 716 were then filled with deionized water and pressurized to 5-7 psi. Mineral oil (15 ul) (Sigma) was placed on the flatplate of a thermocycler and then the microfluidic device/coverglass 700 was placed on the thermocycler. Micro fluidic device 700 was then thermocycled using an initial ramp and either a three-step or two-step thermocycling profile: 1. Initial ramp to 95° C. and maintain for 1 minute (1.0° C./s to 75° C., 0.1° C./sec to 95° C.). 2. Three step thermocycling for 40 cycles (92° C. for 30 sec., 54° C. for 30 sec., and 72° C. for 1 min) or; 3. Two step thermocycling for 40 cycles (92° C. for 30 seconds and 60° C. for 60 sec.) MicroAmp tubes (Applied Biosystems, Foster City, Calif.) with the remaining reaction mixture, designated Macro TaqMan reactions to distinguish them from reactions performed in the microfluidic device, were placed in the GeneAmp PCR System 9700 (Applied Biosystems, Foster City, Calif.) and thermocycled in the 9600 mode. The Macro TaqMan reactions served as macroscopic controls for the reactions performed in the micro fluidic device. The thermocycling protocol was set to match that of the microfluidic device, except that the initial ramp rate was not controlled for the Macro TaqMan reactions. Once thermocycling was completed, the control and guard lines were depressurized and the chip was transferred onto a glass slide (VWR, West Chester, Pa.). The chip was then placed into an Array WoRx Scanner (Applied Precision, Issaquah, Wash.) with a modified carrier. The fluorescence intensity was measured for three different excitation/emission wavelengths: 475/510 nm (FAM), 510/560 nm (VIC), and 580/640 nm (Passive Reference1 (PR1)). The Array Works Software was used to image the fluorescence in the micro fluidic device and to measure the signal and background intensities of each 1 nl well. The results were then analyzed using a Microsoft Excel file to calculate the FAM/PR1 ratio for -actin TaqMan reactions. For conventional Macro TaqMan, positive samples for target DNA were determined using calculations described in the protocol provided by the manufacturer (TaqMan PCR Reagent Kit Protocol). The signal strength was calculated by dividing the FAM/PR1 ratio of the samples by the FAM/PR1 ratio of the controls. A successful reaction was defined as a sample ratio above the 99% confidence threshold level. III. Results Initially, AmpliTaq Gold (Applied Biosystems, Foster City, Calif.) was used in TaqMan reactions and FAM/PR1/Control ratios of 1.5-2.0 were produced, compared to Macro TaqMan reaction ratios of 5.0-14.0. Although results were positive, increased signal strength was desired. Therefore, the AmpliTaq Gold polymerase was substituted with DyNAzyme polymerase due to its increased thermostability, proofreading, and resistance to impurities. The standard Macro TaqMan DyNAzyme concentration of 0.025 U/ul was used in the microfluidic experiments. This polymerase change to DyNAzyme produced FAM/ROX/Control ratios of 3.5-5.8. The signal strength was improved, but it was difficult to achieve consistent results. Because it is know that some proteins stick to PDMS, the concentration of the polymerase was increased and surface modifying additives were included. Two increased concentrations of DyNAzyme were tested, 8× (0.2 U/ul) and 4× (0.1 U/ul) the standard concentration for Macro TaqMan, with 100 pg or 10 pg of genomic DNA per nl in the micro fluidic device. Gelatin, Glycerol, and 0.5% Triton-x-100 were added to prevent the polymerase from attaching to the PDMS. The results of the reactions in the micro fluidic device (chip) and the Macro TaqMan controls are shown in FIG. 8. The microfluidic TaqMan reaction ratios range from 4.9-8.3, while the Macro TaqMan reactions range from 7.7-9.7. Therefore, the signal strength of the TaqMan reactions in chip is up to 87% of the Macro TaqMan reactions. There was no significant difference between 4× or 8× DyNAzyme. The results demonstrate that PCR reactions can be done with greater than 50% signal strength, when compared to the Macro TaqMan reactions, in the microfluidic devices. The results have been consistent through at least four attempts. EXAMPLE 2 Spotting Reagents I. Introduction The purpose of the experiment was to demonstrate successful spotted PCR reactions in a microfluidic device. The term “spotted” in this context, refers to the placement of small droplets of reagents (spots) on a substrate that is then assembled to become part of a microfluidic device. The spotted reagents are generally a subset of the reagent mixture required for performing PCR. II. Procedure A. Spotting of Reagents Routine spotting of reagents was performed via a contact printing process. Reagents were picked up from a set of source wells on metal pins, and deposited by contacting the pins to a target substrate. This printing process is further outlined in FIG. 9. As shown, reagents were picked up from a source (e.g., microtiter plates), and then printed by bringing the loaded pin into contact with the substrate. The wash step consists of agitation in deionized water followed by vacuum drying. The system used to print the reagent spots is a Cartesian Technologies MicroSys 5100 (Irvine, Calif.), employing TeleChem “ChipMaker” brand pins, although other systems can be used as described supra. Pins employed are Telechem ChipMaker 4 pins, which incorporate an electro-milled slot (see FIG. 9) to increase the uptake volume (and hence the number of printable spots). Under the operating conditions employed (typically, 75% relative humidity and temperature approximately 25° C.), in excess of one hundred spots were printed per pin, per loading cycle. Under the conditions above, the volume of reagents spotted onto the PDMS substrate is on the order of 0.1 nL. The dimensions of the pin tip are 125×125 m. The final spot of dried reagent is substantially smaller than this (as small as 7 m in diameter), yet the pin size defines a lower limit to the readily achievable spot spacing. The achievable spacing determines the smallest well-to-well pitch in the final device. Using such a device and the foregoing methods, arrays with spacings of 180 m have been achieved. Arrays built into working chips tend to have spacings from 600 to 1300 microns. Spotting was done using only one pin at a time. The system in use, however, has a pin head which can accommodate up to 32 pins. Printing a standard-size chip (array dimensions of order 20×25 mm) takes under 5 minutes. B. Assembly of Spotted Chips The flow and control layers of the PCR devices are assembled according to the normal MSL process described above. The microfluidic device design is the same as the one described in Example 1. In parallel, a substrate layer composed of 150 m—thick PDMS with component ratio A:B of 30:1 is formed via spin-coating a blank silicon wafer, and then cured for 90 minutes at 80° C. The cured blank substrate layer of PDMS (sealing/substrate layer 724 of FIG. 7A) serves as the target for reagent spotting. Patterns of spots are printed onto the substrate, which is still on the blank wafer. The reagents spotted for PCR reactions were primers and probes, specific to the particular gene to be amplified. The spotted reagent included a 1:1:1 volume ratio of 300 nM -actin forward primer (FP), 300 nM -actin reverse primer (RP), and 200 nM -actin probe (Prb). In some cases, it is useful to further tune the chemistry via concentrating the spotted mixture. It has been found that adjusting the concentrations such that primer and probe concentrations are equal to, or slightly higher than, the normal macroscopic recipe value yields consistently good results. Therefore, the spotted reagent is concentrated to be 3 times and 4 times the concentration of the macro reaction. Concentration of the reagents is performed in a Centrivap heated and evacuated centrifuge and does not alter relative FP:RP:Prb ratios. The increased spot concentration results in the correct final concentration when the reagents are resuspended in a 1 nL reaction volume. Spotted reagents need not be limited to primers and probes; nor must all three (FP, RP and Prb) be spotted. Applications where only the probe, or even one of the primers, is spotted can be performed. Experiments have been conducted in which the sample primer/probe sets spotted were TaqMan -actin and TaqMan RNAse-P. Following the spotting process onto the substrate layer, the combined flow and control layers (i.e., layers 720 and 722 of FIG. 7A) were aligned with the spot pattern and brought into contact. A further bake at 80° C., for 60-90 minutes, was used to bond the substrate to the rest of the chip. After the chip has been assembled, the remaining components of the PCR reaction (described in Example 1) are injected into the flow channels of the chip and the chip is thermocycled as described in Example 1. III. Results PCR reactions have been successfully and repeatably performed using devices where primer (forward and reverse primers) and probe molecules are spotted. An example of data from a chip in which a reaction has been successfully performed is shown in FIG. 10. The spotted reagents have resulted in successful PCR reactions as defined in Example 1. Successful reactions have been performed using 2-stage and 3-stage thermocycling protocols. EXAMPLE 3 Genotyping I. Introduction The purpose of the following experiments was to demonstrate that genotyping experiments can be conducted utilizing a microfluidic device or chip such as described herein. Specifically, these experiments were designed to determine if reactions conducted in the device have sufficient sensitivity and to ensure that other primer/probe sets, besides -actin, can be performed in the microfluidic device. II. Methods/Results A. RNase P Experiment RNase P TaqMan reactions (Applied Biosystems; Foster City, Calif.) were performed in a microfluidic device as described in Example 1 to demonstrate that other primer/probe sets produce detectable results. RNaseP reactions also require a higher level of sensitivity because the RNaseP primer/probe set detects a single copy gene (2 copies/genome) in contrast to the -actin primer/probe set. The -actin set detects a single copy -actin gene and several pseudogenes, which collectively total approximately 17 copies per genome. The RNase P reactions were run with the same components as described in Example 1, with the exception that the -actin primer/probe set was replaced with the RNase P primer/probe set. Further, the RnaseP primer/probe set was used at 4× the manufacturer's recommended value to enhance the fluorescence signal. The VIC dye was conjugated to the probe for RNase P and the analysis focused on VIC/PR1 ratios. The results of one of four experiments are shown in FIG. 11. The VIC/PR1/Control ratios for the Macro TaqMan reactions are 1.23. The corresponding ratios for the TaqMan reactions in the microfluidic device are 1.11 and 1.21. The ratios of the genomic DNA samples in the microfluidic device are above the 99% confidence threshold level. Further, the signal strength of the TaqMan reactions in the microfluidic device is 50% and 93.7% of the Macro TaqMan reactions. The control TaqMan reactions in the microfluidic device have standard deviations of 0.006 and 0.012, demonstrating consistency in the reactions across the micro fluidic device. Therefore, it is determined that the TaqMan reactions in the chip are sensitive enough to detect 2 copies per genome. B. DNA Dilution Experiment To further determine the sensitivity of TaqMan reactions in the microfluidic device, dilutions of genomic DNA were tested using the -actin primer/probe set. Reaction compositions were generally composed as described in Example 1 using 4× DyNAzyme and dilutions of genomic DNA. The genomic DNA was diluted down to 0.25 pg/nl, which corresponds to approximately 1 copy per nl. The result of one dilution series is shown in FIG. 12. According to a Poisson distribution, 37% of the total number of wells should be negative if the average target number is one. Well numbers 5, 6 and 7 are below the calculated threshold and, therefore, negative. This suggests that the β-actin TaqMan reactions in micro fluidic chip can detect an average of one copy per nl. Therefore, the sensitivity of the reactions in the microfluidic device is sufficient to perform genotyping experiments. C. Genotyping Experiment Because TaqMan in the microfluidic device is capable of detecting low target numbers, preliminary testing of SNP (Single Nucleotide Polymorphism) genotyping was performed using the Predetermined Allelic Discrimination kit (Applied Biosystems; Foster City, Calif.) against the CYP2D6 P450 cytochrome gene. The kit contains one primer set and two probes; FAM labeled for the wildtype or reference allele, CYP2D6*1, and VIC labeled for the CYP2D6*3 mutant or variant allele. Positive controls, PCR products, for each allele along with genomic DNA were tested in the device using the same conditions as described in Example 1. The results from one experiment are shown in FIGS. 13 and 14. The experiment has been repeated at least three times to validate the results and to demonstrate reliability. As shown in FIG. 13, the Al-1 (Allele 1, CYP2D6*1 wild type allele) and genomic DNA (100 pg/nl) produced an average VIC/PR1/Control ratio of 3.5 and 2.2, respectively, indicating that the genomic DNA was positive for the CYP2D6*1, wild type allele. These values are above the threshold limit for the reactions. The signal strength of the TaqMan reactions in the microfluidic device is 59% and 40% of the Macro TaqMan controls, respectively. Al-2 (Allele 2, CYP2D6*3 mutant or variant allele), which should be negative in the VIC channel, showed some signal over control (1.5), possibly due to FAM fluorescence leaking into the VIC channel of the detector. The leakage can be minimized with an improved detection process. The Al-2 positive control gave an average FAM/PR1/Control ratio of 3.0, which was 37% of the Macro TaqMan signal and above the calculated threshold limit (see FIG. 14). The genomic samples were negative for the CYP2D6*3 mutant allele, an expected result since the frequency of the CYP2D6*3 allele is low. Again, it appears that there is some leakage of the Al-1, VIC probe into the FAM channel of the detector. Overall, the SNP detection reactions were successful in the microfluidic device. EXAMPLE 4 Verification of PCR by Gel Electrophoresis I. Introduction As an alternative method to prove amplification of DNA was occurring in the microfluidic device, an experiment to detect PCR product by gel electrophoresis was performed. PCR reactions compositions were as described in Example 1, except the TaqMan probe was omitted and the β-actin forward primer was conjugated to FAM. II. Procedure A. Microfluidic Device A three layer microfluidic device, fabricated using the MSL process, was designed and fabricated for conducting the experiments described in this example; FIG. 15 shows a schematic view of the design. The device 1500 generally consists of a sample region 1502 and a control region 1504. Sample region 1502 contains three hundred and forty-one 1 nl reaction sites 1508 represented by the rectangles arrayed along flow channel 1506, which includes inlet via 1510 and outlet via 1512. Control region 1504 contains three control flow channels 1514 each containing ten 1 nl reaction sites 1518, also represented by the rectangles and an inlet via 1516. A network of control lines 1522 isolate each reaction site 1508, 1518 when sufficient pressure is applied to inlet via 1524. A series of guard channels 1520 are included to prevent liquid from evaporating out of the reaction sites 1508, 1518. The device is a three-layer device as described in Example 1 (see FIG. 7A). The entire chip is placed onto a coverslip. B. Experimental Setup Microfluidic device 1500 was loaded and thermocycled using the 3 temperature profile described in Example 1. The remaining reaction sample was thermocycled in the GeneAmp 9700 with the same thermocycling profile as for microfluidic device 1500. The reaction products were recovered after thermocycling was completed. To recover the amplified DNA, 3 μl of water was injected into sample input via 1506 and 3-4 μl of product were removed from outlet via 1512. The reaction products from device 1500 and the Macro reaction were treated with 2 μl of ExoSAP-IT (USB, Cleveland, Ohio), which is composed of DNA Exonuclease I and Shrimp Alkaline Phosphatase, to remove excess nucleotides and primers. The Macro product was diluted from 1:10 to1:106. The product from device 1500 was dehydrated and resuspended in 4 μl of formamide. III. Results Both products, along with negative controls were analyzed, on a polyacrylamide gel. FIG. 15 shows the gel electrophoresis results. The appropriate size DNA band of 294 base pairs in length is observed in FIG. 16. The products from the Macro reactions are shown on the left hand side of the gel and correspond to about 294 base pairs, the expected size of the β-actin PCR product. The negative controls lack the PCR product. Similarly, the product derived from the device gave the expected β-actin PCR product. Therefore, target DNA was amplified in the micro fluidic device. EXAMPLE 5 Massive Partitioning The polymerase chain reaction (PCR) has become an essential tool in molecular biology. Its combination of sensitivity (amplification of single molecules of DNA), specificity (distinguishing single base mismatches) and dynamic range (105 with realtime instrumentation) make it one of the most powerful analytical tools in existence. We demonstrate here that PCR performance improves as the reaction volume is reduced: we have performed 21,000 simultaneous PCR reactions in a single microfluidic chip, in a volume of 90 pL per reaction and with single template molecule sensitivity. FIGS. 17a-17d depict a single bank and dual bank partitioning microfluidic device. where multilayer soft lithography (MSL) (Unger et al, Science 288, 113-116 (2000)),was used to create elastomeric microfluidic chips which use active valves to massively partition each of several liquid samples into a multitude of isolated reaction volumes. After injection of the samples into inlet 1703 which is in communication with branched partitioning channel system 1705 of microfluidic device 1701 (FIG. 17b), 2400 90 pL volumes 1709 of each sample are isolated by closing valves 1707 spaced along (FIG. 17d) simple microfluidic channels. The chip device is then thermocycled on a flat plate thermocycler and imaged in a commercially available fluorescence reader. We assessed the performance of PCR in the chips by varying the concentration of template DNA and measuring the number of wells that gave a positive Taqnnan™ signal. We found that a digital amplification is observed when the average number of copies per well is low (FIGS. 18a and 18b). A mixture of robust positive and clearly negative signals is observed even when the average number of copies per well is below 1; this implies that even a single copy of target can give good amplification. The number of positive wells was consistent with the number of wells calculated to have 1 copy of target by the Poisson distribution (FIG. 19.). This result validates that this system gives amplification consistently even from a single copy of target. Fluorescent signal strengths from microfluidic Taqnnan™ PCR were comparable to macroscopic PCR reactions with the same DNA concentration—even though the macroscopic reactions contained >104 more template copies per reaction. We believe that the primary source of this remarkable fidelity is the effective concentration of the target: a single molecule in a 90 pL volume is 55,000 times more concentrated than a single molecule in a 5 uL volume. Since the number of molecules of target, nt, does not change (i.e. nt=1) and the number of molecules that can produce side reactions, ns, (i.e. primer-dimers and non-complementary DNA sequences in the sample) is linearly proportional to volume (i.e. ns ∝ V), the ratio of target to side reactions is inversely proportional to volume: nt/ns ∝ 1/V. Since side reactions are a primary cause of PCR failure (4), the advantage to reducing the volume of the reaction is clear. PCR amplification from single copies of template has been previously reported (See E. T. Lagally, I. Medintz, R. A. Mathies, Anal Chem 73(3), 565-570 (2001), as well as B. Vogelstein, K. W. Kinzler, PNAS 96, 9236-9241 (1999)). However, current methods that achieve reliable amplification from single copies in a macroscopic volumes often require altered thermocycling protocols (e.g. long extension times, many cycles), precautions against mispriming and non-specific amplification (e.g. “hot start” PCR (thermal activation of the polymerase), “booster” PCR, additives to reduce nonspecific hybridization, etc), and are almost always done with two rounds of PCR, where an aliquot of the first PCR is used as template in the second reaction. In contrast, this system achieves reliable amplification from single copies using standard conditions—off-the-shelf primers and probes and a single-round, standard thermocycling protocol. Being completely enclosed, it is also nearly invulnerable to environmental contamination. The ability to do massive numbers of PCR reactions simultaneously provides definite logistical, cost and time advantages compared to macroscopic volumes (1 chip with 21,000 reactions vs. 219 separate 96 well plates, and the associated time, equipment, and tracking infrastructure). This principle of massive partitioning with a digital PCR readout may be used for absolute quantification of the concentration of target in a sample. It can be used, for example, to genotype a pooled sample of genomic DNA simply by counting the numbers of wells that give a positive for a particular allele, or plurality of alleles as described above. Due to the enhanced resistance to side reactions, it should also be useful in quantifying mutants in a background of wild-type DNA—a problem relevant in cancer detection. The general principle of concentration by partitioning may also be useful in other reactions where detection of single molecules, bacteria, viruses or cells is of interest (e.g. ELISA reactions for protein detection). Digital PCR is described by Brown, et al., U.S. Pat. No. 6,143,496, titled “Method of sampling, amplifying and quantifying segement of nucleic acid, polymerase chain reaction assembly having nanoliter-sized chambers and methods of filling chambers”, and by Vogelstein, et al, U.S. Pat. No. 6,446,706, titled “Digital PCR”, both of which are hereby incorporated by reference in their entirety. The small volumes achievable using microfluidics allow both a massive degree of parallelization and very high target-to-background concentration ratios. High target-to-background ratios allow single-molecule amplification fidelity. These factors suggest that for PCR, smaller really is better. The invention provides for methods and devices for conducting digital PCR in a microfluidic environment comprising the steps of: providing a microfluidic device having a fluid channel therein, said fluid channel having two or more valves associated therewith, the valves, when actuated, being capable of partitioning the fluid channel into two or more reaction sites or chambers; introducing a sample containing at least one target nucleic acid polymer, actuating the valves to partition the fluid sample into two or more portions, wherein at least one portion contains a target nucleic acid polymer and another portion does not contain a target nucleic acid polymer, amplifying the target nucleic acid polymer, and, determining the number of portions of the fluid channel that contained the target molecule. In preferred embodiments, the microfluidic device comprises an elastomeric material, and more preferably, comprises at least one layer comprising an elastomeric material. In certain preferred embodiments, the microfluidic device further comprises a deflectable membrane wherein the deflectable membrane is deflectable into and out of the fluid channel to control fluid flow within the fluid channel and/or to partition one portion of the fluid channel from another, preferably wherein the deflectable membrane is integral to a layer of the microfluidic device having a channel or recess formed therein, and preferably wherein the deflectable membrane is formed where a first channel in a first layer is overlapped by a second channel in a second layer of the microfluidic device. In some embodiments, the sample fluid contains all of the components needed for conducting an amplification reaction, while in other embodiments, the microfluidic device contains at least one component of an amplification reaction prior to the introduction of the sample fluid. In some embodiments, the microfluidic device further comprises a detection reagent, preferably one or more nucleic acid polymers complimentary to a least a portion of the target nucleic acid polymer, preferably a plurality of different nucleic acid polymers spatially arrayed within a reaction site or chamber of the microfluidic device. Amplification may be achieved by thermocycling reactions such as PCR, or by isothermal reactions, such as described by Van Ness et al., in U.S. patent application Ser. No. 10/196,740 which has publishes as US 2003/0138800 A1, which is herein incorporated by reference in its entirety for the purpose of teaching an isothermic amplification scheme. The invention further provides for a protein microcalorimetry assay using a fluorescent dye, for example SYBER green™, to measure the conformational changes of a protein, such as denaturation, especially if a protein's denaturation temperature changes when the protein interacts with another moiety such as a ligand or compound or other protein. An additional benefit of using SYBR Green™ is that it us used at lower wavelengths than other UV range dyes thus reducing background problems typically associated with many plastic materials. EXAMPLE 6 Detection of rare targets among high background genetic material samples K-Ras Experiment: K-ras codon 12 mutant genomic DNA was obtained from MIA PaCa2 cell line was obtained from the Allan Balmain Laboratory at the University of California, San Francisco. The mutant genomic DNA was extracted using standard extraction protocols. For controls, one cell line, HELA (ATCC) was cultured and its DNA extracted per standard protocol, and a second control was obtained as purified human genomic DNA from PROMEGA™ corporation. Reaction cocktails contained 50% of 2× master mix from a TAQMAN™ kit sold by ABI™ corporation, a final concentration of 0.25% TWEEN™ 20 from SIGMA™ corporation, mutation specific primers at a concentration of 800 nM, wild-type non-extendible primer at 500 nM, a universal probe at 200 nM designed to function in accordance with the TAQMAN™ protocol specific for the present application, the balance being made up with DI water. The above-mentioned cocktail was divided into several different aliquots, to which each received an amount of target genomic DNA and/or “background” DNA. Specifically, the first reaction was a no-template control which received no DNA to establish a baseline signal. The second aliquot received 100 pg of mutant target DNA to serve as a positive control. The third aliquot received 100 pg of mutant DNA along with 500 ng of wild-type (from PROMEGA™) DNA. The forth aliquot received 100 pg of mutant DNA along with 1 μg of HELA (ATCC) wildtype DNA. The fifth aliquot received 100 pg of mutant DNA along 1 μg of wild type (PROMEGA™) DNA. The forth and fifth aliquots were to demonstrate the ability of the system to discern low concentrations of target among two different types of relatively high concentration “background” DNA. And, the sixth aliquot received 1 μg of wild type (PROMEGA™) DNA only as negative control. A chip was made in accordance as described above in the present application, and, the chip used a silicon wafer as a substrate, and the elastomeric block comprised a third lower lever used to form channels from the recesses in the lower recess bearing layer of the elastomeric block, wherein the chip had twelve sample channels, each channel having 1,200 partitioning valves to create approximately 1,200 isolated chambers from each sample loaded into each sample channel through blind filling. Once each sample had been loaded into its respective sample channel, the sample channels were partitioned by applying a hydraulic force to the control channels that formed the partitioning valves along each sample channel. In this particular instance, the hydraulic fluid comprised water and PEG 3,350 mw average (from HAMPTON RESEARCH™ corporation) at a concentration of 25% w/v. The hydraulic fluidic was pressurized to a pressure of 35 PSI and held closed during the PCR reaction. Amplification by PCR was performed in a real-time manner, as described in the TAQMAN™ kit using a modified EPPENDORF™ thermocycler that had a suction metallic block having a tortuous channel system thereon, the metallic block being disposed between the side of the silicon wafer opposite the elastomeric block and the thermal control surface of the thermocycler, wherein a vacuum source was applied to the tortuous channel system to urged the silicon wafer into near homogeneous thermal contact between the silicon wafer and the thermocycler thermal control surface as described in copending patent application Ser. No. 11/043,895, filed on Feb. 14, 2005, which is herein incorporated by reference in its entirety. As an alternative to using the vacuum chuck to hold down the chip and to establish thermal contact, a film of oil, such as mineral oil, may be used to achieve thermal conduction between the thermal control surface and the exposed silicon portion of the chip. A thermocycling profile comprising 2 minute UNG clean up step at 52 degrees C., followed by a “hot start” at 95 degrees C. for ten minutes, followed by forty cycles of ramping between 25 seconds at 95 degrees C. to 40 seconds at 58 degrees C., operating the thermocycler at its fastest ramp rate between each temperature change. At the end of each 58 degree C. round, an two different images were taken of the chip using white light source that was filtered in accordance with the two different fluorophores used for the two color analysis. Ratio analysis was conducted between the two different color images to produce real-time amplification curves. Another experiment was performed using a chip similar to the above-mentioned chip, however, this chip one sample channel able to partition the sample channel into approximately 10,000 separate chambers. The sample comprises a cocktail as described above, and further including 100 pg of mutant DNA and 7 μg of wild type HELA DNA The number of cycles of amplification in this instance was only 30, of which the last cycle included an extension period of five minutes at 72 degrees C. Although the experiment was monitored in real-time as described above, it was appreciated that the assay could be performed as an end-point type assay. References incorporated herein by reference: 1. Unger et al, Science 288, 113-116 (2000). 2. The sample channels and control lines are loaded by “blind filling”—PDMS is sufficiently gas permeable that liquid pressurized at a few psi drives the gas out of the channels, leaving them completely filled with liquid. See Hansen et al, PNAS 99, 16531-16536 (2002) 3. A 294 bp segment of the human β-actin gene was amplified using a 5′-exonuclease assay (Taqman). The data in FIG. 1c was taken with a dark-quencher based probe, as large numbers of these primer-probe sets are becoming commercially available. Reactions contained 1× Taqman buffer A (50 mM KCl, 10 mM Tris-HCl, 0.01 M EDTA, 60 nM Passive Reference 1, pH 8.3), 4 mM MgCl2, 200 nM dATP, dCTP, dTTP, 400 nM dUTP, 300 nM forward primer, 300 nM reverse primer, 200 nM probe, 0.01 U/uL Amperase UNG (all from Applied Biosystems, Foster City, Calif.), 0.2 U/uL DyNAzyme (Finnzyme, Espoo, Finland), 0.5% Triton-x-100, 0.8 ug/ul Gelatin (Calbiochem, San Diego, Calif.), 5.0% Glycerol, deionized H2O and human male genomic DNA (Promega). 4. Quantitative PCR Technology, Chapter on “Gene Quantification”, L J McBride, K Livak, M Lucero, et al, Editor, Francois Ferre, Birkauser, Boston, Mass. p 97-110, 1998. 5. See E. T. Lagally, I. Medintz, R. A. Mathies, Anal Chem 73(3), 565-570 (2001), as well as B. Vogelstein, K. W. Kinzler, PNAS 96, 9236-9241 (1999) It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent or patent application were specifically and individually indicated to be so incorporated by reference. | <SOH> BACKGROUND <EOH>Recently, there have been concerted efforts to develop and manufacture microfluidic systems to perform various chemical and biochemical analyses and syntheses, both for preparative and analytical applications. The goal to make such devices arises because of the significant benefits that can be realized from miniaturization with respect to analyses and syntheses conducted on a macro scale. Such benefits include a substantial reduction in time, cost and the space requirements for the devices utilized to conduct the analysis or synthesis. Additionally, microfluidic devices have the potential to be adapted for use with automated systems, thereby providing the additional benefits of further cost reductions and decreased operator errors because of the reduction in human involvement. Microfluidic devices have been proposed for use in a variety of applications, including, for instance, capillary electrophoresis, gas chromatography and cell separations. However, realization of these benefits has often been thwarted because of various complications associated with the microfluidic devices that have thus far been manufactured. For instance, many of the current microfluidic devices are manufactured from silica-based substrates; these materials are difficult and complicated to machine and devices made from such materials are fragile. Furthermore, transport of fluid through many existing microfluidic devices requires regulation of complicated electrical fields to transport fluids in a controlled fashion through the device. Thus, in view of the foregoing benefits that can be achieved with microfluidic devices but the current limitations of existing devices, there remains a need for microfluidic devices designed for use in conducting a variety of chemical and biochemical analyses. Because of its importance in modern biochemistry, there is a particular need for devices that can be utilized to conduct a variety of nucleic acid amplification reactions, while having sufficient versatility for use in other types of analyses as well. Devices with the ability to conduct nucleic acid amplifications would have diverse utilities. For example, such devices could be used as an analytical tool to determine whether a particular target nucleic acid of interest is present or absent in a sample. Thus, the devices could be utilized to test for the presence of particular pathogens (e.g., viruses, bacteria or fungi), and for identification purposes (e.g., paternity and forensic applications). Such devices could also be utilized to detect or characterize specific nucleic acids previously correlated with particular diseases or genetic disorders. When used as analytical tools, the devices could also be utilized to conduct genotyping analyses and gene expression analyses (e.g., differential gene expression studies). Alternatively, the devices can be used in a preparative fashion to amplify sufficient nucleic acid for further analysis such as sequencing of amplified product, cell-typing, DNA fingerprinting and the like. Amplified products can also be used in various genetic engineering applications, such as insertion into a vector that can then be used to transform cells for the production of a desired protein product. | <SOH> SUMMARY <EOH>A variety of devices and methods for conducting microfluidic analyses are provided herein, including devices that can be utilized to conduct thermal cycling reactions such as nucleic acid amplification reactions. The devices differ from conventional microfluidic devices in that they include elastomeric components; in some instances, much or all of the device is composed of elastomeric material. Certain devices are designed to conduct thermal cycling reactions (e.g., PCR) with devices that include one or more elastomeric valves to regulate solution flow through the device. Thus, methods for conducting amplification reactions with devices of this design are also provided. Some of the devices include blind flow channels which include a region that functions as a reaction site. Certain such devices include a flow channel formed within an elastomeric material, and a plurality of blind flow channels in fluid communication with the flow channel, with a region of each blind flow channel defining a reaction site. The devices can also include one or more control channels overlaying and intersecting each of the blind flow channels, wherein an elastomeric membrane separates the one or more control channels from the blind flow channels at each intersection. The elastomeric membrane in such devices is disposed to be deflected into or withdrawn from the blind flow channel in response to an actuation force. The devices can optionally further include a plurality of guard channels formed within the elastomeric material and overlaying the flow channel and/or one or more of the reaction sites. The guard channels are designed to have fluid flow therethrough to reduce evaporation from the flow channels and reaction sites of the device. Additionally, the devices can optionally include one or more reagents deposited within each of the reaction sites. In certain devices, the flow channel is one of a plurality of flow channels, each of the flow channels in fluid communication with multiple blind flow channels which branch therefrom. Of devices of this design, in some instances the plurality of flow channels are interconnected with one another such that fluid can be introduced into each of the reaction sites via a single inlet. In other devices, however, the plurality of flow channels are isolated from each other such that fluid introduced into one flow channel cannot flow to another flow channel, and each flow channel comprises an inlet at one or both ends into which fluid can be introduced. Other devices include an array of reaction sites having a density of at least 50 sites/cm 2 , with the reaction sites typically formed within an elastomeric material. Other devices have even higher densities such as at least 250, 500 or 1000 sites/cm 2 , for example. Still other device include a reaction site formed within an elastomeric substrate, at which a reagent for conducting a reaction is non-covalently immobilized. The reagent can be one or more reagents for conducting essentially any type of reaction. The reagent in some devices includes one reagents for conducting a nucleic acid amplification reaction. Thus, in some devices the reagent comprises a primer, polymerase and one or more nucleotides. In other devices, the reagent is a nucleic acid template. A variety of matrix or array-based devices are also provided. Certain of these devices include: (i) a first plurality of flow channels formed in an elastomeric substrate, (ii) a second plurality of flow channels formed in the elastomeric substrate that intersect the first plurality of flow channels to define an array of reaction sites, (iii) a plurality of isolation valves disposed within the first and second plurality of flow channels that can be actuated to isolate solution within each of the reaction sites from solution at other reaction sites, and (iv) a plurality of guard channels overlaying one or more of the flow channels and/or one or more of the reaction sites to prevent evaporation of solution therefrom. The foregoing devices can be utilized to conduct a number of different types of reactions, including those involving temperature regulation (e.g., thermocycling of nucleic acid analyses). Methods conducted with certain blind channel type devices involve providing a microfluidic device that comprises a flow channel formed within an elastomeric material; and a plurality of blind flow channels in fluid communication with the flow channel, with an end region of each blind flow channel defining a reaction site. At least one reagent is introduced into each of the reaction sites, and then a reaction is detected at one or more of the reaction sites. The method can optionally include heating the at least one reagent within the reaction site. Thus, for example, a method can involve introducing the components for a nucleic acid amplification reaction and then thermocycling the components to form amplified product. Other methods involve providing a microfluidic device comprising one or more reaction sites, each reaction site comprising a first reagent for conducting an analysis that is non-covalently deposited on an elastomeric substrate. A second reagent is then introduced into the one or more reaction sites, whereby the first and second reagents mix to form a reaction mixture. A reaction between the first and second reagents at one or more of the reaction sites is subsequently detected. Still other methods involve providing a microfluidic device comprising an array of reaction sites formed within a substrate and having a density of at least 50 sites/cm 2 . At least one reagent is introduced into each of the reaction sites. A reaction at one or more of the reaction sites is then detected. Yet other methods involve providing a microfluidic device comprising at least one reaction site which is formed within an elastomeric substrate and a plurality of guard channels also formed within the elastomeric substrate. At least one reagent is introduced into each of the reaction sites and then heated within the reaction sites. A fluid is flowed through the guard channels before or during heating to reduce evaporation from the at least one reaction site. A reaction within the at least one reaction site is subsequently detected. Additional devices designed to reduce evaporation of fluid from the device are also provided. In general, such devices comprise a cavity that is part of a microfluidic network formed in an elastomeric substrate; and a plurality of guard channels overlaying the cavity and separated from the cavity by an elastomeric membrane. The guard channel in such devices is sized (i) to allow solution flow therethrough, and (ii) such that there is not a substantial reduction in solution flow in, out or through the cavity due to deflection of the membrane(s) upon application of an actuation force to the guard channels. Other such devices include (i) one or more flow channels and/or one or more reaction sites; and (ii) a plurality of guard channels overlaying the microfluidic system and separated therefrom by elastomer, wherein the spacing between guard channels is between 1 μm to 1 mm. In other devices the spacing is between 5 μm and 500 μm, in other devices between 10 μm and 100 μm, and in still other devices between 40 μm and 75 μm. In other embodiments of the invention provide for a microfluidic device have one or more sample channels having a plurality of valves in communication therewith, wherein each sample channel, when filled with a sample, can be partitioned into sub-samples for conducting analysis, such as amplification, for example, but not limited to PCR, including TAQMAN™, and endpoint PCR, and isothermal amplification techniques, such as INVADER™. Such microfluidic devices may have some sample channels devoted to partition and analyze known control samples, while other sample channels may be used to partition and analyze one or more test samples. The arrangement of the separate sample channels may be interdigitated or laid out as plots among the device surface, the latter being preferred for optimizing conditions for conducting analysis on a routine basis. One advantage of partitioning a sample is to reduce the apparent concentration of a high background of wild type sample containing a low, such as one, two, three, four, five, or six orders of magnitude lower concentration of a mutant sample than the wild type sample. For example, when analyzing a sample containing a high concentration of wild-type DNA that contains a very small, several orders of magnitude, such as 10 less copies than the wild type. By partitioning the sample many fold, such as by 100, 1,000, 10,000, 100,000, or 1,000,000 fold, the ratio in each partition between wild type and mutant DNA is changed from the original ratio such that the likelihood of background PCR product that would be produced relative the amount of PCR product produced from the target mutant is minimized to yield a valid signal indicating the presence of the mutant DNA target in the particular partitioned chamber. There may also be benefits afforded by conducting the reaction in very small volumes that are obtainable in certain embodiments of the present invention, in that by conducting the reaction in a small volume raises the concentration of target to the volume of the total reaction. In another embodiment, the invention provides a method for analyzing the presence of a specific gene, for example but not limited to an oncogene point mutation in a patient suspected of having a tumor if the tumor releases genetic material into the body, in particular, the blood stream, even though other non-oncogenic genetic material may be present in the blood stream in great excess, including one, two, three, four, five, and six orders of magnitude greater excess than the target oncogenic target genetic material. For example, in the K-ras point mutation at codon 12 occurs in about 70 to 95% of the cells of this cancer, wherein some or all of the cells may release genetic material containing the K-ras point mutation at codon 12 which can be detected by the methods described herein using the devices herein. In yet another embodiment, a sample may contain whole cells that when analyzed, for example but not limited to, by PCR, the cells lyse and make their genetic material available for amplification. Other oncogenic point mutations and genetic diseases that produce amplifiable genetic material in low quantities relative to the background genetic material normally present Compositions for conducting nucleic acid analyses in reaction sites of certain microfluidic devices are also provided. Certain such compositions include one or more of the following: an agent that blocks protein binding sites on an elastomeric material and a detergent. The blocking agent is typically selected from the group consisting of a protein (e.g., gelatin or albumin, such as bovine serum albumin (BSA)). The detergent can be SDS or Triton, for example | C12Q168 | 20171107 | 20180315 | 64124.0 | C12Q168 | 1 | KIM, YOUNG J | THERMAL REACTION DEVICE AND METHOD FOR USING THE SAME | UNDISCOUNTED | 1 | CONT-ACCEPTED | C12Q | 2,017 |
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15,805,934 | PENDING | LISINOPRIL FORMULATIONS | Provided herein are stable lisinopril oral liquid formulations. Also provided herein are methods of using lisinopril oral liquid formulations for the treatment of certain diseases including hypertension, heart failure and acute myocardial infarction. | 1. A method of treating hypertension in a subject comprising administering to that subject a therapeutically effective amount of a stable oral liquid formulation, comprising: (i) about 1 mg/ml lisinopril or a pharmaceutically acceptable salt or solvate thereof; (ii) a sweetener selected from the group consisting of xylitol, mannitol, sucralose, saccharin, and pharmaceutically acceptable salts thereof; (iii) a buffer comprising citric acid and sodium citrate; (iv) a preservative selected from the group consisting of sodium benzoate, benzoic acid, sorbic acid, methylparaben, propylparaben, and pharmaceutically acceptable salts thereof; and (v) water; provided that when the preservative is a paraben, then the sweetener is not xylitol or mannitol; and wherein the formulation is stable at about 25±5° C. for at least 6 months. 2. The method of claim 1, wherein lisinopril is lisinopril dihydrate. 3. The method of claim 1, wherein the pH is about 4.9. 4. The method of claim 1, wherein the formulation is stable at about 25±5° C. for at least 24 months. 5. The method of claim 1, wherein the hypertension is primary (essential) hypertension. 6. The method of claim 1, wherein the hypertension is secondary hypertension. 7. The method of claim 1, wherein the subject has blood pressure values greater than or equal to 140/90 mm Hg. 8. The method of claim 1, wherein the subject is elderly. 9. The method of claim 1, wherein the subject is a child. 10. The method of claim 1, wherein the formulation is further administered in combination with an agent selected from the group consisting of diuretics, beta blockers, alpha blockers, mixed alpha and beta blockers, calcium channel blockers, angiotensin II receptor antagonists, ACE inhibitors, aldosterone antagonists, and alpha-2 agonists. 11. A method of treating heart failure in a subject comprising administering to that subject a therapeutically effective amount of a stable oral liquid formulation, comprising: (i) about 1 mg/ml lisinopril or a pharmaceutically acceptable salt or solvate thereof; (ii) a sweetener selected from the group consisting of xylitol, mannitol, sucralose, saccharin, and pharmaceutically acceptable salts thereof; (iii) a buffer comprising citric acid and sodium citrate; (iv) a preservative selected from the group consisting of sodium benzoate, benzoic acid, sorbic acid, methylparaben, propylparaben, and pharmaceutically acceptable salts thereof; and (v) water; provided that when the preservative is a paraben, then the sweetener is not xylitol or mannitol; and wherein the formulation is stable at about 25±5° C. for at least 6 months. 12. The method of claim 11, wherein lisinopril is lisinopril dihydrate. 13. The method of claim 11, wherein the pH is about 4.9. 14. The method of claim 11, wherein the formulation is stable at about 25±5° C. for at least 24 months. 15. The method of claim 11, wherein the subject is not responding adequately to diuretics and digitalis. 16. A method of treating a hemodynamically stable subject within 24 hours of acute myocardial infarction comprising administering to that subject a therapeutically effective amount of a stable oral liquid formulation, comprising: (i) about 1 mg/ml lisinopril or a pharmaceutically acceptable salt or solvate thereof; (ii) a sweetener selected from the group consisting of xylitol, mannitol, sucralose, saccharin, and pharmaceutically acceptable salts thereof; (iii) a buffer comprising citric acid and sodium citrate; (iv) a preservative selected from the group consisting of sodium benzoate, benzoic acid, sorbic acid, methylparaben, propylparaben, and pharmaceutically acceptable salts thereof; and (v) water; provided that when the preservative is a paraben, then the sweetener is not xylitol or mannitol; and wherein the formulation is stable at about 25±5° C. for at least 6 months. 17. The method of claim 16, wherein lisinopril is lisinopril dihydrate. 18. The method of claim 16, wherein the pH is about 4.9. 19. The method of claim 16, wherein the formulation is stable at about 25±5° C. for at least 24 months. 20. The method of claim 16, wherein the formulation is further administered in combination with an agent selected from the group consisting of beta blockers, aspirin, and thrombolytics. | CROSS-REFERENCE This application is a continuation of U.S. patent application Ser. No. 15/483,691, filed Apr. 10, 2017, which is a continuation of U.S. patent application Ser. No. 15/268,095, filed Sep. 16, 2016 (now U.S. Pat. No. 9,616,096, issued Apr. 11, 2017), which is a continuation of U.S. patent application Ser. No. 14/934,752, filed Nov. 6, 2015 (now U.S. Pat. No. 9,463,183, issued Oct. 11, 2016), which claims the benefit of U.S. Provisional Patent Application No. 62/249,011, filed Oct. 30, 2015, all of which are incorporated herein by reference in their entirety. BACKGROUND OF THE INVENTION Hypertension, or high blood pressure, is a serious health issue in many countries. According to the National Heart Blood and Lung Institute, it is thought that about 1 in 3 adults in the United States alone have hypertension. Left unchecked, hypertension is considered a substantial risk factor for cardiovascular and other diseases including coronary heart disease, myocardial infarction, congestive heart failure, stroke and kidney failure. Hypertension is classified as primary (essential) hypertension or secondary hypertension. Primary hypertension has no known cause and may be related to a number of environmental, lifestyle and genetic factors such as stress, obesity, smoking, inactivity and sodium intake. Secondary hypertension can be caused by drug or surgical interventions or by abnormalities in the renal, cardiovascular or endocrine system. A number of antihypertensive drugs are available for treating hypertension. Various therapeutic classes of antihypertensive drugs include alpha-adrenergic blockers, beta-adrenergic blockers, calcium-channel blockers, hypotensives, mineralcorticoid antagonists, central alpha-agonists, diuretics and rennin-angiotensin-aldosterone inhibitors which include angiotensin II receptor antagonists (ARB) and angiotensin-converting enzyme (ACE) inhibitors. Angiotensin-converting enzyme (ACE) inhibitors inhibit angiotensin-converting enzyme (ACE), a peptydyl dipeptidase that catalyzes angiotension I to angiotension II, a potent vasoconstrictor involved in regulating blood pressure. Lisinopril is a drug belonging to the angiotensin-converting enzyme (ACE) inhibitor class of medications. Lisinopril IUPAC name is N2-[(1S)-1-carboxy-3-phenylpropyl]-L-lysyl-L-proline. Its structural formula is as follows: Lisinopril is currently administered in the form of oral tablets, (e.g., Prinivil®, Zestril®). In addition to the treatment of hypertension, lisinopril tablets have been used for the treatment of heart failure and acute myocardial infarction. SUMMARY OF THE INVENTION Provided herein are lisinopril oral liquid formulations. In one aspect, the lisinopril oral liquid formulation comprises (i) lisinopril or a pharmaceutically acceptable salt or solvate thereof, (ii) a sweetener that is xylitol, (iii) a buffer comprising citric acid (iv) a preservative that is sodium benzoate, and (v) water; wherein the pH of the formulation is between about 4 and about 5; and wherein the formulation is stable at about 25±5° C. for at least 12 months. In some embodiments, the lisinopril is lisinopril dihydrate. In some embodiments, the formulation further comprises a flavoring agent. In some embodiments, the formulation further comprises a second sweetener. In some embodiments, the second sweetener is sodium saccharin or sucralose. In some embodiments, the pH is about 4.9. In some embodiments, the formulation is stable at about 25±5° C. for at least 18 months. In some embodiments, the formulation is stable at about 25±5° C. for at least 24 months. In some embodiments, the buffer further comprises sodium citrate. In some embodiments, the amount of lisinopril or a pharmaceutically acceptable salt or solvate thereof is about 0.8 to about 1.2 mg/ml. In some embodiments, the amount of xylitol is about 140 to about 160 mg/ml. In some embodiments, the amount of citric acid in the buffer is about 0.5 to about 1.2 mg/ml. In some embodiments, the amount of sodium citrate in the buffer is about 1.2 to about 1.7 mg/ml. In some embodiments, the amount of the sodium benzoate is about 0.5 to about 1.2 mg/ml. In one aspect, the lisinopril oral liquid formulation comprises (i) about 1 mg/ml lisinopril or a pharmaceutically acceptable salt or solvate thereof, (ii) about 150 mg/ml of a sweetener that is xylitol, (iii) a buffer comprising about 0.86 mg/ml citric acid, (iv) about 0.8 mg/ml of a preservative that is sodium benzoate; and (v) water; wherein the pH of the formulation is between about 4 and about 5; and wherein the formulation is stable at about 25±5° C. for at least 12 months. In some embodiments, the lisinopril is lisinopril dihydrate. In some embodiments, the formulation further comprises a flavoring agent. In some embodiments, the formulation further comprises a second sweetener. In some embodiments, the second sweetener is sodium saccharin or sucralose. In some embodiments, the pH is about 4.9. In some embodiments, the formulation is stable at about 25±5° C. for at least 18 months. In some embodiments, the formulation is stable at about 25±5° C. for at least 24 months. In some embodiments, the buffer further comprises sodium citrate. In some embodiments, the buffer further comprises about 1.44 mg/ml sodium citrate. In some embodiments, the amount of lisinopril or a pharmaceutically acceptable salt or solvate thereof is about 0.5 to about 1% (w/w of solids). In some embodiments, the amount of xylitol is about 95 to about 98% (w/w of solids). In some embodiments, the amount of citric acid in the buffer is about 0.3 to about 0.7% (w/w of solids). In some embodiments, the amount of sodium citrate in the buffer is about 0.7 to about 1.3% (w/w of solids). In some embodiments, the amount of sodium benzoate is about 0.4 to about 1.2% (w/w of solids). In another aspect, the lisinopril oral liquid formulation comprises (i) about 0.7% (w/w of solids) lisinopril or a pharmaceutically acceptable salt or solvate thereof, (ii) about 97.3% (w/w of solids) of a sweetener that is xylitol, (iii) a buffer comprising about 0.01 molar citrate, (iv) about 0.52% (w/w of solids) of a preservative that is sodium benzoate, and (v) water; wherein the pH of the formulation is between about 4 and about 5; and wherein the formulation is stable at about 25±5° C. for at least 12 months. In some embodiments, the lisinopril is lisinopril dihydrate. In some embodiments, the formulation further comprises a flavoring agent. In some embodiments, the formulation further comprises a second sweetener. In some embodiments, the second sweetener is sodium saccharin or sucralose. In some embodiments, the pH is about 4.9. In some embodiments, the formulation is stable at about 25±5° C. for at least 18 months. In some embodiments, the formulation is stable at about 25±5° C. for at least 24 months. In some embodiments, the buffer comprises citric acid and sodium citrate. In another aspect, the lisinopril oral liquid formulation consists of (i) about 1 mg/ml lisinopril or a pharmaceutically acceptable salt or solvate thereof, (ii) about 150 mg/ml of a sweetener that is xylitol, (iii) a buffer comprising about 0.86 mg/ml citric acid and about 1.44 mg/ml sodium citrate, (iv) about 0.8 mg/ml of a preservative that is sodium benzoate, (v) and water; wherein the pH of the formulation is between about 4 and about 5 adjusted by sodium hydroxide or hydrochloric acid; and wherein the formulation is stable at about 25±5° C. for at least 12 months. In some embodiments, the formulation is stable at about 25±5° C. for at least 24 months. In some embodiments, the pH is about 4.9. Also provided herein are methods of treating hypertension comprising administering to a patient in need thereof a lisinopril oral liquid formulation described herein. In some embodiments, the hypertension is primary (essential) hypertension. In some embodiments, the hypertension is secondary hypertension. In some embodiments, the subject with hypertension has blood pressure values greater than or equal to 140/90 mm Hg. Also provided herein are methods of treating prehypertension comprising administering to a patient in need thereof a lisinopril oral liquid formulation described herein. In some embodiments, the subject with prehypertension has blood pressure values of about 120-139/80-89 mm Hg. Also provided herein are methods of treating heart failure or acute myocardial infarction comprising administering to a patient in need thereof a lisinopril oral liquid formulation described herein. In some embodiments, the subject is an adult. In some embodiments, the subject is elderly. In some embodiments, the subject is a child. In some embodiments, the lisinopril oral liquid formulation is administered to the subject in a fasted state. In some embodiments, the lisinopril oral liquid formulation is administered to the subject in a fed state. In some embodiments, the lisinopril oral liquid formulation is further administered in combination with an agent selected from the group consisting of diuretics, beta blockers, alpha blockers, mixed alpha and beta blockers, calcium channel blockers, angiotensin II receptor antagonists, ACE inhibitors, aldosterone antagonists, and alpha-2 agonists. Also provided herein is a process for preparing a stable oral liquid formulation comprising lisinopril, xylitol, a buffer, and sodium benzoate, the process which comprises the step of adding about 0.86 mg/ml anhydrous citric acid, about 1.44 mg/ml anhydrous sodium citrate, about 0.80 mg/ml sodium benzoate, about 1.09 mg/ml lisinopril dihydrate, and about 150 mg/ml xylitol to water; adjusting the volume to the desired volume by adding more water; and adjusting the pH to 4.9 by adding sodium hydroxide or hydrochloric acid. INCORPORATION BY REFERENCE All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which: FIG. 1: Degradant formation in lisinopril formulations after 145 hours at 60° C. (Δ-Lisinopril diketopiperazine, □-hydrolysate). FIG. 2: Chromatograms showing esterification degradation peaks in formulation 1 (containing lisinopril, parabens and xylitol) and placebo 1 (containing parabens and xylitol) versus formulation 2 (containing lisinopril and paraben but no sugar alcohol) and placebo 2 (containing paraben but no sugar alcohol). DETAILED DESCRIPTION OF THE INVENTION Provided herein are stable lisinopril oral liquid formulations. Also provided herein are stable lisinopril powder formulations for reconstitution for oral liquid administration. These lisinopril formulations described herein are useful for the treatment of hypertension, prehypertension, heart failure as well as acute myocardial infarction. The formulations are advantageous over conventional solid dosage administration of lisinopril ranging from ease of administration, accuracy of dosing, accessibility to additional patient populations such as to children and the elderly, and an increased patient compliance to medication. It is generally known that certain segments of the population have difficulty ingesting and swallowing solid oral dosage forms such as tablets and capsules. As many as a quarter of the total population has this difficulty. Often, this leads to non-compliance with the recommended medical therapy with the solid dosage forms, thereby resulting in rending the therapy ineffective. Further, solid dosage forms are not recommended for children or elderly due to increased risk in choking. Furthermore, the dose of lisinopril to be given to children is calculated according to the child's weight. When the calculated dose is something other than the amount present in one or more intact solid dosage forms, the solid dosage form must be divided to provide the correct dose. This leads to inaccurate dosing when solid dosages forms, such as tablets, are compounded to prepare other formulations for children. For lisinopril, the current solution to overcoming the use of the tablet form is for a compounding pharmacist to pulverize and crush the lisinopril tablet(s) into a powder via mortar and pestle and reconstitute the powder in some liquid form. However forming a lisinopril oral liquid in this fashion has significant drawbacks including large variability in the actual dosage, incomplete solubilizing of the lisinopril tablet in the liquid, rapid instability, inconsistent formulation methods per compounding pharmacy, and a number of other potential issues. The crushed tablet liquid formulation may also be potentially unsafe due to contamination with residual drugs and other substances from the mortar and pestle or other crushing agent. The present embodiments provide a safe and effective oral administration of lisinopril for the treatment of hypertension and other disorders. In particular, the embodiments provide stable lisinopril oral liquid formulations as well as lisinopril powder formulations for reconstitution for oral liquid administration. As used herein, “lisinopril” refers to lisinopril base, its salt, or solvate or derivative or isomer or polymorph thereof. Suitable compounds include the free base, the organic and inorganic salts, isomers, isomer salts, solvates, polymorphs, complexes etc. U.S. Pat. No. 4,374,829, U.S. Pat. No. 4,472,380, and CA 1,275,350 disclose exemplary methods in the preparation of lisinopril. In some embodiments, the lisinopril used in the formulations described herein is a lisinopril salt. In some instances, the lisinopril used in the formulations described herein is a lisinopril hydrate. In some instances, the lisinopril used in the formulations described herein is lisinopril monohydrate. In some instances, the lisinopril used in the formulations described herein is lisinopril dihydrate. Other ACE inhibitors are contemplated in the formulations within and include but are not limited to quinapril, indolapril, ramipril, perindopril, benazepril, imidapril, zofenopril, trandolapril, fosinopril, captopril, and their salts, solvates, derivatives, polymorphs, complexes, thereof. Lisinopril Oral Liquid Formulations Oral liquids include, but are not limited to, solutions (both aqueous and nonaqueous), suspensions, emulsions, syrups, slurries, juices, elixirs, dispersions, and the like. It is envisioned that solution/suspensions are also included where certain components described herein are in a solution while other components are in a suspension. In one aspect, the lisinopril oral liquid formulation described herein comprise lisinopril, a preservative, a sweetening agent, a buffer, and water. In one embodiment, the sweetening agent is xylitol. In some embodiments, the sweetening agent is sucralose. In some embodiments, the sweetener is saccharin. In another embodiment, the preservative is sodium benzoate. In yet another embodiment, the preservative is one or more paraben preservatives. In yet another embodiment, the buffer comprises citric acid. In yet another embodiment, the buffer comprises citric acid and sodium citrate. In yet another embodiment, the buffer comprises phosphoric acid or salts thereof. In one aspect, the lisinopril oral liquid formulation described herein comprises lisinopril, xylitol, sodium citrate, citric acid, sodium benzoate, and water. In some embodiments, the lisinopril oral liquid formulation herein further comprises a flavoring agent. In some embodiments, lisinopril is present in about 0.8 mg/ml to about 1.2 mg/ml in the oral liquid formulation. In other embodiments, lisinopril is present in about 0.8 mg/ml, 0.81 mg/ml, about 0.82 mg/ml, about 0.83 mg/ml, about 0.84 mg/ml, about 0.85 mg/ml, about 0.86 mg/ml, about 0.87 mg/ml, about 0.88 mg/ml, about 0.89 mg/ml, about 0.9 mg/ml, about 0.91 mg/ml, about 0.92 mg/ml, about 0.93 mg/ml, about 0.94 mg/ml, about 0.95 mg/ml, about 0.96 mg/ml, about 0.97 mg/ml, about 0.98 mg/ml, about 0.99 mg/ml, about 1 mg/ml, about 1.01 mg/ml, about 1.02, mg/ml, about 1.03 mg/ml, about 1.04 mg/ml, about 1.05 mg/ml, about 1.06 mg/ml, about 1.07 mg/ml, about 1.08 mg/ml, about 1.09 mg/ml, about 1.1 mg/ml, about 1.11 mg/ml, about 1.12, mg/ml, about 1.13 mg/ml, about 1.14 mg/ml, about 1.15 mg/ml, about 1.16 mg/ml, about 1.17 mg/ml, about 1.18 mg/ml, about 1.19 mg/ml, or about 1.2 mg/ml in the liquid oral formulation. In some embodiments, lisinopril is present in about 1 mg/ml in the oral liquid formulation. In some embodiments, lisinopril is present in about 0.5% w/w to about 5% w/w of the solids in the oral liquid formulation. In other embodiments, Lisinopril is present in about 0.5% w/w, about 0.55% w/w, about 0.6% w/w, about 0.65% w/w, about 0.7% w/w, about 0.75% w/w, about 0.8% w/w, about 0.85% w/w, about 0.9% w/w, about 0.95% w/w, about 1% w/w, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about 2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w, about 3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6% w/w, about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, or about 5% w/w of the solids in the oral liquid formulation. In some embodiments, lisinopril is present in about 0.5% w/w to about 1% w/w of the solids in the oral liquid formulation. In some embodiments, lisinopril is present in about 0.6% w/w to about 0.8% w/w of the solids in the oral liquid formulation. In some embodiments, lisinopril is present in about 0.7% w/w of the solids in the oral liquid formulation. In some embodiments, lisinopril is present in about 10% w/w to about 25% w/w of the solids in the oral liquid formulation. In other embodiments, lisinopril is present in about 10% w/w, about 10.5% w/w, about 11% w/w, about 11.5% w/w, about 12% w/w, about 12.5% w/w, about 13% w/w, about 13.5% w/w, about 14% w/w, about 14.5% w/w, about 15% w/w, about 15.5% w/w, about 16% w/w, about 16.5% w/w, about 17% w/w, about 17.5% w/w, about 18% w/w, about 18.5% w/w, about 19% w/w, about 19.5% w/w, about 20% w/w, about 20.5% w/w, about 21% w/w, about 21.5% w/w, about 22% w/w, about 22.5% w/w, about 23% w/w, about 23.5% w/w, about 24% w/w, about 24.5% w/w, or about 25% w/w of the solids in the oral liquid formulation. In some embodiments, lisinopril is present in about 14% w/w to about 16% w/w of the solids in the oral liquid formulation. In some embodiments, lisinopril is present in about 17% w/w to about 19% w/w of the solids in the oral liquid formulation. In some embodiments, lisinopril is present in about 20% w/w to about 22% w/w of the solids in the oral liquid formulation. Sweetener in the Lisinopril Oral Liquid Formulations Sweeteners or sweetening agents include any compounds that provide a sweet taste. This includes natural and synthetic sugars, natural and artificial sweeteners, natural extracts and any material that initiates a sweet sensation in a subject. In some embodiments, a solid/powder sweetener is used in the oral liquid formulation described herein. In other embodiments, a liquid sweetener is used in the oral liquid formulation described herein. Sugars illustratively include glucose, fructose, sucrose, xylitol, tagatose, sucralose, maltitol, isomaltulose, Isomalt™ (hydrogenated isomaltulose), lactitol, sorbitol, erythritol, trehalose, maltodextrin, polydextrose, and the like. Other sweeteners illustratively include glycerin, inulin, erythritol, maltol, acesulfame and salts thereof, e.g., acesulfame potassium, alitame, aspartame, neotame, sodium cyclamate, saccharin and salts thereof, e.g., saccharin sodium or saccharin calcium, neohesperidin dihydrochalcone, stevioside, thaumatin, and the like. Sweeteners can be used in the form of crude or refined products such as hydrogenated starch hydrolysates, maltitol syrup, high fructose corn syrup, etc., and as branded products, e.g., Sweet Am™ liquid (Product Code 918.003-propylene glycol, ethyl alcohol, and proprietary artificial flavor combination, Flavors of North America) and Sweet Am™ powder (Product Code 918.005—maltodextrin, sorbitol, and fructose combination and Product Code 918.010—water, propylene glycol, sorbitol, fructose, and proprietary natural and artificial flavor combination, Flavors of North America), ProSweet™ (1-10% proprietary plant/vegetable extract and 90-99% dextrose combination, Viriginia Dare), Maltisweet™ (maltitol solution, Ingredion), Sorbo™ (sorbitol and sorbitol/xylitol solution, SPI Polyols), Invertose™ (high fructose corn syrup, Ingredion), Rebalance M60 and X60 (sucralose and maltodextrin, Tate and Lyle), and Ora-Sweet® sugar-free flavored syrup (Paddock Laboratories, Inc.). Sweeteners can be used singly or in combinations of two or more. Suitable concentrations of different sweeteners can be selected based on published information, manufacturers' data sheets and by routine testing. In some embodiments, the lisinopril oral liquid formulation described herein comprises a sweetening agent. In some embodiments, the sweetening agent is sucralose. In some embodiments, the sweetening agent is xylitol. In some embodiments, the sweetener is saccharin. In some embodiments, the sweetening agent is xylitol. In some embodiments, xylitol is present in about 140 mg/ml to about 160 mg/ml in the oral liquid formulation. In other embodiments, xylitol is present in about 140 mg/ml, about 141 mg/ml, about, 142 mg/ml, about 143 mg/ml, about 144 mg/ml, about 145 mg/ml, about 146 mg/ml, about 147 mg/ml, about 148 mg/ml, about 149 mg/ml, about 150 mg/ml, about 151 mg/ml, about 152 mg/ml, about 153 mg/ml, about 154 mg/ml, about 155 mg/ml, about 156 mg/ml, about 157 mg/ml, about 158 mg/ml, about 159 mg/ml, or about 160 mg/ml in the oral liquid formulation. In some embodiments, xylitol is present in about 150 mg/ml in the oral liquid formulation. In some embodiments, xylitol is present in about 80% w/w to about 99% w/w of the solids in the oral liquid formulation. In other embodiments, xylitol is present in about 80% w/w, about 81% w/w, about 82% w/w, about 83% w/w, about 84% w/w, about 85% w/w, about 86% w/w, about 87% w/w, about 88% w/w, about 89% w/w, about 90% w/w, about 91% w/w, about 92% w/w, about 93% w/w, about 94% w/w, about 95% w/w, about 96% w/w, about 97% w/w, about 98% w/w, about 99% w/w of the solids in the oral liquid formulation. In some embodiments, xylitol is present in about 96% w/w to about 98% w/w of the solids in the oral liquid formulation. In some embodiments, xylitol is present in about 97% w/w of the solids in the oral liquid formulation. In some embodiments, the sweetening agent is sucralose. In some embodiments, sucralose is present in about 0.5 mg/ml to about 3 mg/ml in the oral liquid formulation. In other embodiments, sucralose is present in about 0.5 mg/ml, about 0.6 mg/ml, about 0.7 mg/ml, about 0.8 mg/ml, about 0.9 mg/ml, about 1 mg/ml, about 1.1 mg/ml, about, 1.2 mg/ml, about 1.3 mg/ml, about 1.4 mg/ml, about 1.5 mg/ml, about 1.6 mg/ml, about 1.7 mg/ml, about 1.8 mg/ml, about 1.9 mg/ml, about 2 mg/ml, about 2.1 mg/ml, about 2.2 mg/ml, about 2.3 mg/ml, about 2.4 mg/ml, about 2.5 mg/ml, about 2.6 mg/ml, about 2.7 mg/ml, about 2.8 mg/ml, about 2.9 mg/ml, or about 3 mg/ml in the oral liquid formulation. In some embodiments, sucralose is present in about 2 mg/ml in the oral liquid formulation. In some embodiments, sucralose is present in about 0.7 mg/mL in the oral liquid formulation. In some embodiments, sucralose is present in about 10% w/w to about 40% w/w of the solids in the oral liquid formulation. In other embodiments, sucralose is present in about 10% w/w, about 10.5% w/w, about 11% w/w, about 11.5% w/w, about 12% w/w, about 12.5% w/w, about 13% w/w, about 13.5% w/w, about 14% w/w, about 14.5% w/w, about 15% w/w, about 15.5% w/w, about 16% w/w, about 16.5% w/w, about 17% w/w, about 17.5% w/w, about 18% w/w, about 18.5% w/w, about 19% w/w, about 19.5% w/w, about 20% w/w, about 20.5% w/w, about 21% w/w, about 21.5% w/w, about 22% w/w, about 22.5% w/w, about 23% w/w, about 23.5% w/w, about 24% w/w, about 24.5% w/w, about 25% w/w, about 25.5% w/w, about 26% w/w, about 26.5% w/w, about 27% w/w, about 27.5% w/w, about 28% w/w, about 28.5% w/w, about 29% w/w, about 29.5% w/w, about 30% w/w, about 30.5% w/w, about 31% w/w, about 31.5% w/w, about 32% w/w, about 32.5% w/w, about 33% w/w, about 33.5% w/w, about 34% w/w, about 34.5% w/w, about 35% w/w, about 35.5% w/w, about 36% w/w, about 36.5% w/w, about 37% w/w, about 37.5% w/w, about 38% w/w, about 38.5% w/w, about 39% w/w, about 39.5% w/w, or about 40% w/w of the solids in the oral liquid formulation. In some embodiments, sucralose is present in about 34% w/w to about 35% w/w of the solids in the oral liquid formulation. In some embodiments, sucralose is present in about 28% w/w to about 30% w/w of the solids in the oral liquid formulation. In some embodiments, sucralose is present in about 12% w/w to about 15% w/w of the solids in the oral liquid formulation. In some embodiments, the sweetening agent is saccharin. In some embodiments, saccharin is present in about 1 mg/ml to about 3 mg/ml in the oral liquid formulation. In other embodiments, saccharin is present in about 1 mg/ml, about 1.1 mg/ml, about, 1.2 mg/ml, about 1.3 mg/ml, about 1.4 mg/ml, about 1.5 mg/ml, about 1.6 mg/ml, about 1.7 mg/ml, about 1.8 mg/ml, about 1.9 mg/ml, about 2 mg/ml, about 2.1 mg/ml, about 2.2 mg/ml, about 2.3 mg/ml, about 2.4 mg/ml, about 2.5 mg/ml, about 2.6 mg/ml, about 2.7 mg/ml, about 2.8 mg/ml, about 2.9 mg/ml, or about 3 mg/ml in the oral liquid formulation. In some embodiments, saccharin is present in about 2 mg/ml in the oral liquid formulation. In some embodiments, saccharin is present in about 1% w/w to about 3% w/w of the solids in the oral liquid formulation. In other embodiments, saccharin is present in about 1% w/w, 1.1% w/w, about 1.2% w/w, 1.3% w/w, about 1.4% w/w, 1.5% w/w, about 1.6% w/w, 1.7% w/w, about 1.8% w/w, 1.9% w/w, about 2% w/w, 2.1% w/w, about 2.2% w/w, 2.3% w/w, about 2.4% w/w, 2.5% w/w, about 2.6% w/w, 2.7% w/w, about 2.8% w/w, 2.9% w/w, or 3% w/w of the solids in the oral liquid formulation. In some embodiments, saccharin is present in about 1.7% w/w to about 1.9% w/w of the solids in the oral liquid formulation. Preservative in the Lisinopril Oral Liquid Formulations Preservatives include anti-microbials, anti-oxidants, and agents that enhance sterility. Exemplary preservatives include ascorbic acid, ascorbyl palmitate, BHA, BHT, citric acid, erythorbic acid, fumaric acid, malic acid, propyl gallate, sodium ascorbate, sodium bisulfate, sodium metabisulfite, sodium sulfite, parabens (such as methylparaben, ethylparaben, propylparaben, butylparaben and their salts), benzoic acid, sodium benzoate, potassium sorbate, vanillin, and the like. In some embodiments, the lisinopril oral liquid formulation described herein comprises a preservative. In some embodiments, the preservative is a paraben and the sweetener is not a sugar (such as, but not limited to glucose, fructose, sucrose, lactose, maltose) or a sugar alcohol (such as, but not limited to xylitol, mannitol, lactitol, maltitol, sorbitol). In some embodiments, the preservative is sodium benzoate. In some embodiments, modulation of the pH is desired to provide the best antimicrobial activity of the preservative, sodium benzoate. In some embodiments, the antimicrobial activity of sodium benzoate drops when the pH is increased above 5. In some embodiments, the pH of the lisinopril oral liquid formulation described herein is less than about 5.1. In some embodiments, the pH of the lisinopril oral liquid formulation described herein is less than about 5. In some embodiments, the pH of the lisinopril oral liquid formulation described herein is between about 4 and about 5. In some embodiments, the pH of the lisinopril oral liquid formulation described herein is about 4, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5, about 5.1, or about 5.2. In some embodiments, sodium benzoate is present in about 0.5 mg/ml to about 1.2 mg/ml in the oral liquid formulation. In other embodiments, sodium benzoate is present in about 0.5 mg/ml, about 0.55 mg/ml, about 0.6 mg/ml, about 0.65 mg/ml, about 0.7 mg/ml, about 0.75 mg/ml, about 0.8 mg/ml, about 0.85 mg/ml, about 0.9 mg/ml, about 0.95 mg/ml, about 1 mg/ml, about 1.05 mg/ml, about 1.1 mg/ml, about 1.15 mg/ml, or about 1.2 mg/ml in the liquid oral formulation. In some embodiments, sodium benzoate is present in about 0.8 mg/ml in the oral liquid formulation. In some embodiments, sodium benzoate is present in about 0.1% w/w to about 5% w/w of the powder formulation. In other embodiments, sodium benzoate is present in about 0.1% w/w, about 0.15% w/w, about 0.2% w/w, about 0.25% w/w, about 0.30% w/w, about 0.35% w/w, about 0.40% w/w, about 0.45% w/w, about 0.50% w/w, about 0.55% w/w, about 0.60% w/w, about 0.65% w/w, about 0.70% w/w, about 0.75% w/w, about 0.80% w/w, about 0.85% w/w, about 0.90% w/w, about 0.95% w/w, about 1% w/w, about 1.5% w/w, about 2% w/w, about 3% w/w, about 3.5% w/w, about 4% w/w, about 4.5% w/w, or about 5% w/w of the powder formulation. In some embodiments, sodium benzoate is present in about 0.4% w/w to about 1.2% w/w of the powder formulation. In some embodiments, sodium benzoate is present in about 0.52% w/w of the powder formulation. In some embodiments, sodium benzoate is present in about 10% w/w to about 17% w/w of the solids in the oral liquid formulation. In other embodiments, sodium benzoate is present in about 10% w/w, about 10.5% w/w, about 11% w/w, about 11.5% w/w, about 12% w/w, about 12.5% w/w, about 13% w/w, about 13.5% w/w, about 14% w/w, about 14.5% w/w, about 15% w/w, about 15.5% w/w, about 16% w/w, about 16.5% w/w, or about 17% w/w of the solids in the oral liquid formulation. In some embodiments, sodium benzoate is present in about 12% w/w to about 17% w/w of the solids in the oral liquid formulation. In some embodiments, sodium benzoate is present in an amount sufficient to provide antimicrobial effectiveness to the lisinopril oral liquid formulation described herein (see table D-1) In some embodiments, the preservative is a paraben. In some embodiments, the preservative is a mixture of parabens. In some embodiments, the paraben or mixture of parabens is present in about 0.1 mg/ml to about 2 mg/ml in the oral liquid formulation. In other embodiments, the paraben or mixture of parabens is present in about 0.1 mg/ml, about 0.2 mg/ml, about 0.3 mg/ml, about 0.4 mg/ml, about 0.5 mg/ml, about 0.6 mg/ml, about 0.7 mg/ml, about 0.8 mg/ml, about 0.9 mg/ml, about 1 mg/ml, about 1.1 mg/ml, about 1.2 mg/ml, about 1.3 mg/ml, about 1.4 mg/ml, or about 1.5 mg/ml, about 1.6 mg/ml, about 1.7 mg/ml, about 1.8 mg/ml, about 1.9 mg/ml, or about 2 mg/ml in the liquid oral formulation. In some embodiments, the paraben or mixture of parabens is present in about 1.6 mg/ml to about 2 mg/ml in the oral liquid formulation. In some embodiments, the paraben or mixture of parabens is present in about 1.6 mg/ml to about 1.8 mg/ml in the oral liquid formulation. In some embodiments, the paraben or mixture of parabens is present in about 0.1 mg/ml to about 0.2 mg/ml in the oral liquid formulation. In some embodiments, the paraben or mixture of parabens is present in about 2% w/w to about 30% w/w of the solids in the oral liquid formulation. In other embodiments, the paraben or mixture of parabens is present in about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w, about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w, about 10% w/w, about 11% w/w, about 12% w/w, about 13% w/w, about 14% w/w, about 15% w/w, about 16% w/w, about 17% w/w, about 18% w/w, about 19% w/w, about 20% w/w, about 21% w/w, about 22% w/w, about 23% w/w, about 24% w/w, about 25% w/w, about 26% w/w, about 27% w/w, about 28% w/w, about 29% w/w, or about 30% w/w of the solids in the oral liquid formulation. In some embodiments, the paraben or mixture of parabens is present in about 2% w/w to about 3% w/w of the solids in the oral liquid formulation. In some embodiments, the paraben or mixture of parabens is present in about 23% w/w to about 26% w/w of the solids in the oral liquid formulation. In some embodiments, the paraben or mixture of parabens is present in about 26% w/w to about 30% w/w of the solids in the oral liquid formulation. Sweetener and Preservative Incompatibility As shown in the examples and in FIG. 2, paraben preservatives (especially methylparaben) can react with selected sugars (glucose, fructose, sucrose, lactose, maltose) and sugar alcohols (xylitol, mannitol, lactitol, maltitol, sorbitol) to form transesterification reaction products. This can be undesirable from a formulation and stability standpoint as the transesterification creates additional degradants. In some embodiments, the lisinopril oral liquid formulation described herein does not comprise a paraben preservative. In further embodiments, the lisinopril oral liquid formulation described herein does not comprise a paraben preservative when the formulation also comprises a sugar or sugar alcohol. pH of Lisinopril Oral Liquid Formulations Buffering agents maintain the pH of the lisinopril oral liquid formulation described herein. Non-limiting examples of buffering agents include, but are not limited to sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium glucomate, aluminum hydroxide, aluminum hydroxide/sodium bicarbonate co-precipitate, mixture of an amino acid and a buffer, a mixture of aluminum glycinate and a buffer, a mixture of an acid salt of an amino acid and a buffer, and a mixture of an alkali salt of an amino acid and a buffer. Additional buffering agents include citric acid, sodium citrate, sodium tartrate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogenphosphate, dipotassium hydrogenphosphate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate, and other calcium salts. Some buffering agents also impart effervescent qualities when a powder is reconstituted in a solution. In some embodiments, the lisinopril oral liquid formulation described herein comprises a buffer. In some embodiments, the buffer in the lisinopril oral liquid formulation described herein comprises citric acid. In some embodiments, the buffer in the lisinopril oral liquid formulation described herein comprises citric acid and sodium citrate. In some embodiments, the buffer in the lisinopril oral liquid formulation described herein comprises phosphoric acid. In some embodiments, the buffer in the lisinopril oral liquid formulation described herein comprises sodium phosphate. In some embodiments, the buffer concentration is between about 5 mM and about 50 mM. In some embodiments, the buffer concentration is between about 5 mM and about 20 mM. In some embodiments, the buffer concentration is about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 11 mM, about 12 mM, about 13 mM, about 14 mM, about 15 mM, about 16 mM, about 17 mM, about 18 mM, about 19 mM, or about 20 mM. In some embodiments, the buffer concentration is about 5 mM. In some embodiments, the buffer concentration is about 10 mM. In some embodiments, the buffer concentration is about 20 mM. In some embodiments, modulation of the pH is desired to provide the lowest impurity profile. In the exemplary stability studies, the main lisinopril degradants are lisinopril diketopiperazine (also known as: Related Compound A) and lisinopril hydrolysate: In some embodiments, the percentage of lisinopril diketopiperazine (Related Compound A) and lisinopril hydrolysate formation is increased when the pH is below 4. (See tables A-2, B-2, C-2, F-2, and FIG. 1). In some embodiments, the pH of the lisinopril oral liquid formulation described herein is less than about 4. In some embodiments, the pH of the lisinopril oral liquid formulation described herein is more than about 5. In some embodiments, the pH of the lisinopril oral liquid formulation described herein is between about 4 and about 5. In some embodiments, the pH of the lisinopril oral liquid formulation described herein is about 4, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, or about 5. In some embodiments, the pH of the lisinopril oral liquid formulation described herein is between about 5 and about 8. In some embodiments, citric acid is present in about 0.50 mg/ml to about 5.5 mg/ml in the oral liquid formulation. In other embodiments, citric acid is present in about 0.50 mg/ml to about 2 mg/mL in the oral liquid formulation. In other embodiments, citric acid is present in about 0.50 mg/ml, about 0.55 mg/ml, about 0.60 mg/ml, about 0.65 mg/ml, about 0.70 mg/ml, about 0.75 mg/ml, about 0.80 mg/ml, about 0.85 mg/ml, about 0.90 mg/ml, about 0.95 mg/ml, about 1.0 mg/ml, about 1.05 mg/ml, about 1.1 mg/ml, about 1.15 mg/ml, about 1.2 mg/ml, 1.25 mg/ml, about 1.30 mg/ml, about 1.35 mg/ml, about 1.4 mg/ml, about 1.45 mg/ml, about 1.5 mg/ml, about 1.55 mg/ml, about 1.6 mg/ml, about 1.65 mg/ml, about 1.7 mg/ml, about 1.75 mg/ml, about 1.80 mg/ml, about 1.85 mg/ml, about 1.9 mg/ml, about 1.95 mg/ml, or about 2 mg/ml in the oral liquid formulation. In some embodiments, citric acid is present in about 0.86 mg/ml in the oral liquid formulation. In some embodiments, citric acid is present in about 1.92 mg/ml in the oral liquid formulation. In some embodiments, citric acid is present in about 5.5 mg/ml in the oral liquid formulation. In some embodiments, citric acid is present in about 0.1% w/w to about 5% w/w of the solids in the oral liquid formulation. In other embodiments, citric acid is present in about 0.10% w/w, about 0.15% w/w, about 0.20% w/w, about 0.25% w/w, about 0.30% w/w, about 0.35% w/w, about 0.40% w/w, about 0.45% w/w, about 0.50% w/w, about 0.55% w/w, about 0.60% w/w, about 0.65% w/w, about 0.70% w/w, about 0.75% w/w, about 0.80% w/w, about 0.85% w/w, about 0.90% w/w, about 0.95% w/w, about 1% w/w, about 1.5% w/w, about 2% w/w, about 2.5% w/w, about 3% w/w, about 3.5% w/w, about 4% w/w, about 4.5% w/w, or about 5% w/w of the solids in the oral liquid formulation. In some embodiments, citric acid is present in about 0.55% w/w the solids in the oral liquid formulation. In some embodiments, citric acid is present in about 15% w/w to about 35% w/w of the powder formulation. In other embodiments, citric acid is present in about 15% w/w, about 15.5% w/w, about 16 w/w, about 16.5% w/w, about 17% w/w, about 17.5% w/w, about 18% w/w, about 18.5% w/w, about 19% w/w, about 19.5% w/w, about 20% w/w, about 20.5% w/w, about 21% w/w, about 21.5% w/w, about 22% w/w, about 22.5% w/w, about 23% w/w, about 23.5% w/w, about 24% w/w, about 24.5% w/w, about 25% w/w, about 25.5% w/w, about 26% w/w, about 26.5% w/w, about 27% w/w, about 27.5% w/w, about 28% w/w, about 28.5% w/w, about 29% w/w, about 29.5% w/w, about 30% w/w, about 30.5% w/w, about 31% w/w, about 31.5% w/w, about 32% w/w, about 32.5% w/w, about 33% w/w, about 33.5% w/w, about 34% w/w, about 34.5% w/w, or about 35% w/w of the solids in the oral liquid formulation. In some embodiments, citric acid is present in about 0.55% w/w the solids in the oral liquid formulation. In some embodiments, sodium citrate is present in about 1.2 mg/ml to about 8.8 mg/ml in the oral liquid formulation. In other embodiments, sodium citrate is present in about 1.2 mg/ml to about 1.7 mg/mL in the oral liquid formulation. In other embodiments, sodium citrate is present in about 1.2 mg/ml, about 1.25 mg/ml, about 1.30 mg/ml, about 1.35 mg/ml, about 1.40 mg/ml, about 1.45 mg/ml, about 1.50 mg/ml, about 1.55 mg/ml, about 1.60 mg/ml, about 1.65 mg/ml, or about 1.7 mg/ml in the oral liquid formulation. In some embodiments, sodium citrate is present in about 1.44 mg/ml in the oral liquid formulation. In some embodiments, sodium citrate is present in about 8.8 mg/ml in the oral liquid formulation. In some embodiments, sodium citrate is present in about 0.1% w/w to about 5% w/w of the solids in the oral liquid formulation. In other embodiments, citric acid is present in about 0.10% w/w, about 0.15% w/w, about 0.20% w/w, about 0.25% w/w, about 0.30% w/w, about 0.35% w/w, about 0.40% w/w, about 0.45% w/w, about 0.50% w/w, about 0.55% w/w, about 0.60% w/w, about 0.65% w/w, about 0.70% w/w, about 0.75% w/w, about 0.80% w/w, about 0.85% w/w, about 0.90% w/w, about 0.95% w/w, about 1% w/w, about 1.5% w/w, about 2% w/w, about 2.5% w/w, about 3% w/w, about 3.5% w/w, about 4% w/w, about 4.5% w/w, or about 5% w/w of the solids in the oral liquid formulation. In some embodiments, sodium citrate is present in about 0.93% w/w of the solids in the oral liquid formulation. In other embodiments, sodium citrate is present in about 25% w/w to about 35% w/w of the solids in the oral liquid formulation. In other embodiments, citric acid is present in about 25% w/w, about 25.5% w/w, about 26% w/w, about 26.5% w/w, about 27% w/w, about 27.5% w/w, about 28% w/w, about 28.5% w/w, about 29% w/w, about 29.5% w/w, or about 30% w/w, about 30.5% w/w, about 31% w/w, about 31.5% w/w, about 32% w/w, about 32.5% w/w, about 33% w/w, about 33.5% w/w, about 34% w/w, about 34.5% w/w, or about 35% w/w of the solids in the oral liquid formulation. In some embodiments, sodium citrate is present in about 30% w/w of the solids in the oral liquid formulation. In other embodiments, sodium citrate is not added to the formulation. Additional Excipients In further embodiments, the lisinopril oral liquid formulation described herein comprises additional excipients including, but not limited to, glidants, flavoring agents, coloring agents and thickeners. Additional excipients such as bulking agents, tonicity agents and chelating agents are within the scope of the embodiments. Glidants are substances that improve flowability of a powder. Suitable glidants include, but are not limited to, calcium phosphate tribasic, calcium silicate, cellulose (powdered), colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, silicon dioxide, starch, talc and the like. In some embodiments, the lisinopril powder formulations described herein comprise a glidant. In another embodiment, the lisinopril oral liquid formulation described herein comprises a flavoring agent or flavorant to enhance the taste or aroma of the formulation in liquid form. Suitable natural or synthetic flavoring agents can be selected from standard reference books, for example Fenaroli's Handbook of Flavor Ingredients, 3rd edition (1995). Non-limiting examples of suitable natural flavors, some of which can readily be simulated with synthetic agents or combinations thereof, include almond, anise, apple, apricot, bergamot, blackberry, blackcurrant, blueberry, cacao, caramel, cherry, cinnamon, clove, coffee, coriander, cranberry, cumin, dill, eucalyptus, fennel, fig, ginger, grape, grapefruit, guava, hop, lemon, licorice, lime, malt, mandarin, molasses, nutmeg, mixed berry, orange, peach, pear, peppermint, pineapple, raspberry, rose, spearmint, strawberry, tangerine, tea, vanilla, wintergreen, etc. Also useful, particularly where the formulation is intended primarily for pediatric use, is tutti-frutti or bubblegum flavor, a compounded flavoring agent based on fruit flavors. Presently preferred flavoring agents include anise, cinnamon, cacao, orange, peppermint, cherry (in particular wild cherry), grape, bubblegum, vanilla, and mixed berry. Flavoring agents can be used singly or in combinations of two or more. In further embodiments, the lisinopril oral liquid formulation described herein comprises a coloring agent for identity and/or aesthetic purposes. Suitable coloring agents illustratively include FD&C Red No. 3, FD&C Red No. 20, FD&C Red No. 40, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, caramel, ferric oxide and mixtures thereof. In further embodiments, the lisinopril oral liquid formulation described herein comprises a thickener. Thickeners impart viscosity or weight to the resultant liquid forms from the lisinopril formulation described herein. Exemplary thickeners include dextrin, cellulose derivatives (ethylcellulose, hydroxyethyl cellulose, methylcellulose, hypromellose, and the like) starches, pectin, polyethylene glycol, polyethylene oxide, trehalose and certain gums (xanthan gum, locust bean gum, etc.). In certain embodiments, the lisinopril oral liquid formulations comprise a thickener. Additional excipients are contemplated in the lisinopril oral liquid formulation embodiments. These additional excipients are selected based on function and compatibility with the lisinopril oral liquid formulations described herein and may be found, for example in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, (Easton, Pa.: Mack Publishing Co 1975); Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms (New York, N.Y.: Marcel Decker 1980); and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed (Lippincott Williams & Wilkins 1999), herein incorporated by reference in their entirety. Preparation of Lisinopril Oral Liquid Formulation Preparation of the lisinopril oral liquid formulation described herein includes any known pharmaceutical method. In one embodiment, the lisinopril oral liquid formulation described herein is prepared by dissolving the buffer, the preservative, lisinopril, and the sweetener in water and adjusting the pH as needed with sodium hydroxide or hydrochloric acid. In one embodiment, the oral lisinopril oral liquid formulation described herein is prepared by dissolving citric acid anhydrous, sodium citrate anhydrous, sodium benzoate, lisinopril dihydrate, and xylitol in water and adjusting the pH as needed with sodium hydroxide or hydrochloric acid. In some embodiments, the order of addition does not matter. In some embodiments, the lisinopril dissolves slightly slower if added after the xylitol. In some embodiments, the pH does not need to be adjusted with sodium hydroxide or hydrochloric acid. Provided herein is a process for preparing a stable oral liquid formulation comprising lisinopril, xylitol, a buffer, and sodium benzoate, the process which comprises the step of adding about 0.86 mg/ml anhydrous citric acid, about 1.44 mg/ml anhydrous sodium citrate anhydrous, about 0.80 mg/ml sodium benzoate, about 1.09 mg/ml lisinopril dihydrate, and about 150 mg/ml xylitol to water; adjusting the volume to the desired volume by adding more water; and adjusting the pH to 4.9 by adding sodium hydroxide or hydrochloric acid. Stability The main lisinopril degradants are lisinopril diketopiperazine (also known as: Related Compound A) and lisinopril hydrolysate. The lisinopril oral liquid formulations described herein are stable in various storage conditions including refrigerated, ambient and accelerated conditions. Stable as used herein refer to lisinopril oral liquid formulations having about 95% or greater of the initial lisinopril amount and about 5% w/w or less total impurities or related substances at the end of a given storage period. The percentage of impurities is calculated from the amount of impurities relative to the amount of lisinopril. Stability is assessed by HPLC or any other known testing method. In some embodiments, the stable lisinopril oral liquid formulations have about 5% w/w, about 4% w/w, about 3% w/w, about 2.5% w/w, about 2% w/w, about 1.5% w/w, about 1% w/w, or about 0.5% w/w total impurities or related substances. In other embodiments, the stable lisinopril oral liquid formulations have about 5% w/w total impurities or related substances. In yet other embodiments, the stable lisinopril oral liquid formulations have about 4% w/w total impurities or related substances. In yet other embodiments, the stable lisinopril oral liquid formulations have about 3% w/w total impurities or related substances. In yet other embodiments, the stable lisinopril oral liquid formulations have about 2% w/w total impurities or related substances. In yet other embodiments, the stable lisinopril oral liquid formulations have about 1% w/w total impurities or related substances. At refrigerated and ambient conditions, the lisinopril oral liquid formulations described herein are stable for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, at least 30 months and at least 36 months. At accelerated conditions, the lisinopril oral liquid formulations described herein are stable for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months or at least 12 months. Accelerated conditions include temperature and/or relative humidity (RH) that are above ambient levels (e.g. 25±5° C.; 55±10% RH). In some instances, an accelerated condition is at about 30° C., about 35° C., about 40° C., about 45° C., about 50° C., about 55° C. or about 60° C. In other instances, an accelerated condition is above 65% RH, about 70% RH, about 75% RH or about 80% RH. In further instances, an accelerated condition is about 40° C. or 60° C. at ambient humidity. In yet further instances, an accelerated condition is about 40° C. at 75±5% RH humidity. Provided herein are various embodiments of lisinopril oral liquid formulations. In one aspect, the lisinopril oral liquid formulation comprises (i) lisinopril or a pharmaceutically acceptable salt or solvate thereof, (ii) a sweetener that is xylitol, (iii) a buffer comprising citric acid (iv) a preservative that is sodium benzoate, and (v) water; wherein the pH of the formulation is between about 4 and about 5; and wherein the formulation is stable at about 25±5° C. for at least 12 months. In some embodiments, the buffer further comprises sodium citrate. In one aspect, the lisinopril oral liquid formulation comprises (i) about 1 mg/ml lisinopril or a pharmaceutically acceptable salt or solvate thereof, (ii) about 150 mg/ml of a sweetener that is xylitol, (iii) a buffer comprising about 0.86 mg/ml citric acid, (iv) about 0.8 mg/ml of a preservative that is sodium benzoate; and (v) water; wherein the pH of the formulation is between about 4 and about 5; and wherein the formulation is stable at about 25±5° C. for at least 12 months. In some embodiments, the buffer further comprises about 1.44 mg/ml sodium citrate. In one aspect, the lisinopril oral liquid formulation comprises (i) lisinopril or a pharmaceutically acceptable salt or solvate thereof, (ii) a sweetener that is sucralose, (iii) a buffer comprising citric acid, (iv) a preservative that is sodium benzoate; and (v) water wherein the formulation is stable at about 25±5° C. for at least 12 months. In one aspect, the lisinopril oral liquid formulation comprises (i) about 1 mg/ml lisinopril or a pharmaceutically acceptable salt or solvate thereof, (ii) about 2 mg/ml of a sweetener that is sucralose, (iii) a buffer comprising about 1.92 mg/ml citric acid, (iv) about 0.8 mg/ml of a preservative that is sodium benzoate; and (v) water wherein the formulation is stable at about 25±5° C. for at least 12 months. In one aspect, the lisinopril oral liquid formulation comprises (i) about 1 mg/ml lisinopril or a pharmaceutically acceptable salt or solvate thereof, (ii) about 0.7 mg/ml of a sweetener that is sucralose, (iii) a buffer comprising about 1.92 mg/ml citric acid, (iv) about 0.8 mg/ml of a preservative that is sodium benzoate; and (v) water wherein the formulation is stable at about 25±5° C. for at least 12 months. In one aspect, the lisinopril oral liquid formulation comprises (i) lisinopril or a pharmaceutically acceptable salt or solvate thereof, (ii) of a sweetener that is sucralose, (iii) a buffer comprising citric acid, (iv) a preservative that is methyl paraben, (v) a preservative that is propylparaben, and (vi) water; wherein the formulation is stable at about 25±5° C. for at least 12 months. In one aspect, the lisinopril oral liquid formulation comprises (i) about 1 mg/ml lisinopril or a pharmaceutically acceptable salt or solvate thereof, (ii) about 2 mg/ml of a sweetener that is sucralose, (iii) a buffer comprising about 1.92 mg/ml citric acid, (iv) about 1.72 mg/ml of a preservative that is methyl paraben sodium, (v) about 0.17 mg/mL of a preservative that is propylparaben sodium, and (vi) water; wherein the formulation is stable at about 25±5° C. for at least 12 months. In one aspect, the lisinopril oral liquid formulation comprises (i) lisinopril or a pharmaceutically acceptable salt or solvate thereof, (ii) a sweetener that is xylitol, (iii) a buffer comprising citric acid, (iv) a preservative that is sodium benzoate; and (v) water; wherein the formulation is stable at about 25±5° C. for at least 12 months. In one aspect, the lisinopril oral liquid formulation comprises (i) about 1 mg/ml lisinopril or a pharmaceutically acceptable salt or solvate thereof, (ii) about 150 mg/ml of a sweetener that is xylitol, (iii) a buffer comprising about 1.92 mg/ml citric acid, (iv) about 0.8 mg/ml of a preservative that is sodium benzoate; and (v) water; wherein the formulation is stable at about 25±5° C. for at least 12 months. In one aspect, the lisinopril oral liquid formulation, comprises (i) lisinopril or a pharmaceutically acceptable salt or solvate thereof, (ii) a sweetener that is xylitol, (iii) a buffer comprising citric acid, (iv) a preservative that is methyl paraben, (v) a preservative that is propylparaben; and (vi) water; wherein the formulation is stable at about 25±5° C. for at least 12 months. In one aspect, the lisinopril oral liquid formulation comprises (i) about 1 mg/ml lisinopril or a pharmaceutically acceptable salt or solvate thereof, (ii) about 150 mg/ml of a sweetener that is xylitol, (iii) a buffer comprising about 1.92 mg/ml citric acid, (iv) about 1.72 mg/ml of a preservative that is methyl paraben sodium, (v) about 0.17 mg/mL of a preservative that is propylparaben sodium; and (vi) water; wherein the formulation is stable at about 25±5° C. for at least 12 months. In one aspect, the lisinopril oral liquid formulation comprises (i) lisinopril or a pharmaceutically acceptable salt or solvate thereof, (ii) a sweetener that is xylitol, (iii) a second sweetener that is sucralose (iv) a buffer comprising citric acid, (v) a preservative that is methyl paraben, (vi) a preservative that is propylparaben; and (vii) water; wherein the formulation is stable at about 25±5° C. for at least 12 months. In one aspect, the lisinopril oral liquid formulation comprises (i) about 1 mg/ml lisinopril or a pharmaceutically acceptable salt or solvate thereof, (ii) about 100 mg/ml of a sweetener that is xylitol, (iii) about 2 mg/ml of a second sweetener that is sucralose (iv) a buffer comprising about 1.92 mg/ml citric acid, (v) about 1.72 mg/ml of a preservative that is methyl paraben sodium, (vi) about 0.17 mg/mL of a preservative that is propylparaben sodium; and (vii) water; wherein the formulation is stable at about 25±5° C. for at least 12 months. In one aspect, the lisinopril oral liquid formulation comprises (i) lisinopril or a pharmaceutically acceptable salt or solvate thereof, (ii) a sweetener that is sucralose, (iii) a buffer comprising sodium phosphate, (iv) a preservative that is methyl paraben, (v) a preservative that is propylparaben, and (vi) water; wherein the formulation is stable at about 25±5° C. for at least 12 months. In one aspect, the lisinopril oral liquid formulation comprises (i) about 1 mg/ml lisinopril or a pharmaceutically acceptable salt or solvate thereof, (ii) about 0.7 mg/ml of a sweetener that is sucralose, (iii) a buffer comprising about 2.4 mg/ml monobasic sodium phosphate, (iv) about 1.72 mg/ml of a preservative that is methyl paraben sodium, (v) about 0.225 mg/mL of a preservative that is propylparaben sodium, and (vi) water; wherein the formulation is stable at about 25±5° C. for at least 12 months. Lisinopril Powder Formulations In another aspect, lisinopril oral liquid formulations described herein are prepared from the reconstitution of a lisinopril powder formulation. In some embodiments, the lisinopril powder formulation comprising lisinopril, a sweetener, a preservative, and optionally an excipient is dissolved in water, a buffer, other aqueous solvent, or a liquid to form a lisinopril oral liquid formulation. In one embodiment, the sweetening agent is xylitol. In one embodiment, the sweetener is mannitol. In one embodiment, the sweetening agent is sucralose. In another embodiment, the preservative is sodium benzoate. In one embodiment, the preservative is a paraben preservative. In one aspect, the lisinopril powder formulation described herein comprises lisinopril, xylitol, and sodium benzoate. In some embodiments, the lisinopril powder formulation herein further comprises a flavoring agent. In some embodiments, the lisinopril powder formulation herein further comprises one or more buffering agents. In some embodiments, lisinopril is present in about 0.5% w/w to about 5% w/w of the powder formulation. In other embodiments, Lisinopril is present in about 0.5% w/w, about 0.55% w/w, about 0.6% w/w, about 0.65% w/w, about 0.7% w/w, about 0.75% w/w, about 0.8% w/w, about 0.85% w/w, about 0.9% w/w, about 0.95% w/w, about 1% w/w, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about 2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w, about 3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6% w/w, about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, or about 5% w/w of the powder formulation. In some embodiments, lisinopril is present in about 0.5% w/w to about 1% w/w of the powder formulation. In some embodiments, lisinopril is present in about 0.6% w/w to about 0.8% w/w of the powder formulation. In some embodiments, lisinopril is present in about 0.7% w/w of the powder formulation. In some embodiments, lisinopril is present in about 10% w/w to about 20% w/w of the powder formulation. In other embodiments, lisinopril is present in about 10% w/w, about 10.5% w/w, about 11 w/w, about 11.5% w/w, about 12% w/w, about 12.5% w/w, about 13% w/w, about 13.5% w/w, about 14% w/w, about 14.5% w/w, about 15% w/w, about 15.5% w/w, about 16% w/w, about 16.5% w/w, about 17% w/w, about 17.5% w/w, about 18% w/w, about 18.5% w/w, about 19% w/w, about 19.5% w/w, or about 20% w/w of the powder formulation. In some embodiments, lisinopril is present in about 14% w/w to about 16% w/w of the powder formulation. In some embodiments, lisinopril is present in about 17% w/w to about 19% w/w of the powder formulation. Various amounts and concentrations of other components (sweeteners, buffers, preservatives, and the like) in the lisinopril powder formulations are found in the previous section describing the amounts and concentrations for the analogous lisinopril oral liquid formulations. For example, in some embodiments where sucralose is present in about 20% w/w to about 40% w/w of the solids in the oral liquid formulation; in an analogous lisinopril powder formulation, sucralose would be about 20% w/w to about 40% w/w in the powder formulation. In some embodiments where sodium benzoate is present in about 10% w/w to about 15% w/w of the solids in the oral liquid formulation, in an analogous lisinopril powder formulation sodium benzoate is present in about 10% w/w to about 15% w/w in the powder formulation. Liquid vehicles suitable for the lisinopril powder formulations to be reconstituted into an oral solution described herein are selected for a particular oral liquid formulation (solution, suspension, etc.) as well as other qualities such as clarity, toxicity, viscosity, compatibility with excipients, chemical inertness, palatability, odor, color and economy. Exemplary liquid vehicles include water, ethyl alcohol, glycerin, propylene glycol, syrup (sugar or other sweetener based, e.g., Ora-Sweet® SF sugar-free flavored syrup), juices (apple, grape, orange, cranberry, cherry, tomato and the like), other beverages (tea, coffee, soft drinks, milk and the like), oils (olive, soybean, corn, mineral, castor and the like), and combinations or mixtures thereof. Certain liquid vehicles, e.g., oil and water, can be combined together to form emulsions. In some embodiments, water is used for as a vehicle for a lisinopril oral liquid formulation. In other embodiments, a syrup is used for as a vehicle for a lisinopril oral liquid formulation. In yet other embodiments, a juice is used for as a vehicle for a lisinopril oral liquid formulation. Buffering agents maintain the pH of the liquid lisinopril formulation. Non-limiting examples of buffering agents include, but are not limited to sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate, aluminum hydroxide, aluminum hydroxide/sodium bicarbonate co precipitate, mixture of an amino acid and a buffer, a mixture of aluminum glycinate and a buffer, a mixture of an acid salt of an amino acid and a buffer, and a mixture of an alkali salt of an amino acid and a buffer. Additional buffering agents include citric acid, sodium citrate, sodium tartarate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogenphosphate, dipotassium hydrogenphosphate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate, and other calcium salts. Some buffering agents also impart effervescent qualities when a powder is reconstituted in a solution. In some embodiments, the reconstituted oral liquid formulation comprises a buffer. In some embodiments, the buffer comprises citric acid and sodium citrate. In further embodiments, the lisinopril powder formulation described herein comprises additional excipients including, but not limited to, glidants, flavoring agents, coloring agents and thickeners. Additional excipients such as bulking agents, tonicity agents and chelating agents are within the scope of the embodiments. Glidants are substances that improve flowability of a powder. Suitable glidants include, but are not limited to, calcium phosphate tribasic, calcium silicate, cellulose (powdered), colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, silicon dioxide, starch, talc and the like. In some embodiments, the lisinopril powder formulations described herein comprise a glidant. In another embodiment, the lisinopril powder formulation described herein comprises a flavoring agent or flavorant to enhance the taste or aroma of the formulation in liquid form. Suitable natural or synthetic flavoring agents can be selected from standard reference books, for example Fenaroli's Handbook of Flavor Ingredients, 3rd edition (1995). Non-limiting examples of suitable natural flavors, some of which can readily be simulated with synthetic agents or combinations thereof, include almond, anise, apple, apricot, bergamot, blackberry, blackcurrant, blueberry, cacao, caramel, cherry, cinnamon, clove, coffee, coriander, cranberry, cumin, dill, eucalyptus, fennel, fig, ginger, grape, grapefruit, guava, hop, lemon, licorice, lime, malt, mandarin, molasses, nutmeg, mixed berry, orange, peach, pear, peppermint, pineapple, raspberry, rose, spearmint, strawberry, tangerine, tea, vanilla, wintergreen, etc. Also useful, particularly where the formulation is intended primarily for pediatric use, is tutti-frutti or bubblegum flavor, a compounded flavoring agent based on fruit flavors. Presently preferred flavoring agents include anise, cinnamon, cacao, orange, peppermint, cherry (in particular wild cherry), grape, bubblegum, vanilla, and mixed berry. Flavoring agents can be used singly or in combinations of two or more. In further embodiments, the lisinopril powder formulation described herein comprises a coloring agent for identity and/or aesthetic purposes. Suitable coloring agents illustratively include FD&C Red No. 3, FD&C Red No. 20, FD&C Red No. 40, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, caramel, ferric oxide and mixtures thereof. In further embodiments, the lisinopril powder formulation described herein comprises a thickener. Thickeners impart viscosity or weight to the resultant liquid forms from the lisinopril formulation described herein. Exemplary thickeners include dextrin, cellulose derivatives (ethylcellulose, hydroxyethyl cellulose, methylcellulose, hypromellose, and the like) starches, pectin, polyethylene glycol, polyethylene oxide, trehalose and certain gums (xanthan gum, locust bean gum, etc.). Additional excipients are contemplated in the lisinopril powder formulation embodiments. These additional excipients are selected based on function and compatibility with the lisinopril powder formulation described herein and may be found, for example in Remington: The Science and Practice of Pharmacy, Nineteeth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, (Easton, Pa.: Mack Publishing Co 1975); Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms (New York, N.Y.: Marcel Decker 1980); and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed (Lippincott Williams & Wilkins 1999), herein incorporated by reference in their entirety. In some embodiments, the lisinopril oral liquid formulation prepared from the powder formulations described herein are homogenous. Homogenous liquids as used herein refer to those liquids that are uniform in appearance, identity, consistency and drug concentration per volume. Non-homogenous liquids include such liquids that have varied coloring, viscosity and/or aggregation of solid particulates, as well as non-uniform drug concentration in a given unit volume. Homogeneity in liquids are assessed by qualitative identification or appearance tests and/or quantitative HPLC testing or the like. The mixing methods and excipients described herein are selected to impart a homogenous quality to a resultant lisinopril oral liquid formulation. Mixing methods encompass any type of mixing that result in a homogenous lisinopril oral liquid formulation. In some embodiments, a quantity of a lisinopril powder formulation is added to a liquid vehicle and then mixed by a stirring, shaking, swirling, agitation element or a combination thereof. In certain instances, a fraction of a lisinopril powder formulation (i.e., one-half, one-third, one-fourth, etc.) is added to a liquid vehicle, mixed by stirring, shaking, swirling, agitation or a combination thereof, and the subsequent powder fraction(s) is added and mixed. In other embodiments, a liquid vehicle is added to a lisinopril powder formulation in a container, for example, a bottle, vial, bag, beaker, syringe, or the like. The container is then mixed by stirring, shaking, swirling, agitation, inversion or a combination thereof. In certain instances, a fractional volume of the liquid vehicle (i.e., one-half, one-third, one-fourth volume, etc.) is added to a lisinopril powder formulation in a container, mixed by stirring, shaking, swirling, agitation, inversion or a combination thereof; and the subsequent liquid fraction(s) is added and mixed. In certain instances, a one-half fractional volume of the liquid vehicle is added to a lisinopril powder formulation in a container and mixing by shaking; the other one-half fractional volume of the liquid vehicle is then subsequently added and mixed. In any of the above embodiments, mixing (i.e., stirring, shaking, swirling, agitation, inversion or a combination thereof) occurs for a certain time intervals such as about 10 seconds, about 20 seconds, about 30 seconds, about 45 seconds, about 60 seconds, about 90 seconds, about 120 seconds, about 2.5 minutes, about 3 minutes, about 3.5 minutes, about 4 minutes, or about 5 minutes. In embodiments, where there are two or more mixing steps, the time intervals for each mixing can be the same (e.g., 2×10 seconds) or different (e.g., 10 seconds for first mixing and 20 seconds for second mixing) In any of the above embodiments, a lisinopril oral liquid formulation is allowed to stand for a period of time such as about 10 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours or about 2 hours, to allow any air bubbles resultant from any of the mixing methods to dissipate. Stability of Lisinopril Powder Formulations The lisinopril powder formulations described herein are stable in various storage conditions including refrigerated, ambient and accelerated conditions. Stable as used herein refer to lisinopril powder formulations having about 95% or greater of the initial lisinopril amount and 5% w/w or less total impurities or related substances at the end of a given storage period. The percentage of impurities is calculated from the amount of impurities relative to the amount of lisinopril. Stability is assessed by HPLC or any other known testing method. In some embodiments, the stable lisinopril powder formulations have about 5% w/w, about 4% w/w, about 3% w/w, about 2.5% w/w, about 2% w/w, about 1.5% w/w, about 1% w/w, or about 0.5% w/w total impurities or related substances. In other embodiments, the stable lisinopril powder formulations have about 5% w/w total impurities or related substances. In yet other embodiments, the stable lisinopril powder formulations have about 4% w/w total impurities or related substances. In yet other embodiments, the stable lisinopril powder formulations have about 3% w/w total impurities or related substances. In yet other embodiments, the stable lisinopril powder formulations have about 2% w/w total impurities or related substances. In yet other embodiments, the stable lisinopril powder formulations have about 1% w/w total impurities or related substances. At refrigerated and ambient conditions, in some embodiments, the lisinopril powder formulations described herein are stable for at least 1 week, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 16 weeks, 20 weeks, at least 24 weeks, at least 30 weeks, or at least 36 weeks. At accelerated conditions, in some embodiments, the lisinopril powder formulations described herein are stable for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks or at least 12 weeks. Accelerated conditions include temperature and/or relative humidity (RH) that are above ambient levels (e.g. 25±4° C.; 55±10% RH). In some instances, an accelerated condition is at about 30° C., about 35° C., about 40° C., about 45° C., about 50° C., about 55° C. or about 60° C. In other instances, an accelerated condition is above 65% RH, about 70% RH, about 75% RH or about 80% RH. In further instances, an accelerated condition is about 40° C. or 60° C. at ambient humidity. In yet further instances, an accelerated condition is about 40° C. at 75±5% RH humidity. Kits and Articles of Manufacture For the lisinopril powder and liquid formulations described herein, kits and articles of manufacture are also described. Such kits can comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein including a lisinopril powder or liquid formulation. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers can be formed from a variety of materials such as glass or plastic. A kit will typically may comprise one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user standpoint for a lisinopril powder or liquid formulation described herein. Non-limiting examples of such materials include, but not limited to, buffers, diluents, filters, needles, syringes, syringe adapter, carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and package inserts with instructions for use associated with a lisinopril powder or liquid formulation. A set of instructions will also typically be included. A label can be on or associated with the container. A label can be on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label can be associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. A label can be used to indicate that the contents are to be used for a specific therapeutic application. The label can also indicate directions for use of the contents, such as in the methods described herein. Methods Provided herein, in one aspect, are methods of treatment comprising administration of the lisinopril oral liquid formulations described herein to a subject. In some embodiments, the lisinopril oral liquid formulations described herein treat hypertension in a subject. Hypertension as used herein includes both primary (essential) hypertension or secondary hypertension. In certain instances, hypertension is classified in cases when blood pressure values are greater than or equal to 140/90 (systolic/diastolic) mm Hg in a subject. In certain instances, the lisinopril oral liquid formulations described herein treat a subject having a blood pressure value greater than or equal to 140/90 mm Hg. In certain instances, the lisinopril oral liquid formulations described herein treat primary (essential) hypertension in a subject. In other instances, the lisinopril oral liquid formulations described herein treat secondary hypertension in a subject. In other embodiments, the lisinopril oral liquid formulations described herein treat prehypertension in a subject. Prehypertension as used herein refers to cases where a subject's blood pressure is elevated above normal but not to the level considered to be hypertension. In some instances, prehypertension is classified in cases when blood pressure values are 120-139/80-89 mm Hg. In certain instances, the lisinopril oral liquid formulations described herein treat a subject having a blood pressure value of 120-139/80-89 mm Hg. In yet other embodiments, the lisinopril oral liquid formulations described herein are prophylactically administered to subjects suspected of having, predisposed to, or at risk of developing hypertension. In some embodiments, the administration of lisinopril oral liquid formulations described herein allow for early intervention prior to onset of hypertension. In certain embodiments, upon detection of a biomarker, environmental, genetic factor, or other marker, the lisinopril oral liquid formulations described herein are prophylactically administered to subjects. In further embodiments, the lisinopril oral liquid formulations described herein treat heart failure (e.g., symptomatic congestive), asymptomatic left ventricular dysfunction, myocardial infarction, diabetic nephropathy and chronic renal failure. In certain instances, the lisinopril oral liquid formulations described herein is indicated as adjunctive therapy in the management of heart failure in patients who are not responding adequately to diuretics and digitalis. In certain instances, the lisinopril oral liquid formulations described herein treat symptomatic congestive heart failure. In other instances, the lisinopril oral liquid formulations described herein treat asymptomatic left ventricular dysfunction. In further instances, the lisinopril oral liquid formulations described herein treat myocardial infarction. In further instances, the lisinopril oral liquid formulations described herein treat hemodynamically stable patients within 24 h of acute myocardial infarction. In yet further instances, the lisinopril oral liquid formulations described herein treat diabetic nephropathy. In yet further instances, the lisinopril oral liquid formulations described herein treat chronic renal failure. In yet further instances, the lisinopril oral liquid formulations described herein is used in preventing renal and retinal complications of diabetes. Dosing In one aspect, the lisinopril oral liquid formulations are used for the treatment of diseases and conditions described herein. In addition, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of lisinopril oral liquid formulations in therapeutically effective amounts to said subject. Dosages of lisinopril oral liquid formulations described can be determined by any suitable method. Maximum tolerated doses (MTD) and maximum response doses (MRD) for lisinopril can be determined via established animal and human experimental protocols as well as in the examples described herein. For example, toxicity and therapeutic efficacy of lisinopril can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50. Lisinopril dosages exhibiting high therapeutic indices are of interest. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. Additional relative dosages, represented as a percent of maximal response or of maximum tolerated dose, are readily obtained via the protocols. In some embodiments, the amount of a given lisinopril oral liquid formulation that corresponds to such an amount varies depending upon factors such as the particular lisinopril salt or solvate, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but can nevertheless be determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the liquid formulation type, the condition being treated, and the subject or host being treated. In some embodiments, the lisinopril oral liquid formulations described herein are provided in a dose per day from about 0.01 mg to 100 mg, from about 0.1 mg to about 80 mg, from about 1 to about 60, from about 2 mg to about 40 mg of lisinopril. In certain embodiments, the lisinopril oral liquid formulations described herein are provided in a daily dose of about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.4 mg, about 0.6 mg, about 0.8 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 76, mg, about 80 mg, about 85 mg, about 90 mg or about 100 mg, or any range derivable therein. In certain instances, the lisinopril oral liquid formulations described herein are provided in a dose per day of about 1 mg. In certain instances, the lisinopril oral liquid formulations described herein are provided in a dose per day of about 2 mg. In certain instances, the lisinopril oral liquid formulations described herein are provided in a dose per day of about 3 mg. In certain instances, the lisinopril oral liquid formulations described herein are provided in a dose per day of about 4 mg. In certain instances, the lisinopril oral liquid formulations described herein are provided in a dose per day of about 5 mg. In certain instances, the lisinopril oral liquid formulations described herein are provided in a dose per day of about 6 mg. In certain instances, the lisinopril oral liquid formulations described herein are provided in a dose per day of about 7 mg. In certain instances, the lisinopril oral liquid formulations described herein are provided in a dose per day of about 8 mg. In certain instances, the lisinopril oral liquid formulations described herein are provided in a dose per day of about 9 mg. In certain instances, the lisinopril oral liquid formulations described herein are provided in a dose per day of about 10 mg. In certain instances, the lisinopril oral liquid formulations described herein are provided in a dose per day of about 11 mg. In certain instances, the lisinopril oral liquid formulations described herein are provided in a dose per day of about 12 mg. The dose per day described herein can be given once per day or multiple times per day in the form of sub-doses given b.i.d., t.i.d., q.i.d., or the like where the number of sub-doses equal the dose per day. In further embodiments, the daily dosages appropriate for the lisinopril oral liquid formulations described herein are from about 0.01 to about 1.0 mg/kg per body weight. In one embodiment, the daily dosages appropriate for the lisinopril oral liquid formulations are from about 0.02 to about 0.8 mg/kg lisinopril per body weight. In another embodiment, the daily dosage appropriate for the lisinopril oral liquid formulations are from about 0.05 to about 0.6 mg/kg per body weight. In another embodiment, the daily dosage appropriate for the lisinopril oral liquid formulations is about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about 0.10 mg/kg, about 0.15 mg/kg, about 0.20 mg/kg, about 0.25 mg/kg, about 0.30 mg/kg, about 0.40 mg/kg, about 0.50 mg/kg, about 0.60 mg/kg, about 0.61 mg/kg, about 0.62 mg/kg, about 0.63 mg/kg, about 0.64 mg/kg, or about 0.65 mg/kg. In other embodiments the lisinopril oral liquid formulations are provided at the maximum tolerated dose (MTD) for lisinopril. In other embodiments, the amount of the lisinopril oral liquid formulations administered is from about 10% to about 90% of the maximum tolerated dose (MTD), from about 25% to about 75% of the MTD, or about 50% of the MTD. In particular embodiments, the amount of the lisinopril oral liquid formulations administered is from about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or higher, or any range derivable therein, of the MTD for lisinopril. In further embodiments, the lisinopril oral liquid formulations are provided in a dosage that is similar, comparable or equivalent to a dosage of a known lisinopril tablet formulation. In other embodiments, the lisinopril oral liquid formulations are provided in a dosage that provides similar, comparable or equivalent pharmacokinetic parameters (e.g., AUC, Cmax, Tmax, Cmin, T1/2) as a dosage of a known lisinopril tablet formulation. Similar, comparable or equivalent pharmacokinetic parameters, in some instances, refer to within 80% to 125%, 80% to 120%, 85% to 125%, 90% to 110%, or increments therein, of the given values. It should be recognized that the ranges can, but need not be symmetrical, e.g., 85% to 105%. Administration Administration of a lisinopril oral liquid formulation is at a dosage described herein or at other dose levels and formulations determined and contemplated by a medical practitioner. In certain embodiments, the lisinopril oral liquid formulations described herein are administered for prophylactic and/or therapeutic treatments. In certain therapeutic applications, the lisinopril oral liquid formulations are administered to a patient already suffering from a disease, e.g., hypertension, in an amount sufficient to cure the disease or at least partially arrest or ameliorate the symptoms, e.g., lower blood pressure. Amounts effective for this use depend on the severity of the disease, previous therapy, the patient's health status, weight, and response to the lisinopril formulations, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation clinical trial. In prophylactic applications, the lisinopril oral liquid formulations described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, e.g., hypertension. Such an amount is defined to be a “prophylactically effective amount or dose.” In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in a patient, effective amounts for this use will depend on the risk or susceptibility of developing the particular disease, previous therapy, the patient's health status and response to the lisinopril formulations, and the judgment of the treating physician. In certain embodiments wherein the patient's condition does not improve, upon the doctor's discretion the administration of a lisinopril oral liquid formulation described herein are administered chronically, that is, for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disease. In other embodiments, administration of a lisinopril oral liquid formulation continues until complete or partial response of a disease. In certain embodiments wherein a patient's status does improve, the dose of a lisinopril oral liquid formulation being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”). In specific embodiments, the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, and 365 days. The dose reduction during a drug holiday is, by way of example only, by 10%400%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%. In some embodiments, lisinopril oral liquid formulations described herein are administered chronically. For example, in some embodiments, a lisinopril oral liquid formulation is administered as a continuous dose, i.e., administered daily to a subject. In some other embodiments, lisinopril oral liquid formulations described herein are administered intermittently (e.g. drug holiday that includes a period of time in which the formulation is not administered or is administered in a reduced amount). In some embodiments a lisinopril oral liquid formulation is administered to a subject who is in a fasted state. A fasted state refers to a subject who has gone without food or fasted for a certain period of time. General fasting periods include at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 14 hours and at least 16 hours without food. In some embodiments, a lisinopril oral liquid formulation is administered orally to a subject who is in a fasted state for at least 8 hours. In other embodiments, a lisinopril oral liquid formulation is administered to a subject who is in a fasted state for at least 10 hours. In yet other embodiments, a lisinopril oral liquid formulation is administered to a subject who is in a fasted state for at least 12 hours. In other embodiments, a lisinopril oral liquid formulation is administered to a subject who has fasted overnight. In other embodiments a lisinopril oral liquid formulation is administered to a subject who is in a fed state. A fed state refers to a subject who has taken food or has had a meal. In certain embodiments, a lisinopril oral liquid formulation is administered to a subject in a fed state 5 minutes post-meal, 10 minutes post-meal, 15 minutes post-meal, 20 minutes post-meal, 30 minutes post-meal, 40 minutes post-meal, 50 minutes post-meal, 1 hour post-meal, or 2 hours post-meal. In certain instances, a lisinopril oral liquid formulation is administered to a subject in a fed state 30 minutes post-meal. In other instances, a lisinopril oral liquid formulation is administered to a subject in a fed state 1 hour post-meal. In yet further embodiments, a lisinopril oral liquid formulation is administered to a subject with food. In further embodiments described herein, a lisinopril oral liquid formulation is administered at a certain time of day for the entire administration period. For example, a lisinopril oral liquid formulation can be administered at a certain time in the morning, in the evening, or prior to bed. In certain instances, a lisinopril oral liquid formulation is administered in the morning. In other embodiments, a lisinopril oral liquid formulation can be administered at different times of the day for the entire administration period. For example, a lisinopril oral liquid formulation can be administered on 8:00 am in the morning for the first day, 12 pm noon for the next day or administration, 4 pm in the afternoon for the third day or administration, and so on. Further Combinations The treatment of certain diseases or conditions (e.g., hypertension, heart failure, myocardial infarction and the like) in a subject with a lisinopril oral liquid formulation described herein encompass additional therapies and treatment regimens with other agents in some embodiments. Such additional therapies and treatment regimens can include another therapy, e.g., additional anti-hypertensives, for treatment of the particular disease or condition in some embodiments. Alternatively, in other embodiments, additional therapies and treatment regimens include other agents used to treat adjunct conditions associated with the disease or condition or a side effect from the lisinopril oral liquid formulation in the therapy. Additional agents for use in combination with a lisinopril oral liquid formulation described herein include, but are not limited to, diuretics (loop, thiazide, potassium-sparing, and the like), beta blockers (metoprolol, propanolol, pronethalol, and the like), alpha blockers (phentolamine, phenoxybenzamine, tamsulosin, prazosin, and the like), mixed alpha and beta blockers (bucindolol, carvedilol, labetalol), calcium channel blockers (dihydropyridines such as nifedipine, amlodipine, etc., dilitazem, verapamil and the like), angiotensin II receptor antagonists (saralasin, losartan, eprosartin, irbesartan, valsartan, and the like), other ACE inhibitors (captopril, quinapril, ramipril, enalapril, zofenopril, and the like), aldosterone antagonists (eplerenone, spironolactone and the like), vasodilators (hydralazine and the like) and alpha-2 agonists (clonidine, moxonidine, guanabenz and the like). Certain Definitions Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments described herein, certain preferred methods, devices, and materials are now described. As used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural reference unless the context clearly dictates otherwise. Thus, for example, reference to “an excipient” is a reference to one or more excipients and equivalents thereof known to those skilled in the art, and so forth. The term “about” is used to indicate that a value includes the standard level of error for the device or method being employed to determine the value. The use of the term “or” in the claims is used to mean “and/or” unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and to “and/or.” The terms “comprise,” “have” and “include” are open-ended linking verbs. Any forms or tenses of one or more of these verbs, such as “comprises,” “comprising,” “has,” “having,” “includes” and “including,” are also open-ended. For example, any method that “comprises,” “has” or “includes” one or more steps is not limited to possessing only those one or more steps and also covers other unlisted steps. “Optional” or “optionally” may be taken to mean that the subsequently described structure, event or circumstance may or may not occur, and that the description includes instances where the events occurs and instances where it does not. As used herein, the term “therapeutic” means an agent utilized to treat, combat, ameliorate, prevent or improve an unwanted condition or disease of a patient. In some embodiments, a therapeutic agent such as lisinopril is directed to the treatment and/or the amelioration of, reversal of, or stabilization of the symptoms of hypertension described herein. “Administering” when used in conjunction with a therapeutic means to administer a therapeutic systemically or locally, as directly into or onto a target tissue, or to administer a therapeutic to a patient whereby the therapeutic positively impacts the tissue to which it is targeted. Thus, as used herein, the term “administering”, when used in conjunction with a lisinopril formulation, can include, but is not limited to, providing a lisinopril formulation into or onto the target tissue; providing a lisinopril formulation systemically to a patient by, e.g., oral administration whereby the therapeutic reaches the target tissue or cells. “Administering” a formulation may be accomplished by injection, topical administration, and oral administration or by other methods alone or in combination with other known techniques. The term “animal” as used herein includes, but is not limited to, humans and non-human vertebrates such as wild, domestic and farm animals. As used herein, the terms “patient,” “subject” and “individual” are intended to include living organisms in which certain conditions as described herein can occur. Examples include humans, monkeys, cows, sheep, goats, dogs, cats, mice, rats, and transgenic species thereof. In a preferred embodiment, the patient is a primate. In certain embodiments, the primate or subject is a human. In certain instances, the human is an adult. In certain instances, the human is child. In further instances, the human is 12 years of age or younger. In certain instances, the human is elderly. In other instances, the human is 60 years of age or older. Other examples of subjects include experimental animals such as mice, rats, dogs, cats, goats, sheep, pigs, and cows. The experimental animal can be an animal model for a disorder, e.g., a transgenic mouse with hypertensive pathology. A patient can be a human suffering from hypertension, or its variants or etiological forms. By “pharmaceutically acceptable”, it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The term “pharmaceutical formulation” shall mean a formulation comprising at least one active ingredient, whereby the formulation is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human). Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan. A “therapeutically effective amount” or “effective amount” as used herein refers to the amount of active compound or pharmaceutical agent that elicits a biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease, (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology), and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology). As such, a non-limiting example of a “therapeutically effective amount” or “effective amount” of a formulation of the present disclosure may be used to inhibit, block, or reverse the activation, migration, or proliferation of cells or to effectively treat hypertension or ameliorate the symptoms of hypertension. The terms “treat,” “treated,” “treatment,” or “treating” as used herein refers to both therapeutic treatment in some embodiments and prophylactic or preventative measures in other embodiments, wherein the object is to prevent or slow (lessen) an undesired physiological condition, disorder or disease, or to obtain beneficial or desired clinical results. For the purposes described herein, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. A prophylactic benefit of treatment includes prevention of a condition, retarding the progress of a condition, stabilization of a condition, or decreasing the likelihood of occurrence of a condition. As used herein, “treat,” “treated,” “treatment,” or “treating” includes prophylaxis in some embodiments. EXAMPLES The following examples are intended to illustrate but not limit the disclosed embodiments. Example A: Effect of pH on the Formation of Degradants in Lisinopril Formulations at 60° C. Formulations were prepared containing lisinopril according to Table A-1. The components were dissolved in ˜15 mL water then additional water was added to bring each solution to 20 mL. The pH was adjusted to the final value with ˜1N HCl or ˜0.5N NaOH. Five milliliters of each formulation were transferred to each of four 3-dram glass screw-capped vials with Teflon inserts in the caps. The vials were placed into a 60° C. heating chamber then removed and analyzed by HPLC at times of zero, ˜48 and ˜145 hours. TABLE A-1 Formulation (in mg) of Lisinopril Formulations at Varying pH and 50 mM Citrate Buffer Formulation Component A1 A2 A3 A4 A5 Lisinopril dihydratea 21.78 21.78 21.78 21.78 21.78 Mannitol 1000 1000 1000 1000 Xylitol 1000 Citric acid, anhydrous 153.6 107.6 107.6 107.6 61.4 Sodium citrate, dihydrate 45.6 100 100 100 155 Sodium benzoate 20.0 20.0 20.0 20.0 20.0 Methylparaben sodium 34.4 Sucralose 15.0 15.0 15.0 15.0 15.0 Sodium chloride 50.0 50.0 50.0 50.0 50.0 Grape flavor (powdered) 10.0 10.0 10.0 10.0 10.0 Water qs qs qs qs qs 20 mL 20 mL 20 mL 20 mL 20 mL pH 3.21 4.05 4.05 4.27 4.81 a= equivalent to 1 mg/mL lisinopril qs = sufficient quantity The results of the HPLC analysis for the two main degradants in the samples, lisinopril diketopiperazine and lisinopril hydrolysate, are provided in Table A-2. TABLE A-2 Primary Degradants Present in the Formulations (% w/w of lisinopril) Formulation Hours at 60° C. A1 A2 A3 A4 A5 Lisinopril Diketopiperazine 0 0.05 0.04 0.05 0.04 0.04 45.5 2.51 0.78 0.74 0.46 0.20 145.5 7.93 2.36 2.16 1.39 0.48 Lisinopril Hydrolysate 0 0.11 0.11 0.11 0.11 0.11 45.5 0.35 0.25 0.22 0.23 0.22 145.5 0.85 0.54 0.46 0.50 0.48 Example B: Stability of Powder and Solution Formulations of Lisinopril Powder formulations were prepared according to Table B-1. All components in each formulation except mannitol or xylitol were added to a 2.5 L polypropylene screw capped bottle. The bottle was mixed by inversion in a Turbula mixer for 5 minutes. One-half of the mannitol or xylitol was then added, the components mixed for 5 minutes, then the other half of the mannitol or xylitol was added and a final mix of 5 minutes was completed. Five gram aliquots of each formulation were placed into opaque high density polyethylene bottles. The bottles were screw-capped and placed into storage at room temperature (19-23° C.) and at 40° C.±2° C. One liter of solution formulation was prepared for each formulation by adding 66.67 grams of each powdered formulation to a 1 liter volumetric flask and adding about 500 mL water. The powder was dissolved with mixing then the contents of the flask were brought to 1 L with additional water. Fifty milliliter aliquots of each formulation were placed into HDPE bottles. The bottles were screw-capped and placed into storage at 5° C.±3° C., at room temperature (19-23° C.) and at 40° C.±2° C. At various times, bottles were removed from the storage condition and analyzed. The powder bottles were constituted with purified water to yield a final volume in each bottle of 75 mL. TABLE B-1 Formulation of Lisinopril Formulations Component B1 B2 B3 B4 B5 Powder Formulation (grams) Lisinopril dihydratea 10.4 10.4 10.4 10.4 3.05 Mannitol 481.7 485.0 487.7 484.4 Xylitol 141.2 Citric acid, anhydrous 43.3 52.8 38.38 29.0 12.7 Sodium citrate, 65.4 52.4 71.9 84.4 19.2 anhydrous Potassium sorbate 9.57 9.57 Sodium benzoate 9.57 9.57 2.81 Methylparaben sodium 11.0 11.01 3.35 3.35 3.23 Sucralose 7.18 7.18 7.18 7.18 2.10 Grape flavor (powdered) 9.57 9.57 9.57 9.57 2.81 Total solids 638.0 638.0 638.0 638.0 187.0 Liquid Formulations (mg/mL) Lisinopril dihydrateb 1.09 1.09 1.09 1.09 1.09 Mannitol 50.33 50.68 50.96 50.62 Xylitol 50.33 Citric acid, anhydrous 4.52 5.52 4.01 3.03 4.52 Sodium citrate, 6.83 5.48 7.51 8.83 6.83 anhydrous Potassium sorbate 1.00 1.00 Sodium benzoate 1.00 1.00 1.00 Methylparaben sodium 1.15 1.15 0.35 0.35 1.15 Sucralose 0.75 0.75 0.75 0.75 0.75 Grape flavor (powdered) 1.00 1.00 1.00 1.00 1.00 Purified water qs qs qs qs qs Measured pH 4.7 4.3 4.8 5.2 4.7 a= contained ~8.4% water of hydration to yield 1.0 mg/mL lisinopril upon constitution with water qs = sufficient quantity b= equivalent to 1 mg/mL lisinopril The results of the HPLC analysis for the diketopiperazine and hydrolysate degradants in the samples are provided in Table B-2. TABLE B-2 Degradant Content After Storage (% w/w of lisinopril) Storage Formulation ° C. Weeks B1 B2 B3 B4 B5 Powder Formulations Diketopiperazine 19-23 0 <0.05 <0.05 <0.05 <0.05 <0.05 4 <0.05 0.05 <0.05 <0.05 <0.05 8 0.05 0.06 0.05 0.05 0.07 12 0.07 0.07 <0.05 <0.05 40 0 <0.05 <0.05 <0.05 <0.05 <0.05 4 0.05 0.05 0.05 <0.05 0.06 8 0.07 0.07 0.06 0.05 0.09 12 0.10 0.10 0.09 0.07 Lisinopril hydrolysate 19-23 0 0.03 <0.05 <0.05 <0.05 <0.05 4 0.04 <0.05 <0.05 <0.05 0.05 8 0.05 0.05 <0.05 <0.05 0.05 12 0.05 0.05 0.05 <0.05 40 0 0.03 <0.05 <0.05 <0.05 <0.05 4 0.04 <0.05 <0.05 <0.05 0.05 8 0.05 0.05 <0.05 0.05 0.05 12 0.04 0.05 0.06 0.05 Liquid Formulations Diketopiperazine 19-23 0 0.05 0.05 0.06 <0.05 <0.05 4 0.06 0.09 0.06 <0.05 0.07 8 0.09 0.13 0.07 0.05 0.10 12 0.12 0.18 0.12 0.11 40 0 0.05 0.05 0.06 <0.05 <0.05 4 0.23 0.46 0.19 0.11 0.23 8 0.42 0.87 0.35 0.15 0.46 12 0.67 1.40 0.59 0.27 Lisinopril hydrolysate 19-23 0 <0.05 <0.05 <0.05 <0.05 <0.05 4 <0.05 <0.05 0.05 <0.05 0.05 8 0.05 0.05 0.05 0.05 0.05 12 0.05 0.05 0.05 0.06 40 0 <0.05 <0.05 <0.05 <0.05 <0.05 4 0.08 0.08 0.10 0.07 0.13 8 0.15 0.16 0.15 0.14 0.17 12 0.17 0.19 0.20 0.16 Additionally the parabens also reacted with the sugar alcohols (xylitol and mannitol) to create new transesterification degradants. Example C: Stability of Powder and Solution Formulations of Lisinopril with Alternate Sweeteners Powder formulations were prepared according to Table C-1. All components in each formulation except mannitol or xylitol were mixed in a mortar and pestle then the mannitol or xylitol was added to the mortar in increments with mixing to achieve geometric dilution. The final blend was transferred to a 2.5 L polypropylene screw capped bottle and the bottle was mixed by inversion in a Turbula mixer for 10 minutes. Aliquots (2.4 g) of each formulation were placed into opaque high density polyethylene bottles. The bottles were screw-capped and placed into storage at room temperature (19-23° C.) and at 40° C.±2° C. One liter of solution formulation was prepared for each formulation by adding 60.0 grams of powdered formulation C2 or C3, or 160 g of powdered formula C1 to one liter volumetric flasks and adding about 500 mL water. The powder was dissolved with mixing then the contents of the flasks were brought to 1 L with additional water. Forty milliliter aliquots of each formulation were placed into HDPE bottles. The bottles were screw-capped and placed into storage at room temperature (19-23° C.) and at 40° C.±2° C. At various times, bottles were removed from the storage condition and analyzed. The powder bottles were constituted with purified water to yield a final volume in each bottle of 40 mL. TABLE C-1 Formulation of Lisinopril Formulations C1 C2 C3 Powder Formulations (grams) Lisinopril dihydratea 2.87 2.87 2.87 Xylitol 408.1 138.34 Mannitol 136.22 Citric acid, anhydrous 2.32 2.32 2.32 Sodium citrate, anhydrous 3.70 3.70 3.70 Sodium benzoate 2.64 2.64 2.64 Sodium saccharin 5.94 Sucralose (as Rebalance X60) 7.92 Grape flavor (powdered) 2.64 2.64 2.64 Total solids 422.32 158.45 158.32 Liquid Formulations (mg/mL) Lisinopril dihydrateb 1.09 1.09 1.09 Xylitol 154.60 52.4 Mannitol 51.60 Citric acid, anhydrous 0.88 0.88 0.88 Sodium citrate, anhydrous 1.40 1.40 1.40 Sodium benzoate 1.00 1.00 1.00 Sodium saccharin 2.25 Sucralose (as Rebalance X60) 3.00 Grape flavor (powdered) 1.00 1.00 1.00 Purified water qs qs qs Measured pH 4.8 4.8 4.8 a= contained ~8.4% water. Yields 1.0 mg/mL lisinopril upon constitution with water qs = sufficient quantity b= equivalent to 1 mg/mL lisinopril The results for pH and the HPLC analysis for degradants in the samples are provided in Table C-2. TABLE C-2 Degradant Content After Storage (% w/w of Lisinopril) Storage Formulation ° C. weeks C1 C2* C3 Powder Formulations Diketopiperazine 19-23 0 0.05 0.06 0.05 4 0.05 0.10 <0.05 8 0.05 0.12 <0.05 12 0.06 0.13 <0.05 26 0.08 0.15 0.05 40 0 0.05 0.06 0.05 4 0.12 0.23 0.08 8 0.19 0.40 0.12 12 0.21 0.49 0.11 26 0.27 0.66 0.16 Lisinopril hydrolysate 19-23 0 0.06 0.05 4 0.05 0.05 8 <0.05 0.05 12 <0.05 <0.05 26 0.05 0.05 40 0 0.06 0.05 4 0.05 0.05 8 0.05 0.05 12 0.05 0.05 26 0.05 0.05 Liquid Formulations Diketopiperazine 19-23 0 <0.05 0.05 0.05 4 0.05 0.08 0.06 8 0.05 0.11 0.06 12 0.06 0.11 0.06 26 0.10 0.14 0.10 40 0 <0.05 0.05 0.05 4 0.16 0.20 0.17 8 0.30 0.34 0.30 12 0.45 0.49 0.45 26 0.87 0.90 0.83 Lisinopril hydrolysate 19-23 0 0.05 0.05 4 <0.05 0.05 8 0.05 0.05 12 0.05 0.05 26 0.06 0.06 40 0 0.05 0.05 4 0.08 0.09 8 0.12 0.13 12 0.19 0.19 26 0.36 0.36 *Hydrolysate could not be quantitated in the presence of saccharin Example D: Antimicrobial Effectiveness Testing at pH 4.8 Lisinopril formulations were prepared containing differing amounts of the antimicrobial preservative, sodium benzoate. The formulations were then tested for antimicrobial effectiveness (AET) according to the procedures in the 2014 United States Pharmacopeia 37, Chapter <51> for category 3 products. The formulation of the formulations and the AET results are included in Table D-1. TABLE D-1 Formulation and AET Testing Results Formulation D1 D2 D3 D4 D5 Formulation (mg/mL) Lisinopril dihydratea 1.089 1.089 1.089 1.089 1.089 Xylitol 155 155 155 155 155 Citric acid anhydrous 0.88 0.88 0.88 0.88 0.88 Sodium citrate anhydrous 1.40 1.40 1.40 1.40 1.40 Sodium benzoate 1.00 0.80 0.60 0.40 0.20 Grape Flavor 1.00 1.00 1.00 1.00 1.00 Water qs qs qs qs qs HCl/NaOH as needed to achieve pH Measured pH 4.8 4.8 4.8 4.8 4.8 AET Results USP <51> Pass Pass Pass Fail Fail a= equivalent to 1 mg/mL lisinopril Example E: Antimicrobial Effectiveness Testing at pH 5.0 and 5.1 Formulations were prepared containing differing amounts of the antimicrobial preservative, sodium benzoate and at pH values of 5.0 or 5.1. The formulations were then tested for antimicrobial effectiveness (AET) according to the procedures in the 2015 United States Pharmacopeia 38, Chapter <51> for category 3 products. The formulation of the formulations and the AET results are included in Table E-1. TABLE E-1 Formulation and AET Testing Results Formulation E1 E2 E3 E4 E5 E6 Formulation (mg/mL) Lisinopril 1.089 1.089 1.089 1.089 1.089 1.089 dihydratea Xylitol 150.0 150.0 150.0 150.0 150.0 150.0 Citric acid 0.86 0.86 0.86 0.86 0.86 0.86 anhydrous Sodium citrate 1.43 1.43 1.43 1.43 1.43 1.43 anhydrous Sodium benzoate 0.80 0.76 0.72 0.68 0.64 0.72 Water qs qs qs qs qs qs HCl/NaOH as needed to achieve pH Measured pH 5.0 5.0 5.0 5.0 5.0 5.1 AET Results USP <51> Pass Pass Pass Pass Pass Pass a = equivalent to 1 mg/mL lisinopril Example F: Stability of Solution Formulations of Lisinopril Solution formulations were prepared according to Table F-1. The components were dissolved in about 80% of the final volume of water then additional water was added to bring the solution to final volume. The pH was adjusted to the target pH with hydrochloric acid or sodium hydroxide The solutions were dispensed into HDPE bottles, 40 mL of formulations F1-F6 into 75 mL bottles, and 150 mL of formulation F7 into 150 mL bottles. The bottles were screw-capped and placed into controlled condition storage at 5° C.±3° C., room temperature (19-23° C.) and at 40° C.±2° C. At various times, bottles were removed from the storage condition and analyzed. The results are shown in Table F-2. TABLE F-1 Formulation (mg/mL) of Lisinopril Ready to Use Liquid Formulations Formulation F1 F2 F3 F4 F5 F6 F7 Lisinopril dihydratea 1.09 1.09 1.09 1.09 1.09 1.09 1.09 Xylitol 150.0 150.0 150.0 100.0 150.0 Citric acid anhydrous 1.92 1.92 1.92 1.92 1.92 1.92 0.86 Sodium citrate anhydrous 1.44 Sodium benzoate 0.80 0.80 0.80 0.80 Methylparaben sodium 1.72 1.72 1.72 Propylparaben sodium 0.17 0.17 0.17 Glycerin 10.0 Saccharin sodium 2.00 Sucralose USP 2.00 2.00 Water qs 1 mL qs 1 mL qs 1 mL qs 1 mL qs 1 mL qs 1 mL qs 1 mL HCl/NaOH as needed to achieve pH Target pH 4.8 4.8 4.8 5.2 5.2 5.2 5.0 a = equivalent to 1 mg/mL lisinopril TABLE F-2 Degradant Content After Storage (% w/w of Lisinopril) Storage Formulation ° C. weeks F1 F2 F3 F4 F5 F6* F7 Lisinopril Diketopiperazine 19-23 0 <0.05 0.05 0.05 0.05 0.06 0.05 <0.05 4 0.05 0.05 0.05 <0.05 <0.05 0.07 <0.05 8 0.07 0.06 0.06 <0.05 <0.05 0.08 0.05 12 0.07 0.07 0.07 0.06 0.06 0.06 0.05 26 0.12 0.12 0.11 0.09 0.08 0.09 0.07 52 0.17 0.17 0.16 0.12 0.09 0.11 40 0 <0.05 0.05 0.05 0.05 0.06 0.05 <0.05 4 0.20 0.21 0.20 0.10 0.10 0.12 0.14 8 0.39 0.35 0.33 0.18 0.14 0.18 0.27 12 0.51 0.49 0.45 0.25 0.22 0.23 0.36 26 1.13 1.11 1.04 0.56 0.49 0.54 0.71 52 1.93 1.89 1.72 0.90 0.83 0.89 Lisinopril Hydrolysate 19-23 0 0.05 <0.05 0.05 0.06 <0.05 0.05 4 0.05 0.05 0.05 0.06 0.06 0.05 8 0.05 0.05 0.06 0.05 0.05 <0.05 12 0.05 0.05 0.05 0.04 0.05 <0.05 26 0.07 0.07 0.07 0.06 0.07 0.05 52 0.08 0.08 0.08 0.06 0.08 40 0 0.05 <0.05 0.05 0.06 <0.05 0.05 4 0.11 0.11 0.11 0.08 0.10 0.11 8 0.17 0.16 0.16 0.11 0.14 0.13 12 0.18 0.18 0.18 0.12 0.17 0.18 26 0.45 0.46 0.49 0.31 0.44 0.36 52 0.87 0.89 0.91 0.62 0.84 *Hydrolysate could not be quantitated in the presence of saccharin Example G: Lisinopril Formulation at Higher pH A solution formulation was prepared at pH 8.0 according to Table G-1. The components were dissolved in about 80% of the final volume of water then additional water was added to bring the solution to final volume. The pH was adjusted to the target pH with hydrochloric acid or sodium hydroxide. TABLE G-1 Formulation of Lisinopril Ready to Use Liquid Formulation at Higher pH Component mg/mL Lisinopril dihydratea 1.09 Monobasic sodium phosphate anhydrous 2.40 Methylparaben sodium 1.72 Propylparaben sodium 0.225 Sucralose USP 0.70 Water qs HCl/NaOH as needed to achieve pH Target pH 8.0 a= equivalent to 1 mg/mL lisinopril Example H: Lisinopril Formulation Containing Less Sucralose A solution formulation was prepared according to Table H-1. The components were dissolved in about 80% of the final volume of water then additional water was added to bring the solution to final volume. The pH was adjusted to the target pH with hydrochloric acid or sodium hydroxide. TABLE H-1 Formulation of Lisinopril Ready to Use Liquid Formulation With less Sucralose Component mg/mL Lisinopril dihydratea 1.09 Citric acid anhydrous 0.86 Sodium citrate anhydrous 1.44 Sodium benzoate 0.80 Sucralose USP 0.70 Water qs HCl/NaOH as needed to achieve pH pH 4.9 a= equivalent to 1 mg/mL lisinopril Example I: Clinical Trial: Bioavailability Study of 10 mg Lisinopril Oral Solution Vs. Zestril® 10 mg Tablets Under Fasted Conditions The objective of this open-label, randomized, two period, two treatment crossover study was to compare the oral bioavailability of a test formulation of 10 mL of lisinopril oral solution, 1 mg/M1 (formulation F-7), to an equivalent oral dose of the commercially available comparator product, Zestril® lisinopril 10 mg tablet, when administered under fasted conditions in healthy adults. Study design: Fifty-six healthy adult subjects received a single 10 mL dose of lisinopril oral solution, 1 mg/mL, formulation F-7 (Treatment A), in one period and a separate single dose of Zestril®10 mg tablet (Treatment B) in another period. Screening assessments were performed by the investigator or designee within 28 days prior to study start. Each treatment was administered after an overnight fast of at least 10 hours. Treatment A was administered via a 10 mL oral dosing syringe and followed with 240 mL of room temperature tap water. Treatment B was administered with 240 mL of room temperature tap water. The subjects fasted for 4 hours after dosing. Except for the 240 mL of room temperature water provided with the dose, no water was consumed for 1 hour prior through 1 hour postdose. Each drug administration was separated by a washout period of at least 7 days. During each study period, meals were the same and scheduled at approximately the same times relative to dose. In addition, during each period, blood samples were obtained prior to and following each dose at selected times through 96 hours postdose. Pharmacokinetic samples were analyzed for lisinopril using a validated analytical method; appropriate pharmacokinetic parameters were calculated for each formulation using non-compartmental methods. Blood was also drawn and urine collected for clinical laboratory testing at screening and at the end of the study. Statistical Methods: The concentration-time data were analyzed using noncompartmental methods in Phoenix™ WinNonlin® (Version 6.3, Pharsight Corporation). Concentration-time data that were below the limit of quantitation (BLQ) were treated as zero in the data summarization and descriptive statistics. In the pharmacokinetic analysis, BLQ concentrations were treated as zero from time-zero up to the time at which the first quantifiable concentration was observed; embedded and/or terminal BLQ concentrations were treated as “missing”. Actual sample times were used for all pharmacokinetic and statistical analyses. Analysis of variance (ANOVA) and the Schuirmann's two one-sided t-test procedures at the 5% significance level were applied to the log-transformed pharmacokinetic exposure parameters, Cmax, AUClast, and AUCinf. The 90% confidence interval for the ratio of the geometric means (Test/Reference) was calculated. Bioequivalence was declared if the lower and upper confidence intervals of the log-transformed parameters were within 80% to 125%. Results: Based on the geometric mean ratios of lisinopril AUCs (Test/Reference for AUClast and AUCinf), the bioavailability of the test formulation relative to the reference product was approximately 94% to 95%. The geometric mean ratio of lisinopril Cmax was 94.11%. The 90% confidence intervals about the geometric mean ratios (Test/Reference) of lisinopril Cmax and AUCs were within the accepted 80% to 125% range, indicating no significant difference. Example J: Clinical Trial: Bioavailability Study of 10 mg Lisinopril Oral Solution Vs. Zestril® 10 mg Tablets Under Fed Conditions This study was conduct the same as in example G, with the exceptions that only 52 subjects were analyzed for pharmacokinetic parameters, and the dose administration followed a 10-hour overnight fast, followed by the ingestion of a Food and Drug Administration standard high-calorie, high-fat breakfast meal. Results: Based on the geometric mean ratios of lisinopril AUCs (Test/Reference for AUClast and AUCinf), the bioavailability of the test formulation relative to the reference product was approximately 99% to 101%. The geometric mean ratio of lisinopril Cmax was 99.45%. The 90% confidence intervals about the geometric mean ratios (Test/Reference) of lisinopril Cmax and AUCs were within the accepted 80% to 125% range, indicating no significant difference. While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby. | <SOH> BACKGROUND OF THE INVENTION <EOH>Hypertension, or high blood pressure, is a serious health issue in many countries. According to the National Heart Blood and Lung Institute, it is thought that about 1 in 3 adults in the United States alone have hypertension. Left unchecked, hypertension is considered a substantial risk factor for cardiovascular and other diseases including coronary heart disease, myocardial infarction, congestive heart failure, stroke and kidney failure. Hypertension is classified as primary (essential) hypertension or secondary hypertension. Primary hypertension has no known cause and may be related to a number of environmental, lifestyle and genetic factors such as stress, obesity, smoking, inactivity and sodium intake. Secondary hypertension can be caused by drug or surgical interventions or by abnormalities in the renal, cardiovascular or endocrine system. A number of antihypertensive drugs are available for treating hypertension. Various therapeutic classes of antihypertensive drugs include alpha-adrenergic blockers, beta-adrenergic blockers, calcium-channel blockers, hypotensives, mineralcorticoid antagonists, central alpha-agonists, diuretics and rennin-angiotensin-aldosterone inhibitors which include angiotensin II receptor antagonists (ARB) and angiotensin-converting enzyme (ACE) inhibitors. Angiotensin-converting enzyme (ACE) inhibitors inhibit angiotensin-converting enzyme (ACE), a peptydyl dipeptidase that catalyzes angiotension I to angiotension II, a potent vasoconstrictor involved in regulating blood pressure. Lisinopril is a drug belonging to the angiotensin-converting enzyme (ACE) inhibitor class of medications. Lisinopril IUPAC name is N 2 -[(1S)-1-carboxy-3-phenylpropyl]-L-lysyl-L-proline. Its structural formula is as follows: Lisinopril is currently administered in the form of oral tablets, (e.g., Prinivil®, Zestril®). In addition to the treatment of hypertension, lisinopril tablets have been used for the treatment of heart failure and acute myocardial infarction. | <SOH> SUMMARY OF THE INVENTION <EOH>Provided herein are lisinopril oral liquid formulations. In one aspect, the lisinopril oral liquid formulation comprises (i) lisinopril or a pharmaceutically acceptable salt or solvate thereof, (ii) a sweetener that is xylitol, (iii) a buffer comprising citric acid (iv) a preservative that is sodium benzoate, and (v) water; wherein the pH of the formulation is between about 4 and about 5; and wherein the formulation is stable at about 25±5° C. for at least 12 months. In some embodiments, the lisinopril is lisinopril dihydrate. In some embodiments, the formulation further comprises a flavoring agent. In some embodiments, the formulation further comprises a second sweetener. In some embodiments, the second sweetener is sodium saccharin or sucralose. In some embodiments, the pH is about 4.9. In some embodiments, the formulation is stable at about 25±5° C. for at least 18 months. In some embodiments, the formulation is stable at about 25±5° C. for at least 24 months. In some embodiments, the buffer further comprises sodium citrate. In some embodiments, the amount of lisinopril or a pharmaceutically acceptable salt or solvate thereof is about 0.8 to about 1.2 mg/ml. In some embodiments, the amount of xylitol is about 140 to about 160 mg/ml. In some embodiments, the amount of citric acid in the buffer is about 0.5 to about 1.2 mg/ml. In some embodiments, the amount of sodium citrate in the buffer is about 1.2 to about 1.7 mg/ml. In some embodiments, the amount of the sodium benzoate is about 0.5 to about 1.2 mg/ml. In one aspect, the lisinopril oral liquid formulation comprises (i) about 1 mg/ml lisinopril or a pharmaceutically acceptable salt or solvate thereof, (ii) about 150 mg/ml of a sweetener that is xylitol, (iii) a buffer comprising about 0.86 mg/ml citric acid, (iv) about 0.8 mg/ml of a preservative that is sodium benzoate; and (v) water; wherein the pH of the formulation is between about 4 and about 5; and wherein the formulation is stable at about 25±5° C. for at least 12 months. In some embodiments, the lisinopril is lisinopril dihydrate. In some embodiments, the formulation further comprises a flavoring agent. In some embodiments, the formulation further comprises a second sweetener. In some embodiments, the second sweetener is sodium saccharin or sucralose. In some embodiments, the pH is about 4.9. In some embodiments, the formulation is stable at about 25±5° C. for at least 18 months. In some embodiments, the formulation is stable at about 25±5° C. for at least 24 months. In some embodiments, the buffer further comprises sodium citrate. In some embodiments, the buffer further comprises about 1.44 mg/ml sodium citrate. In some embodiments, the amount of lisinopril or a pharmaceutically acceptable salt or solvate thereof is about 0.5 to about 1% (w/w of solids). In some embodiments, the amount of xylitol is about 95 to about 98% (w/w of solids). In some embodiments, the amount of citric acid in the buffer is about 0.3 to about 0.7% (w/w of solids). In some embodiments, the amount of sodium citrate in the buffer is about 0.7 to about 1.3% (w/w of solids). In some embodiments, the amount of sodium benzoate is about 0.4 to about 1.2% (w/w of solids). In another aspect, the lisinopril oral liquid formulation comprises (i) about 0.7% (w/w of solids) lisinopril or a pharmaceutically acceptable salt or solvate thereof, (ii) about 97.3% (w/w of solids) of a sweetener that is xylitol, (iii) a buffer comprising about 0.01 molar citrate, (iv) about 0.52% (w/w of solids) of a preservative that is sodium benzoate, and (v) water; wherein the pH of the formulation is between about 4 and about 5; and wherein the formulation is stable at about 25±5° C. for at least 12 months. In some embodiments, the lisinopril is lisinopril dihydrate. In some embodiments, the formulation further comprises a flavoring agent. In some embodiments, the formulation further comprises a second sweetener. In some embodiments, the second sweetener is sodium saccharin or sucralose. In some embodiments, the pH is about 4.9. In some embodiments, the formulation is stable at about 25±5° C. for at least 18 months. In some embodiments, the formulation is stable at about 25±5° C. for at least 24 months. In some embodiments, the buffer comprises citric acid and sodium citrate. In another aspect, the lisinopril oral liquid formulation consists of (i) about 1 mg/ml lisinopril or a pharmaceutically acceptable salt or solvate thereof, (ii) about 150 mg/ml of a sweetener that is xylitol, (iii) a buffer comprising about 0.86 mg/ml citric acid and about 1.44 mg/ml sodium citrate, (iv) about 0.8 mg/ml of a preservative that is sodium benzoate, (v) and water; wherein the pH of the formulation is between about 4 and about 5 adjusted by sodium hydroxide or hydrochloric acid; and wherein the formulation is stable at about 25±5° C. for at least 12 months. In some embodiments, the formulation is stable at about 25±5° C. for at least 24 months. In some embodiments, the pH is about 4.9. Also provided herein are methods of treating hypertension comprising administering to a patient in need thereof a lisinopril oral liquid formulation described herein. In some embodiments, the hypertension is primary (essential) hypertension. In some embodiments, the hypertension is secondary hypertension. In some embodiments, the subject with hypertension has blood pressure values greater than or equal to 140/90 mm Hg. Also provided herein are methods of treating prehypertension comprising administering to a patient in need thereof a lisinopril oral liquid formulation described herein. In some embodiments, the subject with prehypertension has blood pressure values of about 120-139/80-89 mm Hg. Also provided herein are methods of treating heart failure or acute myocardial infarction comprising administering to a patient in need thereof a lisinopril oral liquid formulation described herein. In some embodiments, the subject is an adult. In some embodiments, the subject is elderly. In some embodiments, the subject is a child. In some embodiments, the lisinopril oral liquid formulation is administered to the subject in a fasted state. In some embodiments, the lisinopril oral liquid formulation is administered to the subject in a fed state. In some embodiments, the lisinopril oral liquid formulation is further administered in combination with an agent selected from the group consisting of diuretics, beta blockers, alpha blockers, mixed alpha and beta blockers, calcium channel blockers, angiotensin II receptor antagonists, ACE inhibitors, aldosterone antagonists, and alpha-2 agonists. Also provided herein is a process for preparing a stable oral liquid formulation comprising lisinopril, xylitol, a buffer, and sodium benzoate, the process which comprises the step of adding about 0.86 mg/ml anhydrous citric acid, about 1.44 mg/ml anhydrous sodium citrate, about 0.80 mg/ml sodium benzoate, about 1.09 mg/ml lisinopril dihydrate, and about 150 mg/ml xylitol to water; adjusting the volume to the desired volume by adding more water; and adjusting the pH to 4.9 by adding sodium hydroxide or hydrochloric acid. | A61K3805 | 20171107 | 20180322 | 73178.0 | A61K3805 | 1 | BASQUILL, SEAN M | LISINOPRIL FORMULATIONS | UNDISCOUNTED | 1 | CONT-ACCEPTED | A61K | 2,017 |
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15,806,964 | PENDING | SALTS AND CRYSTALLINE FORMS OF AN APOPTOSIS-INDUCING AGENT | Salts and crystalline forms of 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}-sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide are suitable active pharmaceutical ingredients for pharmaceutical compositions useful in treatment of a disease characterized by overexpression of one or more anti-apoptotic Bcl-2 family proteins, for example cancer. | 1. A compound 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide (Compound 1) in a crystalline form, wherein the crystalline form is Compound 1 free base hydrate, characterized by a powder X-ray diffraction pattern having five or more peaks selected from those at 3.3, 6.4, 7.1, 7.3, 10.1, 11.4, 13.2, 14.4, 14.6, 15.1, 15.8, 16.2, 17.2, 17.6, 18.0, 18.6, 19.0, 19.5, 19.8, 20.2, 20.7, 21.0, 22.5, 23.0, 26.0, 28.9, and 29.2 degrees 2θ (pattern D), each peak being ±0.2 degrees 2θ, when measured at about 25° C. with Cu Kα radiation at 1.54178 Å. 2. A pharmaceutical composition comprising the compound of claim 1 and one or more pharmaceutically acceptable excipients. 3. A process for preparing a pharmaceutical solution of Compound 1 comprising dissolving the compound of claim 1 in a pharmaceutically acceptable solvent or mixture of solvents. 4. A method for treating a disease characterized by apoptotic dysfunction and/or overexpression of an anti-apoptotic Bcl-2 family protein, comprising administering to a subject having the disease a therapeutically effective amount of (a) the compound of claim 1 or (b) a pharmaceutical composition comprising the compound of claim 1 and one or more pharmaceutically acceptable excipients. 5. The method of claim 4, wherein the compound or pharmaceutical composition is administered by an oral, parenteral, sublingual, buccal, intranasal, pulmonary, topical, transdermal, intradermal, ocular, otic, rectal, vaginal, intragastric, intracranial, intrasynovial or intra-articular route. 6. The method of claim 4, wherein the disease is a neoplastic, immune, or autoimmune disease. 7. The method of claim 6, wherein the neoplastic disease is selected from the group consisting of cancer, mesothelioma, bladder cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, bone cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal and/or duodenal) cancer, chronic lymphocytic leukemia, esophageal cancer, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, testicular cancer, hepatocellular (hepatic and/or biliary duct) cancer, primary or secondary central nervous system tumor, primary or secondary brain tumor, Hodgkin's disease, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphoma, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, multiple myeloma, oral cancer, non-small-cell lung cancer, prostate cancer, small-cell lung cancer, cancer of the kidney and/or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system, primary central nervous system lymphoma, non Hodgkin's lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocortical cancer, gall bladder cancer, cancer of the spleen, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma and combinations thereof. 8. The method of claim 6, wherein the neoplastic disease is a lymphoid malignancy. 9. The method of claim 8, wherein the lymphoid malignancy is non-Hodgkin's lymphoma, chronic lymphoid leukemia, or acute lymphocytic leukemia. 10. The method of claim 4, wherein the therapeutically effective amount is administered orally in a dose of about 50 to about 1000 mg Compound 1 per day at an average treatment interval of about 3 hours to about 7 days. 11. The method of claim 4, wherein the therapeutically effective amount is administered orally once daily in a dose of about 200 to about 400 mg Compound 1 free base equivalent per day. 12. A method for treating a disease characterized by apoptotic dysfunction and/or overexpression of an anti-apoptotic Bcl-2 family protein, comprising administering a solution or dispersion of the compound of claim 1 to a subject having the disease. 13. The method of claim 12, wherein the solution is administered by an oral, parenteral, sublingual, buccal, intranasal, pulmonary, topical, transdermal, intradermal, ocular, otic, rectal, vaginal, intragastric, intracranial, intrasynovial or intra-articular route. 14. The method of claim 12, wherein the disease is a neoplastic, immune, or autoimmune disease. 15. The method of claim 14, wherein the neoplastic disease is selected from the group consisting of cancer, mesothelioma, bladder cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, bone cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal and/or duodenal) cancer, chronic lymphocytic leukemia, esophageal cancer, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, testicular cancer, hepatocellular (hepatic and/or biliary duct) cancer, primary or secondary central nervous system tumor, primary or secondary brain tumor, Hodgkin's disease, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphoma, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, multiple myeloma, oral cancer, non-small-cell lung cancer, prostate cancer, small-cell lung cancer, cancer of the kidney and/or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system, primary central nervous system lymphoma, non Hodgkin's lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocortical cancer, gall bladder cancer, cancer of the spleen, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma and combinations thereof. 16. The method of claim 14, wherein the neoplastic disease is a lymphoid malignancy. 17. The method of claim 16, wherein the lymphoid malignancy is non-Hodgkin's lymphoma, chronic lymphoid leukemia, or acute lymphocytic leukemia. 18. The method of claim 12, wherein the solution is administered orally in a dose of about 50 to about 1000 mg Compound 1 per day at an average treatment interval of about 3 hours to about 7 days. 19. The method of claim 12, wherein the solution is administered orally once daily in a dose of about 200 to about 400 mg Compound 1 free base equivalent per day. | CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. application Ser. No. 14/957,097 (published as U.S. Pub. No. 2016/0083384), filed Dec. 2, 2015, which is hereby incorporated by reference as if set forth in its entirety. U.S. application Ser. No. 14/957,097 is a divisional application of U.S. application Ser. No. 14/228,132 (issued as U.S. Pat. No. 9,238,649 B2), filed Mar. 27, 2014, which is hereby incorporated by reference as if set forth in its entirety. U.S. application Ser. No. 14/228,132 is a continuation application of U.S. application Ser. No. 13/301,257 (issued as U.S. Pat. No. 8,722,657 B2), filed Nov. 21, 2011, which is hereby incorporated by reference as if set forth in its entirety. U.S. application Ser. No. 13/301,257 claims the benefit of U.S. provisional application Ser. No. 61/416,656, filed Nov. 23, 2010, which is hereby incorporated by reference as if set forth in its entirety. Cross-reference is also made, without claim to benefit of priority or admission as to prior art status, to the following pending U.S. application containing subject matter related to the present application: Ser. No. 12/787,682 (published as U.S. Pub. No. 2010/0305122 and issued as U.S. Pat. No. 8,546,399 B2) titled “Apoptosis-inducing Agents for the Treatment of Cancer and Immune and Autoimmune Diseases,” the entire disclosure of which is incorporated herein by reference. FIELD OF THE INVENTION The present invention relates to salts and crystalline forms of an apoptosis-inducing agent, to pharmaceutical dosage forms comprising such salts and crystalline forms, to processes for preparing salts and crystalline forms, and to methods of use thereof for treating diseases characterized by overexpression of anti-apoptotic Bcl-2 family proteins. BACKGROUND OF THE INVENTION Overexpression of Bcl-2 proteins correlates with resistance to chemotherapy, clinical outcome, disease progression, overall prognosis or a combination thereof in various cancers and disorders of the immune system. Evasion of apoptosis is a hallmark of cancer (Hanahan & Weinberg (2000) Cell 100:57-70). Cancer cells must overcome a continual bombardment by cellular stresses such as DNA damage, oncogene activation, aberrant cell cycle progression and harsh microenvironments that would cause normal cells to undergo apoptosis. One of the primary means by which cancer cells evade apoptosis is by up-regulation of anti-apoptotic proteins of the Bcl-2 family. A particular type of neoplastic disease for which improved therapies are needed is non-Hodgkin's lymphoma (NHL). NHL is the sixth most prevalent type of new cancer in the U.S. and occurs primarily in patients 60-70 years of age. NHL is not a single disease but a family of related diseases, which are classified on the basis of several characteristics including clinical attributes and histology. One method of classification places different histological subtypes into two major categories based on natural history of the disease, i.e., whether the disease is indolent or aggressive. In general, indolent subtypes grow slowly and are generally incurable, whereas aggressive subtypes grow rapidly and are potentially curable. Follicular lymphomas are the most common indolent subtype, and diffuse large-cell lymphomas constitute the most common aggressive subtype. The oncoprotein Bcl-2 was originally described in non-Hodgkin's B-cell lymphoma. Treatment of follicular lymphoma typically consists of biologically-based or combination chemotherapy. Combination therapy with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) is routinely used, as is combination therapy with rituximab, cyclophosphamide, vincristine and prednisone (RCVP). Single-agent therapy with rituximab (targeting CD20, a phosphoprotein uniformly expressed on the surface of B-cells) or fludarabine is also used. Addition of rituximab to chemotherapy regimens can provide improved response rate and increased progression-free survival. Radioimmunotherapy agents, high-dose chemotherapy and stem cell transplants can be used to treat refractory or relapsed NHL. Currently, there is not an approved treatment regimen that produces a cure, and current guidelines recommend that patients be treated in the context of a clinical trial, even in a first-line setting. First-line treatment of patients with aggressive large B-cell lymphoma typically consists of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), or dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (DA-EPOCH-R). Most lymphomas respond initially to any one of these therapies, but tumors typically recur and eventually become refractory. As the number of regimens patients receive increases, the more chemotherapy-resistant the disease becomes. Average response to first-line therapy is approximately 75%, 60% to second-line, 50% to third-line, and about 35-40% to fourth-line therapy. Response rates approaching 20% with a single agent in a multiple relapsed setting are considered positive and warrant further study. Other neoplastic diseases for which improved therapies are needed include leukemias such as chronic lymphocytic leukemia (like NHL, a B-cell lymphoma) and acute lymphocytic leukemia. Chronic lymphoid leukemia (CLL) is the most common type of leukemia. CLL is primarily a disease of adults, more than 75% of people newly diagnosed being over the age of 50, but in rare cases it is also found in children. Combination chemotherapies are the prevalent treatment, for example fludarabine with cyclophosphamide and/or rituximab, or more complex combinations such as CHOP or R-CHOP. Acute lymphocytic leukemia, also known as acute lymphoblastic leukemia (ALL), is primarily a childhood disease, once with essentially zero survival but now with up to 75% survival due to combination chemotherapies similar to those mentioned above. New therapies are still needed to provide further improvement in survival rates. Current chemotherapeutic agents elicit their antitumor response by inducing apoptosis through a variety of mechanisms. However, many tumors ultimately become resistant to these agents. Bcl-2 and Bcl-XL have been shown to confer chemotherapy resistance in short-term survival assays in vitro and, more recently, in vivo. This suggests that if improved therapies aimed at suppressing the function of Bcl-2 and Bcl-XL can be developed, such chemotherapy-resistance could be successfully overcome. Involvement of Bcl-2 proteins in bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, CLL, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer and the like is described in International Patent Publication Nos. WO 2005/024636 and WO 2005/049593. Involvement of Bcl-2 proteins in immune and autoimmune diseases is described, for example, by Puck & Zhu (2003) Current Allergy and Asthma Reports 3:378-384; Shimazaki et al. (2000) British Journal of Haematology 110(3):584-590; Rengan et al. (2000) Blood 95(4):1283-1292; and Holzelova et al. (2004) New England Journal of Medicine 351(14):1409-1418. Involvement of Bcl-2 proteins in bone marrow transplant rejection is disclosed in United States Patent Application Publication No. US 2008/0182845. Compounds that occupy a binding site on Bcl-2 proteins are known. To be therapeutically useful by oral administration, such compounds desirably have high binding affinity, exhibiting for example Ki<1 nM, preferably <0.1 nM, more preferably <0.01 nM, to proteins of the Bcl-2 family, specifically Bcl-2, Bcl-XL and Bcl-w. It is further desirable that they be formulated in a manner that provides high systemic exposure after oral administration. A typical measure of systemic exposure after oral administration of a compound is the area under the curve (AUC) resulting from graphing plasma concentration of the compound versus time from oral administration. Apoptosis-inducing drugs that target Bcl-2 family proteins such as Bcl-2 and Bcl-XL are best administered according to a regimen that provides continual, for example daily, replenishment of the plasma concentration, to maintain the concentration in a therapeutically effective range. This can be achieved by daily parenteral, e.g., intravenous (i.v.) or intraperitoneal (i.p.) administration. However, daily parenteral administration is often not practical in a clinical setting, particularly for outpatients. To enhance clinical utility of an apoptosis-inducing agent, for example as a chemotherapeutic in cancer patients, a dosage form with acceptable oral bioavailability would be highly desirable. Such a dosage form, and a regimen for oral administration thereof, would represent an important advance in treatment of many types of cancer, including NHL, CLL and ALL, and would more readily enable combination therapies with other chemotherapeutics. Different crystalline forms of an apoptosis-inducing agent can provide different properties with respect to stability, solubility, dissolution rate, hardness, compressibility and melting point, among other physical and mechanical properties. Because ease of manufacture, formulation, storage and transport of an apoptosis-inducing agent is dependent on at least some of these properties, there is a need in the chemical and therapeutic arts for identification of new salts and crystalline forms of apoptosis-inducing agents and ways for reproducibly generating such salts and crystalline forms. SUMMARY OF THE INVENTION The present disclosure relates to salts and crystalline forms of an apoptosis-inducing agent, referred to herein as “Compound 1,” which has the systematic name 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pheny}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide, and which can be depicted by the formula: Following synthesis of Compound 1, as described herein, the product may be recovered as a powder in an amorphous state. An amorphous form of Compound 1 may not be well suited for use as an active pharmaceutical ingredient (API) for various types of downstream formulations. More particularly, an amorphous form of Compound 1 can be difficult and therefore expensive to purify and can present process control problems. The present disclosure provides a series of novel salts and crystalline forms of Compound 1 suitable for use as API in a wide variety of formulation types, including those where the API is present in particulate form together with excipients, for example in orally deliverable tablets or capsules. The salts and crystalline forms of Compound 1 may also be useful where the crystalline form is converted to a non-crystalline form (e.g., solution or amorphous form) when formulated. Also included are ways to prepare the salts and crystalline forms of Compound 1. Salt and crystalline forms of Compound 1 can be used to modulate and/or improve the physicochemical properties of the API, including solid state properties (e.g., crystallinity, hygroscopicity, melting point, hydration potential, polymorphism, etc.), pharmaceutical properties (e.g., solubility/dissolution rate, stability, compatibility, etc.), and crystallization characteristics (e.g., purity, yield, morphology, etc.), as non-limiting examples. In some embodiments, the salt or crystalline form of Compound 1 includes those of Compound 1 free base anhydrate having PXRD pattern A, Compound 1 free base anhydrate having PXRD pattern B, Compound 1 free base hydrate having PXRD pattern C, Compound 1 free base hydrate having PXRD pattern D, Compound 1 free base dichloromethane solvate having pattern E, Compound 1 free base ethyl acetate solvate having PXRD pattern F, Compound 1 free base ethyl acetate solvate having PXRD pattern G, Compound 1 free base acetonitrile solvate having PXRD pattern H, Compound 1 free base acetonitrile solvate having PXRD pattern I, Compound 1 free base acetone solvate having PXRD pattern J, Compound 1 hydrochloride having PXRD pattern K, Compound 1 hydrochloride hydrate having PXRD pattern L, Compound 1 sulfate having PXRD pattern M, and Compound 1 free base tetrahydrofuran (THF) solvate having PXRD pattern N, each having the respective powder X-ray diffraction patterns as described herein. In some embodiments, the crystalline forms of Compound 1 free base dichloromethane solvate, Compound 1 free base acetonitrile solvate, Compound 1 hydrochloride, and Compound 1 free base tetrahydrofuran solvate have the respective crystal lattice parameters as described herein. In another embodiment, Compound 1 hydrochloride is provided. In another embodiment, Compound 1 sulfate is provided. In some embodiments, an API composition is provided comprising Compound 1 as the API, in which at least a portion, for example at least about 10%, of the Compound 1 in the composition is in a salt or crystalline form. In some embodiments, greater than 95% or essentially 100% of the API in such a composition is a salt or crystalline form of Compound 1. In some embodiments, a pharmaceutical composition is provided that comprises a salt or crystalline form of Compound 1 as described herein and one or more pharmaceutically acceptable excipients. In some embodiments, a process for preparing a pharmaceutical solution composition of Compound 1 is provided, where the process comprises dissolving a salt or crystalline form of Compound 1 as described herein with a pharmaceutically acceptable solvent or mixture of solvents. In some embodiments, a method for treating a disease characterized by apoptotic dysfunction and/or overexpression of an anti-apoptotic Bcl-2 family protein is provided, where the method comprises administering to a subject having the disease a therapeutically effective amount of (a) a salt or crystalline form of Compound 1 as described herein or (b) a pharmaceutical composition comprising a salt or crystalline form of Compound 1 as described herein and one or more pharmaceutically acceptable excipients. In some embodiments, a method for treating a disease characterized by apoptotic dysfunction and/or overexpression of an anti-apoptotic Bcl-2 family protein is provided, where the method comprises preparing a solution or dispersion of a salt or crystalline form of Compound 1 described herein in a pharmaceutically acceptable solvent or mixture of solvents, and administering the resulting solution or dispersion in a therapeutically effective amount to a subject having the disease. Additional embodiments of the invention, including particular aspects of those provided above, will be found in, or will be evident from, the detailed description that follows. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a PXRD scan of Compound 1 anhydrate designated pattern A. FIG. 2 is a PXRD scan of Compound 1 anhydrate designated pattern B. FIG. 3 is a PXRD scan of Compound 1 hydrate designated pattern C. FIG. 4 is a PXRD scan of Compound 1 hydrate designated pattern D. FIG. 5 is a calculated PXRD pattern of Compound 1 dichloromethane solvate designated pattern E. FIG. 6 is a PXRD scan of Compound 1 ethyl acetate solvate designated pattern F. FIG. 7 is a PXRD scan of Compound 1 ethyl acetate solvate designated pattern G. FIG. 8 is a calculated PXRD pattern of Compound 1 acetonitrile solvate designated pattern H. FIG. 9 is a PXRD scan of Compound 1 acetonitrile solvate designated pattern I. FIG. 10 is a PXRD scan of Compound 1 acetone solvate designated pattern J. FIG. 11 is a calculated PXRD pattern of Compound 1 hydrochloride designated pattern K. FIG. 12 is a PXRD scan of Compound 1 hydrochloride hydrate designated pattern L. FIG. 13 is a PXRD scan of Compound 1 sulfate designated pattern M. FIG. 14 is a PXRD scan of Compound 1 tetrahydrofuran solvate designated pattern N. DETAILED DESCRIPTION The term “free base” is used for convenience herein to refer to Compound 1 parent compound as distinct from any salt thereof, while recognizing that the parent compound, strictly speaking, is zwitterionic at neutral conditions and thus does not always behave as a true base. An apoptosis-inducing agent, referred to herein as Compound 1, has the systematic name 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2, 3-b]pyri din-5-yloxy)benzamide, and can be depicted by the formula: In various embodiments, salts and crystalline forms of Compound 1 are provided. Crystalline forms include solvates, hydrates, anhydrates, and salts of Compound 1. In contrast to an amorphous form of Compound 1 free base and an amorphous form of a Compound 1 salt, a crystalline form is characterized by the presence of observable peaks in a powder x-ray diffraction (PXRD) pattern measured on the crystalline form. For crystalline forms prepared to yield suitably sized single-crystals, the crystalline form can be further characterized through an experimental determination of the unit cell parameters, the identification of the crystallographic space group to which a single crystal belongs, or both of these. Once the unit cell parameters are known, the location of the diffraction peaks, and in particular the 20 values of the peaks in a PXRD pattern can be calculated, to further characterize the crystalline form. Of course, the PXRD pattern can also be measured experimentally for such crystalline forms. If not only the cell parameters but a three dimensional single crystal structure is known, then not only the positions but also the intensity of the peaks in the diffraction pattern can be calculated in further characterization of the crystalline form. The PXRD patterns measured or calculated for the salts and crystalline forms reported herein represent a fingerprint that can be compared to other experimentally determined patterns to find a match. Identity of the respective crystalline forms is established by overlap or match of an experimentally determined PXRD pattern with the PXRD pattern of the crystalline forms reported herein. In various embodiments, the salts and crystalline forms are characterized by exhibiting at least one of the PXRD peaks reported here. Thus, in various embodiments, a salt or crystalline form is characterized by a match of two or more peaks, a match of 3 or more peaks, 4 or more peaks, or 5 or more peaks, and so on, from the respective PXRD patterns. An embodiment of the synthesis of Compound 1 (free base) and representative intermediate compounds is presented below. The exemplified compounds are named using ACD/ChemSketch Version 5.06 (5 Jun. 2001, Advanced Chemistry Development Inc., Toronto, Ontario), ACD/ChemSketch Version 12.01 (13 May 2009), Advanced Chemistry Development Inc., Toronto, Ontario), or ChemDraw® Ver. 9.0.5 (CambridgeSoft, Cambridge, Mass.). Intermediates are named using ChemDraw® Ver. 9.0.5 (CambridgeSoft, Cambridge, Mass.). Synthesis of Compound 1 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide Compound A 3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide A mixture of 4-fluoro-3-nitrobenzenesulfonamide (2.18 g), 1-(tetrahydropyran-4-yl)methylamine (1.14 g), and triethylamine (1 g) in tetrahydrofuran (30 mL) were stirred overnight, neutralized with concentrated HCl and concentrated. The residue was suspended in ethyl acetate and the precipitates were collected, washed with water and dried to provide the title compound. Compound B methyl 4,4-dimethyl-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate To a suspension of hexane washed NaH (17 g) in dichloromethane (700 mL) was added 5,5-dimethyl-2-methoxycarbonylcyclohexanone (38.5 g) dropwise at 0° C. After stirring for 30 minutes, the mixture was cooled to −78° C. and trifluoroacetic anhydride (40 mL) was added. The reaction mixture was warmed to room temperature and stirred for 24 hours. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated to give the product. Compound C methyl 2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarboxylate Compound B (62.15 g), 4-chlorophenylboronic acid (32.24 g), CsF (64 g) and tetrakis(triphenylphosphine)palladium(0) (2 g) in 2:1 dimethoxyethane/methanol (600 mL) were heated to 70° C. for 24 hours. The mixture was concentrated. Ether (4×200 mL) was added and the mixture was filtered. The combined ether solution was concentrated to give the product. Compound D (2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol To a mixture of LiBH4 (13 g), Compound C (53.8 g) and ether (400 mL), was added methanol (25 mL) slowly by syringe. The mixture was stirred at room temperature for 24 hours. The reaction was quenched with 1N HCl with ice-cooling. The mixture was diluted with water and extracted with ether (3×100 mL). The extracts were dried (Na2SO4), filtered, and concentrated. The crude product was chromatographed on silica gel with 0-30% ethyl acetate/hexanes. Compound E tert-butyl 4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-carboxylate Mesyl Chloride (7.5 mL) was added via syringe to Compound D (29.3 g) and triethylamine (30 mL) in CH2Cl2 (500 mL) at 0° C., and the mixture was stirred for 1 minute. N-t-butoxycarbonylpiperazine (25 g) was added and the mixture was stirred at room temperature for 24 hours. The suspension was washed with brine, dried, (Na2SO4), filtered, and concentrated. The crude product was chromatographed on silica gel with 10-20% ethyl acetate/hexanes. Compound F 1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine Compound E (200 mg) and triethylsilane (1 mL) were stirred in dichloromethane (15 mL) and trifluoroacetic acid (15 mL) for 1 hour. The mixture was concentrated, taken up in ethyl acetate, washed twice with NaH2PO4, and brine, and dried (Na2SO4), filtered and concentrated. Compound G 5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine To a mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (15.4 g) in tetrahydrofuran (250 mL) was added 1M lithium hexamethyldisilazide in tetrahydrofuran (86 mL), and after 10 minutes, TIPS-Cl (triisopropylchlorosilane) (18.2 mL) was added. The mixture was stirred at room temperature for 24 hours. The reaction was diluted with ether, and the resulting solution was washed twice with water. The extracts were dried (Na2SO4), filtered, and concentrated. The crude product was chromatographed on silica gel with 10% ethyl acetate/hexanes. Compound H 1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-ol To a mixture of Compound G (24.3 g) in tetrahydrofuran (500 mL) at −78° C. was added 2.5M BuLi (30.3 mL). After 2 minutes, trimethylborate (11.5 mL) was added, and the mixture was allowed to warm to room temperature over 1 hour. The reaction was poured into water, extracted thee times with ethyl acetate, and the combined extracts were washed with brine and concentrated. The crude product was taken up in tetrahydrofuran (200 mL) at 0° C., and 1M NaOH (69 mL) was added, followed by 30% H2O2 (8.43 mL), and the solution was stirred for 1 hour. Na2S2O3 (10 g) was added, and the pH was adjusted to 4-5 with concentrated HCl and solid NaH2PO4. The solution was extracted twice with ethyl acetate, and the combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The crude product was chromatographed on silica gel with 5-25% ethyl acetate/hexanes. Compound I methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-fluorobenzoate A mixture of Compound H (8.5 g), methyl 2,4-difluorobenzoate (7.05 g), and K3PO4 (9.32 g) in diglyme (40 mL) at 115° C. was stirred for 24 hours. The reaction was cooled, diluted with ether (600 mL), and washed twice with water, and brine, and concentrated. The crude product was chromatographed on silica gel with 2-50% ethyl acetate/hexanes. Compound J methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate A mixture of Compound I (1.55 g), Compound F (2.42 g), and HK2PO4 (1.42 g) in dimethylsulfoxide (20 mL) at 135° C. was stirred for 24 hours. The reaction was cooled, diluted with ether (400 mL), and washed with 3×1M NaOH, and brine, and concentrated. The crude product was chromatographed on silica gel with 10-50% ethyl acetate/hexanes. Compound K 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid Compound J (200 mg) in dioxane (10 mL) and 1M NaOH (6 mL) at 50° C. was stirred for 24 hours. The reaction was cooled, added to NaH2PO4 solution, and extracted thee times with ethyl acetate. The combined extracts were washed with brine, and concentrated to give the pure product. Compound L (Compound 1 Free Base) 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide Compound K (3.39 g), Compound A (1.87 g), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (2.39 g), and 4-dimethylaminopyridine (1.09 g) were stirred in CH2Cl2 (40 mL) for 24 hours. The reaction was cooled and chromatographed on silica gel with 25-100% ethyl acetate/hexanes, then 10% methanol/ethyl acetate with 1% acetic acid, to give the product (1.62 g, 32%) as a solid. 1H NMR (300 MHz, dimethylsulfoxide-d6) 11.65 (brs, 1H), 8.55 (br s, 1H), 8.04 (d, 1H), 7.89 (dd, 1H), 7.51 (m, 3H), 7.33 (d, 2H), 7.08 (m, 1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.39 (d, 1H), 6.19 (d, 1H), 3.84 (m, 1H), 3.30 (m, 4H), 3.07 (m, 4H), 2.73 (m, 2H), 2.18 (m, 6H), 1.95 (m, 2H), 1.61 (dd, 2H), 1.38 (m, 2H), 1.24 (m, 4H), 0.92 (s, 6H). Preparation of Compound 1 free base is also described in Example 5 of U.S. application Ser. No. 12/787,682 (published as U.S. 2010/0305122) titled “Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases,” the entire disclosure of which is incorporated herein by reference. A solid can be prepared from the chromatography eluate; for example, by using freeze-drying, precipitation, or rotary evaporation techniques. The product of this process can be a solid that is amorphous in character. Salts and crystal forms of Compound 1 have been prepared as described in the following examples. Compound 1 Free Base Anhydrate (PXRD Pattern A) The following two routes can prepare this crystalline form, where drying at ambient conditions involves leaving the solid material at room temperature and exposed to air overnight. For example, solvent can be allowed to evaporate. Example 1 Compound 1 free base dichloromethane solvate having pattern E (see below) was dried at ambient conditions. Example 2 Compound 1 free base ethyl acetate solvate having pattern F (see below) was dried at ambient conditions. Powder X-ray diffraction pattern and peak listing are shown in FIG. 1 and Table 1, respectively. TABLE 1 Peak Listing for Compound 1 Free Base Anhydrate Pattern A Peak Position (°2θ) 6.3 7.1 9.0 9.5 12.5 14.5 14.7 15.9 16.9 18.9 Compound 1 Free Base Anhydrate (PXRD Pattern B) Example 3 Compound 1 free base acetonitrile solvate pattern H was dried at ambient conditions. Powder X-ray diffraction pattern and peak listing are shown in FIG. 2 and Table 2, respectively. TABLE 2 Peak Listing for Compound 1 Free Base Anhydrate Pattern B Peak Position (°2θ) 5.8 7.7 8.3 9.9 13.0 13.3 14.2 15.3 16.6 17.9 18.3 19.8 20.7 21.2 21.9 22.5 23.6 24.1 Compound 1 Free Base Hydrate (PXRD Pattern C) The free base hydrate, characterized by Pattern C, can be prepared in three ways. Example 4 Compound 1 free base methanol solvate was dried at ambient conditions. Example 5 Compound 1 free base ethanol solvate was dried at ambient conditions. Example 6 Compound 1 free base 2-propanol solvate was dried at ambient conditions. Powder X-ray diffraction pattern and peak listing are shown in FIG. 3 and Table 3, respectively. TABLE 3 Peak Listing for Compound 1 Free Base Hydrate Pattern C Peak Position (°2θ) 5.8 7.6 7.9 10.7 11.7 14.0 15.3 15.8 17.4 18.3 19.9 20.4 20.7 22.5 24.9 25.8 26.7 Compound 1 Free Base Hydrate (PXRD Pattern D) Example 7 Compound 1 free base ethyl acetate solvate pattern G was dried at ambient conditions. Powder X-ray diffraction pattern and peak listing are shown in FIG. 4 and Table 4, respectively. TABLE 4 Peak Listing for Compound 1 Free Base Hydrate Pattern D Peak Position (°2θ) 3.3 6.4 7.1 7.3 10.1 11.4 13.2 14.4 14.6 15.1 15.8 16.2 17.2 17.6 18.0 18.6 19.0 19.5 19.8 20.2 20.7 21.0 22.5 23.0 26.0 28.9 29.2 Compound 1 Free Base Dichloromethane Solvate (PXRD Pattern E) Example 8 Compound 1 free base solid was suspended in dichloromethane at ambient temperatures to reach its solubility. After equilibrating, the solids were isolated at ambient temperature. Powder X-ray diffraction pattern and peak listing are shown in FIG. 5 and Table 5A, respectively. Crystallographic information is listed in Table 5B. TABLE 5A Calculated PXRD Peak Listing for Compound 1 Free Base Dichloromethane Solvate Pattern E Peak Position (°2θ) 5.9 7.1 9.6 10.0 10.7 11.1 13.2 14.8 18.2 TABLE 5B Structural Information for Compound 1 Free Base Dichloromethane Solvate Single Crystal Crystal Form Compound 1 Free Base Dichloromethane Solvate Lattice Type Monoclinic Space Group P21/n a (Å) 13.873 b (Å) 12.349 c (Å) 29.996 α (°) 90.00 β (°) 92.259 γ (°) 90.00 Volume (Å3) 5134.85 Z 4 Compound 1 Free Base Ethyl Acetate Solvate (PXRD Pattern F) Example 9 Compound 1 free base solid was suspended in ethyl acetate at ambient temperatures to reach its solubility. After equilibrating, the solids were isolated at ambient temperature. Powder X-ray diffraction pattern and peak listing are shown in FIG. 6 and Table 6, respectively. TABLE 6 PXRD Peak Listing for Compound 1 Free Base Ethyl Acetate Solvate Pattern F Peak Position (°2θ) 5.8 7.1 9.5 9.9 10.6 11.6 13.1 13.8 14.8 16.0 17.9 20.2 21.2 23.2 24.4 26.4 Compound 1 Free Base Ethyl Acetate Solvate (PXRD Pattern G) Example 10 Compound 1 free base solid was suspended in ethyl acetate saturated with water at ambient temperatures to reach its solubility. After equilibrating, the solids were isolated at ambient temperature. Powder X-ray diffraction pattern and peak listing shown in FIG. 7 and Table 7, respectively. TABLE 7 PXRD Peak Listing for Compound 1 Free Base Ethyl Acetate Solvate Pattern G Peak Position (°2θ) 3.3 6.5 7.0 7.3 9.2 9.7 11.2 11.4 11.9 12.9 14.4 14.9 15.8 16.2 17.2 17.4 17.8 18.5 18.9 19.4 20.1 20.7 20.9 22.0 22.7 23.4 23.8 24.7 25.9 27.0 28.9 Compound 1 Free Base Acetonitrile Solvate (PXRD Pattern H) Example 11 Compound 1 free base solid was suspended in acetonitrile at ambient temperatures to reach its solubility. After equilibrating, the solids were isolated at ambient temperature. Powder X-ray diffraction pattern and peak listing are shown in FIG. 8 and Table 8A, respectively. Crystallographic information is listed in Table 8B. TABLE 8A Calculated PXRD Peak Listing for Compound 1 Free Base Acetonitrile Solvate Pattern H Peak Position (°2θ) 5.8 7.4 7.6 10.2 13.0 13.6 14.9 16.4 17.0 17.5 18.2 19.4 19.7 20.4 21.0 21.2 21.8 22.4 22.9 24.2 24.3 26.1 29.2 TABLE 8B Structural information for Compound 1 Free Base Acetonitrile Solvate H Single Crystal Crystal Form Compound 1 Free Base Acetonitrile Solvate A Lattice Type Triclinic Space Group P1 a (Å) 12.836 b (Å) 13.144 c (Å) 15.411 α (°) 92.746 β (°) 95.941 γ (°) 113.833 Volume (Å3) 2354.06 Z 2 Compound 1 Free Base Acetonitrile Solvate (PXRD Pattern I) Example 12 To a solution of 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid (16 g, 28 mmol) and 3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide (8.83 g, 28 mmol) in DCM (300 mL) was added EDCI (10.74 g, 56 mmol) and DMAP (6.85 g, 56 mmol). The mixture was stirred at r.t. overnight. LC/MS showed the expected product as a single peak. The mixture was diluted with DCM (500 ml) and washed with aq. NaHCO3, water, brine and dried over Na2SO4. The residue after evaporation of solvent was dissolved in DCM and loaded on a column and eluted with 30% ethyl acetate in DCM followed by 1 to 2% MeOH in DCM to give 24.5 g pure product (95% purity) which was dissolved in DMSO and MeOH (1:1) and TFA (2eq) and loaded on a 330 g C18 column (6 g a time) to give 13.5 g pure (>99.7% purity) product (55% yield). The API was extracted using dichloromethane and then, the solvent was removed using rotary evaporator. The resulting solid was suspended in acetonitrile at ambient temperatures to reach its solubility. After equilibrating, the solids were isolated at ambient temperature. Powder X-ray diffraction pattern and peak listing are shown in FIG. 9 and Table 9, respectively. TABLE 9 PXRD Peak Listing for Compound 1 Free Base Acetonitrile Solvate Pattern I Peak Position (°2θ) 6.4 6.9 7.7 8.8 9.4 11.1 12.3 12.8 16.5 17.0 17.4 18.3 18.6 19.0 19.2 20.3 21.6 22.3 22.9 23.7 Compound 1 Free Base Acetone Solvate (PXRD Pattern J) Example 13 Compound 1 free base solid was suspended in acetone at ambient temperatures to reach its solubility. After equilibrating, the solids were isolated at ambient temperature. Powder X-ray diffraction pattern and peak listing are shown in FIG. 10 and Table 10, respectively. TABLE 10 PXRD Peak Listing for Compound 1 Free Base Acetone Solvate Pattern J Peak Position (°2θ) 6.0 6.8 8.0 9.0 9.7 11.2 11.9 12.6 14.7 15.0 15.2 15.8 16.4 16.6 17.6 17.8 17.9 18.7 20.2 20.8 21.6 22.2 22.6 23.3 23.8 24.0 24.4 26.8 27.1 28.0 28.2 Compound 1 Hydrochloride (PXRD Pattern K) Example 14 Compound 1 free base solid (16 mg, 0.018 mmol) was suspended in 0.5 mL of acetonitrile. Hydrochloric acid (1M, 25 μL) was added to the suspension while stirring (molar ratio of Compound 1:acid=1:1.4). Compound 1 quickly reacted with hydrochloric acid and formed a clear solution. Yellowish solids, which later crystallized from the solution, were confirmed to be Compound 1 hydrochloride in a 1:1 stoichiometric ratio of free base to HCl. Powder X-ray diffraction pattern and peak listing can be seen in FIG. 11, and Table 11A, respectively. Crystallographic information is listed in Table 11B. TABLE 11A Calculated PXRD Peak Listing of Compound 1 Hydrochloride Pattern K Peak Position (°2θ) 5.1 5.9 7.7 9.9 10.2 10.8 13.6 14.0 15.4 15.9 16.2 17.6 18.3 18.7 19.7 19.9 20.1 20.4 20.7 20.9 22.9 26.2 TABLE 11B Structural information for Compound 1 Hydrochloride Crystal Form Compound 1 Hydrochloride Lattice Type Triclinic Space Group P1 a (Å) 10.804 b (Å) 12.372 c (Å) 19.333 α (°) 76.540 β (°) 87.159 γ (°) 70.074 Volume (Å3) 2361.5 Z 2 Compound 1 Hydrochloride Hydrate (PXRD Pattern L) Example 15 Compound 1 hydrochloride solid (having pattern K) was exposed to the air under ambient conditions, and was confirmed to be Compound 1 hydrochloride hydrate. Powder X-ray diffraction pattern and peak listing can be seen in FIG. 12, and Table 12, respectively. TABLE 12 PXRD Peak Listing for Compound 1 Hydrochloride Hydrate Pattern L Peak Position (°2θ) 4.6 8.7 9.6 9.9 12.3 14.9 15.7 17.6 18.1 18.4 19.3 19.6 21.0 23.3 23.9 24.8 26.5 27.2 27.4 29.0 30.1 Compound 1 Sulfate (PXRD Pattern M) Example 16 Compound 1 free base solid (16 mg, 0.018 mmol) was suspended in 0.5 mL of 2-propanol at 70° C. Sulfuric acid (1M, 25 μL) was added to the suspension while stirring (molar ratio of Compound 1:acid=1:1.4). Compound 1 quickly dissolved by reacting with sulfuric acid. Yellowish solids crystallized from the solution immediately after the dissolution occurred. The crystalline solid was confirmed to be Compound 1 sulfate with a stoichiometry of 1:1 using ion chromatography. Powder X-ray diffraction pattern and peak listing can be seen in FIG. 13, and Table 13, respectively. TABLE 13 PXRD Peak Listing for Compound 1 Sulfate Pattern M Peak Position (°2θ) 4.8 7.7 8.3 9.7 10.2 12.0 12.6 14.5 15.4 17.4 17.9 18.4 19.1 19.5 21.0 22.4 23.3 23.9 25.1 26.8 Compound 1 Free Base THF Solvate (PXRD Pattern N) Example 17 Compound 1 free base solid was suspended in tetrahydrofuran (THF) at ambient temperatures to reach its solubility. After equilibrating, the solids were isolated at ambient temperature. Powder X-ray diffraction pattern and peak listing are shown in FIG. 14 and Table 14, respectively. TABLE 14 PXRD Peak Listing for Compound 1 Free Base THF Solvate Pattern N Peak Position (°2θ) 4.0 4.6 8.0 8.5 9.4 14.6 17.1 17.4 17.8 18.1 19.2 19.5 20.1 20.4 20.5 21.7 PXRD data were collected using a G3000 diffractometer (Inel Corp., Artenay, France) equipped with a curved position-sensitive detector and parallel-beam optics. The diffractometer was operated with a copper anode tube (1.5 kW fine focus) at 40 kV and 30 mA. An incident-beam germanium monochromator provided monochromatic radiation Cu-Kα radiation, which has a wavelength of 1.54178 Å. The diffractometer was calibrated using the attenuated direct beam at one-degree intervals. Calibration was checked using a silicon powder line position reference standard (NIST 640c). The instrument was computer-controlled using Symphonix software (Inel Corp., Artenay, France) and the data were analyzed using Jade software (version 6.5, Materials Data, Inc., Livermore, Calif.). The sample was loaded onto an aluminum sample holder and leveled with a glass slide. PXRD peak position measurements are typically ±0.2 degrees two-theta (° 2θ). In some embodiments, the percent crystallinity of any of the salt or crystalline forms of Compound 1 described herein can vary with respect to the total amount of Compound 1. In particular, certain embodiments provide for the percent crystallinity of a salt or crystalline form of Compound 1 being at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least, 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99%. In some embodiments, the percent crystallinity can be substantially 100%, where substantially 100% indicates that the entire amount of Compound 1 appears to be crystalline as best can be determined using methods known in the art. Accordingly, pharmaceutical compositions and therapeutically effective amounts of Compound 1 can include amounts that vary in crystallinity. These include instances where Compound 1 is used as API in various formulations and solid forms, including where an amount of Compound 1 in a solid form is subsequently dissolved, partially dissolved, or suspended or dispersed in a liquid. As noted, in some embodiments API compositions are provided that comprise Compound 1, wherein at least a portion of the Compound 1 in the API composition is in one of the salt or crystalline forms. For example, an API composition containing Compound 1 has at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% or at least 99% of the compound of the composition in one of the salt or crystalline forms. In some embodiments, essentially 100% of the Compound 1 of an API formulation is in a salt or crystalline form as described herein. Any of the crystalline forms of Compound 1, including salts and solvated forms, can be useful as an active pharmaceutical ingredient (API) for preparation of pharmaceutical compositions. However, solvent-free forms are generally preferred for this purpose. A hydrate is considered solvent-free for this purpose. Solvated forms can be, as indicated above, useful as process intermediates in preparation of solvent-free forms. Compound 1 salts and crystalline forms can be used in preparation of pharmaceutical compositions suitable for various routes of administration, including oral, to a subject in need thereof. Thus, in some embodiments, a pharmaceutical composition is provided, comprising a crystalline form of Compound 1 and one or more pharmaceutically acceptable excipients. Such compositions can be prepared using various known processes of pharmacy. In some embodiments, the salt or crystalline form of Compound 1 includes those of Compound 1 free base anhydrate having PXRD pattern A, Compound 1 free base anhydrate having PXRD pattern B, Compound 1 free base hydrate having PXRD pattern C, Compound 1 free base hydrate having PXRD pattern D, Compound 1 free base dichloromethane solvate having pattern E, Compound 1 free base ethyl acetate solvate having PXRD pattern F, Compound 1 free base ethyl acetate solvate having PXRD pattern G, Compound 1 free base acetonitrile solvate having PXRD pattern H, Compound 1 free base acetonitrile solvate having PXRD pattern I, Compound 1 free base acetone solvate having PXRD pattern J, Compound 1 hydrochloride having PXRD pattern K, Compound 1 hydrochloride hydrate having PXRD pattern L, Compound 1 sulfate having PXRD pattern M, and Compound 1 free base tetrahydrofuran (THF) solvate having PXRD pattern N, each having the respective powder X-ray diffraction patterns as described herein. According to any of these embodiments, the composition can be deliverable, for example, by the oral route. Other routes of administration include without limitation parenteral, sublingual, buccal, intranasal, pulmonary, topical, transdermal, intradermal, ocular, otic, rectal, vaginal, intragastric, intracranial, intrasynovial and intra-articular routes. Where it is desired to provide Compound 1 free base or salt in solution form, for example in a liquid formulation for oral or parenteral administration, the Compound 1 free base or salt will not, of course, be present in such a formulation in crystalline form; indeed, the presence of crystals is generally undesired in such a formulation. However, a crystalline form of Compound 1 free base can nonetheless be important as API in a process for preparing such a formulation. Thus, the present disclosure further provides a process for preparing a pharmaceutical solution composition of Compound 1 comprising dissolving a crystalline salt or a crystalline form of Compound 1 free base in a pharmaceutically acceptable solvent or mixture of solvents. Even where the desired formulation is one containing Compound 1 free base in amorphous form, for example a solid melt formulation, a crystalline form of Compound 1 free base can still be useful as API in a process for preparing such a formulation. As API, a crystalline form of Compound 1 free base or mixtures thereof can have advantages over an amorphous form. For example, purification of API to the high degree of purity required by most regulatory authorities can be more efficient and therefore cost less where the API is in crystalline form as opposed to amorphous form. Physical and chemical stability, and therefore shelf-life of the API solid, can also be better for crystalline than amorphous forms. Ease of handling can be improved over the amorphous form, which can be oily or sticky. Drying can be more straightforward and more easily controlled in the case of the crystalline material, which can have a well-defined drying or desolvation temperature, than in the case of the amorphous material, which can have greater affinity for organic solvents and no well-defined drying temperature. Downstream processing using crystalline API can further permit enhanced process control. In preparing a liquid formulation, for example a solution in a lipid carrier, crystalline Compound 1 can dissolve faster and can have a reduced tendency to form a gel during dissolution. These advantages are illustrative and non-limiting. Pharmaceutical compositions comprising crystalline Compound 1 free base, or prepared using crystalline Compound 1 free base or salts of Compound 1 as API, contain Compound 1 in an amount that can be therapeutically effective when the composition is administered to a subject in need thereof according to an appropriate regimen. Dosage amounts are expressed herein as free base equivalent amounts unless the context requires otherwise. Typically, a unit dose (the amount administered at a single time), which can be administered at an appropriate frequency, e.g., twice daily to once weekly, is about 10 to about 1,000 mg. Where frequency of administration is once daily (q.d.), unit dose and daily dose are the same. Illustratively, the unit dose of Compound 1 in a composition of the invention can be about 25 to about 1,000 mg, more typically about 50 to about 500 mg, for example about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450 or about 500 mg. Where the composition is prepared as a discrete dosage form such as a tablet or capsule, a unit dose can be deliverable in a single dosage form or a small plurality of dosage forms, most typically 1 to about 10 dosage forms. The higher the unit dose, the more desirable it becomes to select excipients that permit a relatively high loading of API (in this case Compound 1 free base or salt) in the formulation. Typically, the concentration of Compound 1 in a formulation prepared according to the present disclosure is at least about 1%, e.g., about 1% to about 25%, by weight, but lower and higher concentrations can be acceptable or achievable in specific cases. Illustratively, the Compound 1 free base equivalent concentration in various embodiments is at least about 2%, e.g., about 2% to about 20%, by weight, for example about 5%, about 10% or about 15%, by weight of the formulation. A composition prepared according to the invention comprises, in addition to the API, one or more pharmaceutically acceptable excipients. If the composition is to be prepared in solid form for oral administration, for example as a tablet or capsule, it typically includes at least one or more solid diluents and one or more solid disintegrants. Optionally, the excipients further include one or more binding agents, wetting agents and/or antifrictional agents (lubricants, anti-adherents and/or glidants). Many excipients have two or more functions in a pharmaceutical composition. Characterization herein of a particular excipient as having a certain function, e.g., diluent, disintegrant, binding agent, etc., should not be read as limiting to that function. Further information on excipients can be found in standard reference works such as Handbook of Pharmaceutical Excipients, 3rd ed. (Kibbe, ed. (2000), Washington: American Pharmaceutical Association). Suitable diluents illustratively include, either individually or in combination, lactose, including anhydrous lactose and lactose monohydrate; lactitol; maltitol; mannitol; sorbitol; xylitol; dextrose and dextrose monohydrate; fructose; sucrose and sucrose-based diluents such as compressible sugar, confectioner's sugar and sugar spheres; maltose; inositol; hydrolyzed cereal solids; starches (e.g., corn starch, wheat starch, rice starch, potato starch, tapioca starch, etc.), starch components such as amylose and dextrates, and modified or processed starches such as pregelatinized starch; dextrins; celluloses including powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, food grade sources of α- and amorphous cellulose and powdered cellulose, and cellulose acetate; calcium salts including calcium carbonate, tribasic calcium phosphate, dibasic calcium phosphate dihydrate, monobasic calcium sulfate monohydrate, calcium sulfate and granular calcium lactate trihydrate; magnesium carbonate; magnesium oxide; bentonite; kaolin; sodium chloride; and the like. Such diluents, if present, typically constitute in total about 5% to about 95%, for example about 20% to about 90%, or about 50% to about 85%, by weight of the composition. The diluent or diluents selected preferably exhibit suitable flow properties and, where tablets are desired, compressibility. Microcrystalline cellulose and silicified microcrystalline cellulose are particularly useful diluents, and are optionally used in combination with a water-soluble diluent such as mannitol. Illustratively, a suitable weight ratio of microcrystalline cellulose or silicified microcrystalline cellulose to mannitol is about 10:1 to about 1:1, but ratios outside this range can be useful in particular circumstances. Suitable disintegrants include, either individually or in combination, starches including pregelatinized starch and sodium starch glycolate; clays; magnesium aluminum silicate; cellulose-based disintegrants such as powdered cellulose, microcrystalline cellulose, methylcellulose, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, carmellose sodium and croscarmellose sodium; alginates; povidone; crospovidone; polacrilin potassium; gums such as agar, guar, locust bean, karaya, pectin and tragacanth gums; colloidal silicon dioxide; and the like. One or more disintegrants, if present, typically constitute in total about 0.2% to about 30%, for example about 0.5% to about 20%, or about 1% to about 10%, by weight of the composition. Sodium starch glycolate is a particularly useful disintegrant, and typically constitutes in total about 1% to about 20%, for example about 2% to about 15%, or about 5% to about 10%, by weight of the composition. Binding agents or adhesives are useful excipients, particularly where the composition is in the form of a tablet. Such binding agents and adhesives should impart sufficient cohesion to the blend being tableted to allow for normal processing operations such as sizing, lubrication, compression and packaging, but still allow the tablet to disintegrate and the composition to be absorbed upon ingestion. Suitable binding agents and adhesives include, either individually or in combination, acacia; tragacanth; glucose; polydextrose; starch including pregelatinized starch; gelatin; modified celluloses including methylcellulose, carmellose sodium, hydroxypropylmethyl cellulose (HPMC), hydroxypropylcellulose, hydroxyethylcellulose and ethylcellulose; dextrins including maltodextrin; zein; alginic acid and salts of alginic acid, for example sodium alginate; magnesium aluminum silicate; bentonite; polyethylene glycol (PEG); polyethylene oxide; guar gum; polysaccharide acids; polyvinylpyrrolidone (povidone or PVP), for example povidone K-15, K-30 and K-29/32; polyacrylic acids (carbomers); polymethacrylates; and the like. One or more binding agents and/or adhesives, if present, typically constitute in total about 0.5% to about 25%, for example about 1% to about 15%, or about 1.5% to about 10%, by weight of the composition. Povidone and hydroxypropylcellulose, either individually or in combination, are particularly useful binding agents for tablet formulations, and, if present, typically constitute about 0.5% to about 15%, for example about 1% to about 10%, or about 2% to about 8%, by weight of the composition. Wetting agents, if present, are normally selected to maintain the drug in close association with water, a condition that can improve bioavailability of the composition. Non-limiting examples of surfactants that can be used as wetting agents include, either individually or in combination, quaternary ammonium compounds, for example benzalkonium chloride, benzethonium chloride and cetylpyridinium chloride; dioctyl sodium sulfosuccinate; polyoxyethylene alkylphenyl ethers, for example nonoxynol 9, nonoxynol 10 and octoxynol 9; poloxamers (polyoxyethylene and polyoxypropylene block copolymers); polyoxyethylene fatty acid glycerides and oils, for example polyoxyethylene (8) caprylic/capric mono- and diglycerides, polyoxyethylene (35) castor oil and polyoxyethylene (40) hydrogenated castor oil; polyoxyethylene alkyl ethers, for example ceteth-10, laureth-4, laureth-23, oleth-2, oleth-10, oleth-20, steareth-2, steareth-10, steareth-20, steareth-100 and polyoxyethylene (20) cetostearyl ether; polyoxyethylene fatty acid esters, for example polyoxyethylene (20) stearate, polyoxyethylene (40) stearate and polyoxyethylene (100) stearate; sorbitan esters, for example sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate and sorbitan monostearate; polyoxyethylene sorbitan esters, for example polysorbate 20 and polysorbate 80; propylene glycol fatty acid esters, for example propylene glycol laurate; sodium lauryl sulfate; fatty acids and salts thereof, for example oleic acid, sodium oleate and triethanolamine oleate; glyceryl fatty acid esters, for example glyceryl monooleate, glyceryl monostearate and glyceryl palmitostearate; tyloxapol; and the like. One or more wetting agents, if present, typically constitute in total about 0.1% to about 15%, for example about 0.2% to about 10%, or about 0.5% to about 7%, by weight of the composition. Nonionic surfactants, more particularly poloxamers, are examples of wetting agents that can be useful herein. Illustratively, a poloxamer such as Pluronic™ F127, if present, can constitute about 0.1% to about 10%, for example about 0.2% to about 7%, or about 0.5% to about 5%, by weight of the composition. Lubricants reduce friction between a tableting mixture and tableting equipment during compression of tablet formulations. Suitable lubricants include, either individually or in combination, glyceryl behenate; stearic acid and salts thereof, including magnesium, calcium and sodium stearates; hydrogenated vegetable oils; glyceryl palmitostearate; talc; waxes; sodium benzoate; sodium acetate; sodium fumarate; sodium stearyl fumarate; PEGs (e.g., PEG 4000 and PEG 6000); poloxamers; polyvinyl alcohol; sodium oleate; sodium lauryl sulfate; magnesium lauryl sulfate; and the like. One or more lubricants, if present, typically constitute in total about 0.05% to about 10%, for example about 0.1% to about 5%, or about 0.2% to about 2%, by weight of the composition. Sodium stearyl fumarate is a particularly useful lubricant. Anti-adherents reduce sticking of a tablet formulation to equipment surfaces. Suitable anti-adherents include, either individually or in combination, talc, colloidal silicon dioxide, starch, DL-leucine, sodium lauryl sulfate and metallic stearates. One or more anti-adherents, if present, typically constitute in total about 0.05% to about 10%, for example about 0.1% to about 7%, or about 0.2% to about 5%, by weight of the composition. Colloidal silicon dioxide is a particularly useful anti-adherent. Glidants improve flow properties and reduce static in a tableting mixture. Suitable glidants include, either individually or in combination, colloidal silicon dioxide, starch, powdered cellulose, sodium lauryl sulfate, magnesium trisilicate and metallic stearates. One or more glidants, if present, typically constitute in total about 0.05% to about 10%, for example about 0.1% to about 7%, or about 0.2% to about 5%, by weight of the composition. Colloidal silicon dioxide is a particularly useful glidant. Other excipients such as buffering agents, stabilizers, antioxidants, antimicrobials, colorants, flavors and sweeteners are known in the pharmaceutical art and can be used in compositions of the present invention. Tablets can be uncoated or can comprise a core that is coated, for example with a nonfunctional film or a release-modifying or enteric coating. Capsules can have hard or soft shells comprising, for example, gelatin (in the form of hard gelatin capsules or soft elastic gelatin capsules), starch, carrageenan and/or HPMC, optionally together with one or more plasticizers. A solid orally deliverable composition of the present invention is not limited by any process used to prepare it. Any suitable process of pharmacy can be used, including dry blending with or without direct compression, and wet or dry granulation. If the composition is to be prepared in liquid (including encapsulated liquid) form, the API (e.g., crystalline Compound 1 free base or salt) can be, for example, dissolved in a suitable carrier, typically one comprising a lipid solvent for the API. The higher the unit dose, the more desirable it becomes to select a carrier that permits a relatively high concentration of the drug in solution therein. Typically, the free base equivalent concentration of API in the carrier is at least about 10 mg/ml, e.g., about 10 to about 500 mg/ml, but lower and higher concentrations can be acceptable or achievable in specific cases. Illustratively, the drug concentration in various embodiments is at least about 10 mg/ml, e.g., about 10 to about 250 mg/ml, or at least about 20 mg/ml, e.g., about 20 to about 200 mg/ml, for example about 20, about 25, about 30, about 40, about 50, about 75, about 100 or about 150 mg/ml. The carrier can be substantially non-aqueous, i.e., having no water, or having an amount of water that is small enough to be, in practical terms, essentially non-deleterious to performance or properties of the composition. Typically, the carrier comprises zero to less than about 5% by weight water. It will be understood that certain ingredients useful herein can bind small amounts of water on or within their molecules or supramolecular structures; such bound water if present does not affect the “substantially non-aqueous” character of a carrier as defined herein. In some embodiments, the carrier comprises one or more glyceride materials. Suitable glyceride materials include, without limitation, medium to long chain mono-, di- and triglycerides. The term “medium chain” herein refers to hydrocarbyl chains individually having no less than about 6 and less than about 12 carbon atoms, including for example C8 to C10 chains. Thus glyceride materials comprising caprylyl and capryl chains, e.g., caprylic/capric mono-, di- and/or triglycerides, are examples of “medium chain” glyceride materials herein. The term “long chain” herein refers to hydrocarbyl chains individually having at least about 12, for example about 12 to about 18, carbon atoms, including for example lauryl, myristyl, cetyl, stearyl, oleyl, linoleyl and linolenyl chains. Medium to long chain hydrocarbyl groups in the glyceride materials can be saturated, mono- or polyunsaturated. In one embodiment the carrier comprises a medium chain and/or a long chain triglyceride material. A suitable example of a medium chain triglyceride material is a caprylic/capric triglyceride product such as, for example, Captex 355 EP™ of Abitec Corp. and products substantially equivalent thereto. Suitable examples of long chain triglycerides include any pharmaceutically acceptable vegetable oil, for example canola, coconut, corn, cottonseed, flaxseed, olive, palm, peanut, safflower, sesame, soy and sunflower oils, and mixtures of such oils. Oils of animal, particularly marine animal, origin can also be used, including for example fish oil. In some embodiments the carrier comprises a phospholipid and a pharmaceutically acceptable solubilizing agent for the phospholipid. It will be understood that reference in the singular to a (or the) phospholipid, solubilizing agent or other formulation ingredient herein includes the plural; thus combinations, for example mixtures, of more than one phospholipid, or more than one solubilizing agent, are expressly contemplated herein. The solubilizing agent, or the combination of solubilizing agent and phospholipid, also solubilizes the drug, although other carrier ingredients, such as a surfactant or an alcohol such as ethanol, optionally present in the carrier can in some circumstances provide enhanced solubilization of the drug. Any pharmaceutically acceptable phospholipid or mixture of phospholipids can be used. In general such phospholipids are phosphoric acid esters that yield on hydrolysis phosphoric acid, fatty acid(s), an alcohol and a nitrogenous base. Pharmaceutically acceptable phospholipids can include without limitation phosphatidylcholines, phosphatidylserines and phosphatidylethanolamines. In one embodiment the composition comprises phosphatidylcholine, derived for example from natural lecithin. Any source of lecithin can be used, including animal sources such as egg yolk, but plant sources are generally preferred. Soy is a particularly rich source of lecithin that can provide phosphatidylcholine for use in the present invention. Illustratively, a suitable amount of phospholipid is about 15% to about 75%, for example about 30% to about 60%, by weight of the carrier, although greater and lesser amounts can be useful in particular situations. Ingredients useful as components of the solubilizing agent are not particularly limited and will depend to some extent on the desired concentration of drug and of phospholipid. In one embodiment, the solubilizing agent comprises one or more glycols and/or one or more glyceride materials. Suitable glycols include propylene glycol and polyethylene glycols (PEGs) having molecular weight of about 200 to about 1,000 g/mol, e.g., PEG-400, which has an average molecular weight of about 400 g/mol. Such glycols can provide relatively high solubility of the drug; however the potential for oxidative degradation of the drug can be increased when in solution in a carrier comprising such glycols, for example because of the tendency of glycols to produce superoxides, peroxides and/or free hydroxyl radicals. The higher the glycol content of the carrier, the greater may be the tendency for degradation of a chemically unstable drug. In one embodiment, therefore, one or more glycols are present in a total glycol amount of at least about 1% but less than about 50%, for example less than about 30%, less than about 20%, less than about 15% or less than about 10% by weight of the carrier. In another embodiment, the carrier comprises substantially no glycol. Suitable glyceride materials for use together with a phospholipid include, without limitation, those mentioned above. Where one or more glyceride materials are present as a major component of the solubilizing agent, a suitable total amount of glycerides is an amount effective to solubilize the phospholipid and, in combination with other components of the carrier, effective to maintain the drug and antioxidant in solution. For example, glyceride materials such as medium chain and/or long chain triglycerides can be present in a total glyceride amount of about 5% to about 70%, for example about 15% to about 60% or about 25% to about 50%, by weight of the carrier. Additional solubilizing agents that are other than glycols or glyceride materials can be included if desired. Such agents, for example N-substituted amide solvents such as dimethylformamide (DMF) and N,N-dimethylacetamide (DMA), can, in specific cases, assist in raising the limit of solubility of the drug in the carrier, thereby permitting increased drug loading. However, N-substituted amides including DMF and DMA can present regulatory and/or toxicological issues that restrict the amount of such solvents that can be used in a formulation. Furthermore, the carriers useful herein generally provide adequate solubility of small-molecule drugs of interest herein without such additional agents. Even when a sufficient amount of a glycol or glyceride material is present to solubilize the phospholipid, the resulting carrier solution and/or the drug-carrier system may be rather viscous and difficult or inconvenient to handle. In such cases it may be found desirable to include in the carrier a viscosity reducing agent in an amount effective to provide acceptably low viscosity. An example of such an agent is an alcohol, more particularly ethanol, which is preferably introduced in a form that is substantially free of water, for example 99% ethanol, dehydrated alcohol USP or absolute ethanol. Excessively high concentrations of ethanol should, however, generally be avoided. This is particularly true where, for example, the drug-carrier system is to be administered in a gelatin capsule, because of the tendency of high ethanol concentrations to result in mechanical failure of the capsule. In general, suitable amounts of ethanol are 0% to about 25%, for example about 1% to about 20% or about 3% to about 15%, by weight of the carrier. Optionally, the carrier further comprises a pharmaceutically acceptable non-phospholipid surfactant. One of skill in the art will be able to select a suitable surfactant for use in a composition of the invention. Illustratively, a surfactant such as polysorbate 80 can be included in an amount of 0% to about 5%, for example 0% to about 2% or 0% to about 1%, by weight of the carrier. Conveniently, pre-blended products are available containing a suitable phospholipid+solubilizing agent combination for use in compositions of the present invention. Pre-blended phospholipid+solubilizing agent products can be advantageous in improving ease of preparation of the present compositions. An illustrative example of a pre-blended phospholipid+solubilizing agent product is Phosal 50 PG™, available from Phospholipid GmbH, Germany, which comprises, by weight, not less than 50% phosphatidylcholine, not more than 6% lysophosphatidylcholine, about 35% propylene glycol, about 3% mono- and diglycerides from sunflower oil, about 2% soy fatty acids, about 2% ethanol, and about 0.2% ascorbyl palmitate. Another illustrative example is Phosal 53 MCT™, also available from Phospholipid GmbH, which contains, by weight, not less than 53% phosphatidylcholine, not more than 6% lysophosphatidylcholine, about 29% medium chain triglycerides, 3-6% (typically about 5%) ethanol, about 3% mono- and diglycerides from sunflower oil, about 2% oleic acid, and about 0.2% ascorbyl palmitate (reference composition). A product having the above or substantially equivalent composition, whether sold under the Phosal 53 MCT™ brand or otherwise, is generically referred to herein as “phosphatidylcholine+medium chain triglycerides 53/29”. A product having “substantially equivalent composition” in the present context means having a composition sufficiently similar to the reference composition in its ingredient list and relative amounts of ingredients to exhibit no practical difference in properties with respect to utilization of the product herein. Yet another illustrative example is Phosal 50 SA+™, also available from Phospholipid GmbH, which contains, by weight, not less than 50% phosphatidylcholine and not more than 6% lysophosphatidylcholine in a solubilizing system comprising safflower oil and other ingredients. The phosphatidylcholine component of each of these pre-blended products can be derived from soy lecithin. Products of substantially equivalent composition may be obtainable from other suppliers. A pre-blended product such as Phosal 50 PG™, Phosal 53 MCT™ or Phosal 50 SA+™ can, in some embodiments, constitute substantially the entire carrier system. In other embodiments, additional ingredients are present, for example ethanol (additional to any that may be present in the pre-blended product), non-phospholipid surfactant such as polysorbate 80, polyethylene glycol and/or other ingredients. Such additional ingredients, if present, are typically included in only minor amounts. Illustratively, phosphatidylcholine+medium chain triglycerides 53/29 can be included in the carrier in an amount of about 50% to 100%, for example about 80% to 100%, by weight of the carrier. Without being bound by theory, it is believed that the therapeutic efficacy of Compound 1 is due at least in part to its ability to bind to a Bcl-2 family protein such as Bcl-2, Bcl-XL or Bcl-w in a way that inhibits the anti-apoptotic action of the protein, for example by occupying the BH3 binding groove of the protein. In still further embodiments of the invention, there is provided a method for treating a disease characterized by apoptotic dysfunction and/or overexpression of an anti-apoptotic Bcl-2 family protein, comprising administering to a subject having the disease a therapeutically effective amount of crystalline Compound 1 free base or a pharmaceutical composition comprising a salt or crystalline form of Compound 1 free base and one or more pharmaceutically acceptable excipients. In still further embodiments of the invention, there is provided a method for treating a disease characterized by apoptotic dysfunction and/or overexpression of an anti-apoptotic Bcl-2 family protein is provided, where the method comprises preparing a solution or dispersion of a salt or crystalline form of Compound 1 described herein in a pharmaceutically acceptable solvent or mixture of solvents, and administering the resulting solution or dispersion in a therapeutically effective amount to a subject having the disease. The subject can be human or non-human (e.g., a farm, zoo, work or companion animal, or a laboratory animal used as a model) but in an important embodiment the subject is a human patient in need of the drug, for example to treat a disease characterized by apoptotic dysfunction and/or overexpression of an anti-apoptotic Bcl-2 family protein. A human subject can be male or female and of any age, but is typically an adult. The composition is normally administered in an amount providing a therapeutically effective daily dose of the drug. The term “daily dose” herein means the amount of drug administered per day, regardless of the frequency of administration. For example, if the subject receives a unit dose of 150 mg twice daily, the daily dose is 300 mg. Use of the term “daily dose” will be understood not to imply that the specified dosage amount is necessarily administered once daily. However, in a particular embodiment the dosing frequency is once daily (q.d.), and the daily dose and unit dose are in this embodiment the same thing. What constitutes a therapeutically effective dose depends on the bioavailability of the particular formulation, the subject (including species and body weight of the subject), the disease (e.g., the particular type of cancer) to be treated, the stage and/or severity of the disease, the individual subject's tolerance of the compound, whether the compound is administered in monotherapy or in combination with one or more other drugs, e.g., other chemotherapeutics for treatment of cancer, and other factors. Thus, the daily dose can vary within wide margins, for example from about 10 to about 1,000 mg. Greater or lesser daily doses can be appropriate in specific situations. It will be understood that recitation herein of a “therapeutically effective” dose herein does not necessarily require that the drug be therapeutically effective if only a single such dose is administered; typically therapeutic efficacy depends on the composition being administered repeatedly according to a regimen involving appropriate frequency and duration of administration. It is strongly preferred that, while the daily dose selected is sufficient to provide benefit in terms of treating the cancer, it should not be sufficient to provoke an adverse side-effect to an unacceptable or intolerable degree. A suitable therapeutically effective dose can be selected by the physician of ordinary skill without undue experimentation based on the disclosure herein and on art cited herein, taking into account factors such as those mentioned above. The physician may, for example, start a cancer patient on a course of therapy with a relatively low daily dose and titrate the dose upwards over a period of days or weeks, to reduce risk of adverse side-effects. Illustratively, suitable doses of Compound 1 are generally about 25 to about 1000 mg/day or about 50 to about 1000 mg/day, more typically about 50 to about 500 mg/day or about 200 to about 400 mg/day, for example about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 750 or about 1000 mg/day, administered at an average dosage interval of about 3 hours to about 7 days, for example about 8 hours to about 3 days, or about 12 hours to about 2 days. In most cases a once-daily (q.d.) administration regimen is suitable. An “average dosage interval” herein is defined as a span of time, for example one day or one week, divided by the number of unit doses administered over that span of time. For example, where a drug is administered three times a day, around 8 am, around noon and around 6 pm, the average dosage interval is 8 hours (a 24-hour time span divided by 3). If the drug is formulated as a discrete dosage form such as a tablet or capsule, a plurality (e.g., 2 to about 10) of dosage forms administered at one time is considered a unit dose for the purpose of defining the average dosage interval. Compositions prepared according to the present invention are suitable for use in monotherapy or in combination therapy, for example with other chemotherapeutics or with ionizing radiation. A particular advantage of the present invention is that it permits once-daily oral administration, a regimen which is convenient for the patient who is undergoing treatment with other orally administered drugs on a once-daily regimen. Oral administration is easily accomplished by the patient him/herself or by a caregiver in the patient's home; it is also a convenient route of administration for patients in a hospital or residential care setting. Combination therapies illustratively include administration of a composition comprising (or prepared using as API) one or more crystalline forms of Compound 1 (including crystalline salt forms) concomitantly with one or more of bortezomib, carboplatin, cisplatin, cyclophosphamide, dacarbazine, dexamethasone, docetaxel, doxorubicin, etoposide, fludarabine, hydroxydoxorubicin, irinotecan, paclitaxel, rapamycin, rituximab, vincristine and the like, for example with a polytherapy such as CHOP (cyclophosphamide+hydroxydoxorubicin+vincristine+prednisone), RCVP (rituximab+cyclophosphamide+vincristine+prednisone), R-CHOP (rituximab+CHOP) or DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab). A Compound 1 composition can be administered in combination therapy with one or more therapeutic agents that include, but are not limited to, angiogenesis inhibitors, antiproliferative agents, other apoptosis promoters (for example, Bcl-xL, Bcl-w and Bfl-1 inhibitors), activators of a death receptor pathway, BiTE (bi-specific T-cell engager) antibodies, dual variable domain binding proteins (DVDs), inhibitors of apoptosis proteins (IAPs), microRNAs, mitogen-activated extracellular signal-regulated kinase inhibitors, multivalent binding proteins, poly-ADP (adenosine diphosphate)-ribose polymerase (PARP) inhibitors, small inhibitory ribonucleic acids (siRNAs), kinase inhibitors, receptor tyrosine kinase inhibitors, aurora kinase inhibitors, polo-like kinase inhibitors, bcr-abl kinase inhibitors, growth factor inhibitors, COX-2 inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), antimitotic agents, alkylating agents, antimetabolites, intercalating antibiotics, platinum-containing chemotherapeutic agents, growth factor inhibitors, ionizing radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biologic response modifiers, immunologicals, antibodies, hormonal therapies, retinoids, deltoids, plant alkaloids, proteasome inhibitors, HSP-90 inhibitors, histone deacetylase (HDAC) inhibitors, purine analogs, pyrimidine analogs, MEK inhibitors, CDK inhibitors, ErbB2 receptor inhibitors, mTOR inhibitors as well as other antitumor agents. Angiogenesis inhibitors include, but are not limited to, EGFR inhibitors, PDGFR inhibitors, VEGFR inhibitors, TIE2 inhibitors, IGF1R inhibitors, matrix metalloproteinase 2 (MMP-2) inhibitors, matrix metalloproteinase 9 (MMP-9) inhibitors and thrombospondin analogs. Examples of EGFR inhibitors include, but are not limited to, gefitinib, erlotinib, cetuximab, EMD-7200, ABX-EGF, HR3, IgA antibodies, TP-38 (IVAX), EGFR fusion protein, EGF-vaccine, anti-EGFR immunoliposomes and lapatinib. Examples of PDGFR inhibitors include, but are not limited to, CP-673451 and CP-868596. Examples of VEGFR inhibitors include, but are not limited to, bevacizumab, sunitinib, sorafenib, CP-547632, axitinib, vandetanib, AEE788, AZD-2171, VEGF trap, vatalanib, pegaptanib, IM862, pazopanib, ABT-869 and angiozyme. Bcl-2 family protein inhibitors other than Compound 1 include, but are not limited to, ABT-263, AT-101 ((−)gossypol), Genasense™ Bcl-2-targeting antisense oligonucleotide (G3139 or oblimersen), IPI-194, IPI-565, N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl) methyl)propyl)amino)-3-nitrobenzenesulfonamide) (ABT-737), GX-070 (obatoclax) and the like. Activators of a death receptor pathway include, but are not limited to, TRAIL, antibodies or other agents that target death receptors (e.g., DR4 and DR5) such as apomab, conatumumab, ETR2-STO1, GDC0145 (lexatumumab), HGS-1029, LBY-135, PRO-1762 and trastuzumab. Examples of thrombospondin analogs include, but are not limited to, TSP-1, ABT-510, ABT-567 and ABT-898. Examples of aurora kinase inhibitors include, but are not limited to, VX-680, AZD-1152 and MLN-8054. An example of a polo-like kinase inhibitor includes, but is not limited to, BI-2536. Examples of bcr-abl kinase inhibitors include, but are not limited to, imatinib and dasatinib. Examples of platinum-containing agents include, but are not limited to, cisplatin, carboplatin, eptaplatin, lobaplatin, nedaplatin, oxaliplatin and satraplatin. Examples of mTOR inhibitors include, but are not limited to, CCI-779, rapamycin, temsirolimus, everolimus, RAD001 and AP-23573. Examples of HSP-90 inhibitors include, but are not limited to, geldanamycin, radicicol, 17-AAG, KOS-953, 17-DMAG, CNF-101, CNF-1010, 17-AAG-nab, NCS-683664, efungumab, CNF-2024, PU3, PU24FC1, VER-49009, IPI-504, SNX-2112 and STA-9090. Examples of HDAC inhibitors include, but are not limited to, suberoylanilide hydroxamic acid (SAHA), MS-275, valproic acid, TSA, LAQ-824, trapoxin and depsipeptide. Examples of MEK inhibitors include, but are not limited to, PD-325901, ARRY-142886, ARRY-438162 and PD-98059. Examples of CDK inhibitors include, but are not limited to, flavopyridol, MCS-5A, CVT-2584, seliciclib ZK-304709, PHA-690509, BMI-1040, GPC-286199, BMS-387032, PD-332991 and AZD-5438. Examples of COX-2 inhibitors include, but are not limited to, celecoxib, parecoxib, deracoxib, ABT-963, etoricoxib, lumiracoxib, BMS-347070, RS 57067, NS-398, valdecoxib, rofecoxib, SD-8381, 4-methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoyl-phenyl-1H-pyrrole, T-614, JTE-522, S-2474, SVT-2016, CT-3 and SC-58125. Examples of NSAIDs include, but are not limited to, salsalate, diflunisal, ibuprofen, ketoprofen, nabumetone, piroxicam, naproxen, diclofenac, indomethacin, sulindac, tolmetin, etodolac, ketorolac and oxaprozin. Examples of ErbB2 receptor inhibitors include, but are not limited to, CP-724714, canertinib, trastuzumab, pertuzumab, TAK-165, ionafarnib, GW-282974, EKB-569, PI-166, dHER2, APC-8024, anti-HER/2neu bispecific antibody B7.her2IgG3 and HER2 trifunctional bispecific antibodies mAB AR-209 and mAB 2B-1. Examples of alkylating agents include, but are not limited to, nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, melphalan, busulfan, mitobronitol, carboquone, thiotepa, ranimustine, nimustine, Cloretazine™ (laromustine), AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, carmustine, estramustine, fotemustine, glufosfamide, KW-2170, mafosfamide, mitolactol, lomustine, treosulfan, dacarbazine and temozolomide. Examples of antimetabolites include, but are not limited to, methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil (5-FU) alone or in combination with leucovorin, tegafur, UFT, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S-1, pemetrexed, gemcitabine, fludarabine, 5-azacitidine, capecitabine, cladribine, clofarabine, decitabine, eflornithine, ethenylcytidine, cytosine arabinoside, hydroxyurea, TS-1, melphalan, nelarabine, nolatrexed, disodium pemetrexed, pentostatin, pelitrexol, raltitrexed, triapine, trimetrexate, vidarabine, mycophenolic acid, ocfosfate, pentostatin, tiazofurin, ribavirin, EICAR, hydroxyurea and deferoxamine. Examples of antibiotics include, but are not limited to, intercalating antibiotics, aclarubicin, actinomycin D, amrubicin, annamycin, adriamycin, bleomycin, daunorubicin, doxorubicin (including liposomal doxorubicin), elsamitrucin, epirubicin, galarubicin, idarubicin, mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin, valrubicin, zinostatin and combinations thereof. Examples of topoisomerase inhibiting agents include, but are not limited to, aclarubicin, amonafide, belotecan, camptothecin, 10-hydroxycamptothecin, 9-amino-camptothecin, amsacrine, dexrazoxane, diflomotecan, irinotecan HCl, edotecarin, epirubicin, etoposide, exatecan, becatecarin, gimatecan, lurtotecan, orathecin, BN-80915, mitoxantrone, pirarbicin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide and topotecan. Examples of antibodies include, but are not limited to, rituximab, cetuximab, bevacizumab, trastuzumab, CD40-specific antibodies and IGF1R-specific antibodies, chTNT-1/B, denosumab, edrecolomab, WX G250, zanolimumab, lintuzumab and ticilimumab. Examples of hormonal therapies include, but are not limited to, sevelamer carbonate, trilostane, luteinizing hormone releasing hormone, modrastane, exemestane, leuprolide acetate, buserelin, cetrorelix, deslorelin, histrelin, anastrozole, fosrelin, goserelin, degarelix, doxercalciferol, fadrozole, formestane, tamoxifen, arzoxifene, bicalutamide, abarelix, triptorelin, finasteride, fulvestrant, toremifene, raloxifene, trilostane, lasofoxifene, letrozole, flutamide, megestrol, mifepristone, nilutamide, dexamethasone, prednisone and other glucocorticoids. Examples of retinoids or deltoids include, but are not limited to, seocalcitol, lexacalcitol, fenretinide, aliretinoin, tretinoin, bexarotene and LGD-1550. Examples of plant alkaloids include, but are not limited to, vincristine, vinblastine, vindesine and vinorelbine. Examples of proteasome inhibitors include, but are not limited to, bortezomib, MG-132, NPI-0052 and PR-171. Examples of immunologicals include, but are not limited to, interferons and numerous other immune-enhancing agents. Interferons include interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-1a, interferon gamma-1b, interferon gamma-n1 and combinations thereof. Other agents include filgrastim, lentinan, sizofilan, BCG live, ubenimex, WF-10 (tetrachlorodecaoxide or TCDO), aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab, denileukin, gemtuzumab ozogamicin, ibritumomab, imiquimod, lenograstim, melanoma vaccine, molgramostim, sargramostim, tasonermin, teceleukin, thymalfasin, tositumomab, Virulizin™ immunotherapeutic of Lorus Pharmaceuticals, Z-100 (specific substance of Maruyama or SSM), Zevalin™ (90Y-ibritumomab tiuxetan), epratuzumab, mitumomab, oregovomab, pemtumomab, Provenge™ (sipuleucel-T), teceleukin, Therocys™ (Bacillus Calmette-Guerin), cytotoxic lymphocyte antigen 4 (CTLA4) antibodies and agents capable of blocking CTLA4 such as MDX-010. Examples of biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth, or differentiation of tissue cells to direct them to have anti-tumor activity. Such agents include, but are not limited to, krestin, lentinan, sizofuran, picibanil, PF-3512676 and ubenimex. Examples of pyrimidine analogs include, but are not limited to, 5-fluorouracil, floxuridine, doxifluridine, raltitrexed, cytarabine, cytosine arabinoside, fludarabine, triacetyluridine, troxacitabine and gemcitabine. Examples of purine analogs include, but are not limited to, mercaptopurine and thioguanine. Examples of antimitotic agents include, but are not limited to, N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide, paclitaxel, docetaxel, larotaxel, epothilone D, PNU-100940, batabulin, ixabepilone, patupilone, XRP-9881, vinflunine and ZK-EPO (synthetic epothilone). Examples of radiotherapy include, but are not limited to, external beam radiotherapy (XBRT), teletherapy, brachytherapy, sealed-source radiotherapy and unsealed-source radiotherapy. BiTE antibodies are bi-specific antibodies that direct T-cells to attack cancer cells by simultaneously binding the two cells. The T-cell then attacks the target cancer cell. Examples of BiTE antibodies include, but are not limited to, adecatumumab (Micromet MT201), blinatumomab (Micromet MT103) and the like. Without being limited by theory, one of the mechanisms by which T-cells elicit apoptosis of the target cancer cell is by exocytosis of cytolytic granule components, which include perforin and granzyme B. In this regard, Bcl-2 has been shown to attenuate the induction of apoptosis by both perforin and granzyme B. These data suggest that inhibition of Bcl-2 could enhance the cytotoxic effects elicited by T-cells when targeted to cancer cells (Sutton et al. (1997) J. Immunol. 158:5783-5790). SiRNAs are molecules having endogenous RNA bases or chemically modified nucleotides. The modifications do not abolish cellular activity, but rather impart increased stability and/or increased cellular potency. Examples of chemical modifications include phosphorothioate groups, 2′-deoxynucleotide, 2′-OCH3-containing ribonucleotides, 2′-F-ribonucleotides, 2′-methoxyethyl ribonucleotides, combinations thereof and the like. The siRNA can have varying lengths (e.g., 10-200 bps) and structures (e.g., hairpins, single/double strands, bulges, nicks/gaps, mismatches) and are processed in cells to provide active gene silencing. A double-stranded siRNA (dsRNA) can have the same number of nucleotides on each strand (blunt ends) or asymmetric ends (overhangs). The overhang of 1-2 nucleotides can be present on the sense and/or the antisense strand, as well as present on the 5′- and/or the 3′-ends of a given strand. For example, siRNAs targeting Mcl-1 have been shown to enhance the activity of the apoptosis-promoting agent ABT-263 (Tse et al. (2008) Cancer Res. 68:3421-3428 and references therein). Multivalent binding proteins are binding proteins comprising two or more antigen binding sites. Multivalent binding proteins are engineered to have the three or more antigen binding sites and are generally not naturally occurring antibodies. The term “multispecific binding protein” means a binding protein capable of binding two or more related or unrelated targets. Dual variable domain (DVD) binding proteins are tetravalent or multivalent binding proteins binding proteins comprising two or more antigen binding sites. Such DVDs may be monospecific (i.e., capable of binding one antigen) or multispecific (i.e., capable of binding two or more antigens). DVD binding proteins comprising two heavy-chain DVD polypeptides and two light-chain DVD polypeptides are referred to as DVD Ig's. Each half of a DVD Ig comprises a heavy-chain DVD polypeptide, a light-chain DVD polypeptide, and two antigen binding sites. Each binding site comprises a heavy-chain variable domain and a light-chain variable domain with a total of 6 CDRs involved in antigen binding per antigen binding site. PARP inhibitors include, but are not limited to, ABT-888, olaparib, KU-59436, AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231 and the like. Additionally or alternatively, a composition of the present invention can be administered in combination therapy with one or more antitumor agents selected from ABT-100, N-acetylcolchinol-O-phosphate, acitretin, AE-941, aglycon protopanaxadiol, arglabin, arsenic trioxide, ASO4 adjuvant-adsorbed HPV vaccine, L-asparaginase, atamestane, atrasentan, AVE-8062, bosentan, canfosfamide, Canvaxin™, catumaxomab, CeaVac™, celmoleukin, combretastatin A4P, contusugene ladenovec, Cotara™, cyproterone, deoxycoformycin, dexrazoxane, N,N-diethyl-2-(4-(phenylmethyl)phenoxy)ethanamine, 5,6-dimethylxanthenone-4-acetic acid, docosahexaenoic acid/paclitaxel, discodermolide, efaproxiral, enzastaurin, epothilone B, ethynyluracil, exisulind, falimarev, Gastrimmune™, GMK vaccine, GVAX™, halofuginone, histamine, hydroxycarbamide, ibandronic acid, ibritumomab tiuxetan, IL-13-PE38, inalimarev, interleukin 4, KSB-311, lanreotide, lenalidomide, lonafarnib, lovastatin, 5,10-methylenetetrahydrofolate, mifamurtide, miltefosine, motexafin, oblimersen, OncoVAX™, Osidem™, paclitaxel albumin-stabilized nanoparticle, paclitaxel poliglumex, pamidronate, panitumumab, peginterferon alfa, pegaspargase, phenoxodiol, poly(I)-poly(C12U), procarbazine, ranpirnase, rebimastat, recombinant quadrivalent HPV vaccine, squalamine, staurosporine, STn-KLH vaccine, T4 endonuclase V, tazarotene, 6,6′,7,12-tetramethoxy-2,2′-dimethyl-1β-berbaman, thalidomide, TNFerade™, 131I-tositumomab, trabectedin, triazone, tumor necrosis factor, Ukrain™, vaccinia-MUC-1 vaccine, L-valine-L-boroproline, Vitaxin™, vitespen, zoledronic acid and zorubicin. In one embodiment, a composition comprising (or prepared using as API) one or more crystalline forms of Compound 1 (including crystalline salts) is administered in a therapeutically effective amount to a subject in need thereof to treat a disease during which is overexpressed one or more of antiapoptotic Bcl-2 protein, antiapoptotic Bcl-XL protein and antiapoptotic Bcl-w protein. In another embodiment, a composition comprising (or prepared using as API) one or more crystalline forms of Compound 1 (including crystalline salts) is administered in a therapeutically effective amount to a subject in need thereof to treat a disease of abnormal cell growth and/or dysregulated apoptosis. Examples of such diseases include, but are not limited to, cancer, mesothelioma, bladder cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, bone cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal and/or duodenal) cancer, chronic lymphocytic leukemia, esophageal cancer, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, testicular cancer, hepatocellular (hepatic and/or biliary duct) cancer, primary or secondary central nervous system tumor, primary or secondary brain tumor, Hodgkin's disease, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphoma, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, multiple myeloma, oral cancer, non-small-cell lung cancer, prostate cancer, small-cell lung cancer, cancer of the kidney and/or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system, primary central nervous system lymphoma, non Hodgkin's lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocortical cancer, gall bladder cancer, cancer of the spleen, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma or a combination thereof. In a more particular embodiment, a composition comprising (or prepared using as API) one or more crystalline forms of Compound 1 (including crystalline salts) is administered in a therapeutically effective amount to a subject in need thereof to treat bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small-cell lung cancer, prostate cancer, small-cell lung cancer or spleen cancer. According to any of these embodiments, the composition is administered in combination therapy with one or more additional therapeutic agents. For example, a method for treating mesothelioma, bladder cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, bone cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal and/or duodenal) cancer, chronic lymphocytic leukemia, esophageal cancer, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, testicular cancer, hepatocellular (hepatic and/or biliary duct) cancer, primary or secondary central nervous system tumor, primary or secondary brain tumor, Hodgkin's disease, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphoma, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, multiple myeloma, oral cancer, non-small-cell lung cancer, prostate cancer, small-cell lung cancer, cancer of the kidney and/or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system, primary central nervous system lymphoma, non Hodgkin's lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocortical cancer, gall bladder cancer, cancer of the spleen, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma or a combination thereof in a subject comprises administering to the subject therapeutically effective amounts of (a) a composition comprising (or prepared using as API) crystalline Compound 1 free base and (b) one or more of etoposide, vincristine, CHOP, rituximab, rapamycin, R-CHOP, RCVP, DA-EPOCH-R or bortezomib. In particular embodiments, a composition comprising (or prepared using as API) crystalline Compound 1 free base is administered in a therapeutically effective amount to a subject in need thereof in combination therapy with etoposide, vincristine, CHOP, rituximab, rapamycin, R-CHOP, RCVP, DA-EPOCH-R or bortezomib in a therapeutically effective amount, for treatment of a lymphoid malignancy such as B-cell lymphoma or non-Hodgkin's lymphoma. In another embodiment, a composition of the invention is administered in a therapeutically effective amount to a subject in need thereof to treat an immune or autoimmune disorder. Such disorders include acquired immunodeficiency disease syndrome (AIDS), autoimmune lymphoproliferative syndrome, hemolytic anemia, inflammatory diseases, thrombocytopenia, acute and chronic immune diseases associated with organ transplantation, Addison's disease, allergic diseases, alopecia, alopecia areata, atheromatous disease/arteriosclerosis, atherosclerosis, arthritis (including osteoarthritis, juvenile chronic arthritis, septic arthritis, Lyme arthritis, psoriatic arthritis and reactive arthritis), autoimmune bullous disease, abetalipoproteinia, acquired immunodeficiency-related diseases, acute immune disease associated with organ transplantation, acquired acrocyanosis, acute and chronic parasitic or infectious processes, acute pancreatitis, acute renal failure, acute rheumatic fever, acute transverse myelitis, adenocarcinomas, aerial ectopic beats, adult (acute) respiratory distress syndrome, AIDS dementia complex, alcoholic cirrhosis, alcohol-induced liver injury, alcohol-induced hepatitis, allergic conjunctivitis, allergic contact dermatitis, allergic rhinitis, allergy and asthma, allograft rejection, alpha-1-antitrypsin deficiency, Alzheimer's disease, amyotrophic lateral sclerosis, anemia, angina pectoris, ankylosing spondylitis-associated lung disease, anterior horn cell degeneration, antibody mediated cytotoxicity, antiphospholipid syndrome, anti-receptor hypersensitivity reactions, aortic and peripheral aneurysms, aortic dissection, arterial hypertension, arteriosclerosis, arteriovenous fistula, arthropathy, asthenia, asthma, ataxia, atopic allergy, atrial fibrillation (sustained or paroxysmal), atrial flutter, atrioventricular block, atrophic autoimmune hypothyroidism, autoimmune haemolytic anaemia, autoimmune hepatitis, type-1 autoimmune hepatitis (classical autoimmune or lupoid hepatitis), autoimmune mediated hypoglycemia, autoimmune neutropenia, autoimmune thrombocytopenia, autoimmune thyroid disease, B-cell lymphoma, bone graft rejection, bone marrow transplant (BMT) rejection, bronchiolitis obliterans, bundle branch block, burns, cachexia, cardiac arrhythmias, cardiac stun syndrome, cardiac tumors, cardiomyopathy, cardiopulmonary bypass inflammation response, cartilage transplant rejection, cerebellar cortical degenerations, cerebellar disorders, chaotic or multifocal atrial tachycardia, chemotherapy-associated disorders, chlamydia, choleostatis, chronic alcoholism, chronic active hepatitis, chronic fatigue syndrome, chronic immune disease associated with organ transplantation, chronic eosinophilic pneumonia, chronic inflammatory pathologies, chronic mucocutaneous candidiasis, chronic obstructive pulmonary disease (COPD), chronic salicylate intoxication, colorectal common varied immunodeficiency (common variable hypogammaglobulinemia), conjunctivitis, connective tissue disease-associated interstitial lung disease, contact dermatitis, Coombs-positive hemolytic anemia, cor pulmonale, Creutzfeldt-Jakob disease, cryptogenic autoimmune hepatitis, cryptogenic fibrosing alveolitis, culture-negative sepsis, cystic fibrosis, cytokine therapy-associated disorders, Crohn's disease, dementia pugilistica, demyelinating diseases, dengue hemorrhagic fever, dermatitis, dermatitis scleroderma, dermatologic conditions, dermatomyositis/polymyositis-associated lung disease, diabetes, diabetic arteriosclerotic disease, diabetes mellitus, diffuse Lewy body disease, dilated cardiomyopathy, dilated congestive cardiomyopathy, discoid lupus erythematosus, disorders of the basal ganglia, disseminated intravascular coagulation, Down's Syndrome in middle age, drug-induced interstitial lung disease, drug-induced hepatitis, drug-induced movement disorders induced by drugs which block CNS dopamine receptors, drug sensitivity, eczema, encephalomyelitis, endocarditis, endocrinopathy, enteropathic synovitis, epiglottitis, Epstein-Barr virus infection, erythromelalgia, extrapyramidal and cerebellar disorders, familial hematophagocytic lymphohistiocytosis, fetal thymus implant rejection, Friedreich's ataxia, functional peripheral arterial disorders, female infertility, fibrosis, fibrotic lung disease, fungal sepsis, gas gangrene, gastric ulcer, giant cell arteritis, glomerular nephritis, glomerulonephritides, Goodpasture's syndrome, goitrous autoimmune hypothyroidism (Hashimoto's disease), gouty arthritis, graft rejection of any organ or tissue, graft versus host disease, gram-negative sepsis, gram-positive sepsis, granulomas due to intracellular organisms, group B streptococci (GBS) infection, Graves' disease, hemosiderosis-associated lung disease, hairy cell leukemia, Hallerrorden-Spatz disease, Hashimoto's thyroiditis, hay fever, heart transplant rejection, hemochromatosis, hematopoietic malignancies (leukemia and lymphoma), hemolytic anemia, hemolytic uremic syndrome/thrombolytic thrombocytopenic purpura, hemorrhage, Henoch-Schoenlein purpura, hepatitis A, hepatitis B, hepatitis C, HIV infection/HIV neuropathy, Hodgkin's disease, hypoparathyroidism, Huntington's chorea, hyperkinetic movement disorders, hypersensitivity reactions, hypersensitivity pneumonitis, hyperthyroidism, hypokinetic movement disorders, hypothalamic-pituitary-adrenal axis evaluation, idiopathic Addison's disease, idiopathic leucopenia, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia, idiosyncratic liver disease, infantile spinal muscular atrophy, infectious diseases, inflammation of the aorta, inflammatory bowel disease, insulin dependent diabetes mellitus, interstitial pneumonitis, iridocyclitis/uveitis/optic neuritis, ischemia-reperfusion injury, ischemic stroke, juvenile pernicious anemia, juvenile rheumatoid arthritis, juvenile spinal muscular atrophy, Kaposi's sarcoma, Kawasaki's disease, kidney transplant rejection, legionella, leishmaniasis, leprosy, lesions of the corticospinal system, linear IgA disease, lipidema, liver transplant rejection, Lyme disease, lymphederma, lymphocytic infiltrative lung disease, malaria, male infertility idiopathic or NOS, malignant histiocytosis, malignant melanoma, meningitis, meningococcemia, microscopic vasculitis of the kidneys, migraine headache, mitochondrial multisystem disorder, mixed connective tissue disease, mixed connective tissue disease-associated lung disease, monoclonal gammopathy, multiple myeloma, multiple systems degenerations (Mencel, Dejerine-Thomas, Shy-Drager and Machado-Joseph), myalgic encephalitis/Royal Free Disease, myasthenia gravis, microscopic vasculitis of the kidneys, mycobacterium avium intracellulare, mycobacterium tuberculosis, myelodysplastic syndrome, myocardial infarction, myocardial ischemic disorders, nasopharyngeal carcinoma, neonatal chronic lung disease, nephritis, nephrosis, nephrotic syndrome, neurodegenerative diseases, neurogenic I muscular atrophies, neutropenic fever, non-alcoholic steatohepatitis, occlusion of the abdominal aorta and its branches, occlusive arterial disorders, organ transplant rejection, orchitis/epididymitis, orchitis/vasectomy reversal procedures, organomegaly, osteoarthrosis, osteoporosis, ovarian failure, pancreas transplant rejection, parasitic diseases, parathyroid transplant rejection, Parkinson's disease, pelvic inflammatory disease, pemphigus vulgaris, pemphigus foliaceus, pemphigoid, perennial rhinitis, pericardial disease, peripheral atherlosclerotic disease, peripheral vascular disorders, peritonitis, pernicious anemia, phacogenic uveitis, pneumocystis carinii pneumonia, pneumonia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome), post-perfusion syndrome, post-pump syndrome, post-MI cardiotomy syndrome, postinfectious interstitial lung disease, premature ovarian failure, primary biliary cirrhosis, primary sclerosing hepatitis, primary myxoedema, primary pulmonary hypertension, primary sclerosing cholangitis, primary vasculitis, progressive supranuclear palsy, psoriasis, psoriasis type 1, psoriasis type 2, psoriatic arthropathy, pulmonary hypertension secondary to connective tissue disease, pulmonary manifestation of polyarteritis nodosa, post-inflammatory interstitial lung disease, radiation fibrosis, radiation therapy, Raynaud's phenomenon and disease, Refsum's disease, regular narrow QRS tachycardia, Reiter's disease, renal disease NOS, renovascular hypertension, reperfusion injury, restrictive cardiomyopathy, rheumatoid arthritis-associated interstitial lung disease, rheumatoid spondylitis, sarcoidosis, Schmidt's syndrome, scleroderma, senile chorea, senile dementia of Lewy body type, sepsis syndrome, septic shock, seronegative arthropathies, shock, sickle cell anemia, Sjögren's disease-associated lung disease, Sjögren's syndrome, skin allograft rejection, skin changes syndrome, small bowel transplant rejection, sperm autoimmunity, multiple sclerosis (all subtypes), spinal ataxia, spinocerebellar degenerations, spondyloarthropathy, sporadic polyglandular deficiency type I, sporadic polyglandular deficiency type II, Still's disease, streptococcal myositis, stroke, structural lesions of the cerebellum, subacute sclerosing panencephalitis, sympathetic ophthalmia, syncope, syphilis of the cardiovascular system, systemic anaphylaxis, systemic inflammatory response syndrome, systemic onset juvenile rheumatoid arthritis, systemic lupus erythematosus, systemic lupus erythematosus-associated lung disease, systemic sclerosis, systemic sclerosis-associated interstitial lung disease, T-cell or FAB ALL, Takayasu's disease/arteritis, telangiectasia, Th2-type and Th1-type mediated diseases, thromboangiitis obliterans, thrombocytopenia, thyroiditis, toxicity, toxic shock syndrome, transplants, trauma/hemorrhage, type-2 autoimmune hepatitis (anti-LKM antibody hepatitis), type B insulin resistance with acanthosis nigricans, type III hypersensitivity reactions, type IV hypersensitivity, ulcerative colitic arthropathy, ulcerative colitis, unstable angina, uremia, urosepsis, urticaria, uveitis, valvular heart diseases, varicose veins, vasculitis, vasculitic diffuse lung disease, venous diseases, venous thrombosis, ventricular fibrillation, vitiligo acute liver disease, viral and fungal infections, vital encephalitis/aseptic meningitis, vital-associated hemophagocytic syndrome, Wegener's granulomatosis, Wernicke-Korsakoff syndrome, Wilson's disease, xenograft rejection of any organ or tissue, yersinia and salmonella-associated arthropathy and the like. The present invention also provides a method for maintaining in bloodstream of a human cancer patient a therapeutically effective plasma concentration of Compound 1 and/or one or more metabolites thereof, comprising administering to the subject a pharmaceutical composition as described herein, in a dosage amount equivalent to about 50 to about 500 mg Compound 1 per day, at an average dosage interval of about 3 hours to about 7 days. What constitutes a therapeutically effective plasma concentration depends inter alia on the particular cancer present in the patient, the stage, severity and aggressiveness of the cancer, and the outcome sought (e.g., stabilization, reduction in tumor growth, tumor shrinkage, reduced risk of metastasis, etc.). It is strongly preferred that, while the plasma concentration is sufficient to provide benefit in terms of treating the cancer, it should not be sufficient to provoke an adverse side-effect to an unacceptable or intolerable degree. For treatment of cancer in general and of a lymphoid malignancy such as non-Hodgkin's lymphoma in particular, the plasma concentration of Compound 1 should in most cases be maintained in a range of about 0.5 to about 10 jag/ml. Thus, during a course of Compound 1 therapy, the steady-state Cmax should in general not exceed about 10 jag/ml, and the steady-state Cmin should in general not fall below about 0.5 jag/ml. It will further be found desirable to select, within the ranges provided above, a daily dosage amount and average dosage interval effective to provide a Cmax/Cmin ratio not greater than about 5, for example not greater than about 3, at steady-state. It will be understood that longer dosage intervals will tend to result in greater Cmax/Cmin ratios. Illustratively, at steady-state, an Compound 1 Cmax of about 3 to about 8 μg/ml and Cmin of about 1 to about 5 μg/ml can be targeted by the present method. A daily dosage amount effective to maintain a therapeutically effective Compound 1 plasma level is, according to the present embodiment, about 50 to about 1000 mg. In most cases a suitable daily dosage amount is about 200 to about 400 mg. Illustratively, the daily dosage amount can be for example about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 750 or about 1000 mg. An average dosage interval effective to maintain a therapeutically effective Compound 1 plasma level is, according to the present embodiment, about 3 hours to about 7 days. In most cases, a suitable average dosage interval is about 8 hours to about 3 days, or about 12 hours to about 2 days. A once-daily (q.d.) administration regimen is often suitable. As in other embodiments, administration according to the present embodiment can be with or without food, i.e., in a non-fasting or fasting condition. It is generally preferred to administer the present compositions to a non-fasting patient. When introducing elements of the present disclosure or the preferred embodiments(s) thereof, the articles “a”, “an”, “the” and “said” are intended to mean that there are one or more of the elements. The terms “comprising”, “including” and “having” are intended to be inclusive and mean that there may be additional elements other than the listed elements. As various changes could be made in the above described methods and/or compositions without departing from the scope of the disclosure, it is intended that all matter contained in the above description and shown in the accompanying figures shall be interpreted as illustrative and not be viewed in a limiting sense. | <SOH> BACKGROUND OF THE INVENTION <EOH>Overexpression of Bcl-2 proteins correlates with resistance to chemotherapy, clinical outcome, disease progression, overall prognosis or a combination thereof in various cancers and disorders of the immune system. Evasion of apoptosis is a hallmark of cancer (Hanahan & Weinberg (2000) Cell 100:57-70). Cancer cells must overcome a continual bombardment by cellular stresses such as DNA damage, oncogene activation, aberrant cell cycle progression and harsh microenvironments that would cause normal cells to undergo apoptosis. One of the primary means by which cancer cells evade apoptosis is by up-regulation of anti-apoptotic proteins of the Bcl-2 family. A particular type of neoplastic disease for which improved therapies are needed is non-Hodgkin's lymphoma (NHL). NHL is the sixth most prevalent type of new cancer in the U.S. and occurs primarily in patients 60-70 years of age. NHL is not a single disease but a family of related diseases, which are classified on the basis of several characteristics including clinical attributes and histology. One method of classification places different histological subtypes into two major categories based on natural history of the disease, i.e., whether the disease is indolent or aggressive. In general, indolent subtypes grow slowly and are generally incurable, whereas aggressive subtypes grow rapidly and are potentially curable. Follicular lymphomas are the most common indolent subtype, and diffuse large-cell lymphomas constitute the most common aggressive subtype. The oncoprotein Bcl-2 was originally described in non-Hodgkin's B-cell lymphoma. Treatment of follicular lymphoma typically consists of biologically-based or combination chemotherapy. Combination therapy with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) is routinely used, as is combination therapy with rituximab, cyclophosphamide, vincristine and prednisone (RCVP). Single-agent therapy with rituximab (targeting CD20, a phosphoprotein uniformly expressed on the surface of B-cells) or fludarabine is also used. Addition of rituximab to chemotherapy regimens can provide improved response rate and increased progression-free survival. Radioimmunotherapy agents, high-dose chemotherapy and stem cell transplants can be used to treat refractory or relapsed NHL. Currently, there is not an approved treatment regimen that produces a cure, and current guidelines recommend that patients be treated in the context of a clinical trial, even in a first-line setting. First-line treatment of patients with aggressive large B-cell lymphoma typically consists of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), or dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (DA-EPOCH-R). Most lymphomas respond initially to any one of these therapies, but tumors typically recur and eventually become refractory. As the number of regimens patients receive increases, the more chemotherapy-resistant the disease becomes. Average response to first-line therapy is approximately 75%, 60% to second-line, 50% to third-line, and about 35-40% to fourth-line therapy. Response rates approaching 20% with a single agent in a multiple relapsed setting are considered positive and warrant further study. Other neoplastic diseases for which improved therapies are needed include leukemias such as chronic lymphocytic leukemia (like NHL, a B-cell lymphoma) and acute lymphocytic leukemia. Chronic lymphoid leukemia (CLL) is the most common type of leukemia. CLL is primarily a disease of adults, more than 75% of people newly diagnosed being over the age of 50, but in rare cases it is also found in children. Combination chemotherapies are the prevalent treatment, for example fludarabine with cyclophosphamide and/or rituximab, or more complex combinations such as CHOP or R-CHOP. Acute lymphocytic leukemia, also known as acute lymphoblastic leukemia (ALL), is primarily a childhood disease, once with essentially zero survival but now with up to 75% survival due to combination chemotherapies similar to those mentioned above. New therapies are still needed to provide further improvement in survival rates. Current chemotherapeutic agents elicit their antitumor response by inducing apoptosis through a variety of mechanisms. However, many tumors ultimately become resistant to these agents. Bcl-2 and Bcl-X L have been shown to confer chemotherapy resistance in short-term survival assays in vitro and, more recently, in vivo. This suggests that if improved therapies aimed at suppressing the function of Bcl-2 and Bcl-X L can be developed, such chemotherapy-resistance could be successfully overcome. Involvement of Bcl-2 proteins in bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, CLL, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer and the like is described in International Patent Publication Nos. WO 2005/024636 and WO 2005/049593. Involvement of Bcl-2 proteins in immune and autoimmune diseases is described, for example, by Puck & Zhu (2003) Current Allergy and Asthma Reports 3:378-384; Shimazaki et al. (2000) British Journal of Haematology 110(3):584-590; Rengan et al. (2000) Blood 95(4):1283-1292; and Holzelova et al. (2004) New England Journal of Medicine 351(14):1409-1418. Involvement of Bcl-2 proteins in bone marrow transplant rejection is disclosed in United States Patent Application Publication No. US 2008/0182845. Compounds that occupy a binding site on Bcl-2 proteins are known. To be therapeutically useful by oral administration, such compounds desirably have high binding affinity, exhibiting for example K i <1 nM, preferably <0.1 nM, more preferably <0.01 nM, to proteins of the Bcl-2 family, specifically Bcl-2, Bcl-X L and Bcl-w. It is further desirable that they be formulated in a manner that provides high systemic exposure after oral administration. A typical measure of systemic exposure after oral administration of a compound is the area under the curve (AUC) resulting from graphing plasma concentration of the compound versus time from oral administration. Apoptosis-inducing drugs that target Bcl-2 family proteins such as Bcl-2 and Bcl-X L are best administered according to a regimen that provides continual, for example daily, replenishment of the plasma concentration, to maintain the concentration in a therapeutically effective range. This can be achieved by daily parenteral, e.g., intravenous (i.v.) or intraperitoneal (i.p.) administration. However, daily parenteral administration is often not practical in a clinical setting, particularly for outpatients. To enhance clinical utility of an apoptosis-inducing agent, for example as a chemotherapeutic in cancer patients, a dosage form with acceptable oral bioavailability would be highly desirable. Such a dosage form, and a regimen for oral administration thereof, would represent an important advance in treatment of many types of cancer, including NHL, CLL and ALL, and would more readily enable combination therapies with other chemotherapeutics. Different crystalline forms of an apoptosis-inducing agent can provide different properties with respect to stability, solubility, dissolution rate, hardness, compressibility and melting point, among other physical and mechanical properties. Because ease of manufacture, formulation, storage and transport of an apoptosis-inducing agent is dependent on at least some of these properties, there is a need in the chemical and therapeutic arts for identification of new salts and crystalline forms of apoptosis-inducing agents and ways for reproducibly generating such salts and crystalline forms. | <SOH> SUMMARY OF THE INVENTION <EOH>The present disclosure relates to salts and crystalline forms of an apoptosis-inducing agent, referred to herein as “Compound 1,” which has the systematic name 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pheny}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide, and which can be depicted by the formula: Following synthesis of Compound 1, as described herein, the product may be recovered as a powder in an amorphous state. An amorphous form of Compound 1 may not be well suited for use as an active pharmaceutical ingredient (API) for various types of downstream formulations. More particularly, an amorphous form of Compound 1 can be difficult and therefore expensive to purify and can present process control problems. The present disclosure provides a series of novel salts and crystalline forms of Compound 1 suitable for use as API in a wide variety of formulation types, including those where the API is present in particulate form together with excipients, for example in orally deliverable tablets or capsules. The salts and crystalline forms of Compound 1 may also be useful where the crystalline form is converted to a non-crystalline form (e.g., solution or amorphous form) when formulated. Also included are ways to prepare the salts and crystalline forms of Compound 1. Salt and crystalline forms of Compound 1 can be used to modulate and/or improve the physicochemical properties of the API, including solid state properties (e.g., crystallinity, hygroscopicity, melting point, hydration potential, polymorphism, etc.), pharmaceutical properties (e.g., solubility/dissolution rate, stability, compatibility, etc.), and crystallization characteristics (e.g., purity, yield, morphology, etc.), as non-limiting examples. In some embodiments, the salt or crystalline form of Compound 1 includes those of Compound 1 free base anhydrate having PXRD pattern A, Compound 1 free base anhydrate having PXRD pattern B, Compound 1 free base hydrate having PXRD pattern C, Compound 1 free base hydrate having PXRD pattern D, Compound 1 free base dichloromethane solvate having pattern E, Compound 1 free base ethyl acetate solvate having PXRD pattern F, Compound 1 free base ethyl acetate solvate having PXRD pattern G, Compound 1 free base acetonitrile solvate having PXRD pattern H, Compound 1 free base acetonitrile solvate having PXRD pattern I, Compound 1 free base acetone solvate having PXRD pattern J, Compound 1 hydrochloride having PXRD pattern K, Compound 1 hydrochloride hydrate having PXRD pattern L, Compound 1 sulfate having PXRD pattern M, and Compound 1 free base tetrahydrofuran (THF) solvate having PXRD pattern N, each having the respective powder X-ray diffraction patterns as described herein. In some embodiments, the crystalline forms of Compound 1 free base dichloromethane solvate, Compound 1 free base acetonitrile solvate, Compound 1 hydrochloride, and Compound 1 free base tetrahydrofuran solvate have the respective crystal lattice parameters as described herein. In another embodiment, Compound 1 hydrochloride is provided. In another embodiment, Compound 1 sulfate is provided. In some embodiments, an API composition is provided comprising Compound 1 as the API, in which at least a portion, for example at least about 10%, of the Compound 1 in the composition is in a salt or crystalline form. In some embodiments, greater than 95% or essentially 100% of the API in such a composition is a salt or crystalline form of Compound 1. In some embodiments, a pharmaceutical composition is provided that comprises a salt or crystalline form of Compound 1 as described herein and one or more pharmaceutically acceptable excipients. In some embodiments, a process for preparing a pharmaceutical solution composition of Compound 1 is provided, where the process comprises dissolving a salt or crystalline form of Compound 1 as described herein with a pharmaceutically acceptable solvent or mixture of solvents. In some embodiments, a method for treating a disease characterized by apoptotic dysfunction and/or overexpression of an anti-apoptotic Bcl-2 family protein is provided, where the method comprises administering to a subject having the disease a therapeutically effective amount of (a) a salt or crystalline form of Compound 1 as described herein or (b) a pharmaceutical composition comprising a salt or crystalline form of Compound 1 as described herein and one or more pharmaceutically acceptable excipients. In some embodiments, a method for treating a disease characterized by apoptotic dysfunction and/or overexpression of an anti-apoptotic Bcl-2 family protein is provided, where the method comprises preparing a solution or dispersion of a salt or crystalline form of Compound 1 described herein in a pharmaceutically acceptable solvent or mixture of solvents, and administering the resulting solution or dispersion in a therapeutically effective amount to a subject having the disease. Additional embodiments of the invention, including particular aspects of those provided above, will be found in, or will be evident from, the detailed description that follows. | C07D47104 | 20171108 | 20180308 | 66417.0 | C07D47104 | 2 | PAGONAKIS, ANNA | SALTS AND CRYSTALLINE FORMS OF AN APOPTOSIS-INDUCING AGENT | UNDISCOUNTED | 1 | CONT-ACCEPTED | C07D | 2,017 |
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15,807,867 | PENDING | ELECTRONIC DEVICE CASE WITH A FRICTION SURFACE | A case for use with an electronic device includes a base portion with side portions extending therefrom forming a pocket. The case also includes a first material generally at an exterior of the pocket, forming a majority of an exterior surface of the base portion, and a second material secured to and having a higher coefficient of friction than the first material, generally at an interior of the pocket. The second material protrudes through aperture(s) in the first material at the base portion to protrude from the interior to the exterior of the base portion, and outward from the first material such that the second material contacts a support surface when the base portion is placed thereon. The protruding second material extends away from the aperture(s) on opposing surfaces of the first material at the exterior and interior of the pocket to provide securement between the first and second materials. | 1. A case for use with a portable electronic device, the case comprising: a base portion with side portions extending therefrom, the base portion and side portions forming a pocket configured to surround a back and sides of the portable electronic device; a first material generally being positioned at an exterior of the pocket, wherein a majority of an exterior surface of the base portion is formed from the first material; and a second material generally being positioned at an interior of the pocket, the second material protruding through one or more apertures in the first material at the base portion so that portions of the second material protrude from the interior of the pocket to the exterior surface of the base portion, and protrude outward from the first material at the base portion such that when the base portion of the case is placed on a support surface, the second material contacts the support surface; wherein the second material has a higher coefficient of friction than the first material and is secured to the first material; and wherein the second material protruding through the one or more apertures in the first material at the base portion extends away from the one or more apertures on opposing surfaces of the first material at the exterior of the pocket and the interior of the pocket to provide securement between the first and second materials. 2. The case according to claim 1, wherein the first material is shaped with a gap at one or more regions thereof, wherein the second material fills the gap and protrudes therefrom. 3. The case according to claim 2, wherein the gap in the first material is formed at a corner region of the case. 4. The case according to claim 1, wherein the first material is shaped as a preform member prior to the second material being applied thereto. 5. The case according to claim 4, wherein the second material is over-molded onto the preform. 6. The case according to claim 1, wherein the first material and the second material are molded together. 7. The case according to claim 6, wherein the first material and the second material are integrally molded so that the case forms an integral unit. 8. The case according to claim 7, wherein the first material and the second material are molded together through co-injection molding. 9. The case according to claim 1, wherein the second material is bonded to the first material or is secured to the first material via an adhesive. 10. The case according to claim 1, wherein the second material is configured to surround the portable electronic device at an interior of the first material. 11. The case according to claim 1, wherein the second material is configured to frame a front portion of the portable electronic device. 12. The case according to claim 1, wherein the case is separable into constituent parts configured to slide relative to each other to surround the portable electronic device. 13. The case according to claim 1, wherein the first material of the base portion has a flat configuration. 14. The case according to claim 1, wherein the second material protrudes from the first material at the side portions of the portable electronic device. 15. The case according to claim 1, wherein the first material comprises one or more of plastic, polycarbonate, wood, metal, glass, and leather. 16. The case according to claim 1, wherein the second material is formed from thermoplastic polyethylene (TPE), rubber, or foam. 17. The case according to claim 1, wherein exterior surfaces formed in the first material generally match contours of surfaces of the portable electronic device. 18. The case of claim 1, wherein the first material is glossier than the second material. 19. The case of claim 1, wherein the second material has a greater resiliency than the first material. 20. The case of claim 1, further comprising one or more apertures formed in one or more of the first material and the second material, configured to align with features of the portable electronic device. 21. The case of claim 1, wherein the second material protruding through the one or more apertures in the first material protrudes through adjacent apertures in the first material, and extends between the adjacent apertures on each opposing surfaces of the first material. 22. The case of claim 1, wherein the second material protruding through the one or more apertures in the first material protrudes through a plurality of sets of adjacent apertures in the first material and extends between the adjacent apertures of each set on each opposing surface of the first material. | CROSS-REFERENCE TO PRIOR APPLICATION This application is a continuation of U.S. patent application Ser. No. 15/337,518 filed Oct. 28, 2016, which is a continuation of U.S. patent application Ser. No. 14/174,436 filed Feb. 6, 2014 and claims benefit to U.S. Patent Application 61/761,556 filed Feb. 6, 2013, the contents of which are incorporated herein in their entirety. BACKGROUND Field The present disclosure is generally related to a case for use with a portable electronic device. More specifically, the disclosure relates to a case configured to protect the electronic device from impacts or abrasions. Background Some cases for portable electronic devices, such as cellular phones and personal digital assistants (PDAs), for example, have hard exterior surfaces with low coefficients of friction. Such exterior surfaces may facilitate insertion and removal of the case (and electronic device therein) from a user's pocket. Other cases are formed from a softer cushioning material, tending to have a relatively high coefficient of friction, which may provide greater impact protection to the electronic device. Among other things, the present application discloses improvements to cases for electronic devices. SUMMARY According to an embodiment, a case for use with a portable electronic device includes a base portion with side portions extending therefrom, the base portion and side portions forming a pocket configured to surround a back and sides of the portable electronic device. The case also includes a first material generally being positioned at an exterior of the pocket, wherein a majority of an exterior surface of the base portion is formed from the first material. The case also includes a second material generally being positioned at an interior of the pocket, the second material protruding through one or more apertures in the first material at the base portion so that portions of the second material protrude from the interior of the pocket to the exterior surface of the base portion, and protrude outward from the first material at the base portion such that when the base portion of the case is placed on the support surface, the second material contacts the support surface. The second material has a higher coefficient of friction than the first material and is secured to the first material. The second material protrudes through the one or more apertures in the first material at the base portion extends away from the one or more apertures on opposing surfaces of the first material at the exterior of the pocket and the interior of the pocket to provide securement between the first and second materials. Other features and advantages of the present invention will become apparent from the following detailed description, the accompanying drawings, and the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS Embodiments will now be described, by way of example only, with reference to the accompanying drawings in which corresponding reference symbols indicate corresponding parts, and in which: FIG. 1 illustrates a rear view of an embodiment of an electronic device case; FIG. 2 illustrates a front view of the electronic device case of FIG. 1; FIG. 3 illustrates a right side view of the electronic device case of FIG. 1; FIG. 4 illustrates a left side view of the electronic device case of FIG. 1; FIG. 5 illustrates a top view of the electronic device case of FIG. 1; FIG. 6 illustrates a bottom view of the electronic device case of FIG. 1; FIG. 7 illustrates a perspective view of the electronic device case of FIG. 1; FIG. 8 illustrates a reduced perspective view of the electronic device case of FIG. 1, as depicted in FIG. 7, omitting a material molded therein; FIG. 9 illustrates another reduced perspective view of the electronic device case of FIG. 1; and FIG. 10 illustrates a perspective view of the electronic device case of FIG. 1, as depicted in FIG. 9, including the molded material omitted therefrom. DETAILED DESCRIPTION OF THE ILLUSTRATED EMBODIMENT(S) FIG. 1-6 illustrate rear, front, right side, left side, top, and bottom views of a case 10 in accordance with an embodiment of the present invention. FIG. 7 illustrates a perspective view of the case 10. As depicted in FIGS. 1-7, the case 10 includes a base 20 with sides extending away therefrom, forming a pocket to receive a portable electronic device therein. Specifically, in the illustrated embodiment, the case 10 includes a top 30, a bottom 40, a right side 50a, and a left side 50b. It may be appreciated that the so-called right side 50a appears on the left side of FIG. 1 because FIG. 1 illustrates a rear view of the case 10. In an embodiment, the top 30 and bottom 40 may comprise sides of the case 10 that are each coupled to the sides 50a and 50b through corner joints 60, described in greater detail below. It may be appreciated that the case 10 may be configured to house a variety of portable electronic devices across various embodiments, including but not limited to a cellular phone, PDA, music player (e.g., MP3 player), tablet, gaming device, remote control, and the like. As shown in FIGS. 2 and 7, the top 30, bottom 40, right side 50a, and left side 50b may be coupled by a lip 70 which may surround an opening of the case 10 shaped and configured to receive the portable electronic device therein. It may be appreciated that an interior surface 80 of the base 20, as well as interior surfaces of the top 30, bottom 40, right side 50a, left side 50b, and the lip 70, may define the pocket (with the lip 70 defining the opening of the pocket). In an embodiment, a display screen and/or a user interface of the portable electronic device may face away from the pocket (e.g., may be framed at least partially by the lip 70). As described in greater detail below, the corner joints 60 and/or the lip 70 may be formed of an elastic or otherwise resiliently deformable material, which may facilitate expanding the pocket to receive the portable electronic device within the pocket. It may be appreciated that other configurations of the case 10 may alternatively be possible, including but not limited to cases having multiple components that are separable from each other. For example, slider cases are generally configured with separable pieces that each slide over the portable electronic device, and engage one another (e.g., with a snap fit or friction fit) to secure the portable electronic device therein. It may be appreciated that the case 10 may have features or apertures formed therein, configured to correspond with features on the portable electronic device. For example, as shown in FIGS. 1 and 2, an aperture 90 may extend through the base 20, and may be configured to align with a camera lens on the electronic device. In some embodiments, the aperture 90 may be sized to additionally or alternatively align with a camera flash on the electronic device. In some embodiments, additional apertures may extend through the base 20, so as to align with other features, including but not limited to marketing insignias on the portable electronic device. It may also be appreciated that in some embodiments one or more of the apertures may be merely decorative (e.g., with a repetitive or randomized pattern of apertures formed across at least a portion of the case 10). FIG. 3 illustrates a right side 50a of the case 10. As shown, the right side 50a may include one or more raised features 100 that protrude (e.g., extend outwards) from the remainder of the case 10. As described in greater detail below, in some embodiments the majority of the exterior of the case 10, including at an exterior surface 105a of the right side 50a of the case 10, may generally be formed from a first material 110 while the raised features 100 on the right side 50a of the case 10 may be formed from a second material 120 having a higher coefficient of friction and/or a greater resiliency than the first material 110 generally found at the exterior of the case 10. As shown, in some embodiments the raised features 100 formed of the second material 120 may protrude from a region of the second material 120 that may be generally flush with the first material 110 at the exterior surface 105a of the right side 50a of the case 10. In some embodiments, the second material 120 forming the raised features 100 may be the same material as the material forming the corner joints 60, and/or may have a similar coefficient of friction, higher than that of the first material 110 forming the majority of the exterior of the case 10, and/or may be more resilient than the first material 110. As shown in FIG. 4, illustrating the left side 50b of the case 10, one or more raised features 100 may also be present on the left side 50b of the case 10. Similarly to the right side 50a of the case 10, the raised features 100 may protrude from a region of the second material 120 that may be generally flush with an exterior surface 105b of the left side 50b of the case 10, formed from the first material 110. Similarly to the aperture 90 extending through the base 20, in some embodiments the left side 50a and/or the right side 50b may contain features or apertures formed therein, configured to correspond with features on the portable electronic device. For example, FIG. 4 illustrates a side aperture 130 extending through the right side 50b of the case 10, which may be configured to correspond with a switch (e.g., a mute switch) on the portable electronic device. As further shown, other features, such as button features 140a and 140b may be formed therein, configured to align with and engage buttons of the portable electronic device. While in some embodiments the button features 140a and 140b may be mechanical buttons coupled within the case 10 to transmit a press thereon into a press of the buttons of the portable electronic device, in other embodiments the button features 140a and 140b may be formed from a flexible material, facilitating depression of the button features 140a and 140b. In an embodiment, the button features 140a and 140b (which may correspond with volume buttons of the portable electronic device) may be formed from the same material as the raised features 100. In an embodiment, the button features 140a and 140b and the raised features 100 may be formed from a quantity of the second material 120 at the right side 50b of the case 10 (e.g., where the second material 120 is flexible). FIG. 5 illustrates a top view of the case 10, showing the top 30. In an embodiment, the top 30 is formed from the first material 110 that forms the majority of the exterior of the case 10 (namely, e.g., the exterior of the base 20). As with other faces of the case 10, it may be appreciated that the top 30 may contain features or apertures formed therein, configured to correspond with features on the portable electronic device. In the illustrated embodiment, the top 10 includes a button 150 and a top aperture 160. In an embodiment, the button 150 may be configured to facilitate actuation of a top button on the portable electronic device. While in some embodiments the button 150 may be a mechanical button assembled into the case 10, in other embodiments, such as that illustrated, the button 150 may be formed from a flexible material configured to deform to allow for depression of the top button of the portable electronic device positioned underneath. In some embodiments, such as that shown, the button 150 may be formed from the second material 120, as described in greater detail below. Similarly to the aperture 90 and the side aperture 130, the top aperture 160 may be configured to align with one or more features of the portable electronic device. For example, in an embodiment the top aperture 160 may be configured to align with an audio jack on the portable electronic device. As depicted the bottom view of the case 10 in FIG. 6, a bottom 40 of the case 10 may in some embodiments include one or more bottom apertures 170. In the illustrated embodiment, a central bottom aperture 170 may be configured to align with a data port on the portable electronic device, and may be sized and shaped to receive a data cable therein. In an embodiment, other bottom apertures 170 may be configured to align with a speaker and/or a microphone on the portable electronic device. While separate bottom apertures 170 are provided in the illustrated embodiment, in some embodiments the case 10 may include a single bottom aperture 170 shaped to accommodate multiple features on the portable electronic device. In some embodiments, the one or more bottom apertures 170 may be formed directly in the first material 110 forming the majority of the exterior of the case 10. In some embodiments, such as the illustrated embodiments, however, some of the second material 120, or another material, may be positioned within the bottom apertures 170. For example, in the illustrated embodiment, lips surrounding the bottom apertures 170 comprise some of the second material 120. As appreciated in the views of FIGS. 5 and 6, the raised features 100 protrude from the sides 50a and 50b of the case 10. As such, where the raised features are formed from the second material 120 have a relatively higher coefficient of friction than the first material 110 forming the remainder of the case 10, placing the case 10 on a support surface so that the side 50a or 50b is facing the support surface would cause the higher friction second material 120 to frictionally engage the support surface. Such frictional engagement between the raised features 100 and the support surface may prevent the case 10 from tipping over when placed on its side 50a or 50b, or mitigate a tendency for the case 10 to tip over when the support surface or the case 10 are bumped. Additionally, the raised features 100 at the sides 50a and 50b of the case 10 may serve as a grip for a user of the portable electronic device when the user is holding the portable electronic device. As further shown in FIGS. 5 and 6, a material having a higher coefficient of friction and/or resiliency than the majority of the exterior of the case 10 may also extend below an exterior surface 180 of the base 20, as a base grip 190. As described in greater detail below, it may be appreciated that in some embodiments, the exterior surface 180 of the base 20 may comprise the majority of the exterior of the case 10, and may be formed from the first material 110. In the illustrated embodiment, the base grip 190 may be formed from the second material 120, having a higher coefficient of friction and/or resiliency than the exterior surface 180. Accordingly, where the exterior of the case 10 is predominantly formed from the first material 110, having a relatively smooth configuration (e.g., a relatively lower coefficient of friction), it may be easier for a user to remove the case 10 from a confined space (e.g., a user's pocket) than if a majority of the exterior of the case 10 was formed from a material having a higher coefficient of friction (e.g., the second material 120). It may be appreciated that where a minority of the exterior of the case 10 has the higher coefficient of friction material (e.g., the second material 120) protruding outward from the material having the lower coefficient of friction (e.g., the first material 110), the higher friction material may provide regions of high friction contact when the case 10 is placed on a support surface. For example, it may therefore be appreciated that when the case 10 is placed on a support surface with the base 20 facing the support surface, and the opening of the pocket of the case 10 (defined by the lip 70) facing away from the support surface, the base grip 190 may contact the support surface, as it protrudes from the lower friction exterior surface 180 of the base 20. As indicated above, in some embodiments the base grip 190, the raised features 100, and the corner joints 60 may all be formed from the second material 120. In an embodiment, the base grip 190, the corner joints 60, and/or the raised features 100 may all be coupled by the interior surface 80 of the base 20, which may be formed from a layer of the second material 120, positioned to the interior of the first material 110 forming the exterior surface 180. In some such embodiments, features of the case 10 formed from the first material 110 may be interconnected, with features of the case 10 formed from the second material 120 formed onto or integral with the features formed from the first material 110. An example of such a construction may be appreciated in the illustrated embodiment through consideration of FIGS. 7 and 8, where FIG. 8 illustrates a reduced view of the case 10 as depicted in FIG. 7, showing only those features formed from the first material 110, and excluding those features formed from the second material 120. As shown in FIG. 8, a preform member 200 of the case 10 formed from the first material 110 includes a base portion 210 associated with the base 20. It may be appreciated that the exterior surface 180 of the base portion 210 may be the exterior surface of the base 20 as a whole. As shown, the base portion 210 may be coupled to (and in the illustrated embodiment, integral with) a top portion 220 associated with the top 30, a bottom portion 230 associated with the bottom 40, and side portions 240a and 240b associated with the right side 50a and the left side 50b respectively. As shown, the preform member 200 may include apertures formed therein, which may remain unfilled, or may be only partially filled by the second material 120 when assembling the case 10. For example, in the embodiment of FIG. 8, the aperture 90 that extends through the base 20 may be partially filled by the second material 120, while the second material 120 thereat may include the aperture 90 therein, so that the aperture 90 extends through base 20 in the case 10. As further shown, however, the preform member 200 may include some apertures, like a top button aperture 250, which may be completely filled by a molded portion of the second material 120. In the illustrated embodiment, the top button aperture 250 is filled with a molded amount of the second material 120 so as to form the top button 150, which may flex relative to the top portion 220 so as to allow for depression of a button on the portable electronic device. As additionally shown, in some embodiments gaps 260 may be present at the corners of the preform member 200, which may allow the top 30, bottom 40, and sides 50a and 50b to flex relative to the base portion 210, allowing an area therebetween to expand to facilitate insertion of the portable electronic device. In an embodiment, the preform member 200 as a whole, formed from the first material 110, may be more elastic than the second material 120, and configured to snap back to its original shape after being deformed to allow insertion of the portable electronic device therein. It may be appreciated that the gaps 260 may be filled with the second material 120 to form the corner joints 60. In an embodiment, the second material 120 may be softer than the first material 110, so as to deform with the first material 110 when case 10 is deformed to insert the portable electronic device, but allow for flexibility of the sides of the case 10 at the gaps 260. In some embodiments, the second material 120 may be shaped to protrude out from the gaps 260 defined by the preform member 200, so that the corner joints 60 protrude from the body of the case 10, as illustrated in FIG. 7. It may be appreciated that in some embodiments the corners of the preform member 200 may intersect (e.g., linking the top 30 and/or bottom 40 to either or both of the sides 50a and 50b directly, as well as via the base 20). In some such embodiments, the second material 120 may be formed on top of the intersection, forming corner bumpers that protrude from the corners of the preform member 200. In some embodiments, the apertures formed in the preform member 200 may be configured to receive a quantity of the second material 120 that may be molded, shaped, or otherwise formed to include various desired features therein. For example, side apertures 270a and 270b, formed in the side portions 240a and 240b respectively, may be configured to receive a mass of the second material 120 which itself may be shaped to include the raised portions 100 and (on the left side 50b of the illustrated embodiment) the button features 140a and 140b. As shown in the illustrated embodiment, the side apertures 270a and 270b may be configured with support ribs 280 that are recessed from the exterior opening of the side apertures 270a and 270b, however provide structural stability to the side portions 240a and 240b. It may be appreciated that in some embodiments the support ribs 280 may be partially or completely covered by the second material 120, as viewed from the exterior of the case 10 and/or from the interior of the pocket. As shown in FIG. 7, in the illustrated embodiment at least some of the second material 120 may fill in spaced between each of the support ribs, as well as filling in the side apertures 270a and 270b. In an embodiment where a side aperture 130 is formed in the second material 120 at the left side 50b, it may be appreciated that a support rib 280 may be omitted thereat. In other embodiments, the side aperture 130 may extend through a support rib 280, or the side aperture 130 may otherwise be positioned between support ribs 280. While in some embodiments the first material 110 and the second material 120 may be integrally formed together (e.g., through co-injection molding or similar assembly mechanisms to form a one piece embodiment of the case 10), in the illustrated embodiment, the first material 110 may be formed into the preform member 200 first, before being overmolded with the second material 120. While in some embodiments the preform member 200 may be merely partially cured before the second material 120 is applied and molded therearound, in an embodiment the formation of the preform member 200 may be complete (e.g. cured, removed from the mold, and/or separately assembled) before being combined with the second material 120. In the illustrated embodiment, with the preform member 200 being formed from the first material 110 before application of the second material 120 thereto, it may be appreciated that molding supports may be positioned thereon to facilitate overmolding of the second material 120. In some embodiments the molding supports may be configured to cooperate with the mold in the overmolding process. For example, in an embodiment one or more of the molding supports may be configured to position or align a portion of the mold to facilitate injection of the second material 120. As shown in FIG. 8, in the illustrated embodiment support tabs 290 may be configured to define a maximum application thickness for the overmold of the second material 120 on the interior of the base portion 210 (e.g., for application of the second material 120 to form the interior surface 80 of the case 10). In an embodiment the molding supports may include apertures 300 in the first material 110 which may be configured to facilitate flow of the second material 120 to desired regions of the preform member 200 prior to curing the second material 120. For example, as shown in FIGS. 9, illustrating the exterior surface 180 of the preform member 200, the apertures 300 may extend through the base 20. In the illustrated embodiment, one or more base grip grooves 310 may be formed in the exterior surface 180, and may be configured to direct a flow of the second material 120 when poured or injected onto the base portion 210 of the preform member 200, allowing the second material 120 to form the base grips 190 as well as cover the interior surface 80 of the base portion 20. It may therefore be appreciated that in some embodiments the second material 120 may surround the first material 110, such as by being molded onto opposing faces of the first material 110 (e.g., as the preform member 200), however being connected. It may be appreciated that such a configuration may provide increased structural stability to the case 10. For example, in the illustrated embodiment, the second material 120 may flow through the apertures 300, across the base grip grooves 310, and connect with other portions of the second material 120 before curing. Where the second material 120 coats the interior surface 80 of the base 20, and overlays (and in an embodiment protrudes from) the exterior surface 180 of the base 20, it may be appreciated that the second material 120 may sandwich the first material 110 therebetween. As noted above, in some embodiment the support ribs 280 (formed from the first material 110) may be partially or completely covered by the second material 120. It may be appreciated that the support ribs 280 surrounded by the second material 120 may provide increased structural stability to the sides 50a and 50b of the case 10 in such embodiments. FIG. 10 illustrates a perspective view of an embodiment of the case 10, similar to the view of the preform member 200 in FIG. 9. As shown in the comparison between FIGS. 9 and 10, when the second material 120 is injected or poured onto the preform member 200, the second material 120 may pass through the apertures 300 therein, and traverse the base grip grooves 310 to form the base grips 190. In some embodiments, the molding process may be configured to shape and define an amount by which the base grips 190 extend from the exterior surface 180 of the base 20. For example, in an embodiment the mold may include one or more corresponding grooves that match the base grip grooves 310 of the preform member 200. Accordingly, the shape of the base grips 190 may be defined through a molding process. In an embodiment, the second material 120 protruding through one or more apertures 300 may extend away from the one or more apertures 300 on opposing surfaces of the first material 110 at the exterior surface of the base 20 and the interior surface of the base 20, to provide securement between the first material 110 and the second material 120. In an embodiment, the second material 120 protruding through the one or more apertures 300 in the first material 110 may protrude through adjacent apertures 300, and thus the second material 120 may extend on both the exterior surface of the base 20 and the interior surface of the base 20, as well as in both adjacent apertures 300. In an embodiment the second material 120 protruding through the one or more apertures 300 in the first material 110 may protrude through a plurality of sets of adjacent apertures 300 in the first material 110, and may extend between the adjacent apertures 300 of each set on each opposing surface of the first material 110. As shown, in some embodiments, the molding or other addition of the second material 120 may be configured to position the second material 120 at the gaps 260 so as to form the corner joints 60. The second material 120 may also form the lips around the bottom apertures 170, as shown, as well as fill the side apertures 270a and 270b. It may be appreciated that in embodiments where the raised features 100 are molded from the second material 120, the mold may include grooves configured to shape the second material 120 to create the raised features 100 protruding from the case 10. It may also be appreciated that, in some embodiments, the second material 120 may additionally form the lips 70 surrounding the opening of the case 10 as the second material 120 is molded onto the preform member 200. It may be appreciated that in some embodiments, the lips 70 may also protrude above the opening of the case 10 (e.g., away from a screen of a portable electronic device inserted within the case 10), which may cause the second material 120 to extend outward from the first material 110 in the case 10 at both of the largest opposing faces of the case 10. In an embodiment, such as that shown, an aperture 320 extending through the base 20 may be configured to be filled with the second material 120, and be molded to depict a marketing insignia 330 therein. Other features formed from the second material 120 may additionally or alternatively be formed from the addition of the second material 120 to the preform member 200. Furthermore, it may be appreciated that the molding or other assembly may be performed simultaneously or sequentially in various embodiments. Accordingly, constructing case 10 by overmolding the second material 120 to the preform member 200 is not intended to be limiting. Indeed, in some embodiments the second material 120 may be formed with recessed regions at exterior surfaces thereof, and one or more harder plates of first material 110 may be molded thereon. It may be appreciated that the protruding configuration of the corner joints 60, the raised features 100, the base grips 190, and/or the lips 70 may provide a degree of additional protection to the case 10 and a portable electronic device housed therein. For example, where the first material 110 is glossy or otherwise prone to scratching, the protruding second material 120 may space the first material 110 from support surfaces, reducing a likelihood of the first material 110 being scratched by the support surface or debris thereon. Additionally, where the second material is resilient (e.g. soft and/or flexible), the protruding configuration thereof may provide enhanced impact resistance, such as when the case 10 is dropped and impacts a face or corner thereof. For example, if the case 10 is dropped at a corner thereof, the protruding second material 120 at the corner joint 60 may provide enhanced impact resistance, and mitigate a tendency of the first material 110 adjacent to the gap 260 from impacting and cracking. This additional protection may be particularly beneficial where, like in the illustrated embodiment, the first material 110 is positioned to form the majority of the exterior of the case 10. Furthermore, where the second material 120 has a higher coefficient of friction and/or resiliency than the first material 110, it may be appreciated that the protruding amount of the second material 120 may cause the second material 120 to contact a support surface instead of the first material 110, providing a higher frictional engagement between the case 10 and the support surface. As noted above, such a higher frictional engagement may prevent the case 10 from tipping over when placed on one of the sides 50a or 50b (e.g., through the case 10 and portable electronic device having a high center of gravity in such a position). As described above, the protrusion of the second material 120 from the first material 110 at the base 20 may provide regions of high friction contact when the case 10 is placed on a support surface. In an embodiment, more than half of the exterior of the base 20 (i.e., the surface outside of the pocket) may be formed from the first material 110, while less than half of the exterior of the base 20 may be formed from the second material 120 protruding outwards from the first material 110, so as to form a surface of the second material 120 that may contact a support surface instead of the first material 110 when the base 20 of the case 10 is resting on the support surface. In other embodiments, the second material 120 forming the surface that contacts a support surface may make up a smaller proportion of the exterior of the base 20. For example, the second material 120 protruding from the first material 110 at the exterior of the base 20 may be approximately less than or equal to 40% of the exterior of the base 20. In other embodiments, the second material 120 protruding from the first material 110 at the exterior of the base 20 may be approximately less than or equal to 30% of the exterior of the base 20, approximately less than or equal to 20% of the exterior of the base 20, approximately less than or equal to 10% of the exterior of the base 20, or approximately less than or equal to 10% (e.g., 5%, 1%, or less) of the exterior of the base 20. In an embodiment, the amount of the second material 120 protruding out from the first material 110 at the exterior of the base 20 may be just sufficient to support the base 20 thereon, so as to space the first material 110 from a support surface, so that contact between the support surface and the base 20 is via the second material 120 instead of the first material 110. For example, in an embodiment the second material 120 may protrude from the first material 110 at the exterior of the base 20 at least at three regions, so as to provide a stable support of second material 120 when the base 20 is placed against a support surface. In an embodiment, a protruding amount of second material 120 may be positioned at each corner of the base 20 (e.g., adjacent to the corner joints 60), to provide four points of contact for the second material 120 between the base 20 and the support surface. In some embodiments, such as that illustrated herein, the second material 120 may generally form a ring following a perimeter of the base 20 (e.g., following the base grip grooves 310 in some embodiments), surrounding a substantial amount of the first material 110 of the base 20. In an embodiment, the protruding portions of second material 120 may form thin or elongate shapes across the first material 110 of the base 20. As indicated above, features of the constructions and configurations described herein and illustrated in the Figures may be exemplarity in some embodiments. For example, while in the illustrated embodiment the case 10 is formed from the overmolding of the second material 120 onto the preform member 200, in some embodiments the case 10 may be formed by simultaneously molding the first material 110 and the second material 120. In some such embodiments, the case 10 may be formed using processes such as injection molding. In an embodiment, case 10 is preferably formed from injection-molded plastic. Other constructions are additionally or alternatively possible, including but not limited to creating an assembly through a combination of constituent components, assembled through adhesion with an adhesive, interlocking components, or any other appropriate assembly mechanism. It may additionally be appreciated that dimensions of the case 10 may vary according to the type of electronic device to be held therein. For example, in some embodiments where the first material 110 (e.g., as the preform member 200) is relatively hard or rigid (especially as compared to the second material 120), it may be appreciated that the dimensions thereof may be sufficient to surround the portable electronic device. In an embodiment, the relatively flexible second material 120 may be sized to snugly surround the portable electronic device, and may provide impact protection for the portable electronic device within the first material 110. Additionally, in some embodiments the first material 110 in the case 10 may be shaped to generally match contours of the portable electronic device. For example, the preform member 200 or analogous components of other embodiments of the case 10 may cause the case 10 to generally resemble the portable electronic device. In some embodiments, the case 10 may be formed with the first material 110 (e.g., as the preform member 200) having multiple facets or curves formed on one or more of the base 20, top 30, bottom 40, right side 50a, and left side 50b. In other embodiments, the case 10 may be shaped in a manner that is externally different from the portable electronic device configured to be retained therein. In some embodiments, the second material 120 may be configured to create a pocket shaped to retain the portable electronic device, but may have varying thickness within to fill the space between the pocket and the first material 110 at the exterior of the case 10. Accordingly, it may be appreciated that the generally straight lines and rounded corners depicted in the case 10 illustrated herein are merely exemplary. The materials utilized in the case 10 and/or their properties may also vary across embodiments. For example, while in the illustrated embodiment the first material 110 utilized in the preform member 200 is described as being hard or rigid, in other embodiments the first material 110 may be any appropriate material having less shock absorbing properties than the second material 120. For example, while both the first material 110 and the second material 120 may be flexible in some embodiments, the second material 120 may be more resilient than the first material 110. It may be understood that resilient materials may include materials that can substantially return to its original form after being stretched, moved, bent, or otherwise deformed (within a reasonable tolerance). It may be appreciated that in the art, resiliency may be measured by a durometer. Shore A durometers generally measure the compressive deformability of softer materials, such as rubbers and softer polyurethanes, while Shore D durometers may measure compressive deformability of harder polyurethanes and softer plastics. Rockwell R durometers typically measure compressive deformability of harder polyurethanes and plastics, ranging from Teflon through phenolic, for example. Accordingly, in some embodiments the second material 120 may have a hardness/resiliency on a scale conventionally measured on a Shore A durometer (e.g., a Shore A durometer value between 20-95), while the first material 110 may have a hardness/resiliency on a scale conventionally measured on a Shore D durometer of 25-85, or on a Rockwell R durometer of 50-150. In an embodiment, the first material 110 may be harder or more rigid so as to provide penetrative protection thereto, distributing impact forces applied thereto throughout the first material 110. The comparative softness and resilience of the second material 120 (e.g., having a Shore A durometer value of less than 90) may absorb shocks therein, and give to prevent direct application of forces to the portable electronic device housed therein. It may be appreciated that in some embodiments hardness/resilience and an associated coefficient of friction may be distinct from a coefficient of friction associated with the material and a given reference surface. For example, some harder materials may have a relatively high coefficient of friction, while some softer/resilient materials may have a relatively lower coefficient of friction. Accordingly, the selection of the first material 110 and the second material 120 may vary across embodiments, depending on a desired protruding resilient portion or a desired portion having a higher coefficient of friction. As such, the material selections of the first material 110 and the second material 120 may vary, and may each have different properties, including but not limited to differing hardness/resiliency, and differing coefficients of friction. It may be appreciated that in some embodiments, the same material may have different hardness's/resiliencies, or different coefficients of friction (e.g., with a particular support surface) depending on how the material is prepared. Regardless, in some non-limiting embodiments, the second material 120 may comprise a thermoplastic polymer or a thermoplastic elastomer material, such as thermoplastic polyethylene (TPE) or thermoplastic polyurethane (TPU). Any other resilient material, such as silicone, rubber or foam, may additionally or alternatively be utilized. In contrast, the first material 110 may be more prone to permanent deformation, including cracking, scratching, shearing, or so on. As one non-limiting example, in the illustrated embodiment, where the first material 110 is a molded plastic, the first material 110 may comprise a thermoplastic, including but not limited to thermoplastics such as polycarbonate, acrylonitrile butadiene styrene (ABS), and polyvinyl chloride (PVC). It may be appreciated that the first material 110 need not be formed from molded plastic, but may comprise any other material, including but not limited to wood, metal, glass, leather, or so on, which may be overmolded with or assembled with a resilient or otherwise impact absorbing second material that protrudes from the first material 110 as described herein. In some embodiments, the first material 110 and the second material 120 may have different cosmetic properties. For example, in some embodiments, the first material 110 may have glossy characteristics, while the second material 120 may have matte characteristics. In other embodiments, the converse may be true. In some embodiments, the first material 110 and the second material 120 may be different colors. Additionally, in various embodiments, one or more additional materials may be embedded or combined with either or both of the first material 110 and the second material 120, and may serve cosmetic or functional purposes. For example, different portions of the components of the case 10 described above (e.g., different parts of the preform member 200) may be made from different materials, which may be molded or otherwise assembled before being overmolded or otherwise secured to the second material 120 and/or additional materials that protrude from those portions forming the majority of the exterior of the case 10. In an embodiment, the second material 120 and the first material 110 may be secured to each other through a bond (e.g., as in the molding process) or through adhesion (e.g., via an adhesive). While the principles of the invention have been made clear in the illustrative embodiments set forth above, it will be apparent to those skilled in the art that various modifications may be made to the structure, arrangement, proportion, elements, materials, and components used in the practice of the invention. It will thus be seen that the objects of this invention have been fully and effectively accomplished. It will be realized, however, that the foregoing preferred specific embodiments have been shown and described for the purpose of illustrating the functional and structural principles of this invention and are subject to change without departure from such principles. Therefore, this invention includes all modifications encompassed within the spirit and scope of this disclosure, as recited in the following claims. | <SOH> BACKGROUND <EOH> | <SOH> SUMMARY <EOH>According to an embodiment, a case for use with a portable electronic device includes a base portion with side portions extending therefrom, the base portion and side portions forming a pocket configured to surround a back and sides of the portable electronic device. The case also includes a first material generally being positioned at an exterior of the pocket, wherein a majority of an exterior surface of the base portion is formed from the first material. The case also includes a second material generally being positioned at an interior of the pocket, the second material protruding through one or more apertures in the first material at the base portion so that portions of the second material protrude from the interior of the pocket to the exterior surface of the base portion, and protrude outward from the first material at the base portion such that when the base portion of the case is placed on the support surface, the second material contacts the support surface. The second material has a higher coefficient of friction than the first material and is secured to the first material. The second material protrudes through the one or more apertures in the first material at the base portion extends away from the one or more apertures on opposing surfaces of the first material at the exterior of the pocket and the interior of the pocket to provide securement between the first and second materials. Other features and advantages of the present invention will become apparent from the following detailed description, the accompanying drawings, and the appended claims. | H04B13888 | 20171109 | 20180308 | 69639.0 | H04B13888 | 1 | HU, RUI MENG | ELECTRONIC DEVICE CASE WITH A FRICTION SURFACE | UNDISCOUNTED | 1 | CONT-ACCEPTED | H04B | 2,017 |
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15,808,388 | PENDING | SYSTEMS AND METHODS FOR CASCADED MODEL PREDICTIVE CONTROL | A cascaded model predictive control system includes an inner controller and an outer controller. The outer controller determines an amount of power to defer from a predicted power usage to optimize a total cost of power usage. A power setpoint is calculated based on a difference between the predicted power usage and the amount of power to defer. The inner controller determines an operating setpoint for building equipment in order to achieve the power setpoint. | 1. A heating, ventilation, or air conditioning (HVAC) system for a building, the HVAC system comprising: a building system comprising one or more measurement devices configured to measure at least one of a measured temperature of the building or a measured power usage of the building and generate a feedback signal comprising at least one of the measured temperature of the building or the measured power usage of the building; a load predictor configured to predict a future power usage of the building; an outer controller configured to receive the feedback signal from the building system, receive time-varying pricing information, perform an optimization process to determine an amount of power to defer from the predicted power usage based on the feedback signal and the pricing information, and output a power control signal indicating the amount of power to defer, wherein the amount of power to defer optimizes a total cost of the power usage of the building; an inner controller configured to receive a power setpoint representing a difference between the predicted power usage and the amount of power to defer, determine an operating setpoint for the building system predicted to achieve the power setpoint, and output a second control signal indicating the operating setpoint; and HVAC equipment comprising one or more physical devices, wherein the building system is configured to operate the HVAC equipment to achieve the operating setpoint; wherein at least one of the outer controller or the inner controller is an electronic device comprising a communications interface and a processing circuit. 2. The HVAC system of claim 1, wherein the feedback signal includes both information representative of the measured temperature and information representative of the measured power usage of the building. 3. The HVAC system of claim 2, wherein the outer controller is configured to: receive a dynamic model describing heat transfer characteristics of the building and temperature constraints defining an acceptable range for the measured temperature; use the dynamic model and the feedback signal to estimate a temperature state for the building as a function of power usage; and use an optimization procedure to determine a power usage for the building which minimizes the total cost of the power usage while maintaining the estimated temperature state within the acceptable range. 4. The HVAC system of claim 1, wherein the outer controller and the inner controller have different sampling and control intervals, wherein the sampling and control interval of the outer controller is longer than the sampling and control interval of the inner controller. 5. The HVAC system of claim 1, wherein the outer controller and the inner controller are physically decoupled in location. 6. The HVAC system of claim 1, wherein the time-varying pricing information includes demand charge information defining a cost per unit of power corresponding to a maximum power usage within a pricing period. 7. The HVAC system of claim 6, wherein the time-varying pricing information includes demand charge information for two or more of a plurality of pricing periods. 8. The HVAC system of claim 1, wherein the second control signal includes at least one of: the operating setpoint; or a derivative of the operating setpoint. 9. The HVAC system of claim 1, wherein the power control signal includes at least one of: the power setpoint received by the inner controller; or the amount of power to defer from a predicted power usage, wherein the amount of power to defer is subtracted from the predicted power usage to calculate the power setpoint received by the inner controller. 10. The HVAC system of claim 9, wherein the load predictor configured to: receive the operating setpoint and at least one of: current weather information, past weather information, or past building power usage; and output the predicted power usage, wherein the power control signal is an amount of power to defer from the predicted power usage. 11. A method for heating, ventilating, or air conditioning a building, the method comprising: measuring at least one of a measured temperature of the building or a measured power usage of the building; generating a feedback signal comprising at least one of the measured temperature of the building or the measured power usage of the building; predicting a future power usage of the building based on historical weather and power usage data; performing an optimization process to determine an amount of power to defer from the predicted power usage based on the feedback signal and time-varying pricing information; generating a power control signal indicating the amount of power to defer, wherein the amount of power to defer optimizes a total cost of the power usage of the building; calculating a power setpoint representing a difference between the predicted power usage and the amount of power to defer; determining an operating setpoint predicted to achieve the power setpoint; generating a second control signal indicating the operating setpoint; and operating HVAC equipment to achieve the operating setpoint, the HVAC equipment comprising one or more physical devices. 12. The method of claim 11, wherein the feedback signal includes both information representative of the measured temperature and information representative of the measured power usage of the building. 13. The method of claim 12, further comprising: receiving a dynamic model describing heat transfer characteristics of the building and temperature constraints defining an acceptable range for the measured temperature; using the dynamic model and the feedback signal to estimate a temperature state for the building as a function of power usage; and using an optimization procedure to determine a power usage for the building which minimizes the total cost of the power usage while maintaining the estimated temperature state within the acceptable range. 14. The method of claim 11, wherein the power control signal is generated by an outer controller having a first sampling and control interval and the second control signal is generated by an inner controller having a second sampling and control interval shorter than the first sampling and control interval. 15. The method of claim 11, wherein the power control signal is generated by an outer controller and the second control signal is generated by an inner controller physically decoupled in location from the outer controller. 16. The method of claim 11, wherein the time-varying pricing information includes demand charge information defining a cost per unit of power corresponding to a maximum power usage within a pricing period. 17. The method of claim 16, wherein the time-varying pricing information includes demand charge information for two or more of a plurality of pricing periods. 18. The method of claim 11, wherein the second control signal includes at least one of: the operating setpoint; or a derivative of the operating setpoint. 19. The method of claim 11, further comprising subtracting the amount of power to defer from the predicted power usage to calculate the power setpoint; wherein the power control signal includes at least one of the power setpoint or the amount of power to defer from a predicted power usage. 20. The method of claim 19, further comprising: receiving the operating setpoint and at least one of: current weather information, past weather information, and past building power usage; and outputting the predicted power usage, wherein the power control signal is an amount of power to defer from the predicted power usage. | CROSS-REFERENCE TO RELATED PATENT APPLICATION This application is a continuation of U.S. patent application Ser. No. 13/802,154 filed Mar. 13, 2013, the entire disclosure of which is incorporated by reference herein. BACKGROUND The present disclosure relates to systems and methods for minimizing energy cost in response to time-varying pricing scenarios. The systems and methods described herein may be used for demand response in building or HVAC systems such as those sold by Johnson Controls, Inc. The rates that energy providers charge for energy often vary throughout the day. For example, energy providers may use a rate structure that assigns different energy rates to on-peak, partial-peak, and off-peak time periods. Additionally, energy providers often charge a fee known as a demand charge. A demand charge is a fee corresponding to the peak power (i.e. the rate of energy use) at any given time during a billing period. In a variable pricing scenario that has an on-peak, partial-peak, and off-peak time period, a customer is typically charged a separate demand charge for maximum power use during each pricing period. Energy providers can also offer customers the option to participate in a critical-peak pricing (CPP) program. In a CPP program, certain days throughout a billing period are designated as CPP days. On a CPP day, the on-peak time period is often divided in two or more sub-periods. CPP periods may also have separate demand charges for each sub-period. As an incentive to participate in the CPP program, customers are charged a lower energy rate on non-CPP days during the billing period. Energy providers also often engage in real-time pricing (RTP). RTP energy rates change frequently and can vary quite drastically throughout the day. RTP periods may also have a separate demand charge for each RTP period. It is challenging and difficult for energy customers would like to minimize the cost that they pay for energy where pricing scenarios can be mixed. Control actions can be taken to respond to variable pricing scenarios. One response is to turn off equipment. However, when the energy is used to drive a heating or cooling system for a building, the cost minimization problem is often subject to constraints. For example, it is desirable to maintain the building temperature within an acceptable range. Methods that are more proactive include storing energy in batteries or using ice storage to meet the future cooling loads. A problem with many of these techniques is the requirement for large, expensive, and non-standard equipment. A method that does not require additional equipment is storing energy in the thermal mass of the building. This form of thermal energy storage risks leading to either uncomfortable building zone temperatures or demand charges that are not significantly reduced. One technique is to pre-cool the building to a minimum allowable temperature and to determine the temperature setpoint trajectory that will minimize power use while maintaining the temperature below a maximum allowable value. With this technique, the demand can be curtailed and the zone temperature can remain within temperature comfort bounds. Traditional methods are less than optimal and are unable to handle RTP pricing scenarios with rapidly changing energy prices or CPP pricing scenarios having several regions of interest for both energy and demand charges. Furthermore, traditional methods may have difficulty accounting for varying disturbances to the system or changes to the system which are likely to necessitate re-developing or retraining the underlying model. Energy cost minimization systems and methods are needed to address a plurality of variable pricing schemes including the rapidly changing energy cost structures of CPP and RTP. Additionally, a method is needed which handles the possibility of multiple demand charge regions and which handles varying disturbances and changes to the system without the need to re-train the model. SUMMARY One implementation of the present disclosure is a heating, ventilation, or air conditioning (HVAC) system for a building. The HVAC system includes a building system, a load predictor, an outer controller, an inner controller, and HVAC equipment. The building system includes one or more measurement devices configured to measure at least one of a measured temperature of the building or a measured power usage of the building and generate a feedback signal including at least one of the measured temperature of the building or the measured power usage of the building. The load predictor is configured to predict a future power usage of the building. The outer controller is configured to receive the feedback signal from the building system, receive time-varying pricing information, perform an optimization process to determine an amount of power to defer from the predicted power usage based on the feedback signal and the pricing information, and output a power control signal indicating the amount of power to defer. The amount of power to defer optimizes a total cost of the power usage of the building. The inner controller is configured to receive a power setpoint representing a difference between the predicted power usage and the amount of power to defer, determine an operating setpoint for the building system predicted to achieve the power setpoint, and output a second control signal indicating the operating setpoint. The HVAC equipment include one or more physical devices. The building system is configured to operate the HVAC equipment to achieve the operating setpoint. At least one of the outer controller or the inner controller is an electronic device including a communications interface and a processing circuit. In some embodiments, the feedback signal includes both information representative of the measured temperature and information representative of the measured power usage of the building. In some embodiments, the outer controller is configured to receive a dynamic model describing heat transfer characteristics of the building and temperature constraints defining an acceptable range for the measured temperature. In some embodiments, the outer controller is configured to use the dynamic model and the feedback signal to estimate a temperature state for the building as a function of power usage. In some embodiments, the outer controller is configured to use an optimization procedure to determine a power usage for the building which minimizes the total cost of the power usage while maintaining the estimated temperature state within the acceptable range. In some embodiments, the outer controller and the inner controller have different sampling and control intervals. The sampling and control interval of the outer controller may be longer than the sampling and control interval of the inner controller. In some embodiments, the outer controller and the inner controller are physically decoupled in location. In some embodiments, the time-varying pricing information includes demand charge information defining a cost per unit of power corresponding to a maximum power usage within a pricing period. In some embodiments, the time-varying pricing information includes demand charge information for two or more of a plurality of pricing periods. In some embodiments, the second control signal includes at least one of the operating setpoint or a derivative of the operating setpoint. In some embodiments, the power control signal includes at least one of the power setpoint received by the inner controller or the amount of power to defer from a predicted power usage. In some embodiments, the amount of power to defer is subtracted from the predicted power usage to calculate the power setpoint received by the inner controller. In some embodiments, the load predictor configured to receive the operating setpoint and at least one of current weather information, past weather information, or past building power usage. In some embodiments, the load predictor is configured to output the predicted power usage. The power control signal may be an amount of power to defer from the predicted power usage. Another implementation of the present disclosure is a method for heating, ventilating, or air conditioning a building. The method includes measuring at least one of a measured temperature of the building or a measured power usage of the building, generating a feedback signal including at least one of the measured temperature of the building or the measured power usage of the building, and predicting a future power usage of the building based on historical weather and power usage data. The method includes performing an optimization process to determine an amount of power to defer from the predicted power usage based on the feedback signal and time-varying pricing information and generating a power control signal indicating the amount of power to defer. The amount of power to defer optimizes a total cost of the power usage of the building. The method includes calculating a power setpoint representing a difference between the predicted power usage and the amount of power to defer, determining an operating setpoint predicted to achieve the power setpoint, generating a second control signal indicating the operating setpoint, and operating HVAC equipment to achieve the operating setpoint, the HVAC equipment comprising one or more physical devices. In some embodiments, the feedback signal includes both information representative of the measured temperature and information representative of the measured power usage of the building. In some embodiments, the method includes receiving a dynamic model describing heat transfer characteristics of the building and temperature constraints defining an acceptable range for the measured temperature, using the dynamic model and the feedback signal to estimate a temperature state for the building as a function of power usage, and using an optimization procedure to determine a power usage for the building which minimizes the total cost of the power usage while maintaining the estimated temperature state within the acceptable range. In some embodiments, the power control signal is generated by an outer controller having a first sampling and control interval and the second control signal is generated by an inner controller having a second sampling and control interval shorter than the first sampling and control interval. In some embodiments, the power control signal is generated by an outer controller and the second control signal is generated by an inner controller physically decoupled in location from the outer controller. In some embodiments, the time-varying pricing information includes demand charge information defining a cost per unit of power corresponding to a maximum power usage within a pricing period. In some embodiments, the time-varying pricing information includes demand charge information for two or more of a plurality of pricing periods. In some embodiments, the second control signal includes at least one of the operating setpoint or a derivative of the operating setpoint. In some embodiments, the method includes subtracting the amount of power to defer from the predicted power usage to calculate the power setpoint. In some embodiments, the power control signal includes at least one of the power setpoint or the amount of power to defer from a predicted power usage. In some embodiments, the method includes receiving the operating setpoint and at least one of current weather information, past weather information, and past building power usage. In some embodiments, the method includes outputting the predicted power usage. The power control signal may be an amount of power to defer from the predicted power usage. BRIEF DESCRIPTION OF THE FIGURES FIG. 1 is a chart illustrating an exemplary “time of use” energy rate structure in which the cost of energy depends on the time of use. FIG. 2 is a chart illustrating an exemplary critical-peak pricing structure with multiple pricing levels within the critical peak pricing period. FIG. 3 is a chart illustrating an exemplary real-time pricing structure with many different price levels and a rapidly changing energy cost. FIG. 4 is a flow chart of a process for minimizing the cost of energy in response to a variable energy pricing structure, according to an exemplary embodiment. FIG. 5A is a flowchart of a process for developing a framework energy model for a building system and obtaining system parameters for the framework energy model, according to an exemplary embodiment, according to an exemplary embodiment. FIG. 5B is a block diagram of a model predictive controller including memory on which instructions for the various processes described herein are contained, a processor for carrying out the processes, and a communications interface for sending and receiving data, according to an exemplary embodiment. FIG. 6 is a block diagram of a cascaded model predictive control system featuring an inner MPC controller and an outer MPC controller, according to an exemplary embodiment. FIG. 7 is a detailed block diagram showing the inputs and outputs of the inner MPC controller, according to an exemplary embodiment. FIG. 8 is a detailed block diagram showing the inputs and outputs of the outer MPC controller, according to an exemplary embodiment. FIG. 9 is an energy balance diagram for formulating an energy model of the building system used by the inner MPC controller, according to an exemplary embodiment. FIG. 10 is an energy balance diagram for formulating an energy model of the building system used by the outer MPC controller, according to an exemplary embodiment. FIG. 11 is a flowchart of a process for identifying model parameters in an offline or batch process system identification process using a set of training data, according to an exemplary embodiment. FIG. 12 is a flowchart of a process for recursively identifying updated model parameters and checking the updated model parameters for stability and robustness, according to an exemplary embodiment. FIG. 13 is a flowchart of a process for defining an energy cost function, linearizing the cost function by adding demand charge constraints to the optimization procedure, and masking invalid demand charge constraints, according to an exemplary embodiment. FIG. 14 is a graph showing a plurality of pricing periods, a time-step having a valid demand charge constraint within one pricing period and an invalid demand charge constraint within another pricing period, according to an exemplary embodiment. FIG. 15 is a flowchart of an optimization process for minimizing the result of an energy cost function while satisfying temperature constraints, equality constraints, and demand charge constraints. FIG. 16 is a flowchart of a process for recursively updating an energy model, updating equality constraints and demand charge constraints, and recursively implementing the masking procedure and optimization procedure. DETAILED DESCRIPTION Referring to FIG. 1, a chart 100 illustrating “time of use” (TOU) energy pricing is shown, according to an exemplary embodiment. In a TOU pricing scheme, an energy provider may charge a baseline price 102 for energy used during an off-peak period and a relatively higher price 104 for energy used during an on-peak period. For example, during an off-peak period, energy may cost $0.10 per kWh whereas during an on-peak period, energy may cost $0.20 per kWh. Energy cost may be expressed as a cost per unit of energy using any measure of cost and any measure of energy (e.g., $/kWh, $/J, etc.). Referring now to FIG. 2, a chart 200 illustrating a critical-peak pricing (CPP) structure is shown, according to an exemplary embodiment. In a CPP pricing scenario, a high price 204 may be charged for energy used during the CPP period. For example, an energy provider may charge two to ten times the on-peak energy rate 202 during a CPP period. Certain days in a billing cycle may designated as CPP days and the CPP period may be divided in two or more sub-periods. CPP periods may also have separate demand charges for each sub-period. Referring now to FIG. 3, a chart 300 illustrating a real-time pricing structure is shown, according to an exemplary embodiment. In an RTP structure, energy cost may change as often as once per fifteen minutes and may vary significantly throughout a day or throughout a billing cycle. The systems and methods described herein may be used to minimize energy cost in a building system subject to time-varying energy prices. Referring now to FIG. 4, a flowchart illustrating a process 400 of minimizing energy cost in a building system is shown, according to an exemplary embodiment. Process 400 is shown to include receiving an energy model for the building system (step 402), receiving system state information (e.g., measurements or estimates of current conditions in the building system such as temperature, power use, etc.) (step 404), receiving an energy cost function for the building system (step 406), and using an optimization procedure to minimize the total energy cost for the building system (step 408). As stated above with reference to FIG. 4, process 400 includes receiving an energy model for the building system (step 402). The energy model for the building system (i.e., the system model) may be a mathematical representation of the building system and may be used to predict how the system will respond to various combinations of manipulated inputs and uncontrolled disturbances. For example, the energy model may be used to predict the temperature or power usage of the building in response to a power or temperature setpoint (or other controlled variable). The energy model may describe the energy transfer characteristics of the building. Energy transfer characteristics may include physical traits of the building which are relevant to one or more forms of energy transfer (e.g., thermal conductivity, electrical resistance, etc.). Additionally, the energy model may describe the energy storage characteristics of the building (e.g., thermal capacitance, electrical capacitance, etc.) as well as the objects contained within the building. The energy transfer and energy storage characteristics of the building system may be referred to as system parameters. In some embodiments, step 402 may include receiving a pre-defined system model including all the information needed to accurately predict the building's response (e.g., all the system parameters). In other embodiments, step 402 may include developing the model (e.g., by empirically determining the system parameters). Step 402 may include formulating a system of equations to express future system states and system outputs (e.g., future building temperature, future power usage, etc.) as a function of current system states (e.g., current building temperature, current power usage, etc.) and controllable system inputs (e.g., a power setpoint, a temperature setpoint, etc.). Step 402 may further include accounting for disturbances to the system (e.g., factors that may affect future system states and system outputs other than controllable inputs), developing a framework model using physical principles to describe the energy characteristics of the building system in terms of undefined system parameters, and obtaining system parameters for the framework model. Step 402 may be accomplished using process 500, described in greater detail in reference to FIG. 5. Still referring to FIG. 4, method 400 may include receiving system state information (step 404). Receiving system state information may include conducting and/or receiving measurements or estimates of current building conditions (i.e., current states of the building system) such as building temperature, building power use, etc.). System state information may include information relating to directly measurable system states or may include estimated or calculated quantities. Materials within the building may have a thermal capacitance and therefore may be used to store a thermal load (e.g., a heating or cooling load). System state information may include an estimation of an amount of heat currently stored by the capacitive objects within the building. Still referring to FIG. 4, method 400 may include receiving an energy cost function for the building system (step 406). The energy cost function may be used to calculate a total energy cost within a finite time horizon. Current system state information (e.g., measurements of current power usage) as well as predicted future system states (e.g., estimated future power usage) may be used in combination with time-varying price information for one or more pricing periods (e.g., off-peak, on-peak, critical peak, etc.) to calculate a total cost of energy based on a predicted energy usage. In some embodiments, step 406 may include receiving a pre-defined cost function including all of the information necessary to calculate a total energy cost. A pre-defined cost function may be received from memory (e.g., computer memory or other information storage device), specified by a user, or otherwise received from any other source or process. In other embodiments, step 406 may include defining one or more terms in the cost function using a cost function definition process. Step 406 may include receiving time-varying pricing information for a plurality of pricing periods. Time-varying pricing information may include energy cost information (e.g., price per unit of energy) as well as demand charge information (e.g., price per unit of power) corresponding to a maximum power use within a pricing period. Step 406 may further include receiving a time horizon within which energy cost may be calculated and expressing the total cost of energy within the time horizon as a function of estimated power use. Predicted future power use may be used in combination with energy pricing information for such periods to estimate the cost future energy use. Step 406 may further include expressing the cost function as a liner equation by adding demand charge constraints to the optimization procedure and using a masking procedure to invalidate demand charge constraints for inactive pricing periods. Step 406 may be accomplished using a cost function definition process such as process 1300, described in greater detail in reference to FIG. 13. Still referring to FIG. 4, method 400 may include using an optimization procedure to minimize the total energy cost for the building system (step 408). Step 408 may include receiving temperature constraints, using the energy model and the system state information to formulate equality constraints, and determining an optimal power usage or setpoint to minimize the total cost of energy within a finite time horizon (e.g., minimize the energy cost determined by the cost function) while maintaining building temperature within acceptable bounds. Equality constraints may be used to guarantee that the optimization procedure considers the physical realities of the building system (e.g., energy transfer principles, energy characteristics of the building, etc.) during cost minimization. In other words, equality constraints may be used to predict the building's response (e.g., how the system states and outputs will change) to a projected power usage or temperature setpoint, thereby allowing the energy cost function to be minimized without violating the temperature constraints. Step 408 may be accomplished using an optimization process such as process 1500 described in greater detail in reference to FIG. 15. Referring now to FIG. 5A, a flowchart illustrating a process 500 to develop an energy model for the building system is shown, according to an exemplary embodiment. Process 500 may be used to accomplish step 402 of method 400. Process 500 may include formulating a system of equations to express future system states and system outputs (e.g., future building temperature, future power use, etc.) as a function of current system states (e.g., current building temperature, current power use, etc.) and controllable inputs to the system (e.g., a power setpoint, a temperature setpoint, or other manipulated variables) (step 502). Process 500 may further include accounting for disturbances to the system (e.g., factors other than controllable inputs) such as outside temperature or weather conditions that may affect future system states and system outputs (step 504). Additionally, process 500 may include developing a framework model using physical principles to describe the energy characteristics of the building system in terms of undefined system parameters (step 506), and obtaining system parameters for the framework model (step 508). Still referring to FIG. 5A, process 500 may include formulating a system of equations to express future system states and system outputs as a function of current system states and controllable system inputs (step 502). In an exemplary embodiment, a state space representation is used to express future system states and system outputs in discrete time as a function current system states and inputs to the system 502. However, step 502 may include formulating any type of equation (e.g., linear, quadratic, algebraic, trigonometric, differential, etc.) to express future system states. In the example embodiment, a state space modeling representation may be expressed in discrete time as: x(k+1)=Ax(k)+Bu(k) y(k)=Cx(k)+Du(k) where x represents the states of the system, u represents the manipulated variables which function as inputs to the system, and y represents the outputs of the system. Time may be expressed in discrete intervals (e.g., time-steps) by moving from a time-step k to the next time-step k+1. In the exemplary embodiment, the state space system may be characterized by matrices A, B, C, and D. These four matrices may contain the system parameters (e.g., energy characteristics of the building system) which allow predictions to be made regarding future system states. In some embodiments, the system parameters may be specified in advance, imported from a previously identified system, received from a separate process, specified by a user, or otherwise received or retrieved. In other embodiments, system matrices A, B, C, and D may be identified using a system identification process, described in greater detail in reference to FIG. 11. In further embodiments, the system parameters may be adaptively identified on a recursive basis to account for changes to the building system over time. A recursive system identification process is described in greater detail in reference to FIG. 12. For example, a state space representation for a system with changing model may be expressed as: x(k+1)=A(θ)x(k)+B(θ)u(k) y(k)=C(θ)x(k)+D(θ)u(k) where θ represents variable parameters in the system. A change to the physical geometry of the system (e.g., knocking down a wall) may result in a change to the system parameters. However, a change in disturbances to the system such as heat transfer through the exterior walls (e.g., a change in weather), heat generated from people in the building, or heat dissipated from electrical resistance within the building (e.g., a load change) may not result in a change to the system parameters because no physical change to the building itself has occurred. Still referring to FIG. 5A, process 500 may include accounting for disturbances to the system (step 504). Disturbances to the system may include factors such as external weather conditions, heat generated by people in the building, or heat generated by electrical resistance within the building. In other words, disturbances to the system may include factors having an impact on system states (e.g., building temperature, building power use, etc.) other than controllable inputs to the system. While accounting for disturbances represents a departure from the deterministic state space model, a more robust solution in the presence of disturbances can be achieved by forming a stochastic state space representation. In some embodiments, an observer-based design may be used to allow an estimation of the system states which may not be directly measurable. Additionally, such a design may account for measurement error in system states which have a noise distribution associated with their measurement (e.g., an exact value may not be accurately measurable). The stochastic state space representation for a system can be expressed as: x(k+1)=A(θ)x(k)+B(θ)u(k)+w(k) y(k)=C(θ)x(k)+D(θ)u(k)+v(k) w(k)˜N(0,Q) v(k)˜N(0,R) where w and v are disturbance and measurement noise variables. The solution to this state estimation problem may be given by the function: {circumflex over (x)}(k+1)=A(θ){circumflex over (x)}(k|k−1)+B(θ)u(k)+K(θ)[y(k)−ŷ(k|k−1)] ŷ(k|k−1)=C(θ){circumflex over (x)}(k|k−1)+D(θ)u(k), {circumflex over (x)}(0;θ) where K is the Kalman gain and the hat notation {circumflex over (x)}, ŷ implies an estimate of the state and output respectively. The notation (k+1|k) means the value at time step k+1 given the information at time step k. Therefore the first equation reads “the estimate of the states at time step k+1 given the information up to time step k” and the second equation reads “the estimate of the output at time step k given the information up to time step k−1.” The estimate of the states and outputs are used throughout the cost minimization problem over the prediction and control horizons. Still referring to FIG. 5A, process 500 may further include developing a framework energy model of the building system using physical principles to describe the energy characteristics of the system in terms of undefined system parameters (step 506). The framework energy model may include generalized energy characteristics of the building system (e.g., thermal resistances, thermal capacitances, heat transfer rates, etc.) without determining numerical values for such quantities. In some embodiments, model predictive control (MPC) may be used to develop the framework energy model. MPC is a unifying control methodology that incorporates technologies of feedback control, optimization over a time horizon with constraints, system identification for model parameters, state estimation theory for handling disturbances, and a robust mathematical framework to enable a state of the art controller. An exemplary MPC controller 1700 and diagrams which may develop and use a framework energy model are described in greater detail in reference to FIG. 5B-FIG. 10. In some embodiments a framework energy model for the building system may be developed (step 506) for two or more MPC controllers. Still referring to FIG. 5A, process 500 may further include obtaining system parameters for the framework energy model of the building system (step 508). In some embodiments, the system parameters may be specified in advance, imported from a previously identified system, received from a separate process, specified by a user, or otherwise received or retrieved. In other embodiments, system parameters are identified using a system identification process such as process 1100, described in greater detail in reference to FIG. 11. Referring now to FIG. 5B, a block diagram illustrating the components of a MPC controller 1700 is shown, according to an exemplary embodiment. MPC controller 1700 may include a communications interface 1702 for sending and receiving information such as system state information, pricing information, system model information, setpoint information, or any other type of information to or from any potential source or destination. Communications interface 1702 may include wired or wireless interfaces (e.g., jacks, antennas, transmitters, receivers, transceivers, wire terminals, etc.) for conducting data communications with the system or other data sources. MPC controller 1700 may further include a processing circuit 1705 having a processor 1704 and memory 1706. Processor 1704 can be implemented as a general purpose processor, an application specific integrated circuit (ASIC), one or more field programmable gate arrays (FPGAs), a group of processing components, or other suitable electronic processing components. Memory 1706 may include one or more devices (e.g., RAM, ROM, Flash memory, hard disk storage, etc.) for storing data and/or computer code for completing and/or facilitating the various processes, layers, and modules described in the present disclosure. Memory 1706 may comprise volatile memory or non-volatile memory. Memory 1706 may include database components, object code components, script components, or any other type of information structure for supporting the various activities and information structures described in the present disclosure. According to an exemplary embodiment, the memory 1706 is communicably connected to the processor 1704 and includes computer instructions for executing (e.g., by the processor 1704) one or more processes described herein. Memory 1706 may include an optimization module 1722 for completing an optimization procedure, an identification module 1724 for performing system identification, a state estimation module 1726 to estimate system states based on the data received via the communications interface 1702, and a state prediction module 1728 to predict future system states. Memory 1706 may further include system model information 1712 and cost function information 1714. System model information 1712 may be received via the communications interface 1702 and stored in memory 1706 or may be developed by MPC controller 1700 using identification module 1724, processor 1704, and data received via communications interface 1702. System model information 1712 may relate to one or more energy models of a building system and may be used by processor 1704 in one or more processes using state estimation module 1726, state prediction module 1728, or optimization module 1722. Similarly, cost function information 1714 may be received via the communications interface 1702 and stored in memory 1706, or it may be developed by the MPC controller 1700 using data received via the communications interface 1702. Cost function information 1714 may be used by 1704 processor in one or more processes using the system identification module 1724 or optimization module 1722. In some embodiments, MPC controller 1700 may compensate for an unmeasured disturbance to the system. MPC controller 1700 may be referred to as an offset-free or zero-offset MPC controller. In classical controls, the integral mode in PID controller serves to remove the steady state error of a variable. Similarly, the state space model can be augmented with an integrating disturbance d, as shown in the following equation, to guarantee zero offset in the steady state: [ x ( k + 1 ) d ( k + 1 ) ] = [ A ( θ ) B D 0 I ] [ x ( k ) d ( k ) ] + [ B ( θ ) 0 ] u ( k ) + w ( k ) y ( k ) = [ C ( θ ) C D ] [ x ( k ) d ] x ( k ) + D ( θ ) u ( k ) + v ( k ) The number of integrating disturbances to introduce may equal the number of measurements needed to achieve zero offset, independent from tuning the controller. Referring now to FIG. 6, a cascaded MPC system 600 is shown, according to an exemplary embodiment. System 600 may include an inner MPC controller 602 and an outer MPC controller 604. Inner MPC controller 606 may function within an inner control loop contained within an outer control loop. This inner-outer control loop architecture may be referred to as a “cascaded” control system. Cascaded MPC system 600 disclosed herein has several advantages over a single MPC controller. For example, system 600 may allow inner MPC controller 602 to operate at a shorter sampling and control interval to quickly reject disturbances while outer MPC controller 604 may operate at a longer sampling and control interval to maintain optimal power usage. In some embodiments, the sampling and control execution time of inner MPC controller 602 may be around thirty seconds whereas the sampling and control execution time of outer MPC controller 604 may be around fifteen minutes. The choice of fifteen minutes may be driven by a frequency of changes in energy pricing data (e.g., in the real-time pricing rate structure, energy prices may change as frequently as once per fifteen minutes). However, in other embodiments longer or shorter control times may be used. The cascaded design advantageously permits the development of a less complex energy model than could be achieved with a single comprehensive energy model for the entire building system. Another advantage of the cascaded design is that inner controller 602 and outer controller 604 may be decoupled in location. For example, the outer controller 604 may be implemented off-site or “in the cloud” whereas the inner controller 602 may be run in an on-site building supervisory environment (e.g., a building controller local to a building). In some embodiments, outer controller 604 may receive input from multiple building systems and may interact with multiple inner controllers. Still referring to FIG. 6, inner MPC controller 602 may be responsible for keeping the building's power use 612 (PB) at a power setpoint 622 (Psp) by modulating a temperature setpoint 624 (Tsp). Inner MPC controller 602 may determine the necessary changes in the temperature setpoint 626 ({dot over (T)}sp). As shown, changes 626 may be integrated through integrator block 630 before being sent to the building system 606 as temperature setpoint 624 (Tsp). Outer MPC controller 604 may use energy consumption and demand prices, 626 (CC,k) and 628 (CD,k) respectively, to determine an amount of power that should be deferred 632 (PD). The deferred power 632 may be subtracted from an estimated building load 636. Feed forward predictor 640 may determine the estimated building load 636 using past weather and power use data 638. The specific input and output variables for both inner MPC controller 602 and outer MPC controller 604 are provided for exemplary purposes only and are not intended to limit the scope of invention further than express limitations included in the appended claims. Referring now to FIG. 7, a diagram illustrating the inputs and outputs for inner MPC controller 602 are shown, according to an exemplary embodiment. Inner MPC controller 702 may receive a power setpoint 722 (Psp) as an input. In some embodiments, power setpoint 722 may be an optimal power usage as determined by outer MPC controller 604. In other embodiments, historical weather and power usage data 638 may be used to determine a typical building load 636 (e.g., a predicted or historical amount of energy needed to maintain the building temperature within temperature constraints). If a typical building load 636 is determined, outer MPC controller 604 may be used to determine an amount of power that should be deferred 632. In some embodiments, the amount of deferred power 632 is subtracted from the typical building load 636 before being sent to the inner MPC controller 702 as a power setpoint 722. The amount of deferred power 632 may be positive (e.g., subtracted from the typical building load 636) or negative (e.g., added to the typical building load 636). Still referring to FIG. 7, inner MPC controller 702 may further receive a zone temperature 714 (Tz) as an input. Zone temperature 714 may be a variable representing a state of the system. In a single zone building, zone temperature 714 may be the measured temperature of the single building zone (e.g., a room, floor, area, combination of rooms or floors, etc.). In a more complex building with several zones, zone temperature 714 may be a weighted average of the temperatures of multiple building zones. In some embodiments, the weighted average may be based on the area or volume of one or more zones. Additionally, the weighted average may be based on the relative position of the zone temperatures within the demand response temperature range. For example, zone temperature 714 may be calculated as follows: T z = ∑ i w i ( T z , i - T min , i T max , i - T min , i ) where w is the weight of a zone and Tmax and Tmin represent the minimum and maximum allowable temperatures for that zone. In this case, the variable representing the zone temperatures may be normalized (e.g., between 0 and 1). Zone temperature 714 may be measured directly, calculated from measured quantities (e.g., information representative of a measured temperature), or otherwise generated by the system. Information representative of a measured temperature may be the measured temperature itself or information from which a building temperature may be calculated. Still referring to FIG. 7, inner MPC controller 702 may further receive a current power usage 712 of the building. Current power usage 712 may be received as a feedback input for inner MPC controller 702. Inner MPC controller 702 may attempt to control current power usage 712 to match power setpoint 722. In the exemplary embodiment, current power usage 712 is an amount of power currently used by the building. However, in other embodiments, power usage 712 may represent any other state of the system, depending on the variable or variables sought to be controlled. Power usage 712 may be measured directly from the building system, calculated from measured quantities, or otherwise generated by any other method or process. Still referring to FIG. 7, inner MPC controller 702 may output the derivative of a temperature setpoint {dot over (T)}sp 726. The derivative of the temperature setpoint 726 may be used by inner MPC controller 702 to control power usage 712. In a simple single-zone building, {dot over (T)}sp 726 may be a rate at which the temperature setpoint 624 is to be increased or decreased for the single zone. In multiple-zone buildings, {dot over (T)}sp 726 may be applied to the respective temperature setpoints for each individual zone. In other embodiments having multiple building zones, {dot over (T)}sp 726 may be broken into multiple outputs using a weighted average calculation based on the relative positions of the zone temperatures within the demand response range. In the exemplary embodiment, the derivative of the temperature setpoint 726 may be chosen as the output of the inner MPC controller 702 because the system 606 is expected to perform as a “negative 1” type system. In other words, a step change in the temperature setpoint 624 may cause a very small change in steady-state power usage. Therefore to prevent steady-state offset (or an offset the decays very slowly) the controller 702 may have two integrators. The first integrator may be implicit in the disturbance model of the MPC controller (e.g., included as an integrating disturbance) whereas the second integrator 630 may be explicitly located downstream of inner MPC controller 602, as shown in FIG. 6. Although the exemplary embodiment uses a derivative of temperature setpoint 726 as the output variable for the inner MPC controller 702, other embodiments may use different output variables or additional output variables. Referring now to FIG. 8, a diagram illustrating inputs and outputs for outer MPC controller 604 is shown, according to an exemplary embodiment. Outer MPC controller 604 may be responsible for calculating an amount of power to defer 632, based on current and future energy prices 626 and 628, while maintaining building temperature 614 within acceptable bounds. As long the temperature constraints are satisfied, temperature 614 may be allowed to fluctuate. Thus, the goal of the outer MPC controller 604 is to minimize the cost of energy subject to temperature constraints. Still referring to FIG. 8, outer MPC controller 804 may receive the current zone temperature Tz 814 and the current power usage PB 812 of the building system. As described in reference to FIG. 7, these two variables represent states of building system 606. Both states may be measured directly, calculated from measured quantities, or otherwise generated by building system 606. In some embodiments, controller 804 may receive information representative of a measured temperature and/or information representative of a measured power usage. Information representative of a measured temperature may be the measured temperature itself or information from which a building temperature may be calculated. Information representative of a measured power usage may be the measured power usage itself or information from which a building power usage may be calculated. Still referring to FIG. 8, outer MPC controller 804 may further receive pricing information 826 including energy consumption and demand prices, CC,k and CD,k respectively, according to an exemplary embodiment. The electric consumption price CC,k may be the cost per unit of energy consumed (e.g., $/J or $/kWh). CC,k may be applied as a multiplier to the total amount of energy used in a billing cycle, a pricing period, or any other time period to determine an energy consumption cost. The demand price CD,k may be an additional charge corresponding to the peak power (e.g., maximum rate of energy use) at any given time during a billing period. In a variable pricing scenario that has an on-peak, partial-peak, and off-peak time period, a customer may be charged a separate demand charge for the maximum power used during each pricing period. Pricing information 826 may include consumption and demand prices for one or more pricing periods or pricing levels including off-peak, partial-peak, on-peak, critical-peak, real-time, or any other pricing period or pricing level. In some embodiments, pricing information 826 may include timing information defining the times during which the various consumption prices and demand prices will be in effect. In some embodiments, outer MPC controller 804 may further receive historical weather and power usage data. Historical weather and power usage data may be used to perform a feed-forward estimation of the building's probable power requirements. However, in other embodiments, this estimation may performed by a separate feed-forward module 640, as shown in FIG. 6. In further embodiments, historical weather and power usage data are not considered by the outer MPC controller 804 in determining the optimal power setpoint 822. Referring now to FIG. 9, an energy transfer diagram 900 for building system is shown, according to an exemplary embodiment. Diagram 900 may represent a framework energy model of the building system for the inner MPC controller. In the exemplary embodiment, the building system is modeled in diagram 900 as a single-zone building with a shallow mass and a deep mass. The shallow mass may represent objects and/or materials in the building which have contact with the air inside the building (e.g., immediate wall material, drywall, furniture, floor, ceiling, etc.) whereas the deep mass may represent material which is separated from the air inside the building by the shallow mass (e.g., cement block, foundation, etc.). Referring specifically to FIG. 9(a), T, C, and R, are used to represent temperatures, capacitances, and resistances, respectively, with the associated subscripts d, s, z, and O representing deep mass, shallow mass, zone air, and outside air, respectively. Also shown is the heat supplied 932 by people and electric resistance within the building ({dot over (Q)}L), and the heat supplied 934 (or removed in the case of a negative number) by the HVAC system ({dot over (Q)}HVAC). Referring now to FIG. 9(b), the framework energy model is simplified by eliminating Cd, Cs, and {dot over (Q)}L, thereby significantly reducing the number of parameters in the model. A reduced number of parameters may increase the robustness of system identification and reduce the computational effort of the inner MPC controller. Because the major dynamics of the system may be fast compared to the time constants of the deep mass capacitance 902 (Cd), the shallow mass capacitance 904 (CA and the rate of change of the human and electric load 932 ({dot over (Q)}L), these time varying sources of heat entering the zone temperature node 914 may be treated as a slowly moving disturbance. The slowly moving disturbance 940 may be represented as {dot over (Q)}D which includes conduction and convection of outside air 942, heat transfer from the shallow mass 944, and heat generated from people and electrical use inside the building 932. In the exemplary embodiment, {dot over (Q)}HVAC 934 may be modeled as the output of a PI controller. Thus, the rate of change in zone temperature may be given by the equation: Cz{dot over (T)}z=Kq[KP(Tsp−Tz)+KII]+{dot over (Q)}D and the integral may be given by: İ=Tsp−Tz Additionally, because {dot over (Q)}HVAC 934 represents the power delivered to the system, additional equations may be introduced to compensate for the power lost in transportation. For example, in the case of a water cooled building, the energy balance may be maintained by heating water in the building which may be transported to a chiller/tower system where the heat may be expelled into to the atmosphere. In the exemplary embodiment, the transport process that converts the cooling power delivered to the building system to a power use at a cooling tower may be modeled by an over-damped second-order system with one (shorter) time constant τ1 representing the delay and a second time constant τ2 representing mass of cooling fluid. {umlaut over (P)}+(τ1+τ2){dot over (P)}+(τ1τ2)P=Pss Pss=Ke[Kp(Tsp−Tz)+KII] The additional values that have been introduced are defined as follows: P is the power used by the cooling equipment (e.g., at the cooling/chilling towers), PB is the power usage as measured by the building, Kq is coefficient that converts PID output to heating power, Ke is coefficient that converts PID output to a steady-state power usage by the central plant equipment, and τ1 and τ2 are the time constants of the power transport process. Therefore, in an exemplary embodiment, the entire model needed by the inner MPC controller 602 can be represented by: [ T . z I . P . P ¨ T . sp P . Dist ] = [ - K q K P C z K q K I C z 0 0 K q K P C z 0 - 1 0 0 0 1 0 0 0 0 1 0 0 - K e K p K e K I - τ 1 τ 2 - τ 1 - τ 2 K e K P 0 0 0 0 0 0 0 0 0 0 0 0 0 ] [ T z I P P . T sp P Dist ] + [ 0 0 0 0 0 0 0 0 1 0 0 1 ] [ T . sp P . Dist ] [ T z P B ] = [ 1 0 0 0 0 0 0 0 1 0 0 1 ] [ T z I P P . T sp P . Dist ] where {dot over (Q)}D 940 as well as any power usage by loads other than HVAC equipment may be incorporated into the power disturbance PDist, which may be added to the measured power output PB 612. Advantageously, modeling PDist in such a way may allow for offset free control in the presence of slowly changing disturbances. In the exemplary embodiment, after converting to discrete time and substituting θ variables for the unknown system parameters, the complete inner loop framework energy model may be given by: [ T z ( k + 1 ) I ( k + 1 ) P ( k + 1 ) P . ( k + 1 ) P Dist ( k + 1 ) ] = [ 1 - θ 1 θ 1 θ 2 0 0 0 - 1 1 0 0 0 0 0 1 1 0 - θ 3 θ 2 θ 3 - θ 4 θ 5 1 - θ 4 - θ 5 0 0 0 0 0 1 ] [ T z ( k ) I ( k ) P ( k ) P . ( k ) P Dist ( k ) ] + [ θ 1 1 0 θ 3 0 ] T sp ( k ) [ T z ( k ) P B ( k ) ] = [ 1 0 0 0 0 0 0 1 0 1 ] [ T z ( k ) I ( k ) P ( k ) P . ( k ) P Dist ( k ) ] Although the discrete time model shows PDist as a constant, a Kalman gain (used in the state estimation process) may be used to optimally convert measurement errors to state estimation error, thereby causing PDist to change. Referring now to FIG. 10, an energy transfer diagram 1000 for building system is shown, according to an exemplary embodiment. Diagram 1000 may represent a framework energy model of the building system for the outer MPC controller. Referring specifically FIG. 10(a), a complete energy diagram for the outer loop framework energy model is shown, according to an exemplary embodiment. For the outer control loop, all forms of capacitance 1002, 1004, and 1006 in the building may be included in the model because it may no longer be sufficient to treat the heat transfer from the shallow mass 1044 as a slowly moving disturbance. For example knowledge of the states of these capacitors and how heat is transferred between them may be relevant to a prediction of how zone temperature 1014 will change. In other words, an objective of the outer loop model may be to predict the state of these capacitors. Referring now to FIG. 10(b), a simplified energy diagram for the outer loop framework energy model is shown. Two simplifying assumptions may be made in converting the complete energy diagram (FIG. 10(a)) to the simplified energy diagram (FIG. 10(b)). First, it may be assumed that the energy transferred through external conduction and convection 1042 and the typical load profile at a constant setpoint {dot over (Q)}L2 1032 can be estimated based on time of day and temperature difference between the outside air temperature 1048 and the zone 1014 (e.g., To−Tz). Estimation may performed by the feed forward load predictor 640 shown in FIG. 6. The random portion of the load profile (e.g., the portion that is independent of time of day and temperature difference) may be represented an integrated disturbance {dot over (Q)}D2 1040. Second, in an exemplary embodiment, energy transfer equations describing the model shown in FIG. 10(b) may be expressed as: C z T . z = T s - T z R sz + Q . L 2 + Q . D2 + Q . HVAC C s T . s = T d - T s R ds + T z - T s R sz C s T . s = T d - T s R ds + T z - T s R sz To convert these equations to the framework energy model used by outer MPC controller 604, the heat transfers may be converted to powers that can be measured at the meter by assuming a constant of proportionality between the two. For example, {dot over (Q)}HVAC may be converted to PHVAC by multiplying by a coefficient of performance. In the exemplary embodiment, inputs to the outer MPC controller 604 may be divided into controllable inputs, measured disturbances (e.g., uncontrollable but measurable inputs), and unmeasured disturbances (e.g., uncontrollable and unmeasured inputs). To make this division, the inputs may be reformulated to PC (e.g., the power required to keep the zone temperature constant) and PD (e.g., the deferred power). PD may be a controllable input because it may be possible to control the amount of power to defer. PC may be a measured disturbance because it may be possible to estimate the power required maintain a constant building temperature based the difference between outdoor air temperature and the temperature within the building. In some embodiments, estimation of PC (PL2 and the portion of PHVAC that comes from a constant setpoint) may be performed in a feed forward fashion as shown in FIG. 6. Finally, PD2 may be an unmeasured disturbance and can be viewed as the estimation error in PC. Thus, the framework energy model of the building system used by the outer MPC controller may be expressed as: [ T . d T . s T . z P . D 2 ] = [ - 1 R ds C d 1 R ds C d 0 0 1 R ds C s - ( 1 R ds C s + 1 R sz C s ) 1 R sz C s 0 0 1 R sz C z - 1 R sz C z K 1 0 0 0 0 ] [ T d T s T z P D 2 ] + [ 0 0 0 0 0 0 K 2 ′ 0 0 0 0 1 ] [ P D P C ( T OA - T z , t ) P . D 2 ] [ T z P B ] = [ 0 0 1 0 0 0 0 1 ] [ T d T s T z P D 2 ] + [ 0 0 0 - 1 1 0 ] [ P D P C ( T OA - T z , t ) P . D 2 ] Advantageously, in the exemplary embodiment, PC may be a function of a state of the building system (e.g., PC=f(TOA−Tz,t)). This is a condition that many MPC implementations would not support. The alternative would be to perform feed forward estimation outside the MPC controller. However, this is suboptimal because the feed forward estimator would be unable predict how altering the setpoint 622 would affect Pc because it would have no information regarding the current or predicted zone temperature Tz 1014. For example, presently deferring power will result in the zone temperature 1014 becoming closer to the outside temperature 1048, thereby decreasing the rate of heat transfer 1042 through the walls of the building. By incorporating the load predictor into the MPC controller, this change can be predicted and Pc can be adjusted accordingly. In the exemplary embodiment, the outer loop model can be simplified further by assuming that changes in the deep mass temperature 1052 (Td) occur at a rate that is much slower than the length of time power use can be deferred. With this assumption, the temperature of the deep mass 1052 may be considered a known input and the framework energy model used by outer MPC controller 604 may be expressed as: [ T s ( k + 1 ) T z ( k + 1 ) P D 2 ( k + 1 ) ] = [ 1 - ( θ 1 + θ 2 ) θ 2 0 θ 3 - θ 3 θ 4 0 0 1 ] [ T s ( k ) T z ( k ) P D 2 ( k ) ] + [ θ 1 0 0 0 θ 4 0 0 0 0 ] [ T d ( k ) P D ( k ) P C ( T OA - T z , k ) ] [ T z ( k ) P B ( k ) ] = [ 0 1 0 0 0 1 ] [ T s ( k ) T z ( k ) P D 2 ( k ) ] + [ 0 0 0 0 - 1 1 ] [ T d ( k ) P D ( k ) P C ( T OA - T z , k ) ] Referring now to FIG. 11, a flowchart of a process 1100 to identify unspecified system parameters in a framework model is shown, according to an exemplary embodiment. Process 1100 may use an offline (batch) process to identify system parameters using a set of training data (e.g., sample input and output data used to gauge the response of the building system). However, in other embodiments, other system identification processes may be used. Process 1100 may be used to identify model parameters θ which minimize the cost of prediction error (e.g., the cost of differences between model-predicted outputs and the true system outputs). In the exemplary embodiment, process 1100 may include receiving a framework energy model for the building system (step 1102), receiving training data including system input data and system output data (step 1104), filtering the training data to remove extraneous disturbances (step 1106), receiving a first error cost function based on the difference between the filtered output training data and a model-predicted filtered output (step 1108), and using a first optimization procedure to determine system parameters which minimize the first error cost function within a range of filtered training data (step 1110). In some embodiments, process 1100 may further include receiving a second error cost function based on the difference between non-filtered output training data and a model-predicted non-filtered output (step 1112), and using a second optimization procedure to determine Kalman gain parameters which minimize the second error cost function within a range of non-filtered training data (step 1114). Referring more particularly to FIG. 11, process 1100 includes receiving a framework energy model for the building system (step 1102). The framework energy model may be a framework energy model for the entire system or may be a framework energy model for either the inner MPC controller or outer MPC controller. In the exemplary embodiment, step 506 of process 500 may be used to develop a framework model using a discrete time state space representation of the building system with variable system parameters θ. For example, the framework energy model of the building system used by the inner MPC controller can be expressed as: [ T z ( k + 1 ) I ( k + 1 ) P ( k + 1 ) P . ( k + 1 ) ] = [ 1 - θ 1 θ 1 θ 2 0 0 - 1 1 0 0 0 0 1 1 - θ 3 θ 2 θ 3 - θ 4 θ 5 1 - θ 4 - θ 5 ] [ T z ( k ) I ( k ) P ( k ) P . ( k ) ] + [ θ 1 1 0 θ 3 ] T sp ( k ) [ T z ( k ) P ( k ) ] = [ 1 0 0 0 0 0 1 0 ] [ T z ( k ) I ( k ) P ( k ) P . ( k ) ] and the framework energy model used by the outer MPC controller can be expressed as: [ T s ( k + 1 ) T z ( k + 1 ) ] = [ 1 - ( θ 1 + θ 2 ) θ 2 θ 3 1 - θ 3 ] [ T s ( k ) T z ( k ) ] + [ 0 0 θ 4 0 ] [ P D ( k ) P C ( T OA - T z , t ) ] [ T z P B ] = [ 0 1 0 0 ] [ T s ( k ) T z ( k ) ] + [ 0 0 - 1 1 ] [ P D ( k ) P C ( T OA - T z , t ) ] In both models, terms representing the slowly moving disturbances may be removed as these disturbances may be subsequently accounted for using a Kalman gain, described in greater detail in reference to steps 1112 and 1114. Still referring to FIG. 11, process 1100 may further include receiving training data including system input data and system output data (step 1104). Training data may be received by varying the manipulated inputs to the system and monitoring the resultant system outputs. For example, for the inner MPC controller system model, the temperature setpoint may be varied whereas for the outer MPC controller system model, the power setpoint be varied. For both models, the actual building temperature and building power use may be monitored and recorded as output training data. In other embodiments, other manipulated variables may be varied depending on the framework model used for this step of the system identification process. Still referring to FIG. 11, process 1100 may include filtering the training data to remove extraneous disturbances (step 1106). Step 1106 may be performed to distinguish (a) a change in system outputs caused by varying the manipulated inputs from (b) a change in system outputs caused by external disturbances to the system. For example, in the exemplary embodiment, the effect of heat transfer through the walls of the building PC (T OA−Tz) may be treated as a slowly moving disturbance with dynamics much slower than that of the inner MPC controller system. By filtering the training data, the effect of this disturbance may be eliminated, thereby allowing the actual system parameters θ to be identified with greater accuracy. In the exemplary embodiment, the filter applied to the training data may be a fourth-order high-pass Bessel filter with a cutoff frequency ωc of 1.75*10−3 rad/s. However, in other embodiments, other types of filters may be used, including band-pass filters, low-pass filters, or other types of high-pass filters with different cutoff frequencies. The type of filter may be driven by the frequency characteristics of the effects sought to be eliminated from the training data. For example, the cutoff frequency may be chosen to eliminate the effects of slowly moving disturbances such as weather conditions or internal heat generation within the building while still capturing the dynamics of the system as they exist without external disturbances. Still referring to FIG. 11, process 1100 may further include receiving a first error cost function (step 1108). Because filtered training data may be used for steps 1106-1110, the first error cost function may be based on the difference between the filtered output training data and the model-predicted filtered output (e.g., the error e). In some embodiments, the first error cost function may be pre-defined, received from memory, specified by a user, or otherwise received from any other source or process. In other embodiments, receiving the first error cost function may include defining or deriving the first error cost function. Exemplary first error cost functions may include: l[y(k)−ŷ(k−1)]=l[e(k)]=e2(k) which may be optimal for normally distributed errors, but sensitive to outliers: [ e ( k ) ] = { c 2 σ 2 + c σ - e ( k ) e ( k ) < - c σ e 2 ( k ) - c σ < e ( k ) < c σ c 2 σ 2 - c σ + e ( k ) e ( k ) > c σ which linearizes error cost l for errors e outside specified bounds, and: [ e ( k ) ] = { c 2 σ 2 e ( k ) < - c σ e 2 ( k ) - c σ < e ( k ) < c σ c 2 σ 2 e ( k ) > c σ for which the error cost l does not increase once the error e exceeds a threshold. Still referring to FIG. 11, process 1100 may further include using a first optimization procedure to determine system parameters which minimize the first error cost function over a range of filtered training data (step 1110). Numerous optimization procedures may be used to minimize the first error cost function, including Gauss-Newton, Ninness-Wills, adaptive Gauss-Newton, Gradient Descent, and Levenberg-Marquardt search algorithms. The optimization procedure may use any of these search algorithms, a subset thereof, or any other minimization technique, algorithm, method, or procedure. For optimization purposes, initial system states may be estimated, received from a separate process, specified by a user, or fixed at any value. The first error cost function may be used to determine the cost of prediction error within a range of filtered training data. The range of filtered training data may comprise the entire set of training data or a subset thereof. The training data used by the first error cost function may be automatically specified, chosen by a user, or otherwise determined by any other method or process. Still referring to FIG. 11, process 1100 may further include receiving a second error cost function (step 1112). In some embodiments, the second error cost function may be pre-defined and may simply be received from memory, specified by a user, or otherwise received from any other source or process. In other embodiments, receiving the second error cost includes defining the second error cost function. The second error cost function may use the same error cost algorithm as the first error cost function or it may use a different algorithm. However, unlike the first error cost function, the second error cost function may be based on the difference between the model-predicted output and the actual system output using the non-filtered training data. Still referring to FIG. 11, process 1100 may further include using a second optimization procedure to determine Kalman gain parameters which minimize the second error cost function over a range of non-filtered training data (step 1114). In some embodiments, the Kalman gain can be parameterized and estimated along with the parameters of the system matrix as part of the first optimization procedure. In other embodiments, the system parameters may be estimated first using filtered training data while the Kalman gain parameters are fixed at zero. Then, the system parameters may be fixed and a second optimization procedure may be used to determine optimal Kalman gain parameters which minimize the cost of prediction error using the non-filtered training data. Advantageously, determining the system parameters first allows for a more accurate prediction and reduces the possibility that the optimization procedure will settle on one of the local minima produced by estimating both the system parameters and the Kalman gain parameters simultaneously. Additionally, a separately determined Kalman gain may allow the MPC controller to predict future outputs, estimate system states, and optimally attribute measurement errors to either errors in the state estimate or to measurement noise. Another advantage of process 1100 is the ability to estimate the current value of the load PC. Thus, in the exemplary embodiment, the framework energy model shown in the following equations is used to estimate the steady-state Kalman gain for the building system model used by the inner MPC controller: [ T z ( k + 1 ) I ( k + 1 ) P Δ ( k + 1 ) P . Δ ( k + 1 ) P C ( k + 1 ) ] = [ 1 - θ 1 θ 1 θ 2 0 0 0 - 1 1 0 0 0 0 0 1 1 0 - θ 3 θ 2 θ 3 - θ 4 θ 5 1 - θ 4 - θ 5 0 0 0 0 0 1 ] [ T z ( k ) I ( k ) P Δ ( k ) P . Δ ( k ) P C ( k ) ] + [ θ 1 1 0 θ 3 0 ] T sp ( k ) + v ( k ) [ T z ( k ) P B ( k ) ] = [ 1 0 0 0 0 0 0 1 0 1 ] [ T z ( k ) I ( k ) P Δ ( k ) P . Δ ( k ) P C ( k ) ] + w ( k ) with a parameterized Kalman gain of: K ( θ ) = [ θ 6 θ 7 θ 8 θ 9 θ 10 θ 11 θ 12 θ 13 θ 14 θ 15 ] In the exemplary embodiment, the Kalman gain may be estimated for the outer MPC controller model using the following equations: [ T s ( k + 1 ) T z ( k + 1 ) P D 2 ( k + 1 ) ] = [ 1 - ( θ 1 + θ 2 ) θ 2 0 θ 3 1 - θ 3 θ 4 0 0 ϕ 1 ] [ T s ( k ) T z ( k ) P D 2 ( k ) ] + [ θ 1 0 0 0 0 θ 4 0 0 0 0 0 1 ] [ T d ( k ) P D ( k ) P C ( T OA - T z , k ) P ~ D 2 ( k ) ] [ T z ( k ) P B ( k ) ] = [ 0 1 0 0 0 1 ] [ T s ( k ) T z ( k ) P D 2 ( k ) ] + [ 0 0 0 0 0 - 1 1 0 ] [ T d ( k ) P D ( k ) P C ( T OA - T z , k ) P ~ D 2 ( k ) ] with a parameterized Kalman gain of: K ( θ ) = [ θ 6 θ 7 θ 8 θ 9 θ 10 θ 11 ] The parameters in the A and B matrices may be held constant at the values identified by the first optimization procedure while K is determined by the second optimization procedure using the non-filtered training data. In the exemplary embodiment, initial values for the system states may be estimated by assuming that assumed that the system states are initially at a steady-state (e.g., x−1 is the same as x0). With this assumption the following algebraic equation may be solved to find the initial conditions for the states: xk=Axk+Buk x0=(I−A)−1Bu0. To solve this problem, it can be assumed that because the system states are at a steady-state and the temperature setpoint is constant, the zone temperature Tz is equal to the temperature setpoint. Additionally, the measured power may be assumed to be unchanging (e.g., {dot over (P)}Δ=0) and can be attributed to the heat disturbances. Finally, at the steady-state, powers PΔ and PC may be interchangeable; therefore, PΔ may be set to zero and PC may be set to the current power usage. In this way, the state of the integrator can also be initialized to zero. With these assumptions in place, the process 1100 may identify the Kalman gain parameters using a second optimization procedure (step 1114) while fixing the system parameters at the values determined by the first optimization procedure. Referring now to FIG. 12, a flowchart of a process 1200 to recursively identify model parameters is shown, according to an exemplary embodiment. Recursive system identification has several advantages over batch system identification. For example, in recursive identification, the current knowledge of system parameters may be stored in an identifier “state” which is used to determine the current estimate. The state of the identification algorithm may be updated, and the estimate recalculated, each time a new measurement is obtained. Because recursive identification allows the estimate to be updated with each new measurement, memory requirements may be significantly reduced as it is not required to store each measurement in memory. Additionally, computational time may be significantly reduced because a large number of optimization iterations are no longer required with every measurement. Another advantage of recursive identification is adaptability. For example, a recursive identification process may be able to compensate for slowly changing system parameters and may overcome the difficulty in modeling a changing physical world. In the exemplary embodiment, model inaccuracies may be anticipated and the model may be adjusted recursively through feedback and weighting functions. Initial parameter values and system state values may be determined by the batch processing method 1100 previously disclosed or otherwise received from any other source. Still referring to FIG. 12, process 1200 may include estimating updated values for the model parameters (e.g., the system parameters and/or the Kalman gain parameters, a subset of the system and/or Kalman gain parameters known to be more likely to change, etc.) each time a new data measurement is received (step 1202), checking the estimated model parameters for stability and robustness (step 1204), and either using the estimated model parameters to estimate system states (step 1206), or reverting to previous model parameters (1208). In the exemplary embodiment, step 1202 may include using an estimation process inspired by the extended Kalman filter (EKF). The following derivation adapts the EKF to a generalized case of a multiple-input multiple-output (MIMO) system for use in process 1200. For example, the model parameters 0 may be estimated using the following EKF equations: {circumflex over (θ)}(k+1)={circumflex over (θ)}(k)+L(k)[y(k)−ŷ(k|k−1)], L(k)=Pθ(k)T(k)[(k)Pθ(k)T(k)+R]−1, Pθ(k+1)=Pθ(k)+QP+L(k)[(k)Pθ(k)T(k)+R]LT(k), where the state update matrix is the identity matrix and Pθ(k) is the parameter estimation error covariance. To calculate the time varying equivalent to the measurement equation, C, for the EKF, the generic update equation for normal distributions may be used, as shown in the following equations: {circumflex over (θ)}(k+1)={circumflex over (θ)}(k)+ΣθωΣωω−1[y(k)−ŷ(k|k−1)], Pθ(k+1)=Pθ(k)+QP+ΣθωΣωω−1ΣθωT Σθω=E{[θ(k)−{circumflex over (θ)}(k)][y(k)−ŷ(k|k−1)]T}, Σωω=E{[y(k)−ŷ(k|k−1)][y(k)−ŷ(k|k−1)]T}. where Σθω and Σωω are the cross covariance between the parameter estimation error and the output estimation error and the covariance of the output estimation error, respectively. To calculate these to covariance matrices recursively and obtain the EKF equations shown above, the actual measurement may be approximated linearly as: y ( k ) ≈ C ( θ ^ ( k ) ) · x ^ ( k | k - 1 ) + D ( θ ^ ( k ) ) · u ( k ) + x = x ^ θ = θ ^ ( θ ( k ) - θ ^ ( k ) ) + w ( k ) . Using this linear approximation, the covariances Σθω and Σωω can be approximated as follows: ∑ θω = E { [ θ ( k ) - θ ^ ( k ) ] [ y ( k ) - y ^ ( k | k - 1 ) ] T } , ∑ θω = E { [ θ ( k ) - θ ^ ( k ) ] [ x = x ^ θ = θ ^ ( θ ( k ) - θ ^ ( k ) ) + w ( k ) ] T } , ∑ θω = P θ x = x ^ θ = θ ^ T , ∑ ωω = E { [ y ( k ) - y ^ ( k | k - 1 ) ] [ y ( k ) - y ^ ( k | k - 1 ) ] T } , ∑ ωω = E { [ x = x ^ θ = θ ^ ( θ ( k ) - θ ^ ( k ) ) + w ( k ) ] [ x = x ^ θ = θ ^ ( θ ( k ) - θ ^ ( k ) ) + w ( k ) ] T } , ∑ ωω = x = x ^ θ = θ ^ P θ x = x ^ θ = θ ^ T + R . and used to update the parameter estimates in the EKF equations shown above. In the exemplary embodiment, may be resolved by assuming that the state estimate is equal to the actual state for a given parameter value. While this may not be true due to noise in the system, it may asymptotically true in terms of the expected parameter values. Because the system state estimates are also functions of the model parameters, can then be written as, ( θ ; k ) = d d θ [ C ( θ ) · x ~ ( θ ; k | k - 1 ) + D ( θ ) · u ( k ) ] , and using the product rule, as: ( θ ; k ) = C ( θ ) d d θ x ^ ( θ ; k | k - 1 ) + [ dC d θ 1 x ^ ( θ ; k | k - 1 ) dC d θ 1 x ^ ( θ ; k | k - 1 ) … dC d θ d x ^ ( θ ; k | k - 1 ) ] + [ dD d θ 1 u ( k ) dD d θ 2 u ( k ) … dD d θ d u ( k ) ] , ( θ ; k ) = C ( θ ) η ( θ ; k ) + ( θ ; x ^ , u ; k ) . In the exemplary embodiment, the derivatives of the matrices C and D may be determined by the model parameters, whereas the derivative of the state estimate η may be estimated recursively using in the following equation: η ( θ ; k + 1 ) = d d θ x ^ ( θ ; k + 1 | k ) = d d θ [ ( θ ) x ^ ( θ ; k | k - 1 ) + B ( θ ) u ( k ) + K ( θ ) ɛ ( k ) ] , = A ( θ ) η ( θ ; k ) - K ( θ ) ( θ ; k ) + [ dA d θ 1 x ^ ( θ ; k | k - 1 ) dA d θ 1 x ^ ( θ ; k | k - 1 ) … dA d θ d x ^ ( θ ; k | k - 1 ) ] + [ d B d θ 1 u ( k ) d B d θ 2 u ( k ) … d B d θ d u ( k ) ] + [ dK d θ 1 u ( k ) dK d θ 2 u ( k ) … dK d θ d u ( k ) ] . = A ( θ ) η ( θ ; k ) - K ( θ ) ( θ ; k ) + ( θ ; x ^ , u ; k ) + ɛ ( θ ; ɛ ; k ) where ɛ ( k ) ≡ y ( k ) - y ^ ( k | k - 1 ) Therefore, recursive system identification process 1200 may use the following restated equations to estimate updated values for the model parameters each time a new measurement is obtained (step 1202): ŷ(k|k−1)=C({circumflex over (θ)}(k)){circumflex over (x)}(k|k−1)+D({circumflex over (θ)}(k))u(k) ε(k)=y(k)−ŷ(k|k−1) (k)=C({circumflex over (θ)}(k))η(k)+({circumflex over (θ)}(k); {circumflex over (x)}, u; k) L(k)=Pθ(k)T(k)[(k)Pθ(k)T(k)+R]−1 {circumflex over (θ)}(k+1)={circumflex over (θ)}(k)+L(k)ε(k) Process 1200 may further include includes using the updated model parameters to estimate the system states (step 1206). An EKF could be developed to estimate both the system states and the model parameters simultaneously; however, this configuration may not converge if the noise properties of the system are unknown. Therefore, in an exemplary embodiment, system states may be estimated using a Kalman gain which is dependent on the model parameters according to the following difference equations: {circumflex over (x)}(k+1|k)=A({circumflex over (θ)}(k)){circumflex over (x)}(k|k−1)+B({circumflex over (θ)}(k))u(k)+K({circumflex over (θ)}(k))ε(k), Pθ(k+1)=Pθ(k)+QP+L(k)[(k)Pθ(k)T(k)+R]LT(k), η(k+1)=A({circumflex over (θ)}(k))η(k)−K({circumflex over (θ)}(k))(k)+({circumflex over (θ)}(k); {circumflex over (x)}, u; k)+ε({circumflex over (θ)}(k); ε; k) which follow from the derivation above. Still referring to FIG. 12, process 1200 may further include checking the estimated model parameters for stability and robustness (step 1204) and reverting to previous model parameters if the estimated model parameters are either unstable or non-robust (step 1208). In the exemplary embodiment, step 1204 may be accomplished using the estimated model parameters to update the difference equations shown above and then checking the updated equations for stability. The difference equations may be stable if, for the domain , the parameters are such that the eigenvalues of A−KC are strictly less than one. In other words: θ∈⊂d iff eig{A(θ)−K(θ)C(θ)}<1 Thus, to keep the difference equations stable, the parameter update equation may be replaced with: θ ^ ( k + 1 ) = { θ ^ ( k ) + L ( k ) ɛ ( k ) , θ ^ ( k ) + L ( k ) ɛ ( k ) ∈ θ ^ ( k ) , θ ^ ( k ) + L ( k ) ɛ ( k ) ∉ Therefore, in some embodiments, the model parameters are not updated (step 1208) (e.g., the estimated value is not used and the parameters revert to their previous values) if the estimated values would result in instability. Advantageously, process 1200 achieves improved robustness by considering the effect of outlying raw data. For example, for a squared error cost function, the gradient of the cost function (at a given sample) may be stated as −ε. Thus, process 1200 may be a modified descent process in which the EKF equations (e.g., the parameter update equations used in step 1202) are used to scale and modify the direction of the descent. For example, the gradient of the cost function may be stated as: ∇ J ɛ = - ( k ) d d θ , which when applied to the following cost function, becomes: [ e ( k ) ] = { c 2 σ 2 e ( k ) < - c σ e 2 ( k ) - c σ < e ( k ) < c σ c 2 σ 2 e ( k ) > c σ → ∇ J e = { 0 e ( k ) < - c σ - ( k ) ɛ ( k ) - c σ < e ( k ) < c σ 0 e ( k ) > c σ Thus, in process 1200 the parameter set may not be updated (step 1208) if the output estimation error is large (e.g., exceeds a threshold defined by cσ. Referring now to FIG. 13, a flowchart of a cost function definition process 1300 is shown, according to an exemplary embodiment. Process 1300 may be used to accomplish some or all of step 406 of process 400. In the exemplary embodiment, process 1300 may include receiving time-varying pricing information for a plurality of pricing periods (step 1302), receiving a time horizon (step 1304), expressing the total cost of energy within the time horizon as a function of estimated power use (step 1306), expressing the cost function as a liner equation by adding demand charge constraints to the optimization procedure (step 1308), and using a masking procedure to invalidate demand charge constraints for inactive pricing periods (step 1310). Still referring to FIG. 13, process 1300 may include receiving pricing information including energy charge information and demand charge information for a plurality pricing periods (step 1302). However, in other embodiments, pricing information may include only energy charge information or only demand charge information or such information may pertain to only one pricing period. Energy charge information may include the cost of energy for some or all of the pricing periods. In an exemplary embodiment, the cost of energy is defined on a per-unit basis (e.g., $/Joule, $/kWh, etc.). However, in other embodiments, energy cost may be defined on a progressive or regressive basis, segmented into one or more fixed-cost ranges of energy use, or make use of any other cost structure. Demand charge information may include a cost corresponding to the peak power usage during one or more of the pricing periods (e.g., the maximum power used at any given time within a pricing period or combination of periods). The demand charge may be imposed for some or all of the pricing periods and pricing periods may overlap (e.g., an “anytime” period would overlap with any other period or periods). In an exemplary embodiment, the demand charge information may define the cost of power on a per-unit basis (e.g., $/W, $/kW, etc.). However, in other embodiments, the demand charge may be imposed on a progressive or regressive basis, segmented into one or more fixed-cost ranges of maximum power use, or make use of any other cost structure. In the exemplary embodiment, pricing periods may include two or more different periods chosen from the group consisting of: off-peak, partial-peak, on-peak, critical-peak, and real-time. However, in other embodiments, more or fewer pricing periods may be used. In some embodiments, the critical-peak pricing period may be subdivided into several sub-periods having different energy charges, different demand charges, or both, as shown in FIG. 2. A pricing period may be a time interval during which certain energy charges and/or power demand charges apply. For example, during the off-peak period energy may cost $w per kWh and the demand charge may be $y per kW, whereas during the peak period energy may cost $x per kWh and the demand charge may be $z per kW. Different pricing periods may have (1) the same energy charge but a different demand charge, (2) a different energy charge but the same demand charge, (3) a different energy charge and a different demand charge, or (4) the same energy charge and the same demand charge (e.g., a customer may be charged a separate demand charge for each pricing period despite both periods having the same rates). Two or more pricing periods may overlap and gaps may exist during which no pricing period is active. A pricing period may become inactive at a specified time and reactivate at a later time while still qualifying as the same pricing period (e.g., the on-peak period may recur every day from 9:00 A.M. until 9:00 P.M. as shown in FIG. 1). Energy charge information, demand charge information, and pricing period information, may be received from the same source or from different sources, concurrently or at different times. Still referring to FIG. 13, process 1300 may further include receiving a time horizon (step 1304). A time horizon may define how far into the future to look when predicting future system states or planning future system inputs. The time horizon may function as a prediction horizon, a control horizon, or both, depending on the application of the control system. A prediction horizon may be used by the optimization procedure 1500 to define a time period during which the cost function is minimized. Similarly, the control horizon may be used by the optimization procedure 1500 to define a time period during which the manipulated inputs to the system may be controlled. In the exemplary embodiment, the time horizon may be used as both the prediction horizon and the control horizon and may be set to 5τ (e.g., five times a time constant of the system). However, in other embodiments, other time horizons may be used. The time horizon may be used by both the optimization procedure 1500 to minimize the cost function and by the masking procedure 1310 to selectively mask the inactive demand charge constraints. Still referring to FIG. 13, process 1300 may further include using the time-varying pricing information and the time horizon to express the total cost within the time horizon as a function of estimated power use (step 1306). The optimization problem can be stated mathematically as minimizing the cost function: J ND = ∑ i = 1 ND EC i P i Δ t i + ∑ j = 1 M D C j max Rj ( P j ) subject to the constraints: Tmini<Tz,i<Tmaxi ∀i However, only the first term of this function is linear. The second term of the cost function includes a “max” operation which selects the maximum power usage at any given time during the relevant pricing period. Still referring to FIG. 13, process 1300 may further include expressing the cost function as a linear equation with demand charge constraints on the optimization problem (step 1308). To facilitate implementation of the “max” function in an automated optimization process (e.g., a process which minimizes the cost function within a finite time horizon), the cost function can be expressed as: J k = ∑ i = 1 N p EC i P i Δ t i + ∑ j = 1 M D C Rj P Rj subject to constraints: (Pi−Pj)k≦PR for all i samples within a time horizon and for all j demand charge regions (e.g., pricing periods), where PR represents the maximum power in the region from previous time steps in the billing cycle. For example, the value of PR may initially be zero at the beginning of a billing cycle and may increase due to constraints on the zone temperature Tz. Still referring to FIG. 13, process 1300 may further include masking the demand charge constraints on the optimization problem which apply to inactive pricing periods (step 1310). Step 1310 may be performed because all demand charge constraints may not be valid for each discrete time-step used in the optimization procedure. For example, referring to FIG. 14, the time horizon 1402 may extend from a time-step 1404 (k) in the partial-peak period 1406 to a future time 1408 (k+horizon) in the peak period 1410. At time-step k 1404, the demand charge constraint which applies to the peak period 1410 may be masked (e.g., marked as inactive, invalidated, deleted, erased, etc.) because time-step k 1404 does not occur during the peak period 1410. In other words, the peak pricing period 1410 is “inactive” at time-step k 1404. Similarly, the demand charge constraints which apply to the partial-peak period 1406 may be masked for all time steps within the time horizon 1402 which occur after the partial-peak period 1406 has ended. In the exemplary embodiment, step 1310 (e.g., the masking procedure) may be included as part of process 1300 because step 1310 completes the linearization of the demand charge term by masking invalid constraints. However, in other embodiments, the step 1310 may be implemented as part of the optimization procedure 1500, as part of another process, or as an entirely separate process. In further embodiments, step 1310 may be combined with step 1308 (imposition of the demand charge constraints) so that only valid demand charge constraints are initially imposed. In such embodiments, the term “valid demand charge constraints” may be redundant because all demand charge constraints may be valid. Referring now to FIG. 15, a flowchart illustrating an energy cost optimization process 1500 is shown, according to an exemplary embodiment. Process 1500 may include receiving an energy model of the building system, system state information, temperature constraints, and an energy cost function including demand charge constraints (step 1502), using the energy model and the system state information to formulate equality constraints (step 1504), and determining an optimal power usage or setpoint to minimize the total cost of energy within a finite time horizon (e.g., minimize the energy cost determined by the cost function) while maintaining building temperature within acceptable bounds and satisfying the equality constraints and demand charge constraints (step 1506). Process 1500 may include receiving an energy model of the building system, system state information, temperature constraints, and an energy cost function including demand charge constraints (step 1502). The energy model for the building system may be received as a pre-defined model or may be defined or derived using a model development process such as process 500, described in reference to FIG. 5. The energy model of the building system (e.g., the system model) may be a representation of the used by the optimization procedure to predict future system states. For the outer loop MPC controller, the system model may be used to predict the value of the zone temperature Tz in response to changes to the power setpoint Psp or changes to the amount of power to defer PD. A state space representation of the outer MPC controller system model may be expressed as: [ T s ( k + 1 ) T z ( k + 1 ) P D 2 ( k + 1 ) ] = [ 1 - ( θ 1 + θ 2 ) θ 2 0 θ 3 - θ 3 θ 4 0 0 1 ] [ T s ( k ) T z ( k ) P D 2 ( k ) ] + [ θ 1 0 0 0 θ 4 0 0 0 0 ] [ T d ( k ) P D ( k ) P C ( T OA - T z , k ) ] [ T z ( k ) P B ( k ) ] = [ 0 1 0 0 0 1 ] [ T s ( k ) T z ( k ) P D 2 ( k ) ] + [ 0 0 0 0 - 1 1 ] [ T d ( k ) P D ( k ) P C ( T OA - T z , k ) ] For the inner loop MPC controller, the system model may be used to predict the amount of power used by the building PB in response to changes in the temperature setpoint Tsp. A state space representation of the inner MPC controller system model may be expressed as: [ T z ( k + 1 ) I ( k + 1 ) P ( k + 1 ) P . ( k + 1 ) P Dist ( k + 1 ) ] = [ 1 - θ 1 θ 1 θ 2 0 0 0 - 1 1 0 0 0 0 0 1 1 0 - θ 3 θ 2 θ 3 - θ 4 θ 5 1 - θ 4 - θ 5 0 0 0 0 0 1 ] [ T z ( k ) I ( k ) P ( k ) P . ( k ) P Dist ( k ) ] + [ θ 1 1 0 θ 3 0 ] T sp ( k ) [ T z ( k ) P B ( k ) ] = [ 1 0 0 0 0 0 0 1 0 0 ] [ T z ( k ) I ( k ) P ( k ) P . ( k ) P Dist ( k ) ] K ( θ ) = [ θ 6 θ 7 θ 8 θ 9 θ 10 θ 11 θ 12 θ 13 θ 14 θ 15 ] In some embodiments, the system model may have static system parameters. In other embodiments, the system model may contain variable system parameters which may be altered by the optimization procedure to adapt the model to a changing system. The system model may be fully developed with identified parameters, or the system parameters may need to be identified using a system identification process. If system identification is required, the system parameters θ1-θ5 (and possibly the Kalman gain parameters θ6-θ15) may be identified using a system identification process 1100 and received by optimization process 1500 as part of the system model. System state information may include a current estimation of some or all or the relevant system states. In the state space system models shown above, current system states are represented by the variables having a time step equal to k (e.g., Tz(k), Ts(k), etc.). Initial system states may be estimated, measured, chosen arbitrarily, calculated, received from another process, from a previous iteration of the optimization procedure, specified by a user, or received from any other source. For example, in an exemplary embodiment of the outer MPC controller system model, the system state information may include an estimation of the zone temperature Tz, the shallow mass temperature Ts, and the unmeasured disturbance power PD2. Because PD2 is a slowly changing disturbance, it can be estimated once as its value does not change during the prediction horizon. Temperature constraints may be limitations on the building zone temperature Tz or any other system state. The temperature constraints may include a minimum allowable temperature, a maximum allowable temperature, or both, depending on the application of the control system. Temperature constraints may be received automatically, specified by a user, imported from another process, retrieved from a data base, or otherwise received from any other source. An energy cost function may include information relating to energy prices (e.g., energy charge information, demand charge information, pricing period information, etc.) and may include demand charge constraints as described in reference to FIG. 13. Still referring to FIG. 15, process 1500 may further include using the energy model of the building system and the system state information to formulate equality constraints (step 1504). Equality constraints may be used to guarantee that the optimization procedure considers the physical realities of the building system (e.g., energy transfer principles, energy characteristics of the building, etc.) during cost minimization. In other words, equality constraints may be used to predict the building's response (e.g., how the system states and outputs will change) to a projected power usage or temperature setpoint, thereby allowing the energy cost function to be minimized without violating the temperature constraints. Still referring to FIG. 15, process 1500 may further include determining an optimal power usage which minimizes the total cost within the time horizon while satisfying the equality constraints, the temperature constraints, and the demand charge constraints (step 1506). Many minimization procedures can be employed to perform cost minimization including Gauss-Newton, Ninness-Wills, adaptive Gauss-Newton, Gradient Descent, Levenberg-Marquardt, or any other optimization or search algorithm. In some embodiments, process 1500 may be performed once to determine an optimal power usage within a time horizon. Given a long enough time horizon and a perfectly accurate model, a single use of process 1500 may be satisfactory. However, over time, the system model may lose accuracy due to the difficulty in modeling a changing physical world. Referring now to FIG. 16, a flowchart of a process 1600 illustrating a recursive implementation of process 1500 is shown, according to an exemplary embodiment. Advantageously, process 1600 anticipates model inaccuracies and adjusts the model recursively through feedback and weighting functions. Process 1600 may improve adaptability of the system model and may insure long-term accuracy of the optimization procedure. Still referring to FIG. 16, process 1600 may include receiving system state information, an energy cost function, temperature constraints, and an energy model of the building system including system parameter information (step 1602). The energy model of the building system and system state information may be received from a previously identified system or may be identified using a system identification process such as process 1100, described in detail in reference to FIG. 11. Alternatively, the energy model of the building system may be received from a different process, specified by a user, retrieved from a database, or otherwise received from any other source. The energy cost function may express a total cost of energy as a function of actual or estimated power use within a time horizon. In some embodiments, the energy cost function may be received as a completely defined function. In other embodiments, the energy cost function may be defined using a definition process such as process 1300, described in detail in reference to FIG. 13. To facilitate automated processing, the energy cost function may be expressed as a linear equation by adding demand charge constraints to the optimization procedure. Still referring to FIG. 16, process 1600 may further include using the system state information to formulate demand charge constraints (step 1604). An example demand charge constraint may be stated as (Pi−Pj)k≦PR where PR represents the maximum power in the demand charge region from previous time steps in the billing cycle. In the exemplary embodiment, system state information may information regarding estimated or actual power use for a previous time-step. Thus, system state information may be used to resolve the value of PR in a demand charge constraint. Step 1604 may be substantially equivalent to step 1308 in process 1300. Still referring to FIG. 16, process 1600 may further include using the masking procedure to invalidate the demand charge constraints which apply to inactive pricing periods (step 1606). In some embodiments, step 1606 may be performed because not all of the demand charge constraints are valid for each discrete time step used in the optimization procedure. In other embodiments, only valid demand charge constraints may be initially imposed and step 1606 may be unnecessary. Still referring to FIG. 16, process 1600 may further include using the system model and system state information to formulate equality constraints (step 1608). Step 1608 may allow the optimization procedure to accurately predict the effects of changing inputs to the building system so that the cost function can be minimized without violating the temperature constraints. Still referring to FIG. 16, process 1600 may further include determining an optimal power usage which minimizes the total energy cost as determined by the cost function within a time horizon while satisfying the equality constraints, the temperature constraints, and the demand charge constraints (step 1610). Many minimization procedures can be employed to perform cost minimization including Gauss-Newton, Ninness-Wills, adaptive Gauss-Newton, Gradient Descent, Levenberg-Marquardt, or any other optimization or search algorithm. Still referring to FIG. 16, process 1600 may further include updating the system model and system state information (step 1612). Step 1612 may be accomplished using recursive system identification process 1200, batch system identification process 1100 or any other update process. The updated system model and system state information may be used to update the equality constraints and demand charge constraints a subsequent iteration of the recursive process. For example, the system state information may include power usage information for previous time-steps. This information may be used to update the value of PR if necessary (e.g., if the power used during the last unrecorded time-step was greater than the stored value of PR) so that PR continues to represent the maximum power used in a demand charge region during the current billing cycle. Steps 1604-1612 may be performed recursively. The construction and arrangement of the systems and methods as shown in the various exemplary embodiments are illustrative only. Although only a few embodiments have been described in detail in this disclosure, many modifications are possible (e.g., variations in sizes, dimensions, structures, shapes and proportions of the various elements, values of parameters, mounting arrangements, use of materials, colors, orientations, etc.). For example, the position of elements may be reversed or otherwise varied and the nature or number of discrete elements or positions may be altered or varied. Accordingly, all such modifications are intended to be included within the scope of the present disclosure. The order or sequence of any process or method steps may be varied or re-sequenced according to alternative embodiments. Other substitutions, modifications, changes, and omissions may be made in the design, operating conditions and arrangement of the exemplary embodiments without departing from the scope of the present disclosure. The present disclosure contemplates methods, systems and program products on any machine-readable media for accomplishing various operations. The embodiments of the present disclosure may be implemented using existing computer processors, or by a special purpose computer processor for an appropriate system, incorporated for this or another purpose, or by a hardwired system. Embodiments within the scope of the present disclosure include program products comprising machine-readable media for carrying or having machine-executable instructions or data structures stored thereon. Such machine-readable media can be any available media that can be accessed by a general purpose or special purpose computer or other machine with a processor. By way of example, such machine-readable media can comprise RAM, ROM, EPROM, EEPROM, CD-ROM or other optical disk storage, magnetic disk storage or other magnetic storage devices, or any other medium which can be used to carry or store desired program code in the form of machine-executable instructions or data structures and which can be accessed by a general purpose or special purpose computer or other machine with a processor. Combinations of the above are also included within the scope of machine-readable media. Machine-executable instructions include, for example, instructions and data which cause a general purpose computer, special purpose computer, or special purpose processing machines to perform a certain function or group of functions. Although the figures may show a specific order of method steps, the order of the steps may differ from what is depicted. Also two or more steps may be performed concurrently or with partial concurrence. Such variation will depend on the software and hardware systems chosen and on designer choice. All such variations are within the scope of the disclosure. Likewise, software implementations could be accomplished with standard programming techniques with rule based logic and other logic to accomplish the various connection steps, processing steps, comparison steps and decision steps. | <SOH> BACKGROUND <EOH>The present disclosure relates to systems and methods for minimizing energy cost in response to time-varying pricing scenarios. The systems and methods described herein may be used for demand response in building or HVAC systems such as those sold by Johnson Controls, Inc. The rates that energy providers charge for energy often vary throughout the day. For example, energy providers may use a rate structure that assigns different energy rates to on-peak, partial-peak, and off-peak time periods. Additionally, energy providers often charge a fee known as a demand charge. A demand charge is a fee corresponding to the peak power (i.e. the rate of energy use) at any given time during a billing period. In a variable pricing scenario that has an on-peak, partial-peak, and off-peak time period, a customer is typically charged a separate demand charge for maximum power use during each pricing period. Energy providers can also offer customers the option to participate in a critical-peak pricing (CPP) program. In a CPP program, certain days throughout a billing period are designated as CPP days. On a CPP day, the on-peak time period is often divided in two or more sub-periods. CPP periods may also have separate demand charges for each sub-period. As an incentive to participate in the CPP program, customers are charged a lower energy rate on non-CPP days during the billing period. Energy providers also often engage in real-time pricing (RTP). RTP energy rates change frequently and can vary quite drastically throughout the day. RTP periods may also have a separate demand charge for each RTP period. It is challenging and difficult for energy customers would like to minimize the cost that they pay for energy where pricing scenarios can be mixed. Control actions can be taken to respond to variable pricing scenarios. One response is to turn off equipment. However, when the energy is used to drive a heating or cooling system for a building, the cost minimization problem is often subject to constraints. For example, it is desirable to maintain the building temperature within an acceptable range. Methods that are more proactive include storing energy in batteries or using ice storage to meet the future cooling loads. A problem with many of these techniques is the requirement for large, expensive, and non-standard equipment. A method that does not require additional equipment is storing energy in the thermal mass of the building. This form of thermal energy storage risks leading to either uncomfortable building zone temperatures or demand charges that are not significantly reduced. One technique is to pre-cool the building to a minimum allowable temperature and to determine the temperature setpoint trajectory that will minimize power use while maintaining the temperature below a maximum allowable value. With this technique, the demand can be curtailed and the zone temperature can remain within temperature comfort bounds. Traditional methods are less than optimal and are unable to handle RTP pricing scenarios with rapidly changing energy prices or CPP pricing scenarios having several regions of interest for both energy and demand charges. Furthermore, traditional methods may have difficulty accounting for varying disturbances to the system or changes to the system which are likely to necessitate re-developing or retraining the underlying model. Energy cost minimization systems and methods are needed to address a plurality of variable pricing schemes including the rapidly changing energy cost structures of CPP and RTP. Additionally, a method is needed which handles the possibility of multiple demand charge regions and which handles varying disturbances and changes to the system without the need to re-train the model. | <SOH> SUMMARY <EOH>One implementation of the present disclosure is a heating, ventilation, or air conditioning (HVAC) system for a building. The HVAC system includes a building system, a load predictor, an outer controller, an inner controller, and HVAC equipment. The building system includes one or more measurement devices configured to measure at least one of a measured temperature of the building or a measured power usage of the building and generate a feedback signal including at least one of the measured temperature of the building or the measured power usage of the building. The load predictor is configured to predict a future power usage of the building. The outer controller is configured to receive the feedback signal from the building system, receive time-varying pricing information, perform an optimization process to determine an amount of power to defer from the predicted power usage based on the feedback signal and the pricing information, and output a power control signal indicating the amount of power to defer. The amount of power to defer optimizes a total cost of the power usage of the building. The inner controller is configured to receive a power setpoint representing a difference between the predicted power usage and the amount of power to defer, determine an operating setpoint for the building system predicted to achieve the power setpoint, and output a second control signal indicating the operating setpoint. The HVAC equipment include one or more physical devices. The building system is configured to operate the HVAC equipment to achieve the operating setpoint. At least one of the outer controller or the inner controller is an electronic device including a communications interface and a processing circuit. In some embodiments, the feedback signal includes both information representative of the measured temperature and information representative of the measured power usage of the building. In some embodiments, the outer controller is configured to receive a dynamic model describing heat transfer characteristics of the building and temperature constraints defining an acceptable range for the measured temperature. In some embodiments, the outer controller is configured to use the dynamic model and the feedback signal to estimate a temperature state for the building as a function of power usage. In some embodiments, the outer controller is configured to use an optimization procedure to determine a power usage for the building which minimizes the total cost of the power usage while maintaining the estimated temperature state within the acceptable range. In some embodiments, the outer controller and the inner controller have different sampling and control intervals. The sampling and control interval of the outer controller may be longer than the sampling and control interval of the inner controller. In some embodiments, the outer controller and the inner controller are physically decoupled in location. In some embodiments, the time-varying pricing information includes demand charge information defining a cost per unit of power corresponding to a maximum power usage within a pricing period. In some embodiments, the time-varying pricing information includes demand charge information for two or more of a plurality of pricing periods. In some embodiments, the second control signal includes at least one of the operating setpoint or a derivative of the operating setpoint. In some embodiments, the power control signal includes at least one of the power setpoint received by the inner controller or the amount of power to defer from a predicted power usage. In some embodiments, the amount of power to defer is subtracted from the predicted power usage to calculate the power setpoint received by the inner controller. In some embodiments, the load predictor configured to receive the operating setpoint and at least one of current weather information, past weather information, or past building power usage. In some embodiments, the load predictor is configured to output the predicted power usage. The power control signal may be an amount of power to defer from the predicted power usage. Another implementation of the present disclosure is a method for heating, ventilating, or air conditioning a building. The method includes measuring at least one of a measured temperature of the building or a measured power usage of the building, generating a feedback signal including at least one of the measured temperature of the building or the measured power usage of the building, and predicting a future power usage of the building based on historical weather and power usage data. The method includes performing an optimization process to determine an amount of power to defer from the predicted power usage based on the feedback signal and time-varying pricing information and generating a power control signal indicating the amount of power to defer. The amount of power to defer optimizes a total cost of the power usage of the building. The method includes calculating a power setpoint representing a difference between the predicted power usage and the amount of power to defer, determining an operating setpoint predicted to achieve the power setpoint, generating a second control signal indicating the operating setpoint, and operating HVAC equipment to achieve the operating setpoint, the HVAC equipment comprising one or more physical devices. In some embodiments, the feedback signal includes both information representative of the measured temperature and information representative of the measured power usage of the building. In some embodiments, the method includes receiving a dynamic model describing heat transfer characteristics of the building and temperature constraints defining an acceptable range for the measured temperature, using the dynamic model and the feedback signal to estimate a temperature state for the building as a function of power usage, and using an optimization procedure to determine a power usage for the building which minimizes the total cost of the power usage while maintaining the estimated temperature state within the acceptable range. In some embodiments, the power control signal is generated by an outer controller having a first sampling and control interval and the second control signal is generated by an inner controller having a second sampling and control interval shorter than the first sampling and control interval. In some embodiments, the power control signal is generated by an outer controller and the second control signal is generated by an inner controller physically decoupled in location from the outer controller. In some embodiments, the time-varying pricing information includes demand charge information defining a cost per unit of power corresponding to a maximum power usage within a pricing period. In some embodiments, the time-varying pricing information includes demand charge information for two or more of a plurality of pricing periods. In some embodiments, the second control signal includes at least one of the operating setpoint or a derivative of the operating setpoint. In some embodiments, the method includes subtracting the amount of power to defer from the predicted power usage to calculate the power setpoint. In some embodiments, the power control signal includes at least one of the power setpoint or the amount of power to defer from a predicted power usage. In some embodiments, the method includes receiving the operating setpoint and at least one of current weather information, past weather information, and past building power usage. In some embodiments, the method includes outputting the predicted power usage. The power control signal may be an amount of power to defer from the predicted power usage. | G06Q5006 | 20171109 | 20180315 | 63528.0 | G06Q5006 | 1 | ZEROUAL, OMAR | SYSTEMS AND METHODS FOR CASCADED MODEL PREDICTIVE CONTROL | UNDISCOUNTED | 1 | CONT-ACCEPTED | G06Q | 2,017 |
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15,809,102 | PENDING | METHOD TO PROVIDE AD HOC AND PASSWORD PROTECTED DIGITAL AND VOICE NETWORKS | A method and system includes the ability for individuals to set up an ad hoc digital and voice network easily and rapidly to allow users to coordinate their activities by eliminating the need for pre-entry of data into a web or identifying others by name, phone numbers or email. This method is especially useful for police, fire fighters, military, first responders or other emergency situations for coordinating different organizations at the scene of a disaster to elevate conventional communication problems either up and down the chain of command or cross communication between different emergency units. The method and system provides that the users are only required to enter a specific Server IP address and an ad hoc event name, a password and perhaps the name of the particular unit. | 1-58. (canceled) 59. A method performed by one or more servers each having one or more processors, the method comprising: executing operations on the one or more processors, the operations comprising: obtaining first data provided by a first mobile device corresponding to a vehicle, the first data including a first identifier; permitting the first mobile device corresponding to the vehicle to join a communication network, the permitting based on a determination regarding the first data; obtaining second data provided by a second mobile device corresponding to a participant, the second data including a second identifier associated with the participant; allowing the second mobile device corresponding to the participant to join the communication network, the allowing based on a determination regarding the second data; receiving vehicle location data provided by the first mobile device corresponding to the vehicle, wherein the vehicle location data are associated with the first identifier and indicate a location of the first mobile device; receiving participant location data provided by the second mobile device corresponding to the participant, wherein the participant location data are associated with the second identifier and indicate a location of the second mobile device; sending vehicle map data to the second mobile device corresponding to the participant, wherein the vehicle map data comprise the vehicle location data, and wherein the second mobile device corresponding to the participant is configured to display a vehicle map based at least in part on the vehicle map data; sending participant map data to the first mobile device corresponding to the vehicle, wherein the participant map data comprise the participant location data, and wherein first mobile device corresponding to the vehicle is configured to display a participant map based at least in part on the participant map data; receiving participant selection data provided by the second mobile device corresponding to the participant, the participant selection data corresponding to user input provided via a display of the second mobile device; and based on the participant selection data, performing one or more acts selected from the group consisting of: sending updated participant map data to the first mobile device corresponding to the vehicle, sending updated vehicle map data to the second mobile device corresponding to the participant, and sending a message to the first mobile device corresponding to the vehicle. 60. The method of claim 59, wherein performing the one or more acts comprises sending, based on the participant selection data, the updated vehicle map data to the second mobile device corresponding to the participant, wherein the second mobile device is configured to display the updated vehicle map data within the vehicle map. 61. The method of claim 60, wherein the updated vehicle map data comprise updated vehicle location data indicating an updated location of the first mobile device corresponding to the vehicle. 62. The method of claim 59, wherein performing the one or more acts comprises sending, based on the participant selection data, the updated vehicle map data to the second mobile device corresponding to the participant, wherein the second mobile device is configured to replace the vehicle map with an updated vehicle map on the display of the second mobile device based at least in part on the updated vehicle map data. 63. The method of claim 59, wherein performing the one or more acts comprises sending, based on the participant selection data, the message to the first mobile device corresponding to the vehicle. 64. The method of claim 63, wherein the message to the first mobile device corresponding to the vehicle includes the second identifier and updated participant location data. 65. The method of claim 59, wherein performing the one or more acts comprises sending, based on the participant selection data, the updated participant map data to the first mobile device corresponding to the vehicle, wherein the first mobile device is configured to display the updated participant map data within the participant map. 66. The method of claim 59, wherein performing the one or more acts comprises sending, based on the participant selection data, the updated participant map data to the first mobile device corresponding to the vehicle, wherein the first mobile device is configured to replace the participant map with an updated participant map on the display of the first mobile device based at least in part on the updated participant map data. 67. The method of claim 59, wherein the vehicle map includes a first symbol at a position corresponding to the location of the second mobile device corresponding to the participant. 68. The method of claim 59, wherein the participant map includes a second symbol at a position corresponding to the location of the first mobile device corresponding to the vehicle. 69. The method of claim 59, wherein the vehicle map is interactive. 70. The method of claim 59, wherein the participant map is interactive. 71. A system comprising: one or more servers each having one or more processors, the processors configured to execute instructions to perform operations comprising: obtaining first data provided by a first mobile device corresponding to a vehicle, the first data including a first identifier; permitting the first mobile device corresponding to the vehicle to join a communication network, the permitting based on a determination regarding the first data; obtaining second data provided by a second mobile device corresponding to a participant, the second data including a second identifier associated with the participant; allowing the second mobile device corresponding to the participant to join the communication network, the allowing based on a determination regarding the second data; receiving vehicle location data provided by the first mobile device corresponding to the vehicle, wherein the vehicle location data are associated with the first identifier and indicate a location of the first mobile device; receiving participant location data provided by the second mobile device corresponding to the participant, wherein the participant location data are associated with the second identifier and indicate a location of the second mobile device; sending vehicle map data to the second mobile device corresponding to the participant, wherein the vehicle map data comprise the vehicle location data, and wherein the second mobile device corresponding to the participant is configured to display a vehicle map based at least in part on the vehicle map data; sending participant map data to the first mobile device corresponding to the vehicle, wherein the participant map data comprise the participant location data, and wherein first mobile device corresponding to the vehicle is configured to display a participant map based at least in part on the participant map data; receiving participant selection data provided by the second mobile device corresponding to the participant, the participant selection data corresponding to user input provided via a display of the second mobile device; and based on the participant selection data, performing one or more acts selected from the group consisting of: sending updated participant map data to the first mobile device corresponding to the vehicle, sending updated vehicle map data to the second mobile device corresponding to the participant, and sending a message to the first mobile device corresponding to the vehicle. 72. The system of claim 71, wherein performing the one or more acts comprises sending, based on the participant selection data, the updated vehicle map data to the second mobile device corresponding to the participant, wherein the second mobile device is configured to display the updated vehicle map data within the vehicle map. 73. The system of claim 72, wherein the updated vehicle map data comprise updated vehicle location data indicating an updated location of the first mobile device corresponding to the vehicle. 74. The system of claim 71, wherein performing the one or more acts comprises sending, based on the participant selection data, the updated vehicle map data to the second mobile device corresponding to the participant, wherein the second mobile device is configured to replace the vehicle map with an updated vehicle map on the display of the second mobile device based at least in part on the updated vehicle map data. 75. The system of claim 71, wherein performing the one or more acts comprises sending, based on the participant selection data, the message to the first mobile device corresponding to the vehicle. 76. The system of claim 75, wherein the message to the first mobile device corresponding to the vehicle includes the second identifier and updated participant location data. 77. The system of claim 71, wherein performing the one or more acts comprises sending, based on the participant selection data, the updated participant map data to the first mobile device corresponding to the vehicle, wherein the first mobile device is configured to display the updated participant map data within the participant map. 78. The system of claim 71, wherein performing the one or more acts comprises sending, based on the participant selection data, the updated participant map data to the first mobile device corresponding to the vehicle, wherein the first mobile device is configured to replace the participant map with an updated participant map on the display of the first mobile device based at least in part on the updated participant map data. 79. The system of claim 71, wherein the vehicle map includes a first symbol at a position corresponding to the location of the second mobile device corresponding to the participant. 80. The system of claim 71, wherein the participant map includes a second symbol at a position corresponding to the location of the first mobile device corresponding to the vehicle. 81. The system of claim 71, wherein the vehicle map is interactive. 82. The system of claim 71, wherein the participant map is interactive. | CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation of co-pending U.S. patent application Ser. No. 14/027,410 filed on Sep. 16, 2013, which is a continuation of U.S. patent application Ser. No. 13/751,453 filed Jan. 28, 2013, now U.S. Pat. No. 8,538,393 issued Sep. 17, 2013, which is a continuation-in-part of U.S. patent application Ser. No. 12/761,533 filed on Apr. 16, 2010, now U.S. Pat. No. 8,364,129 issued Jan. 29, 2013, which is a continuation-in-part of U.S. patent application Ser. No. 11/615,472 filed on Dec. 22, 2006, now U.S. Pat. No. 8,126,441 issued on Feb. 28, 2012, which is a continuation-in-part of U.S. patent application Ser. No. 11/308,648 filed Apr. 17, 2006, now U.S. Pat. No. 7,630,724 issued on Dec. 8, 2009, which is a continuation-in-part of U.S. patent application Ser. No. 10/711,490, filed on Sep. 21, 2004, now U.S. Pat. No. 7,031,728 issued on Apr. 18, 2006. All of the proceeding applications are incorporated herein by reference in their entirety BACKGROUND OF THE INVENTION Field of the Invention A communications method and system using a plurality of cellular phones each having an integrated Personal Digital Assistant (PDA) and Global Positioning System (GPS) receiver for the management of two or more people through the use of a communications network. The method and system provide each user with an integrated handheld cellular/PDA/GPS/phone that has Advanced Communication Software application programs (hereinafter referred to as ACS) and databases used in conjunction with a remote Server that enable a user to quickly establish a communication network of cell phone participants having a common temporary ad hoc network using mobile wireless communication devices. The invention includes a method and communication system to quickly set up and provide ad hoc, password protected, digital and voice networks to allow a group of people to be able to set up a network easily and rapidly, especially in an emergency situation. Description of Related Art The purpose of a communications system is to transmit digital messages from a source, located at one point, to user destination(s), located at other point(s) some distance away. A communications system is generally comprised of three basic elements: transmitter, information channel and receiver. One form of communication in recent years is cellular phone telephony. A network of cellular communication systems set up around an area such as the United States allows multiple users to talk to each other, either on individual calls or on group calls. Some cellular phone services enable a cellular phone to engage in conference calls with a small number of users. Furthermore, cellular conference calls can be established through 800 number services. Cellular telephony also now includes systems that include GPS navigation that utilizes satellite navigation. These devices thus unite cellular phone technology with navigation information, computer information transmission and receipt of data. The method and operation of communication devices used herein are described in U.S. Pat. No. 7,031,728 which is hereby incorporated by reference and U.S. Pat. No. 7,630,724. Military, first responder, and other public and private emergency groups need to be able to set up ad hoc digital and voice networks easily and rapidly. These private networks may be temporary or longer lasting in nature. The users need to be able to rapidly coordinate their activities eliminating the need for pre-entry of data into a web and or identifying others by name, phone numbers or email addresses so that all intended participants that enter the agreed ad hoc network name and password are both digitally and voice interconnected. When a user or users leave the network, no data concerning the network participants need be retained. Coordinating different organizations at the scene of a disaster presents several problems as there are voice and digital data (text messages) communications that need to be constantly occurring up and down the chain of command. As an example, communications are required from a police chief to a police captain to a police lieutenant to a police sergeant to a policeman and then back up the same chain of command. Digital data exchange of GPS data or other means provides the location component of the units. Digital chat, text messages, white boards and photo video exchange provide extensive collaboration. However, during a disaster, other first responders such as fire departments must become engaged. While the fire department users may have voice and digital data (text messages) communications up and down their chain of command, these individuals do not have the ability to cross communicate necessarily with police units without a substantial degree of immediate coordination. The method and system in accordance with the present invention described herein discloses how digital communications along with Personal Computer (PC) and PDA devices can be used to quickly establish user specific password protected private ad hoc voice and data networks to enable both data and voice communications up and down their chain of command and simultaneously with different, not pre-known, organizations responding to a disaster. The invention defines a method of accomplishing this by providing all personnel that need to communicate with each other with a PC or PDA which are interconnected to a Server using cellular or other communications. SUMMARY OF THE INVENTION Applicant's communication system and method described herein is embodied in the Advanced Communication Software (ACS) application programs developed by applicant and installed in the integrated PDA/GPS cell phones used herein and remote Servers. A plurality of Internet Protocol (IP) capable PDA/GPS devices each having ACS application programs and databases provides a communication network in conjunction with a remote Server that provides the ability to: a) establish an ad hoc network of devices so that the devices can either broadcast to a group or selectively transmit to each of the other; each PDA/GPS phone starts by requesting access to the Server and identifying a mutually agreed to network name and password and once granted, reports its GPS position and status; the Server then routes the data to all signed on network participants so that each of the devices exchange location, status and other information; (b) force the received information to the recipient's display and enable the recipient to acquire additional information by touching the display screen at a remote phone's location on the PDA display; (c) make calls to or send data to remote phones by touching their display symbols and selecting the appropriate soft switch; (d) layer a sufficient number of soft switches or buttons on the PDA display to perform the above functions without overlaying the map; and (e) allow a polling mode in each cell phone that permits a user to contact other cell phone users that have a common interest or relationship with a password and identifier for communication and to establish quickly a temporary ad hoc network especially in an emergency. A communication Server acts as a forwarder for IP communications between any combination of cell phone/PDA users and/or PC based users. Network participant location, identity and status messages are sent to the Server by each user. Network participant entered tracks are also sent to the Server. Because this network participant location and track data is of interest to all the network participants, the Server forwards the data received from one participant to all other participants, causing their displays automatically, without any operator action, to display the received information, thus providing the information necessary for all network participants to know the identity, location and status of all other network participants. The Server also acts as a forwarder of data addressed from one participant to one or more addressed participants, thus permitting the transmission of free text, preformatted messages, photographs, video, Email and Uniform Resource Locator (URL) data from one network participant to other selected network participants. The above functions can also be accomplished using peer to peer WiFi, WiMax or other peer to peer communications. However, for use with cellular communications and to assure the level of security that cell phone companies require, a centralized static IP routable Server is used. The IP Server also fills another role of being a database from which data can be requested by network participants (i.e. maps, satellite images, and the like) or can be pushed to network participants (i.e. symbology and soft switch changes, and the like). The Server is used to establish an ad hoc network within certain groups using an ad hoc event name and password. This invention provides a method and a system establishing an ad hoc password protected digital and voice network that can be temporarily set up or longer lasting in nature. The invention described herein allows users to rapidly coordinate their activities without having to pre-enter data into a web or identify others by name, E mail addresses or phone numbers. Essentially the users that establish the ad hoc and password protected digital and voice networks are required to enter the Server's IP address and an ad hoc event name and a password. In the case of military and first responders, the name of the user's unit may also be used. This action causes the specific PDA or PC of the user to commence reporting directly to the Server's IP address. Once the Server receives the initial IP message from the user's PDA or PC, the server can commence to exchange data with the user's PDA or PC. The initial IP message may also contain additional data such as a license number and, if desired, a phone number manually entered or automatically acquired by the ACS. The IP address of the PDA and PC unit sending the initial IP message is stored by the Server. The Server then responds with a message notifying the user that his PC/PDA is connected to the Server. The user PDA/PC then reports its GPS location and other status information directly to the Server. This information is retained by the Server even when there are no other devices initially communicating with the Server. When the other user's devices sign on to the Server with the same ad hoc event name and password, the Server software then recognizes all the users and stores their IP addresses in the Server. Thus the Server has all the users IP addresses stored and can pass location and status information among the ad hoc network participants even though the network participants have not entered other network participants' names, phone numbers or email addresses. Thus one of the purposes of the invention is to allow an ad hoc network to be formed on a temporary basis in a rapid manner. When using the PTT feature, the ACS can enable the network participant to: 1. PTT with all that are in the ad hoc digital network, or 2. PTT with select specific network participants, by touching their symbols) and then selecting PTT soft switch or 3. Specify a group of the network participants by assigning their symbols or unit names to a list of network participants and then associating the list with a soft switch whose function is to enable the operator to have PTT communications with all in the list. Since only one person is transmitting on a PTT voice network at any given time, the receiving network participant's ACS can relate the PTT IP address to the IP address of the unit transmitting his identification on the digital ad hoc network. This information can then be used by the other PTT networked participant's ACS to: 1. flash the transmitting unit's name on their PDA/PC screens or 2. if a photograph has been attached to the ad hoc digital network symbol of the PTT transmitting person, to flash that photograph on the receiving unit's PDA/PC display. It is an object of this invention to enable each participant in the communication network to join other ad hoc network participants to form an ad hoc digital and voice network with other cell phone users rapidly for coordinating member activities. In accordance with these and other objects which will become apparent hereinafter, the instant invention will now be described with particular reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows a front plan view of a cellular phone/PDA/GPS having a touch screen. FIG. 2 shows the screen IP address entry menu. FIG. 3 shows ad hoc net names and password screen entry name. FIG. 4 shows a screen entry identifying user. FIG. 5 shows a flow chart of the network as users sign on to the network. FIG. 6 shows a flow chart that depicts how a group commander can command networked PDAs/PCS and radios to load a Push To Talk (PTT) channel. FIG. 7 shows a flow chart that depicts how networked radio units respond to receipt of the Push-to-Talk (PTT) Commanded Channel. FIG. 8 shows a PDA screen geographical display that represents the area covered by the network. FIG. 9 shows a diagram that enables determining location, status, ViOP, PTT, and video communication between adios and cell phones. FIG. 10 shows a diagram that describes enabling non RFID equipped PDA phones to receive RFID tag data. PREFERRED EMBODIMENT OF THE INVENTION A method and communication system that joins a communications network of participants using handheld cell phones having integrated PDA and GPS circuitry with ACS application programs that allow a participant having an ACS equipped cell phone to provide an ad hoc and password protected digital and voice network. A communication Server acts as a forwarder for IP communications between any combination of cell phone/PDA users and/or PC based user. Network participant location, identity and status messages are sent to the Server by each user. Network participant entered tracks are also sent to the Server. Because this data is of interest to all the network participants, the Server forwards the data received from one participant to all other participants, thus providing the information necessary for all network participants to know the identity, location and status of all other network participants. The Server allows the set up of the ad hoc network with an ad hoc event name and a password. The Server also acts as a forwarder of data addressed from one participant to one or more addressed participants, thus permitting the transmission of free text, preformatted messages, photographs, video, email and URL data from one network participant to other selected network participants. Referring now to the drawings and, in particular, to FIG. 1, a small handheld cellular phone 10 is shown that includes a PDA and a GPS communications device integrated in housing 12 that includes an on/off power switch 19, a microphone 38, and a Liquid Crystal Display (LCD) display 16 that is also a touch screen system. The small area 16a is the navigation bar that depicts the telephone, GPS and other status data and the active software. Each cell phone includes a Central Processing Unit (CPU) and databases that store information useful in the communication network. The CPU also includes a symbol generator for creating touch screen display symbols discussed herein. With the touch screen 16, the screen symbols are entered through GPS inputs or by the operator using a stylus 14 (or operator finger) by manipulatively directing the stylus 14 to literally touch display 16. The soft switches 16d displayed on the display 16 are likewise activated by using a stylus 14 and physically and manipulatively directing the stylus to literally touch display 16. The display x, y coordinates of the touched point are known by a CPU in the PDA section of the communication system in housing 12 that can coordinate various information contained in the PDA relative to the x, y coordinate position on the display 16. Inside housing 12 is contained the conventional cellular phone elements including a modem, a CPU for use with a PDA and associated circuitry connected to speaker 24 and microphone 38. A GPS navigational receiver that receives signals from satellites that can determine the latitude and longitude of the cellular phone housing 12 can be internal or external to the housing 12. Conventional PDA/cellular phones are currently on sale and sold as a unit (or with an external connected GPS) that can be used for cellular telephone calls and sending cellular Short Message Service (SMS) and Transmission Control Protocol (TCP) TCP/IP or other messages using the PDA's display 16 and computer CPU. The GPS system including a receiver in housing 12 is capable of determining the latitude and longitude and through SMS, TCP/IP, WiFi or other digital messaging software, to also transmit this latitude and longitude information of housing 12 to other cellular phones in the communication network via cellular communications, WiFi or radio. The device 10 includes a pair of cellular phone hardware activating buttons 20 to turn the cellular phone on and 22 to turn the cellular phone off. Navigation pad actuator 18 is similar to a joy or force stick in that the actuator 18 manually provides movement commands that can be used by the RDA's software to move a cursor on display 16. Switches 26 and 28 are designed to quickly select an operator specified network software program. Speaker 24 and microphone 38 are used for audio messages. Switch 19 at the top left of device 10 is the power on and power off switch for the entire device. The heart of the invention lies in the applicant's ACS application programs provided in the device. The ACS programs are activated by clicking on an icon on the display to turn the ACS programs on or off. Mounted within housing 12 as part of the PDA is the display 16 and the CPU. The internal CPU includes databases and software application programs that provide for a geographical map and georeferenced entities that are shown as display portion 16b that includes as part of the display various areas of interest in the particular local map section. When looking at display 16, the software switches (soft switches) which appear at the very bottom of the display 16d are used to control by touch many of the software driven functions of the cellular phone and PDA. The soft switches are activated through the operator's use of the navigation pad 18, or a small track ball, force stick or similar hardware display cursor pointing device. Alternatively, the operator may choose to activate the software switches by touching the screen with a stylus 14 (or finger) at the switches' 16d locations. When some of the software switches are activated, different software switches appear. The bar display 16d shows the software switches “ZM IN (zoom in),” “ZM OT (zoom out),” “CENT (center)” and “GRAB (pan/grab)” at the bottom of the screen. These software switches enable the operator to perform these functions. The “SWITH (switch)” software switch at the lower right causes a matrix of layered software switches (soft switches) to appear above the bottom row of switches. Through use of the software switches, the operator can also manipulate the geographical map 16b or chart display. When looking at FIG. 1, display symbols depicting permanent geographical locations and buildings are shown. For example, the police station is shown and, when the symbol is touched by the stylus or finger, the latitude and longitude of the symbol's location, as shown in display section 16c, is displayed at the bottom left of the screen. The bottom right side of display 16c is a multifunction inset area that can contain a variety of information including: a) a list of the communication link participants; b) a list of received messages; c) a map, aerial photograph or satellite image with an indication of the zoom and offset location of the main map display, which is indicated by a square that depicts the area actually displayed in the main geographical screen 16b; d) applicable status information; and e) a list of the communication net participants. Each participant user would have a device 10 shown in FIG. 1. Also shown on the display screen 16, specifically the geographical display 16b, is a pair of different looking symbols 30 and 34, a small triangle and a small square, which are not labeled. These symbols 30 and 34 can represent communication net participants having cellular phones in the displayed geographical area that are part of the overall cellular phone communications net, each participant having the same device 10 used. The latitude and longitude of symbol 30 is associated within a database with a specific cell phone number and, if available, its IP address and email address. The screen display 16b, which is a touch screen, provides x and y coordinates of the screen 16b to the CPU's software from a map in a geographical database. The software has an algorithm that relates the x and y coordinates to latitude and longitude and can access a communications net participant's symbol or a fixed or movable entity's symbol as being the one closest to that point. In order to initiate a telephone call to the cellular phone user (communication net participant) represented by symbol (triangle) 30 at a specific latitude and longitude display on chart 16b, the operator touches the triangle 30 symbol with the stylus 14. The user then touches a “call” software switch from a matrix of displayed soft switches that would overlay the display area 16c. Immediately, the cellular phone will initiate a cellular telephone call to the cellular phone user at the geographical location shown that represents symbol 30. A second cellular phone user (communication net participant) is represented by symbol 34 which is a small square (but could be any shape or icon) to represent an individual cellular phone device in the display area. The ring 32 around symbol 30 indicates that the symbol 30 has been touched and that a telephone call can be initiated by touching the soft switch that says “call.” When this is done, the telephone call is initiated. Other types of symbolic elements on the display 16 can indicate that a cellular phone call is in effect. Additionally, the operator can touch both symbol 34 and symbol 30 and can activate a conference call between the two cellular phones and users represented by symbols 30 and 34. Again, a symbolic ring around symbol 34 indicates that a call has been initiated. Equally important, a user can call the police station, or any other specific geographical facility displayed on the map including: buildings, locations of people, vehicles, facilities, restaurants, or the like, whose cellular phone numbers and, if available, Email addresses, IP addresses and their URLs (previously stored in the database) by touching a specific facility location on the map display using the stylus 14 and then touching the cellular phone call switch. As an example, the operator can touch and point to call a restaurant using a soft switch by touching the restaurant location with a stylus and then touching the call soft switch. The cellular phone will then call the restaurant. Thus, using the present invention, each participant can touch and point to call to one or more other net participants symbolically displayed on the map, each of whom has a device as shown in FIG. 1, and can also point to call facilities that had been previously stored in the phone's database. Furthermore, this symbol hooking and soft switch technique can be used to go to a fixed facility's website or to automatically enter the fixed facility's email address in an email. Each cellular phone/PDA/GPS user device is identified on the map display of the other network participant user's phone devices by a display symbol that is generated on each user phone display to indicate each user's own location and identity. Each symbol is placed at the correct geographical location on the user display and is correlated with the map on the display and is transmitted and automatically displayed on the other network participant's PC and PDA devices. The operator of each cellular phone/PDA/GPS device may also enter one or more other fixed entities (buildings, facilities, restaurants, police stations, etc.) and geo-referenced events such as fires, accidents, etc., into its database. This information can be likewise transmitted to all the other participants on the communications net and automatically displayed. The map, fixed entities, events and cellular phone/PDA/GPS device communication net participants' latitude and longitude information is related to the “x” and “y” location on the touch screen display map by a mathematical correlation algorithm. When the cellular phone/PDA/GPS device user uses a stylus or finger to touch one or more of the symbols or a location displayed on the cellular phone map display, the system's software causes the status and latitude and longitude information concerning that symbol or location to be displayed. In order to hook a symbol or “track” such as another net participant which represents an entity on the geo-referenced map display, or a fixed geographical entity such as a restaurant, police station or a new entity observed by a cell phone user which is discussed below, the operator touches at or near the location of a geo-referenced symbol appearing on the cellular phone/PDA display that represents a specific track or specific participant or other entity. The hook application software determines that the stylus (or finger) is pointed close to or at the location of the symbol and puts a circle, square or other indication around the symbol indicating that amplification information concerning the symbol is to be displayed. The operator can hook entered tracks or his own track symbol and add data or change data associated with the indicated symbol. The hook application code then sends a message to the database application code to store the facility or entity's updated data. The display application code retrieves the primary data and amplification data concerning the symbol or entity from the database and displays the information at the correct screen location. The operator can then read the amplification data that relates to that specific symbol at the specific location. The cell phone operator can also select soft switches on the touch screen display to change the primary data and amplification data. Furthermore, the operator can use a similar method of hooking and selecting to activate particular soft switches to take other actions which could include: making cellular phone calls, conference calls, 800 number calls; sending a free text message, operator selected preformatted messages, photographs or videos to the hooked symbol; or to drop an entered symbol. Each known net participant has a cellular phone number, IP address and, if available, Email address that is stored in each participant's device database. To use the communication system, a user starts the PDA/cellular phone device system by turning on the cell phone power and selecting the cell phone and network software which causes: a) the cellular phone to be activated (if it has not already been activated); b) the GPS interface receiver to be established; c) a map of the geographic area where the operator is located and operator's own unit symbol to appear at the correct latitude and longitude on the map on the display; d) the locations of fixed facilities such as restaurants, hotels, fire departments, police stations, and military barracks, that are part of the database to appear as symbols on the map; e) the device selected item read out area which provides amplification information for the communications net participants or the entity that has been hooked (on the display screen) to appear on the display; f) an insert area that contains various data including: the list of net participants, a list of messages to be read, an indication of what portion of the map is being displayed in major map area and other information to appear on the display; and g) a row of primary software created “soft switches” that are always present on the display to appear. For point to call network units and fixed facilities, the application code detects the x, y display screen location of the symbol that is designated by the user's stylus and translates the x, y coordinates to latitude and longitude and then: (1) searches the database to find the symbol at that location, (2) places a “hook” indicator (a circle, square or other shape) around the symbol, (3) displays any amplifying data and (4) obtains the symbol's associated phone number (or, for Voice over IP (VoIP) an IP address) from the database. Upon receiving a “call” designation from the soft switch, the operator's device's ACS causes the appropriate phone number or IP address to be called. Upon receiving an indication that the phone number is being called, the application code places a box around the symbol (color, dashed or the like). When the call is connected, the box changes to indicate that the connection is made. When the other party hangs up, the box disappears. As each of the cell phone participants reports its identity, location and status to the other participants' devices, the received data is automatically geo-referenced and filed in their databases that are accessible by identity and by location. This data is then displayed on each cell phone display. When a request for data is received by touching the display screen, a location search is made by the ACS and a symbol modifier (circle, square, etc.) is generated around the symbol closest to the x, y position of the stylus. When the application code receives a soft switch command to place a phone call or send data, the software uses the phone number (or IP address) associated with the unit to place the call or to send data. If a cell phone device receives a digital message that a call is being received, the receiving cell phone's ACS application code places a box or similar object around the transmitter symbol indicating who the call is from. When the call is answered, the application software changes the visual characteristics of the box. In a similar manner, when a phone receives a digital text message, photograph or video, a box appears around the transmitter's symbol indicating the transmitter of the message. The point to call network devices are network participants and each one has a PC/PDA device with the same software for use as a total participant network. Other situations for calling facilities that are not network participants are also described below. Thus, a user is capable of initiating a cellular phone call by touch only and initiating conference calls by touching the geo-referenced map symbols. Furthermore, by using a similar symbol touching technique, a cellular phone can send user selected messages to cause a remote cellular phone to display and optionally announce emergency and other messages and to optionally elicit a response from the remote cellular phone. All of the network participants have the same communication cell phone/PDA/GPS device described herein. The method and system include the ability of a specific user to provide polling in which other cellular phones, using SMS, internet or WiFi, report periodically based on criteria such as time, speed, distance traveled, or a combination of time, speed and distance traveled. A user can manually poll any or all other cell phone devices that are used by all of the participants in the communication network having the same devices. The receiving cellular phone application code responds to the polling command with the receiving cellular phone's location and status which could include battery level, GPS status, signal strength and entered track data. Optionally, the phone operators can set their phones to report automatically, based on time or distance traveled intervals or another criterion. The soft switch application software causes a visual display of a matrix such as five across by six up (or another matrix) in which switch names are placed on the cellular/PDA display. The soft switch network application software knows the touch screen location of each of the switches in the matrix and the software routines that will be activated upon touching the switch. The bottom row of soft switches displayed on the touch screen retrains visually fixed. These switches concern the functions that are the most often used. One of the switches causes a matrix of other soft switches to appear above the visually fixed soft switches. These switches are function soft switches, the activation of any one of which causes a different matrix of soft switches to appear, which are known as the action soft switches. When the action soft switches appear, the function soft switch, which caused the action soft switches to appear, itself appears as a label in the lower left (or some other standard location) indicating to the operator the function soft switch that has been selected. When the operator selects an action soft switch, the appropriate application software to accomplish the action is activated. Upon receiving a soft switch activation message, the ACS accesses the appropriate task execution software which accomplishes the required tasks including: entry of track data, entry of track amplification data, transmission of alpha/numeric messages, photographs, videos, display of messages to be read, selection of map types, placing voice calls, placing conference calls and 800 conference calls, presenting different potential operator selections, control of the display actions, polling network participants, establishing nets of participants (groups) so that communications with all in the group can be accomplished with a single soft switch action, and dropping a previously entered track. By providing a matrix and layers of soft switches which are easily manipulated by a stylus, each cell phone device in the communication network is extremely efficient in accessing and coordinating the appropriate application program for the device to perform. Users such as emergency groups, police, fire personal, military, first responders and other groups need to be able to set up ad hoc digital and voice networks easily and rapidly. The users need to be able to rapidly coordinate activities eliminating the need for pre-entry data as discussed above. Users are required to enter the Servers' IP address and an ad hoc event name, a password and, for first responders and military, the names of their units. This will normally be controlled by the PDA/PC user's position in the chain of command. For others it can be any selected name and, if desired, password. Referring now to FIG. 2, the PDA/PC screen displays an IP address entry menu. The user inserts the Server's IP address. Thus, as shown in FIG. 2, the user has entered in the cell phone/PDA the Server IP address and port number along with the GPS port listing and other information. Once that information is entered, referring now to FIG. 3, the user now enters the ad hoc event network name which is shown in this example as “Katrina” along with a password. Referring now to FIG. 4, the user then enters the user name or a unit name. FIG. 4 shows the entered user name and a phone number. The phone number may be automatically entered by the ACS or manually entered. The phone number is not required unless using the phone system (not VoIP) to make calls. These are the initial user steps required to establish an ad hoc network or to join onto an existing ad hoc network. Referring now to FIG. 5, these actions cause the user cell phone/PDA or PC to commence reporting to the Server. Upon receipt of the initial message from the user's PDA/PC, which may also contain additional data such as a license number, the Server stores the IP address of the user's PDA/PC unit and responds with a message notifying the user that he or she is connected to the Server. The PDA/PC then automatically commences to report its GPS derived location and other status information to the Server. Since there are no other devices initially communicating with the Server, the Server just retains the information. When other devices sign on to the Server with the same ad hoc event name and password, the Server's software recognizes this and stores their IP addresses. Since the Server has all parties' IP addresses, the server is able to pass location and status information automatically between the ad hoc network participants. This can occur even though the ad hoc network participants have not entered other network participants names, telephone numbers or Email addresses and do not have the other network participants' IP addresses, phone numbers or Email addresses. Once this connection is made, data types that are entered on one display that is of interest to all is sent from the server to all others in the network. Such data types include track location and track amplification data, geo-referenced white boards, and chat. When the PDA/PC user wants to address particular data (a text message, photograph, video clip, voice recording, white board, or chat), the user enters the name of the other ad hoc network participant by either entering a name or touching his or her symbol. Since the Server knows the IP address of the name or symbol, the Server forwards the data appropriately to that network participant. When a unit signs off the network, it transmits a message to the Server which then transmits a message to all the network participants to drop the unit and its associated tracks. If a unit loses communications for a variable time period, the unit's data is flushed from each of the recipient network participants systems according to a variable time period. After a separate variable time period, the Server also flushes the non-reporting units data. As can be seen in FIG. 6, provisions have been made for the PDA/PC to report on multiple networks thus allowing both digital communications up and down the chain of command and with adjacent units that have entered a common ad hoc network name and password. Typically military and First Responder units use Push-to-Talk (PTT) communications. Units in an organization's chain of command typically have instituted a method to establish voice communications between themselves for they know each other's cellular phone numbers, PTT cellular group identifiers and radio frequencies or channel numbers. However, in a disaster there are many different units (fire, police, EMS, Military, and the like) involved all of whom need to establish voice communications between each other. The issue then becomes how to coordinate these PTT voice communications with the ad hoc digital communications so that all on the digital data network automatically also have PTT voice communications with each other. If the PCs and PDAs in a group have manually entered their phone numbers, or the ACS has automatically entered their phone numbers, and sent their phone numbers as part of their initial message to the Server, this data is then sent by the Server to all others in the network. Upon receiving the phone number data, the recipients' ACS loads the cell phones numbers into their databases creating a phone number PTT group common with the digital IP network group. The issue when using radios, however, is different. PTT radio coordination between multiple people is achieved by using a common radio frequency “Channel”. Furthermore, it is desirable to enable it so that, when new network participants join the digital network, they are automatically included in the voice network and, when they leave the digital network, they are automatically dropped from the digital network. As can be seen in FIG. 6 and FIG. 7, a network participant currently can establish a new ad hoc digital network or join an existing ad hoc digital network by entering the ad hoc network name and password into his PDA/PC. To enable voice coordination with all that are a part of the ad hoc digital network, the user then enters (if user is authorized to do so) a Channel or Group number that the user is commanding all in the ad hoc network to establish as their PTT voice net. As seen in FIG. 6, the operator has commanded all to shift to Radio Channel or to a specific PTT cellular or radio channel; i.e. Group 7. This action causes the PTT Channel, or PTT Group 7, to be sent to the other PDA/PC users in the ad hoc password protected network through the Server. As shown in FIG. 6 and FIG. 7, the Group leader enters the Katrina Fire ad hoc network and issues a command which is sent to the Server to cause the PDAs/PCs that are in the Katrina Fire Group to automatically shift their Radio or cellular device to Channel 7. Each PDA cell phone can connect to the user's Radio for control with a USB cable, or WiFi, Bluetooth, or Near Field Communications (NFC) signals or other communications that are contained in the PDA/PC cellular device. This enables the Radios to shift to a common channel. This action is received by the Server which then sends the “Shift to Channel 7 Command” to all network participants in the Katrina Fire ad hoc network. When the PDA/PC/Tablet Katrina Fire network participant's software receives the command to shift its Radio Channel PPT to Group 7, this action causes the PDA's ACS to establish a new Channel 7 group (or to override an old Channel 7 group) that consists of all on the digital ad hoc network. The PC and PDAs then send their radios' digital interfaces messages to shift to Channel 7 or to the frequency associated with Channel 7. The digitally networked PC's and PDA's ACS devices then send a message to all on the digital network that they have shifted to Channel 7 (or to the appropriate frequency) and also further send the Group Leader's identifier and Command to shift to Channel 7 so that the ACS' devices associated with new users joining the digital network will automatically digitally set their radios to Channel 7 or the appropriate frequency. As shown in FIG. 7, each time one of the network participants reports to the Katrina Fire network its Name, Position and Status, it now also reports that it is in PTT Channel 7 enabling the PTT group to grows in size until it encompasses all in the ad hoc password protected digital network. When units drop out of the Common Interest Network or lose communications because they are no longer active or they are out of range, their PTT Channel data is likewise dropped as they dropped out of the digital because their reports have not been received for a set, but adjustable, time period. If a unit rejoins the network, their PTT Name and Phone number is again automatically added to the Katrina Fire Interest Group as they are accepted by the Server into the Katrina Fire Interest digital Group. When using the PTT feature, the ACS can enable the network participant to: 1. PTT with all that are in the ad hoc digital network, or 2. PTT with select specific network participants, by touching their symbol(s) and then selecting PTT soft switch or 3. Specify a group of the network participants by assigning their symbol or unit name to a list of network participants and then associating the list with a soft switch whose function is to enable the operator to have PTT communications with all in the list. Since only one person is transmitting on a PTT voice network at any given time, the receiving network participant's ACS can relate the PTT IP address to the IP address of the unit transmitting his identification on the digital ad hoc network. This information can then be used by the other PTT networked participant's ACS to: 1. flash the transmitting unit's name on their PDA/PC screens or 2. if a photograph has been attached to the ad hoc digital network symbol of the PTT transmitting person, to flash that photograph on the receiving unit's PDA/PC display. Referring now to FIG. 8, for some Emergency events, and in particular military operations, it is desirable to further define ad hoc networks so that the networks encompass only a certain geographical area defined by boundary lines on a map. To accomplish this, an enhancement to the ad hoc digital and voice PTT password protected network is provided. As an example, once the Katrina. Fire digital and PTT network is established, the ad hoc network can be further refined by the Group Leader defining a map area that limits the participating group to only those users within a geographically defined area by the Group Leader, creating on his PC/PDA display a box that defines a geographic area on a map. As shown in FIG. 8, the Latitude/Longitude points that define the rectangle of the boundary area are sent from the Group Leader's device to the Server which relays the data to the other participating unit PC/PDA devices in the Katrina Fire network. When the participating unit devices receive the Latitude/Longitude points, their software computes whether their PC/PDA unit is inside or outside a boundary area. If the users are inside the defined area, the users retain but disregard the Latitude/Longitude data and continue to report on the digital password protected network and to use the commanded PTT channel/frequency. However, if the users are outside the area, the users send a “drop me message” to the Katrina Fire PDA/PC digital network Server and cease reporting on the network. When Katrina Fire network PDA/PC user units leave the defined area or lose communications for a specified, but adjustable, time period, the Server drops the unit from the network and informs all network users that the unit is dropped from the digital network and from voice PTT Channel 7 which causes all others on the network to drop them. When Katrina Fire networked PDA/PC user units re-enter the area, the unit's ACS detects the fact and commences reporting as it receives reports from other network participants it will receive the current PTT channel or frequency. In disasters, battery life is essential as there may not be extra batteries available or a power available to recharge the battery. It is therefore essential to lessen battery utilization. The normal method by which this is accomplished is to not use software that keeps the display on, uses the GPS or transmits on the communications. However, deactivating any one of these processes produces a problem with providing location data to all on the network. With location sharing there are essentially two times when the location information is essential: a) Where the user wants all to know his/her location and status and the location and status of others and b) When the commander wants to know the location and status of all or of a particular unit. When the user wants others to know the user location and status, the user can simply turn on location reporting software which then turns on the display, the GPS and the communications reporting software causing the reporting of the user location to the ad hoc password protected digital network. However, when the commander or someone else wants to know the location and status of the PDA/PC unit that is conserving battery usage by having user display, GPS and communications transmission turned on, the commander has no method to accomplish this. This problem is overcome by enabling the commander to transmit a “turn on” IP message to the battery conserving(s) unit(s) by addressing the message to the ad hoc network Server which then sends an SMS message to the addressed phone. The SMS message will be received as long as the phone is powered on, as SMS is integrated with the cell phone's voice communications. The Server could also send a turn on IP message to networked radios, which will then cause the radio's computer to send a digital message to the receiving PC/PDA to activate the user display and location and status reporting software. Referring now to FIG. 9, the diagram illustrates the enabling of location, status, VoIP, PTT, and video communications between radios and cell phones. The server maintains a temporary retention of names and IP addresses and sends data between all with the same ad hoc name unless addressed to a specific IP address. This requires that there is a radio with digital capabilities attached to the server shown in FIGS. 5, 6, and 7. These radios are set so that they each have a unique IP address. All of the participants have either PDA cell phones or PDAs without cellular. Those that also have PDAs without cellular (or choose not to use cellular) are connected to their radios via a USB cable or Wi-Fi, Bluetooth, or near field communications (NFC) that is part of the PDA/PC OR PDA cell phone. This is illustrated in FIG. 9. Referring now to FIG. 10 the diagram shows enabling non-RFID equipped PDA phones to receive RFID tag data. The server maintains a temporary retention of how Tags relate to names and sends data to local display and to other ACS network participants. Currently RFID tags are used for many functions, one of which is to track personnel inside a building to the room or compartment in which they are located. This is accomplished by RFID readers that are in each of the rooms. When personnel with an RFID tag get within a particular distance or range of the RFID reader, the reader detects their presence and sends it to a central site server via a USB cable or Wi-Fi. The PC connected to the server displays the personnel room locations. With the invention described herein, the server would then send the location to the ACS PDA/PC phones that would be carried by individuals located throughout the building or ship. The PDA/PC phones would display the room or ships compartments and the location of individuals with RFID tags and simultaneously enable PTT, chat, messaging, whiteboards, commands geo-fence penetration alerts or other types of messages between each of the PDA cell phones. The RFID tag would provide room location data of all to all that are on the ACS Wi-Fi network without their PDA cell phone having an RFID Reader attached to it. The operation is explained in detail in FIG. 10. The instant invention has been shown and described herein in what is considered to be the most practical and preferred embodiment. It is recognized, however, that departures may be made there from within the scope of the invention and that obvious modifications will occur to a person skilled in the art. | <SOH> BACKGROUND OF THE INVENTION <EOH> | <SOH> SUMMARY OF THE INVENTION <EOH>Applicant's communication system and method described herein is embodied in the Advanced Communication Software (ACS) application programs developed by applicant and installed in the integrated PDA/GPS cell phones used herein and remote Servers. A plurality of Internet Protocol (IP) capable PDA/GPS devices each having ACS application programs and databases provides a communication network in conjunction with a remote Server that provides the ability to: a) establish an ad hoc network of devices so that the devices can either broadcast to a group or selectively transmit to each of the other; each PDA/GPS phone starts by requesting access to the Server and identifying a mutually agreed to network name and password and once granted, reports its GPS position and status; the Server then routes the data to all signed on network participants so that each of the devices exchange location, status and other information; (b) force the received information to the recipient's display and enable the recipient to acquire additional information by touching the display screen at a remote phone's location on the PDA display; (c) make calls to or send data to remote phones by touching their display symbols and selecting the appropriate soft switch; (d) layer a sufficient number of soft switches or buttons on the PDA display to perform the above functions without overlaying the map; and (e) allow a polling mode in each cell phone that permits a user to contact other cell phone users that have a common interest or relationship with a password and identifier for communication and to establish quickly a temporary ad hoc network especially in an emergency. A communication Server acts as a forwarder for IP communications between any combination of cell phone/PDA users and/or PC based users. Network participant location, identity and status messages are sent to the Server by each user. Network participant entered tracks are also sent to the Server. Because this network participant location and track data is of interest to all the network participants, the Server forwards the data received from one participant to all other participants, causing their displays automatically, without any operator action, to display the received information, thus providing the information necessary for all network participants to know the identity, location and status of all other network participants. The Server also acts as a forwarder of data addressed from one participant to one or more addressed participants, thus permitting the transmission of free text, preformatted messages, photographs, video, Email and Uniform Resource Locator (URL) data from one network participant to other selected network participants. The above functions can also be accomplished using peer to peer WiFi, WiMax or other peer to peer communications. However, for use with cellular communications and to assure the level of security that cell phone companies require, a centralized static IP routable Server is used. The IP Server also fills another role of being a database from which data can be requested by network participants (i.e. maps, satellite images, and the like) or can be pushed to network participants (i.e. symbology and soft switch changes, and the like). The Server is used to establish an ad hoc network within certain groups using an ad hoc event name and password. This invention provides a method and a system establishing an ad hoc password protected digital and voice network that can be temporarily set up or longer lasting in nature. The invention described herein allows users to rapidly coordinate their activities without having to pre-enter data into a web or identify others by name, E mail addresses or phone numbers. Essentially the users that establish the ad hoc and password protected digital and voice networks are required to enter the Server's IP address and an ad hoc event name and a password. In the case of military and first responders, the name of the user's unit may also be used. This action causes the specific PDA or PC of the user to commence reporting directly to the Server's IP address. Once the Server receives the initial IP message from the user's PDA or PC, the server can commence to exchange data with the user's PDA or PC. The initial IP message may also contain additional data such as a license number and, if desired, a phone number manually entered or automatically acquired by the ACS. The IP address of the PDA and PC unit sending the initial IP message is stored by the Server. The Server then responds with a message notifying the user that his PC/PDA is connected to the Server. The user PDA/PC then reports its GPS location and other status information directly to the Server. This information is retained by the Server even when there are no other devices initially communicating with the Server. When the other user's devices sign on to the Server with the same ad hoc event name and password, the Server software then recognizes all the users and stores their IP addresses in the Server. Thus the Server has all the users IP addresses stored and can pass location and status information among the ad hoc network participants even though the network participants have not entered other network participants' names, phone numbers or email addresses. Thus one of the purposes of the invention is to allow an ad hoc network to be formed on a temporary basis in a rapid manner. When using the PTT feature, the ACS can enable the network participant to: 1. PTT with all that are in the ad hoc digital network, or 2. PTT with select specific network participants, by touching their symbols) and then selecting PTT soft switch or 3. Specify a group of the network participants by assigning their symbols or unit names to a list of network participants and then associating the list with a soft switch whose function is to enable the operator to have PTT communications with all in the list. Since only one person is transmitting on a PTT voice network at any given time, the receiving network participant's ACS can relate the PTT IP address to the IP address of the unit transmitting his identification on the digital ad hoc network. This information can then be used by the other PTT networked participant's ACS to: 1. flash the transmitting unit's name on their PDA/PC screens or 2. if a photograph has been attached to the ad hoc digital network symbol of the PTT transmitting person, to flash that photograph on the receiving unit's PDA/PC display. It is an object of this invention to enable each participant in the communication network to join other ad hoc network participants to form an ad hoc digital and voice network with other cell phone users rapidly for coordinating member activities. In accordance with these and other objects which will become apparent hereinafter, the instant invention will now be described with particular reference to the accompanying drawings. | H04M172572 | 20171110 | 20180531 | 59168.0 | H04M1725 | 3 | OBAYANJU, OMONIYI | METHOD TO PROVIDE AD HOC AND PASSWORD PROTECTED DIGITAL AND VOICE NETWORKS | UNDISCOUNTED | 1 | CONT-ACCEPTED | H04M | 2,017 |
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15,811,360 | PENDING | MOISTURE-ERASABLE NOTE TAKING SYSTEM | A method of reusing a notebook provides a notebook having a synthetic-paper page. The method also provides a thermochromic ink pen which, when used to write on the synthetic paper page, leaves thermochromic ink markings. The method further provides a moisture carrier configured to have a liquid diffused therein. The moisture carrier is configured to erase the thermochromic ink markings from the synthetic-paper page by contacting the thermochromic ink markings when the moisture carrier is moist. The method then writes with thermochromic ink on at least a portion of the synthetic-paper page. Liquid is diffused in the moisture carrier, and the portion of the synthetic-paper page having the thermochromic ink is wiped with the moist moisture carrier, such that the thermochromic ink is erased from the synthetic-paper page. | 1. A method of reusing a notebook comprising: providing: a notebook having a synthetic-paper page, a thermochromic ink pen which, when used to write on the synthetic paper page, leaves thermochromic ink markings, and a moisture carrier configured to have a liquid diffused therein, the moisture carrier further configured to erase the thermochromic ink markings from the synthetic-paper page by contacting the thermochromic ink markings when it is moist; writing with thermochromic ink on at least a portion of the synthetic-paper page; and wiping the portion of the synthetic-paper page having the thermochromic ink with the moist moisture carrier such that the thermochromic ink is erased from the synthetic-paper page. 2. The method as defined by claim 1, wherein the thermochromic ink pen is a FRIXION™ thermochromic ink pen. 3. The method as defined by claim 1, wherein the synthetic-paper page has a base layer and a surface layer disposed over the base layer, and wherein the liquid diffused in the moisture carrier does not damage the surface layer of the synthetic-paper page when the synthetic-paper page is wiped to erase the thermochromic ink. 4. The method as defined by claim 1, wherein the synthetic-paper page having a base layer and a surface layer disposed over the base layer, and wherein the surface layer is formed from calcium carbonate. 5. The method as defined by claim 1, wherein the liquid is water. 6. The method as defined by claim 1, wherein the moisture carrier is a cloth or a baby-wipe. 7. A system comprising: a notebook having a synthetic-paper page; and a thermochromic ink pen which, when used to write on the synthetic-paper page, leaves thermochromic ink markings. 8. The system as defined by claim 7, further comprising a moisture carrier configured to have a liquid diffused therein, the moisture carrier further configured to erase the thermochromic ink markings from the synthetic-paper page by contacting the thermochromic ink markings when the liquid is diffused therein. 9. The system as defined by claim 7, wherein the moisture carrier is a cloth, a napkin, a sponge, a paper towel, or a wipe. 10. The system as defined by claim 7, wherein the liquid is water. 11. The system as defined by claim 7, wherein the liquid is alcohol. 12. The system as defined by claim 7, wherein the synthetic-paper page has a base layer and a surface finish layer thereon, and erasing the thermochromic ink markings does not remove the surface finish layer. 13. The system as defined by claim 1, wherein the moisture carrier is a pre-moistened moisture carrier. 14. The system as defined by claim 1, wherein the moisture carrier is a dry moisture carrier. 15. A method of reusing a notebook having a synthetic-paper page, the method comprising: providing a notebook having a synthetic-paper page including thermochromic ink markings on at least a portion of the synthetic-paper page; is and wiping the portion of the synthetic-paper page having the thermochromic ink with a moistened moisture carrier such that the thermochromic ink is erased from the synthetic-paper page. 16. The method as defined by claim 15, wherein providing a notebook having a synthetic-paper page including thermochromic ink markings on at least a portion of the synthetic-paper page comprises: writing with thermochromic ink on at least a portion of the synthetic-paper page. 17. A reusable notebook for use with heat-erasable ink, the reusable notebook comprising: a binding configured to hold a plurality of pages; at least one cover; and a plurality of pages that are moisture-resistant, the pages configured to be written on with heat-erasable ink that is moisture-erasable. 18. The notebook as defined by claim 17 wherein the pages are Polyart®, Appvion Appleton Digital™, Parax™ stone paper, RockStock™ stone paper, Nekoosa™ XM, Nekoosa™ OM, HopSyn DL grade®, and/or Yupo® FPG 80. | PRIORITY This patent application claims the benefit of provisional U.S. patent application No. 62/421,335, filed Nov. 13, 2016, entitled, “Moisture Activated Erasable Pen and Paper System,” and naming Joe Lemay and Jake Epstein as inventors, the disclosure of which is incorporated herein, in its entirety, by reference. FIELD OF THE INVENTION The invention generally relates to a system for note taking and, more particularly, the invention relates to erasing notes with liquid. BACKGROUND OF THE INVENTION Notes are frequently taken using classic pen and paper systems. Students, for example, generally purchase new notebooks every new school year for various subject matters, and/or when a notebook is filled up. Pages of notebooks may go unused, and thus, trees and other natural resources are wasted. Attempts have been made to migrate to other note taking formats, such as digital tablet devices and reusable writing surfaces. Many users prefer the feel of writing with a writing instrument on paper, and thus, do not adjust well to the feel of taking notes with digital devices. Furthermore, many classroom environments do not allow the use of electronic devices. Additionally, reusable writing surfaces, such as whiteboards, may wipe off easily, causing difficulty with note storage and portability. Thermochromic ink pens can be used to write on paper and can be effectively erased. Thermochromic ink typically changes from opaque (i.e., color) to transparent when heat is applied (e.g., due to friction from an eraser being rubbed on the ink, or when the paper with thermochromic ink is placed in an oven or microwave oven). One example of a thermochromic ink pen is the FRIXION™ thermochromic ink pen manufactured by Pilot Corporation. A description of the FRIXION™ thermochromic ink pen can be found in Miki, Masuda, The Science Behind Frixion Erasable Pens, http://www.nippon.com/en/features/c00520/ dated Aug. 24, 2016. Some exemplary thermochromic inks are described in U.S. Pat. No. 4,028,118, U.S. Pat. No. 4,720,301, U.S. Pat. No. 4,720,301, and US Patent No. 8,616,797. Synthetic paper generally contains no wood pulp or natural fibers (as found in standard paper), and is commonly formed from polypropylene resin along with inorganic fibers, although many different types of synthetic papers were known (e.g., including different types of synthetic papers referred to as stone paper). Synthetic paper frequently has a base layer covered with a surface layer. Among other things, the base layer of synthetic paper may be formed, for example, polyethylene, polypropylene, high-density polyethylene, polyester, and other plastics. The surface layer adds a bright surface finish, high opacity and smooth texture. Synthetic-paper is also more durable that traditional paper. Many synthetic papers are tear-resistant, wear-resistant, chemical-resistant, heat-resistant, and/or grease-resistant relative to traditional paper. This makes synthetic paper a good option for use in environments where the notebook could be damaged. For example, when used with many traditional pens and markers, notes and/or publications written on synthetic paper may be read in the bath, pool, spa, shower, or while boating, fishing, skiing, snowmobiling or scuba diving. SUMMARY OF VARIOUS EMBODIMENTS In accordance with one embodiment of the invention, a method of reusing a notebook provides a notebook having a synthetic-paper page. The method also provides a thermochromic ink pen which, when used to write on the synthetic paper page, leaves thermochromic ink markings. The method further provides a moisture carrier configured to have a liquid diffused therein. The moisture carrier is configured to erase the thermochromic ink markings from the synthetic-paper page by contacting the thermochromic ink markings when the moisture carrier is moist. The method then writes with thermochromic ink on at least a portion of the synthetic-paper page. Liquid is diffused in the moisture carrier, and the portion of the synthetic-paper page having the thermochromic ink is wiped with the moist moisture carrier, such that the thermochromic ink is erased from the synthetic-paper page. Among other pens, the thermochromic ink pen may be a FRIXION™ thermochromic ink pen. Among other types of synthetic paper, the synthetic paper may be Polyart®, Appvion Appleton Digital™, Parax™ stone paper, RockStock™ stone paper, Nekoosa™ XM, Nekoosa™ OM, HopSyn DL grade®, and/or Yupo® FPG 80. The synthetic-paper page may have a base layer and a surface layer disposed over the base layer. Among other things, the moisture carrier may be a cloth, a sponge, a napkin, a paper towel, and/or a baby-wipe. The liquid diffused in the moisture carrier may be water and/or isopropyl alcohol. In some embodiments, the liquid diffused in the moisture carrier does not damage the surface layer of the synthetic-paper page when the synthetic-paper page is wiped to erase the thermochromic ink. In some embodiments, the surface layer is formed from calcium carbonate. In accordance with an embodiment of the invention, a system includes a notebook having a synthetic-paper page and a thermochromic ink pen. The thermochromic ink pen may be used to write on the synthetic-paper page. Writing on the page leaves thermochromic ink markings. In some embodiments, the system includes a moisture carrier configured to have a liquid diffused therein. The moisture carrier erases the thermochromic ink markings from the synthetic-paper page by contacting the thermochromic ink markings when the liquid is diffused in the moisture carrier. In accordance with another embodiment of the invention, a method of reusing a notebook having a synthetic-paper page provides a notebook having a synthetic-paper page including thermochromic ink markings on at least a portion of the synthetic-paper page. The method also wipes the portion of the synthetic-paper page having the thermochromic ink with a moistened moisture carrier, such that the thermochromic ink is erased from the synthetic-paper page. In some embodiments, the moisture carrier is a pre-moistened moisture carrier, for example, a wet-wipe or an isopropyl alcohol wipe. In some other embodiments, the moisture carrier is provided as a dry moisture carrier, for example, a dry cloth or paper towel. In accordance with yet another illustrative embodiment, a method reuses a notebook having a synthetic-paper page. The method provides a notebook having a synthetic-paper page, the page having thermochromic ink markings on at least a portion of the synthetic-paper page. The portion of the synthetic-paper page having thermochromic ink is wiped with a moistened moisture carrier, such that the thermochromic ink is erased from the synthetic-paper page. In some embodiments, the method writes with thermochromic ink on at least a portion of the synthetic paper page. In accordance with yet another illustrative embodiment, a reusable notebook for use with heat-erasable ink includes a binding configured to hold a plurality of pages. The notebook also includes at least one cover, and a plurality of pages that are moisture resistant. The pages are configured to be written on with heat-erasable ink that is moisture-erasable. In some embodiments, the pages are Polyart®, Appvion Appleton Digital™, Parax™ stone paper, RockStock™ stone paper, Nekoosa™ XM, Nekoosa™ OM, HopSyn DL grade®, and/or Yupo® FPG 8 paper pages. Illustrative embodiments of the invention are implemented as a computer program product having a computer usable medium with computer readable program code thereon. The computer readable code may be read and utilized by a computer system in accordance with conventional processes. BRIEF DESCRIPTION OF THE DRAWINGS Those skilled in the art should more fully appreciate advantages of various embodiments of the invention from the following “Description of Illustrative Embodiments,” discussed with reference to the drawings summarized immediately below. FIG. 1 schematically shows an erasable writing system in accordance with illustrative embodiments of the invention. FIG. 2 is a picture of the notebook with markings from a variety of different writing utensils on the synthetic-paper page in accordance with illustrative embodiments of the invention. FIG. 3 is a picture of the notebook of FIG. 2 after the markings were dry rubbed in accordance with illustrative embodiments of the invention. FIG. 4 is a picture of the notebook of FIG. 3 after the markings were wiped with water in accordance with illustrative embodiments of the invention. FIGS. 5A-5B are pictures of the notebook of FIG. 4 before and after the markings were wiped with 70% isopropyl alcohol, respectively, in accordance with illustrative embodiments of the invention. FIGS. 6A-6B are before and after pictures, respectively, of markings erased with water in accordance with illustrative embodiments of the invention. FIG. 6C is a close-up picture of FIG. 6B showing imprints left by the thermochromic ink pen in accordance with illustrative embodiments of the invention. FIG. 7A is a picture of FIG. 6C erased with isopropyl alcohol in accordance with illustrative embodiment of the invention. FIG. 7B is a close up of FIG. 7A after the page was scrubbed vigorously with an isopropyl alcohol wipe. FIG. 8 schematically shows a process of using the notebook in accordance with illustrative embodiments of the invention. DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS As discussed above, thermochromic ink pens are generally used to write indelibly on paper, but with the ability to effectively erase thermochromic ink markings through the application of heat that changes the ink from opaque to transparent. Also as discussed above, synthetic paper can be used to protect writings in harsh environments such as from moisture. In illustrative embodiments, a system provides a notebook with synthetic-paper pages and a thermochromic ink pen. A user writes on the pages of the notebook with the thermochromic ink pen, such as, for example, a FRIXION™ thermochromic ink pen manufactured by Pilot Corporation. When the user has finished taking notes and wishes to erase them, the user may erase the notes by wiping the notes off of the page with a moisture carrier (e.g., a cloth, sponge, or paper towel) moistened with water or other appropriate liquid (e.g., alcohol). Details of illustrative embodiments are discussed below. FIG. 1 schematically shows an erasable writing system in accordance with illustrative embodiments of the invention. In accordance with one embodiment of the invention, the system includes a notebook 100 having synthetic-paper pages 104. Like many conventional notebooks, the notebook 100 may have a binding 102 that holds together the plurality of pages 104 and one or more covers 106. A user writes in the notebook 100 with a thermochromic ink writing utensil 110 (referred to generically herein as a “pen”). FIG. 1 shows the notebook 100 with notes written in thermochromic ink 108. After the user has written in the notebook 100, the user may erase the ink 108 using a liquid-diffused moisture carrier 120 (e.g., a wet cloth 120). The inventors discovered and were surprised to find that moisture can erase thermochromic ink 108 when it is on synthetic paper 104 (e.g., using a wet cloth). This surprise was further enhanced given the durability and moisture-rich environments in which synthetic paper 104 may be used along with the seeming indelibility of thermochromic inks (in the absence of heat). It should be noted that the inventors are not privy to the actual chemical composition of the inks in the FRIXION™ thermochromic ink pen and therefore cannot describe, for example, why the ink is seemingly indelible on traditional paper but moisture-erasable or moisture-removable on synthetic paper. The inventors suspect, but have not confirmed, that the mechanism of action for this erasure effect is because thermochromic ink is not absorbed into the synthetic paper 104. However, it should be understood that illustrative embodiments of the invention are intended to cover whatever mode of action is actually in use, and are not limited to the hypothesized mechanism of action. It is hypothesized, as described in provisional application 62/421,335, that the thermochromic ink's pigment particles are sufficiently larger than any pores or imperfections on the surface of the synthetic paper. Thus, the ink pigment particles do not get stuck inside the pores or imperfections of the synthetic paper. In other words, the ink is not absorbed into the paper. Once the solvent of the ink evaporates, the thermochromic pigment is stuck to the surface of the page, but not trapped inside the pores of the page. The dry ink may appear to be permanently bonded to the synthetic page, but once the solvent, such as water is reintroduced, the ink is readily wiped away from the surface of the page. Accordingly, in some embodiments, the size of the thermochromic ink molecules and/or the microcapsule that encapsulates the thermochromic ink is larger than the pore size of the synthetic paper. Tests were performed to confirm that the erasure effect was not caused by a change of temperature of the ink 108. Furthermore, the inventors determined that the thermochromic ink 108 is not completely moisture-erasable from cellulose-based paper. Conversely, non-thermochromic ink (e.g., tested from gel pens, ballpoint pens, dry-erase markers) is not completely and clearly moisture-erasable from synthetic paper. FIG. 2 shows a picture of the notebook 100 with markings 111-119 from a variety of different writing utensils on the synthetic-paper page 104 in accordance with illustrative embodiments of the invention. Tests were performed with a number of writing utensils for comparison: Pilot Frixion thermochromic ink pen 111, a UniBall Signo 207 pen 112, an Expo dry erase marker 113, and Expo Vis-à-Vis wet-erase marker 114, a BiC brite liner highlighter 115, a Sharpie permanent marker 116, a Paper Mate felt tip pen 117, a UniBall micro 0.5 mm ink pen 118, and a BiC XtraLife ball pen 119. FIG. 2 shows the notebook 100 after the markings 111-119 were made on the page 104. FIG. 3 shows a picture of the notebook 100 of FIG. 2 after the markings 111-119 were dry rubbed (e.g., running a finger and/or a dry napkin over the markings 111-119). Prior to dry rubbing the markings 111-119, they were allowed to dry for at least three minutes. The various markings 111-119 were dry rubbed to determine whether they would erase or smudge 122. Both the UniBall Signo 207 marking 112 and the BiC XtraLife ball pen marking 119 showed minimal signs of smudging 122 when compared to the original marking. However, none of the markings erased from the synthetic paper 104, even the Expo dry erase marking 113. FIG. 4 shows a picture of the notebook 100 of FIG. 3 after the markings 111-119 were wiped with water. Specifically, a soaked wet napkin was repeatedly run across all of the markings 111-119. As shown in the figure, only the thermochromic ink 111 was erased. The Expo Vis-à-Vis wet erase markings 114 were lightened, but produced considerable smudging 122. The lack of erasure and smudging 122 are undesirable properties for a reusable note taking system. FIGS. 5A-5B show pictures of the notebook of FIG. 4 before and after the markings 111-119 were wiped with 70% isopropyl alcohol, respectively. FIG. 5A is a picture of the notebook of FIG. 4, except that thermochromic ink marking 111 was redrawn. Otherwise, the other markings 112-119 were left unchanged from FIG. 4. FIG. 5B shows the notebook of FIG. 5A after the page has been wiped with a 70% isopropyl alcohol wipe. As can be seen, the thermochromic ink marking 111, the BiC brite liner highlighter 115 marking, and the BiC XtraLife ball pen marking 119 were erased. Both the Sharpie permanent marker markings 116 and the BiC XtraLife pen markings 119 left behind smudging 122 after being wiped with the alcohol wipes. Thus, only the thermochromic ink marking 111 and the BiC brite liner highlighter markings 115 erased without smudging. It should be noted that the thermochromic ink marking 111 was readily erasable (generally a single swipe with the moisture carrier is necessary), while the highlighter marking 115 required the application of considerable force and multiple swipes to erase significantly. FIGS. 6A-6B are before and after pictures, respectively, of markings 111, 115, and 119 erased with water. As shown in FIG. 6A, the paper 104 has thermochromic ink markings 111, BiC brite liner highlighter markings 115, and BiC XtraLife pen markings 119. All three of these markings 111, 115, and 119 showed varying degrees of erasure with isopropyl alcohol wipes (see FIG. 5B). However, in FIG. 6B, it is clear that only the thermochromic ink markings 111 are erased with water. FIG. 6C is a close up picture of FIG. 6B. Although the markings 111 were erased, their imprint 124 can still be seen on the page 104. As defined in this application, a marking is considered to be “erased” even if it leaves behind an imprint 124 in the page 104. FIG. 7A is a picture of FIG. 6C erased with isopropyl alcohol. The figure shows that the BiC XtraLife pen markings 119 leave behind a smudge 122 that is unsuitable for reusable notebooks 100. A slight shadow 126 is left behind from the erasure of the highlighter marking 115. The thermochromic ink markings 111 were entirely erased. FIG. 7B is a close up of FIG. 7A after the page was scrubbed vigorously with an isopropyl alcohol wipe. Some of the dot-grid pattern on the page 104 was removed by vigorous rubbing with isopropyl alcohol wipes, exposing the base layer 126. In illustrative embodiments, erasing markings 111-119 does not remove the surface layer of the synthetic-paper (e.g., the layer containing the dot-grid pattern). In other words, in some embodiments, the base layer 126 is not exposed by the erasure process. FIG. 8 schematically shows a process of using the notebook in accordance with illustrative embodiments of the invention. The process begins with the presentation of blank pages 801. As mentioned above, pages may be referred to as paper without any intent to limit illustrative embodiments of the invention. The pages 104 can be any synthetic paper and/or waterproof paper from which thermochromic ink can be erased using a moistened moisture carrier as discussed herein. In illustrative embodiments, the synthetic pages 104 are Polyart®, Appvion Appleton Digital™, Parax™ stone paper, RockStock™ stone paper, Nekoosa™ XM, Nekoosa™ OM, HopSyn DL grade®, and/or Yupo® FPG 80. The pages 104 may be water and/or moisture resistant (e.g., Nekoosa™ XM). Like many synthetic-paper pages, illustrative embodiments may have a base layer (e.g., comprising single-layered or multi-layered synthetic resin and/or plastic such as polypropylene) and an ink receptive layer (e.g., ground stone/calcium carbonate, clay, etc.), which is generally waterproof and helps the ink adhere to the page. Content is written or printed on synthetic-paper with thermochromic ink at step 802. The thermochromic ink may include a Leuco dye that can change between colored and colorless forms. The Leuco dye can be Leuco 1, 2, 3, and/or 4. Furthermore, illustrative embodiments include color developer and color change temperature regulator in the thermochromic ink. In some embodiments, the thermochromic ink may be microencapsulated. Illustrative embodiments used Pilot FriXion ball-point gel pens, Pilot FriXion felt-tipped pens and markers, and/or the UniBall phantom. As described above, the paper may be part of a bound notebook or the paper may be separate and loose. The marking is exposed to moisture 805 to return it to its original state so content can be written or printed on it again, which will be described further below. The process can be repeated multiple times. As expressed above, different moisture-erasing techniques can be employed to erase the marking. Optionally, at step 803, the contents written on the originally blank paper can be saved with a digital scanner prior to heating the paper and clearing the contents. After the user writes on the paper with thermochromic ink, the paper can be scanned by a digital scanning process or by taking a digital photograph and performing digital signal processing on the digital photograph to capture and retain the content in a suitable format. For example; the digital content may be saved in a format such that OCR (optical character recognition) may occur for the digital content. Furthermore, at step 804, the digital photographs or scan may optionally undergo enhancement in a computer process for enhancing each image. These processes are described in U.S. patent application Ser. No. 15/211,462, filed Jul. 15, 2016, and in U.S. Provisional Patent Application No. 62/193,915, filed Jul. 17, 2015, herein incorporated by reference in their entireties. After the contents of the paper have been digitized and saved to an appropriate storage location, the markings can be erased. The next step 805 in the process moisture erases the marking. As described above, in some embodiments, the notebook is wiped with a moisture carrier (e.g., a moist cloth, wet napkin, baby-wipe, etc.). In some embodiments, in order to reuse the reusable moisture-erasable notebook, the one or more pages 104 are water-proof, water-resistant, moisture-proof, and/or moisture-resistant (such as with previously described pages 104 Nekoosa™ XM, Nekoosa™ OM, etc.). A person of skill in the art understands that the different types of pages 104 described above are water-proof, water-resistant, moisture-proof and/or moisture-resistant. Additionally, or alternatively, the notebook may be heated to erase the thermochromic ink (e.g., microwaved). It should be recognized that a notebook and thermochromic pen with instructions, or with the intent, for using the pen with the notebook and erasing the notebook using a moisture carrier may be sold together in the form of a packaged kit. Illustrative embodiments of the present invention may be described, without limitation, by the above description. While these embodiments have been described in the clauses by process steps, an apparatus comprising a computer with associated display capable of executing the process steps in the clauses above is also included in the present invention. Likewise, a computer program product including computer executable instructions for executing the process steps in the clauses and stored on a computer readable medium is included within the present invention. Advantages of the invention include that users may have the traditional feel of writing in a notebook without requiring the purchase of multiple notebooks. Furthermore, this system is environmentally-sustainable and does not require the destruction of trees. Although the above discussion discloses various exemplary embodiments of the invention, it should be apparent that those skilled in the art can make various modifications that will achieve some of the advantages of the invention without departing from the true scope of the invention. | <SOH> BACKGROUND OF THE INVENTION <EOH>Notes are frequently taken using classic pen and paper systems. Students, for example, generally purchase new notebooks every new school year for various subject matters, and/or when a notebook is filled up. Pages of notebooks may go unused, and thus, trees and other natural resources are wasted. Attempts have been made to migrate to other note taking formats, such as digital tablet devices and reusable writing surfaces. Many users prefer the feel of writing with a writing instrument on paper, and thus, do not adjust well to the feel of taking notes with digital devices. Furthermore, many classroom environments do not allow the use of electronic devices. Additionally, reusable writing surfaces, such as whiteboards, may wipe off easily, causing difficulty with note storage and portability. Thermochromic ink pens can be used to write on paper and can be effectively erased. Thermochromic ink typically changes from opaque (i.e., color) to transparent when heat is applied (e.g., due to friction from an eraser being rubbed on the ink, or when the paper with thermochromic ink is placed in an oven or microwave oven). One example of a thermochromic ink pen is the FRIXION™ thermochromic ink pen manufactured by Pilot Corporation. A description of the FRIXION™ thermochromic ink pen can be found in Miki, Masuda, The Science Behind Frixion Erasable Pens, http://www.nippon.com/en/features/c00520/ dated Aug. 24, 2016. Some exemplary thermochromic inks are described in U.S. Pat. No. 4,028,118, U.S. Pat. No. 4,720,301, U.S. Pat. No. 4,720,301, and US Patent No. 8,616,797. Synthetic paper generally contains no wood pulp or natural fibers (as found in standard paper), and is commonly formed from polypropylene resin along with inorganic fibers, although many different types of synthetic papers were known (e.g., including different types of synthetic papers referred to as stone paper). Synthetic paper frequently has a base layer covered with a surface layer. Among other things, the base layer of synthetic paper may be formed, for example, polyethylene, polypropylene, high-density polyethylene, polyester, and other plastics. The surface layer adds a bright surface finish, high opacity and smooth texture. Synthetic-paper is also more durable that traditional paper. Many synthetic papers are tear-resistant, wear-resistant, chemical-resistant, heat-resistant, and/or grease-resistant relative to traditional paper. This makes synthetic paper a good option for use in environments where the notebook could be damaged. For example, when used with many traditional pens and markers, notes and/or publications written on synthetic paper may be read in the bath, pool, spa, shower, or while boating, fishing, skiing, snowmobiling or scuba diving. | <SOH> SUMMARY OF VARIOUS EMBODIMENTS <EOH>In accordance with one embodiment of the invention, a method of reusing a notebook provides a notebook having a synthetic-paper page. The method also provides a thermochromic ink pen which, when used to write on the synthetic paper page, leaves thermochromic ink markings. The method further provides a moisture carrier configured to have a liquid diffused therein. The moisture carrier is configured to erase the thermochromic ink markings from the synthetic-paper page by contacting the thermochromic ink markings when the moisture carrier is moist. The method then writes with thermochromic ink on at least a portion of the synthetic-paper page. Liquid is diffused in the moisture carrier, and the portion of the synthetic-paper page having the thermochromic ink is wiped with the moist moisture carrier, such that the thermochromic ink is erased from the synthetic-paper page. Among other pens, the thermochromic ink pen may be a FRIXION™ thermochromic ink pen. Among other types of synthetic paper, the synthetic paper may be Polyart®, Appvion Appleton Digital™, Parax™ stone paper, RockStock™ stone paper, Nekoosa™ XM, Nekoosa™ OM, HopSyn DL grade®, and/or Yupo® FPG 80. The synthetic-paper page may have a base layer and a surface layer disposed over the base layer. Among other things, the moisture carrier may be a cloth, a sponge, a napkin, a paper towel, and/or a baby-wipe. The liquid diffused in the moisture carrier may be water and/or isopropyl alcohol. In some embodiments, the liquid diffused in the moisture carrier does not damage the surface layer of the synthetic-paper page when the synthetic-paper page is wiped to erase the thermochromic ink. In some embodiments, the surface layer is formed from calcium carbonate. In accordance with an embodiment of the invention, a system includes a notebook having a synthetic-paper page and a thermochromic ink pen. The thermochromic ink pen may be used to write on the synthetic-paper page. Writing on the page leaves thermochromic ink markings. In some embodiments, the system includes a moisture carrier configured to have a liquid diffused therein. The moisture carrier erases the thermochromic ink markings from the synthetic-paper page by contacting the thermochromic ink markings when the liquid is diffused in the moisture carrier. In accordance with another embodiment of the invention, a method of reusing a notebook having a synthetic-paper page provides a notebook having a synthetic-paper page including thermochromic ink markings on at least a portion of the synthetic-paper page. The method also wipes the portion of the synthetic-paper page having the thermochromic ink with a moistened moisture carrier, such that the thermochromic ink is erased from the synthetic-paper page. In some embodiments, the moisture carrier is a pre-moistened moisture carrier, for example, a wet-wipe or an isopropyl alcohol wipe. In some other embodiments, the moisture carrier is provided as a dry moisture carrier, for example, a dry cloth or paper towel. In accordance with yet another illustrative embodiment, a method reuses a notebook having a synthetic-paper page. The method provides a notebook having a synthetic-paper page, the page having thermochromic ink markings on at least a portion of the synthetic-paper page. The portion of the synthetic-paper page having thermochromic ink is wiped with a moistened moisture carrier, such that the thermochromic ink is erased from the synthetic-paper page. In some embodiments, the method writes with thermochromic ink on at least a portion of the synthetic paper page. In accordance with yet another illustrative embodiment, a reusable notebook for use with heat-erasable ink includes a binding configured to hold a plurality of pages. The notebook also includes at least one cover, and a plurality of pages that are moisture resistant. The pages are configured to be written on with heat-erasable ink that is moisture-erasable. In some embodiments, the pages are Polyart®, Appvion Appleton Digital™, Parax™ stone paper, RockStock™ stone paper, Nekoosa™ XM, Nekoosa™ OM, HopSyn DL grade®, and/or Yupo® FPG 8 paper pages. Illustrative embodiments of the invention are implemented as a computer program product having a computer usable medium with computer readable program code thereon. The computer readable code may be read and utilized by a computer system in accordance with conventional processes. | B43L100 | 20171113 | 20180517 | 64829.0 | B43L100 | 1 | FERNSTROM, KURT | MOISTURE-ERASABLE NOTE TAKING SYSTEM | SMALL | 0 | ACCEPTED | B43L | 2,017 |
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15,813,096 | PENDING | VAPORIZATION DEVICE SYSTEMS AND METHODS | Vaporization devices and methods of operating them. In particular, described herein are vaporizer cartridges for controlling the power applied to a resistive heater. | 1.-20. (canceled) 21. An apparatus comprising: a cartridge having a non-cylindrical shape and comprising: a heater chamber having a first side and a second side opposite the first side; a first heater contact comprising a first exposed heater contact tab and a first fixation site, the first fixation site disposed proximate to the first side; a second heater contact comprising a second exposed heater contact tab and a second fixation site, the second fixation site disposed proximate to the second side; a wick; and a resistive heating element in contact with the wick, the resistive heating element attached to the first fixation site and the second fixation site, wherein the wick and the resistive heating element are suspended between the first fixation site and the second fixation site, and wherein the resistive heating element is configured to generate an aerosol from a vaporizable material; and a body having a non-cylindrical shape and comprising: a cartridge receptacle configured to insertably receive the cartridge, the heater chamber disposed within the cartridge receptacle when the cartridge is insertably received within the cartridge receptacle; a first receptacle contact positioned to electrically couple with one of the first exposed heater contact tab and the second exposed heater contact tab, when the cartridge is insertably received within the cartridge receptacle; and a second receptacle contact positioned to electrically couple with the other of the first exposed heater contact tab and the second exposed heater contact tab, when the cartridge is insertably received within the cartridge receptacle. 22. The apparatus of claim 21, wherein the first exposed heater contact tab comprises a first surface area disposed at a third side of the cartridge, wherein the second exposed heater contact tab comprises a second surface area disposed at the third side, and wherein the third side is substantially perpendicular to the first side of the cartridge and substantially perpendicular the second side of the cartridge. 23. The apparatus of claim 22, wherein the first surface area and the second surface area are disposed in a plane parallel to the third side of the cartridge. 24. The apparatus of claim 21, wherein the cartridge further comprises: a plastic enclosure configured to receive and further define the heater chamber, the first heater contact further comprising a first surface disposed to further define the heater chamber, the first side comprising the first surface, the second heater contact further comprising a second surface disposed to further define the heater chamber, the second side comprising the second surface. 25. The apparatus of claim 24, wherein the plastic enclosure comprises: a first opening, the first heater contact extending through the first opening, the first exposed heater contact tab disposed outside of the heater chamber, the first fixation site disposed within the heater chamber and proximate to the first surface; and a second opening, the second heater contact extending through the second opening, the second exposed heater contact tab disposed outside of the heater chamber, the second fixation site disposed within the heater chamber and proximate to the second surface. 26. The apparatus of claim 24, wherein the resistive heating element comprises: a coil wrapped around the wick; a first end extending from the coil, the first end attached to the first fixation site; and a second end extending from the coil, the second end attached to the second fixation site. 27. The apparatus of claim 26, wherein at least a portion of the first end is disposed between the first surface of the first heater contact and the first side of the heater chamber, and wherein at least a portion of the second end is disposed between the second surface of the second heater contact and the second side of the heater chamber. 28. The apparatus of claim 26, wherein the first end is attached to the first fixation site by tensile force, and wherein the second end is attached to the second fixation site by tensile force. 29. The apparatus of claim 24, wherein the first surface and the second surface define a volume therebetween, at least a portion of the wick and at least a portion of the resistive heating element disposed within the volume. 30. The apparatus of claim 24, wherein the cartridge further comprises: a first shape formed from electrically conductive material, the first shape comprising the first heater contact; and a second shape formed from electrically conductive material, the second shape comprising the second heater contact, the first shape substantially the same as the second shape. 31. The apparatus of claim 21, wherein the first heater contact and the second heater contact are configured to complete an electrical circuit with the first receptacle contact and the second receptacle contact to provide power to the resistive heating element. 32. The apparatus of claim 21, wherein the wick is configured to contact the vaporizable material and draw the vaporizable material towards the resistive heating element. 33. The apparatus of claim 21, wherein the cartridge has a proximal end and a distal end opposite the proximal end, and wherein the cartridge further comprises: a mouthpiece at the proximal end, the first heater contact and the second heater contact positioned proximate to the distal end. 34. The apparatus of claim 33, wherein the first exposed heater contact tab and the second exposed heater contact tab are disposed in a plane parallel to the proximal end and parallel to the distal end. 35. The apparatus of claim 33, wherein the mouthpiece comprises a condensation chamber, and wherein the mouthpiece further comprises an aerosol outlet in fluid communication with the condensation chamber. 36. The apparatus of claim 33, wherein the cartridge further comprises: a storage compartment configured to hold the vaporizable material, the storage compartment comprising four exterior walls between the distal end and the proximal end. 37. The apparatus of claim 36, wherein the four exterior walls are disposed to form a generally rectangular shape. 38. The apparatus of claim 36, wherein the mouthpiece is opaque and the vaporizable material is visible through a surface of the storage compartment. 39. The apparatus of claim 21, wherein the first heater contact and the second heater contact comprise a heat sink configured to absorb and dissipate heat produced by the resistive heating element. 40. A cartridge for insertion into a receptacle of a vaporizer device, the cartridge having a non-cylindrical shape and comprising: a heater chamber having a first side and a second side opposite the first side, the heater chamber configured to be disposed within the receptacle when the cartridge is inserted into the cartridge receptacle; a first heater contact comprising a first exposed heater contact tab and a first fixation site, the first fixation site disposed proximate to the first side, the first exposed heater contact tab positioned and configured to electrically couple with one of a first receptacle contact within the receptacle and a second receptacle contact within the receptacle, when the cartridge is inserted into the receptacle; a second heater contact comprising a second exposed heater contact tab and a second fixation site, the second fixation site disposed proximate to the second side, the second exposed heater contact tab positioned and configured to electrically couple with the other of the first receptacle contact and the second receptacle contact, when the cartridge is inserted into the receptacle; a wick; and a resistive heating element in contact with the wick, the resistive heating element attached to the first fixation site and the second fixation site, wherein the wick and the resistive heating element are suspended between the first fixation site and the second fixation site, and wherein the resistive heating element is configured to generate an aerosol from a vaporizable material. | CROSS REFERENCE TO RELATED APPLICATIONS This patent application claims priority as a continuation-in-part of U.S. patent application Ser. No. 15/053,927, titled “VAPORIZATION DEVICE SYSTEMS AND METHODS,” filed on Feb. 25, 2016, which is a continuation-in-part of U.S. patent application Ser. No. 14/581,666, filed on Dec. 23, 2014 and titled “VAPORIZATION DEVICE SYSTEMS AND METHODS”, Publication No. US-2015-0208729-A1, which claims priority to U.S. Provisional Patent Application No. 61/920,225, filed on Dec. 23, 2013, U.S. Provisional Patent Application No. 61/936,593, filed on Feb. 6, 2014, and U.S. Provisional Patent Application No. 61/937,755, filed on Feb. 10, 2014. This patent application also claims priority to U.S. Provisional patent application No. 62/294,281, titled “SECURELY ATTACHING CARTRIDGES FOR VAPORIZER DEVICES,” filed on Feb. 11, 2016. Each of these applications are herein incorporated by reference in their entirety. INCORPORATION BY REFERENCE All publications and patent applications mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. BACKGROUND Electronic inhalable aerosol devices (e.g., vaporization devices, electronic vaping devices, etc.) and particularly electronic aerosol devices, typically utilize a vaporizable material that is vaporized to create an aerosol vapor capable of delivering an active ingredient to a user. Control of the temperature of the resistive heater must be maintained (e.g., as part of a control loop), and this control may be based on the resistance of the resistive heating element. Many of the battery-powered vaporizers described to date include a reusable batter-containing device portion that connects to one or more cartridges containing the consumable vaporizable material. As the cartridges are used up, they are removed and replaced with fresh ones. It may be particularly useful to have the cartridge be integrated with a mouthpiece that the user can draw on to receive vapor. However, a number of surprising disadvantages may result in this configuration, particular to non-cylindrical shapes. For example, the use of a cartridge at the proximal end of the device, which is also held by the user's mouth, particularly where the cartridge is held in the vaporizer device by a friction- or a snap-fit, may result in instability in the electrical contacts, particularly with cartridges of greater than 1 cm length. Described herein are apparatuses and methods that may address the issues discussed above. SUMMARY OF THE DISCLOSURE The present invention relates generally to apparatuses, including systems and devices, for vaporizing material to form an inhalable aerosol. Specifically, these apparatuses may include vaporizers. In particular, described herein are cartridges that are configured for use with a vaporizer (e.g., vaporizer device) having a rechargeable power supply that includes a proximal cartridge-receiving opening. These cartridges are specifically adapted to be releasably but securely held within the cartridge-receiving opening of the vaporizer and resist disruption of the electrical contact with the controller and power supply in the vaporizer even when held by the user's mouth. For example, described herein are cartridge devices holding a vaporizable material for securely coupling with an electronic inhalable aerosol device. A device may include: a mouthpiece; a fluid storage compartment holding a vaporizable material; a base configured to fit into a rectangular opening that is between 13-14 mm deep, 4.5-5.5 mm wide, and 13-14 mm long, the base having a bottom surface comprising a first electrical contact and a second electrical contact, a first locking gap on a first lateral surface of the base, and a second locking gap on a second lateral surface of the base that is opposite first lateral surface. A cartridge device holding a vaporizable material for securely coupling with an electronic inhalable aerosol device may include: a mouthpiece; a fluid storage compartment holding a vaporizable material; a base configured to fit into a rectangular opening that is between 13-14 mm deep, 4.5-5.5 mm wide, and 13-14 mm long, the base having a length of at least 10 mm, and a bottom surface comprising a first electrical contact and a second electrical contact, a first locking gap on a first lateral surface of the base positioned between 3-4 mm above the bottom surface, and a second locking gap on a second lateral surface of the base that is opposite first lateral surface. A cartridge device holding a vaporizable material for securely coupling with an electronic inhalable aerosol device, the device comprising: a mouthpiece; a fluid storage compartment holding a vaporizable material; a rectangular base having a pair of minor sides that are between greater than 10 mm deep and between 4.5-5.5 mm wide, and a pair of major sides that are greater than 10 mm deep and between 13-14 mm wide, a bottom surface comprising a first electrical contact and a second electrical contact, and a first locking gap on a first lateral surface of the base positioned between 3-4 mm above the bottom surface, and a second locking gap on a second lateral surface of the base that is opposite first lateral surface. Any of these devices may also typically include a wick in fluid communication with the vaporizable material; and a resistive heating element in fluid contact with the wick and in electrical contact with the first and second electrical contacts. In general, applicants have found that, for cartridges having a base that fits into the rectangular opening of a vaporizer (particularly one that is between 13-14 mm deep, 4.5-5.5 mm wide, and 13-14 mm long), the it is beneficial to have a length of the base (which is generally the connection region of the base for interfacing into the rectangular opening) that is greater than 10 mm, however when the base is greater than 10 mm (e.g., greater than 11 mm, greater than 12 mm, greater than 13 mm), the stability of the cartridge and in particular the electrical contacts, may be greatly enhanced if the cartridge includes one or more (e.g., two) locking gaps near the bottom surface of the cartridge into which a complimentary detent on the vaporizer can couple to. In particular, it may be beneficial to have the first and second locking gaps within 6 mm of the bottom surface, and more specifically within 3-4 mm of the bottom surface. The first and second lateral surfaces may be separated from each other by between 13-14 mm, e.g., they may be on the short sides of a cartridge base having a rectangular cross-section (a rectangular base). As mentioned, any of these cartridges may include a wick extending through the fluid storage compartment and into the vaporizable material, a resistive heating element in contact with the first and second electrical contacts, and a heating chamber in electrical contact with the first and second electrical contacts. It may also be beneficial to include one or more (e.g., two) detents extending from a major surface (e.g., two major surfaces) of the base, such as from a third and/or fourth lateral wall of the base. The cartridge may include any appropriate vaporizable material, such as a nicotine salt solution. In general, the mouthpiece may be attached opposite from the base. The fluid storage compartment may also comprises an air path extending there through (e.g., a cannula or tube). In some variations at least part of the fluid storage compartment may be within the base. The compartment may be transparent (e.g., made from a plastic or polymeric material that is clear) or opaque, allowing the user to see how much fluid is left. In general, the locking gap(s) may be a channel in the first lateral surface (e.g., a channel transversely across the first lateral surface parallel to the bottom surface), an opening or hole in the first lateral surface, and/or a hole in the first lateral surface. The locking gap is generally a gap that is surrounded at least on the upper and lower (proximal and distal) sides by the lateral wall to allow the detent on the vaporizer to engage therewith. The locking gap may be generally between 0.1 mm and 2 mm wide (e.g., between a lower value of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, etc. and an upper value of about 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, etc., where the upper value is always greater than the lower value). Also described are vaporizers and method of using them with cartridges, including those described herein. In some variations, the apparatuses described herein may include an inhalable aerosol comprising: an oven comprising an oven chamber and a heater for heating a vapor forming medium in the oven chamber to generate a vapor; a condenser comprising a condensation chamber in which at least a fraction of the vapor condenses to form the inhalable aerosol; an air inlet that originates a first airflow path that includes the oven chamber; and an aeration vent that originates a second airflow path that allows air from the aeration vent to join the first airflow path prior to or within the condensation chamber and downstream from the oven chamber thereby forming a joined path, wherein the joined path is configured to deliver the inhalable aerosol formed in the condensation chamber to a user. The oven may be within a body of the device. The device may further comprise a mouthpiece, wherein the mouthpiece comprises at least one of the air inlet, the aeration vent, and the condenser. The mouthpiece may be separable from the oven. The mouthpiece may be integral to a body of the device, wherein the body comprises the oven. The device may further comprise a body that comprises the oven, the condenser, the air inlet, and the aeration vent. The mouthpiece may be separable from the body. In some variations, the oven chamber may comprise an oven chamber inlet and an oven chamber outlet, and the oven further comprises a first valve at the oven chamber inlet, and a second valve at the oven chamber outlet. The aeration vent may comprise a third valve. The first valve, or said second valve may be chosen from the group of a check valve, a clack valve, a non-return valve, and a one-way valve. The third valve may be chosen from the group of a check valve, a clack valve, a non-return valve, and a one-way valve. The first or second valve may be mechanically actuated. The first or second valve may be electronically actuated. The first valve or second valve may be manually actuated. The third valve may be mechanically actuated. The third valve may be mechanically actuated. The third valve may be electronically actuated. The third valve may be manually actuated. In some variations, the device may further comprise a body that comprises at least one of: a power source, a printed circuit board, a switch, and a temperature regulator. The device may further comprise a temperature regulator in communication with a temperature sensor. The temperature sensor may be the heater. The power source may be rechargeable. The power source may be removable. The oven may further comprise an access lid. The vapor forming medium may comprise tobacco. The vapor forming medium may comprise a botanical. The vapor forming medium may be heated in the oven chamber wherein the vapor forming medium may comprise a humectant to produce the vapor, wherein the vapor comprises a gas phase humectant. The vapor may be mixed in the condensation chamber with air from the aeration vent to produce the inhalable aerosol comprising particle diameters of average size of about 1 micron. The vapor forming medium may be heated in the oven chamber, wherein the vapor is mixed in the condensation chamber with air from the aeration vent to produce the inhalable aerosol comprising particle diameters of average size of less than or equal to 0.9 micron. The vapor forming medium may be heated in the oven chamber, wherein the vapor is mixed in the condensation chamber with air from the aeration vent to produce the inhalable aerosol comprising particle diameters of average size of less than or equal to 0.8 micron. The vapor forming medium may be heated in the oven chamber, wherein the vapor is mixed in the condensation chamber with air from the aeration vent to produce the inhalable aerosol comprising particle diameters of average size of less than or equal to 0.7 micron. The vapor forming medium may be heated in the oven chamber, wherein the vapor is mixed in the condensation chamber with air from the aeration vent to produce the inhalable aerosol comprising particle diameters of average size of less than or equal to 0.6 micron. The vapor forming medium may be heated in the oven chamber, wherein the vapor is mixed in the condensation chamber with air from the aeration vent to produce the inhalable aerosol comprising particle diameters of average size of less than or equal to 0.5 micron. In some variations, the humectant may comprise glycerol as a vapor-forming medium. The humectant may comprise vegetable glycerol. The humectant may comprise propylene glycol. The humectant may comprise a ratio of vegetable glycerol to propylene glycol. The ratio may be about 100:0 vegetable glycerol to propylene glycol. The ratio may be about 90:10 vegetable glycerol to propylene glycol. The ratio may be about 80:20 vegetable glycerol to propylene glycol. The ratio may be about 70:30 vegetable glycerol to propylene glycol. The ratio may be about 60:40 vegetable glycerol to propylene glycol. The ratio may be about 50:50 vegetable glycerol to propylene glycol. The humectant may comprise a flavorant. The vapor forming medium may be heated to its pyrolytic temperature. The vapor forming medium may heated to 200° C. at most. The vapor forming medium may be heated to 160° C. at most. The inhalable aerosol may be cooled to a temperature of about 50°-70° C. at most, before exiting the aerosol outlet of the mouthpiece. Also described herein are methods for generating an inhalable aerosol. Such a method may comprise: providing an inhalable aerosol generating device wherein the device comprises: an oven comprising an oven chamber and a heater for heating a vapor forming medium in the oven chamber and for forming a vapor therein; a condenser comprising a condensation chamber in which the vapor forms the inhalable aerosol; an air inlet that originates a first airflow path that includes the oven chamber; and an aeration vent that originates a second airflow path that allows air from the aeration vent to join the first airflow path prior to or within the condensation chamber and downstream from the oven chamber thereby forming a joined path, wherein the joined path is configured to deliver the inhalable aerosol formed in the condensation chamber to a user. The oven may be within a body of the device. The device may further comprise a mouthpiece, wherein the mouthpiece comprises at least one of the air inlet, the aeration vent, and the condenser. The mouthpiece may be separable from the oven. The mouthpiece may be integral to a body of the device, wherein the body comprises the oven. The method may further comprise a body that comprises the oven, the condenser, the air inlet, and the aeration vent. The mouthpiece may be separable from the body. The oven chamber may comprise an oven chamber inlet and an oven chamber outlet, and the oven further comprises a first valve at the oven chamber inlet, and a second valve at the oven chamber outlet. The vapor forming medium may comprise tobacco. The vapor forming medium may comprise a botanical. The vapor forming medium may be heated in the oven chamber wherein the vapor forming medium may comprise a humectant to produce the vapor, wherein the vapor comprises a gas phase humectant. The vapor may comprise particle diameters of average mass of about 1 micron. The vapor may comprise particle diameters of average mass of about 0.9 micron. The vapor may comprise particle diameters of average mass of about 0.8 micron. The vapor may comprise particle diameters of average mass of about 0.7 micron. The vapor may comprise particle diameters of average mass of about 0.6 micron. The vapor may comprise particle diameters of average mass of about 0.5 micron. In some variations, the humectant may comprise glycerol as a vapor-forming medium. The humectant may comprise vegetable glycerol. The humectant may comprise propylene glycol. The humectant may comprise a ratio of vegetable glycerol to propylene glycol. The ratio may be about 100:0 vegetable glycerol to propylene glycol. The ratio may be about 90:10 vegetable glycerol to propylene glycol. The ratio may be about 80:20 vegetable glycerol to propylene glycol. The ratio may be about 70:30 vegetable glycerol to propylene glycol. The ratio may be about 60:40 vegetable glycerol to propylene glycol. The ratio may be about 50:50 vegetable glycerol to propylene glycol. The humectant may comprise a flavorant. The vapor forming medium may be heated to its pyrolytic temperature. The vapor forming medium may heated to 200° C. at most. The vapor forming medium may be heated to 160° C. at most. The inhalable aerosol may be cooled to a temperature of about 50°-70° C. at most, before exiting the aerosol outlet of the mouthpiece. The device may be user serviceable. The device may not be user serviceable. A method for generating an inhalable aerosol may include: providing a vaporization device, wherein said device produces a vapor comprising particle diameters of average mass of about 1 micron or less, wherein said vapor is formed by heating a vapor forming medium in an oven chamber to a first temperature below the pyrolytic temperature of said vapor forming medium, and cooling said vapor in a condensation chamber to a second temperature below the first temperature, before exiting an aerosol outlet of said device. A method of manufacturing a device for generating an inhalable aerosol may include: providing said device comprising a mouthpiece comprising an aerosol outlet at a first end of the device; an oven comprising an oven chamber and a heater for heating a vapor forming medium in the oven chamber and for forming a vapor therein, a condenser comprising a condensation chamber in which the vapor forms the inhalable aerosol, an air inlet that originates a first airflow path that includes the oven chamber and then the condensation chamber, an aeration vent that originates a second airflow path that joins the first airflow path prior to or within the condensation chamber after the vapor is formed in the oven chamber, wherein the joined first airflow path and second airflow path are configured to deliver the inhalable aerosol formed in the condensation chamber through the aerosol outlet of the mouthpiece to a user. The method may further comprise providing the device comprising a power source or battery, a printed circuit board, a temperature regulator or operational switches. A device for generating an inhalable aerosol may comprise a mouthpiece comprising an aerosol outlet at a first end of the device and an air inlet that originates a first airflow path; an oven comprising an oven chamber that is in the first airflow path and includes the oven chamber and a heater for heating a vapor forming medium in the oven chamber and for forming a vapor therein; a condenser comprising a condensation chamber in which the vapor forms the inhalable aerosol; and an aeration vent that originates a second airflow path that allows air from the aeration vent to join the first airflow path prior to or within the condensation chamber and downstream from the oven chamber thereby forming a joined path, wherein the joined path is configured to deliver the inhalable aerosol formed in the condensation chamber through the aerosol outlet of the mouthpiece to a user. Also described herein are vaporization devices and methods of operating them. In particular, described herein are methods for controlling the temperature of a resistive heater (e.g., resistive heating element) by controlling the power applied to a resistive heater of a vaporization device by measuring the resistance of the resistive heater at discrete intervals before (e.g., baseline or ambient temperature) and during vaporization (e.g., during heating to vaporize a material within the device). Changes in the resistance during heating may be linearly related to the temperature of the resistive heater over the operational range, and therefore may be used to control the power applied to heat the resistive heater during operation. Also described herein are vaporization devices that are configured to measure the resistance of the resistive heater during heating (e.g., during a pause in the application of power to heat the resistive heater) and to control the application of power to the resistive heater based on the resistance values. In general, in any of the methods and apparatuses described herein, the control circuitry (which may include one or more circuits, a microcontroller, and/or control logic) may compare a resistance of the resistive heater during heating, e.g., following a sensor input indicating that a user wishes to withdraw vapor, to a target resistance of the heating element. The target resistance is typically the resistance of the resistive heater at a desired (and in some cases estimated) target vaporization temperature. The apparatus and methods may be configured to offer multiple and/or adjustable vaporization temperatures. In some variations, the target resistance is an approximation or estimate of the resistance of the resistive heater when the resistive heater is heated to the target temperature (or temperature ranges). In some variations, the target reference is based on a baseline resistance for the resistive heater and/or the percent change in resistance from baseline resistance for the resistive heater at a target temperature. In general, the baseline resistance may be referred to as the resistance of the resistive heater at an ambient temperature. For example, a method of controlling a vaporization device may include: placing a vaporizable material in thermal contact with a resistive heater; applying power to the resistive heater to heat the vaporizable material; measuring the resistance of the resistive heater; and adjusting the applied power to the resistive heater based on the difference between the resistance of the resistive heater and a target resistance of the heating element. In some variations, the target resistance is based on a reference resistance. For example, the reference resistance may be approximately the resistance of the coil at target temperature. This reference resistance may be calculated, estimated or approximated (as described herein) or it may be determined empirically based on the resistance values of the resistive heater at one or more target temperatures. In some variations, the target resistance is based on the resistance of the resistive heater at an ambient temperature. For example, the target resistance may be estimated based on the electrical properties of the resistive heater, e.g., the temperature coefficient of resistance or TCR, of the resistive heater (e.g., “resistive heating element” or “vaporizing element”). For example, a vaporization device (e.g., an electronic vaporizer device) may include a puff sensor, a power source (e.g., battery, capacitor, etc.), a heating element controller (e.g., microcontroller), and a resistive heater. A separate temperature sensor may also be included to determine an actual temperature of ambient temperature and/or the resistive heater, or a temperature sensor may be part of the heating element controller. However, in general, the microcontroller may control the temperature of the resistive heater (e.g., resistive coil, etc.) based on a change in resistance due to temperature (e.g., TCR). In general, the heater may be any appropriate resistive heater, such as a resistive coil. The heater is typically coupled to the heater controller so that the heater controller applies power (e.g., from the power source) to the heater. The heater controller may include regulatory control logic to regulate the temperature of the heater by adjusting the applied power. The heater controller may include a dedicated or general-purpose processor, circuitry, or the like and is generally connected to the power source and may receive input from the power source to regulate the applied power to the heater. For example, any of these apparatuses may include logic for determining the temperature of the heater based on the TCR. The resistance of the heater (e.g., a resistive heater) may be measured (Rheater) during operation of the apparatus and compared to a target resistance, which is typically the resistance of the resistive heater at the target temperature. In some cases this resistance may be estimated from the resistance of the resistive hearing element at ambient temperature (baseline). In some variations, a reference resistor (Rreference) may be used to set the target resistance. The ratio of the heater resistance to the reference resistance (Rheater/Rreference) is linearly related to the temperature (above room temp) of the heater, and may be directly converted to a calibrated temperature. For example, a change in temperature of the heater relative to room temperature may be calculated using an expression such as (Rheater/Rreference−1)*(1/TCR), where TCR is the temperature coefficient of resistivity for the heater. In one example, TCR for a particular device heater is 0.00014/° C. In determining the partial doses and doses described herein, the temperature value used (e.g., the temperature of the vaporizable material during a dose interval, T1, described in more detail below) may refer to the unitless resistive ratio (e.g., Rheater/Rrefrerence) or it may refer to the normalized/corrected temperature (e.g., in ° C.). When controlling a vaporization device by comparing a measure resistance of a resistive heater to a target resistance, the target resistance may be initially calculated and may be factory preset and/or calibrated by a user-initiated event. For example, the target resistance of the resistive heater during operation of the apparatus may be set by the percent change in baseline resistance plus the baseline resistance of the resistive heater, as will be described in more detail below. As mentioned, the resistance of the heating element at ambient is the baseline resistance. For example, the target resistance may be based on the resistance of the resistive heater at an ambient temperature and a target change in temperature of the resistive heater. As mentioned above, the target resistance of the resistive heater may be based on a target heating element temperature. Any of the apparatuses and methods for using them herein may include determining the target resistance of the resistive heater based on a resistance of the resistive heater at ambient temperature and a percent change in a resistance of the resistive heater at an ambient temperature. In any of the methods and apparatuses described herein, the resistance of the resistive heater may be measured (using a resistive measurement circuit) and compared to a target resistance by using a voltage divider. Alternatively or additionally any of the methods and apparatuses described herein may compare a measured resistance of the resistive heater to a target resistance using a Wheatstone bridge and thereby adjust the power to increase/decrease the applied power based on this comparison. In any of the variations described herein, adjusting the applied power to the resistive heater may comprise comparing the resistance (actual resistance) of the resistive heater to a target resistance using a voltage divider, Wheatstone bridge, amplified Wheatstone bridge, or RC charge time circuit. As mentioned above, a target resistance of the resistive heater and therefore target temperature may be determined using a baseline resistance measurement taken from the resistive heater. The apparatus and/or method may approximate a baseline resistance for the resistive heater by waiting an appropriate length of time (e.g., 1 second, 10 seconds, 30 seconds, 1 minute, 1.5 minutes, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 11 minutes, 12 minutes, 15 minutes, 20 minutes, etc.) from the last application of energy to the resistive heater to measure a resistance (or series of resistance that may be averaged, etc.) representing the baseline resistance for the resistive heater. In some variations a plurality of measurements made when heating/applying power to the resistive heater is prevented may be analyzed by the apparatus to determine when the resistance values do not vary outside of a predetermined range (e.g., when the resistive heater has ‘cooled’ down, and therefore the resistance is no longer changing due to temperature decreasing/increasing), for example, when the rate of change of the resistance of the heating element over time is below some stability threshold. For example, any of the methods and apparatuses described herein may measure the resistance of the resistive heater an ambient temperature by measuring the resistance of the resistive heater after a predetermined time since power was last applied to the resistive heater. As mentioned above, the predetermined time period may be seconds, minutes, etc. In any of these variations the baseline resistance may be stored in a long-term memory (including volatile, non-volatile or semi-volatile memory). Storing a baseline resistance (“the resistance of the resistive heater an ambient temperature”) may be done periodically (e.g., once per 2 minute, 5 minutes, 10 minutes, 1 hour, etc., or every time a particular event occurs, such as loading vaporizable material), or once for a single time. Any of these methods may also include calculating an absolute target coil temperature from an actual device temperature. As mentioned, above, based on the material properties of the resistive heater (e.g., coil) the resistance and/or change in resistance over time may be used calculate an actual temperature, which may be presented to a user, e.g., on the face of the device, or communicated to an “app” or other output type. In any of the methods and apparatuses described herein, the apparatus may detect the resistance of the resistive heater only when power is not being applied to the resistive heater while detecting the resistance; once the resistance detection is complete, power may again be applied (and this application may be modified by the control logic described herein). For example, in any of these devices and methods the resistance of the resistive heater may be measured only when suspending the application of power to the resistive heater. For example, a method of controlling a vaporization device may include: placing a vaporizable material in thermal contact with a resistive heater; applying power to the resistive heater to heat the vaporizable material; suspending the application of power to the resistive heater while measuring the resistance of the resistive heater; and adjusting the applied power to the resistive heater based on the difference between the resistance of the heating element and a target resistance of the resistive heater, wherein measuring the resistance of the resistive heater comprises measuring the resistance using a voltage divider, Wheatstone bridge, amplified Wheatstone bridge, or RC charge time circuit. For example, a vaporization device may include: a microcontroller; a reservoir configured to hold a vaporizable material; a resistive heater configured to thermally contact the vaporizable material from the reservoir; a resistance measurement circuit connected to the microcontroller configured to measure the resistance of the resistive heater; and a power source, wherein the microcontroller applies power from the power source to heat the resistive heater and adjusts the applied power based on the difference between the resistance of the resistive heater and a target resistance of the resistive heater. A vaporization device may include: a microcontroller; a reservoir configured to hold a vaporizable material; a resistive heater configured to thermally contact the vaporizable material from the reservoir; a resistance measurement circuit connected to the microcontroller configured to measure the resistance of the resistive heater; a power source; and a sensor having an output connected to the microcontroller, wherein the microcontroller is configured to determine when the resistive heater applies power from the power source to heat the resistive heater; a target resistance circuit configured to determine a target resistance, the target resistance circuit comprising one of: a voltage divider, a Wheatstone bridge, an amplified Wheatstone bridge, or an RC charge time circuit, wherein the microcontroller applies power from the power source to heat the resistive heater and adjusts the applied power based on the difference between the resistance of the resistive heater and the target resistance of the resistive heater. In any of the methods and apparatuses (e.g., devices and systems) described herein, the apparatus may be configured to be triggered by a user drawing on or otherwise indicating that they would like to begin vaporization of the vaporizing material. This user-initiated start may be detected by a sensor, such as a pressure sensor (“puff sensor”) configured to detect draw. The sensor may generally have an output that is connected to the controller (e.g., microcontroller), and the microcontroller may be configured to determine when the resistive heater applies power from the power source to heat the resistive heater. For example, a vaporizing device as described herein may include a pressure sensor having an output connected to the microcontroller, wherein the microcontroller is configured to determine when the resistive heater applies power from the power source to heat the resistive heater. In general, any of the apparatuses described herein may be adapted to perform any of the methods described herein, including determining if an instantaneous (ongoing) resistance measurement of the resistive heater is above/below and/or within a tolerable range of a target resistance. Any of these apparatuses may also determine the target resistance. As mentioned, this may be determined empirically and set to a resistance value, and/or it may be calculated. For example, any of these apparatuses (e.g., devices) may include a target resistance circuit configured to determine the target resistance, the target resistance circuit comprising one of: a voltage divider, a Wheatstone bridge, an amplified Wheatstone bridge, or an RC charge time circuit. Alternatively or additionally, a voltage divider, a Wheatstone bridge, an amplified Wheatstone bridge, or an RC charge time circuit may be included as part of the microcontroller or other circuitry that compares the measured resistance of the resistive heater to a target resistance. For example, a target resistance circuit may be configured to determine the target resistance and/or compare the measured resistance of the resistive heater to the target resistance. The target resistance circuit comprising a voltage divider having a reference resistance equivalent to the target resistance. A target resistance circuit may be configured to determine the target resistance, the target resistance circuit comprising a Wheatstone bridge, wherein the target resistance is calculated by adding a resistance of the resistive heater at an ambient temperature and a target change in temperature of the resistive heater. As mentioned, any of these apparatuses may include a memory configured to store a resistance of the resistive heater at an ambient temperature. Further, any of these apparatuses may include a temperature input coupled to the microcontroller and configured to provide an actual device temperature. The device temperature may be sensed and/or provided by any appropriate sensor, including thermistor, thermocouple, resistive temperature sensor, silicone bandgap temperature sensor, etc. The measured device temperature may be used to calculate a target resistance that corresponds to a certain resistive heater (e.g., coil) temperature. In some variations the apparatus may display and/or output an an estimate of the temperature of the resistive heater. The apparatus may include a display or may communicate (e.g., wirelessly) with another apparatus that receives the temperature or resistance values. The devices described herein may include an inhalable aerosol comprising: an oven comprising an oven chamber and a heater for heating a vapor forming medium in the oven chamber to generate a vapor; a condenser comprising a condensation chamber in which at least a fraction of the vapor condenses to form the inhalable aerosol; an air inlet that originates a first airflow path that includes the oven chamber; and an aeration vent that originates a second airflow path that allows air from the aeration vent to join the first airflow path prior to or within the condensation chamber and downstream from the oven chamber thereby forming a joined path, wherein the joined path is configured to deliver the inhalable aerosol formed in the condensation chamber to a user. In any of these variations the oven is within a body of the device. The device may further comprise a mouthpiece, wherein the mouthpiece comprises at least one of the air inlet, the aeration vent, and the condenser. The mouthpiece may be separable from the oven. The mouthpiece may be integral to a body of the device, wherein the body comprises the oven. The device may further comprise a body that comprises the oven, the condenser, the air inlet, and the aeration vent. The mouthpiece may be separable from the body. In some variations, the oven chamber may comprise an oven chamber inlet and an oven chamber outlet, and the oven further comprises a first valve at the oven chamber inlet, and a second valve at the oven chamber outlet. The aeration vent may comprise a third valve. The first valve, or said second valve may be chosen from the group of a check valve, a clack valve, a non-return valve, and a one-way valve. The third valve may be chosen from the group of a check valve, a clack valve, a non-return valve, and a one-way valve. The first or second valve may be mechanically actuated. The first or second valve may be electronically actuated. The first valve or second valve may be manually actuated. The third valve may be mechanically actuated. The third valve may be mechanically actuated. The third valve may be electronically actuated. The third valve may be manually actuated. In any of these variations, the device may further comprise a body that comprises at least one of: a power source, a printed circuit board, a switch, and a temperature regulator. The device may further comprise a temperature regulator in communication with a temperature sensor. The temperature sensor may be the heater. The power source may be rechargeable. The power source may be removable. The oven may further comprise an access lid. The vapor forming medium may comprise tobacco. The vapor forming medium may comprise a botanical. The vapor forming medium may be heated in the oven chamber wherein the vapor forming medium may comprise a humectant to produce the vapor, wherein the vapor comprises a gas phase humectant. The vapor may be mixed in the condensation chamber with air from the aeration vent to produce the inhalable aerosol comprising particle diameters of average size of about 1 micron. The vapor forming medium may be heated in the oven chamber, wherein the vapor is mixed in the condensation chamber with air from the aeration vent to produce the inhalable aerosol comprising particle diameters of average size of less than or equal to 0.9 micron. The vapor forming medium may be heated in the oven chamber, wherein the vapor is mixed in the condensation chamber with air from the aeration vent to produce the inhalable aerosol comprising particle diameters of average size of less than or equal to 0.8 micron. The vapor forming medium may be heated in the oven chamber, wherein the vapor is mixed in the condensation chamber with air from the aeration vent to produce the inhalable aerosol comprising particle diameters of average size of less than or equal to 0.7 micron. The vapor forming medium may be heated in the oven chamber, wherein the vapor is mixed in the condensation chamber with air from the aeration vent to produce the inhalable aerosol comprising particle diameters of average size of less than or equal to 0.6 micron. The vapor forming medium may be heated in the oven chamber, wherein the vapor is mixed in the condensation chamber with air from the aeration vent to produce the inhalable aerosol comprising particle diameters of average size of less than or equal to 0.5 micron. In any of these variations, the humectant may comprise glycerol as a vapor-forming medium. The humectant may comprise vegetable glycerol. The humectant may comprise propylene glycol. The humectant may comprise a ratio of vegetable glycerol to propylene glycol. The ratio may be about 100:0 vegetable glycerol to propylene glycol. The ratio may be about 90:10 vegetable glycerol to propylene glycol. The ratio may be about 80:20 vegetable glycerol to propylene glycol. The ratio may be about 70:30 vegetable glycerol to propylene glycol. The ratio may be about 60:40 vegetable glycerol to propylene glycol. The ratio may be about 50:50 vegetable glycerol to propylene glycol. The humectant may comprise a flavorant. The vapor forming medium may be heated to its pyrolytic temperature. The vapor forming medium may heated to 200° C. at most. The vapor forming medium may be heated to 160° C. at most. The inhalable aerosol may be cooled to a temperature of about 50°-70° C. at most, before exiting the aerosol outlet of the mouthpiece. In any of these variations, the method comprises A method for generating an inhalable aerosol, the method comprising: providing an inhalable aerosol generating device wherein the device comprises: an oven comprising an oven chamber and a heater for heating a vapor forming medium in the oven chamber and for forming a vapor therein; a condenser comprising a condensation chamber in which the vapor forms the inhalable aerosol; an air inlet that originates a first airflow path that includes the oven chamber; and an aeration vent that originates a second airflow path that allows air from the aeration vent to join the first airflow path prior to or within the condensation chamber and downstream from the oven chamber thereby forming a joined path, wherein the joined path is configured to deliver the inhalable aerosol formed in the condensation chamber to a user. In any of these variations the oven is within a body of the device. The device may further comprise a mouthpiece, wherein the mouthpiece comprises at least one of the air inlet, the aeration vent, and the condenser. The mouthpiece may be separable from the oven. The mouthpiece may be integral to a body of the device, wherein the body comprises the oven. The method may further comprise a body that comprises the oven, the condenser, the air inlet, and the aeration vent. The mouthpiece may be separable from the body. In any of these variations, the oven chamber may comprise an oven chamber inlet and an oven chamber outlet, and the oven further comprises a first valve at the oven chamber inlet, and a second valve at the oven chamber outlet. The vapor forming medium may comprise tobacco. The vapor forming medium may comprise a botanical. The vapor forming medium may be heated in the oven chamber wherein the vapor forming medium may comprise a humectant to produce the vapor, wherein the vapor comprises a gas phase humectant. The vapor may comprise particle diameters of average mass of about 1 micron. The vapor may comprise particle diameters of average mass of about 0.9 micron. The vapor may comprise particle diameters of average mass of about 0.8 micron. The vapor may comprise particle diameters of average mass of about 0.7 micron. The vapor may comprise particle diameters of average mass of about 0.6 micron. The vapor may comprise particle diameters of average mass of about 0.5 micron. In any of these variations, the humectant may comprise glycerol as a vapor-forming medium. The humectant may comprise vegetable glycerol. The humectant may comprise propylene glycol. The humectant may comprise a ratio of vegetable glycerol to propylene glycol. The ratio may be about 100:0 vegetable glycerol to propylene glycol. The ratio may be about 90:10 vegetable glycerol to propylene glycol. The ratio may be about 80:20 vegetable glycerol to propylene glycol. The ratio may be about 70:30 vegetable glycerol to propylene glycol. The ratio may be about 60:40 vegetable glycerol to propylene glycol. The ratio may be about 50:50 vegetable glycerol to propylene glycol. The humectant may comprise a flavorant. The vapor forming medium may be heated to its pyrolytic temperature. The vapor forming medium may heated to 200° C. at most. The vapor forming medium may be heated to 160° C. at most. The inhalable aerosol may be cooled to a temperature of about 50°-70° C. at most, before exiting the aerosol outlet of the mouthpiece. In any of these variations, the device may be user serviceable. The device may not be user serviceable. In any of these variations, a method for generating an inhalable aerosol, the method comprising: providing a vaporization device, wherein said device produces a vapor comprising particle diameters of average mass of about 1 micron or less, wherein said vapor is formed by heating a vapor forming medium in an oven chamber to a first temperature below the pyrolytic temperature of said vapor forming medium, and cooling said vapor in a condensation chamber to a second temperature below the first temperature, before exiting an aerosol outlet of said device. In any of these variations, a method of manufacturing a device for generating an inhalable aerosol comprising: providing said device comprising a mouthpiece comprising an aerosol outlet at a first end of the device; an oven comprising an oven chamber and a heater for heating a vapor forming medium in the oven chamber and for forming a vapor therein, a condenser comprising a condensation chamber in which the vapor forms the inhalable aerosol, an air inlet that originates a first airflow path that includes the oven chamber and then the condensation chamber, an aeration vent that originates a second airflow path that joins the first airflow path prior to or within the condensation chamber after the vapor is formed in the oven chamber, wherein the joined first airflow path and second airflow path are configured to deliver the inhalable aerosol formed in the condensation chamber through the aerosol outlet of the mouthpiece to a user. The method may further comprise providing the device comprising a power source or battery, a printed circuit board, a temperature regulator or operational switches. In any of these variations a device for generating an inhalable aerosol may comprise a mouthpiece comprising an aerosol outlet at a first end of the device and an air inlet that originates a first airflow path; an oven comprising an oven chamber that is in the first airflow path and includes the oven chamber and a heater for heating a vapor forming medium in the oven chamber and for forming a vapor therein; a condenser comprising a condensation chamber in which the vapor forms the inhalable aerosol; and an aeration vent that originates a second airflow path that allows air from the aeration vent to join the first airflow path prior to or within the condensation chamber and downstream from the oven chamber thereby forming a joined path, wherein the joined path is configured to deliver the inhalable aerosol formed in the condensation chamber through the aerosol outlet of the mouthpiece to a user. In any of these variations a device for generating an inhalable aerosol may comprise: a mouthpiece comprising an aerosol outlet at a first end of the device, an air inlet that originates a first airflow path, and an aeration vent that originates a second airflow path that allows air from the aeration vent to join the first airflow path; an oven comprising an oven chamber that is in the first airflow path and includes the oven chamber and a heater for heating a vapor forming medium in the oven chamber and for forming a vapor therein; and a condenser comprising a condensation chamber in which the vapor forms the inhalable aerosol and wherein air from the aeration vent joins the first airflow path prior to or within the condensation chamber and downstream from the oven chamber thereby forming a joined path, wherein the joined path is configured to deliver the inhalable aerosol through the aerosol outlet of the mouthpiece to a user. In any of these variations, a device for generating an inhalable aerosol may comprise: a device body comprising a cartridge receptacle; a cartridge comprising: a fluid storage compartment, and a channel integral to an exterior surface of the cartridge, and an air inlet passage formed by the channel and an internal surface of the cartridge receptacle when the cartridge is inserted into the cartridge receptacle; wherein the channel forms a first side of the air inlet passage, and an internal surface of the cartridge receptacle forms a second side of the air inlet passage. In any of these variations, a device for generating an inhalable aerosol may comprise: a device body comprising a cartridge receptacle; a cartridge comprising: a fluid storage compartment, and a channel integral to an exterior surface of the cartridge, and an air inlet passage formed by the channel and an internal surface of the cartridge receptacle when the cartridge is inserted into the cartridge receptacle; wherein the channel forms a first side of the air inlet passage, and an internal surface of the cartridge receptacle forms a second side of the air inlet passage. In any of these variations the channel may comprise at least one of a groove, a trough, a depression, a dent, a furrow, a trench, a crease, and a gutter. The integral channel may comprise walls that are either recessed into the surface or protrude from the surface where it is formed. The internal side walls of the channel may form additional sides of the air inlet passage. The cartridge may further comprise a second air passage in fluid communication with the air inlet passage to the fluid storage compartment, wherein the second air passage is formed through the material of the cartridge. The cartridge may further comprise a heater. The heater may be attached to a first end of the cartridge. In any of these variations the heater may comprise a heater chamber, a first pair of heater contacts, a fluid wick, and a resistive heating element in contact with the wick, wherein the first pair of heater contacts comprise thin plates affixed about the sides of the heater chamber, and wherein the fluid wick and resistive heating element are suspended therebetween. The first pair of heater contacts may further comprise a formed shape that comprises a tab having a flexible spring value that extends out of the heater to couple to complete a circuit with the device body. The first pair of heater contacts may be a heat sink that absorbs and dissipates excessive heat produced by the resistive heating element. The first pair of heater contacts may contact a heat shield that protects the heater chamber from excessive heat produced by the resistive heating element. The first pair of heater contacts may be press-fit to an attachment feature on the exterior wall of the first end of the cartridge. The heater may enclose a first end of the cartridge and a first end of the fluid storage compartment. The heater may comprise a first condensation chamber. The heater may comprise more than one first condensation chamber. The first condensation chamber may be formed along an exterior wall of the cartridge. The cartridge may further comprise a mouthpiece. The mouthpiece may be attached to a second end of the cartridge. The mouthpiece may comprise a second condensation chamber. The mouthpiece may comprise more than one second condensation chamber. The second condensation chamber may be formed along an exterior wall of the cartridge. In any of these variations the cartridge may comprise a first condensation chamber and a second condensation chamber. The first condensation chamber and the second condensation chamber may be in fluid communication. The mouthpiece may comprise an aerosol outlet in fluid communication with the second condensation chamber. The mouthpiece may comprise more than one aerosol outlet in fluid communication with more than one the second condensation chamber. The mouthpiece may enclose a second end of the cartridge and a second end of the fluid storage compartment. In any of these variations, the device may comprise an airflow path comprising an air inlet passage, a second air passage, a heater chamber, a first condensation chamber, a second condensation chamber, and an aerosol outlet. The airflow path may comprise more than one air inlet passage, a heater chamber, more than one first condensation chamber, more than one second condensation chamber, more than one second condensation chamber, and more than one aerosol outlet. The heater may be in fluid communication with the fluid storage compartment. The fluid storage compartment may be capable of retaining condensed aerosol fluid. The condensed aerosol fluid may comprise a nicotine formulation. The condensed aerosol fluid may comprise a humectant. The humectant may comprise propylene glycol. The humectant may comprise vegetable glycerin. In any of these variations the cartridge may be detachable. In any of these variations the cartridge may be receptacle and the detachable cartridge form a separable coupling. The separable coupling may comprise a friction assembly, a snap-fit assembly or a magnetic assembly. The cartridge may comprise a fluid storage compartment, a heater affixed to a first end with a snap-fit coupling, and a mouthpiece affixed to a second end with a snap-fit coupling. In any of these variations, a device for generating an inhalable aerosol may comprise: a device body comprising a cartridge receptacle for receiving a cartridge; wherein an interior surface of the cartridge receptacle forms a first side of an air inlet passage when a cartridge comprising a channel integral to an exterior surface is inserted into the cartridge receptacle, and wherein the channel forms a second side of the air inlet passage. In any of these variations, a device for generating an inhalable aerosol may comprise: a device body comprising a cartridge receptacle for receiving a cartridge; wherein the cartridge receptacle comprises a channel integral to an interior surface and forms a first side of an air inlet passage when a cartridge is inserted into the cartridge receptacle, and wherein an exterior surface of the cartridge forms a second side of the air inlet passage. In any of these variations, A cartridge for a device for generating an inhalable aerosol comprising: a fluid storage compartment; a channel integral to an exterior surface, wherein the channel forms a first side of an air inlet passage; and wherein an internal surface of a cartridge receptacle in the device forms a second side of the air inlet passage when the cartridge is inserted into the cartridge receptacle. In any of these variations, a cartridge for a device for generating an inhalable aerosol may comprise: a fluid storage compartment, wherein an exterior surface of the cartridge forms a first side of an air inlet channel when inserted into a device body comprising a cartridge receptacle, and wherein the cartridge receptacle further comprises a channel integral to an interior surface, and wherein the channel forms a second side of the air inlet passage. The cartridge may further comprise a second air passage in fluid communication with the channel, wherein the second air passage is formed through the material of the cartridge from an exterior surface of the cartridge to the fluid storage compartment. The cartridge may comprise at least one of: a groove, a trough, a depression, a dent, a furrow, a trench, a crease, and a gutter. The integral channel may comprise walls that are either recessed into the surface or protrude from the surface where it is formed. The internal side walls of the channel may form additional sides of the air inlet passage. In any of these variations, a device for generating an inhalable aerosol may comprise: a cartridge comprising; a fluid storage compartment; a heater affixed to a first end comprising; a first heater contact, a resistive heating element affixed to the first heater contact; a device body comprising; a cartridge receptacle for receiving the cartridge; a second heater contact adapted to receive the first heater contact and to complete a circuit; a power source connected to the second heater contact; a printed circuit board (PCB) connected to the power source and the second heater contact; wherein the PCB is configured to detect the absence of fluid based on the measured resistance of the resistive heating element, and turn off the device. The printed circuit board (PCB) may comprise a microcontroller; switches; circuitry comprising a reference resister; and an algorithm comprising logic for control parameters; wherein the microcontroller cycles the switches at fixed intervals to measure the resistance of the resistive heating element relative to the reference resistor, and applies the algorithm control parameters to control the temperature of the resistive heating element. The micro-controller may instruct the device to turn itself off when the resistance exceeds the control parameter threshold indicating that the resistive heating element is dry. In any of these variations, a cartridge for a device for generating an inhalable aerosol may comprise: a fluid storage compartment; a heater affixed to a first end comprising: a heater chamber, a first pair of heater contacts, a fluid wick, and a resistive heating element in contact with the wick; wherein the first pair of heater contacts comprise thin plates affixed about the sides of the heater chamber, and wherein the fluid wick and resistive heating element are suspended therebetween. The first pair of heater contacts may further comprise: a formed shape that comprises a tab having a flexible spring value that extends out of the heater to complete a circuit with the device body. The heater contacts may be configured to mate with a second pair of heater contacts in a cartridge receptacle of the device body to complete a circuit. The first pair of heater contacts may also be a heat sink that absorbs and dissipates excessive heat produced by the resistive heating element. The first pair of heater contacts may be a heat shield that protects the heater chamber from excessive heat produced by the resistive heating element. In any of these variations, a cartridge for a device for generating an inhalable aerosol may comprise: a heater comprising; a heater chamber, a pair of thin plate heater contacts therein, a fluid wick positioned between the heater contacts, and a resistive heating element in contact with the wick; wherein the heater contacts each comprise a fixation site wherein the resistive heating element is tensioned therebetween. In any of these variations, a cartridge for a device for generating an inhalable aerosol may comprise a heater, wherein the heater is attached to a first end of the cartridge. The heater may enclose a first end of the cartridge and a first end of the fluid storage compartment. The heater may comprise more than one first condensation chamber. The heater may comprise a first condensation chamber. The condensation chamber may be formed along an exterior wall of the cartridge. In any of these variations, a cartridge for a device for generating an inhalable aerosol may comprise a fluid storage compartment; and a mouthpiece, wherein the mouthpiece is attached to a second end of the cartridge. The mouthpiece may enclose a second end of the cartridge and a second end of the fluid storage compartment. The mouthpiece may comprise a second condensation chamber. The mouthpiece may comprise more than one second condensation chamber. The second condensation chamber may be formed along an exterior wall of the cartridge. In any of these variations, a cartridge for a device for generating an inhalable aerosol may comprise: a fluid storage compartment; a heater affixed to a first end; and a mouthpiece affixed to a second end; wherein the heater comprises a first condensation chamber and the mouthpiece comprises a second condensation chamber. The heater may comprise more than one first condensation chamber and the mouthpiece comprises more than one second condensation chamber. The first condensation chamber and the second condensation chamber may be in fluid communication. The mouthpiece may comprise an aerosol outlet in fluid communication with the second condensation chamber. The mouthpiece may comprise two to more aerosol outlets. The cartridge may meet ISO recycling standards. The cartridge may meet ISO recycling standards for plastic waste. In any of these variations, a device for generating an inhalable aerosol may comprise: a device body comprising a cartridge receptacle; and a detachable cartridge; wherein the cartridge receptacle and the detachable cartridge form a separable coupling, wherein the separable coupling comprises a friction assembly, a snap-fit assembly or a magnetic assembly. In any of these variations, a method of fabricating a device for generating an inhalable aerosol may comprise: providing a device body comprising a cartridge receptacle; and providing a detachable cartridge; wherein the cartridge receptacle and the detachable cartridge form a separable coupling comprising a friction assembly, a snap-fit assembly or a magnetic assembly. In any of these variations, a method of fabricating a cartridge for a device for generating an inhalable aerosol may comprise: providing a fluid storage compartment; affixing a heater to a first end with a snap-fit coupling; and affixing a mouthpiece to a second end with a snap-fit coupling. In any of these variations A cartridge for a device for generating an inhalable aerosol with an airflow path comprising: a channel comprising a portion of an air inlet passage; a second air passage in fluid communication with the channel; a heater chamber in fluid communication with the second air passage; a first condensation chamber in fluid communication with the heater chamber; a second condensation chamber in fluid communication with the first condensation chamber; and an aerosol outlet in fluid communication with second condensation chamber. In any of these variations, a cartridge for a device for generating an inhalable aerosol may comprise: a fluid storage compartment; a heater affixed to a first end; and a mouthpiece affixed to a second end; wherein said mouthpiece comprises two or more aerosol outlets. In any of these variations, a system for providing power to an electronic device for generating an inhalable vapor, the system may comprise; a rechargeable power storage device housed within the electronic device for generating an inhalable vapor; two or more pins that are accessible from an exterior surface of the electronic device for generating an inhalable vapor, wherein the charging pins are in electrical communication with the rechargeable power storage device; a charging cradle comprising two or more charging contacts configured to provided power to the rechargeable storage device, wherein the device charging pins are reversible such that the device is charged in the charging cradle for charging with a first charging pin on the device in contact a first charging contact on the charging cradle and a second charging pin on the device in contact with second charging contact on the charging cradle and with the first charging pin on the device in contact with second charging contact on the charging cradle and the second charging pin on the device in contact with the first charging contact on the charging cradle. The charging pins may be visible on an exterior housing of the device. The user may permanently disable the device by opening the housing. The user may permanently destroy the device by opening the housing. Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in this art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is an illustrative cross-sectional view of an exemplary vaporization device. FIG. 2 is an illustrative cross-sectional view of an exemplary vaporization device with various electronic features and valves. FIG. 3 is an illustrative sectional view of another exemplary vaporization device comprising a condensation chamber, air inlet and aeration vent in the mouthpiece. FIGS. 4A-4C is an illustrative example of an oven section of another exemplary vaporization device configuration with a access lid, comprising an oven having an air inlet, air outlet, and an additional aeration vent in the airflow pathway, after the oven. FIG. 5 is an illustrative isometric view of an assembled inhalable aerosol device. FIGS. 6A-6D are illustrative arrangements and section views of the device body and sub-components. FIG. 7A is an illustrative isometric view of an assembled cartridge. FIG. 7B is an illustrative exploded isometric view of a cartridge assembly FIG. 7C is a side section view of FIG. 7A illustrating the inlet channel, inlet hole and relative placement of the wick, resistive heating element, and heater contacts, and the heater chamber inside of the heater. FIG. 8A is an illustrative end section view of an exemplary cartridge inside the heater. FIG. 8B is an illustrative side view of the cartridge with the cap removed and heater shown in shadow/outline. FIGS. 9A-9L illustrate an exemplary sequence of one assembly method for a cartridge. FIGS. 10A-10C are illustrative sequences showing the airflow/vapor path for the cartridge. FIGS. 11, 12, and 13 represent an illustrative assembly sequence for assembling the main components of the device. FIG. 14 illustrates front, side and section views of the assembled inhalable aerosol device. FIG. 15 is an illustrative view of an activated, assembled inhalable aerosol device. FIGS. 16A-16C are representative illustrations of a charging device for the aerosol device and the application of the charger with the device. FIGS. 17A and 17B are representative illustrations of a proportional-integral-derivative controller (PID) block diagram and circuit diagram representing the essential components in a device to control coil temperature. FIG. 17C is another example of a PID block diagram similar to that of FIG. 17A, in which the resistance of the resistive heater may be used to control the temperature of the apparatuses described herein. FIG. 17D is an example of a circuit showing one variation of the measurement circuit used in the PID block diagram shown in FIG. 17C. Specifically, this is an amplified Wheatstone bridge resistance measurement circuit. FIG. 18 is a device with charging contacts visible from an exterior housing of the device. FIG. 19 is an exploded view of a charging assembly of a device. FIG. 20 is a detailed view of a charging assembly of a device. FIG. 21 is a detailed view of charging pins in a charging assembly of a device. FIG. 22 is a device in a charging cradle. FIG. 23 is a circuit provided on a PCB configured to permit a device to comprise reversible charging contacts. FIGS. 24A and 24B show top and bottom perspective views, respectively of a cartridge device holding a vaporizable material for securely coupling with an electronic inhalable aerosol device as described herein. FIGS. 25A and 25B show front a side views, respectively, of the cartridge of FIGS. 24A-24B. FIG. 26A shows a section through a cartridge device holding a vaporizable material for securely coupling with an electronic inhalable aerosol device and indicates exemplary dimensions (in mm). FIG. 26B shows a side view of the cartridge of FIG. 26A, indicating where the sectional view of FIG. 26A was taken. FIGS. 27A and 27B show an exemplary vaporizer device without a cartridge attached. FIG. 27A is a side view and FIG. 27B shows a sectional view with exemplary dimensions of the rectangular opening for holding and making electrical contact with a cartridge. FIG. 28A shows a perspective view of a vaporizer coupled to a cartridge as described herein. FIG. 28B shows a side view of the vaporizer of FIG. 28A. FIG. 28C shows a sectional view through the vaporizer of FIG. 28B taken through the dashed line. FIG. 28D is an enlarged view of the region showing the electrical and mechanical connection between the cartridge and the vaporizer indicted by the circular region D. FIGS. 29A-29D illustrate side profiles of alternative variations of cartridges as described herein. DETAILED DESCRIPTION Provided herein are systems and methods for generating a vapor from a material. The vapor may be delivered for inhalation by a user. The material may be a solid, liquid, powder, solution, paste, gel, or any a material with any other physical consistency. The vapor may be delivered to the user for inhalation by a vaporization device. The vaporization device may be a handheld vaporization device. The vaporization device may be held in one hand by the user. The vaporization device may comprise a cartridge having one or more heating elements the heating element may be a resistive heating element. The heating element may heat the material such that the temperature of the material increases. Vapor may be generated as a result of heating the material. Energy may be required to operate the heating element, the energy may be derived from a battery in electrical communication with the heating element. Alternatively a chemical reaction (e.g., combustion or other exothermic reaction) may provide energy to the heating element. One or more aspects of the vaporization device may be designed and/or controlled in order to deliver a vapor with one or more specified properties to the user. For example, aspects of the vaporization device that may be designed and/or controlled to deliver the vapor with specified properties may comprise the heating temperature, heating mechanism, device air inlets, internal volume of the device, and/or composition of the material. In some cases, a vaporization device may have an “atomizer” or “cartomizer” configured to heat an aerosol forming solution (e.g., vaporizable material). The aerosol forming solution may comprise glycerin and/or propylene glycol. The vaporizable material may be heated to a sufficient temperature such that it may vaporize. An atomizer may be a device or system configured to generate an aerosol. The atomizer may comprise a small heating element configured to heat and/or vaporize at least a portion of the vaporizable material and a wicking material that may draw a liquid vaporizable material in to the atomizer. The wicking material may comprise silica fibers, cotton, ceramic, hemp, stainless steel mesh, and/or rope cables. The wicking material may be configured to draw the liquid vaporizable material in to the atomizer without a pump or other mechanical moving part. A resistance wire may be wrapped around the wicking material and then connected to a positive and negative pole of a current source (e.g., energy source). The resistance wire may be a coil. When the resistance wire is activated the resistance wire (or coil) may have a temperature increase as a result of the current flowing through the resistive wire to generate heat. The heat may be transferred to at least a portion of the vaporizable material through conductive, convective, and/or radiative heat transfer such that at least a portion of the vaporizable material vaporizes. Alternatively or in addition to the atomizer, the vaporization device may comprise a “cartomizer” to generate an aerosol from the vaporizable material for inhalation by the user. The cartomizer may comprise a cartridge and an atomizer. The cartomizer may comprise a heating element surrounded by a liquid-soaked poly-foam that acts as holder for the vaporizable material (e.g., the liquid). The cartomizer may be reusable, rebuildable, refillable, and/or disposable. The cartomizer may be used with a tank for extra storage of a vaporizable material. Air may be drawn into the vaporization device to carry the vaporized aerosol away from the heating element, where it then cools and condenses to form liquid particles suspended in air, which may then be drawn out of the mouthpiece by the user. The vaporization of at least a portion of the vaporizable material may occur at lower temperatures in the vaporization device compared to temperatures required to generate an inhalable vapor in a cigarette. A cigarette may be a device in which a smokable material is burned to generate an inhalable vapor. The lower temperature of the vaporization device may result in less decomposition and/or reaction of the vaporized material, and therefore produce an aerosol with many fewer chemical components compared to a cigarette. In some cases, the vaporization device may generate an aerosol with fewer chemical components that may be harmful to human health compared to a cigarette. Additionally, the vaporization device aerosol particles may undergo nearly complete evaporation in the heating process, the nearly complete evaporation may yield an average particle size (e.g., diameter) value that may be smaller than the average particle size in tobacco or botanical based effluent. A vaporization device may be a device configured to extract for inhalation one or more active ingredients of plant material, tobacco, and/or a botanical, or other herbs or blends. A vaporization device may be used with pure chemicals and/or humectants that may or may not be mixed with plant material. Vaporization may be alternative to burning (smoking) that may avoid the inhalation of many irritating and/or toxic carcinogenic by-products which may result from the pyrolytic process of burning tobacco or botanical products above 300° C. The vaporization device may operate at a temperature at or below 300° C. A vaporizer (e.g., vaporization device) may not have an atomizer or cartomizer. Instead the device may comprise an oven. The oven may be at least partially closed. The oven may have a closable opening. The oven may be wrapped with a heating element, alternatively the heating element may be in thermal communication with the oven through another mechanism. A vaporizable material may be placed directly in the oven or in a cartridge fitted in the oven. The heating element in thermal communication with the oven may heat a vaporizable material mass in order to create a gas phase vapor. The heating element may heat the vaporizable material through conductive, convective, and/or radiative heat transfer. The vapor may be released to a vaporization chamber where the gas phase vapor may condense, forming an aerosol cloud having typical liquid vapor particles with particles having a diameter of average mass of approximately 1 micron or greater. In some cases the diameter of average mass may be approximately 0.1-1 micron. A used herein, the term “vapor” may generally refer to a substance in the gas phase at a temperature lower than its critical point. The vapor may be condensed to a liquid or to a solid by increasing its pressure without reducing the temperature. As used herein, the term “aerosol” may generally refer to a colloid of fine solid particles or liquid droplets in air or another gas. Examples of aerosols may include clouds, haze, and smoke, including the smoke from tobacco or botanical products. The liquid or solid particles in an aerosol may have varying diameters of average mass that may range from monodisperse aerosols, producible in the laboratory, and containing particles of uniform size; to polydisperse colloidal systems, exhibiting a range of particle sizes. As the sizes of these particles become larger, they have a greater settling speed which causes them to settle out of the aerosol faster, making the appearance of the aerosol less dense and to shorten the time in which the aerosol will linger in air. Interestingly, an aerosol with smaller particles will appear thicker or denser because it has more particles. Particle number has a much bigger impact on light scattering than particle size (at least for the considered ranges of particle size), thus allowing for a vapor cloud with many more smaller particles to appear denser than a cloud having fewer, but larger particle sizes. As used herein the term “humectant” may generally refer to as a substance that is used to keep things moist. A humectant may attract and retain moisture in the air by absorption, allowing the water to be used by other substances. Humectants are also commonly used in many tobaccos or botanicals and electronic vaporization products to keep products moist and as vapor-forming medium. Examples include propylene glycol, sugar polyols such as glycerol, glycerin, and honey. Rapid Aeration In some cases, the vaporization device may be configured to deliver an aerosol with a high particle density. The particle density of the aerosol may refer to the number of the aerosol droplets relative to the volume of air (or other dry gas) between the aerosol droplets. A dense aerosol may easily be visible to a user. In some cases the user may inhale the aerosol and at least a fraction of the aerosol particles may impinge on the lungs and/or mouth of the user. The user may exhale residual aerosol after inhaling the aerosol. When the aerosol is dense the residual aerosol may have sufficient particle density such that the exhaled aerosol is visible to the user. In some cases, a user may prefer the visual effect and/or mouth feel of a dense aerosol. A vaporization device may comprise a vaporizable material. The vaporizable material may be contained in a cartridge or the vaporizable material may be loosely placed in one or more cavities the vaporization device. A heating element may be provided in the device to elevate the temperature of the vaporizable material such that at least a portion of the vaporizable material forms a vapor. The heating element may heat the vaporizable material by convective heat transfer, conductive heat transfer, and/or radiative heat transfer. The heating element may heat the cartridge and/or the cavity in which the vaporizable material is stored. Vapor formed upon heating the vaporizable material may be delivered to the user. The vapor may be transported through the device from a first position in the device to a second position in the device. In some cases, the first position may be a location where at least a portion of the vapor was generated, for example, the cartridge or cavity or an area adjacent to the cartridge or cavity. The second position may be a mouthpiece. The user may suck on the mouthpiece to inhale the vapor. At least a fraction of the vapor may condense after the vapor is generated and before the vapor is inhaled by the user. The vapor may condense in a condensation chamber. The condensation chamber may be a portion of the device that the vapor passes through before delivery to the user. In some cases, the device may include at least one aeration vent, placed in the condensation chamber of the vaporization device. The aeration vent may be configured to introduce ambient air (or other gas) into the vaporization chamber. The air introduced into the vaporization chamber may have a temperature lower than the temperature of a gas and/or gas/vapor mixture in the condensation chamber. Introduction of the relatively lower temperature gas into the vaporization chamber may provide rapid cooling of the heated gas vapor mixture that was generated by heating the vaporizable material. Rapid cooling of the gas vapor mixture may generate a dense aerosol comprising a high concentration of liquid droplets having a smaller diameter and/or smaller average mass compared to an aerosol that is not rapidly cooled prior to inhalation by the user. An aerosol with a high concentration of liquid droplets having a smaller diameter and/or smaller average mass compared to an aerosol that is not rapidly cooled prior to inhalation by the user may be formed in a two-step process. The first step may occur in the oven chamber where the vaporizable material (e.g., tobacco and/or botanical and humectant blend) may be heated to an elevated temperature. At the elevated temperature, evaporation may happen faster than at room temperature and the oven chamber may fill with the vapor phase of the humectants. The humectant may continue to evaporate until the partial pressure of the humectant is equal to the saturation pressure. At this point, the gas is said to have a saturation ratio of 1 (S=Ppartial1/Psat). In the second step, the gas (e.g., vapor and air) may exit the oven and enter a condenser or condensation chamber and begin to cool. As the gas phase vapor cools, the saturation pressure may decrease. As the saturation pressure decreases, the saturation ratio may increase and the vapor may begin to condense, forming droplets. In some devices, with the absence of added cooling aeration, the cooling may be relatively slower such that high saturation pressures may not be reached, and the droplets that form in the devices without added cooling aeration may be relatively larger and fewer in numbers. When cooler air is introduced, a temperature gradient may be formed between the cooler air and the relatively warmer gas in the device. Mixing between the cooler air and the relatively warmer gas in a confined space inside of the vaporization device may lead to rapid cooling. The rapid cooling may generate high saturation ratios, small particles, and high concentrations of smaller particles, forming a thicker, denser vapor cloud compared to particles generated in a device without the aeration vents. For the purpose of this disclosure, when referring to ratios of humectants such as vegetable glycerol or propylene glycol, “about” means a variation of 5%, 10%, 20% or 25% depending on the embodiment. For the purpose of this disclosure, when referring to a diameter of average mass in particle sizes, “about” means a variation of 5%, 10%, 20% or 25% depending on the embodiment. A vaporization device configured to rapidly cool a vapor may comprise: a mouthpiece comprising an aerosol outlet at a first end of the device; an oven comprising an oven chamber and a heater for heating a vapor forming medium in the oven chamber and for forming a vapor therein; a condenser comprising a condensation chamber in which the vapor forms the inhalable aerosol; an air inlet that originates a first airflow path that includes the oven chamber and then the condensation chamber, an aeration vent that originates a second airflow path that joins the first airflow path prior to or within the condensation chamber after the vapor is formed in the oven chamber, wherein the joined first airflow path and second airflow path are configured to deliver the inhalable aerosol formed in the condensation chamber through the aerosol outlet of the mouthpiece to a user. In some embodiments, the oven is within a body of the device. The oven chamber may comprise an oven chamber inlet and an oven chamber outlet. The oven may further comprise a first valve at the oven chamber inlet, and a second valve at the oven chamber outlet. The oven may be contained within a device housing. In some cases the body of the device may comprise the aeration vent and/or the condenser. The body of the device may comprise one or more air inlets. The body of the device may comprise a housing that holds and/or at least partially contains one or more elements of the device. The mouthpiece may be connected to the body. The mouthpiece may be connected to the oven. The mouthpiece may be connected to a housing that at least partially encloses the oven. In some cases, the mouthpiece may be separable from the oven, the body, and/or the housing that at least partially encloses the oven. The mouthpiece may comprise at least one of the air inlet, the aeration vent, and the condenser. The mouthpiece may be integral to the body of the device. The body of the device may comprise the oven. In some cases, the one or more aeration vents may comprise a valve. The valve may regulate a flow rate of air entering the device through the aeration vent. The valve may be controlled through a mechanical and/or electrical control system. A vaporization device configured to rapidly cool a vapor may comprise: a body, a mouthpiece, an aerosol outlet, a condenser with a condensation chamber, a heater, an oven with an oven chamber, a primary airflow inlet, and at least one aeration vent provided in the body, downstream of the oven, and upstream of the mouthpiece. FIG. 1 shows an example of a vaporization device configured to rapidly cool a vapor. The device 100, may comprise a body 101. The body may house and/or integrate with one or more components of the device. The body may house and/or integrate with a mouthpiece 102. The mouthpiece 102 may have an aerosol outlet 122. A user may inhale the generated aerosol through the aerosol outlet 122 on the mouthpiece 102. The body may house and/or integrate with an oven region 104. The oven region 104 may comprise an oven chamber where vapor forming medium 106 may be placed. The vapor forming medium may include tobacco and/or botanicals, with or without a secondary humectant. In some cases the vapor forming medium may be contained in a removable and/or refillable cartridge. Air may be drawn into the device through a primary air inlet 121. The primary air inlet 121 may be on an end of the device 100 opposite the mouthpiece 102. Alternatively, the primary air inlet 121 may be adjacent to the mouthpiece 102. In some cases, a pressure drop sufficient to pull air into the device through the primary air inlet 121 may be due to a user puffing on the mouthpiece 102. The vapor forming medium (e.g., vaporizable material) may be heated in the oven chamber by a heater 105, to generate elevated temperature gas phases (vapor) of the tobacco or botanical and humectant/vapor forming components. The heater 105 may transfer heat to the vapor forming medium through conductive, convective, and/or radiative heat transfer. The generated vapor may be drawn out of the oven region and into the condensation chamber 103a, of the condenser 103 where the vapors may begin to cool and condense into micro-particles or droplets suspended in air, thus creating the initial formation of an aerosol, before being drawn out of the mouthpiece through the aerosol outlet 122. In some cases, relatively cooler air may be introduced into the condensation chamber 103a, through an aeration vent 107 such that the vapor condenses more rapidly compared to a vapor in a device without the aeration vent 107. Rapidly cooling the vapor may create a denser aerosol cloud having particles with a diameter of average mass of less than or equal to about 1 micron, and depending on the mixture ratio of the vapor-forming humectant, particles with a diameter of average mass of less than or equal to about 0.5 micron Also described herein are devices for generating an inhalable aerosol said device comprising a body with a mouthpiece at one end, an attached body at the other end comprising a condensation chamber, a heater, an oven, wherein the oven comprises a first valve in the airflow path at the primary airflow inlet of the oven chamber, and a second valve at the outlet end of the oven chamber, and at least one aeration vent provided in the body, downstream of the oven, and upstream of the mouthpiece. FIG. 2 shows a diagram of an alternative embodiment of the vaporization device 200. The vaporization device may have a body 201. The body 201 may integrate with and/or contain one or more components of the device. The body may integrate with or be connected to a mouthpiece 202 The body may comprise an oven region 204, with an oven chamber 204a having a first constricting valve 208 in the primary air inlet of the oven chamber and a second constricting valve 209 at the oven chamber outlet. The oven chamber 204a may be sealed with a tobacco or botanical and/or humectant/vapor forming medium 206 therein. The seal may be an air tight and/or liquid tight seal. The heater may be provided to the oven chamber with a heater 205. The heater 205 may be in thermal communication with the oven, for example the heater may be surrounding the oven chamber during the vaporization process. Heater may contact the oven. The heater may be wrapped around the oven. Before inhalation and before air is drawn in through a primary air inlet 221, pressure may build in the sealed oven chamber as heat is continually added. The pressure may build due to a phase change of the vaporizable material. Elevated temperature gas phases (vapor) of the tobacco or botanical and humectant/vapor forming components may be achieved by continually adding heat to the oven. This heated pressurization process may generate even higher saturation ratios when the valves 208, 209 are opened during inhalation. The higher saturation ratios may cause relatively higher particle concentrations of gas phase humectant in the resultant aerosol. When the vapor is drawn out of the oven region and into the condensation chamber 203a of the condenser 203, for example by inhalation by the user, the gas phase humectant vapors may be exposed to additional air through an aeration vent 207, and the vapors may begin to cool and condense into droplets suspended in air. As described previously the aerosol may be drawn through the mouthpiece 222 by the user. This condensation process may be further refined by adding an additional valve 210, to the aeration vent 207 to further control the air-vapor mixture process. FIG. 2 also illustrates an exemplary embodiment of the additional components which would be found in a vaporizing device, including a power source or battery 211, a printed circuit board 212, a temperature regulator 213, and operational switches (not shown), housed within an internal electronics housing 214, to isolate them from the damaging effects of the moisture in the vapor and/or aerosol. The additional components may be found in a vaporizing device that may or may not comprise an aeration vent as described above. In some embodiments of the vaporization device, components of the device are user serviceable, such as the power source or battery. These components may be replaceable or rechargeable. Also described herein are devices for generating an inhalable aerosol said device comprising a first body, a mouthpiece having an aerosol outlet, a condensation chamber within a condenser and an airflow inlet and channel, an attached second body, comprising a heater and oven with an oven chamber, wherein said airflow channel is upstream of the oven and the mouthpiece outlet to provide airflow through the device, across the oven, and into the condensation chamber where an auxiliary aeration vent is provided. FIG. 3 shows a section view of a vaporization device 300. The device 300 may comprise a body 301. The body may be connected to or integral with a mouthpiece 302 at one end. The mouthpiece may comprise a condensation chamber 303a within a condenser section 303 and an airflow inlet 321 and air channel 323. The device body may comprise a proximally located oven 304 comprising an oven chamber 304a. The oven chamber may be in the body of the device. A vapor forming medium 306 (e.g., vaporizable material) comprising tobacco or botanical and humectant vapor forming medium may be placed in the oven. The vapor forming medium may be in direct contact with an air channel 323 from the mouthpiece. The tobacco or botanical may be heated by heater 305 surrounding the oven chamber, to generate elevated temperature gas phases (vapor) of the tobacco or botanical and humectant/vapor forming components and air drawn in through a primary air inlet 321, across the oven, and into the condensation chamber 303a of the condenser region 303 due to a user puffing on the mouthpiece. Once in the condensation chamber where the gas phase humectant vapors begin to cool and condense into droplets suspended in air, additional air is allowed to enter through aeration vent 307, thus, once again creating a denser aerosol cloud having particles with a diameter of average mass of less than a typical vaporization device without an added aeration vent, before being drawn out of the mouthpiece through the aerosol outlet 322. The device may comprises a mouthpiece comprising an aerosol outlet at a first end of the device and an air inlet that originates a first airflow path; an oven comprising an oven chamber that is in the first airflow path and includes the oven chamber and a heater for heating a vapor forming medium in the oven chamber and for forming a vapor therein, a condenser comprising a condensation chamber in which the vapor forms the inhalable aerosol, an aeration vent that originates a second airflow path that allows air from the aeration vent to join the first airflow path prior to or within the condensation chamber and downstream from the oven chamber thereby forming a joined path, wherein the joined path is configured to deliver the inhalable aerosol formed in the condensation chamber through the aerosol outlet of the mouthpiece to a user. The device may comprise a mouthpiece comprising an aerosol outlet at a first end of the device, an air inlet that originates a first airflow path, and an aeration vent that originates a second airflow path that allows air from the aeration vent to join the first airflow path; an oven comprising an oven chamber that is in the first airflow path and includes the oven chamber and a heater for heating a vapor forming medium in the oven chamber and for forming a vapor therein, a condenser comprising a condensation chamber in which the vapor forms the inhalable aerosol and wherein air from the aeration vent joins the first airflow path prior to or within the condensation chamber and downstream from the oven chamber thereby forming a joined path, wherein the joined path is configured to deliver the inhalable aerosol through the aerosol outlet of the mouthpiece to a user, as illustrated in exemplary FIG. 3. The device may comprise a body with one or more separable components. For example, the mouthpiece may be separably attached to the body comprising the condensation chamber, a heater, and an oven, as illustrated in exemplary FIG. 1 or 2. The device may comprise a body with one or more separable components. For example, the mouthpiece may be separably attached to the body. The mouthpiece may comprise the condensation chamber, and may be attached to or immediately adjacent to the oven and which is separable from the body comprising a heater, and the oven, as illustrated in exemplary FIG. 3. The at least one aeration vent may be located in the condensation chamber of the condenser, as illustrated in exemplary FIG. 1, 2, or 3. The at least one aeration vent may comprise a third valve in the airflow path of the at least one aeration vent, as illustrated in exemplary FIG. 2. The first, second and third valve is a check valve, a clack valve, a non-return valve, or a one-way valve. In any of the preceding variations, the first, second or third valve may be mechanically actuated, electronically actuated or manually actuated. One skilled in the art will recognize after reading this disclosure that this device may be modified in a way such that any one, or each of these openings or vents could be configured to have a different combination or variation of mechanisms as described to control airflow, pressure and temperature of the vapor created and aerosol being generated by these device configurations, including a manually operated opening or vent with or without a valve. The device may further comprise at least one of: a power source, a printed circuit board, a switch, and a temperature regulator. Alternately, one skilled in the art would recognize that each configuration previously described will also accommodate said power source (battery), switch, printed circuit board, or temperature regulator as appropriate, in the body. The device may be disposable when the supply of pre-packaged aerosol-forming media is exhausted. Alternatively, the device may be rechargeable such that the battery may be rechargeable or replaceable, and /or the aerosol-forming media may be refilled, by the user/operator of the device. Still further, the device may be rechargeable such that the battery may be rechargeable or replaceable, and/or the operator may also add or refill a tobacco or botanical component, in addition to a refillable or replaceable aerosol-forming media to the device. As illustrated in FIG. 1, 2 or 3, the vaporization device may comprise tobacco or a botanical heated in said oven chamber, wherein said tobacco or botanical further comprises humectants to produce an aerosol comprising gas phase components of the humectant and tobacco or botanical. The gas phase humectant and tobacco or botanical vapor produced by said heated aerosol forming media 106, 206, 306 may further be mixed with air from a special aeration vent 107, 207, 307 after exiting the oven area 104, 204, 304 and entering a condensation chamber 103a, 203a, 303a to cool and condense said gas phase vapors to produce a far denser, thicker aerosol comprising more particles than would have otherwise been produced without the extra cooling air, with a diameter of average mass of less than or equal to about 1 micron. Each aerosol configuration produced by mixing the gas phase vapors with the cool air may comprise a different range of particles, for example; with a diameter of average mass of less than or equal to about 0.9 micron; less than or equal to about 0.8 micron; less than or equal to about 0.7 micron; less than or equal to about 0.6 micron; and even an aerosol comprising particle diameters of average mass of less than or equal to about 0.5 micron. The possible variations and ranges of aerosol density are great in that the possible number of combinations of temperature, pressure, tobacco or botanical choices and humectant selections are numerous. However, by excluding the tobacco or botanical choices and limiting the temperatures ranges and the humectant ratios to those described herein, the inventor has demonstrated that this device will produce a far denser, thicker aerosol comprising more particles than would have otherwise been produced without the extra cooling air, with a diameter of average mass of less than or equal to about 1 micron. The humectant may comprise glycerol or vegetable glycerol as a vapor-forming medium. The humectant may comprise propylene glycol as a vapor-forming medium. In preferred embodiments, the humectant may comprise a ratio of vegetable glycerol to propylene glycol as a vapor-forming medium. The ranges of said ratio may vary between a ratio of about 100:0 vegetable glycerol to propylene glycol and a ratio of about 50:50 vegetable glycerol to propylene glycol. The difference in preferred ratios within the above stated range may vary by as little as 1, for example, said ratio may be about 99:1 vegetable glycerol to propylene glycol. However, more commonly said ratios would vary in increments of about 5, for example, about 95:5 vegetable glycerol to propylene glycol; or about 85:15 vegetable glycerol to propylene glycol; or about 55:45 vegetable glycerol to propylene glycol. In a preferred embodiment the ratio for the vapor forming medium will be between the ratios of about 80:20 vegetable glycerol to propylene glycol, and about 60:40 vegetable glycerol to propylene glycol. In a most preferred embodiment, the ratio for the vapor forming medium will be about 70:30 vegetable glycerol to propylene glycol. In any of the preferred embodiments, the humectant may further comprise flavoring products. These flavorings may include enhancers comprising cocoa solids, licorice, tobacco or botanical extracts, and various sugars, to name but a few. The tobacco or botanical may be heated in the oven up to its pyrolytic temperature, which as noted previously is most commonly measured in the range of 300-1000° C. In preferred embodiments, the tobacco or botanical is heated to about 300° C. at most. In other preferred embodiments, the tobacco or botanical is heated to about 200° C. at most. In still other preferred embodiments, the tobacco or botanical is heated to about 160° C. at most. It should be noted that in these lower temperature ranges (<300° C.), pyrolysis of tobacco or botanical does not typically occur, yet vapor formation of the tobacco or botanical components and flavoring products does occur. In addition, vapor formation of the components of the humectant, mixed at various ratios will also occur, resulting in nearly complete vaporization, depending on the temperature, since propylene glycol has a boiling point of about 180°-190° C. and vegetable glycerin will boil at approximately 280°-290° C. In still other preferred embodiments, the aerosol produced by said heated tobacco or botanical and humectant is mixed with air provided through an aeration vent. In still other preferred embodiments, the aerosol produced by said heated tobacco or botanical and humectant mixed with air, is cooled to a temperature of about 50°-70° C. at most, and even as low as 35° C. before exiting the mouthpiece, depending on the air temperature being mixed into the condensation chamber. In some embodiments, the temperature is cooled to about 35°-55° C. at most, and may have a fluctuating range of ± about 10° C. or more within the overall range of about 35°-70° C. Also described herein are vaporization devices for generating an inhalable aerosol comprising a unique oven configuration, wherein said oven comprises an access lid and an auxiliary aeration vent located within the airflow channel immediately downstream of the oven and before the aeration chamber. In this configuration, the user may directly access the oven by removing the access lid, providing the user with the ability to recharge the device with vaporization material. In addition, having the added aeration vent in the airflow channel immediately after the oven and ahead of the vaporization chamber provides the user with added control over the amount of air entering the aeration chamber downstream and the cooling rate of the aerosol before it enters the aeration chamber. As noted in FIGS. 4A-4C, the device 400 may comprise a body 401, having an air inlet 421 allowing initial air for the heating process into the oven region 404. After heating the tobacco or botanical, and humectant (heater not shown), the gas phase humectant vapor generated may travel down the airflow channel 423, passing the added aeration vent 407 wherein the user may selectively increase airflow into the heated vapor. The user may selectively increase and/or decrease the airflow to the heated vapor by controlling a valve in communication with the aeration vent 407. In some cases, the device may not have an aeration vent. Airflow into the heated vapor through the aeration vent may decrease the vapor temperature before exiting the airflow channel at the outlet 422, and increase the condensation rate and vapor density by decreasing the diameter of the vapor particles within the aeration chamber (not shown), thus producing a thicker, denser vapor compared to the vapor generated by a device without the aeration vent. The user may also access the oven chamber 404a to recharge or reload the device 400, through an access lid 430 provided therein, making the device user serviceable. The access lid may be provided on a device with or without an aeration vent. Provided herein is a method for generating an inhalable aerosol, the method comprising: providing an vaporization device, wherein said device produces a vapor comprising particle diameters of average mass of about 1 micron or less, wherein the vapor is formed by heating a vapor forming medium in an oven chamber of the device to a first temperature below the pyrolytic temperature of the vapor forming medium, and cooling the vapor in a condensation chamber to a temperature below the first temperature, before exiting an aerosol outlet of said device. In some embodiments the vapor may be cooled by mixing relatively cooler air with the vapor in the condensation chamber during the condensation phase, after leaving the oven, where condensation of the gas phase humectants occurs more rapidly due to high saturation ratios being achieved at the moment of aeration, producing a higher concentration of smaller particles, with fewer by-products, in a denser aerosol, than would normally occur in a standard vaporization or aerosol generating device. In some embodiments, formation of an inhalable aerosol is a two-step process. The first step occurs in the oven where the tobacco or botanical and humectant blend is heated to an elevated temperature. At the elevated temperature, evaporation happens faster than at room temperature and the oven chamber fills with the vapor phase of the humectants. The humectant will continue to evaporate until the partial pressure of the humectant is equal to the saturation pressure. At this point, the gas is said to have a saturation ratio of 1 (S=Ppartial/Psat). In the second step, the gas leaves the oven chamber, passes to a condensation chamber in a condenser and begins to cool. As the gas phase vapor cools, the saturation pressure also goes down, causing the saturation ratio to rise, and the vapor to condensate, forming droplets. When cooling air is introduced, the large temperature gradient between the two fluids mixing in a confined space leads to very rapid cooling, causing high saturation ratios, small particles, and higher concentrations of smaller particles, forming a thicker, denser vapor cloud. Provided herein is a method for generating an inhalable aerosol comprising: a vaporization device having a body with a mouthpiece at one end, and an attached body at the other end comprising; a condenser with a condensation chamber, a heater, an oven with an oven chamber, and at least one aeration vent provided in the body, downstream of the oven, and upstream of the mouthpiece, wherein tobacco or botanical comprising a humectant is heated in said oven chamber to produce a vapor comprising gas phase humectants. As previously described, a vaporization device having an auxiliary aeration vent located in the condensation chamber capable of supplying cool air (relative to the heated gas components) to the gas phase vapors and tobacco or botanical components exiting the oven region, may be utilized to provide a method for generating a far denser, thicker aerosol comprising more particles than would have otherwise been produced without the extra cooling air, with a diameter of average mass of less than or equal to about 1 micron. In another aspect, provided herein is a method for generating an inhalable aerosol comprising: a vaporization device, having a body with a mouthpiece at one end, and an attached body at the other end comprising: a condenser with a condensation chamber, a heater, an oven with an oven chamber, wherein said oven chamber further comprises a first valve in the airflow path at the inlet end of the oven chamber, and a second valve at the outlet end of the oven chamber; and at least one aeration vent provided in said body, downstream of the oven, and upstream of the mouthpiece wherein tobacco or botanical comprising a humectant is heated in said oven chamber to produce a vapor comprising gas phase humectants. As illustrated in exemplary FIG. 2, by sealing the oven chamber 204a with a tobacco or botanical and humectant vapor forming medium 206 therein, and applying heat with the heater 205 during the vaporization process, before inhalation and air is drawn in through a primary air inlet 221, the pressure will build in the oven chamber as heat is continually added with an electronic heating circuit generated through the combination of the battery 211, printed circuit board 212, temperature regulator 213, and operator controlled switches (not shown), to generate even greater elevated temperature gas phase humectants (vapor) of the tobacco or botanical and humectant vapor forming components. This heated pressurization process generates even higher saturation ratios when the valves 208, 209 are opened during inhalation, which cause higher particle concentrations in the resultant aerosol, when the vapor is drawn out of the oven region and into the condensation chamber 203a, where they are again exposed to additional air through an aeration vent 207, and the vapors begin to cool and condense into droplets suspended in air, as described previously before the aerosol is withdrawn through the mouthpiece 222. The inventor also notes that this condensation process may be further refined by adding an additional valve 210, to the aeration vent 207 to further control the air-vapor mixture process. In some embodiments of any one of the inventive methods, the first, second and/or third valve is a one-way valve, a check valve, a clack valve, or a non-return valve. The first, second and/or third valve may be mechanically actuated. The first, second and/or third valve may be electronically actuated. The first, second and/or third valve may be automatically actuated. The first, second and/or third valve may be manually actuated either directly by a user or indirectly in response to an input command from a user to a control system that actuates the first, second and/or third valve. In other aspects of the inventive methods, said device further comprises at least one of: a power source, a printed circuit board, or a temperature regulator. In any of the preceding aspects of the inventive method, one skilled in the art will recognize after reading this disclosure that this method may be modified in a way such that any one, or each of these openings or vents could be configured to have a different combination or variation of mechanisms or electronics as described to control airflow, pressure and temperature of the vapor created and aerosol being generated by these device configurations, including a manually operated opening or vent with or without a valve. The possible variations and ranges of aerosol density are great in that the possible number of temperature, pressure, tobacco or botanical choices and humectant selections and combinations are numerous. However, by excluding the tobacco or botanical choices and limiting the temperatures to within the ranges and the humectant ratios described herein, the inventor has demonstrated a method for generating a far denser, thicker aerosol comprising more particles than would have otherwise been produced without the extra cooling air, with a diameter of average mass of less than or equal to 1 micron. In some embodiments of the inventive methods, the humectant comprises a ratio of vegetable glycerol to propylene glycol as a vapor-forming medium. The ranges of said ratio will vary between a ratio of about 100:0 vegetable glycerol to propylene glycol and a ratio of about 50:50 vegetable glycerol to propylene glycol. The difference in preferred ratios within the above stated range may vary by as little as 1, for example, said ratio may be about 99:1 vegetable glycerol to propylene glycol. However, more commonly said ratios would vary in increments of 5, for example, about 95:5 vegetable glycerol to propylene glycol; or about 85:15 vegetable glycerol to propylene glycol; or about 55:45 vegetable glycerol to propylene glycol. Because vegetable glycerol is less volatile than propylene glycol, it will recondense in greater proportions. A humectant with higher concentrations of glycerol will generate a thicker aerosol. The addition of propylene glycol will lead to an aerosol with a reduced concentration of condensed phase particles and an increased concentration of vapor phase effluent. This vapor phase effluent is often perceived as a tickle or harshness in the throat when the aerosol is inhaled. To some consumers, varying degrees of this sensation may be desirable. The ratio of vegetable glycerol to propylene glycol may be manipulated to balance aerosol thickness with the right amount of “throat tickle.” In a preferred embodiment of the method, the ratio for the vapor forming medium will be between the ratios of about 80:20 vegetable glycerol to propylene glycol, and about 60:40 vegetable glycerol to propylene glycol. In a most preferred embodiment of the method, the ratio for the vapor forming medium will be about 70:30 vegetable glycerol to propylene glycol. On will envision that there will be blends with varying ratios for consumers with varying preferences. In any of the preferred embodiments of the method, the humectant further comprises flavoring products. These flavorings include enhancers such as cocoa solids, licorice, tobacco or botanical extracts, and various sugars, to name a few. In some embodiments of the method, the tobacco or botanical is heated to its pyrolytic temperature. In preferred embodiments of the method, the tobacco or botanical is heated to about 300° C. at most. In other preferred embodiments of the method, the tobacco or botanical is heated to about 200° C. at most. In still other embodiments of the method, the tobacco or botanical is heated to about 160° C. at most. As noted previously, at these lower temperatures, (<300° C.), pyrolysis of tobacco or botanical does not typically occur, yet vapor formation of the tobacco or botanical components and flavoring products does occur. As may be inferred from the data supplied by Baker et al., an aerosol produced at these temperatures is also substantially free from Hoffman analytes or at least 70% less Hoffman analytes than a common tobacco or botanical cigarette and scores significantly better on the Ames test than a substance generated by burning a common cigarette. In addition, vapor formation of the components of the humectant, mixed at various ratios will also occur, resulting in nearly complete vaporization, depending on the temperature, since propylene glycol has a boiling point of about 180°-190° C. and vegetable glycerin will boil at approximately 280°-290° C. In any one of the preceding methods, said inhalable aerosol produced by tobacco or a botanical comprising a humectant and heated in said oven produces an aerosol comprising gas phase humectants is further mixed with air provided through an aeration vent. In any one of the preceding methods, said aerosol produced by said heated tobacco or botanical and humectant mixed with air, is cooled to a temperature of about 50°-70° C., and even as low as 35° C., before exiting the mouthpiece. In some embodiments, the temperature is cooled to about 35°-55° C. at most, and may have a fluctuating range of ± about 10° C. or more within the overall range of about 35°-70° C. In some embodiments of the method, the vapor comprising gas phase humectant may be mixed with air to produce an aerosol comprising particle diameters of average mass of less than or equal to about 1 micron. In other embodiments of the method, each aerosol configuration produced by mixing the gas phase vapors with the cool air may comprise a different range of particles, for example; with a diameter of average mass of less than or equal to about 0.9 micron; less than or equal to about 0.8 micron; less than or equal to about 0.7 micron; less than or equal to about 0.6 micron; and even an aerosol comprising particle diameters of average mass of less than or equal to about 0.5 micron. Cartridge Design and Vapor Generation from Material in Cartridge In some cases, a vaporization device may be configured to generate an inhalable aerosol. A device may be a self-contained vaporization device. The device may comprise an elongated body which functions to complement aspects of a separable and recyclable cartridge with air inlet channels, air passages, multiple condensation chambers, flexible heater contacts, and multiple aerosol outlets. Additionally, the cartridge may be configured for ease of manufacture and assembly. Provided herein is a vaporization device for generating an inhalable aerosol. The device may comprise a device body, a separable cartridge assembly further comprising a heater, at least one condensation chamber, and a mouthpiece. The device provides for compact assembly and disassembly of components with detachable couplings; overheat shut-off protection for the resistive heating element; an air inlet passage (an enclosed channel) formed by the assembly of the device body and a separable cartridge; at least one condensation chamber within the separable cartridge assembly; heater contacts; and one or more refillable, reusable, and/or recyclable components. Provided herein is a device for generating an inhalable aerosol comprising: a device body comprising a cartridge receptacle; a cartridge comprising: a storage compartment, and a channel integral to an exterior surface of the cartridge, and an air inlet passage formed by the channel and an internal surface of the cartridge receptacle when the cartridge is inserted into the cartridge receptacle. The cartridge may be formed from a metal, plastic, ceramic, and/or composite material. The storage compartment may hold a vaporizable material. FIG. 7A shows an example of a cartridge 30 for use in the device. The vaporizable material may be a liquid at or near room temperature. In some cases the vaporizable material may be a liquid below room temperature. The channel may form a first side of the air inlet passage, and an internal surface of the cartridge receptacle may form a second side of the air inlet passage, as illustrated in various non-limiting aspects of FIGS. 5-6D, 7C,8A, 8B, and 10A Provided herein is a device for generating an inhalable aerosol. The device may comprise a body that houses, contains, and or integrates with one or more components of the device. The device body may comprise a cartridge receptacle. The cartridge receptacle may comprise a channel integral to an interior surface of the cartridge receptacle; and an air inlet passage formed by the channel and an external surface of the cartridge when the cartridge is inserted into the cartridge receptacle. A cartridge may be fitted and/or inserted into the cartridge receptacle. The cartridge may have a fluid storage compartment. The channel may form a first side of the air inlet passage, and an external surface of the cartridge forms a second side of the air inlet passage. The channel may comprise at least one of: a groove; a trough; a track; a depression; a dent; a furrow; a trench; a crease; and a gutter. The integral channel may comprise walls that are either recessed into the surface or protrude from the surface where it is formed. The internal side walls of the channel may form additional sides of the air inlet passage. The channel may have a round, oval, square, rectangular, or other shaped cross section. The channel may have a closed cross section. The channel may be about 0.1 cm, 0.5 cm, 1 cm, 2 cm, or 5 cm wide. The channel may be about 0.1 mm, 0.5 mm, 1 mm, 2 mm, or 5 mm deep. The channel may be about 0.1 cm, 0.5 cm, 1 cm, 2 cm, or 5 cm long. There may be at least 1 channel. In some embodiments, the cartridge may further comprise a second air passage in fluid communication with the air inlet passage to the fluid storage compartment, wherein the second air passage is formed through the material of the cartridge. FIGS. 5-7C show various views of a compact electronic device assembly 10 for generating an inhalable aerosol. The compact electronic device 10 may comprise a device body 20 with a cartridge receptacle 21 for receiving a cartridge 30. The device body may have a square or rectangular cross section. Alternatively, the cross section of the body may be any other regular or irregular shape. The cartridge receptacle may be shaped to receive an opened cartridge 30a or “pod”. The cartridge may be opened when a protective cap is removed from a surface of the cartridge. In some cases, the cartridge may be opened when a hole or opening is formed on a surface of the cartridge. The pod 30a may be inserted into an open end of the cartridge receptacle 21 so that an exposed first heater contact tips 33a on the heater contacts 33 of the pod make contact with the second heater contacts 22 of the device body, thus forming the device assembly 10. Referring to FIG. 14, it is apparent in the plan view that when the pod 30a is inserted into the notched body of the cartridge receptacle 21, the channel air inlet 50 is left exposed. The size of the channel air inlet 50 may be varied by altering the configuration of the notch in the cartridge receptacle 21. The device body may further comprise a rechargeable battery, a printed circuit board (PCB) 24 containing a microcontroller with the operating logic and software instructions for the device, a pressure switch 27 for sensing the user's puffing action to activate the heater circuit, an indicator light 26, charging contacts (not shown), and an optional charging magnet or magnetic contact (not shown). The cartridge may further comprise a heater 36. The heater may be powered by the rechargeable battery. The temperature of the heater may be controlled by the microcontroller. The heater may be attached to a first end of the cartridge. In some embodiments, the heater may comprise a heater chamber 37, a first pair of heater contacts 33, 33′, a fluid wick 34, and a resistive heating element 35 in contact with the wick. The first pair of heater contacts may comprise thin plates affixed about the sides of the heater chamber. The fluid wick and resistive heating element may be suspended between the heater contacts. In some embodiments, there may be two or more resistive heating elements 35, 35′ and two or more wicks 34, 34′. In some of the embodiments, the heater contact 33 may comprise: a flat plate; a male contact; a female receptacle, or both; a flexible contact and/or copper alloy or another electrically conductive material. The first pair of heater contacts may further comprise a formed shape that may comprise a tab (e.g., flange) having a flexible spring value that extends out of the heater to complete a circuit with the device body. The first pair of heater contact may be a heat sink that absorb and dissipate excessive heat produced by the resistive heating element. Alternatively, the first pair of heater contacts may be a heat shield that protects the heater chamber from excessive heat produced by the resistive heating element. The first pair of heater contacts may be press-fit to an attachment feature on the exterior wall of the first end of the cartridge. The heater may enclose a first end of the cartridge and a first end of the fluid storage compartment. As illustrated in the exploded assembly of FIG. 7B, a heater enclosure may comprises two or more heater contacts 33, each comprising a flat plate which may be machined or stamped from a copper alloy or similar electrically conductive material. The flexibility of the tip is provided by the cut-away clearance feature 33b created below the male contact point tip 33a which capitalizes on the inherent spring capacity of the metal sheet or plate material. Another advantage and improvement of this type of contact is the reduced space requirement, simplified construction of a spring contact point (versus a pogo pin) and the easy of assembly. The heater may comprise a first condensation chamber. The heater may comprise more one or more additional condensation chambers in addition to the first condensation chamber. The first condensation chamber may be formed along an exterior wall of the cartridge. In some cases, the cartridge (e.g., pod) is configured for ease of manufacturing and assembly. The cartridge may comprise an enclosure. The enclosure may be a tank. The tank may comprise an interior fluid storage compartment 32. The interior fluid storage compartment 32 which is open at one or both ends and comprises raised rails on the side edges 45b and 46b. The cartridge may be formed from plastic, metal, composite, and/or a ceramic material. The cartridge may be rigid or flexible. The tank may further comprise a set of first heater contact plates 33 formed from copper alloy or another electrically conductive material, having a thin cut-out 33b below the contact tips 33a (to create a flexible tab) which are affixed to the sides of the first end of the tank and straddle the open-sided end 53 of the tank. The plates may affix to pins, or posts as shown in FIG. 7B or 5, or may be attached by other common means such as compression beneath the enclosure 36. A fluid wick 34 having a resistive heating element 35 wrapped around it, is placed between the first heater contact plates 33, and attached thereto. A heater 36, comprising raised internal edges on the internal end (not shown), a thin mixing zone (not shown), and primary condensation channel covers 45a that slide over the rails 45b on the sides of the tank on the first half of the tank, creating a primary condensation channel/chamber 45. In addition, a small male snap feature 39b located at the end of the channel cover is configured fall into a female snap feature 39a, located mid-body on the side of the tank, creating a snap-fit assembly. As will be further clarified below, the combination of the open-sided end 53, the protruding tips 33a of the contact plates 33, the fluid wick 34 having a resistive heating element 35, enclosed in the open end of the fluid storage tank, under the heater 36, with a thin mixing zone therein, creates an efficient heater system. In addition, the primary condensation channel covers 45a which slide over the rails 45b on the sides of the tank create an integrated, easily assembled, primary condensation chamber 45, all within the heater at the first end of the cartridge 30 or pod 30a. In some embodiments of the device, as illustrated in FIGS. 9A-9L, the heater may encloses at least a first end of the cartridge. The enclosed first end of the cartridge may include the heater and the interior fluid storage compartment. In some embodiments, the heater further comprises at least one first condensation chamber 45. FIGS. 9A-9L show diagramed steps that mat be performed to assemble a cartomizer and/or mouthpiece. In 9A-9B the fluid storage compartment 32a may be oriented such that the heater inlet 53 faces upward. The heater contacts 33 may be inserted into the fluid storage compartment. Flexible tabs 33a may be inserted into the heater contacts 33. In a FIG. 9D the resistive heating element 35 may be wound on to the wick 34. In FIG. 9E the wick 34 and heater 35 may be placed on the fluid storage compartment. One or more free ends of the heater may sit outside the heater contacts. The one or more free ends may be soldered in place, rested in a groove, or snapped into a fitted location. At least a fraction of the one or more free ends may be in communication with the heater contacts 33. In a FIG. 9F the heater enclosure 36 may be snapped in place. The heater enclosure 36 may be fitted on the fluid storage compartment. FIG. 9G shows the heater enclosure 36 is in place on the fluid storage compartment. In FIG. 9H the fluid storage compartment can be flipped over. In FIG. 9I the mouthpiece 31 can be fitted on the fluid storage compartment. FIG. 9J shows the mouthpiece 31 in place on the fluid storage compartment. In FIG. 9K an end 49 can be fitted on the fluid storage compartment opposite the mouthpiece. FIG. 9L shows a fully assembled cartridge 30. FIG. 7B shows an exploded view of the assembled cartridge 30. Depending on the size of the heater and/or heater chamber, the heater may have more than one wick 34 and resistive heating element 35. In some embodiments, the first pair of heater contacts 33 further comprises a formed shape that comprises a tab 33a having a flexible spring value that extends out of the heater. In some embodiments, the cartridge 30 comprises heater contacts 33 which are inserted into the cartridge receptacle 21 of the device body 20 wherein, the flexible tabs 33a insert into a second pair of heater contacts 22 to complete a circuit with the device body. The first pair of heater contacts 33 may be a heat sink that absorbs and dissipates excessive heat produced by the resistive heating element 35. The first pair of heater contacts 33 may be a heat shield that protects the heater chamber from excessive heat produced by the resistive heating element 35. The first pair of heater contacts may be press-fit to an attachment feature on the exterior wall of the first end of the cartridge. The heater 36 may enclose a first end of the cartridge and a first end of the fluid storage compartment 32a. The heater may comprise a first condensation chamber 45. The heater may comprise at least one additional condensation chamber 45, 45′, 45″, etc. The first condensation chamber may be formed along an exterior wall of the cartridge. In still other embodiments of the device, the cartridge may further comprise a mouthpiece 31, wherein the mouthpiece comprises at least one aerosol outlet channel/secondary condensation chamber 46; and at least one aerosol outlet 47. The mouthpiece may be attached to a second end of the cartridge. The second end of the cartridge with the mouthpiece may be exposed when the cartridge is inserted in the device. The mouthpiece may comprise more than one second condensation chamber 46, 46′, 46″, etc. The second condensation chamber is formed along an exterior wall of the cartridge. The mouthpiece 31 may enclose the second end of the cartridge and interior fluid storage compartment. The partially assembled (e.g., mouthpiece removed) unit may be inverted and filled with a vaporizable fluid through the opposite, remaining (second) open end. Once filled, a snap-on mouthpiece 31 that also closes and seals the second end of the tank is inserted over the end. It also comprises raised internal edges (not shown), and aerosol outlet channel covers 46a that may slide over the rails 46b located on the sides of the second half of the tank, creating aerosol outlet channels/secondary condensation chambers 46. The aerosol outlet channels/secondary condensation chambers 46 slide over the end of primary condensation chamber 45, at a transition area 57, to create a junction for the vapor leaving the primary chamber and proceed out through the aerosol outlets 47, at the end of the aerosol outlet channels 46 and user-end of the mouthpiece 31. The cartridge may comprise a first condensation chamber and a second condensation chamber 45, 46. The cartridge may comprise more than one first condensation chamber and more than one second condensation chamber 45, 46, 45′, 46′, etc. In some embodiments of the device, a first condensation chamber 45 may be formed along the outside of the cartridge fluid storage compartment 31. In some embodiments of the device an aerosol outlet 47 exists at the end of aerosol outlet chamber 46. In some embodiments of the device, a first and second condensation chamber 45, 46 may be formed along the outside of one side of the cartridge fluid storage compartment 31. In some embodiments the second condensation chamber may be an aerosol outlet chamber. In some embodiments another pair of first and/or second condensation chambers 45′, 46′ is formed along the outside of the cartridge fluid storage compartment 31 on another side of the device. In some embodiments another aerosol outlet 47′ will also exist at the end of the second pair of condensation chambers 45′, 46′. In any one of the embodiments, the first condensation chamber and the second condensation chamber may be in fluid communication as illustrated in FIG. 10C. In some embodiments, the mouthpiece may comprise an aerosol outlet 47 in fluid communication with the second condensation chamber 46. The mouthpiece may comprise more than one aerosol outlet 47, 47′ in fluid communication with more than one the second condensation chamber 46, 46′. The mouthpiece may enclose a second end of the cartridge and a second end of the fluid storage compartment. In each of the embodiments described herein, the cartridge may comprise an airflow path comprising: an air inlet passage; a heater; at least a first condensation chamber; an aerosol outlet chamber, and an outlet port. In some of the embodiments described herein, the cartridge comprises an airflow path comprising: an air inlet passage; a heater; a first condensation chamber; a secondary condensation chamber; and an outlet port. In still other embodiments described herein the cartridge may comprise an airflow path comprising at least one air inlet passage; a heater; at least one first condensation chamber; at least one secondary condensation chamber; and at least one outlet port. As illustrated in FIGS. 10A-10C, an airflow path is created when the user draws on the mouthpiece 31 to create a suction (e.g., a puff), which essentially pulls air through the channel air inlet opening 50, through the air inlet passage 51, and into the heater chamber 37 through the second air passage (tank air inlet hole) 41 at the tank air inlet 52, then into the heater inlet 53. At this point, the pressure sensor has sensed the user's puff, and activated the circuit to the resistive heating element 35, which in turn, begins to generate vapor from the vapor fluid (e-juice). As air enters the heater inlet 53, it begins to mix and circulate in a narrow chamber above and around the wick 34 and between the heater contacts 33, generating heat, and dense, concentrated vapor as it mixes in the flow path 54 created by the sealing structure obstacles 44. FIG. 8A shows a detailed view of the sealing structure obstacles 44. Ultimately the vapor may be drawn, out of the heater along an air path 55 near the shoulder of the heater and into the primary condensation chamber 45 where the vapor expands and begins to cool. As the expanding vapor moves along the airflow path, it makes a transition from the primary condensation chamber 45 through a transition area 57, creating a junction for the vapor leaving the primary chamber, and entering the second vapor chamber 46, and proceeds out through the aerosol outlets 47, at the end of the mouthpiece 31 to the user. As illustrated in FIGS. 10A-10C, the device may have a dual set of air inlet passages 50-53, dual first condensation chambers 55/45, dual second condensation chambers and aeration channels 57/46, and/or dual aerosol outlet vents 47. Alternatively, the device may have an airflow path comprising: an air inlet passage 50, 51; a second air passage 41; a heater chamber 37; a first condensation chamber 45; a second condensation chamber 46; and/or an aerosol outlet 47. In some cases, the devise may have an airflow path comprising: more than one air inlet passage; more than one second air passage; a heater chamber; more than one first condensation chamber; more than one second condensation chamber; and more than one aerosol outlet as clearly illustrated in FIGS. 10A-10C. In any one of the embodiments described herein, the heater 36 may be in fluid communication with the internal fluid storage compartment 32a. In each of the embodiments described herein, the fluid storage compartment 32 is in fluid communication with the heater chamber 37, wherein the fluid storage compartment is capable of retaining condensed aerosol fluid, as illustrated in FIGS. 10A, 10C and 14. In some embodiments of the device, the condensed aerosol fluid may comprise a nicotine formulation. In some embodiments, the condensed aerosol fluid may comprise a humectant. In some embodiments, the humectant may comprise propylene glycol. In some embodiments, the humectant may comprise vegetable glycerin. In some cases, the cartridge may be detachable from the device body. In some embodiments, the cartridge receptacle and the detachable cartridge may form a separable coupling. In some embodiments the separable coupling may comprise a friction assembly. As illustrated in FIGS. 11-14, the device may have a press-fit (friction) assembly between the cartridge pod 30a and the device receptacle. Additionally, a dent/friction capture such as 43 may be utilized to capture the pod 30a to the device receptacle or to hold a protective cap 38 on the pod, as further illustrated in FIG. 8B. In other embodiments, the separable coupling may comprise a snap-fit or snap-lock assembly. In still other embodiments the separable coupling may comprise a magnetic assembly. In any one of the embodiments described herein, the cartridge components may comprise a snap-fit or snap-lock assembly, as illustrated in FIG. 5. In any one of the embodiments, the cartridge components may be reusable, refillable, and/or recyclable. The design of these cartridge components lend themselves to the use of such recyclable plastic materials as polypropylene, for the majority of components. In some embodiments of the device 10, the cartridge 30 may comprise: a fluid storage compartment 32; a heater 36 affixed to a first end with a snap-fit coupling 39a, 39b; and a mouthpiece 31 affixed to a second end with a snap-fit coupling 39c, 39d (not shown—but similar to 39a and 39b). The heater 36 may be in fluid communication with the fluid storage compartment 32. The fluid storage compartment may be capable of retaining condensed aerosol fluid. The condensed aerosol fluid may comprise a nicotine formulation. The condensed aerosol fluid may comprise a humectant. The humectant may comprise propylene glycol and/or vegetable glycerin. Provided herein is a device for generating an inhalable aerosol comprising: a device body 20 comprising a cartridge receptacle 21 for receiving a cartridge 30; wherein an interior surface of the cartridge receptacle forms a first side of an air inlet passage 51 when a cartridge comprising a channel integral 40 to an exterior surface is inserted into the cartridge receptacle 21, and wherein the channel forms a second side of the air inlet passage 51. Provided herein is a device for generating an inhalable aerosol comprising: a device body 20 comprising a cartridge receptacle 21 for receiving a cartridge 30; wherein the cartridge receptacle comprises a channel integral to an interior surface and forms a first side of an air inlet passage when a cartridge is inserted into the cartridge receptacle, and wherein an exterior surface of the cartridge forms a second side of the air inlet passage 51. Provided herein is a cartridge 30 for a device for generating an inhalable aerosol 10 comprising: a fluid storage compartment 32; a channel integral 40 to an exterior surface, wherein the channel forms a first side of an air inlet passage 51; and wherein an internal surface of a cartridge receptacle 21 in the device forms a second side of the air inlet passage 51 when the cartridge is inserted into the cartridge receptacle. Provided herein is a cartridge 30 for a device for generating an inhalable aerosol 10 comprising a fluid storage compartment 32, wherein an exterior surface of the cartridge forms a first side of an air inlet channel 51 when inserted into a device body 10 comprising a cartridge receptacle 21, and wherein the cartridge receptacle further comprises a channel integral to an interior surface, and wherein the channel forms a second side of the air inlet passage 51. In some embodiments, the cartridge further comprises a second air passage 41 in fluid communication with the channel 40, wherein the second air passage 41 is formed through the material of the cartridge 32 from an exterior surface of the cartridge to the internal fluid storage compartment 32a. In some embodiments of the device body cartridge receptacle 21 or the cartridge 30, the integral channel 40 comprises at least one of: a groove; a trough; a depression; a dent; a furrow; a trench; a crease; and a gutter. In some embodiments of the device body cartridge receptacle 21 or the cartridge 30, the integral channel 40 comprises walls that are either recessed into the surface or protrude from the surface where it is formed. In some embodiments of the device body cartridge receptacle 21 or the cartridge 30, the internal side walls of the channel 40 form additional sides of the air inlet passage 51. Provided herein is a device for generating an inhalable aerosol comprising: a cartridge comprising; a fluid storage compartment; a heater affixed to a first end comprising; a first heater contact, a resistive heating element affixed to the first heater contact; a device body comprising; a cartridge receptacle for receiving the cartridge; a second heater contact adapted to receive the first heater contact and to complete a circuit; a power source connected to the second heater contact; a printed circuit board (PCB) connected to the power source and the second heater contact; wherein the PCB is configured to detect the absence of fluid based on the measured resistance of the resistive heating element, and turn off the device. Referring now to FIGS. 13, 14, and 15, in some embodiments, the device body further comprises at least one: second heater contact 22 (best shown in FIG. 6C detail); a battery 23; a printed circuit board 24; a pressure sensor 27; and an indicator light 26. In some embodiments, the printed circuit board (PCB) further comprises: a microcontroller; switches; circuitry comprising a reference resister; and an algorithm comprising logic for control parameters; wherein the microcontroller cycles the switches at fixed intervals to measure the resistance of the resistive heating element relative to the reference resistor, and applies the algorithm control parameters to control the temperature of the resistive heating element. As illustrated in the basic block diagram of FIG. 17A, the device utilizes a proportional-integral-derivative controller or PID control law. A PID controller calculates an “error” value as the difference between a measured process variable and a desired SetPoint. When PID control is enabled, power to the coil is monitored to determine whether or not acceptable vaporization is occurring. With a given airflow over the coil, more power will be required to hold the coil at a given temperature if the device is producing vapor (heat is removed from the coil to form vapor). If power required to keep the coil at the set temperature drops below a threshold, the device indicates that it cannot currently produce vapor. Under normal operating conditions, this indicates that there is not enough liquid in the wick for normal vaporization to occur. In some embodiments, the micro-controller instructs the device to turn itself off when the resistance exceeds the control parameter threshold indicating that the resistive heating element is dry. In still other embodiments, the printed circuit board further comprises logic capable of detecting the presence of condensed aerosol fluid in the fluid storage compartment and is capable of turning off power to the heating contact(s) when the condensed aerosol fluid is not detected. When the microcontroller is running the PID temperature control algorithm 70, the difference between a set point and the coil temperature (error) is used to control power to the coil so that the coil quickly reaches the set point temperature, (e.g., between 200° C. and 400° C.). When the over-temperature algorithm is used, power is constant until the coil reaches an over-temperature threshold, (e.g., between 200° C. and 400° C.); (FIG. 17A applies: set point temperature is over-temperature threshold; constant power until error reaches 0). The essential components of the device used to control the resistive heating element coil temperature are further illustrated in the circuit diagram of FIG. 17B. Wherein, BATT 23 is the battery; MCU 72 is the microcontroller; Q1 (76) and Q2 (77) are P-channel MOSFETs (switches); R_COIL 74 is the resistance of the coil. R_REF 75 is a fixed reference resistor used to measure R_COIL 74 through a voltage divider 73. The battery powers the microcontroller. The microcontroller turns on Q2 for 1 ms every 100 ms so that the voltage between R_REF and R_COIL (a voltage divider) may be measured by the MCU at V_MEAS. When Q2 is off, the control law controls Q1 with PWM (pulse width modulation) to power the coil (battery discharges through Q1 and R_COIL when Q1 is on). In some embodiments of the device, the device body further comprises at least one: second heater contact; a power switch; a pressure sensor; and an indicator light. In some embodiments of the device body, the second heater contact 22 may comprise: a female receptacle; or a male contact, or both, a flexible contact; or copper alloy or another electrically conductive material. In some embodiments of the device body, the battery supplies power to the second heater contact, pressure sensor, indicator light and the printed circuit board. In some embodiments, the battery is rechargeable. In some embodiments, the indicator light 26 indicates the status of the device and/or the battery or both. In some embodiments of the device, the first heater contact and the second heater contact complete a circuit that allows current to flow through the heating contacts when the device body and detachable cartridge are assembled, which may be controlled by an on/off switch. Alternatively, the device can be turned on an off by a puff sensor. The puff sensor may comprise a capacitive membrane. The capacitive membrane may be similar to a capacitive membrane used in a microphone. In some embodiments of the device, there is also an auxiliary charging unit for recharging the battery 23 in the device body. As illustrated in FIGS. 16A-16C, the charging unit 60, may comprise a USB device with a plug for a power source 63 and protective cap 64, with a cradle 61 for capturing the device body 20 (with or without the cartridge installed). The cradle may further comprise either a magnet or a magnetic contact 62 to securely hold the device body in place during charging. As illustrated in FIG. 6B, the device body further comprises a mating charging contact 28 and a magnet or magnetic contact 29 for the auxiliary charging unit. FIG. 16C is an illustrative example of the device 20 being charged in a power source 65 (laptop computer or tablet). In some cases the microcontroller on the PCB may be configured to monitor the temperature of the heater such that the vaporizable material is heated to a prescribed temperature. The prescribed temperature may be an input provided by the user. A temperature sensor may be in communication with the microcontroller to provide an input temperature to the microcontroller for temperature regulation. A temperature sensor may be a thermistor, thermocouple, thermometer, or any other temperature sensors. In some cases, the heating element may simultaneously perform as both a heater and a temperature sensor. The heating element may differ from a thermistor by having a resistance with a relatively lower dependence on temperature. The heating element may comprise a resistance temperature detector. The resistance of the heating element may be an input to the microcontroller. In some cases, the resistance may be determined by the microcontroller based on a measurement from a circuit with a resistor with at least one known resistance, for example, a Wheatstone bridge. Alternatively, the resistance of the heating element may be measured with a resistive voltage divider in contact with the heating element and a resistor with a known and substantially constant resistance. The measurement of the resistance of the heating element may be amplified by an amplifier. The amplifier may be a standard op amp or instrumentation amplifier. The amplified signal may be substantially free of noise. In some cases, a charge time for a voltage divider between the heating element and a capacitor may be determined to calculate the resistance of the heating element. In some cases, the microcontroller must deactivate the heating element during resistance measurements. The resistance of the heating element may be a function of the temperature of the heating element such that the temperature may be directly determined from resistance measurements. Determining the temperature directly from the heating element resistance measurement rather than from an additional temperature sensor may generate a more accurate measurement because unknown contact thermal resistance between the temperature sensor and the heating element is eliminated. Additionally, the temperature measurement may be determined directly and therefore faster and without a time lag associated with attaining equilibrium between the heating element and a temperature sensor in contact with the heating element. FIG. 17C is another example of a PID control block diagram similar to that shown in FIG. 17A, and FIG. 17D is an example of a resistance measurement circuit used in this PID control scheme. In FIG. 17C, the block diagram includes a measurement circuit that can measure the resistance of the resistive heater (e.g., coil) and provide an analog signal to the microcontroller, a device temperature, which can be measured directly by the microcontroller and/or input into the microcontroller, and an input from a sensor (e.g., a pressure sensor, a button, or any other sensor) that may be used by the microcontroller to determine when the resistive heart should be heated, e.g., when the user is drawing on the device or when the device is scheduled to be set at a warmer temperature (e.g., a standby temperature). In FIG. 17C, a signal from the measurement circuit goes directly to the microcontroller and to a summing block. In the measurement circuit, an example of which is shown in FIG. 17D (similar to the one shown in FIG. 17B), signal from the measurement circuit are fed directly to the microcontroller. The summing block in FIG. 17C is representative of the function which may be performed by the microcontroller when the device is heating; the summing block may show that error (e.g., in this case, a target Resistance minus a measured resistance of the resistive heater) is used by a control algorithm to calculate the power to be applied to the coil until the next coil measurement is taken. In the example shown in FIGS. 17C-17D, signal from the measurement circuit may also go directly to the microcontroller in FIG. 17C; the resistive heater may be used to determine a baseline resistance (also referred to herein as the resistance of the resistive hater at an ambient temperature), when the device has not been heating the resistive heater, e.g., when some time has passed since the device was last heating. Alternatively or additionally, the baseline resistance may be determined by determining when coil resistance is changing with time at a rate that is below some stability threshold. Thus, resistance measurements of the coil may be used to determine a baseline resistance for the coil at ambient temperature. A known baseline resistance may be used to calculate a target resistance that correlates to a target rise in coil temperature. The baseline (which may also be referred to as the resistance of the resistive heater at ambient temperature) may also be used to calculate the target resistance. The device temperature can be used to calculate an absolute target coil temperature as opposed to a target temperature rise. For example, a device temperature may be used to calculate absolute target coil temperature for more precise temperature control. The circuit shown in FIG. 17B is one embodiment of a resistance measurement circuit comprising a voltage divider using a preset reference resistance. For the reference resistor approach (alternatively referred to as a voltage divider approach) shown in 17B, the reference resistor may be roughly the same resistance as the coil at target resistance (operating temperature). For example, this may be 1-2 Ohms. The circuit shown in FIG. 17D is another variation of a resistance measurement (or comparison) circuit. As before, in this example, the resistance of the heating element may be a function of the temperature of the heating element such that the temperature may be directly determined from resistance measurements. The resistance of the heating element is roughly linear with the temperature of the heating element. In FIG. 17D, the circuit includes a Wheatstone bridge connected to a differential op amp circuit. The measurement circuit is powered when Q2 is held on via the RM_PWR signal from the microcontroller (RM=Resistance Measurement). Q2 is normally off to save battery life. In general, the apparatuses described herein stop applying power to the resistive heater to measure the resistance of the resistive heater. In FIG. 17D, when heating, the device must stop heating periodically (turn Q1 off) to measure coil resistance. One voltage divider in the bridge is between the Coil and R1, the other voltage divider is between R2 and R3 and optionally R4, R5, and R6. R4, R5, and R6 are each connected to open drain outputs from the microcontroller so that the R3 can be in parallel with any combination of R4, R5, and R6 to tune the R2/R3 voltage divider. An algorithm tunes the R2/R3 voltage divider via open drain control of RM_SCALE_0, RM_SCALE_1, and RM_SCALE_2 so that the voltage at the R2/R3 divider is just below the voltage of the R_COIL/R1 divider, so that the output of the op amp is between positive battery voltage and ground, which allows small changes in coil resistance to result in measureable changes in the op amp's output voltage. U2, R7, R8, R9, and R10 comprise the differential op amp circuit. As is standard in differential op amp circuits, R9/R7=R10/R8, R9>>R7, and the circuit has a voltage gain, A=R9/R7, such that the op amp outputs HM_OUT=A(V+−V−) when 0≦A(V+−V−)≦V_BAT, where V+ is the R_COIL/R1 divider voltage, V− is the tuned R2/R3 divider voltage, and V_BAT is the positive battery voltage. In this example, the microcontroller performs an analog to digital conversion to measure HM_OUT, and then based on the values of R1 through R10 and the selected measurement scale, calculates resistance of the coil. When the coil has not been heated for some amount of time (e.g., greater than 10 sec, 20 sec, 30 sec, 1 min, 2 min, 3 min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, 15 min, 20 min, 30 min, etc.) and/or the resistance of the coil is steady, the microcontroller may save calculated resistance as the baseline resistance for the coil. A target resistance for the coil is calculated by adding a percentage change of baseline resistance to the baseline resistance. When the microcontroller detects via the pressure sensor that the user is drawing from the device, it outputs a PWM signal on HEATER to power the coil through Q1. PWM duty cycle is always limited to a max duty cycle that corresponds to a set maximum average power in the coil calculated using battery voltage measurements and coil resistance measurements. This allows for consistent heat-up performance throughout a battery discharge cycle. A PID control algorithm uses the difference between target coil resistance and measured coil resistance to set PWM duty cycle (limited by max duty cycle) to hold measured resistance at target resistance. The PID control algorithm holds the coil at a controlled temperature regardless of air flow rate and wicking performance to ensure a consistent experience (e.g., vaporization experience, including “flavor”) across the full range of use cases and allow for higher power at faster draw rates. In general, the control law may update at any appropriate rate. For example, in some variations, the control law updates at 20 Hz. In this example, when heating, PWM control of Q1 is disabled and Q1 is held off for 2 ms every 50 ms to allow for stable coil resistance measurements. In another variation, the control law may update at 250-1000 Hz. In the example shown in FIG. 17D, the number of steps between max and min measureable analog voltage may be controlled by the configuration. For example, precise temperature control (+/−1° C. or better) maybe achieved with a few hundred steps between measured baseline resistance and target resistance. In some variations, the number of steps may be approximately 4096. With variations in resistance between cartridges (e.g., +/−10% nominal coil resistance) and potential running changes to nominal cartridge resistance, it may be advantages to have several narrower measurement scales so that resistance can be measured at higher resolution than could be achieved if one fixed measurement scale had to be wide enough to measure all cartridges that a device might see. For example, R4, R5, and R6 may have values that allow for eight overlapping resistance measurement scales that allow for roughly five times the sensitivity of a single fixed scale covering the same range of resistances that are measurable by eight scales combined. More or less than eight measurement ranges may be used. For example, in the variation shown in FIG. 17D, in some instances the measurement circuit may have a total range of 1.31-2.61 Ohm and a sensitivity of roughly 0.3 mOhm, which may allow for temperature setting increments and average coil temperature control to within +/−0.75° C. (e.g., a nominal coil resistance*TCR=1.5 Ohm*0.00014/° C.=0.21 mOhm/° C., 0.3 mOhm/(0.21 mOhm/° C.)=1.4° C. sensitivity). In some variations, R_COIL is 1.5 Ohm nominally, R1=100 Ohm, R2=162 Ohm, R3=10 kOhm, R4=28.7 kOhm, R5=57.6 kOhm, R6=115 kOhm, R7=R9=2 kOhm, R8=R10=698 kOhm. As mentioned above, heater resistance is roughly linear with temperature. Changes in heater resistance may be roughly proportional to changes in temperature. With a coil at some resistance, Rbaseline, at some initial temperature, ΔT=(Rcoil/Rbaseline−1)/TCR is a good approximation of coil temperature rise. Using an amplified Wheatstone bridge configuration similar to that shown in FIG. 17D, the device may calculate target resistance using baseline resistance and a fixed target percentage change in resistance, 4.0%. For coils with TCR of, as an example, 0.00014/° C., this may correspond to a 285° C. temperature rise (e.g., 0.04/(0.00014/° C.)=285° C.). In general, the device doesn't need to calculate temperature; these calculations can be done beforehand, and the device can simply use a target percentage change in resistance to control temperature. For some baseline resistance, coil TCR, and target temperature change, target heater resistance may be: Rtarget=Rbaseline (1+TCR*ΔT). Solved for ΔT, this is ΔT=(Rtarget/Rbaseline−1)/TCR. Some device variations may calculate and provide (e.g., display, transmit, etc.) actual temperature so users can see actual temperatures during heat up or set a temperature in the device instead of setting a target percentage change in resistance. Alternatively or additionally, the device may use measured ambient temperature and a target temperature (e.g., a temperature set point) to calculate a target resistance that corresponds to the target temperature. The target resistance may be determined from a baseline resistance at ambient temperature, coil TCR, target temperature, and ambient temperature. For example, a target heater resistance may be expressed as Rtarget/Rbaseline(1+TCR*(Tset−Tamb)). Solved for Tset, this gives: Tset=(Rtarget/Rbaseline−1)/TCR+Tamb. Some device variations may calculate and provide (e.g., display, transmit, etc.) actual temperature so users can see actual temperatures during heat up or set a temperature in the device instead of setting a target resistance or target percentage change in resistance. For the voltage divider approach, if Rreference is sufficiently close to Rbaseline, temperature change is approximately ΔT=(Rcoil/Rreference−Rbaseline/Rreference)/TCR. As mentioned above, any of the device variations described herein may be configured to control the temperature only after a sensor indicates that vaporization is required. For example, a pressure sensor (e.g., “puff sensor”) may be used to determine when the coil should be heated. This sensor may function as essentially an on off switch for heating under PID control. Additionally, in some variations, the sensor may also control baseline resistance determination. For example baseline resistance may be prevented until at least some predetermined time period (e.g., 10 sec, 15 sec, 20 sec, 30 sec, 45 sec, 1 min, 2 min, etc.) after the last puff. Provided herein is a device for generating an inhalable aerosol comprising: a cartridge comprising a first heater contact; a device body comprising; a cartridge receptacle for receiving the cartridge; a second heater contact adapted to receive the first heater contact and to complete a circuit; a power source connected to the second heater contact; a printed circuit board (PCB) connected to the power source and the second heater contact; and a single button interface; wherein the PCB is configured with circuitry and an algorithm comprising logic for a child safety feature. In some embodiments, the algorithm requires a code provided by the user to activate the device. In some embodiments; the code is entered by the user with the single button interface. In still further embodiments the single button interface is the also the power switch. Provided herein is a cartridge 30 for a device 10 for generating an inhalable aerosol comprising: a fluid storage compartment 32; a heater 36 affixed to a first end comprising: a heater chamber 37, a first pair of heater contacts 33, a fluid wick 34, and a resistive heating element 35 in contact with the wick; wherein the first pair of heater contacts 33 comprise thin plates affixed about the sides of the heater chamber 37, and wherein the fluid wick 34 and resistive heating element 35 are suspended there between. Depending on the size of the heater or heater chamber, the heater may have more than one wick 34, 34′ and resistive heating element 35, 35′. In some embodiments, the first pair of heater contacts further comprise a formed shape that comprises a tab 33a having a flexible spring value that extends out of the heater 36 to complete a circuit with the device body 20. In some embodiments, the heater contacts 33 are configured to mate with a second pair of heater contacts 22 in a cartridge receptacle 21 of the device body 20 to complete a circuit. In some embodiments, the first pair of heater contacts is also a heat sink that absorbs and dissipates excessive heat produced by the resistive heating element. In some embodiments, the first pair of heater contacts is a heat shield that protects the heater chamber from excessive heat produced by the resistive heating element. Provided herein is a cartridge 30 for a device for generating an inhalable aerosol 10 comprising: a heater 36 comprising; a heater chamber 37, a pair of thin plate heater contacts 33 therein, a fluid wick 34 positioned between the heater contacts 33, and a resistive heating element 35 in contact with the wick; wherein the heater contacts 33 each comprise a fixation site 33c wherein the resistive heating element 35 is tensioned there between. As will be obvious to one skilled in the art after reviewing the assembly method illustrated in FIG. 9, the heater contacts 33 simply snap or rest on locator pins on either side of the air inlet 53 on the first end of the cartridge interior fluid storage compartment, creating a spacious vaporization chamber containing the at least one wick 34 and at least one heating element 35. Provided herein is a cartridge 30 for a device for generating an inhalable aerosol 10 comprising a heater 36 attached to a first end of the cartridge. In some embodiments, the heater encloses a first end of the cartridge and a first end of the fluid storage compartment 32, 32a. In some embodiments, the heater comprises a first condensation chamber 45. In some embodiments, the heater comprises more than one first condensation chamber 45, 45′. In some embodiments, the condensation chamber is formed along an exterior wall of the cartridge 45b. As noted previously, and described in FIGS. 10A, 10B and 10C, the airflow path through the heater and heater chamber generates vapor within the heater circulating air path 54, which then exits through the heater exits 55 into a first (primary) condensation chamber 45, which is formed by components of the tank body comprising the primary condensation channel/chamber rails 45b, the primary condensation channel cover 45a, (the outer side wall of the heater enclosure). Provided herein is a cartridge 30 for a device for generating an inhalable aerosol 10 comprising a fluid storage compartment 32 and a mouthpiece 31, wherein the mouthpiece is attached to a second end of the cartridge and further comprises at least one aerosol outlet 47. In some embodiments, the mouthpiece 31 encloses a second end of the cartridge 30 and a second end of the fluid storage compartment 32, 32a. Additionally, as clearly illustrated in FIG. 10C in some embodiments the mouthpiece also contains a second condensation chamber 46 prior to the aerosol outlet 47, which is formed by components of the tank body 32 comprising the secondary condensation channel/chamber rails 46b, the second condensation channel cover 46a, (the outer side wall of the mouthpiece). Still further, the mouthpiece may contain yet another aerosol outlet 47′ and another (second) condensation chamber 46′ prior to the aerosol outlet, on another side of the cartridge. In other embodiments, the mouthpiece comprises more than one second condensation chamber 46, 46′. In some preferred embodiments, the second condensation chamber is formed along an exterior wall of the cartridge 46b. In each of the embodiments described herein, the cartridge 30 comprises an airflow path comprising: an air inlet channel and passage 40, 41, 42; a heater chamber 37; at least a first condensation chamber 45; and an outlet port 47. In some of the embodiments described herein, the cartridge 30 comprises an airflow path comprising: an air inlet channel and passage 40, 41, 42; a heater chamber 37; a first condensation chamber 45; a second condensation chamber 46; and an outlet port 47. In still other embodiments described herein the cartridge 30 may comprise an airflow path comprising at least one air inlet channel and passage 40, 41, 42; a heater chamber 37; at least one first condensation chamber 45; at least one second condensation chamber 46; and at least one outlet port 47. In each of the embodiments described herein, the fluid storage compartment 32 is in fluid communication with the heater 36, wherein the fluid storage compartment is capable of retaining condensed aerosol fluid. In some embodiments of the device, the condensed aerosol fluid comprises a nicotine formulation. In some embodiments, the condensed aerosol fluid comprises a humectant. In some embodiments, the humectant comprises propylene glycol. In some embodiments, the humectant comprises vegetable glycerin. Provided herein is a cartridge 30 for a device for generating an inhalable aerosol 10 comprising: a fluid storage compartment 32; a heater 36 affixed to a first end; and a mouthpiece 31 affixed to a second end; wherein the heater comprises a first condensation chamber 45 and the mouthpiece comprises a second condensation chamber 46. In some embodiments, the heater comprises more than one first condensation chamber 45, 45′ and the mouthpiece comprises more than one second condensation chamber 46, 46′. In some embodiments, the first condensation chamber and the second condensation chamber are in fluid communication. As illustrated in FIG. 10C, the first and second condensation chambers have a common transition area 57, 57′, for fluid communication. In some embodiments, the mouthpiece comprises an aerosol outlet 47 in fluid communication with the second condensation chamber 46. In some embodiments, the mouthpiece comprises two or more aerosol outlets 47, 47′. In some embodiments, the mouthpiece comprises two or more aerosol outlets 47, 47′ in fluid communication with the two or more second condensation chambers 46, 46′. In any one of the embodiments, the cartridge meets ISO recycling standards. In any one of the embodiments, the cartridge meets ISO recycling standards for plastic waste. And in still other embodiments, the plastic components of the cartridge are composed of polylactic acid (PLA), wherein the PLA components are compostable and or degradable. Provided herein is a device for generating an inhalable aerosol 10 comprising a device body 20 comprising a cartridge receptacle 21; and a detachable cartridge 30; wherein the cartridge receptacle and the detachable cartridge form a separable coupling, and wherein the separable coupling comprises a friction assembly, a snap-fit assembly or a magnetic assembly. In other embodiments of the device, the cartridge is a detachable assembly. In any one of the embodiments described herein, the cartridge components may comprise a snap-lock assembly such as illustrated by snap features 39a and 39b. In any one of the embodiments, the cartridge components are recyclable. Provided herein is a method of fabricating a device for generating an inhalable aerosol comprising: providing a device body comprising a cartridge receptacle; and providing a detachable cartridge; wherein the cartridge receptacle and the detachable cartridge form a separable coupling comprising a friction assembly, a snap-fit assembly or a magnetic assembly when the cartridge is inserted into the cartridge receptacle. Provided herein is a method of making a device 10 for generating an inhalable aerosol comprising: providing a device body 20 with a cartridge receptacle 21 comprising one or more interior coupling surfaces 21a, 21b, 21c . . . ; and further providing a cartridge 30 comprising: one or more exterior coupling surfaces 36a, 36b, 36c, . . . , a second end and a first end; a tank 32 comprising an interior fluid storage compartment 32a; at least one channel 40 on at least one exterior coupling surface, wherein the at least one channel forms one side of at least one air inlet passage 51, and wherein at least one interior wall of the cartridge receptacle forms at least one side one side of at least one air inlet passage 51when the detachable cartridge is inserted into the cartridge receptacle. FIG. 9 provides an illustrative example of a method of assembling such a device. In some embodiments of the method, the cartridge 30 is assembled with a protective removable end cap 38 to protect the exposed heater contact tabs 33a protruding from the heater 36. Provided herein is a method of fabricating a cartridge for a device for generating an inhalable aerosol comprising: providing a fluid storage compartment; affixing a heater to a first end with a snap-fit coupling; and affixing a mouthpiece to a second end with a snap-fit coupling. Provided herein is a cartridge 30 for a device for generating an inhalable aerosol 10 with an airflow path comprising: a channel 50 comprising a portion of an air inlet passage 51; a second air passage 41 in fluid communication with the channel; a heater chamber 37 in fluid communication with the second air passage; a first condensation chamber 45 in fluid communication with the heater chamber; a second condensation chamber 46 in fluid communication with the first condensation chamber; and an aerosol outlet 47 in fluid communication with second condensation chamber. Provided herein is a device 10 for generating an inhalable aerosol adapted to receive a removable cartridge 30, wherein the cartridge comprises a fluid storage compartment or tank 32; an air inlet 41; a heater 36, a protective removable end cap 38, and a mouthpiece 31. Charging In some cases, the vaporization device may comprise a power source. The power source may be configured to provide power to a control system, one or more heating elements, one or more sensors, one or more lights, one or more indicators, and/or any other system on the electronic cigarette that requires a power source. The power source may be an energy storage device. The power source may be a battery or a capacitor. In some cases, the power source may be a rechargeable battery. The battery may be contained within a housing of the device. In some cases the battery may be removed from the housing for charging. Alternatively, the battery may remain in the housing while the battery is being charged. Two or more charge contact may be provided on an exterior surface of the device housing. The two or more charge contacts may be in electrical communication with the battery such that the battery may be charged by applying a charging source to the two or more charge contacts without removing the battery from the housing. FIG. 18 shows a device 1800 with charge contacts 1801. The charge contacts 1801 may be accessible from an exterior surface of a device housing 1802. The charge contacts 1801 may be in electrical communication with an energy storage device (e.g., battery) inside of the device housing 1802. In some cases, the device housing may not comprise an opening through which the user may access components in the device housing. The user may not be able to remove the battery and/or other energy storage device from the housing. In order to open the device housing a user must destroy or permanently disengage the charge contacts. In some cases, the device may fail to function after a user breaks open the housing. FIG. 19 shows an exploded view of a charging assembly 1900 in an electronic vaporization device. The housing (not shown) has been removed from the exploded view in FIG. 19. The charge contact pins 1901 may be visible on the exterior of the housing. The charge contact pins 1901 may be in electrical communication with a power storage device of the electronic vaporization device. When the device is connected to a power source (e.g., during charging of the device) the charging pins may facilitate electrical communication between the power storage device inside of the electronic vaporization device and the power source outside of the housing of the vaporization device. The charge contact pins 1901 may be held in place by a retaining bezel 1902. The charge contact pins 1901 may be in electrical communication with a charger flex 1903. The charging pins may contact the charger flex such that a need for soldering of the charger pins to an electrical connection to be in electrical communication with the power source may be eliminated. The charger flex may be soldered to a printed circuit board (PCB). The charger flex may be in electrical communication with the power storage device through the PCB. The charger flex may be held in place by a bent spring retainer 1904. FIG. 20 shows the bent spring retainer in an initial position 2001 and a deflected position 2002. The bent spring retainer may hold the retaining bezel in a fixed location. The bent spring retainer may deflect only in one direction when the charging assembly is enclosed in the housing of the electronic vaporization device. FIG. 21 shows a location of the charger pins 2101 when the electronic vaporization device is fully assembled with the charging pins 2101 contact the charging flex 2102. When the device is fully assembled at least a portion of the retaining bezel may be fitted in an indentation 2103 on the inside of the housing 2104. In some cases, disassembling the electronic vaporization device may destroy the bezel such that the device cannot be reassembled after disassembly. A user may place the electronic smoking device in a charging cradle. The charging cradle may be a holder with charging contact configured to mate or couple with the charging pins on the electronic smoking device to provide charge to the energy storage device in the electronic vaporization device from a power source (e.g., wall outlet, generator, and/or external power storage device). FIG. 22 shows a device 2302 in a charging cradle 2301. The charging cable may be connected to a wall outlet, USB, or any other power source. The charging pins (not shown) on the device 2302 may be connected to charging contacts (not shown) on the charging cradle 2301. The device may be configured such that when the device is placed in the cradle for charging a first charging pin on the device may contact a first charging contact on the charging cradle and a second charging pin on the device may contact a second charging contact on the charging cradle or the first charging pin on the device may contact a second charging contact on the charging cradle and the second charging pin on the device may contact the first charging contact on the charging cradle. The charging pins on the device and the charging contacts on the cradle may be in contact in any orientation. The charging pins on the device and the charging contacts on the cradle may be agnostic as to whether they are current inlets or outlets. Each of the charging pins on the device and the charging contacts on the cradle may be negative or positive. The charging pins on the device may be reversible. FIG. 23 shows a circuit 2400 that may permit the charging pins on the device to be reversible. The circuit 2400 may be provided on a PCB in electrical communication with the charging pins. The circuit 2400 may comprise a metal-oxide-semiconductor field-effect transistor (MOSFET) H bridge. The MOSFET H bridge may rectify a change in voltage across the charging pins when the charging pins are reversed from a first configuration where in a first configuration the device is placed in the cradle for charging with the first charging pin on the device in contact with the first charging contact on the charging cradle to a second charging pin on the device in contact with the second charging contact on the charging cradle to a second configuration where the first charging pin on the device is in contact with the second charging contact on the charging cradle and the second charging pin on the device is in contact with the first charging contact on the charging cradle. The MOSFET H bridge may rectify the change in voltage with an efficient current path. As shown in FIG. 23 the MOSFET H bridge may comprise two or more n-channel MOSFETs and two or more p-channel MOSFETs. The n-channel and p-channel MOSFETs may be arranged in an H bridge. Sources of p-channels MOSFETs (Q1 and Q3) may be in electrical communication. Similarly, sources of n-channel FETs (Q2 and Q4) may be in electrical communication. Drains of pairs of n and p MOSFETs (Q1 with Q2 and Q3 with Q4) may be in electrical communication. TA common drain from one n and p pair may be in electrical communication with one or more gates of the other n and p pair and/or vice versa. Charge contacts (CH1 and CH2) may be in electrical communication to common drains separately. A common source of the n MOSFETs may be in electrical communication to PCB ground (GND). The common source of the p MOSFETs may be in electrical communication with the PCB's charge controller input voltage (CH+). When CH1 voltage is greater than CH2 voltage by the MOSFET gate threshold voltages, Q1 and Q4 may be “on,” connecting CH1 to CH+ and CH2 to GND. When CH2 voltage is greater than CH1 voltage by the FET gate threshold voltages, Q2 and Q3 may be “on,” connecting CH1 to GND and CH2 to CH+. For example, whether there is 9V or −9V across CH1 to CH2, CH+ will be 9V above GND. Alternatively, a diode bridge could be used, however the MOSFET bridge may be more efficient compared to the diode bridge. In some cases the charging cradle may be configured to be a smart charger. The smart charger may put the battery of the device in series with a USB input to charge the device at a higher current compared to a typical charging current. In some cases, the device may charge at a rate up to about 2 amps (A), 4 A, 5 A, 6 A, 7 A, 10 A, or 15 A. In some cases, the smart charger may comprise a battery, power from the battery may be used to charge the device battery. When the battery in the smart charger has a charge below a predetermined threshold charge, the smart charger may simultaneously charge the battery in the smart charger and the battery in the device. Cartridge/Vaporizer Attachment Any of the cartridges described herein may be adapted for securely coupling with an electronic inhalable aerosol device (“vaporizer”) as discussed above. In particular described herein are cartridge designs that address the unrecognized problem of maintaining adequate electrical contact between a mouthpiece-containing cartridge and a rectangular vaporizer coupling region, particularly when the mouthpiece is held in a user's mouth. Any of the cartridges described herein may be particularly well adapted for securing to a vaporizer by including a base region that mates with the rectangular coupling region of the vaporizer, where the base unit fits into a rectangular opening that is between 13-14 mm deep, 4.5-5.5 mm wide, and 13-14 mm long. The base having generally includes a bottom surface having a first electrical contact and a second electrical contact. In particular, any of the cartridges described herein may include a first locking gap on a first lateral surface of the base, and a second locking gap on a second lateral surface of the base that is opposite first lateral surface. For example FIGS. 24A and 24B illustrate another variation of a cartridge similar to that shown in FIGS. 7A-15, discussed above, having a base region 2401 with at least one locking gap 2404 on the first minor lateral wall 2407. A second locking gap (not shown) may be present on the opposite minor lateral wall. One or both major lateral walls 2418 may include a detent 2421. Any of these cartridges may also include a mouthpiece 2409, which may be at an end that is opposite of the bottom 2422 of the cartridge, on which a pair of tabs (electrodes 2411) are positioned, shown in FIG. 24A (as previously described, above) bent over the distal end of the cartridge. FIGS. 25A and 25B show front and side views, respectively, of this example. In FIGS. 24A-25B the locking gaps 2404, 2404′ on either side are shown as channels in the side (lateral) walls. They may extend across the entire side wall, parallel to the bottom as shown, or they may extend only partially through and may preferably be centered relative to the width of the wall. In other variations the locking gap may be a divot, pit, opening, or hole (though not into the internal volume holding the vaporizable material). In general, the inventors have found that the vertical position of the locking gap may be important in maintaining the stability of the cartridge in the vaporizer, particularly in cartridges having a rectangular base region that is longer than 10 mm. Optimally, the locking gap may be between about 1 and 5 mm from the bottom of the base region, and more specifically, between about 3 and 4 mm (e.g., approximately 3.3 mm), as shown in FIG. 26A which indicates exemplary dimensions for the section through FIG. 26B. The cartridges shown in FIGS. 24A-24B also include a detent 2421 that is positioned between about 7 and 11 mm up from the bottom of the cartridge. The detent may help hold the cartridge base in the vaporizer, and may cooperate with the locking gap, but is optional (and shown in dashed lines in FIGS. 2A-25B. In FIGS. 24A-25B the cartridge base is also transparent, and shows an internal air channel (cannula 2505). FIGS. 27A-27B show another example of a vaporizer including a battery and control circuitry. FIGS. 27A and 27B also illustrate the mating region 2704. In this example, the mating region includes two detents 2706 that may mate with the locking gaps on the cartridge when it is inserted into the vaporizer. Exemplary dimensions for the mating region are shown. In this example the locking detents (which complement the locking gaps on the cartridge) are indentations that project into the mating region. These locking determent may be a ridge, pin, or other projection (including spring-loaded members). FIGS. 28A-28D show an example of a vaporizer 2803 into which a cartridge 2801 has been securely loaded. In FIG. 28A the cartridge has been snapped into position so that the locking gaps of the cartridge engage with the locking detents in the vaporizer. FIG. 28B is side view and FIG. 28C show a sectional view; an enlarged portion of the sectional view is shown in FIG. 28D, showing the base of the cartridge seated in the mating region of the vaporizer. With the cartridge secured as shown, good electrical contact 2805 may be maintained. Although the cartridges shown in FIGS. 24A-28D are similar, and include a proximal mouthpiece and distal base that are nearly equivalent in size, with the reservoir for the vaporizable material between them and the wick, resistive heater, heating chamber and electrodes at the distal most end (near the bottom of the base), many other cartridge configurations are possible while still securely seating into a vaporizer having the same vaporizer mating region shown in FIGS. 28A-28B. For example, FIGS. 29A-29D illustrate alternative variations of cartridges having similar electrode. In FIG. 29A the base region includes two projecting feet that include locking gaps, and the electrodes on the base (not shown) connect via electrical traces (e.g. wires, etc.) to a heating element, wick and the reservoir nearer to the distal end (not visible). In FIG. 29B the base extends further than 11 mm (e.g., 20-30 mm) and may house the reservoir (fluid storage compartment). Similarly in FIG. 29C the base region is the same as in FIG. 29B, but the more proximal portion is enlarged. In FIG. 29D the fluid non-base portion of the cartridge (more proximal than the base region) may have a different dimension. All of the variations shown in FIGS. 29A-29D, as in the variations shown in FIG. 24A-25B, may mate with the same vaporizer, and because of the dimensions of the base region, may be securely held and maintain electrical contact, even when a user is holding the device in their mouth. When a feature or element is herein referred to as being “on” another feature or element, it can be directly on the other feature or element or intervening features and/or elements may also be present. In contrast, when a feature or element is referred to as being “directly on” another feature or element, there are no intervening features or elements present. It will also be understood that, when a feature or element is referred to as being “connected”, “attached” or “coupled” to another feature or element, it can be directly connected, attached or coupled to the other feature or element or intervening features or elements may be present. In contrast, when a feature or element is referred to as being “directly connected”, “directly attached” or “directly coupled” to another feature or element, there are no intervening features or elements present. Although described or shown with respect to one embodiment, the features and elements so described or shown can apply to other embodiments. It will also be appreciated by those of skill in the art that references to a structure or feature that is disposed “adjacent” another feature may have portions that overlap or underlie the adjacent feature. Terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. For example, as used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms “comprises” and/or “comprising,” when used in this specification, specify the presence of stated features, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, steps, operations, elements, components, and/or groups thereof. As used herein, the term “and/or” includes any and all combinations of one or more of the associated listed items and may be abbreviated as “/”. Spatially relative terms, such as “under”, “below”, “lower”, “over”, “upper” and the like, may be used herein for ease of description to describe one element or feature's relationship to another element(s) or feature(s) as illustrated in the figures. It will be understood that the spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if a device in the figures is inverted, elements described as “under” or “beneath” other elements or features would then be oriented “over” the other elements or features. Thus, the exemplary term “under” can encompass both an orientation of over and under. The device may be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly. Similarly, the terms “upwardly”, “downwardly”, “vertical”, “horizontal” and the like are used herein for the purpose of explanation only unless specifically indicated otherwise. Although the terms “first” and “second” may be used herein to describe various features/elements (including steps), these features/elements should not be limited by these terms, unless the context indicates otherwise. These terms may be used to distinguish one feature/element from another feature/element. Thus, a first feature/element discussed below could be termed a second feature/element, and similarly, a second feature/element discussed below could be termed a first feature/element without departing from the teachings of the present invention. Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising” means various components can be co-jointly employed in the methods and articles (e.g., compositions and apparatuses including device and methods). For example, the term “comprising” will be understood to imply the inclusion of any stated elements or steps but not the exclusion of any other elements or steps. In general, any of the apparatuses and methods described herein should be understood to be inclusive, but all or a sub-set of the components and/or steps may alternatively be exclusive, and may be expressed as “consisting of” or alternatively “consisting essentially of” the various components, steps, sub-components or sub-steps. As used herein in the specification and claims, including as used in the examples and unless otherwise expressly specified, all numbers may be read as if prefaced by the word “about” or “approximately,” even if the term does not expressly appear. The phrase “about” or “approximately” may be used when describing magnitude and/or position to indicate that the value and/or position described is within a reasonable expected range of values and/or positions. For example, a numeric value may have a value that is +/−0.1% of the stated value (or range of values), +/−1% of the stated value (or range of values), +/−2% of the stated value (or range of values), +/−5% of the stated value (or range of values), +/−10% of the stated value (or range of values), etc. Any numerical values given herein should also be understood to include about or approximately that value, unless the context indicates otherwise. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Any numerical range recited herein is intended to include all sub-ranges subsumed therein. It is also understood that when a value is disclosed that “less than or equal to” the value, “greater than or equal to the value” and possible ranges between values are also disclosed, as appropriately understood by the skilled artisan. For example, if the value “X” is disclosed the “less than or equal to X” as well as “greater than or equal to X” (e.g., where X is a numerical value) is also disclosed. It is also understood that the throughout the application, data is provided in a number of different formats, and that this data, represents endpoints and starting points, and ranges for any combination of the data points. For example, if a particular data point “10” and a particular data point “15” are disclosed, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as well as between 10 and 15. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed. Although various illustrative embodiments are described above, any of a number of changes may be made to various embodiments without departing from the scope of the invention as described by the claims. For example, the order in which various described method steps are performed may often be changed in alternative embodiments, and in other alternative embodiments one or more method steps may be skipped altogether. Optional features of various device and system embodiments may be included in some embodiments and not in others. Therefore, the foregoing description is provided primarily for exemplary purposes and should not be interpreted to limit the scope of the invention as it is set forth in the claims. The examples and illustrations included herein show, by way of illustration and not of limitation, specific embodiments in which the subject matter may be practiced. As mentioned, other embodiments may be utilized and derived there from, such that structural and logical substitutions and changes may be made without departing from the scope of this disclosure. Such embodiments of the inventive subject matter may be referred to herein individually or collectively by the term “invention” merely for convenience and without intending to voluntarily limit the scope of this application to any single invention or inventive concept, if more than one is, in fact, disclosed. Thus, although specific embodiments have been illustrated and described herein, any arrangement calculated to achieve the same purpose may be substituted for the specific embodiments shown. This disclosure is intended to cover any and all adaptations or variations of various embodiments. Combinations of the above embodiments, and other embodiments not specifically described herein, will be apparent to those of skill in the art upon reviewing the above description. | <SOH> BACKGROUND <EOH>Electronic inhalable aerosol devices (e.g., vaporization devices, electronic vaping devices, etc.) and particularly electronic aerosol devices, typically utilize a vaporizable material that is vaporized to create an aerosol vapor capable of delivering an active ingredient to a user. Control of the temperature of the resistive heater must be maintained (e.g., as part of a control loop), and this control may be based on the resistance of the resistive heating element. Many of the battery-powered vaporizers described to date include a reusable batter-containing device portion that connects to one or more cartridges containing the consumable vaporizable material. As the cartridges are used up, they are removed and replaced with fresh ones. It may be particularly useful to have the cartridge be integrated with a mouthpiece that the user can draw on to receive vapor. However, a number of surprising disadvantages may result in this configuration, particular to non-cylindrical shapes. For example, the use of a cartridge at the proximal end of the device, which is also held by the user's mouth, particularly where the cartridge is held in the vaporizer device by a friction- or a snap-fit, may result in instability in the electrical contacts, particularly with cartridges of greater than 1 cm length. Described herein are apparatuses and methods that may address the issues discussed above. | <SOH> SUMMARY OF THE DISCLOSURE <EOH>The present invention relates generally to apparatuses, including systems and devices, for vaporizing material to form an inhalable aerosol. Specifically, these apparatuses may include vaporizers. In particular, described herein are cartridges that are configured for use with a vaporizer (e.g., vaporizer device) having a rechargeable power supply that includes a proximal cartridge-receiving opening. These cartridges are specifically adapted to be releasably but securely held within the cartridge-receiving opening of the vaporizer and resist disruption of the electrical contact with the controller and power supply in the vaporizer even when held by the user's mouth. For example, described herein are cartridge devices holding a vaporizable material for securely coupling with an electronic inhalable aerosol device. A device may include: a mouthpiece; a fluid storage compartment holding a vaporizable material; a base configured to fit into a rectangular opening that is between 13-14 mm deep, 4.5-5.5 mm wide, and 13-14 mm long, the base having a bottom surface comprising a first electrical contact and a second electrical contact, a first locking gap on a first lateral surface of the base, and a second locking gap on a second lateral surface of the base that is opposite first lateral surface. A cartridge device holding a vaporizable material for securely coupling with an electronic inhalable aerosol device may include: a mouthpiece; a fluid storage compartment holding a vaporizable material; a base configured to fit into a rectangular opening that is between 13-14 mm deep, 4.5-5.5 mm wide, and 13-14 mm long, the base having a length of at least 10 mm, and a bottom surface comprising a first electrical contact and a second electrical contact, a first locking gap on a first lateral surface of the base positioned between 3-4 mm above the bottom surface, and a second locking gap on a second lateral surface of the base that is opposite first lateral surface. A cartridge device holding a vaporizable material for securely coupling with an electronic inhalable aerosol device, the device comprising: a mouthpiece; a fluid storage compartment holding a vaporizable material; a rectangular base having a pair of minor sides that are between greater than 10 mm deep and between 4.5-5.5 mm wide, and a pair of major sides that are greater than 10 mm deep and between 13-14 mm wide, a bottom surface comprising a first electrical contact and a second electrical contact, and a first locking gap on a first lateral surface of the base positioned between 3-4 mm above the bottom surface, and a second locking gap on a second lateral surface of the base that is opposite first lateral surface. Any of these devices may also typically include a wick in fluid communication with the vaporizable material; and a resistive heating element in fluid contact with the wick and in electrical contact with the first and second electrical contacts. In general, applicants have found that, for cartridges having a base that fits into the rectangular opening of a vaporizer (particularly one that is between 13-14 mm deep, 4.5-5.5 mm wide, and 13-14 mm long), the it is beneficial to have a length of the base (which is generally the connection region of the base for interfacing into the rectangular opening) that is greater than 10 mm, however when the base is greater than 10 mm (e.g., greater than 11 mm, greater than 12 mm, greater than 13 mm), the stability of the cartridge and in particular the electrical contacts, may be greatly enhanced if the cartridge includes one or more (e.g., two) locking gaps near the bottom surface of the cartridge into which a complimentary detent on the vaporizer can couple to. In particular, it may be beneficial to have the first and second locking gaps within 6 mm of the bottom surface, and more specifically within 3-4 mm of the bottom surface. The first and second lateral surfaces may be separated from each other by between 13-14 mm, e.g., they may be on the short sides of a cartridge base having a rectangular cross-section (a rectangular base). As mentioned, any of these cartridges may include a wick extending through the fluid storage compartment and into the vaporizable material, a resistive heating element in contact with the first and second electrical contacts, and a heating chamber in electrical contact with the first and second electrical contacts. It may also be beneficial to include one or more (e.g., two) detents extending from a major surface (e.g., two major surfaces) of the base, such as from a third and/or fourth lateral wall of the base. The cartridge may include any appropriate vaporizable material, such as a nicotine salt solution. In general, the mouthpiece may be attached opposite from the base. The fluid storage compartment may also comprises an air path extending there through (e.g., a cannula or tube). In some variations at least part of the fluid storage compartment may be within the base. The compartment may be transparent (e.g., made from a plastic or polymeric material that is clear) or opaque, allowing the user to see how much fluid is left. In general, the locking gap(s) may be a channel in the first lateral surface (e.g., a channel transversely across the first lateral surface parallel to the bottom surface), an opening or hole in the first lateral surface, and/or a hole in the first lateral surface. The locking gap is generally a gap that is surrounded at least on the upper and lower (proximal and distal) sides by the lateral wall to allow the detent on the vaporizer to engage therewith. The locking gap may be generally between 0.1 mm and 2 mm wide (e.g., between a lower value of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, etc. and an upper value of about 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, etc., where the upper value is always greater than the lower value). Also described are vaporizers and method of using them with cartridges, including those described herein. In some variations, the apparatuses described herein may include an inhalable aerosol comprising: an oven comprising an oven chamber and a heater for heating a vapor forming medium in the oven chamber to generate a vapor; a condenser comprising a condensation chamber in which at least a fraction of the vapor condenses to form the inhalable aerosol; an air inlet that originates a first airflow path that includes the oven chamber; and an aeration vent that originates a second airflow path that allows air from the aeration vent to join the first airflow path prior to or within the condensation chamber and downstream from the oven chamber thereby forming a joined path, wherein the joined path is configured to deliver the inhalable aerosol formed in the condensation chamber to a user. The oven may be within a body of the device. The device may further comprise a mouthpiece, wherein the mouthpiece comprises at least one of the air inlet, the aeration vent, and the condenser. The mouthpiece may be separable from the oven. The mouthpiece may be integral to a body of the device, wherein the body comprises the oven. The device may further comprise a body that comprises the oven, the condenser, the air inlet, and the aeration vent. The mouthpiece may be separable from the body. In some variations, the oven chamber may comprise an oven chamber inlet and an oven chamber outlet, and the oven further comprises a first valve at the oven chamber inlet, and a second valve at the oven chamber outlet. The aeration vent may comprise a third valve. The first valve, or said second valve may be chosen from the group of a check valve, a clack valve, a non-return valve, and a one-way valve. The third valve may be chosen from the group of a check valve, a clack valve, a non-return valve, and a one-way valve. The first or second valve may be mechanically actuated. The first or second valve may be electronically actuated. The first valve or second valve may be manually actuated. The third valve may be mechanically actuated. The third valve may be mechanically actuated. The third valve may be electronically actuated. The third valve may be manually actuated. In some variations, the device may further comprise a body that comprises at least one of: a power source, a printed circuit board, a switch, and a temperature regulator. The device may further comprise a temperature regulator in communication with a temperature sensor. The temperature sensor may be the heater. The power source may be rechargeable. The power source may be removable. The oven may further comprise an access lid. The vapor forming medium may comprise tobacco. The vapor forming medium may comprise a botanical. The vapor forming medium may be heated in the oven chamber wherein the vapor forming medium may comprise a humectant to produce the vapor, wherein the vapor comprises a gas phase humectant. The vapor may be mixed in the condensation chamber with air from the aeration vent to produce the inhalable aerosol comprising particle diameters of average size of about 1 micron. The vapor forming medium may be heated in the oven chamber, wherein the vapor is mixed in the condensation chamber with air from the aeration vent to produce the inhalable aerosol comprising particle diameters of average size of less than or equal to 0.9 micron. The vapor forming medium may be heated in the oven chamber, wherein the vapor is mixed in the condensation chamber with air from the aeration vent to produce the inhalable aerosol comprising particle diameters of average size of less than or equal to 0.8 micron. The vapor forming medium may be heated in the oven chamber, wherein the vapor is mixed in the condensation chamber with air from the aeration vent to produce the inhalable aerosol comprising particle diameters of average size of less than or equal to 0.7 micron. The vapor forming medium may be heated in the oven chamber, wherein the vapor is mixed in the condensation chamber with air from the aeration vent to produce the inhalable aerosol comprising particle diameters of average size of less than or equal to 0.6 micron. The vapor forming medium may be heated in the oven chamber, wherein the vapor is mixed in the condensation chamber with air from the aeration vent to produce the inhalable aerosol comprising particle diameters of average size of less than or equal to 0.5 micron. In some variations, the humectant may comprise glycerol as a vapor-forming medium. The humectant may comprise vegetable glycerol. The humectant may comprise propylene glycol. The humectant may comprise a ratio of vegetable glycerol to propylene glycol. The ratio may be about 100:0 vegetable glycerol to propylene glycol. The ratio may be about 90:10 vegetable glycerol to propylene glycol. The ratio may be about 80:20 vegetable glycerol to propylene glycol. The ratio may be about 70:30 vegetable glycerol to propylene glycol. The ratio may be about 60:40 vegetable glycerol to propylene glycol. The ratio may be about 50:50 vegetable glycerol to propylene glycol. The humectant may comprise a flavorant. The vapor forming medium may be heated to its pyrolytic temperature. The vapor forming medium may heated to 200° C. at most. The vapor forming medium may be heated to 160° C. at most. The inhalable aerosol may be cooled to a temperature of about 50°-70° C. at most, before exiting the aerosol outlet of the mouthpiece. Also described herein are methods for generating an inhalable aerosol. Such a method may comprise: providing an inhalable aerosol generating device wherein the device comprises: an oven comprising an oven chamber and a heater for heating a vapor forming medium in the oven chamber and for forming a vapor therein; a condenser comprising a condensation chamber in which the vapor forms the inhalable aerosol; an air inlet that originates a first airflow path that includes the oven chamber; and an aeration vent that originates a second airflow path that allows air from the aeration vent to join the first airflow path prior to or within the condensation chamber and downstream from the oven chamber thereby forming a joined path, wherein the joined path is configured to deliver the inhalable aerosol formed in the condensation chamber to a user. The oven may be within a body of the device. The device may further comprise a mouthpiece, wherein the mouthpiece comprises at least one of the air inlet, the aeration vent, and the condenser. The mouthpiece may be separable from the oven. The mouthpiece may be integral to a body of the device, wherein the body comprises the oven. The method may further comprise a body that comprises the oven, the condenser, the air inlet, and the aeration vent. The mouthpiece may be separable from the body. The oven chamber may comprise an oven chamber inlet and an oven chamber outlet, and the oven further comprises a first valve at the oven chamber inlet, and a second valve at the oven chamber outlet. The vapor forming medium may comprise tobacco. The vapor forming medium may comprise a botanical. The vapor forming medium may be heated in the oven chamber wherein the vapor forming medium may comprise a humectant to produce the vapor, wherein the vapor comprises a gas phase humectant. The vapor may comprise particle diameters of average mass of about 1 micron. The vapor may comprise particle diameters of average mass of about 0.9 micron. The vapor may comprise particle diameters of average mass of about 0.8 micron. The vapor may comprise particle diameters of average mass of about 0.7 micron. The vapor may comprise particle diameters of average mass of about 0.6 micron. The vapor may comprise particle diameters of average mass of about 0.5 micron. In some variations, the humectant may comprise glycerol as a vapor-forming medium. The humectant may comprise vegetable glycerol. The humectant may comprise propylene glycol. The humectant may comprise a ratio of vegetable glycerol to propylene glycol. The ratio may be about 100:0 vegetable glycerol to propylene glycol. The ratio may be about 90:10 vegetable glycerol to propylene glycol. The ratio may be about 80:20 vegetable glycerol to propylene glycol. The ratio may be about 70:30 vegetable glycerol to propylene glycol. The ratio may be about 60:40 vegetable glycerol to propylene glycol. The ratio may be about 50:50 vegetable glycerol to propylene glycol. The humectant may comprise a flavorant. The vapor forming medium may be heated to its pyrolytic temperature. The vapor forming medium may heated to 200° C. at most. The vapor forming medium may be heated to 160° C. at most. The inhalable aerosol may be cooled to a temperature of about 50°-70° C. at most, before exiting the aerosol outlet of the mouthpiece. The device may be user serviceable. The device may not be user serviceable. A method for generating an inhalable aerosol may include: providing a vaporization device, wherein said device produces a vapor comprising particle diameters of average mass of about 1 micron or less, wherein said vapor is formed by heating a vapor forming medium in an oven chamber to a first temperature below the pyrolytic temperature of said vapor forming medium, and cooling said vapor in a condensation chamber to a second temperature below the first temperature, before exiting an aerosol outlet of said device. A method of manufacturing a device for generating an inhalable aerosol may include: providing said device comprising a mouthpiece comprising an aerosol outlet at a first end of the device; an oven comprising an oven chamber and a heater for heating a vapor forming medium in the oven chamber and for forming a vapor therein, a condenser comprising a condensation chamber in which the vapor forms the inhalable aerosol, an air inlet that originates a first airflow path that includes the oven chamber and then the condensation chamber, an aeration vent that originates a second airflow path that joins the first airflow path prior to or within the condensation chamber after the vapor is formed in the oven chamber, wherein the joined first airflow path and second airflow path are configured to deliver the inhalable aerosol formed in the condensation chamber through the aerosol outlet of the mouthpiece to a user. The method may further comprise providing the device comprising a power source or battery, a printed circuit board, a temperature regulator or operational switches. A device for generating an inhalable aerosol may comprise a mouthpiece comprising an aerosol outlet at a first end of the device and an air inlet that originates a first airflow path; an oven comprising an oven chamber that is in the first airflow path and includes the oven chamber and a heater for heating a vapor forming medium in the oven chamber and for forming a vapor therein; a condenser comprising a condensation chamber in which the vapor forms the inhalable aerosol; and an aeration vent that originates a second airflow path that allows air from the aeration vent to join the first airflow path prior to or within the condensation chamber and downstream from the oven chamber thereby forming a joined path, wherein the joined path is configured to deliver the inhalable aerosol formed in the condensation chamber through the aerosol outlet of the mouthpiece to a user. Also described herein are vaporization devices and methods of operating them. In particular, described herein are methods for controlling the temperature of a resistive heater (e.g., resistive heating element) by controlling the power applied to a resistive heater of a vaporization device by measuring the resistance of the resistive heater at discrete intervals before (e.g., baseline or ambient temperature) and during vaporization (e.g., during heating to vaporize a material within the device). Changes in the resistance during heating may be linearly related to the temperature of the resistive heater over the operational range, and therefore may be used to control the power applied to heat the resistive heater during operation. Also described herein are vaporization devices that are configured to measure the resistance of the resistive heater during heating (e.g., during a pause in the application of power to heat the resistive heater) and to control the application of power to the resistive heater based on the resistance values. In general, in any of the methods and apparatuses described herein, the control circuitry (which may include one or more circuits, a microcontroller, and/or control logic) may compare a resistance of the resistive heater during heating, e.g., following a sensor input indicating that a user wishes to withdraw vapor, to a target resistance of the heating element. The target resistance is typically the resistance of the resistive heater at a desired (and in some cases estimated) target vaporization temperature. The apparatus and methods may be configured to offer multiple and/or adjustable vaporization temperatures. In some variations, the target resistance is an approximation or estimate of the resistance of the resistive heater when the resistive heater is heated to the target temperature (or temperature ranges). In some variations, the target reference is based on a baseline resistance for the resistive heater and/or the percent change in resistance from baseline resistance for the resistive heater at a target temperature. In general, the baseline resistance may be referred to as the resistance of the resistive heater at an ambient temperature. For example, a method of controlling a vaporization device may include: placing a vaporizable material in thermal contact with a resistive heater; applying power to the resistive heater to heat the vaporizable material; measuring the resistance of the resistive heater; and adjusting the applied power to the resistive heater based on the difference between the resistance of the resistive heater and a target resistance of the heating element. In some variations, the target resistance is based on a reference resistance. For example, the reference resistance may be approximately the resistance of the coil at target temperature. This reference resistance may be calculated, estimated or approximated (as described herein) or it may be determined empirically based on the resistance values of the resistive heater at one or more target temperatures. In some variations, the target resistance is based on the resistance of the resistive heater at an ambient temperature. For example, the target resistance may be estimated based on the electrical properties of the resistive heater, e.g., the temperature coefficient of resistance or TCR, of the resistive heater (e.g., “resistive heating element” or “vaporizing element”). For example, a vaporization device (e.g., an electronic vaporizer device) may include a puff sensor, a power source (e.g., battery, capacitor, etc.), a heating element controller (e.g., microcontroller), and a resistive heater. A separate temperature sensor may also be included to determine an actual temperature of ambient temperature and/or the resistive heater, or a temperature sensor may be part of the heating element controller. However, in general, the microcontroller may control the temperature of the resistive heater (e.g., resistive coil, etc.) based on a change in resistance due to temperature (e.g., TCR). In general, the heater may be any appropriate resistive heater, such as a resistive coil. The heater is typically coupled to the heater controller so that the heater controller applies power (e.g., from the power source) to the heater. The heater controller may include regulatory control logic to regulate the temperature of the heater by adjusting the applied power. The heater controller may include a dedicated or general-purpose processor, circuitry, or the like and is generally connected to the power source and may receive input from the power source to regulate the applied power to the heater. For example, any of these apparatuses may include logic for determining the temperature of the heater based on the TCR. The resistance of the heater (e.g., a resistive heater) may be measured (R heater ) during operation of the apparatus and compared to a target resistance, which is typically the resistance of the resistive heater at the target temperature. In some cases this resistance may be estimated from the resistance of the resistive hearing element at ambient temperature (baseline). In some variations, a reference resistor (R reference ) may be used to set the target resistance. The ratio of the heater resistance to the reference resistance (R heater /R reference ) is linearly related to the temperature (above room temp) of the heater, and may be directly converted to a calibrated temperature. For example, a change in temperature of the heater relative to room temperature may be calculated using an expression such as (R heater /R reference −1)*(1/TCR), where TCR is the temperature coefficient of resistivity for the heater. In one example, TCR for a particular device heater is 0.00014/° C. In determining the partial doses and doses described herein, the temperature value used (e.g., the temperature of the vaporizable material during a dose interval, T 1 , described in more detail below) may refer to the unitless resistive ratio (e.g., R heater /R refrerence ) or it may refer to the normalized/corrected temperature (e.g., in ° C.). When controlling a vaporization device by comparing a measure resistance of a resistive heater to a target resistance, the target resistance may be initially calculated and may be factory preset and/or calibrated by a user-initiated event. For example, the target resistance of the resistive heater during operation of the apparatus may be set by the percent change in baseline resistance plus the baseline resistance of the resistive heater, as will be described in more detail below. As mentioned, the resistance of the heating element at ambient is the baseline resistance. For example, the target resistance may be based on the resistance of the resistive heater at an ambient temperature and a target change in temperature of the resistive heater. As mentioned above, the target resistance of the resistive heater may be based on a target heating element temperature. Any of the apparatuses and methods for using them herein may include determining the target resistance of the resistive heater based on a resistance of the resistive heater at ambient temperature and a percent change in a resistance of the resistive heater at an ambient temperature. In any of the methods and apparatuses described herein, the resistance of the resistive heater may be measured (using a resistive measurement circuit) and compared to a target resistance by using a voltage divider. Alternatively or additionally any of the methods and apparatuses described herein may compare a measured resistance of the resistive heater to a target resistance using a Wheatstone bridge and thereby adjust the power to increase/decrease the applied power based on this comparison. In any of the variations described herein, adjusting the applied power to the resistive heater may comprise comparing the resistance (actual resistance) of the resistive heater to a target resistance using a voltage divider, Wheatstone bridge, amplified Wheatstone bridge, or RC charge time circuit. As mentioned above, a target resistance of the resistive heater and therefore target temperature may be determined using a baseline resistance measurement taken from the resistive heater. The apparatus and/or method may approximate a baseline resistance for the resistive heater by waiting an appropriate length of time (e.g., 1 second, 10 seconds, 30 seconds, 1 minute, 1.5 minutes, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 11 minutes, 12 minutes, 15 minutes, 20 minutes, etc.) from the last application of energy to the resistive heater to measure a resistance (or series of resistance that may be averaged, etc.) representing the baseline resistance for the resistive heater. In some variations a plurality of measurements made when heating/applying power to the resistive heater is prevented may be analyzed by the apparatus to determine when the resistance values do not vary outside of a predetermined range (e.g., when the resistive heater has ‘cooled’ down, and therefore the resistance is no longer changing due to temperature decreasing/increasing), for example, when the rate of change of the resistance of the heating element over time is below some stability threshold. For example, any of the methods and apparatuses described herein may measure the resistance of the resistive heater an ambient temperature by measuring the resistance of the resistive heater after a predetermined time since power was last applied to the resistive heater. As mentioned above, the predetermined time period may be seconds, minutes, etc. In any of these variations the baseline resistance may be stored in a long-term memory (including volatile, non-volatile or semi-volatile memory). Storing a baseline resistance (“the resistance of the resistive heater an ambient temperature”) may be done periodically (e.g., once per 2 minute, 5 minutes, 10 minutes, 1 hour, etc., or every time a particular event occurs, such as loading vaporizable material), or once for a single time. Any of these methods may also include calculating an absolute target coil temperature from an actual device temperature. As mentioned, above, based on the material properties of the resistive heater (e.g., coil) the resistance and/or change in resistance over time may be used calculate an actual temperature, which may be presented to a user, e.g., on the face of the device, or communicated to an “app” or other output type. In any of the methods and apparatuses described herein, the apparatus may detect the resistance of the resistive heater only when power is not being applied to the resistive heater while detecting the resistance; once the resistance detection is complete, power may again be applied (and this application may be modified by the control logic described herein). For example, in any of these devices and methods the resistance of the resistive heater may be measured only when suspending the application of power to the resistive heater. For example, a method of controlling a vaporization device may include: placing a vaporizable material in thermal contact with a resistive heater; applying power to the resistive heater to heat the vaporizable material; suspending the application of power to the resistive heater while measuring the resistance of the resistive heater; and adjusting the applied power to the resistive heater based on the difference between the resistance of the heating element and a target resistance of the resistive heater, wherein measuring the resistance of the resistive heater comprises measuring the resistance using a voltage divider, Wheatstone bridge, amplified Wheatstone bridge, or RC charge time circuit. For example, a vaporization device may include: a microcontroller; a reservoir configured to hold a vaporizable material; a resistive heater configured to thermally contact the vaporizable material from the reservoir; a resistance measurement circuit connected to the microcontroller configured to measure the resistance of the resistive heater; and a power source, wherein the microcontroller applies power from the power source to heat the resistive heater and adjusts the applied power based on the difference between the resistance of the resistive heater and a target resistance of the resistive heater. A vaporization device may include: a microcontroller; a reservoir configured to hold a vaporizable material; a resistive heater configured to thermally contact the vaporizable material from the reservoir; a resistance measurement circuit connected to the microcontroller configured to measure the resistance of the resistive heater; a power source; and a sensor having an output connected to the microcontroller, wherein the microcontroller is configured to determine when the resistive heater applies power from the power source to heat the resistive heater; a target resistance circuit configured to determine a target resistance, the target resistance circuit comprising one of: a voltage divider, a Wheatstone bridge, an amplified Wheatstone bridge, or an RC charge time circuit, wherein the microcontroller applies power from the power source to heat the resistive heater and adjusts the applied power based on the difference between the resistance of the resistive heater and the target resistance of the resistive heater. In any of the methods and apparatuses (e.g., devices and systems) described herein, the apparatus may be configured to be triggered by a user drawing on or otherwise indicating that they would like to begin vaporization of the vaporizing material. This user-initiated start may be detected by a sensor, such as a pressure sensor (“puff sensor”) configured to detect draw. The sensor may generally have an output that is connected to the controller (e.g., microcontroller), and the microcontroller may be configured to determine when the resistive heater applies power from the power source to heat the resistive heater. For example, a vaporizing device as described herein may include a pressure sensor having an output connected to the microcontroller, wherein the microcontroller is configured to determine when the resistive heater applies power from the power source to heat the resistive heater. In general, any of the apparatuses described herein may be adapted to perform any of the methods described herein, including determining if an instantaneous (ongoing) resistance measurement of the resistive heater is above/below and/or within a tolerable range of a target resistance. Any of these apparatuses may also determine the target resistance. As mentioned, this may be determined empirically and set to a resistance value, and/or it may be calculated. For example, any of these apparatuses (e.g., devices) may include a target resistance circuit configured to determine the target resistance, the target resistance circuit comprising one of: a voltage divider, a Wheatstone bridge, an amplified Wheatstone bridge, or an RC charge time circuit. Alternatively or additionally, a voltage divider, a Wheatstone bridge, an amplified Wheatstone bridge, or an RC charge time circuit may be included as part of the microcontroller or other circuitry that compares the measured resistance of the resistive heater to a target resistance. For example, a target resistance circuit may be configured to determine the target resistance and/or compare the measured resistance of the resistive heater to the target resistance. The target resistance circuit comprising a voltage divider having a reference resistance equivalent to the target resistance. A target resistance circuit may be configured to determine the target resistance, the target resistance circuit comprising a Wheatstone bridge, wherein the target resistance is calculated by adding a resistance of the resistive heater at an ambient temperature and a target change in temperature of the resistive heater. As mentioned, any of these apparatuses may include a memory configured to store a resistance of the resistive heater at an ambient temperature. Further, any of these apparatuses may include a temperature input coupled to the microcontroller and configured to provide an actual device temperature. The device temperature may be sensed and/or provided by any appropriate sensor, including thermistor, thermocouple, resistive temperature sensor, silicone bandgap temperature sensor, etc. The measured device temperature may be used to calculate a target resistance that corresponds to a certain resistive heater (e.g., coil) temperature. In some variations the apparatus may display and/or output an an estimate of the temperature of the resistive heater. The apparatus may include a display or may communicate (e.g., wirelessly) with another apparatus that receives the temperature or resistance values. The devices described herein may include an inhalable aerosol comprising: an oven comprising an oven chamber and a heater for heating a vapor forming medium in the oven chamber to generate a vapor; a condenser comprising a condensation chamber in which at least a fraction of the vapor condenses to form the inhalable aerosol; an air inlet that originates a first airflow path that includes the oven chamber; and an aeration vent that originates a second airflow path that allows air from the aeration vent to join the first airflow path prior to or within the condensation chamber and downstream from the oven chamber thereby forming a joined path, wherein the joined path is configured to deliver the inhalable aerosol formed in the condensation chamber to a user. In any of these variations the oven is within a body of the device. The device may further comprise a mouthpiece, wherein the mouthpiece comprises at least one of the air inlet, the aeration vent, and the condenser. The mouthpiece may be separable from the oven. The mouthpiece may be integral to a body of the device, wherein the body comprises the oven. The device may further comprise a body that comprises the oven, the condenser, the air inlet, and the aeration vent. The mouthpiece may be separable from the body. In some variations, the oven chamber may comprise an oven chamber inlet and an oven chamber outlet, and the oven further comprises a first valve at the oven chamber inlet, and a second valve at the oven chamber outlet. The aeration vent may comprise a third valve. The first valve, or said second valve may be chosen from the group of a check valve, a clack valve, a non-return valve, and a one-way valve. The third valve may be chosen from the group of a check valve, a clack valve, a non-return valve, and a one-way valve. The first or second valve may be mechanically actuated. The first or second valve may be electronically actuated. The first valve or second valve may be manually actuated. The third valve may be mechanically actuated. The third valve may be mechanically actuated. The third valve may be electronically actuated. The third valve may be manually actuated. In any of these variations, the device may further comprise a body that comprises at least one of: a power source, a printed circuit board, a switch, and a temperature regulator. The device may further comprise a temperature regulator in communication with a temperature sensor. The temperature sensor may be the heater. The power source may be rechargeable. The power source may be removable. The oven may further comprise an access lid. The vapor forming medium may comprise tobacco. The vapor forming medium may comprise a botanical. The vapor forming medium may be heated in the oven chamber wherein the vapor forming medium may comprise a humectant to produce the vapor, wherein the vapor comprises a gas phase humectant. The vapor may be mixed in the condensation chamber with air from the aeration vent to produce the inhalable aerosol comprising particle diameters of average size of about 1 micron. The vapor forming medium may be heated in the oven chamber, wherein the vapor is mixed in the condensation chamber with air from the aeration vent to produce the inhalable aerosol comprising particle diameters of average size of less than or equal to 0 . 9 micron. The vapor forming medium may be heated in the oven chamber, wherein the vapor is mixed in the condensation chamber with air from the aeration vent to produce the inhalable aerosol comprising particle diameters of average size of less than or equal to 0.8 micron. The vapor forming medium may be heated in the oven chamber, wherein the vapor is mixed in the condensation chamber with air from the aeration vent to produce the inhalable aerosol comprising particle diameters of average size of less than or equal to 0.7 micron. The vapor forming medium may be heated in the oven chamber, wherein the vapor is mixed in the condensation chamber with air from the aeration vent to produce the inhalable aerosol comprising particle diameters of average size of less than or equal to 0.6 micron. The vapor forming medium may be heated in the oven chamber, wherein the vapor is mixed in the condensation chamber with air from the aeration vent to produce the inhalable aerosol comprising particle diameters of average size of less than or equal to 0.5 micron. In any of these variations, the humectant may comprise glycerol as a vapor-forming medium. The humectant may comprise vegetable glycerol. The humectant may comprise propylene glycol. The humectant may comprise a ratio of vegetable glycerol to propylene glycol. The ratio may be about 100:0 vegetable glycerol to propylene glycol. The ratio may be about 90:10 vegetable glycerol to propylene glycol. The ratio may be about 80:20 vegetable glycerol to propylene glycol. The ratio may be about 70:30 vegetable glycerol to propylene glycol. The ratio may be about 60:40 vegetable glycerol to propylene glycol. The ratio may be about 50:50 vegetable glycerol to propylene glycol. The humectant may comprise a flavorant. The vapor forming medium may be heated to its pyrolytic temperature. The vapor forming medium may heated to 200° C. at most. The vapor forming medium may be heated to 160° C. at most. The inhalable aerosol may be cooled to a temperature of about 50°-70° C. at most, before exiting the aerosol outlet of the mouthpiece. In any of these variations, the method comprises A method for generating an inhalable aerosol, the method comprising: providing an inhalable aerosol generating device wherein the device comprises: an oven comprising an oven chamber and a heater for heating a vapor forming medium in the oven chamber and for forming a vapor therein; a condenser comprising a condensation chamber in which the vapor forms the inhalable aerosol; an air inlet that originates a first airflow path that includes the oven chamber; and an aeration vent that originates a second airflow path that allows air from the aeration vent to join the first airflow path prior to or within the condensation chamber and downstream from the oven chamber thereby forming a joined path, wherein the joined path is configured to deliver the inhalable aerosol formed in the condensation chamber to a user. In any of these variations the oven is within a body of the device. The device may further comprise a mouthpiece, wherein the mouthpiece comprises at least one of the air inlet, the aeration vent, and the condenser. The mouthpiece may be separable from the oven. The mouthpiece may be integral to a body of the device, wherein the body comprises the oven. The method may further comprise a body that comprises the oven, the condenser, the air inlet, and the aeration vent. The mouthpiece may be separable from the body. In any of these variations, the oven chamber may comprise an oven chamber inlet and an oven chamber outlet, and the oven further comprises a first valve at the oven chamber inlet, and a second valve at the oven chamber outlet. The vapor forming medium may comprise tobacco. The vapor forming medium may comprise a botanical. The vapor forming medium may be heated in the oven chamber wherein the vapor forming medium may comprise a humectant to produce the vapor, wherein the vapor comprises a gas phase humectant. The vapor may comprise particle diameters of average mass of about 1 micron. The vapor may comprise particle diameters of average mass of about 0.9 micron. The vapor may comprise particle diameters of average mass of about 0.8 micron. The vapor may comprise particle diameters of average mass of about 0.7 micron. The vapor may comprise particle diameters of average mass of about 0.6 micron. The vapor may comprise particle diameters of average mass of about 0.5 micron. In any of these variations, the humectant may comprise glycerol as a vapor-forming medium. The humectant may comprise vegetable glycerol. The humectant may comprise propylene glycol. The humectant may comprise a ratio of vegetable glycerol to propylene glycol. The ratio may be about 100:0 vegetable glycerol to propylene glycol. The ratio may be about 90:10 vegetable glycerol to propylene glycol. The ratio may be about 80:20 vegetable glycerol to propylene glycol. The ratio may be about 70:30 vegetable glycerol to propylene glycol. The ratio may be about 60:40 vegetable glycerol to propylene glycol. The ratio may be about 50:50 vegetable glycerol to propylene glycol. The humectant may comprise a flavorant. The vapor forming medium may be heated to its pyrolytic temperature. The vapor forming medium may heated to 200° C. at most. The vapor forming medium may be heated to 160° C. at most. The inhalable aerosol may be cooled to a temperature of about 50°-70° C. at most, before exiting the aerosol outlet of the mouthpiece. In any of these variations, the device may be user serviceable. The device may not be user serviceable. In any of these variations, a method for generating an inhalable aerosol, the method comprising: providing a vaporization device, wherein said device produces a vapor comprising particle diameters of average mass of about 1 micron or less, wherein said vapor is formed by heating a vapor forming medium in an oven chamber to a first temperature below the pyrolytic temperature of said vapor forming medium, and cooling said vapor in a condensation chamber to a second temperature below the first temperature, before exiting an aerosol outlet of said device. In any of these variations, a method of manufacturing a device for generating an inhalable aerosol comprising: providing said device comprising a mouthpiece comprising an aerosol outlet at a first end of the device; an oven comprising an oven chamber and a heater for heating a vapor forming medium in the oven chamber and for forming a vapor therein, a condenser comprising a condensation chamber in which the vapor forms the inhalable aerosol, an air inlet that originates a first airflow path that includes the oven chamber and then the condensation chamber, an aeration vent that originates a second airflow path that joins the first airflow path prior to or within the condensation chamber after the vapor is formed in the oven chamber, wherein the joined first airflow path and second airflow path are configured to deliver the inhalable aerosol formed in the condensation chamber through the aerosol outlet of the mouthpiece to a user. The method may further comprise providing the device comprising a power source or battery, a printed circuit board, a temperature regulator or operational switches. In any of these variations a device for generating an inhalable aerosol may comprise a mouthpiece comprising an aerosol outlet at a first end of the device and an air inlet that originates a first airflow path; an oven comprising an oven chamber that is in the first airflow path and includes the oven chamber and a heater for heating a vapor forming medium in the oven chamber and for forming a vapor therein; a condenser comprising a condensation chamber in which the vapor forms the inhalable aerosol; and an aeration vent that originates a second airflow path that allows air from the aeration vent to join the first airflow path prior to or within the condensation chamber and downstream from the oven chamber thereby forming a joined path, wherein the joined path is configured to deliver the inhalable aerosol formed in the condensation chamber through the aerosol outlet of the mouthpiece to a user. In any of these variations a device for generating an inhalable aerosol may comprise: a mouthpiece comprising an aerosol outlet at a first end of the device, an air inlet that originates a first airflow path, and an aeration vent that originates a second airflow path that allows air from the aeration vent to join the first airflow path; an oven comprising an oven chamber that is in the first airflow path and includes the oven chamber and a heater for heating a vapor forming medium in the oven chamber and for forming a vapor therein; and a condenser comprising a condensation chamber in which the vapor forms the inhalable aerosol and wherein air from the aeration vent joins the first airflow path prior to or within the condensation chamber and downstream from the oven chamber thereby forming a joined path, wherein the joined path is configured to deliver the inhalable aerosol through the aerosol outlet of the mouthpiece to a user. In any of these variations, a device for generating an inhalable aerosol may comprise: a device body comprising a cartridge receptacle; a cartridge comprising: a fluid storage compartment, and a channel integral to an exterior surface of the cartridge, and an air inlet passage formed by the channel and an internal surface of the cartridge receptacle when the cartridge is inserted into the cartridge receptacle; wherein the channel forms a first side of the air inlet passage, and an internal surface of the cartridge receptacle forms a second side of the air inlet passage. In any of these variations, a device for generating an inhalable aerosol may comprise: a device body comprising a cartridge receptacle; a cartridge comprising: a fluid storage compartment, and a channel integral to an exterior surface of the cartridge, and an air inlet passage formed by the channel and an internal surface of the cartridge receptacle when the cartridge is inserted into the cartridge receptacle; wherein the channel forms a first side of the air inlet passage, and an internal surface of the cartridge receptacle forms a second side of the air inlet passage. In any of these variations the channel may comprise at least one of a groove, a trough, a depression, a dent, a furrow, a trench, a crease, and a gutter. The integral channel may comprise walls that are either recessed into the surface or protrude from the surface where it is formed. The internal side walls of the channel may form additional sides of the air inlet passage. The cartridge may further comprise a second air passage in fluid communication with the air inlet passage to the fluid storage compartment, wherein the second air passage is formed through the material of the cartridge. The cartridge may further comprise a heater. The heater may be attached to a first end of the cartridge. In any of these variations the heater may comprise a heater chamber, a first pair of heater contacts, a fluid wick, and a resistive heating element in contact with the wick, wherein the first pair of heater contacts comprise thin plates affixed about the sides of the heater chamber, and wherein the fluid wick and resistive heating element are suspended therebetween. The first pair of heater contacts may further comprise a formed shape that comprises a tab having a flexible spring value that extends out of the heater to couple to complete a circuit with the device body. The first pair of heater contacts may be a heat sink that absorbs and dissipates excessive heat produced by the resistive heating element. The first pair of heater contacts may contact a heat shield that protects the heater chamber from excessive heat produced by the resistive heating element. The first pair of heater contacts may be press-fit to an attachment feature on the exterior wall of the first end of the cartridge. The heater may enclose a first end of the cartridge and a first end of the fluid storage compartment. The heater may comprise a first condensation chamber. The heater may comprise more than one first condensation chamber. The first condensation chamber may be formed along an exterior wall of the cartridge. The cartridge may further comprise a mouthpiece. The mouthpiece may be attached to a second end of the cartridge. The mouthpiece may comprise a second condensation chamber. The mouthpiece may comprise more than one second condensation chamber. The second condensation chamber may be formed along an exterior wall of the cartridge. In any of these variations the cartridge may comprise a first condensation chamber and a second condensation chamber. The first condensation chamber and the second condensation chamber may be in fluid communication. The mouthpiece may comprise an aerosol outlet in fluid communication with the second condensation chamber. The mouthpiece may comprise more than one aerosol outlet in fluid communication with more than one the second condensation chamber. The mouthpiece may enclose a second end of the cartridge and a second end of the fluid storage compartment. In any of these variations, the device may comprise an airflow path comprising an air inlet passage, a second air passage, a heater chamber, a first condensation chamber, a second condensation chamber, and an aerosol outlet. The airflow path may comprise more than one air inlet passage, a heater chamber, more than one first condensation chamber, more than one second condensation chamber, more than one second condensation chamber, and more than one aerosol outlet. The heater may be in fluid communication with the fluid storage compartment. The fluid storage compartment may be capable of retaining condensed aerosol fluid. The condensed aerosol fluid may comprise a nicotine formulation. The condensed aerosol fluid may comprise a humectant. The humectant may comprise propylene glycol. The humectant may comprise vegetable glycerin. In any of these variations the cartridge may be detachable. In any of these variations the cartridge may be receptacle and the detachable cartridge form a separable coupling. The separable coupling may comprise a friction assembly, a snap-fit assembly or a magnetic assembly. The cartridge may comprise a fluid storage compartment, a heater affixed to a first end with a snap-fit coupling, and a mouthpiece affixed to a second end with a snap-fit coupling. In any of these variations, a device for generating an inhalable aerosol may comprise: a device body comprising a cartridge receptacle for receiving a cartridge; wherein an interior surface of the cartridge receptacle forms a first side of an air inlet passage when a cartridge comprising a channel integral to an exterior surface is inserted into the cartridge receptacle, and wherein the channel forms a second side of the air inlet passage. In any of these variations, a device for generating an inhalable aerosol may comprise: a device body comprising a cartridge receptacle for receiving a cartridge; wherein the cartridge receptacle comprises a channel integral to an interior surface and forms a first side of an air inlet passage when a cartridge is inserted into the cartridge receptacle, and wherein an exterior surface of the cartridge forms a second side of the air inlet passage. In any of these variations, A cartridge for a device for generating an inhalable aerosol comprising: a fluid storage compartment; a channel integral to an exterior surface, wherein the channel forms a first side of an air inlet passage; and wherein an internal surface of a cartridge receptacle in the device forms a second side of the air inlet passage when the cartridge is inserted into the cartridge receptacle. In any of these variations, a cartridge for a device for generating an inhalable aerosol may comprise: a fluid storage compartment, wherein an exterior surface of the cartridge forms a first side of an air inlet channel when inserted into a device body comprising a cartridge receptacle, and wherein the cartridge receptacle further comprises a channel integral to an interior surface, and wherein the channel forms a second side of the air inlet passage. The cartridge may further comprise a second air passage in fluid communication with the channel, wherein the second air passage is formed through the material of the cartridge from an exterior surface of the cartridge to the fluid storage compartment. The cartridge may comprise at least one of: a groove, a trough, a depression, a dent, a furrow, a trench, a crease, and a gutter. The integral channel may comprise walls that are either recessed into the surface or protrude from the surface where it is formed. The internal side walls of the channel may form additional sides of the air inlet passage. In any of these variations, a device for generating an inhalable aerosol may comprise: a cartridge comprising; a fluid storage compartment; a heater affixed to a first end comprising; a first heater contact, a resistive heating element affixed to the first heater contact; a device body comprising; a cartridge receptacle for receiving the cartridge; a second heater contact adapted to receive the first heater contact and to complete a circuit; a power source connected to the second heater contact; a printed circuit board (PCB) connected to the power source and the second heater contact; wherein the PCB is configured to detect the absence of fluid based on the measured resistance of the resistive heating element, and turn off the device. The printed circuit board (PCB) may comprise a microcontroller; switches; circuitry comprising a reference resister; and an algorithm comprising logic for control parameters; wherein the microcontroller cycles the switches at fixed intervals to measure the resistance of the resistive heating element relative to the reference resistor, and applies the algorithm control parameters to control the temperature of the resistive heating element. The micro-controller may instruct the device to turn itself off when the resistance exceeds the control parameter threshold indicating that the resistive heating element is dry. In any of these variations, a cartridge for a device for generating an inhalable aerosol may comprise: a fluid storage compartment; a heater affixed to a first end comprising: a heater chamber, a first pair of heater contacts, a fluid wick, and a resistive heating element in contact with the wick; wherein the first pair of heater contacts comprise thin plates affixed about the sides of the heater chamber, and wherein the fluid wick and resistive heating element are suspended therebetween. The first pair of heater contacts may further comprise: a formed shape that comprises a tab having a flexible spring value that extends out of the heater to complete a circuit with the device body. The heater contacts may be configured to mate with a second pair of heater contacts in a cartridge receptacle of the device body to complete a circuit. The first pair of heater contacts may also be a heat sink that absorbs and dissipates excessive heat produced by the resistive heating element. The first pair of heater contacts may be a heat shield that protects the heater chamber from excessive heat produced by the resistive heating element. In any of these variations, a cartridge for a device for generating an inhalable aerosol may comprise: a heater comprising; a heater chamber, a pair of thin plate heater contacts therein, a fluid wick positioned between the heater contacts, and a resistive heating element in contact with the wick; wherein the heater contacts each comprise a fixation site wherein the resistive heating element is tensioned therebetween. In any of these variations, a cartridge for a device for generating an inhalable aerosol may comprise a heater, wherein the heater is attached to a first end of the cartridge. The heater may enclose a first end of the cartridge and a first end of the fluid storage compartment. The heater may comprise more than one first condensation chamber. The heater may comprise a first condensation chamber. The condensation chamber may be formed along an exterior wall of the cartridge. In any of these variations, a cartridge for a device for generating an inhalable aerosol may comprise a fluid storage compartment; and a mouthpiece, wherein the mouthpiece is attached to a second end of the cartridge. The mouthpiece may enclose a second end of the cartridge and a second end of the fluid storage compartment. The mouthpiece may comprise a second condensation chamber. The mouthpiece may comprise more than one second condensation chamber. The second condensation chamber may be formed along an exterior wall of the cartridge. In any of these variations, a cartridge for a device for generating an inhalable aerosol may comprise: a fluid storage compartment; a heater affixed to a first end; and a mouthpiece affixed to a second end; wherein the heater comprises a first condensation chamber and the mouthpiece comprises a second condensation chamber. The heater may comprise more than one first condensation chamber and the mouthpiece comprises more than one second condensation chamber. The first condensation chamber and the second condensation chamber may be in fluid communication. The mouthpiece may comprise an aerosol outlet in fluid communication with the second condensation chamber. The mouthpiece may comprise two to more aerosol outlets. The cartridge may meet ISO recycling standards. The cartridge may meet ISO recycling standards for plastic waste. In any of these variations, a device for generating an inhalable aerosol may comprise: a device body comprising a cartridge receptacle; and a detachable cartridge; wherein the cartridge receptacle and the detachable cartridge form a separable coupling, wherein the separable coupling comprises a friction assembly, a snap-fit assembly or a magnetic assembly. In any of these variations, a method of fabricating a device for generating an inhalable aerosol may comprise: providing a device body comprising a cartridge receptacle; and providing a detachable cartridge; wherein the cartridge receptacle and the detachable cartridge form a separable coupling comprising a friction assembly, a snap-fit assembly or a magnetic assembly. In any of these variations, a method of fabricating a cartridge for a device for generating an inhalable aerosol may comprise: providing a fluid storage compartment; affixing a heater to a first end with a snap-fit coupling; and affixing a mouthpiece to a second end with a snap-fit coupling. In any of these variations A cartridge for a device for generating an inhalable aerosol with an airflow path comprising: a channel comprising a portion of an air inlet passage; a second air passage in fluid communication with the channel; a heater chamber in fluid communication with the second air passage; a first condensation chamber in fluid communication with the heater chamber; a second condensation chamber in fluid communication with the first condensation chamber; and an aerosol outlet in fluid communication with second condensation chamber. In any of these variations, a cartridge for a device for generating an inhalable aerosol may comprise: a fluid storage compartment; a heater affixed to a first end; and a mouthpiece affixed to a second end; wherein said mouthpiece comprises two or more aerosol outlets. In any of these variations, a system for providing power to an electronic device for generating an inhalable vapor, the system may comprise; a rechargeable power storage device housed within the electronic device for generating an inhalable vapor; two or more pins that are accessible from an exterior surface of the electronic device for generating an inhalable vapor, wherein the charging pins are in electrical communication with the rechargeable power storage device; a charging cradle comprising two or more charging contacts configured to provided power to the rechargeable storage device, wherein the device charging pins are reversible such that the device is charged in the charging cradle for charging with a first charging pin on the device in contact a first charging contact on the charging cradle and a second charging pin on the device in contact with second charging contact on the charging cradle and with the first charging pin on the device in contact with second charging contact on the charging cradle and the second charging pin on the device in contact with the first charging contact on the charging cradle. The charging pins may be visible on an exterior housing of the device. The user may permanently disable the device by opening the housing. The user may permanently destroy the device by opening the housing. Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in this art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive. | A24F47008 | 20171114 | 20180308 | 67573.0 | A24F4700 | 14 | MORENO HERNANDEZ, JERZI H | VAPORIZATION DEVICE SYSTEMS AND METHODS | UNDISCOUNTED | 1 | CONT-ACCEPTED | A24F | 2,017 |
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